Appendix 16 1 1 - Comments PDF

Cipla Limited
Confidential
Appendix 16.1.1
Protocol No: CIP_DSG_01

Clinical Study Report Version 1.0 Dated XX Oct 2016
Protocol and Protocol Amendments
Table of Contents
Clinical Study Protocol Version 1.0 Dated 18 Jun 2016
Clinical Study Protocol Version 1.1 Dated 26 Feb 2016
Summary of Changes
Protocol Clarification Form
1 of 167
Protocol Number: CIP-DSG-01

Version: 1.0
Date: 18 Jun 2015
CLINICAL STUDY PROTOCOL

A Prospective, Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, ParallelGroup Bioequivalence Study with Clinical Endpoints Comparing Generic Diclofenac
Sodium Topical Gel 1% of Cipla Limited, India to Voltaren Gel (a Diclofenac Sodium
Topical Gel 1%) of Endo Pharmaceuticals Inc., USA in Subjects with Osteoarthritis of
the Knee
Protocol Number:
CIP-DSG-01
Version/Date:
Version 1.0 / 18 Jun 2015
Clinical Trial Phase:
Bioequivalence Study
Sponsor:
Cipla Limited
R & D Center, LBS Marg
Vikhroli (W), Mumbai-400083, India
Contract Research
Organization:
Max Neeman International

Max House, 1, Dr. Jha Marg, Okhla Phase III
New Delhi-110020, India
Investigational Product:
Diclofenac Sodium Topical Gel 1%
CONFIDENTIALITY STATEMENT
This protocol is a confidential document owned by Cipla Limited. Any unpublished information contained in it may
not be disclosed to a third party without prior written approval of Cipla Limited. However, the document may be
disclosed to an Institutional Ethics Committee or a statutory regulatory authority under a similar condition of
confidentiality.
Confidential
Page 1 of 63
2 of 167

Version: 1.0
Date: 18 Jun 2015
CONTACT DETAILS
Sponsor
Cipla Limited
Sponsor Representative
Dr. Dhiraj Abhyankar

Head - Clinical Research & Development
R & D Center, 8th Floor
North Block, LBS Marg
Vikhroli (W), Mumbai-400083
Phone: +91 22 25756847
E-mail: Dhiraj.Abhyankar@cipla.com
Clinical Research Organization

Address: Max House, 1, Dr. Jha Marg, Okhla Phase III,
Phone: +91 11 40772100
Protocol Author [Medical writer]
Dr. Urmila Jetley

Max Neeman International, First Floor, Ready Money
Terrace 167, Dr. A. B. Road, Worli Naka, Mumbai400018, India
Phone: +91 22 24931391
E-mail: Urmila.Jetley@maxneeman.com
Biostatistician
Mr. Santosh Kumar

Max Neeman International, Max House,1, Dr. Jha
Marg, Okhla Phase III, New Delhi 110020, India
Phone: +91.11.40772100 Ext: 2774
E-mail: Santosh1.Kumar@maxneeman.com
Investigator Responsible for

Conducting the Study and Study
Site(s)
This information is documented separately in the

dossier to be submitted to regulatory authority.
Clinical Laboratory and other

Medical and Technical
Department(s) and Institutions
involved in the Study

Confidential
Page 2 of 63
3 of 167

Version: 1.0
Date: 18 Jun 2015
SPONSOR'S DECLARATION
I, on behalf of Cipla Limited, India have read, understood & approved this Protocol. I agree to
comply with all requirements regarding the obligations of Sponsor and all other pertinent
requirements of the International Conference on Harmonization of technical requirements for
registration of pharmaceuticals for human use guideline for Good Clinical Practice ICH E6
(amended version), the Code of Federal Regulations on the Protection of Human Subjects (45
CFR Part 46), in accordance with Declaration of Helsinki (amended version), ICMR guidelines
for Biomedical Research on Human Subjects (amended version) & Schedule Y of Drugs and
Cosmetics Act and Rules (amended version) released by Central Drugs Standard Control
Organization, India, Good Clinical Laboratory practice (GCLP) and applicable regulatory
guidelines.
Sponsor's Representative:
Name: Dr. Dhiraj Abhyankar
~/l
Date: 18 Jon 2~1\ .
"--C-J
Signature:
Confidential
Page 3 of63
4 of 167

Version: 1.0
Date: 18 Jun 1015
CRO Approv'a l Page
I have prepared version 1.0 of study protocol (ID: CIP-DSG-0 1), dated 18 June 2015 .
To the best of my knowledge, the protocol is accurate and complete. I approve this version as the
final copy and consider it acceptable for regulatory submission.
Protocol Author:
Dr.
Urmil~t
Signature:
Jetley
Date: 18 Jun 2015
Study Biostatistician:
Mr. Santod:J-h
Kum r
Signature
Date: 18 Jun 2015
Confidential
Page 4 of63
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l. the rurdersigned" declare that I have rf,ad and Llnderstood thrs pfotocol and hereb_v agrer t{}
condllct tlie stutiv ln acr:or.lance with thrs protocoland to compll'rvith all requlrements regardlng
the trbltgatrons ol' rnvestr$ators and all other pertrnent reqursnrsnts of the Internatronal
llenlbren{re on Harm*nizati*n *f teohnrcal requirements ibr regrstrltion et'pharmaceuticais ibr
hum,an use guideline fr:r {-ior:d illinrcal [}ractice lfH Eb {amendecl vns}oni. the Code of Federal
I{eslilatrrtrs on the Proler":tron of [{uman Sub..;ects (115 CFR []'lrrt.J6]" in accordance wrih
llccl*rattrtn ol'ilelsrrrkr {*mcnded verlri n),1{,'}\{R guidelrnes fbr []rrrnrerJrcal Research rn [.lumirn
Srrh;ci:ts ianendtd version) E: St:hedulc Y ul-Drugs and Cusnielrr:s Act and llr"rlrs {anrncled
vcrsrun) rclcascd bl,Ccntral l)rugs Stanelard l'rntri.ii Organiziilrun lnilra and prinrriplcs on {iond
1;rhrrattrv llraclicu, and al I regulatorr rcquiren":ents lor ineludins ,rli elenrenls recluircrl 1'or *n
lnitrluliorral Rcvieiv Bu*rd ilRni 1o assess study nsks anil bene l'ils
We tirrlher agree ta *nsurs that all assr;ciatcs assrstrng in th{: rlrrdtrct rrl':tud1- are rnti-rrnrcil
rcg.rt rl
rt
g tlrcrr uhl
g..rl
rons
lacfce lo c*rlpiy n'rth all relcvant
Stanclard Operating Pr*e*drrri {SL)Ps) requrred firr tht:

eondutl r;f'thrs sturlv iind rvr,ruld dercumcn! anv signilicant devralr*n ,.r{iurrins during thc str-xlv
Prinrip;r I I nlrstig*tar;
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Signatur*:
Dnte: {i" -.
fonfidenfi:rl
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9 of 167
I l- .----, -----------r---'
Protocol Numbe.r' CIP-DSG,0 I
Versioli: 1.0
oaler t'g fun:,20ts,
' ,,,
IN\/ESTL-G OR'SDECIARATION
i, the undersigne4, deciare that I have read and understood this protocol and hereby agree to
eonduct th-es,tr:dy in accordanpe with this protoo<il anil'to comp-ly'with,:all requirements regarding
the ,ollig4tions of investigalo;!, antl all other pertinent requirements of the International
Conferenoe on Hlqnonization oftechnioal requirements for registratio:r of pharmaceuticals for
human use guideline fur Good Clinical Fractice ICH E6 (amended version), the Code of Federdl
Regqlptions on the Protection of Human Subjects (45 CFR Part 46), in accordance with
Declaration of llelsinki (arnended vQrfion),ICMR guidelines for Biomeclical Research on Human
Suhjects (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
version) released by Central L)rug_q Standard Control Organization, india and principles on Good
l,aboratory Practice, an,l all regulatory requirements for including all elements required for an
Institutional Review Board (IRB) to assess study risks and benefits
We furrher agree to cnsure that
regarding their obl i gations.
all
associates assisting
in the conduct of study arc informed
I agree.to comply with all relevant Standard Operating Procedures (SOPs) required for rhe
eonduct of this study and would docurrent any significant dcviation occurring during the study"
Principa I Investigator:
Name:
Oe"
hut q0 &++f
Date:
Confidential
Page 5
of63
10 of 167
Prolocol Number: CIP-DSG-0
Version i.0
Date: l 8 "lun 20l
INVESTIGATOR'S
Df, CLARATTON
[" the undersigned, declare that I have fead and understood this protocol and hereby agree to
conduct the study in accordance wilh this protocol and to comply with all requirements rcgarding
the oLrligations of investigators and all other peflinent requirements of the International
Cgnferenes on Harmonization of technical requirements for registration of,pharmaceuticals for
human use guideline for Good Clinical Practice ICH E6 (amended version), the Code of Federal
Regulations on the Protection of Human Subjects (45 CFR Part 46), in accordance with
Deelaralion of llelsinki (amended version),ICMR guidelines for Biomedical Research on Human
Subjccts (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
version) re leased by Central Drugs Standard Contr<-rl Organization, India and principles on Good
l.aboratory Practice" and all rcgulatory requirements for including all elements required for an
Institutionat Review Board (lRB) to assess strldy risks and benefits.
We furthcr agree to ensure that ail associatss assisting in the conducl of study are informed
rgard in g
their obligations.
I agrcc," tr: comply with all relevant Standard Operating Procedures (SOPs) required lor the
conducl of this study and would document any .signitlcant deviation occurring during the study.
Principa I lnlestigator:
Name:
Dc" 8a1^6-4r1- P--U,
Signature:
Date:
q}}
L3 S\rt-.tg
Confrdential
9-otS
Page 5
of53
11 of 167
Protccul frkunher {:tF-fl5tj-t'i
Vcrsron i ti
l)*te I t'i J *n
2{J I
IN
V p;S'l'
{;A'r(}R's o E{].A RA'n{} \*
l. the uriderstgned. declar* th*1 I
lr;n,s fe;td and rndrjr$tor)d thrs protocul and herebl. agree to

i:onduet the stud-r'in acc*rrlan{e \rtth f.hrs prrlocol and to ci"}mply rvrth all requirsi}tL:nts regardrng
the obligations of invesiigalnrs rnri lll othcr pcrtincnt re.luirumsnts of the Internatignal
f'trnfbrence on l'lnrm*rriz-;lticn til" l*chnrc;rl rrr.luircrncnts fi:r reg,rstrurtron nf pharmaccuticuls tirr
huniiin Llse gltldeltne ttlr ti$ed d'ltntcal I'ractrcc ICI{ f6 (amr:ndecl verslfin}. the 1;ar.1e of Feclrral
Reguiattt:ns {}n the Prol*rttetl *l'llum;rn Sub.jects {45 CIrR Piul 4{r), ln accordance with
Declaration uf Helsinki {i:mendcd vcrsronJ.lCI{R guidelrnes firr Iliamedrcal Research on l{'man
Sub";e*ts {amended versiun} & Sr:hrdulr Y c{' lJrugs and fr:smetrcs Act and Rrjles iamendeii
verslon) released try C*nt;'al Drugs $tnnilard Ccintrel Orguniznti6n" lndia antl principles on {.iooil
l.ahoratorv Practice. antl all r*gttlatorv rr{."lilrfcncnts fbr includrng all elcnreiits requrreil lirr an
Instrrutronal Reyrelr, B*alrl{lRlli tc lssrs.r sturil'risks and bcne.lits
We fl.rrlirer aSrec to rnsilre th*l

t'g.ard rng thcrr ohl gatrtrn ;
tlll
;tssultalt:s assrslrng rn
th( enrrciuct o1'stq1v arc
rrif"r-rrnrcr"1
I ag.rer to c*ntpl1' with all
rclcvant Standard Operating Proeedures ISOPs) requrred tirr the

l'ttnducl of thls studv and lv*ulcl rire itntrtrt arrv signilicant rJcvralion occurnng during lhe st'dy
llri nriptl I nvrstig*t*r:
,\*mr:
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l']rge 5 ot'6"i
12 of 167
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Versrun | 0
f,)at* lS lun l{)i!
\Y fi STIG,\"I'OR'S I}E('
I-A
I{ATIf]N
l, the undcrslgnrd. der:lare lhat I
lrave read iinrj understood this pr*tocr:l and hercbl, agree ro

with lhis protocrl and to ronlFrly tvith
reqLrrr*nrsnts regarding
"ll ,rf th* lntcrm{rorral
the obligatr{}n: of tnvt'sitgators and all other per{rnent requirenrenlo
{lcrnl-ercnce Lrtr l{arrr,rJtrtz'l1lon oi'technical requrriiments f"or rcgistration of
Jrhurmace utre irls ibr
human use gurdelint lbl Good Clrtrical Practrce ICF{ i:6 lamendcd versr*n)- in* Cu,i* oil:ederal
R.egulatrons $r the flri:rrclrun ot'l{uman Sublecls (4_5 CIrR parl 4{r}" in;trrcr)rdunce
wrtlr
I)eciaration ol Helsrnkr iarlended vcrsron]t"lCfufR gurcielrnes for Eicimedical Rcsearch nn Huniun
SLrhleets {anientlrcl vrrstitn} & $chccJule Y lf []rugs and Cnsrnrtics Acl ilrr6 ltulcs
{amcni1cri
vrr'llon) relea:cd hv t. entral Drugs Standard Control {}rgianrz:rtr*n. Indra and prrnciplcs r.rn (ir,rr:rj
l-,aboiaturl Prauttce-,lnil all regr-rlator.v requirernerrls t*r Lncluciing ali elern*nts requrred fbr an
lnstitutu:nal Rr:r'irra ilsard {lRIJltrr assess stildy nsks and hsnellrs
cOnducl the sturlv ln accordancc
lVc {irrlhcr 38rer li) r'ltsrtre that etl assocr*tcs assrstine in the conilrrct
r*gard rn* lhcrr 0hl r{*tri_rns
*f
stud\, ,ile rnlilrrled
I a.gr*e lti riimpll'tr':lh t:.il rclcvant $tand*rd {lperattn{i Fri:c*durr:s {SOPsi rgg1111g,1 f6r the
c$nilucl i:f {hrs sturjv arrd iltluld ducut'tict"tt an1'srgr:riiciint d*vratlon urrlurrinq du'ng the :itu;1,
Prinripal Inlesfigator;
N*me:
Pq .s#s*J-L-
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Sigrrature: lb*+pt.""
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13 of 167
Protocol Number: CJP-DSG-0 I

Version: 1.0
Date: 18 Jun 2015
INVESTIGATOR'S DECLARATION
I
I
\
I, the undersigned, declare that I have read and understood this protocol and hereby agree to
conduct the study in accordance with this protocol and to comply with all requirements regarding
the obligations of investigators and all other pertinent requirements of the International
Conference on Harmonization of technical requirements for registration of pharmaceuticals for
Declaration of Helsinki (amended version),ICMR guidelines for Biomedical Research on Human
Subjects (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
version) released by Central Drugs Standard Control Organization, India and principles on Good
Laboratory Practice, and all regulatory requirements for including all elements required for an
Institutional Review Board (IRB) to assess study risks and benefits.
We further agree to ensure that all associates assisting in the conduct of study are informed
regarding their obligations.
I agree to comply with all relevant Standard Operating Procedures (SOPs) required for the
conduct of this study and would document any significant deviation occurring during the study.
Principal Investigator:
,.., . ~ {L-~ "\ l.( fK"1
Name:
'{,\ _ _.. .
Signature:
Date:
Confidential
'--WI
?--~ \ b l \{
Page 5 of63
14 of 167
Protocol Number. CIP-DSG-0 I
Version
1.0
Datc: 18 Jun 2015
INVESTIGATOR'S DECLTIRATION
.[, the undersigrred, declare that I have read and understood this protocol and hereby agree to
the obligations of investigators and all other pertinent requirements of the Intemational
Regulations on the Protection of Human Subjects (45 CFR Parl 46), in accordance with
Declaration of Helsinki (amended version),lCMR guidelines for Biomedical Research on Human
Institutional Review Board {IRB) to assess study risks and benefits.
We further aglee to ensure that all associates assisting in the conduct erf study are informed
regard ing their obl igations.
I agree to comply with all relevant Standard Operating Procedures {SOPs) required for the
conduct of this study and would document any significant deviation occuning during the study-
\\
*<o
{
t;**
ur)
Principel Invcsfigator:
Name:
pp.
pr:.c.
Signaturc:
Date: ,9 d
lc6 I
./U-E( CL,a+^sfitt viT
,*r
SUOSTIASTAilA HO$PITAL
t tt,l*l,t F,IHOOAIIR
ul|{xA, vAnAxA$l-21100u, u.P
,I
Conlidcnfial
Page 5
of63
15 of 167
Protocol Number: CIP-DSG-0 t

Version: I "0
Dat; lE lun2015
l" the undersigned, declare that I have read and understood this protocol and hereby agree to
eonduct the study in accordance with this protocol and to comply with all requirements regarding
of investigators and all other pertinent requirements of the International

eonference on Harmonizatjon of technical requirements for registration of pharmaceuticals for
human use guideline for Cood etinical Practice ICH E6 (amended version), the Code of Federal
Regulations on the Protection of Human Subjects (45 CFR Part 46), in accordanie with
Subjects (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (arnended
version) released by Central Drugs Standard Control Organization, lndia and principles on Csod
l,aboratory Practice, and all regulaiory requirernents for including all elements required for an
lnstitutional Review Board {lRB) to assess study risks and benefits.
the obligations
We further agree to ensure that

regarding their obl igations.
all associates assisting in the conduct of study are informed
condust of this study and would doeument any significant deviation occurring during the study"
Princlpal Investigator:
Name:
bf
Signature:
Date:
QGI
Confidentirl
slts
Page 5
of 63
16 of 167
Protocol Number CIP-DSG .i1!
Verswn ! 0
Pate Ill Jun 20 15
-------..---------- ------------------li\VESTIGATOR'S I>ECLARAHO'\
L. the understgnecL dedan: that I have read and understood this protocol and hereby agree to
conduct the stud; m accordance with this protocol and to comply wtth all rcqutremcms regardmg
the ohl!gauons of im esttga1ors and all other per1ment requirements of the InternatiOnal
Conference on IhumontzatJOn of technical requirements for reg1stratl0n of pharmaceuta:als tor
human use gu11.ielme for CiooJ Cltmcal Practice ICH E6 (amended versron). the Code <)f Federal
Rcgulntlons on the Prote<:tJOn or Human Subjects (45 C FR Part 46 ). 111 accordanct: wllh
Dccluutwn of Hdsmk1 (amended \ersionUCMR gwddme~ for BIOmcdH:al Research on Human
Subjects (amended versiOn) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
vers~nn) released bv Central Drugs Standard Cnntrol Organiza1ton, fndia and pnncipks on Uood
Luboratory Practice, and all regulatory requm.:ments for mcludmg all elements reqUJrt:d for an
lnstJtuttonal Review noard (!R B) to t~sse.ss study nsks and benefits
We further agree to ensure that all associates as:-nstmg m the conduct of study are mkn meJ
rcgardmg then obltgatwns
1 agree to wrnply w1th all relevant Standard Opcratmg Prucedures !SOPs) requn
for the
conduct olthts :->tudv and would docurnent any s1gntflcant devwtHJn occurrmg Jurmg the study
Prindpal hnrstigator:
\ame:
PFZ Se4:TI\
Signature:
_______________________
-------------,_,
Confidtntial
Page 5 of63
17 of 167
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18 of 167
Protocol Numberr CIp_DSG_0

I
versron:1.0
Date: 18 Jun 2015
II\IVESTIGAT
I, the undersighed, declare that I
,S
DECLARATION
have read and.
understood this protocol and

conouct.the.study in accordance
hereby agree ro
with this nro ocol and to comply
wlth all ,.quir...n#regarding
rne
obhgatlons
of
investigators and
ai
Conference on Harmon jzaion

of t..f,"i..1
use guideline for GooJ Cii"r."r
!uma1
Regulations on the protection
Declaration of Helsinki
lamenOeJ
Subjects (amended version)
A S"fr"Jri.
released by CentraiDrugs Si"J".a
;,:1i*) p-raqtice,
and all
l.ab3raforV
Institutional Reyiew Board
ffnfij t"
.lpr pertinent requirements of the
i,*.
;i H;;;
v";;i;;
?
,rd;;;;;;,
We further agrqe to ensure that

regarding their qbligations.
agree
conduct
}tr.
and Rules (amenOeO

ontrol Organization, India and principles'on
Good
for.i.ncluding all elements ,.qrir"J
Tls
Ahn
it
fo.
nsKs and benefits.
assoc
assisting
to comply with all relevant Sta

ofthis study and would document
Principan Inves{igator:
4R guidelines for Biomedical

Research on Uu,oun
f Drugs and Cosmetics Act
"r'..*'r,
all
International
ll.-Tilr for registrarion of pharmaceuti.A, fo,

fCH E6 (amended version), ifr.
CoO. of p.O..ut
ubjects (45 CFR part 46), in
accordance with
in the conduct of study are infonned
.Operating Procedures (SOps) required for the

significant deviation occurring during
the studv.
.5
Name:
Signature:
Date:
un
Urar""
ri
Ag- o c'
-"/'a
Confidential
Page 5
of63
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21 of 167

Version: 1.0
Date: 18 Jun 2015
PROTOCOL SYNOPSIS
Title
A Prospective, Multi-Center, Randomized, Double-Blind, VehicleControlled, Parallel-Group Bioequivalence Study with Clinical
Endpoints Comparing Generic Diclofenac Sodium Topical Gel 1% of
Cipla Ltd., India to Voltaren Gel (a Diclofenac Sodium Topical Gel
1%) of Endo Pharmaceuticals Inc., USA in Subjects with Osteoarthritis
of the Knee.
Protocol Number
CIP-DSG-01
Study Objective
To compare clinical efficacy, safety and tolerability of generic

Diclofenac Sodium Topical Gel 1% of Cipla Ltd., India with Voltaren
Gel (a Diclofenac Sodium Topical Gel 1%) of Endo Pharmaceuticals
Inc., USA and Vehicle of Diclofenac Sodium Topical Gel 1%
(manufactured by Cipla Ltd., India) in subjects with osteoarthritis (OA)
of the knee.
Efficacy endpoints
Primary efficacy endpoint
The primary endpoint of the study is:
Mean change in the Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC) pain score in target knee from
baseline to week 4
Secondary efficacy endpoints

The secondary efficacy endpoints of the study are:
Study Endpoints
Mean change in pain on movement (POM) on a Visual Analog

Scale (VAS) for target knee from baseline to week 4
Mean change in Patient Global Assessment (PGA) score from
baseline to week 4
Safety endpoints
The safety endpoints of the study are:
Study Design
Confidential
Proportion of subjects with adverse events (AEs) and serious

adverse events
Change in physical examination, vital signs, and clinical
laboratory tests (hematology and biochemistry parameters) from
baseline to week 4
This is a prospective, randomized, double-blind, vehicle-controlled,

parallel-group, bioequivalence study with clinical endpoints to be
performed at approximately 23 study centers across India. A minimum
of 990 subjects (330 in each treatment group) with OA of the knee will
Page 6 of 63
23 of 167

Version: 1.0
Date: 18 Jun 2015
be randomized (considering 10% drop outs) to get an evaluable data of

at least 900 subjects in a 1:1:1 ratio at baseline visit to the following 3
treatment groups:
Test group: Generic Diclofenac Sodium Topical Gel 1% or

Reference group: Voltaren Gel (Diclofenac Sodium Topical Gel
1%) or
Control (placebo) group: Vehicle of Diclofenac Sodium Topical
Gel 1%
The total study duration for the subjects will be approximately 7 weeks,
including 4 weeks of treatment.
There will be 5 study visits:
Visit 1: Screening visit (day -21 to day -15 / week -3)
Visit 2: Eligibility visit / Run-in period (day -14 to day -1 / week

-2)
Visit 3: Baseline / randomization visit (day 0)
Visit 4: Interim visit (day 14 4 / week 2)
Visit 5: End of study (EOS) visit (day 28 4 / week 4)
The eligible subjects will enter a washout period (run-in period) of 7

days or 5 plasma elimination half-lives of the discontinued medication
(whichever is longer) during which other topical products applied to
knees, including corticosteroids, pain medications, anticoagulants,
angiotensin converting enzyme (ACE-inhibitors) will be discontinued.
At baseline, subjects will be randomized to 1 of the 3 treatment groups
and 4 g of either generic Diclofenac Sodium topical gel 1%, or reference
product, or vehicle will be applied to the target knee. Study medications
will be applied to the target knee 4 times daily for 4 weeks. The subject
should not take shower / bathe for at least 1 h after the application but
should wash the hands after use. Both efficacy and safety assessments
will be done during the study. Subjects will be permitted to use
acetaminophen / paracetamol (up to 4 g / day) as a rescue therapy for
residual knee or other body pain throughout the study.
Subject diaries will be dispensed to subjects at baseline. During the
study, subjects will be required to use subject diaries in order to record
the date and time of study treatments, any missed treatments, use of
acetaminophen / paracetamol (rescue medication), use of concomitant
medications, and AE(s) experienced or intolerability to study
medication. These subject diaries will be reviewed at visits 4 and 5 and
will be collected from the subjects at visit 5 (day 28 4 / week 4).
Confidential
Page 7 of 63
24 of 167

Version: 1.0
Date: 18 Jun 2015
Efficacy
Assessments
Safety Assessments
Other Clinical and

Laboratory
Investigations
Confidential
WOMAC pain score will be determined by subjects responses

to 5 questions (how much pain the subject feels while walking
on a flat surface, going up or down stairs, at night while in
bed, sitting or lying, and standing upright) using a 5-point
Likert scale (0 = none; 1 = mild, 2 = moderate, 3 = severe, 4 =
extreme)
POM will be evaluated using 0-100 mm scale of VAS (where
score of 0 indicates no pain and a score of 100 indicates worst
imaginable pain)
PGA will be evaluated where the subject will give a global selfassessment of target knee OA condition using 5-point Likert
scale (0 = very well, 1 = well, 2 = fair, 3 = poor, 4 = very poor)
to rate his/her OA
AEs will be collected and evaluated for relatedness, severity,
seriousness, and outcome
Physical examination
Vital signs (pulse rate, respiratory rate, systolic and diastolic
blood pressure, oral body temperature)
Laboratory parameters
o Hematology
Hematocrit
Red blood cells
Hemoglobin
Platelets
White blood cells with differential blood count
o Biochemistry
Alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and gamma glutaryl
transpeptidase
Total bilirubin
Creatinine
Urea
Sodium, potassium, calcium, phosphorus, bicarbonate
Fasting plasma glucose
The following are the laboratory tests which will be carried out at visit 1
(screening visit):
Urinalysis
o Urine pregnancy test
Page 8 of 63
25 of 167

Version: 1.0
Date: 18 Jun 2015
Serology
o Human Immunodeficiency Virus (HIV) antibody (I and II)

o Hepatitis B Virus surface antigen (HBsAg)
Hepatitis C Virus (HCV) antibodies
12 Lead ECG (at Screening and EOS visit)
A subject will be eligible for inclusion in the study if he / she fulfils the
following criteria:
Inclusion Criteria
Confidential
1. Male or non-pregnant female aged 35 years with a clinical

diagnosis of OA of the knee according to the American College
of Rheumatology (ACR) criteria:
a. Pain in the knee and presence of at least 3 of the following
ACR criteria: age 50 years; stiffness lasting for < 30 min;
bony tenderness; crepitus; bony enlargement; no palpable
warmth, and including:
i. Symptoms for at least 6 months prior to screening, and
ii. Knee (not referred) pain for 15 days of the preceding
month (periarticular knee pain due to OA and not due to
other conditions such as bursitis, tendonitis, etc.), and
iii. The pain in the target knee required the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or
acetaminophen / paracetamol (topical or oral treatments)
2. Had an X-ray of the target knee, taken no more than 1 year before
baseline, showing evidence of OA with Kellgren-Lawrence grade
1-3 disease
3. After discontinuing all pain medications for at least 7 days, had at
least moderate POM for target knee, defined as a baseline score of
50 mm on a 0-100 mm VAS immediately prior to
randomization, and a baseline WOMAC pain subscale of at least
9 immediately prior to randomization
4. Able to tolerate rescue medication (i.e., acetaminophen /
paracetamol)
5. Subjects willing to refrain from using any other OA treatment
during the 4-week treatment period, other than the study
treatment, and rescue medication
6. Subjects willing to give written informed consent and provide
audio-visual recording of the consent process
7. Willing and able to comply with the study requirements
8. Not pregnant / not planning to be pregnant / not a lactating
female. Women of childbearing potential and male subjects were
included in the study if they are willing to use an appropriate
method of contraception
Page 9 of 63
26 of 167

Version: 1.0
Date: 18 Jun 2015
A subject will not be eligible for inclusion in this study if he / she meets
any of the following criteria:
Exclusion Criteria
Confidential
1. X-ray showing evidence of OA with Kellgren-Lawrence grade 4

disease
2. History of OA pain in the contralateral knee requiring
medication within 1 year prior to screening
3. After discontinuing all pain medications for at least 7 days, had a
baseline score of 20 mm on a 0-100 mm VAS for the
contralateral knee immediately prior to randomization
4. History of secondary OA, rheumatoid arthritis, chronic
inflammatory disease (e.g., colitis) or fibromyalgia
5. History of asthma, hypertension, myocardial infarction,
thrombotic events, stroke, congestive heart failure, impaired
renal function or liver disease
6. History of gastrointestinal (GI) bleeding or peptic ulcer disease
7. Known allergy to aspirin or NSAID
8. Elevated transaminases at screening (i.e., AST or ALT more than
2 times the upper limit of normal at screening visit)
9. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics,
lithium, or methotrexate within the past 30 days prior to entry
into the study
10. Concomitant acetyl salicylic acid therapy other than a stable low
dose used for cardiac prophylaxis (max 162 mg daily) taken for
at least 3 months prior to enrolment and maintained throughout
the duration of the study
11. Any other topical products applied to the target site
12. Use of systemic corticosteroid or immunosuppressive drugs
13. Use of pain medication other than acetaminophen / paracetamol
14. Any other acute or chronic illness that in the opinion of the
investigator could compromise the integrity of the study data or
place the subject at risk by participating in the study
15. Receipt of any drug as a part of a research within 30 days prior to
screening
16. Previous participation in this study
17. Recent history of knee injury or surgery
18. Subjects who are alcohol or drug dependent i.e. substance of
abuse
19. Subjects having clinically significant liver, kidney, or cardiac
dysfunction
20. Subjects having history of hypersensitivity reactions to
Page 10 of 63
27 of 167

Version: 1.0
Date: 18 Jun 2015
diclofenac sodium gel or any of its excipients

21. A positive serology test result for HIV antibody (I & II), HBsAg,
and / or HCV antibodies
Test Product, Dose,

Route, Regimen
Reference Product,
Dose, Route,
Regimen
Prohibited
Medications /
Restrictions in the
Study
The test product is generic Diclofenac Sodium Topical Gel 1%. It is

manufactured by Cipla Ltd., India and is available in the form of a
topical gel containing 1% of diclofenac sodium. Each subject will apply
approximately 4 g dose of the gel on the target knee 4 times daily for 4
weeks.
Vehicle: Manufactured by Cipla Ltd., India in the form of a topical gel.
Each subject will apply approximately 4 g dose of the gel on the target
knee 4 times daily for 4 weeks.
The reference product is Voltaren Gel (diclofenac sodium topical gel
1%). It is manufactured by Novartis Consumer Health, Inc., USA OR
Novartis Pharma Produktions GmbH, Germany and marketed by Endo
Pharmaceuticals, Inc., USA. It is available in the form of a topical gel
containing 1% of diclofenac sodium. Each subject will apply
weeks.
1. Any other topical products applied to the knee
2. ACE-inhibitors, anticoagulants, cyclosporine, diuretics, lithium,
methotrexate, oral NSAIDs or aspirin [except for cardiac
prophylaxis (max 162 mg daily) taken for at least 3 months prior
to enrolment and maintained throughout the duration of the
study]
3. Systemic corticosteroid or immunosuppressive drugs
4. Pain medication other than acetaminophen / paracetamol
Subjects will be instructed not to use moisturizers, sunscreen, creams,
lotions, powders, avoid exposure to sunlight and sunlamps, not use any
type of bandage or occlusive dressing or heating pad on the treatment
area, not allow the gel to come in contact with the eyes or mucous
membranes, and not apply the gel to open skin wounds, infections,
inflammations, or exfoliative dermatitis on the treatment area (target
knee) for the entire study duration.
Sample size calculation
Sample Size
Confidential
A sample size of 300 in each group will have at least 80% power to
detect a difference in means of 1.1 (change in WOMAC pain score from
baseline to final) between active treatment (5.8) and control- vehicle arm
(4.7) assuming that the common SD is 4.54 using a two group t-test with
a 0.05 two-sided significance level (assuming both active treatment
groups are compared with vehicle at 0.05 level of significance and no
multiplicity adjustment is performed). Assuming approximately 10%
Page 11 of 63
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Version: 1.0
Date: 18 Jun 2015
subjects will not qualify for mITT population, 330 subjects will be
needed to be enrolled in each group to demonstrate superiority of both
active treatments over vehicle.
When the sample size in each group is 240, a two-group design will
have 85% power to reject both the null hypotheses; the 1st hypothesis is
that the ratio of the test mean to the reference mean is below 0.800 and
the 2nd null hypothesis is that the ratio of test mean to the reference mean
is above 1.250; the test and reference mean are not equivalent, in favour
of the alternative hypothesis that the means of the two groups are
equivalent, assuming that the expected ratio of means is 1.0, the
coefficient of variation for the standard is approximately 0.78, that data
will be analyzed in the original scale using Sasabuchi t-tests for the ratio
of means, and that each t-test is made at the 5.0% level. Assuming
approximately 27% subjects do not qualify for PP population; minimum
330 subjects will be enrolled in each group to demonstrate
bioequivalence of two diclofenac formulations.
Thus this study will need to randomize 990 subjects (330 in each
treatment group) with OA of the knee, to get an evaluable data of at least
900 subjects in a 1:1:1 ratio at baseline visit to the 3 treatment groups,
Vehicle of Diclofenac Sodium Topical Gel, Diclofenac Test and
Diclofenac Reference formulation.
Data Analysis and Statistical Considerations
The descriptive statistics for continuous variables will be presented with
number (n) of non-missing observations, mean, standard deviation (SD),
median, and minimum and maximum (range). For categorical data, the
descriptive statistics will be presented with number of exposed subjects
and number (n) with percentage of observations in various categories of
the endpoint, where percentage will be based on the exposed subjects.
Descriptive analyses will also include graphical presentation of data,
wherever appropriate. Individual data listings will also be provided.
Statistical
Methodology
Analysis populations
The following are the 3 analysis populations: per-protocol (PP),
modified intent-to-treat (mITT), and safety population.
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PP population: includes all randomized subjects who meet all

inclusion / exclusion criteria, are compliant with the assigned
study treatment (used at least 75% and no more than 125% of
study treatment doses), returns to the study site for visit 5 / week
4 within the specified window ( 4 days) or discontinues from
the study as a treatment failure, and do not have any protocol
violations. The PP population will be used for the bioequivalence
evaluation of test versus reference. Subjects who will be
discontinued early from the study due to lack of treatment effect
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will be included in the PP population, using last observation

carried forward (LOCF)
mITT population: includes all randomized subjects who meet
all inclusion / exclusion criteria, receive study treatment, and
return for at least one post-baseline visit.
mITT population will be used to compare both test and reference
products to vehicle, as a test of study sensitivity. Subjects who
discontinue early for other reasons will be excluded from the PP
population but will be included in the mITT population using
LOCF.
Safety population: includes all randomized subjects who receive
study treatment
Primary efficacy analysis
To establish bioequivalence for the primary endpoint, 90% confidence
interval (CI) for the test / reference ratio of mean change from baseline
to week 4 must be contained within [0.80, 1.25] for a continuous
variable, using the PP population.
The compound hypothesis to be tested is:
H0: T / R 1 or T / R 2 versus HA : 1 < T / R < 2
Where T = mean of test product and R = mean of reference product
Typically, we reject H0 with type I error = 0.05 (two 1-sided tests), if
90% CI for the ratio of means between test and reference products (T /
R) is contained within the interval [1, 2], where 1 = 0.80 and 2 =
1.25.
Rejection of the null hypothesis H0 supports the conclusion of
equivalence of the two products. Similarly, superiority of test and
reference over vehicle will be tested with a 1-sided test using type 1
error of 0.05.
General linear model will be used to test at baseline covariate factors.
The primary efficacy data will be calculated using sample number,
mean, SD, minimum, maximum and 90% CI.
A general linear regression model will be used to compare the average
change in WOMAC pain score from baseline to week 4 with the use of
treatment as factors and baseline values as covariates.
Comparison to baseline analysis of treatment effects with relevant test
will be described in a statistical analysis plan.
Secondary efficacy analysis
change in POM (using VAS score) and PGA (using Likert scale) from
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baseline to week 4 with the use of treatment as factors and baseline

values as covariates.
As a parameter for determining adequate study sensitivity, both test
product and reference should be statistically superior to vehicle (p <
0.05, two-sided) for the primary endpoint using the mITT study
population and LOCF.
Safety analyses
All safety endpoints will be analyzed based on descriptive statistics as
described above for continuous and categorical variables.
The AEs will be coded by system organ classification (SOC) and
preferred term (PT) using the latest version of Medical Dictionary for
Drug Regulatory Affairs.
All AEs will be listed and categorized before dosing and after dosing.
All AEs which occur after the first dose of the study medication will be
categorized as treatment emergent AEs i.e. AEs with onset date on or
after the first dose of the study medication. The AEs will be tabulated
and summarized for each treatment group. All AEs will be collected,
evaluated, and tabulated by SOC, PT, date of onset, description,
relationship to study medication, seriousness, severity, action taken,
outcome, and date of resolution for each treatment group.
Actual visit wise summary and Change values from baseline to week 4
for other safety measures like physical examination, vital signs, different
lab parameters [hematology and biochemistry] will also be summarized
as per standard convention. The descriptive statistics for continuous
variables will be presented with number (n) of non-missing
observations, mean, SD, median, and minimum and maximum (range).
For categorical data, the descriptive statistics will be presented with
number of exposed patients and number (n) with percentage of
observations in various categories of the endpoint, where percentage will
be based on the exposed patients. Shift table for change from baseline to
week 4 in categorical response will also be prepared where needed.
Ethical Aspects
Confidential
The study will be conducted in compliance with International

Conference on Harmonization-Good Clinical Practice Guidelines, the
Helsinki Declaration, 21 Code of Federal Regulations (CFR) 320.38,
320.63, and 320.36, 21 CFR 58, ICH E6, and local regulatory
requirement (Indian Good Clinical Practice, Schedule Y, and Indian
Council of Medical Research). This protocol and any amendments will
be submitted to an Institutional Ethics Committee, in agreement with
local regulations, for formal approval of the study conduct.
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TABLE OF CONTENTS
1
CONTACT DETAILS .................................................................................................. 2
2
INTRODUCTION....................................................................................................... 21
2.1
Background ................................................................................................................... 21
2.2
Name and Description of Investigational Product(s) .................................................... 22
2.3
Indication ...................................................................................................................... 22
2.4
Non-Clinical Studies ..................................................................................................... 22
2.5
Clinical Data to Date ..................................................................................................... 23
2.6
Adverse Reactions ........................................................................................................ 24
2.7
Risks and Benefits for Study Subjects ......................................................................... 25
2.8
Rationale for the Current Study .................................................................................... 26
2.9
Compliance Statement .................................................................................................. 26
2.10
Description of the Study Population ............................................................................. 26
3
4
4.1
STUDY OBJECTIVE ................................................................................................. 26

STUDY DESIGN ......................................................................................................... 26
Efficacy Endpoints ........................................................................................................ 26
4.1.1 Primary Efficacy Endpoint ........................................................................................... 26

4.1.2 Secondary Efficacy Endpoints ...................................................................................... 27
4.2
Safety Endpoints ........................................................................................................... 27
4.3
Description of Type and Design of Study..................................................................... 27
4.3.1 Description of the Sequence and Duration of Events during Study ............................. 30
4.3.1.1 Visit 1 (Day -21 to Day -15 / Week -3 / Screening Visit) ................................ 30
4.3.1.2 Visit 2 (Day -14 to Day -1 / Week -2 / Eligibility Visit / Run-in Period) ........ 31
4.3.1.3 Visit 3 (Day 0 / Week 0 / Baseline Visit) ......................................................... 31
4.3.1.4 Visit 4 (Day 14 4 / Week 2 / Interim Visit) ................................................... 32
4.3.1.5 Visit 5 (Day 28 4 / Week 4 / End of Study) ................................................... 34
4.3.2 Unscheduled Visits ....................................................................................................... 35
4.4
Measures Taken to Avoid Bias ..................................................................................... 35
4.4.1 Randomization .............................................................................................................. 35

4.4.2 Blinding......................................................................................................................... 35
4.5
Accountability Procedures for the Investigational Product .......................................... 36
4.6
Maintenance of Study Treatment Randomization Codes and Procedures for

Breaking Codes ............................................................................................................. 36
4.6.1 Emergency Unblinding of an Individual Subject.......................................................... 36

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4.7
Identification of Any Data to be Directly Recorded on Case Report Forms ................ 36
5
5.1
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................... 36

Inclusion Criteria .......................................................................................................... 36
5.2
Exclusion Criteria ......................................................................................................... 37
5.3
Subject Withdrawal Criteria ......................................................................................... 38
6
6.1
TREATMENT OF SUBJECTS ................................................................................. 39

Investigational Medicinal Product ................................................................................ 39
6.2
Dosage Regimen ........................................................................................................... 39
6.2.1 Dispensing (Labeling) and Compliance........................................................................ 40

6.2.2 Storage Condition ......................................................................................................... 40
6.3
Handling of Study Medication ...................................................................................... 40
6.4
Retention of Study Medication Samples....................................................................... 41
6.5
Medication(s) / Treatment(s) Permitted and Not Permitted Before and / or During

the Study ....................................................................................................................... 41
6.5.1 Medication(s) / Treatment(s) Permitted ........................................................................ 41

6.5.2 Medications / Treatment(s) Not Permitted ................................................................... 41
6.5.3 Procedure(s) for Monitoring Subject Compliance ........................................................ 42
7
7.1
STUDY ASSESSMENTS ........................................................................................... 42

Efficacy Assessments.................................................................................................... 42
8
8.1
ASSESSMENT OF SAFETY ..................................................................................... 43

Adverse Events ............................................................................................................. 43
8.1.1 Definition of Adverse Event ......................................................................................... 43

8.1.2 Serious Adverse Event .................................................................................................. 44
8.1.3 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters ..... 44
8.1.4 Documentation and Reporting of Serious Adverse Events........................................... 44
8.1.5 Procedures for Eliciting Reports of and Reporting Adverse Event and Intercurrent
Illnesses ......................................................................................................................... 45
8.1.5.1 Eliciting, Documentation and Reporting of Adverse Events ........................... 45
8.1.6 Rating of Adverse Events ............................................................................................. 46
8.2
Emergency Contact ....................................................................................................... 48
8.3
Physical Examination.................................................................................................... 48
8.4
Vital Signs ..................................................................................................................... 49
8.5
Laboratory Evaluations ................................................................................................. 49
8.6
12 Lead Electrocardiogram ........................................................................................... 49
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9
9.1
STATISTICS ............................................................................................................... 50
Statistical Method ......................................................................................................... 50
9.1.1 Demographic and Other Baseline Characteristics ........................................................ 50

9.1.2 Decoding of Randomization ......................................................................................... 50
9.1.3 Primary Analysis (Efficacy Analysis): ......................................................................... 50
9.1.4 Secondary Analysis (Efficacy Analysis): ..................................................................... 51
9.1.5 Safety Analysis ............................................................................................................. 51
9.2
Sample Size................................................................................................................... 52
9.3
Level of Significance .................................................................................................... 52
9.4
Study Termination Criteria ........................................................................................... 52
9.4.1 Withdrawal Criteria ...................................................................................................... 52

9.4.2 Withdrawn Subject Data Collection ............................................................................. 53
9.4.3 Replacement of Subjects ............................................................................................... 53
9.5
Missing Data ................................................................................................................. 54
9.6
Procedures for Reporting Deviations from Original Statistical Plan ............................ 54
9.7
Study Population ........................................................................................................... 54
10
10.1
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS .................................... 54

Monitoring .................................................................................................................... 54
10.2
Documentation at the Study Site................................................................................... 55
10.3
Subject's Data and Data Protection ............................................................................... 55
10.4
Data Management and Analysis ................................................................................... 55
10.5
Amendments to the Protocol ......................................................................................... 56
11
11.1
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 56

Audit ............................................................................................................................. 56
12
12.1
ETHICS ....................................................................................................................... 56
Institutional Ethics Committee or Institutional Review Board ..................................... 56
12.2
Ethical Conduct of the Study ........................................................................................ 56
12.3
Subject Information and Consent.................................................................................. 57
13
14
15
16
17
18
DATA HANDLING AND RECORD KEEPING ..................................................... 57

FINANCING AND INSURANCE ............................................................................. 57
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ........................... 58
PUBLICATION POLICY .......................................................................................... 58
REFERENCES ............................................................................................................ 58
APPENDICES ............................................................................................................. 60
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LIST OF TABLES:
Table 1: Summary of Clinical Studies on Diclofenac Sodium Topical Gel 1%,
Diclofenac Sodium Topical Solution 1.5% and Oral Diclofenac 50 mg: ..................24
Table 2: Study flow chart .........................................................................................................29
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LIST OF ABBREVIATIONS
ACE
Angiotensin Converting Enzyme
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BA
Bioavailability
BE
Bioequivalence
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
COX-2
Cyclooxygenase-2
CRF
Case Report Form
CRO
Contract Research Organisation
CSR
Clinical Study Report
CT
Clinical Trial
DCGI
Drugs Controller General of India
DSG
Diclofenac Sodium Gel
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
EOS
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
GGT
Gamma Glutaryl Transpeptidase
GI
Gastrointestinal
Hb
Hemoglobin
HBsAg
Hepatitis B Virus
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HCT
Hematocrit
HCV
Hepatitis C Virus
HEENT
Head-Eyes-Ear-Nose-Throat
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH-GCP
International Conference on Harmonization-Good Clinical Practice
IEC
Institutional Ethics Committee
IP
Investigational Product
IWRS
Interactive Web Response System
LAR
Legally Acceptable Representative
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Affairs
mITT
Modified Intent-to-Treat
MNI
NSAID
Non-steroidal anti-Inflammatory Drugs
OA
Osteoarthritis
OARSI
Osteoarthritis Research Society International
PGA
Patient Global Assessment
POM
Pain on Movement
PP
Per Protocol
PT
Preferred Term
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
VAS
Visual Analogue Scale
WBC
White Blood Cells
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index
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INTRODUCTION
2.1
Background
Osteoarthritis (OA) is a highly prevalent chronic joint disease characterized by cartilage loss,
synovial inflammation, and bone remodeling. Occurring most frequent in the knee, the
prevalence of OA in this joint increases with age from approximately 1% in people aged 25-34
years to > 30% in people aged 75 years. Radiographic evidence of knee OA is present in 37%
of US adults aged 60 years. Signs and symptoms of OA include joint pain, stiffness, restricted
motion, and crepitus (creaking or crackling) on motion. OA is associated with substantial
disability and diminished productivity (Baraf et al, 2011).
Currently recommended non-pharmacological and pharmacological treatment of OA aims to
control pain and physical dysfunction while avoiding therapeutic adverse effects. Non-steroidal
anti-inflammatory drugs (NSAIDs) are commonly used for the management of OA and are
effective in relieving the pain and physical dysfunction. However, their use is associated with
deleterious gastrointestinal (GI) effects, ranging from mild heartburn and bloating to serious
ulceration, perforation, obstruction, and bleeding, and with hepatic and renal toxic effects. The
newer cyclooxygenase-2 (COX-2) selective NSAIDs reported efficacious results with
diminished risk of GI toxicity. However, their reported safety profile came under scrutiny with
suggestion of other serious harmful effects, including increased incidence of thrombotic
cardiovascular events (Tugwell P et al, 2015). These risks increase with dose and duration of
treatment and patients age (Baraf et al, 2011).
International guidelines on OA care recommend the use of topical NSAIDs as an alternative to
oral NSAIDs (Baraf et al, 2011). Also, the OA Research Society International guidelines
recommended topical NSAIDs as a first-line therapy for patients with OA and it was observed
that the topical NSAIDs had an equivalent efficacy and a lower frequency of adverse events
(AEs) compared with oral NSAIDs. The lower systemic availability of the topical NSAIDs
compared with oral NSAIDs may be the basis of lower frequency of AEs seen with topical
NSAIDs as compared to oral NSAIDs (Peniston et al, 2012 and Roth et al, 2012).
Topical NSAIDs are a relatively new option in the US for the relief of OA pain with the first
receiving US Food and Drug Administration (FDA) approval in 2007 (diclofenac sodium 1% gel
[DSG]; Voltaren Gel; Novartis Consumer Health, Inc., Parsippany, NJ). Topical NSAIDs are a
first-line alternative for knee OA with equivalent efficacy compared to oral NSAIDs and have a,
lower NSAID exposure (Baraf et al, 2010). Topical diclofenac is effectively absorbed in the knee
and hand; however, the plasma concentrations remain very low (Argoff et al, 2011). Therapeutic
doses of DSG (16 g / day; contains 160 mg of diclofenac sodium) applied to one knee produced
peak plasma diclofenac levels approximately 150-fold lower than therapeutic doses of oral
diclofenac (150 mg / day). NSAIDs applied topically could achieve therapeutic concentration in
the tissues proximal to the application site with only low, relatively safe serum concentrations
and may mitigate the risk of drug-drug interactions. This would avoid adverse GI events,
eliminate first pass metabolism, and reduce the risk of AEs related to high serum concentration
often needed for efficacy with systemic dosage forms (Peniston et al, 2013, Heyneman et al,
2000).
Diclofenac sodium is an NSAID with anti-inflammatory, anti-nociception, and antipyretic effects
and has been in widespread therapeutic use for approximately 30 years (Gan, 2010; Zacher et al,
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2008; Scholer et al, 1986). Diclofenac sodium inhibits the enzyme, COX-2, an early component
in the arachidonic acid cascade. By inhibiting COX-2, diclofenac prevents the formation of
thromboxanes, prostaglandins, and prostacyclin. Diclofenac also inhibits the production of
leukotrienes by decreasing arachidonic acid release and increasing its uptake. Diclofenac is
among the most effective inhibitors of prostaglandin E2 (PGE2) production and has been
reported to be 3 to 1000 times more potent on a molar basis compared with other NSAIDs in its
ability to inhibit COX-2 activity (Gan, 2010). Pharmacokinetic evidence indicates that DSG 1%
is the lowest effective dose of NSAID to achieve effective relief. In 2012, Peniston et al. reported
DSG 1% to be efficacious for the relief of OA pain in the hand and knee (Peniston et al, 2012).
2.2
Name and Description of Investigational Product(s)
Synonym
: DSG 1%
Active substance
: Diclofenac sodium
IUPAC / Chemical name
: 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid,
monosodium salt
Molecular formula
: C14H10Cl2NNaO2
Molecular weight
: 318.14
Manufactured by
: Cipla Limited
Specific storage conditions
: Store at 25C (77F); excursions permitted to 15-30C

(59-86F).
Keep from freezing
2.3
Indication
The intended usage of the product is for the relief of the pain of osteoarthritis of joints amenable
to topical treatment, such as the knees and those of the hands.
The intended usage of the medication in the study is treatment for the relief of the pain of OA of
knee.
2.4
Non-Clinical Studies
The following is the non-clinical data of Voltaren Gel.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent
for 2 years at doses up to 2 mg / kg / day resulted in no significant increase in tumor incidence
corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat,
respectively) of the maximum human topical dose of Voltaren Gel (based on bioavailability and
body surface area comparison).
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In a dermal carcinogenicity study conducted in albino mice, daily topical application of a DSG
product for two years at concentration up to 0.035% diclofenac sodium (a 29 - fold lower
diclofenac sodium concentration than present in Voltaren Gel) did not increase neoplasm
incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of a
DSG product at doses up to 0.035% diclofenac sodium (a 29 - fold lower diclofenac sodium
concentration than present in Voltaren Gel) resulted in an earlier median time of onset of
tumors.
Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests, including
bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal
aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal
aberration assay of bone marrow cells.
Diclofenac did not affect male or female fertility in rats at doses up to 4 mg / kg / day which
induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than
the maximum human topical dose of Voltaren Gel (based on bioavailability and body surface
area comparison) (Voltaren Gel Package Insert, Novartis Consumer Health, Inc., NJ, 2014).
2.5
Clinical Data to Date
Oral NSAIDs used for the treatment of OA have dose-related risks for GI, cardiovascular and
renal systems, particularly in the elderly patients. Hence, topical NSAIDs may provide an
alternative to oral NSAIDs to relieve pain from OA as it mitigates the above risk due to its
reduced systemic exposure (Baraf et al, 2010; 2011).
Various studies reported DSG to be effective and well tolerated in patients with symptomatic OA
in knee. Table 1 summarizes the details of the previous published reports on topical DSG 1% and
1.5%.
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Table 1: Summary of Clinical Studies on Diclofenac Sodium Topical Gel 1%, Diclofenac
Sodium Topical Solution 1.5% and Oral Diclofenac 50 mg:
Drug
Duration
of
treatment
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
Current
status
(Reference)
Completed
(Argoff et al.,
2011)
Completed
(Baraf et al.,
2010)
Completed
(Peniston et
al., 2013)
Completed
(Peniston et
al., 2012)
n=622
12 weeks
(3 times
daily)
Completed
(Tugwell et
al.,2015)
Pooled data
n=1426
12 weeks
(4 times
daily)
Completed
(Baraf et al.,
2011)
Sample Size
Study
Indication
Treatment groups
Long-term
safety and
tolerability
OA of knee
1% DSG and 1%
vehicle gel
Pooled data
n=1426
DSG
Safety and
efficacy
OA of knee
1% DSG and 1%
vehicle gel
n=420
DSG
Post-hoc
analysis
OA of knee
1% DSG and 1%
vehicle gel
n=254
DSG
Long-term
safety
OA of knee
1% DSG and placebo
n=583
Topical
Diclofenac
Solution
Equivalence
Study
OA of knee
1.5% Topical
Diclofenac Solution
and Oral Diclofenac
(50 mg)
DSG
Safety and
efficacy
OA of knee
1% DSG and 1%
vehicle gel
2.6
Adverse Reactions
DSG
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
During clinical development, 913 patients were exposed to Voltaren Gel in randomized,
double-blind, multicenter, vehicle-controlled, parallel-group study in OA of the superficial joints
of the extremities. Of these, 513 patients received Voltaren Gel for knee OA and 400 were
treated for hand OA. Additionally, 583 patients were exposed to Voltaren Gel in an
uncontrolled, open-label, long-term safety trial in knee OA. Of these, 355 patients were treated
for OA of 1 knee and 228 were treated for OA of both knees. Duration of exposure ranged from
8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety
trial.
Short-Term Placebo-Controlled Trials: Adverse reactions observed in at least 1% of patients
treated with Voltaren Gel: Non-serious adverse reactions, application site reactions, were
reported during the short-term placebo-controlled studies comparing Voltaren Gel and placebo
(vehicle gel) over study periods ranging from 8 to 12 weeks (16 g per day). These were the only
adverse reactions that occurred in > 1% of the treated patients with a greater frequency in the
Voltaren Gel group (7%) than the placebo group (2%).
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Application site dermatitis was the most frequent type of application site reaction and was
reported by 4% of patients treated with Voltaren Gel compared to 1% of placebo patients.
In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for
patients treated with Voltaren Gel and 3% for patients in the placebo group. Application site
reactions, including application site dermatitis was the most frequent reason for treatment
discontinuation
Long-Term Open-Label Safety Trial:
In the open-label, long-term safety study, distribution of adverse reactions was similar to that in
the placebo-controlled studies. In this study, patients were treated for up to 1 year with Voltaren
Gel up to 32 g per day and application site dermatitis was observed in 11% of the patients.
Adverse reactions that led to discontinuation of the study drug were experienced in 12% of the
patients. The most common adverse reaction that led to discontinuation of the study was
application site dermatitis, which was experienced by 6% of patients (Voltaren Gel Package
Insert, Novartis Consumer Health, Inc., Parsippany, 2014).
2.7
Risks and Benefits for Study Subjects
Topical NSAIDs are a first-line alternative for knee OA with equivalent efficacy compared to
oral NSAIDs and have a lower NSAID exposure (Baraf et al, 2010). Topical diclofenac is
effectively absorbed in the knee and hand; however, the plasma concentrations remain very low
(Argoff et al, 2011). Therapeutic doses of DSG (16 g / day; contains 160 mg of diclofenac
sodium) applied to one knee produced peak plasma diclofenac levels approximately 150-fold
lower than therapeutic doses of oral diclofenac (150 mg / day). NSAIDs applied topically could
achieve therapeutic concentration in the tissues proximal to the application site with only low,
relatively safe serum concentrations and may mitigate the risk of drug-drug interactions. This
would avoid adverse GI events, eliminate first pass metabolism, and reduce the risk of AEs
related to high serum concentration often needed for efficacy with systemic dosage forms
(Peniston et al, 2013, Heyneman et al, 2000).
Various studies have reported 1% DSG topical gel to be safe and effective in subjects with OA
Table 1 of the knee.
In this study, the participants will receive multiple doses of either test, reference or vehicle
product as per randomization. As reported in various clinical trials the study subjects may
experience some adverse events during the study. Most common adverse reactions (incidence >
2% of patients treated with DSG, 1% and greater than placebo) were application site reactions,
including dermatitis.
NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) events including bleeding,
ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal.
Elevations of one or more liver tests may occur during therapy with diclofenac sodium.
Anaphylactoid reactions may occur in patients with the aspirin triad or in patients without prior
exposure to DSG 1%. NSAIDs can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can
be fatal. (Voltaren Gel Package Insert, Novartis Consumer Health, Inc., Parsippany, 2014).
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2.8
Rationale for the Current Study
The study medication in the present study is a gel formulation that contains the diclofenac
sodium as its active ingredient. Various studies have reported 1% DSG topical gel to be safe and
effective in patients of OA (Table 1). In addition, peak plasma diclofenac levels were
approximately 150-fold lower in patients treated with topical diclofenac sodium (16 g / day;
contains 160 mg of diclofenac sodium) compared to therapeutic doses of oral diclofenac (150 mg
/ day).
In this multi-center, randomized, double-blind, vehicle-controlled, parallel-group study, clinical
efficacy, safety, and tolerability of DSG 1% of Cipla Ltd., India will be compared to Voltaren
Gel (a Diclofenac Sodium Topical Gel 1%) of Endo Pharmaceuticals Inc., USA in subjects with
OA of the knee.
2.9
Compliance Statement
The study protocol, amendments to the protocol (if applicable), informed consent form (ICF),
and consent form updates (if applicable) will be submitted to the Drug Controller General of
India (DCGI), which is constituted according to local law to obtain approval before initiation of
the study and as applicable thereafter. The study will only be initiated after receipt of the
approval from the DCGI. The study will be carried out in conformity with International
Conference on Harmonization-Good Clinical Practice (ICH-GCP), the Helsinki Declaration, 21
Code of Federal Regulations (CFR) 320.38, 320.63, and 320.36, 21 CFR 58, ICH E6, and local
regulatory requirement (Indian Good Clinical Practice, Schedule Y, and Indian Council of
Medical Research) and applicable regulatory requirements. Subject confidentiality will be
maintained during all audits.
2.10 Description of the Study Population
Male or non-pregnant female aged 35 years with a clinical diagnosis of OA of the knee
according to the American College of Rheumatology (ACR) criteria at screening will be enrolled
in the study.
3
STUDY OBJECTIVE
To compare clinical efficacy, safety and tolerability of generic Diclofenac Sodium Topical Gel
1% of Cipla Ltd., India with Voltaren Gel (a Diclofenac Sodium Topical Gel 1%) of Endo
Pharmaceuticals Inc., USA and Vehicle of Diclofenac Sodium Topical Gel 1% (manufactured by
Cipla Ltd., India) in subjects with OA of the knee.
4
STUDY DESIGN
4.1
Efficacy Endpoints
4.1.1 Primary Efficacy Endpoint

The primary efficacy endpoint of the study is:
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Mean change in the Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) pain score in target knee from baseline to week 4
4.1.2 Secondary Efficacy Endpoints

4.2
Mean change in pain on movement (POM) on a Visual Analog Scale (VAS) for target
knee from baseline to week 4
Mean change in patient global assessment (PGA) score from baseline to week 4
Safety Endpoints
4.3
Proportion of subjects with AEs and serious adverse events (SAEs)

Change in, physical examination, vital signs, and clinical laboratory tests (hematology
and biochemistry parameters), from baseline to week 4
Description of Type and Design of Study
This is a prospective, randomized, double blind, vehicle-controlled, parallel-group,

bioequivalence (BE) study with clinical endpoints to be performed at approximately 23 study
centers across India. A minimum of 990 subjects (330 in each treatment group) with OA of the
knee will be randomized (considering 10% drop outs) to get an evaluable data of at least 900 in a
1:1:1 ratio at baseline visit to the following 3 treatment groups:
Test group: Generic Diclofenac Sodium Topical Gel 1%
Reference group: Voltaren Gel (Diclofenac Sodium Topical Gel 1%)
Control (placebo) group: Vehicle of Diclofenac Sodium Topical Gel 1%
The total study duration for the subjects will be approximately 7 weeks, including 4 weeks of
treatment.
Visit 1: Screening visit (day-21 to day -15 / week -3)

Visit 2: Eligibility visit / Run-in period (day -14 to day -1 / week -2)
In order to qualify for participation in the study, the subject must present with a clinical
diagnosis of OA of the knee according to the ACR criteria [i.e. Pain in the knee and presence of
at least 3 of the following ACR criteria: age 50 years; stiffness lasting for < 30 min; bony
tenderness; crepitus; bony enlargement; no palpable warmth], including:
Symptoms for at least 6 months prior to screening, and

Knee (not referred) pain for 15 days of the preceding month (periarticular knee pain due
to OA and not due to other conditions such as bursitis, tendonitis, etc.), and
The pain in the target knee required the use of NSAIDs or acetaminophen / paracetamol
(topical or oral treatments)
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The eligible subjects will enter a washout period (run-in period) of 7 days or 5 plasma
elimination half-lives of the discontinued medication (whichever is longer) during which other
topical products applied to knees, including corticosteroids, pain medications, anticoagulants,
At baseline, subjects will be randomized to 1 of the 3 treatment groups and 4 g of either generic
Diclofenac Sodium topical gel 1%, or reference product, or vehicle will be applied to the target
knee. Study medications will be applied to the target knee 4 times daily for 4 weeks. The subject
should not take shower / bathe for at least 1 h after the application but should wash the hands
after use. Both efficacy and safety assessments will be done during the study (Table 2). Subjects
will be permitted to use acetaminophen / paracetamol (up to 4 g / day) as a rescue therapy for
Subject diaries will be dispensed to subjects at baseline. During the study, subjects will be
required to use subject diaries in order to record the date and time of study treatments, any
missed treatments, use of acetaminophen / paracetamol (rescue medication), use of concomitant
medications, and AE(s) experienced or intolerability to study medication. These subject diaries
will be reviewed at visits 4 and 5 and collected from the subjects at visit 5 (day 28 4 / week 4).
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Table 2: Study flow chart

Parameters
Visit
Day / Week
Informed Consent
Screening
Visit
1
Day -21 to
Day -15 /
Week -3
X
Inclusion/Exclusion Criteria
Medical/Surgical History
Subject Demographics
Prior Medication History

X-ray of Target Knee
Laboratory Testsb
12 Lead ECG
Physical Examination
Vital Signs
Urine Pregnancy Test
Efficacy Assessments:
X
X
X
X
X
X
X
Eligibility Visit /
Run-in period
2
Day -14 to Day -1 /
Week -2
Baseline
/random
ization
visit
3
Treatment Phase
Interim Visit
End of
Study Visit
5a
Day 0
Day 14 ( 4) /
Week 2
Day 28 ( 4) /
Week 4
X
X
X
X
X
X
X
WOMAC pain score, POM using

VAS Score; PGA using Likert
scale
Randomization
Dispensing of Study
Medicationc
Collect Study Medication
Dispense Rescue
Medications
Dispense Subject Diaryd
Review Subject Diaryd
Collect Subject Diaryd
Concomitant Medication
AE/SAE Recordinge
Accountability &
Compliance Check of Study
Drugs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
aIf
the subjects participation is prematurely terminated at any point during the course of the study, the EOS visit assessments
(week 4) will be performed during that visit.
bLaboratory tests, including hematology tests (HCT, RBC, Hb, platelets, WBC with differential blood count) and biochemistry
tests (ALT, AST, GGT, total bilirubin, creatinine, urea, sodium, potassium, calcium, phosphorus & bicarbonate, FPG) will be
evaluated at visits 1, 3, and 5.
Serology tests, including evaluation of HIV antibody (I and II), HBsAg and HCV antibodies will be done at screening visit 1.
cStudy medication will be dispensed at baseline and visit 4.
dSubject diary will be dispensed at baseline, the diary will be reviewed at visits 4 and 5 and collected at visit 5.
eAE reporting will begin from the time of signing the informed consent form until visit 5.
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4.3.1 Description of the Sequence and Duration of Events during Study

4.3.1.1 Visit 1 (Day -21 to Day -15 / Week -3 / Screening Visit)
The following assessments will be performed at this visit:
Subjects will sign the ICF. Once informed consent is obtained, the subject will be
enrolled in the study. Audio-video recording of the process will be done.
Inclusion and exclusion criteria will be checked
Recording of medical / surgical history
Collection of demographic information (age [years], height [cm] and weight [Kg])
Recording of prior medication history
X-ray of target knee
Laboratory tests
o Hematology: haematocrit (HCT), red blood cells (RBC), hemoglobin (Hb), platelet,
white blood cells (WBC),with differential blood count
o Biochemistry: Alanine aminotransferase (ALT), aspartate aminotransferase (AST),
gamma glutaryl transpeptidase (GGT), total bilirubin, creatinine, urea, sodium,
potassium, calcium, phosphorus, bicarbonate, and fasting plasma glucose (FPG)
o Serology
Human Immunodeficiency Virus (HIV) antibody (I and II)
Hepatitis B Virus surface antigen (HBsAg)
12-Lead ECG
o Head-eyes-ear-nose-throat (HEENT)
o Cardiovascular system
o Respiratory system
o Nervous system
o Gastrointestinal system
o Musculo-skeletal system
o Urogenital system
o Others, if required
Vital signs (pulse rate [beats / min], respiratory rate [breaths / min], systolic and diastolic
BP (Blood Pressure) [mm / Hg], and body temperature [C]). Subjects must remain in a
seated position for 5 min before vital signs are obtained
Urine pregnancy test (UPT)
Recording of concomitant medications
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Recording of AE / SAE
4.3.1.2 Visit 2 (Day -14 to Day -1 / Week -2 / Eligibility Visit / Run-in Period)
o HEENT
o Nervous system
o Urogenital system
BP [mm / Hg], and body temperature [C]). Subjects must remain in a seated position for
5 min before vital signs are obtained
Recording of AE / SAE, if any
4.3.1.3 Visit 3 (Day 0 / Week 0 / Baseline Visit)

Subjects will be evaluated for Inclusion/Exclusion criteria, including assessment of the

subjects OA after discontinuing all pain medication for at least 7 days:
o Subject must have at least moderate POM for target knee, defined as a baseline score
of 50mm on a 0-100 mm VAS immediately prior to randomization, and
o A baseline WOMAC pain subscale of at least 9 immediately prior to randomization.
Laboratory tests
o Hematology: HCT, RBC, Hb, platelet, WBC, including differential count
o Biochemistry: ALT, AST, GGT, total bilirubin, creatinine, urea, sodium, potassium,
calcium, phosphorus, bicarbonate, and FPG
o HEENT
o Nervous system
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o Urogenital system
Efficacy assessments
o WOMAC pain score
o POM using VAS score
o PGA using Likert scale
Subject randomization in 1:1:1 ratio to either of the 3 treatment groups.

Dispensing of study medication
o Subjects will be provided with 3 tubes of study medication (each tube will contain
100 g of study medication) sufficient to last for 14 days, study duration of 2 weeks
treatment of the target knee. The study medication will be supplied along with
dosing card to standardize the amount of study medication applied to the target knee
Dispensing of subject diary
o Subjects will be provided with a subject diary and instructions on how and when to
complete the subject diary. The subjects will record all the treatments administered,
including date and time, and any treatments missed. In addition, will record all the
AEs experienced, use of concomitant medication, and rescue medication, including
date and time. Subjects will also be instructed to call the study site if they experience
any severe intolerability (i.e., local skin reactions) to study medication.
Subjects will be provided with rescue medication paracetamol / acetaminophen and

instructed to record the date, time and quantity of paracetamol / acetaminophen used.
Subjects will be instructed that they cannot use more than 4 grams per day
Accountability of study medication
o Subjects will be instructed to bring all the study medication (used tubes, unused or
partially used) at the next study visit and should not throw any study medication.
Total amount of tubes dispensed to a subject will be recorded
4.3.1.4 Visit 4 (Day 14 4 / Week 2 / Interim Visit)

o HEENT
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o Nervous system
o Urogenital system
o WOMAC pain score
Collection of study medication
All the used tubes will be collected from a subject and will be instructed to bring
used, unused, and partially used tubes at the next visit for accountability purpose.
Additional rescue medication will be dispensed to the subjects based on the
requirement
o Subjects will be provided with 2 new tubes of study medication (each tube will
contain 100 g of study medication) along with the partially used tube from baseline,
sufficient to last for 14 days, study duration of 2 weeks treatment of the target knee.
The study medication will be supplied along with dosing card to standardize the
amount of study medication applied to the target knee
o In case an additional tube is to be dispensed to the subject so as to suffice the dosing
for 14 days, the reason for the same will be recorded and the tube will be dispensed
on receiving the details from IWRS
Dispense additional rescue medication, paracetamol / acetaminophen (if required).
Subject will be instructed to record the date, time and quantity of paracetamol /
acetaminophen used. Subjects will be instructed that they cannot use more than 4 grams
per day
Subject diary will be reviewed
o

Accountability of study medications with the help of subject dairies (by counting the
number of used tubes returned). A subject is said to be 100% compliant to the study
medication if he / she applies 224 g of the study medication and have a partially used
tube containing 76 g of the gel [300 g-224g = 76g]). This partially used tube will be
returned to the subject by the site personnel. Subjects will be considered compliant with
the assigned study treatment if they have used at least 75% and no more than 125% of the
study treatment doses
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4.3.1.5 Visit 5 (Day 28 4 / Week 4 / End of Study)

Laboratory tests
o Hematology: HCT, RBC, Hb, platelet, WBC, with differential count
o Biochemistry: ALT, AST, and GGT, Total bilirubin, Creatinine, Urea, Sodium,
potassium, calcium, phosphorus, bicarbonate, FPG
o UPT
12-Lead ECG
o HEENT
o Nervous system
o Urogenital system
5 min before vital signs are obtained.
Efficacy Assessments
o WOMAC pain score
Collection of used, unused, or partially used study medication

Collect and review subject diary

number of used tubes returned). From week 2 to week 4, a subject must use 224 g of the
study medication and should not have any partially used tube [in case no additional tube
was dispensed]. Subjects will be considered compliant with the assigned study treatment
if they have used at least 75% and no more than 125% of the study treatment doses
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4.3.2 Unscheduled Visits

An unscheduled visit is defined as any visit that occurs outside the schedule of visits. Data
collected during the unscheduled visit will be recorded on the electronic case report form (eCRF)
document with the Unscheduled visit ID box marked but will not be included in the analysis. If
the unscheduled visit results in premature termination / withdrawal, then all the procedures
enlisted under Visit 5 will be performed.
4.4
Measures Taken to Avoid Bias
All subjects and investigators will be masked to the treatment assigned until completion of the
trial to minimise any subject- or investigator-induced bias in the outcome measures.
4.4.1 Randomization
Approximately 990 subjects (330 in each treatment group) with OA of the knee will be
randomized (considering 10% drop outs) to get an evaluable data of at least 900 subjects in a

Block randomization will be used for subject randomization into the 3 treatment groups. The
randomization list will be prepared by Max Neeman International (MNI) using a validated
computer program, statistical analysis system (SAS) for Windows version 9.3 / Proc PLAN
(SAS Institute Inc., Cary, NC, USA). An interactive web response system (IWRS) method
containing randomization codes will be used to randomize the eligible subject to the treatment
groups.
4.4.2 Blinding
This will be a double blinded and randomized study. The packaging of the test, reference, and
vehicle will be similar in appearance so that the subject and all relevant personnel involved with
the conduct and interpretation of the study (including investigator, investigational site personnel,
and the sponsor, CRO study team or designees staff) will be blinded to the treatment allocation.
Final randomization list will be kept strictly confidential, filed securely by the independent
biostatistician, and accessible only to authorized persons per sponsor (or designee) standard
operating procedures until completion of the study.
A treating physician may request unblinding of study medication on an individual subject, if it is
essential for the clinical management of the subjects health, to ensure safety. If a treating
physician requires unblinding of study medication on a subject, e.g. for management of SAE, the
request will be made telephonically to the MNI medical monitor/sponsor, followed by a written
request. Upon receipt of such request, the identity of the treating physician as well as the
subjects identifiers will be confirmed by MNI medical monitor/sponsor before actual unblinding
of subjects treatment assignment by the investigator. The date and reason for unblinding has to
be documented in the source document (medical record) and CRF, accordingly. The MNI
medical monitor or designee is required to contact and inform the sponsor regarding unblinding
of the subjects treatment.
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Any accidental unblinding will be recorded as a protocol deviation and the subjects continuation
or discontinuation from the study will be decided after discussion with MNI and sponsors
medical monitors. In case there is any need to open the investigator blinding of trial medication
for clinical management of subjects health during the trial or in case of occurrence of a SAE
subject will be withdrawn from the trial.
4.5
Accountability Procedures for the Investigational Product
A study medication accountability log will be maintained by the study staff. This record will
document receipt, dispensing, and return of tubes containing study medication. Accountability
will be performed by reviewing the accountability records and by checking the randomization
number entered in the eCRF. After visit 5 EOS, all used and unused tubes containing study
medication will be shipped to third party for storage or destruction as per sponsors
communication.
4.6
Maintenance of Study Treatment Randomization Codes and Procedures for Breaking

Codes
A central randomization schedule will be generated by the study biostatistician. Subjects will be
randomized 1:1:1 to 1 of the 3 treatment groups. Randomization will be performed with a
computer program generated randomization schedule assigning the subjects in the sequence of
their appearance to treatment groups.
4.6.1 Emergency Unblinding of an Individual Subject
If it is medically imperative to know which study treatment the subject is receiving, emergency
unblinding will be done through IWRS. The investigator or his / her designee will unblind the
code when medically needed, without identifying other subjects treatment. Every attempt must
be made to contact the sponsor before the code is unblinded. The person who unblinds the
randomization code must record the date, time and the reason for emergency unblinding in the
subjects medical record / study documents / eCRF. In such cases, the subject will be
discontinued from the study.
Treatment failures and withdrawn subjects will not be re-randomized and will not be reentered
into the study. A subject may be designated a treatment failure by the investigator if, in the
investigators opinion, the subject has failed to show sufficient benefit from treatment over a
reasonable period of compliant (applied at least 75% of doses of study medication) exposure to
justify continuation in the study.
4.7
Identification of Any Data to be Directly Recorded on Case Report Forms
Not applicable since eCRF will be used in the study.

5
SELECTION AND WITHDRAWAL OF SUBJECTS
5.1
Inclusion Criteria
A subject will be eligible for inclusion in the study if he / she fulfills the following criteria:
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1. Male or non-pregnant female aged 35 years with a clinical diagnosis of OA of the knee
according to the ACR criteria,:
a. Pain in the knee and presence of at least 3 of the following ACR criteria: age 50
years; stiffness lasting for < 30 min; bony tenderness; crepitus; bony enlargement; no
palpable warmth, and including:
ii. Knee (not referred) pain for 15 days of the preceding month (periarticular knee
pain due to OA and not due to other conditions such as bursitis, tendonitis, etc.),
and
iii. The pain in the target knee required the use of NSAIDs or acetaminophen /
paracetamol (topical or oral treatments)
2. Had an X-ray of the target knee, taken no more than 1 year before baseline, showing
evidence of OA with Kellgren-Lawrence grade 1-3 disease
3. After discontinuing all pain medications for at least 7 days, had at least moderate POM
for target knee, defined as a baseline score of 50 mm on a 0-100 mm VAS immediately
prior to randomization, and a baseline WOMAC pain subscale of at least 9 immediately
prior to randomization
4. Able to tolerate rescue medication (i.e., acetaminophen / paracetamol)
5. Subjects willing to refrain from using any other OA treatment during the 4-week
treatment period, other than the study treatment, and rescue medication
6. Subjects willing to give written informed consent and provide audio-visual recording of
the consent process
8. Not pregnant / not planning to be pregnant/ not a lactating female. Women of
childbearing potential and male subjects were included in the study if they are willing to
use an appropriate method of contraception
5.2
Exclusion Criteria
A subject will not be considered eligible for inclusion in this study if he / she meets any of the
following criteria:
1. X-ray showing evidence of OA with Kellgren-Lawrence grade 4 disease
2. History of OA pain in the contralateral knee requiring medication within 1 year prior to
screening
3. After discontinuing all pain medications for at least 7 days, had a baseline score of 20
mm on a 0-100 mm VAS for the contralateral knee immediately prior to randomization
4. History of secondary OA, rheumatoid arthritis, chronic inflammatory disease (e.g.,
colitis) or fibromyalgia.
5. History of asthma, hypertension, myocardial infarction, thrombotic events, stroke,
congestive heart failure, impaired renal function or liver disease
6. History of GI bleeding or peptic ulcer disease
8. Elevated transaminases at screening (i.e., AST or ALT more than 2 times the upper limit
of normal at screening visit)
9. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics, lithium, or methotrexate
within the past 30 days prior to entry into the study
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10. Concomitant acetyl salicylic acid therapy other than a stable low dose used for cardiac
prophylaxis (max 162 mg daily) taken for at least 3 months prior to enrolment and
maintained throughout the duration of the study
14. Any other acute or chronic illness that in the opinion of the investigator could
compromise the integrity of the study data or place the subject at risk by participating in
the study
15. Receipt of any drug as a part of a research within 30 days prior to screening
18. Subjects who are alcohol or drug dependent i.e. substance of abuse
19. Subjects having clinically significant liver, kidney, or cardiac dysfunction
20. Subjects having history of hypersensitivity reactions to DSG or any of its excipients
21. A positive serology test result for HIV antibody (I & II), HBsAg, and / or HCV
antibodies
5.3
Subject Withdrawal Criteria
Subjects will have the right to withdraw from the study at any time and for any reason without
prejudice to her / his future medical care by the physician or at the institution. The investigator
can withdraw subjects from the study in the following situations: in the event of intercurrent
illness, AEs, treatment failure, and protocol violation.
Withdrawal of consent means that the subject does not wish to or is unable to continue further
study participation. The investigator will discuss with the subject the most appropriate way to
withdraw to ensure the subjects health. For a subject prematurely discontinuing from the study,
besides scheduled study assessments for that visit, the investigator will perform all EOS
assessments at that visit itself.
The reasons for subject withdrawal from the study may include:
Withdrawal of consent
Lost to follow-up
Subject non-compliance / significant protocol deviation
Any AE or SAE
Requirement of prohibited concomitant medication
Study termination by the sponsor
As per investigators discretion, continuation in the study would be detrimental to the
subjects well being
Any other reason
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TREATMENT OF SUBJECTS
6.1
Investigational Medicinal Product
The three treatments in this study will be as follows:

Test Product: The test product is generic Diclofenac Sodium Topical Gel 1%. It is
manufactured by Cipla Ltd, India and is available in the form of a topical gel containing 1% of
diclofenac sodium. Each subject will apply approximately 4 g dose of the gel on the target knee 4
times daily for 4 weeks.
Vehicle: Manufactured by Cipla Limited, India in the form of a topical gel. Each subject will
apply approximately 4 g dose of the gel on the target knee 4 times daily for 4 weeks.
Reference Product: The reference product is Voltaren gel (diclofenac sodium topical gel 1%).
It is manufactured by: Novartis Consumer Health, Inc., USA OR Novartis Pharma Produktions
GmbH, Germany and marketed by Endo Pharmaceuticals, Inc., USA. It is available in the form
of a topical gel containing 1% of diclofenac sodium. Each subject will apply approximately 4 g
dose of the gel on the target knee 4 times daily for 4 weeks.
The assigned study medications (gel tubes) will be labelled. Each label will clearly disclose the
protocol number, subject randomization number, subject initials, directions for use, storage
statement, caution statement, and sponsors name.
All the tubes of study medication will be of the similar size, shape, cap configuration, color and
will be labelled in a similar manner in order to maintain blinding.
Each subject will be assigned study medication at the time of randomization (visit 3 / Day 0).
Study medication will be dispensed at baseline (Day 0) and visit 4 (Day 14 / Week 2). Subject
will be provided with 3 tubes (1 tube = 100 g of study medication), adequate enough to last for
14 days, 2-week treatment period. At week 2 (visit 4 / Day 14), subjects will be provided with 2
new tubes of study medication (each tube will contain 100 g of study medication) along with the
partially used tube from baseline, sufficient to last for 14 days (2 weeks treatment of the target
knee). In case an additional tube is to be dispensed to the subject so as to suffice the dosing for
14 days, the reason for the same will be recorded and the tube will be dispensed on receiving the
details from IWRS.
6.2
Dosage Regimen
The dosage regimen in this study is that approved for the reference product. Each randomized
subject will receive study medication at visit 3 / baseline. Subjects will be instructed to apply 4 g
of study medication on the target treated knee 4 times daily for 4 weeks. Each treatment should
be applied laterally, medially, anteriorly, immediately proximal and to 4 inches (10 cm) distal
to the knee. Subjects will be provided with detailed application instructions along with a dosing
card to standardize the amount applied. For this purpose, subjects will place the dosing card on a
flat surface so that they can read the print. The treatment gel should be squeezed onto the dosing
card evenly upto the 4 g line, making sure the gel covers the entire 4 g area of the dosing card.
The subjects will have to apply their knee using the dosing card. Study medication should be
applied to the affected knee area and gently rubbed the skin using hands. The target treatment
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area should not be occluded. The date and time of application will be recorded in the subject
diary. After using the dosing card, it should be rinsed, and dried until next use.
6.2.1 Dispensing (Labeling) and Compliance
The investigational product (IP) will be dispensed by the unblinded pharmacist to the
investigator or designee as per the randomization list provided by the unblinded biostatistician.
Access to the dispensed IP must be provided only to the investigator or designee or pharmacist.
All the test, reference, and vehicle products will have a similar packaging in terms of size, shape,
cap configuration and color to maintain blinding.
The label on each tube will have the following information:
Study Identification Code
Batch/ Code Number
Expiry Date
Storage instructions
Site Number
Subject Number
The statement For Clinical Study Use Only
6.2.2 Storage Condition
The tube must be stored at 20C to 25C (68F to 77F). Keep from freezing. Store the dosing
card with DSG.
6.3
Handling of Study Medication
The study medication will be supplied in 100 g tubes provided by the sponsor. The blinded tubes
will be labeled and packaged by a third party vendor so that neither the subject, the investigator,
and nor the sponsor can identify the treatment. Study medication will be packaged for individual
subjects with each receiving three 100 g tubes at baseline and two 100 g new tubes along with
partially used tube from baseline at visit 4, In case an additional tube is to be dispensed to the
subject so as to suffice the dosing for 14 days, the reason for the same will be recorded and the
tube will be dispensed on receiving the details from IWRS.
All study medication will be dispensed by a qualified study personnel designated by the
investigator. Study medication used to conduct this study will be maintained under adequate
security by the investigator. Study medications will be stored at 25C (77F); excursions
permitted to 15-30C (59-86F) and kept from freezing in a secured area. Documentation of
appropriate daily (when study site is open) study medication storage temperature must be
maintained throughout the study. The investigator will not supply study medications to any
person not enrolled in this study, or to any physician or scientist except those named as subinvestigators.
Subjects will be instructed to return both used and unused tubes of study medication at visit 4 /
Interim visit (week 2) and at visit 5 (week 4). All the used and unused tubes of study medication
will be collected at visit 5 / EOS for study medication inventory. The study site personnel will
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keep a running inventory of the study medication dispensed and the number of tubes (used,
unused, and partially used) that are returned. Forms will be provided to the investigator to
document all the medication received, all study medication dispensed by the site, and study
medication used by each subject. The dispensing and return of study medication at subsequent
study visits will also be recorded in the drug dispensing log. At the conclusion of the study, all
unused, partially used, and empty tubes will be inventoried by the monitor and returned to
sponsor.
6.4
Retention of Study Medication Samples
Each study site where study medication is dispensed to at least 1 subject will be required to
randomly select 1 block (containing 3 consecutively numbered subject boxes) of study
medication from initial shipment to be maintained as retain samples. The investigator will
maintain one randomly selected block of study medication for each additional shipment of study
medication received or as per the specification in the IMP shipment document. As per the 21
CFR 320.38 and 320.63 and the guidance Handling and retention of bioavailability and BE
Testing Samples, Each reserve sample shall be stored under conditions consistent with the
product labeling [25C (77F); excursions permitted to 15-30C (59-86F)] and in an area
segregated from the area where testing is conducted and with access limited to authorized
personnel. Retain samples shall be stored for a period of at least 5 years following the date on
which the application or supplemental application is approved, or, if such application or
supplemental application is not approved, at least 5 years following the date of completion of the
study in which the sample from which the reserve sample was obtained was used. Retention
samples should not be returned to the sponsor at any time.
6.5
Medication(s) / Treatment(s) Permitted and Not Permitted Before and / or During the
Study
6.5.1 Medication(s) / Treatment(s) Permitted

Generally, subjects will be allowed to continue taking stable (non-analgesic) medications that
would not interfere with the metabolism of diclofenac sodium.
Physical therapy will be permitted if started at least 1 month before screening but could not be
initiated or changed during the study. Similarly, exercise regimens and the application of heat or
cold compressions could not be started, discontinued or changed during the study.
Rescue Medications
The use of acetaminophen / paracetamol (upto 4 g per day) will be permitted as rescue therapy
for residual knee or other body pain throughout the study. Rescue medication will be recorded in
the subject diary.
6.5.2 Medications / Treatment(s) Not Permitted
The prescription and over-the-counter drug products that are prohibited during the study include:
Any other tropical products applied to the knees
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ACE-inhibitors, anticoagulants, cyclosporine, diuretics, lithium, methotrexate, oral

NSAIDs, aspirin [except for cardiac prophylaxis (max 162 mg daily) taken for at least 3
months prior to enrolment and maintained throughout the duration of the study]
Systemic corticosteroids or immunosuppressive drugs
Pain medication other than acetaminophen / paracetamol
Subjects will be instructed not to use moisturizers, sunscreen, creams, lotions, powders, avoid
exposure to sunlight and sunlamps, not use any type of bandage or occlusive dressing or heating
pad on the treatment area, not allow the gel to come in contact with the eyes or mucous
membranes, and not apply the gel to open skin wounds, infections, inflammations, or exfoliative
dermatitis on the treatment area (target knee) for the entire study duration.
6.5.3 Procedure(s) for Monitoring Subject Compliance
Treatment compliance will be monitored by reviewing the subject diaries and the total number of
applications and missed applications. Subjects are to apply 16 g (4 g four times daily) of the
assigned study medication to the target treated knee for 4 weeks. At visits 4 and 5, the subject
diary will be reviewed and the used and unused tubes will be collected at visit 5. Subjects who
applied too much or too little medication will be reinstructed on proper dosing. Subjects will be
considered compliant with the assigned study treatment if they use at least 75% and no more than
125% of study treatment doses.
The date of the first application, the date of the last application, the total number of applications,
and the total number of missed applications will be recorded by the study coordinator on the
subjects eCRF. At visit 5, subject diary will be kept at the study center as a part of the source
documentation records. Rescue medication consumption will also be monitored by reviewing the
diaries. The investigator is responsible for the accountability of study drug, reconciliation, and
for recording maintenance throughout the course of the study in accordance with all applicable
regulatory requirements.
7
STUDY ASSESSMENTS
7.1
The enrolled subjects will be assessed for OA after discontinuing all pain medication for at least
7 days (subject must have at least moderate POM for target knee, defined as a baseline score of
50 mm on a 0-100 mm VAS immediately prior to randomization, and a baseline WOMAC pain
score of at least 9 immediately prior to randomization). Any existing conditions in that area will
be noted with respect to how they might affect the application of the study medication. The
efficacy assessments will be conducted at visits 3-5.
The WOMAC pain score (pain score = 0 to 20) and PGA of target knee OA will be done by
using a 5-point Likert scale (i.e., 0 = none; 1 = mild, 2 = moderate, 3 = severe, 4 = extreme).
The following 5 questions pertain to the amount of pain the subject is currently experiencing in
the target knee when:
Q1 Walking on a flat surface (S1)
Q2 Going up or down stairs (S2)
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Q3 At night while in bed (S3)

Q4 Sitting or lying (S4)
Q5 Standing upright (S5)
POM is evaluated using VAS. It is a continuous scale, usually 100 mm in length, anchored by 2
verbal descriptors, one for each symptom extreme (no pain and worst pain imaginable).
Subjects are asked to rate their pain by placing a mark on the line corresponding to their current
level of pain. The distance along the line from the no pain marker is then measured with a ruler
giving a pain score out of 10.
Source: Huskisson EC. Measurement of pain. Lancet. 1974 Nov 9; 2 (7889): 1127-31
PGA will be evaluated at visits 3-5, where the subject will give a global self-assessment of target
knee OA condition using 5-point Likert scale (0 = very well, 1 = well, 2 = fair, 3 = poor, 4 = very
poor) to rate his / her OA, and will be recorded on the eCRF.
8
ASSESSMENT OF SAFETY
8.1
Adverse Events
8.1.1 Definition of Adverse Event

An AE is defined in the ICH-GCP as any untoward medical occurrence in a subject or clinical
investigation subject administered a pharmaceutical product and which does not necessarily have
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a IP, whether or not
considered related to the IP (ICH E6:1.2).
All abnormal laboratory findings should be classified as clinically significant or nonclinically significant by investigator as per his clinical judgment. Only clinically significant
abnormal laboratory values should be considered as an AE.
Worsening of a pre-existing medical condition should be considered as an AE if there is either an
increase in severity, frequency, or duration of the condition or an association with significantly
worse outcomes.
Pre-existing conditions that have not worsened are not considered AEs.
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8.1.2 Serious Adverse Event

A SAE is any untoward medical occurrence that at any dose fulfills one or more of the
following:
results in death
is life-threatening*
requires in subject hospitalisation or prolongation of existing hospitalisation
results in persistent or significant disability / incapacity
is a congenital anomaly / birth defect
is an important medical event: important medical event in the definition of serious
refers to those events which may not be immediately life-threatening, or result in death,
or hospitalization, but from medical and scientific judgment may jeopardize the subject
and / or may require medical or surgical intervention to prevent one of the other
outcomes listed above. Examples of such events are intensive treatment in an emergency
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not
result in hospitalization
*NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the
subject was at risk of death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe.
Hospitalization is to be considered only hospital stay for 24 hours. The following

hospitalizations should not be reported as SAEs:
Hospitalization or prolongation of hospitalization needed for procedures required by the
clinical trial protocol
Hospitalization or prolongation of hospitalization as part of a routine procedure followed
by the center
Hospitalization for a survey visit, annual physicals, or social reasons
Elective (pre-planned) hospitalizations for a pre-existing condition that had not worsened
from baseline (e.g. elective or scheduled surgery arranged prior to start of the study)
Admissions not associated with an AE (e.g. social hospitalization for purposes of respite care)
8.1.3 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters
All AEs will be collected on eCRFs from the time the subject signs the ICF until study exit. Any
SAE that is ongoing at the time the subject exits the study must be followed until the event is
resolved or there is a satisfactory explanation which meets one of the following outcomes:
Resolved (With residual effects or without residual effects)

Death
Unknown (Despite adequate follow-up)
8.1.4 Documentation and Reporting of Serious Adverse Events

All SAEs will be recorded from the time a subject signs the ICF till the end of the study.
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All SAEs, regardless of causal relationship will be reported by the site to sponsor /
designee, Licensing Authority i.e. the DCGI, and institutional ethics committee (IEC) of
the site within 24 hours of occurrence through the initial SAE form.
Follow-up information on an existing SAE that is fatal or life-threatening will be reported
by the investigator after the initial report. Where appropriate, hospitalisation or autopsy
reports will be made available. All SAEs will be followed up until resolution (i.e.,
asymptomatic, stabilisation or death)
The investigator and sponsor / sponsor designee will prepare and submit a detailed
analysed report of all the SAEs to the Head of the Institution where the trial is being
conducted, to the Chairman of the IEC that accorded approval for conduct of the trial and
the Licensing Authority within 14 days. This notification will be as per the Appendix XI
of Schedule Y
If the SAE resolves after the submission of the 14 day analysed report, the investigator
will prepare and submit a second analysed report upon resolution of the SAE.
Report serious adverse events by phone and facsimile to:
Sponsor Details
Dr. Sachin Naik

Telephone (direct line): 022 2575 6459
Mobile Number: (0)8879935397
Email: sachin.naik@cipla.com
drugsafety@cipla.com
Regulatory Authority
Central Drugs Standard Control Organization

Directorate General of Health Services
Ministry of Health and Family Welfare
Government of India
FDA Bhavan, ITO, Kotla Road,
New Delhi -110002
Phone: 91-11-23236975 / 23236971
Fax: 91-11-23236973
E-mail:- dci@nb.nic.in
Illnesses
8.1.5.1 Eliciting, Documentation and Reporting of Adverse Events
Information on AE will be derived by questioning the subjects in general terms (e.g. "How do
you feel? or How have you been feeling since the last questioning? respectively), by subjects'
spontaneous reports, or by observation.
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AEs will be documented on the source documents and eCRFs. Trained monitors will check the
entries in the source documents. The AE will be transcribed to the AE eCRF-pages. The
following information will be given for each AE:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Description of the AE (verbatim term / diagnosis)

Date of onset
Date of resolution
Severity (mild, moderate, severe)
Causality or relationship to the study medication
Seriousness
Action taken (with regard to study medication)
Other action (to treat the event)
Outcome
8.1.6 Rating of Adverse Events

The investigator should describe an AE regarding severity, relatedness, and outcome of every
AE:
Severity will be described as follows:
Mild: The AE does not interfere in a significant manner with the subjects normal
functioning level, but may be an annoyance
Moderate: The AE produces some impairment of functioning but is not hazardous to

health, but is uncomfortable and / or an embarrassment
Severe: The AE produces significant impairment of functioning or incapacitation and is a

hazard to the subject
The duration of the event will be described by the start date and end date.
The causal relationship of the event to use of the IP is described in terms of related or not related
to the IP, wherein related AEs includes Certain, Probable and Possible and not related
includes Unlikely and Unassessable
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Causality term
Certain
Assessment criteria
Probable
Possible
Unlikely
Unassessable
Event or laboratory test abnormality, with plausible

time relationship to drug intake
Cannot be explained by disease or other drugs
Response to withdrawal plausible
(pharmacologically, pathologically)
Event definitive pharmacologically or
phenomenologically (i.e. an objective and specific
medical disorder or a recognized pharmacological
phenomenon)
Rechallenge satisfactory, if necessary
Event or laboratory test abnormality, with reasonable
Unlikely to be attributed to disease or other drugs
Response to withdrawal clinically reasonable
Rechallenge not required
Could also be explained by disease or other drugs
Information on drug withdrawal may be lacking or
unclear
Event or laboratory test abnormality, with a time to
drug intake that makes a relationship improbable (but
not impossible)
Disease or other drugs provide plausible explanations
Report suggesting an adverse reaction
Cannot be judged because information is insufficient
or contradictory
Data cannot be supplemented or verified
The outcome of all AEs will be reported based on the following definitions, independent of
whether they are serious or non-serious AEs, their severity, or their relationship to the IP:
Recovered: Fully recovered, or by medical or surgical treatment the condition has

returned to the level observed at the first study related activity after the subject signed the
informed consent
Recovering: The condition is improving and the subject is expected to recover from the
event. This term should only be used when the subject has completed the study
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Recovered with sequelae: As a result of the AE, the subject suffered persistent and
significant disability / incapacity (e.g. became blind, deaf, paralyzed)
Not recovered
Fatal
Unknown: This term should only be used in cases where the subject is lost to follow-up
Each AE will be followed to satisfactory clinical resolution. An IP-related event (adverse drug
reaction) is an AE that is judged by the investigator or the sponsor / sponsors designee to be
either certainly related, probably related or possibly related to the study IP.
8.2
Emergency Contact
In case of any emergency, following personal should be contacted:

Name: Dr. Subhranshu Nayak (Medical Monitor)
Address: Max Neeman International, Max House, 1, Dr. Jha Marg, Okhla Phase-III
New Delhi-110020
Ph: 011-26324059, 011-40772100; Extn: 2745
Fax:-+91.11.41001945
Email ID: Subhranshu.Nayak@maxneeman.com & safety @maxneeman.com
Mobile: +91- 9643430098
The medical monitor will provide the guidance in case of any emergency related to safety of the
subject.
8.3
A physical examination will be performed at all study visits. The physical examination will
consist of examination of the following body systems:
HEENT
Cardiovascular system
Respiratory system
Nervous system
Gastrointestinal system
Musculo-skeletal system
Urogenital system
Others, if required
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8.4
Vital Signs
Vital signs (pulse rate [beats / min], respiratory rate [breaths / min], systolic and diastolic BP
[mm / Hg], and body temperature [C]) will be recorded at each study visit, after the subject has
rested in a seated position for at least 5 min.
8.5
Laboratory Evaluations
Blood and urine samples will be collected for laboratory evaluations at visit 1, 3, and 5. All the
laboratory assessments (serology, hematology, biochemistry, and UPT) will be carried out in
local laboratories of the respective study sites. The following are the laboratory tests:
Hematology
o HCT
o RBC
o Hb
o Platelets
o WBC with differential blood count
Biochemistry
o ALT, AST, and GGT

o Total bilirubin
o Creatinine
o Urea
o Sodium, potassium, calcium, phosphorus, bicarbonate
o FPG
Urinalysis
o Urine pregnancy test*- All female subjects of childbearing potential will undergo a
UPT at visits 1 and 5.
Serology*
o HIV antibody (I and II)
o HBsAg
o HCV antibodies
o
*Serology and Urine pregnancy tests are the eligibility tests.
8.6
12 Lead Electrocardiogram
12 Lead ECG will be evaluated at Screening and EOS visit.
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STATISTICS
9.1
Statistical Method
All the statistical tests will be carried out as two-sided on 5% level of significance unless
otherwise stated. The descriptive statistics for continuous variables will be presented with
number (n) of non-missing observations, mean, standard deviation (SD), median, and minimum
and maximum (range). For categorical data, the descriptive statistics will be presented with
number of exposed subjects and number (n) with percentage of observations in various
categories of the endpoint, where percentage will be based on the exposed subjects. Descriptive
analyses will also include graphical presentations of data wherever appropriate. Individual data
listings will also be provided.
A detailed statistical analysis plan (SAP) will be finalized providing detailed methods for the
analyses outlined below before the database is locked and prior to analysis of the study being
carried out. Any deviations from the analyses described below will be included in the SAP.
9.1.1 Demographic and Other Baseline Characteristics
Demographic variables and subject characteristics will be summarized descriptively by treatment
assignment and overall. Demographic variables will include age, weight and height. Variables
that are measured on a continuous scale, such as the age of the subject at the time of enrollment,
the number of non-missing observations (n), mean, median, SD, minimum, and maximum will
be tabulated by treatment assignment and overall for the randomized population. Variables that
are measured on a categorical scale will be summarized using frequencies and percentages by
treatment assignment and overall for the safety population.
9.1.2 Decoding of Randomization
The study blind may be broken in case of an emergency when the information of the treatment
assigned is essential for medical management of the subject. The investigator must notify the
sponsor within 24 hours after determining that it is necessary to unblind the treatment
assignment. The investigator must also indicate in source documents and in the eCRF that the
blind was broken and provide the date, time, and reason for breaking the blind. Any AE or SAE
that requires breaking the blind must be recorded and reported as specified in this protocol.
9.1.3 Primary Analysis (Efficacy Analysis):
To establish bioequivalence for the primary endpoint, 90% confidence interval (CI) for the test /
reference ratio of mean change from baseline to week 4 must be contained within [0.80, 1.25] for
a continuous variable, using the per-protocol (PP) population.
Where T = mean of test treatment and R = mean of reference product
Typically, we reject H0 with type I error = 0.05 (two 1-sided tests), if 90% CI for the ratio of
means between test and reference products (T / R) is contained within the interval [1, 2],
where 1 = 0.80 and 2 = 1.25.
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Rejection of the null hypothesis H0 supports the conclusion of equivalence of the two products.
Similarly, superiority of test and reference over vehicle will be tested with a 1-sided test using
type 1 error of 0.05.
The primary efficacy data will be calculated using sample number, mean, SD, minimum,
maximum and 90% CI.
A general linear regression model will be used to compare the average change in WOMAC pain
score from baseline to week 4 with the use of treatment as factors and baseline values as
covariates.
Comparison to baseline analysis of treatment effects with relevant test will be described in a
statistical analysis plan.
9.1.4 Secondary Analysis (Efficacy Analysis):
A general linear regression model will be used to compare the average change in POM (using
VAS score) and PGA (using Likert scale) from baseline to week 4 with the use of treatment as
factors and baseline values as covariates.
As a parameter for determining adequate study sensitivity, both test product and reference should
be statistically superior to vehicle (p < 0.05, two-sided) for the primary endpoint using the
modified intent-to-treat (mITT) study population and last observation carried forward (LOCF).
9.1.5 Safety Analysis
All safety endpoints will be analyzed based on descriptive statistics as described above for
continuous and categorical variables.
The AEs will be coded by system organ classification (SOC) and preferred term (PT) using the
latest version of Medical Dictionary for Drug Regulatory Affairs.
All AEs will be listed and categorized before dosing and after dosing. All AEs which occur after
the first dose of the study medication will be categorized as treatment emergent AEs i.e. AEs
with onset date on or after the first dose of the study medication. The AEs will be tabulated and
summarized for each treatment group. All AEs will be collected, evaluated and tabulated by
SOC, PT, date of onset, description, relationship to study medication, seriousness, severity,
action taken, outcome, and date of resolution for each treatment group.
Actual visit wise summary and Change values from baseline to week 4 for other safety measures
like physical examination, vital signs, different lab parameters [hematology and biochemistry]
will also be summarized as per standard convention. The descriptive statistics for continuous
variables will be presented with number (n) of non-missing observations, mean, SD, median, and
minimum and maximum (range). For categorical data, the descriptive statistics will be presented
with number of exposed patients and number (n) with percentage of observations in various
categories of the endpoint, where percentage will be based on the exposed patients. Shift table
for change from baseline to week 4 in categorical response will also be prepared where needed.
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9.2
Sample Size
A sample size of 300 in each group will have at least 80% power to detect a difference in means
of 1.1 (change in WOMAC pain score from baseline to final) between active treatment (5.8) and
control- vehicle arm (4.7) assuming that the common SD is 4.54 using a two group t-test with a
0.05 two-sided significance level (assuming both active treatment groups are compared with
vehicle at 0.05 level of significance and no multiplicity adjustment is performed). Assuming
approximately 10% subjects will not qualify for mITT population, 330 subjects will be needed to
be enrolled in each group to demonstrate superiority of both active treatments over vehicle.
When the sample size in each group is 240, a two-group design will have 85% power to reject
both the null hypotheses; the 1st hypothesis is that the ratio of the test mean to the reference mean
is below 0.800 and the 2nd null hypothesis is that the ratio of test mean to the reference mean is
above 1.250; the test and reference mean are not equivalent, in favour of the alternative
hypothesis that the means of the two groups are equivalent, assuming that the expected ratio of
means is 1.0, the coefficient of variation for the standard is approximately 0.78, that data will be
analyzed in the original scale using Sasabuchi t-tests for the ratio of means, and that each t-test is
made at the 5.0% level. Assuming approximately 27% subjects do not qualify for PP population;
minimum 330 subjects will be enrolled in each group to demonstrate bioequivalence of two
diclofenac formulations.
Thus this study will need to randomize 990 subjects (330 in each treatment group) with OA of
the knee, to get an evaluable data of at least 900 subjects in a 1:1:1 ratio at baseline visit to the 3
treatment groups, Vehicle of Diclofenac Sodium Topical Gel, Diclofenac Test and Diclofenac
Reference formulation.
9.3
Level of Significance
The data will be summarized descriptively including the sample number, mean, SD, minimum,
median, maximum, and the 95% CI. Applicable comparative tests will have 0.05 significance
level.
9.4
Study Termination Criteria
9.4.1 Withdrawal Criteria

Subjects may be withdrawn from the study (i.e. in these withdrawn subjects, IP will not be
further administered and any study procedures will not be carried out but they will be included in
the safety analyses) for the following reasons:
Lost to follow-up
Subject non-compliance/significant protocol deviation
Any AE or SAE
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Per investigators discretion, continuation in the study would be detrimental to the

subjects well being
Any other reason
In all cases, the reason for and date of withdrawal must be recorded in eCRF and in the subjects
medical records. The subject must be followed up to establish whether the reason was an AE,
and, if so, this must be reported in accordance with the procedures in Section 8.
The investigator must make every effort to contact subject who are lost to follow-up. Attempts to
contact such subject must be documented in the subjects records (e.g., dates and times of
attempted telephone contact).
Any subject may be withdrawn from the study at the discretion of the investigator. The subject is
also free to terminate his / her participation at any time. An EOS visit will then be organized.
9.4.2 Withdrawn Subject Data Collection
The principal investigator and / or other investigator involved in the study will document the
reason for the subject withdrawal as follows:
Lost to follow-up: Subject who leaves the study unnotified or do not attend the study visit
or cannot be contacted by phone. Repeated efforts should be made to locate and recall
them if possible and to determine their health status at a minimum
Significant protocol deviation/violation: Non follow-up for safety or efficacy procedures
required for the study, or repeated missing of study medication doses. Protocol violation
will be considered when the subject is not included as per protocol-defined eligibility
criteria
Subject non-compliance: Repeated missing of study medication doses or any other
procedures in the study which would affect study objectives or subjects safety
AE or SAE: An AE form must be completed. All subjects irrespective of the time of
drop-out will be considered for safety analysis. Clinically significant abnormal value not
explained by a laboratory error or being not a known or abnormal value commonly
observed in this type of population will also be considered as an AE or SAE, and
recorded on AE form as applicable
Requirement of prohibited concomitant medication: Concomitant medication page of
eCRF must be completed
subjects well being
Any, other reason: If no above mentioned reasons are applicable, then please specify
other reason
9.4.3 Replacement of Subjects

Subjects will not be replaced.
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9.5
Missing Data
Missing data points will be dealt using appropriate statistical techniques, depending on the nature
of the data.
9.6
Procedures for Reporting Deviations from Original Statistical Plan
Any post-hoc, or unplanned, analyses not identified in SAP will be clearly identified in the
respective clinical study report (CSR).
9.7
Study Population
The following are the 3 analysis populations: PP, mITT, and safety population.
10
PP population: includes all randomized subjects who meet all inclusion / exclusion
criteria, are compliant with the assigned study treatment (used at least 75% and no more
than 125% of study treatment doses), returns to the study site for visit 5 / week 4 within
the specified window ( 4 days) or discontinues from the study as a treatment failure, and
do not have any protocol violations. The PP population will be used for the
bioequivalence evaluation of test versus reference. Subjects who will be discontinued
early from the study due to lack of treatment effect will be included in the PP population,
using LOCF.
mITT population: includes all randomized subjects who meet all inclusion / exclusion
criteria, receive study treatment, and return for at least one post-baseline visit. mITT
population will be used to compare both test and reference products to vehicle, as a test
of study sensitivity. Subjects who discontinue early for other reasons will be excluded
from the PP population but will be included in the mITT population using LOCF.
Safety population: includes all randomized subjects who receive study treatment
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS
10.1 Monitoring
In accordance with applicable regulations and ICH-GCP guidelines, sponsor or its designees
monitors will contact the site prior to the start of the study to review with the site staff the
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and
sponsor's requirements. When reviewing the data collection procedures, the discussion will also
include identification, agreement, and documentation of data items for which the eCRF will
serve as the source document.
Sponsor and or its designee will monitor the study for protocol compliance verifying the
following, but not limited to:
Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol and any other
study agreements, ICH-GCP guidelines, and all applicable regulatory requirements
Data reported is authentic, accurate, and complete
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The investigator agrees to allow the monitor direct access to all relevant documents for the
purpose of verification of available data.
10.2 Documentation at the Study Site
All data related to the study will be documented in the eCRF. This eCRF is developed to record
the data requested by the protocol. The investigator will ensure the accuracy, completeness,
legibility, and timeliness of the data recorded in the eCRF. At the beginning of the study, a site
master file will be established at the investigational site. The investigator will maintain the study
documents as specified in the ICH-GCP and as required by the applicable regulatory
requirements. The investigator will take measures to prevent accidental or premature destruction
of these documents. Prior to the start of the study, a signature and delegation list will be
completed showing the signatures and hand-written initials of all who are authorized to entry
data or make corrections in the eCRF. The investigator will permit study-related monitoring,
audits, and regulatory inspection, providing direct access to source data / documents.
10.3 Subject's Data and Data Protection
To protect the subject's identity, subject initials and a subject number will be assigned by the
investigator to each study subject and used in lieu of the subject's name when the investigator
reports AEs and / or other study-related data. Personal information will be treated as confidential
but may need to be reviewed by authorized representatives of the sponsor (monitor and auditor,
respectively) and regulatory authorities. The subject's consent for direct access to his original
medical records for data verification purposes has to be obtained prior to a subject's participation
in the study.
The investigator must maintain a list of names and identifying information (e.g. initials, date of
birth, subject identification code and date of study entry) of all subjects enrolled in the study. The
investigator will keep the subject identification code list in the site master file.
10.4 Data Management and Analysis
Data management based on GCP refers to the activities defined for achieving routines for
entering subject information in a database in an efficient and error-free manner.
Data management routines include procedures for handling the eCRFs, database set up and
handling, data entry and verification, data validation, and documentation of activities performed,
including information on discrepancies in the procedure.
All of the AEs, including SAEs reported in the study will be entered in the study database. The
initial notification of SAEs will also be entered into the safety database for coding, medical
evaluation, and notification to regulatory authorities according to national regulatory
requirements. Before database lock, SAE reconciliation will be performed between the safety
and study databases.
Data will be entered and verified in a validated database. Data will be validated continuously by
running logic checks and manual reviews. For any discrepancies identified in study database,
queries will be generated in clinical data management system for resolution. When the data have
been entered, verified, and validated, the database will be locked for analysis.
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10.5 Amendments to the Protocol

The investigator will not implement any deviation from, or changes to the protocol without
agreement by sponsor and prior review and documented approval / favorable opinion from the
IEC of an amendment, except where necessary to eliminate immediate hazards to study subject
or when the changes involve only logistical or administrative aspects of the study (e.g. change in
monitor(s), change in telephone numbers).
All changes or deviations of the trial must be confirmed in writing. Amendment(s) will be signed
off in the same way as the protocol and submitted to the applicable authorities and IEC.
11
QUALITY CONTROL AND QUALITY ASSURANCE
11.1 Audit
To ensure compliance with ICH-GCP guidelines and all applicable regulatory requirements, the
sponsor may conduct a quality assurance audit following intimation and appointment. Regulatory
agencies may also conduct a regulatory inspection of this study. Such audits / inspections can
occur at any time during or after completion of the study. If an audit or inspection occurs, the
investigator and institution agree to allow the auditor / inspector direct access to all relevant
documents and to allocate his / her time and the time of his / her staff to the auditor / inspector to
discuss findings and any relevant issues.
12
ETHICS
Before initiation of the study, sponsor will seek permission from the regulatory authorities for
conducting the study. All documents required by the appropriate authorities will be submitted.
Any notification / submission will be dated and contain sufficient information to identify the
protocol.
12.1 Institutional Ethics Committee or Institutional Review Board
The study protocol, amendments to the protocol (if applicable), IP information, ICF, and consent
form updates (if applicable) will be submitted to the IEC, which is constituted according to local
law to obtain approval before initiation of the study. This study will be initiated after the protocol
is reviewed and approved by the concerned IEC. The approval should be kept on file in the site
master file with a copy in the trial master file. The investigator will report promptly to the IEC
new information that may adversely affect the safety of the subjects or the conduct of the trial.
The present study will be registered on Clinical Trials Registry-India (www.ctri.nic.in).
12.2 Ethical Conduct of the Study
The study will be conducted in compliance with International Conference on HarmonizationGood Clinical Practice Guidelines, the Helsinki Declaration, 21 CFR 320.38, 320.63, and
320.36, 21 CFR 58, ICH E6, and local regulatory requirement (Indian Good Clinical Practice,
Schedule Y, and Indian Council of Medical Research). This protocol and any amendments will
be submitted to an IEC, in agreement with local regulations, for formal approval of the study
conduct.
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12.3 Subject Information and Consent

Subject will be screened and included in the study only after giving them adequate and
appropriate information, and obtaining a written informed consent which will be audio-visually
recorded. The subject will be given sufficient time to consider the studys implications before
deciding to participate. The subject will be provided with a copy of the signed ICF. The
confidentiality of the subjects records will be maintained.
Should there be any amendments to the protocol, such that would directly affect the subjects
participation in the study e.g., a change in any procedure, the ICF will be amended to incorporate
this modification and the subject must agree to sign this amended form indicating that they reconsent to continue their participation in the study.
The investigator is responsible for obtaining the subjects freely given written consent. The
consent form must be signed by the subject or legally acceptable representative and the
investigator-designated research professional obtaining the consent.
13
DATA HANDLING AND RECORD KEEPING
The investigator must maintain all documentation relating to this study. Essential documents (as
defined in the ICH-GCP) and all raw data generated in connection with this study, together with
a copy of this protocol, signed ICDs and the final report will be archived for at least 15 years as
per the ICH guideline for good clinical practice.. These documents must be retained for a longer
period, however, if required by the applicable regulatory requirement(s) or if needed by sponsor.
In any case, all study records such as but not limited to eCRF, regulatory documents, subject
identification code list, subject files, and other source data that support eCRFs must be retained
for at least 5-years after the completion or discontinuation of the study The investigator must
notify sponsor or its designee of any changes in the archival arrangements, including, but not
limited to, archival at an off-site facility, transfer of ownership of the records in the event the
investigator leaves the site. These documents must be retained for a longer period, however, if
required by the applicable regulatory requirement(s) or if needed by sponsor.
Sponsor will notify the investigator in writing when the study-related records are no longer
needed.
14
FINANCING AND INSURANCE
Cipla Limited is the sponsor of this study and all agreements between the investigator and
sponsor or its designee will be signed prior to inclusion of the first subject in the clinical study.
The agreement must clearly state the rights and obligations of the parties concerned and include
a detailed financial settlement.
Every subject participating in the study will be insured in accordance with the local legal
requirements against study related injuries to the subject, which may occur during the study.
Excluded from this, however, are injuries to health and deteriorations of illnesses already
present, which would have occurred or continued to exist even if the subject had not taken part in
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this clinical study. Any injury to health, which might have occurred as a result of participation in
the clinical study, must be reported by the investigator.
The sponsor is self-insured which covers product liability and subject injuries.
15
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS
A CSR, according to the ICH Guideline for Structure and Content of CSRs, will be prepared by
MNI in close collaboration with sponsor upon full completion of the study. The final report will
be compiled and sent as per e-CTD (Module 5) format. All copies of supplementary documents
such as approved final version of protocol along with all appendices, IEC approval letter, List of
IEC members, CVs of investigators, all patient CRFs, adverse event form (if any),
Investigational Medicinal Product accountability records, Randomization list, Summary report of
statistical analysis, Protocol deviations, Demographics and Baseline characteristics and Safety
data will be submitted to sponsor with the final study report. It shall contain particularly Study
Protocol, Clinical data and Statistical Report.
16
PUBLICATION POLICY
This CSR, as well as any discovery and improvement related to IP, shall be the property of the
sponsor.
Neither the complete nor any part of the results of the study carried out under this protocol, nor
any of the information provided by the sponsor for the purposes of performing the study, will be
published or passed on to any third party without the consent of sponsor. Any investigator
involved with this study is obligated to provide the sponsor with complete test results and all data
derived from the study.
The investigator agrees to keep strictly confidential all unpublished information and results
concerning this study. Unpublished information must not be published or disclosed without
sponsors prior written approval.
17
REFERENCES
Argoff CE, and Gloth MF (2011). Topical nonsteroidal anti-inflammatory drugs for
management of osteoarthritis in long-term care patients. Therapeutics and Clinical Risk
Management 7:393-399.
Baraf Herbert SB, Gloth MF, Barthel RH, Gold MS, and Altman RD (2011). Safety and
Efficay of Topical Diclofenac Sodium Gel for Knee Osteoarthritis in Elderly and
Younger Patients. Pooled Data from Three Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled, MultiCentre Trials. Drugs Aging 28 (1):27-40.
Efficay of Topical Diclofenac Sodium 1% Gel in Knee Osteoarthritis: A Randomized
Controlled Trial. The Physician and Sports Medicine. 1SSN-0091-3847 38 (2):19-28.
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Date: 18 Jun 2015
Draft
Guidance
on
Diclofenac
Sodium,
Recommended
Mar
2011.
http://www.fda.gov./downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm244644.pdf
Guidance for Industry Handling and Retention of BA and BE Testing Samples. US FDA
May2004.
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126836.pdf
http://www.fizjoterapeutom.pl/attachments/article/348/2008-4404b1-05-WOMACQuestionnaire.pdf
Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med
Res Opin. 2010; 26(7): 1715-31
Heyneman CA et al.Oral versus Topical NSAIDs in Rheumatic Diseases (2000);
60(3):555-574
Huskisson EC. Measurement of pain. Lancet. 1974 Nov 9; 2 (7889): 1127-31
Peniston JH, Gold MS, Wieman MS and Alwine LK (2012). Long-term tolerability of
diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities.
Therapeutics and Clinical Risk Management 7:517-523.
Peniston JH, Gold MS, Wieman MS and Alwine LK (2013). Tolerability of diclofenac
sodium 1% gel with concomitant medications known to interact with diclofenac.
Roth SH, and Fuller P (2012). Pooled safety analysis of diclofenac topical solution 1.5%
(w/w) in the treatment of osteoarthritis in patients aged 75 years or older. Clinical
Interventions in Aging 7:127-137.
Scholer DW, Ku EC, Boettcher I, Schweizer A. Pharmacology of diclofenac sodium. Am
J Med. 1986; 80(4B): 34-8
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
http://www.performanceptpc.com/paperwork/womac.pdf
Tugwell PS, Wells GA, and Shainhouse ZJ (2015). Equivalence study of a topical
diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment
of osteoarthritis of the knee: a randomized controlled trial. The Journal of Rheumatology
31 (10):2002-2012.
Voltaren Gel Package Insert, Novartis Consumer Health, Inc., Parsippany, 2014
WOMAC Osteoarthritis Index LK3.1 (IK).
Zacher J, Altman R, Bellamy N, Brhlmann P, Da Silva J, Huskisson E, Taylor RS.
Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr
Med Res Opin.2008; 24(4): 925-50
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18
APPENDICES
Appendix 1:
WOMAC Questionnaire
Appendix 2:
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Date: 18 Jun 2015
Appendix 1: WOMAC Pain Score

Instructions to Patients
WOMAC Pain Score questions will be asked in the following format. Please mark your
answers by putting X in one of the boxes
Examples:
1. If you put your X in the box on the far left as shown below,
none
mild
moderate
severe
extreme
then you are indicating that you feel no pain

2. If you put your X in the box on the far right as shown below,
none
mild
moderate
severe
extreme
then you are indicating that you feel extreme pain

3. Please note that:
a. the further to the right you place your X, the more pain you feel
b. the further to the left you place your X, the less pain you feel
c. please do not place X, outside any of the boxes
You will be asked to indicate on this type of scale the amount of pain you have felt during
the last 48 hours.
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WOMAC PAIN SCORE

Think about the pain you felt during the last 48 hours caused by osteoarthritis in your
target knee
Please mark your answers with an X
QUESTION: How much pain you have had.
1. when walking on a flat surface?
none
mild
moderate
severe
extreme
severe
extreme
2. when going up or down the stairs?

none
mild
moderate
3. at night while in bed? (that is pain that disturbs your sleep)

none
mild
moderate
severe
extreme
moderate
severe
extreme
moderate
severe
extreme
4. while sitting or lying down?

none
mild
5. while standing?
none
mild
Study Co-ordinators Use

PAIN 1
PAIN 2
PAIN 3
PAIN 4
PAIN 5
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Appendix 2: Visual Analogue Scale

Pain on movement (POM) is evaluated using Visual Analogue Scale (VAS). It is a subjective
measure of pain. It is a continuous scale, usually 100 mm in length, anchored by 2 verbal
descriptors, one for each symptom extreme (no pain and worst pain imaginable). Subjects are
asked to rate their pain by placing a mark on the line corresponding to their current level of pain.
The distance along the line from the no pain marker is then measured with a ruler giving a pain
score out of 10.
Interpretation of Score
The score can be used as a baseline assessment of pain with follow-up measures providing an
indication of whether pain is reducing. The scores can also be used to evaluate treatment
effectiveness
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Version: 1.1
Date: 26 Feb 2016
CLINICAL STUDY PROTOCOL

A Prospective, Multi-Center, Randomized, Double-Blind, Vehicle-Controlled, ParallelGroup Bioequivalence Study with Clinical Endpoints Comparing Generic Diclofenac
Sodium Topical Gel 1% of Cipla Limited, India to Voltaren Gel (a Diclofenac Sodium
Topical Gel 1%) of Endo Pharmaceuticals Inc., USA in Subjects with Osteoarthritis of
the Knee
Protocol Number:
CIP-DSG-01
Version/Date:
Version 1.1 / 26 Feb 2016
Clinical Trial Phase:
Bioequivalence Study
Sponsor:
Cipla Limited
Contract Research
Organization:
JSS Medical Research India Ltd

Plot 12/2, 6th Floor, Vatika Mindscapes Tower- B
Sarai Khwaja Metro Station, NH-2, Mathura Road
Sector 27 D, Faridabad, Haryana- 121003, India
Investigational Product:
Diclofenac Sodium Topical Gel 1%
CONFIDENTIALITY STATEMENT
This protocol is a confidential document owned by Cipla Limited. Any unpublished information contained in it may
not be disclosed to a third party without prior written approval of Cipla Limited. However, the document may be
disclosed to an Institutional Ethics Committee or a statutory regulatory authority under a similar condition of
confidentiality.
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Date: 26 Feb 2016
CONTACT DETAILS
Sponsor
Cipla Limited
Sponsor Representative

Head - Clinical Research & Development
R & D Center, 8th Floor
North Block, LBS Marg
Vikhroli (W), Mumbai-400083
Phone: +91 22 25756847
E-mail: Dhiraj.Abhyankar@cipla.com
Clinical Research Organization
JSS Medical Research India Ltd

Plot 12/2, 6th Floor, Vatika Mindscapes Tower- B
Sarai Khwaja Metro Station, NH-2, Mathura Road
Sector 27 D, Faridabad, Haryana- 121003, India
Protocol Author [Medical writer]
Phone: +91 0129 6613500

Dr. Urmila Jetley
JSS Medical Research India Ltd, First Floor, Ready
Money Terrace 167 Dr. A. B. Road, Worli Naka,
Mumbai-400018, India
Biostatistician
Phone: +91 22 24931391

E-mail: Urmila.Gupta@ jssresearch.com
Mr. Santosh Kumar
JSS Medical Research India Ltd, Plot 12/2, 6th Floor,
Vatika Mindscapes Tower- B, Sarai Khwaja Metro
Station, NH-2, Mathura Road, Sector 27 D, Faridabad,
Haryana- 121003, India
Investigator Responsible for

Conducting the Study and Study
Site(s)
Clinical Laboratory and other
Medical and Technical
Department(s) and Institutions
involved in the Study
Confidential
Phone: +91 11 129 6613500

E-mail: Santosh.Kumar@ jssresearch.com
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Protocol Number: Cl P-DSG-0 I

Version: 1.1
Date: 26 Feb 2016
SPONSOR'S DECLARATION
I, on behalf of Cipla Limited, India have read, understood & approved this Protocol. I agree to
comply with all requirements regarding the obligations of Sponsor and all other pertinent
requirements of the International Conference on Harmonization of technical requirements for
registration of pharmaceuticals for human use guideline for Good Clinical Practice ICH E6
(amended version), the Code of Federal Regulations on the Protection of Human Subjects (45
CFR Part 46), in accordance with Declaration of Helsinki (amended version), ICMR guidelines
for Biomedical Research on Human Subjects (amended version) & Schedule Y of Drugs and
Cosmetics Act and Rules (amended version) released by Central Drugs Standard Control
Organization, India, Good Clinical Laboratory practice (GCLP) and applicable regulatory
guidelines.
Sponsor's Representative:
Name: Dr. Dbiraj Abbyankar
Signature:
~~
Date: o r !1/1 ~
Confidential
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Version: 1.1
Date: 26 Feb 2016
CRO Approval Page
I have prepared version 1.1 of study protocol (10: CIP-DSG-0 1), dated 26 February 2016.
To the best of my knowledge, the protocol is accurate and complete. I approve this version as the
final copy and consider it acceptable for regulatory submission.
Protocol Author:
Dr. Urmila Jetley
~~~
26 Feb-1~16
Signature:
Date:
Study Biostatijfician:
Signature.
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Version: 1.1
Date: 26 Feb 2016
Name:
Signature:
Date:
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Pn>to<OI Numl>cr. OP-DSG-01

Version: 1- I
Date: 26 Peb 20 I6
I, the undersigned, declare !hat I have read and understood this protocol and hereby agree to
the study in accordance with this protocol and to comply with all requirements regarding
the obligation~ of investigators and all other pertinent requirements of the International
Conference on Harmonization of technocal requirements for registration of pharmaoeuticals for
human use guideline for Good Clinical Practice ICJ:I E6 (amended version), the Code of federal
Regulations on the Protection of Human Subjects (45 CFR Pan 46), in accordance wilh
Declaration ofHelsmki (amended version),lCMR guidelines for B1omedicnl Research on Human
'ersion) released by Central Drugs Standard Control Organi:tarion, India and principles on Oood
Laboratory Prncrice, and all regulatory requirements for including all elements required for an
lnsrirutoonal Revie~ Board (IRB) to assess study n5Xs sod benefits,
cond~t
We further agree to ensure that all associates assisling in the conduct of study arc informed
regardmg their obligations.
I agree to comply with all rele,.ant Standard Operating Procedures (SOPs) required for the
r/
ame:
D-r
G,!J..'~Cll/0.. ~
~ ~v--
~ \? \ II.
Sienture:
Oate:
Coolid<Otlll
Pages of6J
~---------
Pru1ow:
~umber:
CIP-DSG-u:
Vetsion: 1.1
Oare- 26 Feb 10!6
- - - - - ------
11'11\'E.STIGATOR'S DECLARATION
!, the undersigned, declare thol l have read and understood this protocol and hereby agree to
the obligations of investigator!> and all other pertinent requirements of the lnternalion,1l
Conference on Harmoniz,ation of technical requirements for registration of pllarmaccuticah for
Subjects (amended version) & Schctlule Y of Drugs and Cosmetics Act and Rules (amended
Institutional Review Board (IRB) to ~ssess study risks and benefits.
We further agree to ensure that all associates assisting in the conduct of
~tudy
are infonned
nogartling their obligations.

cond"<t of~;~~old do'"ment '"Y ,;gn i"""' devioti on """"' ng d"dn g the ,ornly
Printipal
Jnv~:-
Name: '1> R,5
Ml~ I) IT
R t}MTe ke
Signature:
Date;
o3( .MI+P.) 2.{) (b

DR. S~w'fRUTI RAMTEKE
MD
ARTHRITIS & RHEUMATISM CLINIC
Jasleen Ho3prtalt Pa11chasheet Cllcwk,
DhantoiL NAGPUR-10
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Pro loW! Number; CIP-DSG-01
Version: 1.1
Date: 26 Feb 2016
J, the undersigned, declare that I have read and understood this protocol and hereby agree to
Conference on Hannonization of technical requirements for registration of pharmaceuticals for
Regulations on the Protection of Human Subjects (45 CFR Part 46), in acrordnnce with
Declaration of Helsinki (amended version),ICMR guidelines for Biomedical Research on Hum::m
version) released by Central Drugs Stnndard Control Organization, Jndia and principles on Good
Labomtory Practice, and all regulatory requirements for including all elements required for an
We further agree tc ensure that oli associates assisting in the conduct of study arc infonned
l agree to comply with all relevant Stondard Operating Procedures (SOPs) required for the'
conduct ofthls study and would document any significant deviation occurring during the srudy.
Name:
Signotnre:
Date:
~
3 - 3 - \ C.
Confidential
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Protocol Numher: CJP-DSG-01

Version; Ll
Date; 26 Feb 20!6
Laboratory Practice, and all regulatory requirements for including all clements required for an
Colldeotlal
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~~----------------
Protocol Number: CIP DSG-01
Version: 1.1
Dnte: 26 Feb 2016
I!'JVESTIGA TOR'S DECLARATION
!, the undersigned, declare that I have read and understood this protocol and hereby agree to
the obligations of inve;,iigators and all other pertinent requirements of the International
Conference ou HannoniZBtion of technical requirements for registrution of pharmaceuticals for
human use guideline for Good Clinical Practice ICH E6 (amended ver.;ion), the Code ofFederal
Declaration of Helsinki (amended vcrsion),JCMR guidelines for H1omedical Research on Human
version) released by Central Drugs Standard Control Organizarion, India and principles on Good
Laboratory Practice, and all regulatory requircment~ for including all elements required fur an
We further agree to ensure that all assodates assisting in the conduct of study are informed
I agree to compl} with all rc:lcvant Standard Operating Procedures (SOPs) required for the
cooduct of this study and would document any significant deviation occurring during the study
Principalln~~ewg11tor:
[)~
l'i'ame: 'J)X .J:
~ 'r
:::~tnr~C,
Conf"ldential
CCALtAv 2 0 lb
Page 5 of 6J
90 of 167
Protocol Number CIP"DSC-Ol
Version; J.l
Date: 26 Feb 201h
I, the undersigm:J, Jcclare that ! have read and under::.tood this protocol and hereby agree to
conduct the studv in accordance with this protocol and to comply with all requirements regarding
the obligation' of investigators and all other pertinent requirements of the International
Conference on Hannonization of technical requirements for registration of pharmaceuticals for
human use guitlcline for Good Clinical Practice ICH E6 (amended version), the Cotle of Federal
Reguluiions on the Protection of Human Subjects (45 CFR Part 46), in accordance with
Declaration of l h:lsinki (amended version).ICMR guidelines for Hiomedical Research on I Iuman
Subjects (amcnJcd version) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
version) relca~ed by Central Drug!S Standard Control Organization, India antl principles on Good
I ,aboratory Practice, untl all regula!Or)' requirement!'. for mcluding all elements required fi1r an
ln,.titutional Review Board (IRR) to assess study risks and benefits.
We further agree to ~.:nsure that all associates assisting in the conduct of study arc mformed
regarding their ubligation$.
I u~,;n.:c to comply with ull relevant Standard Operating Procedures (SOPs) required for the
conduct of this ~tudy antl would document any significant dcvtation occurring during the stud)
Signature:
.
/i{~s=M
"d)\6
()/l-c.h.
J.--
DR. SUSHIL MANKAR

PROFESSOR & HOD
Department ot Orthoapedics
NKP Salve Institute of Mcd!c.al Science &
Research Centre & Lata MangeshkM
Hospital, Ni\gpur
Confideulial
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Proro.:11 '.urn~r UPO'-t 0'

\erJt
II
Date .!fJ ftb 2016
I, the unders1gned, dccla:l! ~hat I have ~d ano understood th1s prot~l n::d hereb> ngree to
conduct the stud) m nccord.::nce w.l~l thts protocol nnd lO ;.or;nply w11h all rcqmrem.:nt:;. rcgard tng
the obltgatons c1 '"' esttl!ator' ~.nd all o:hcr per11rcn1 requir~m~nts of the lmemlltional
Comerence on Harmont7Jllion ol techncal requrrerr.ent~ lor regrslrntlon nf phsnnaceul:cals for
htll'l:tll use gUJJehne lor GOOd Ctm.cal Prn tree ICtl F..6 (amendr:tJ H"r tOn), the Cede ol Federal
Regulnllons on the Prote~uon of llumllll ~UbJetts ( :~ CFR Pa1 46). m a~coniance wnh
Dcclarr.taor. ofHti'Htkt (amended vtrsrnn),IC~!R gu1dehnc~ for Baotned1cal Rc,eateh on Human
<it.~Jeca (nmendcd 'iC'rSIOn) t.:
hedu!c Y of Drugs und Cosrne:tt.s Act nou Ruk' (omend~d
>en;tort) released b) Ccntrnl Drugs !>umdard Con:ral Organa:t.aton, India and vrmc:pks on Good
t nbC'rulory Prilcttce, ar,d ull rc:guhnoy rCQllllt''lenls :c mcludmg 1111 t-ltments required for an
ln~llh Ilona! Rc\ rcw Board ORA) ll :nsc'~ ~;udy 11s s nnd hePelit.\
\It~ Jurther !I r .:~ h) ens are lh.tt all
regsrt!mg their obhgvttons
AS$0C13lcs IISSJ~ttng 111
the conduc1 of study arc tnformcd
I agree :o :omply w11h ull re!ev1~1 Sto~nda1d Oper.tting ProeeJurcs (SOl's) !cqurred ;or the
conduct oflh.s stud) nnJ would document An;' :.rgntfitllnt dt:\rlluon occurnng during tile su;t.ly
}'t iucip:~llnH,Iil!.ttru:
'
-r. 5 ~.:r.,.., ..,

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tl~tt
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l'a~;e ~
of '-l
93 of 167

Version: !J
Date: 26 Feb 2016
Institutional Review Board (IRB) to as'sess study risks and benefits.
We further agree to ensure that all associates assisting in the conduct of study are infonned
Name:
Signature:
Date:
Confidential
":PI'" ~i"' t'; ""'~~

~
"1 /3J~cl(i:>
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Protrnxl Number C!P-OSG-Dl

Ll
Vc~ion;
Date: 26 h;b .Z{)J6
INVESTIGATOR'S DEClARATION
J, the undersigned, declare that l have read and understood this protocol and hereby agree to
the obligations of inve!.tigators and all other pertinent rcqu1rernents of the International
Conference on Harmonization of t~hnical requir~ments for registration of pharmaceuticals for
human uw guideline for Good Clinical Practice 1CH E6 (amended version), the Code of Federal
Declaration of Helsinki (amended ver~ion),ICMR guidelines for Biomedical Research on Human
Subjects (amended version) & Schedule Y of Drugs and Cosmetics Act and Rule~ (amended
version) released by Central Drugs Standard Control Orgunil.ution, India and principles on Good
We furiher agree to ensure t!wt all associates assisting in the
~.:ondud
of study arc informed
I agree to comply with all relevant Standard Operating Procedu(es (SOPs) required for the
condud of this study and would document any significant deviation occurring during the study.
Jrindpal lnYestigator:
Name:
Signature:
ltJ ftL.-
IL. TY'I IT fl... {J
~ ~
Date:
-------------------------------
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Protocn! Number: CW.OSG--01

Version: 1.1
D;.tt:: 26 Feh 2016
11\"VESTJGATOR s DECLAliATlON
l, the undersigned, declare that I have read and understood this protocol and hereby agree to
conduct the study in acc:ordance with this protocol and to comply with all requirements regarding
Conference on Harmoni7_ation of technical requirements for registration of pharmaceuticals for
human use guideline for Good Clinical Practice ICH E6 (amended version), the Code ofFedetal
Regulations on lhe Protection of Human Subjects (45 CFR Part 46), in accordance with
version) released by Central Drugs Slandard Contr<ll Organization, India and principles on Good
Laboratory Practice, and all regulatory rcquir~ments for including ull clements required for an
Institutional Review Board (lRB) to assess study risks and benefits.
We further agree to et1sure that all associates assisting in the conduct of study arc informed
I agn.:e to comply with all relevant Standaru Operating Procedures (SOJ>s) required for the
ccmJuct thls study and -.vould document any significant deviation occurring. during the study.
Principallnvestigator;
:"a me:
Signature:
Confidential
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Protocol Number: ClP-DSG-01

Version: U
Date: 26 Feb 2016
INVESTIGATOR'S I>ECLARATION
conduct the study in accordance with this protocol and to comply with all requirements regarding,
the ohligations of investigators and all other pertinent requirements of the International
human use guideline tor Good Clinical Practice ICH E6 (amended version), the Code of Federal
We further agree ro ensure that all associates assisting in the conduct of study are informed
l agree to comply with all relevant Standard Operating Procedures (SOPs) required for the
conduct of this study and would document any significant deviation occurring during the study
Name:~
A-Mtl
Signature:
~~ff'O'
Date:
.~HM.-.Mit
0'2. J 0 "l../ fL.<> I b
Confldtntlal
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Protocol Number: ClP-DSG-0 l

Version; I.!
Date: 26 feb 2016
fNVESTIGATOR'S DECLARATION
conduct the study in accordance with this protocol and to comply with all requirements regan1ing
the obligations of imestigators and all other pertinent requirements of the Jnlernational
Conference on Harmoni7.2tion of technical requirements for registration of phailllaceuticals for
human use guideline for Good Clinical Practice JCH E6 (amended version), the Code of Federal
Declaratton of Helsinki (amended version),lCMR guidelines tor Riomedical Research on Human
SubjectS (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (amended
Lahoratory Practice, and all regulatory requirements for including all elements required for an
Institutional Review Board (1RB) to assess study risks and benefits.
,,,
I agree to comply with all relevant StandJrd Operating Procedures (SOPs) required for the
conduct of this ~iudy and would document any significant deviation occurring during the study.
Princ.ipai Innstigator:
Name:
Signature!
Date:
________________ _______
,
CunlidentiBl
-----~------------
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.J;;L .ll-~--------_j_
_____________, - --- - - - - - - - -
f'wlocol Number: CIP-OSG-Ol

Version; i.l
Da.,; 26 Feb 2015
---~------------------~-
I, the undersigned, declare tlnn f have read and understood this protocol and hereby agree to
conduct the study in accordance with thts protocol and m comply with all requirements regarding
the ohligation~ of investigators and all orhcr peninent requirements of the International
Conference on Hamwni7..atiun of technical requirements for registration of pharmaceuticals for
human use guideline far Good Clinicai Pn.Jcticc ICH E6 (amended ver~ion), the Code of Federal
Regulations on the Protection of Human Subjects (45 CFR Part 46), in acCGrdance with
Subjects (amended version) & Schedule Y of Drugs and Cosmetics Act and Rules (amende-d
InstitutiOnal Revic"' Board (IRB) to asses:S study risks and benefits.
We further agree to ensure that all associates assisting in the wnduct of study are infonncd
regarding their ubligations.

l agree to comply with all relevant Standard Operatir,g Procedures (SOPs) required for the
conduct of this study and wculd document any significant deviation occurring during the study.
Prindpallnvesti.gato~r:
t
Name:r;})'lS" ,
~~ Q '(Jd
Slgoature:
Date:
~~
(s
}2clG
--------------------
Confid.,otial
!'age 5 ofl53
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Protocol Numbec ('('PoDSG-01

Venion: L i
___ __ ____ ------
Drne: 2(1 Fell 2CI6
;.........
J~'VESTIGATOR'S
"
DECLARATION
I, the undersigned, declare that I have read and understood this protocol and hereby agree w
conduct the study m accordance wirh this protocol and to comply with ail requirements regarding
the obligations of investigators and all other pertinent requirements of the fntemational
human u5e guideline for Good Clinical Practice lCH E6 (amended version), the Code of federal
Regulations on the Protection of Human Suhjects (45 CFR Part 46), m accordance with
Declaration of Helsinki (amended Ycrsion),JCMR guidelines for Biomedical Research on Hurr;an
Subjects (amended version) & Schedule Y of Dn;gs and Cosmetics Act and Rules (amended
version) releasr~ by Central Drugs Standard Control Organization, India :mJ principles on Good
Laboratory Practice. and all regulatory requirements for including all elements required for an
Institutional Review Iloard (JR3) to assess sUJdy risks and benefits.
We further agree to ensure that all associates assisting in the conduct of :.iudy are infonned
I agree to wmply with all relevant ~tandard Operating Procedures (SOPs) required for the
conduct ofth;s study nnd would document any significant deviation occurring during the study.
Con lidfnti.al
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PROTOCOL SYNOPSIS
Title
A Prospective, Multi-Center, Randomized, Double-Blind, VehicleControlled, Parallel-Group Bioequivalence Study with Clinical
Endpoints Comparing Generic Diclofenac Sodium Topical Gel 1% of
Cipla Ltd., India to Voltaren Gel (a Diclofenac Sodium Topical Gel
1%) of Endo Pharmaceuticals Inc., USA in Subjects with Osteoarthritis
of the Knee.
Protocol Number
CIP-DSG-01
Study Objective
To compare clinical efficacy, safety and tolerability of generic

Diclofenac Sodium Topical Gel 1% of Cipla Ltd., India with Voltaren
Gel (a Diclofenac Sodium Topical Gel 1%) of Endo Pharmaceuticals
Inc., USA and Vehicle of Diclofenac Sodium Topical Gel 1%
(manufactured by Cipla Ltd., India) in subjects with osteoarthritis (OA)
of the knee.
Efficacy endpoints
Primary efficacy endpoint
The primary endpoint of the study is:
Mean change in the Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC) pain score in target knee from
baseline to week 4
Secondary efficacy endpoints

Study Endpoints
Mean change in pain on movement (POM) on a Visual Analog

Scale (VAS) for target knee from baseline to week 4
Mean change in Patient Global Assessment (PGA) score from
baseline to week 4
Safety endpoints
Study Design
Confidential
Proportion of subjects with adverse events (AEs) and serious

adverse events
Change in physical examination, vital signs, and clinical
laboratory tests (hematology and biochemistry parameters) from
baseline to week 4
This is a prospective, randomized, double-blind, vehicle-controlled,

parallel-group, bioequivalence study with clinical endpoints to be
performed at approximately 23 study centers across India. A minimum
of 990 subjects (330 in each treatment group) with OA of the knee will
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be randomized (considering 10% drop outs) to get an evaluable data of

at least 900 subjects in a 1:1:1 ratio at baseline visit to the following 3
treatment groups:
Test group: Generic Diclofenac Sodium Topical Gel 1% or

Reference group: Voltaren Gel (Diclofenac Sodium Topical Gel
1%) or
Control (placebo) group: Vehicle of Diclofenac Sodium Topical
Gel 1%
The total study duration for the subjects will be approximately 7 weeks,
including 4 weeks of treatment.
Visit 1: Screening visit (day -21 to day -15 / week -3)
Visit 2: Eligibility visit / Run-in period (day -14 to day -1 / week

-2)
The eligible subjects will enter a washout period (run-in period) of 7

days or 5 plasma elimination half-lives of the discontinued medication
(whichever is longer) during which other topical products applied to
knees, including corticosteroids, pain medications, anticoagulants,
At baseline, subjects will be randomized to 1 of the 3 treatment groups
and 4 g of either generic Diclofenac Sodium topical gel 1%, or reference
product, or vehicle will be applied to the target knee. Study medications
will be applied to the target knee 4 times daily for 4 weeks. The subject
should not take shower / bathe for at least 1 h after the application but
should wash the hands after use. Both efficacy and safety assessments
will be done during the study. Subjects will be permitted to use
acetaminophen / paracetamol (up to 4 g / day) as a rescue therapy for
Subject diaries will be dispensed to subjects at baseline. During the
study, subjects will be required to use subject diaries in order to record
the date and time of study treatments, any missed treatments, use of
acetaminophen / paracetamol (rescue medication), use of concomitant
medications, and AE(s) experienced or intolerability to study
medication. These subject diaries will be reviewed at visits 4 and 5 and
will be collected from the subjects at visit 5 (day 28 4 / week 4).
Confidential
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Efficacy
Assessments
Safety Assessments
Other Clinical and

Laboratory
Investigations
Confidential
WOMAC pain score will be determined by subjects responses

to 5 questions (how much pain the subject feels while walking
on a flat surface, going up or down stairs, at night while in
bed, sitting or lying, and standing upright) using a 5-point
Likert scale (0 = none; 1 = mild, 2 = moderate, 3 = severe, 4 =
extreme)
POM will be evaluated using 0-100 mm scale of VAS (where
score of 0 indicates no pain and a score of 100 indicates worst
imaginable pain)
PGA will be evaluated where the subject will give a global selfassessment of target knee OA condition using 5-point Likert
scale (0 = very well, 1 = well, 2 = fair, 3 = poor, 4 = very poor)
to rate his/her OA
AEs will be collected and evaluated for relatedness, severity,
seriousness, and outcome
Vital signs (pulse rate, respiratory rate, systolic and diastolic
blood pressure, oral body temperature)
Laboratory parameters
o Hematology
Hematocrit
Red blood cells
Hemoglobin
Platelets
White blood cells with differential blood count
o Biochemistry
Alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and gamma glutaryl
transpeptidase
Total bilirubin
Creatinine
Urea
Sodium, potassium, calcium, phosphorus, bicarbonate
Fasting plasma glucose
The following are the laboratory tests which will be carried out at visit 1
(screening visit):
Urinalysis
o Urine pregnancy test
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Serology
o Human Immunodeficiency Virus (HIV) antibody (I and II)

o Hepatitis B Virus surface antigen (HBsAg)
12 Lead ECG (at Screening and EOS visit)
A subject will be eligible for inclusion in the study if he / she fulfils the
following criteria:
Inclusion Criteria
Confidential
1. Male or non-pregnant female aged 35 years with a clinical

diagnosis of OA of the knee according to the American College
of Rheumatology (ACR) criteria:
a. Pain in the knee and presence of at least 3 of the following
ACR criteria: age 50 years; stiffness lasting for < 30 min;
bony tenderness; crepitus; bony enlargement; no palpable
warmth, and including:
ii. Knee (not referred) pain for 15 days of the preceding
month (periarticular knee pain due to OA and not due to
other conditions such as bursitis, tendonitis, etc.), and
iii. The pain in the target knee required the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or
acetaminophen / paracetamol (topical or oral treatments)
2. Had an X-ray of the target knee, taken no more than 1 year before
baseline, showing evidence of OA with Kellgren-Lawrence grade
1-3 disease
3. After discontinuing all pain medications for at least 7 days, had at
least moderate POM for target knee, defined as a baseline score of
50 mm on a 0-100 mm VAS immediately prior to
randomization, and a baseline WOMAC pain subscale of at least
9 immediately prior to randomization
4. Able to tolerate rescue medication (i.e., acetaminophen /
paracetamol)
5. Subjects willing to refrain from using any other OA treatment
during the 4-week treatment period, other than the study
treatment, and rescue medication
6. Subjects willing to give written informed consent and provide
audio-visual recording of the consent process
8. Not pregnant / not planning to be pregnant / not a lactating
female. Women of childbearing potential and male subjects were
included in the study if they are willing to use an appropriate
method of contraception
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A subject will not be eligible for inclusion in this study if he / she meets
any of the following criteria:
Exclusion Criteria
Confidential
1. X-ray showing evidence of OA with Kellgren-Lawrence grade 4

disease
2. History of OA pain in the contralateral knee requiring
medication within 1 year prior to screening
3. After discontinuing all pain medications for at least 7 days, had a
baseline score of 20 mm on a 0-100 mm VAS for the
contralateral knee immediately prior to randomization
4. History of secondary OA, rheumatoid arthritis, chronic
inflammatory disease (e.g., colitis) or fibromyalgia
5. History of asthma, hypertension, myocardial infarction,
thrombotic events, stroke, congestive heart failure, impaired
renal function or liver disease
6. History of gastrointestinal (GI) bleeding or peptic ulcer disease
8. Elevated transaminases at screening (i.e., AST or ALT more than
2 times the upper limit of normal at screening visit)
9. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics,
lithium, or methotrexate within the past 30 days prior to entry
into the study
10. Concomitant acetyl salicylic acid therapy other than a stable low
dose used for cardiac prophylaxis (max 162 mg daily) taken for
at least 3 months prior to enrolment and maintained throughout
the duration of the study
14. Any other acute or chronic illness that in the opinion of the
investigator could compromise the integrity of the study data or
place the subject at risk by participating in the study
15. Receipt of any drug as a part of a research within 30 days prior to
screening
18. Subjects who are alcohol or drug dependent i.e. substance of
abuse
19. Subjects having clinically significant liver, kidney, or cardiac
dysfunction
20. Subjects having history of hypersensitivity reactions to
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diclofenac sodium gel or any of its excipients

21. A positive serology test result for HIV antibody (I & II), HBsAg,
and / or HCV antibodies
Test Product, Dose,

Route, Regimen
Reference Product,
Dose, Route,
Regimen
Prohibited
Medications /
Restrictions in the
Study
The test product is generic Diclofenac Sodium Topical Gel 1%. It is

manufactured by Cipla Ltd., India and is available in the form of a
topical gel containing 1% of diclofenac sodium. Each subject will apply
weeks.
Vehicle: Manufactured by Cipla Ltd., India in the form of a topical gel.
Each subject will apply approximately 4 g dose of the gel on the target
knee 4 times daily for 4 weeks.
The reference product is Voltaren Gel (diclofenac sodium topical gel
1%). It is manufactured by Novartis Consumer Health, Inc., USA OR
Novartis Pharma Produktions GmbH, Germany and marketed by Endo
Pharmaceuticals, Inc., USA. It is available in the form of a topical gel
containing 1% of diclofenac sodium. Each subject will apply
weeks.
1. Any other topical products applied to the knee
2. ACE-inhibitors, anticoagulants, cyclosporine, diuretics, lithium,
methotrexate, oral NSAIDs or aspirin [except for cardiac
prophylaxis (max 162 mg daily) taken for at least 3 months prior
to enrolment and maintained throughout the duration of the
study]
3. Systemic corticosteroid or immunosuppressive drugs
4. Pain medication other than acetaminophen / paracetamol
Subjects will be instructed not to use moisturizers, sunscreen, creams,
lotions, powders, avoid exposure to sunlight and sunlamps, not use any
type of bandage or occlusive dressing or heating pad on the treatment
area, not allow the gel to come in contact with the eyes or mucous
membranes, and not apply the gel to open skin wounds, infections,
inflammations, or exfoliative dermatitis on the treatment area (target
knee) for the entire study duration.
Sample size calculation
Sample Size
Confidential
A sample size of 300 in each group will have at least 80% power to
detect a difference in means of 1.1 (change in WOMAC pain score from
baseline to final) between active treatment (5.8) and control- vehicle arm
(4.7) assuming that the common SD is 4.54 using a two group t-test with
a 0.05 two-sided significance level (assuming both active treatment
groups are compared with vehicle at 0.05 level of significance and no
multiplicity adjustment is performed). Assuming approximately 10%
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subjects will not qualify for mITT population, 330 subjects will be
needed to be enrolled in each group to demonstrate superiority of both
active treatments over vehicle.
When the sample size in each group is 240, a two-group design will
have 85% power to reject both the null hypotheses; the 1st hypothesis is
that the ratio of the test mean to the reference mean is below 0.800 and
the 2nd null hypothesis is that the ratio of test mean to the reference mean
is above 1.250; the test and reference mean are not equivalent, in favour
of the alternative hypothesis that the means of the two groups are
equivalent, assuming that the expected ratio of means is 1.0, the
coefficient of variation for the standard is approximately 0.78, that data
will be analyzed in the original scale using Sasabuchi t-tests for the ratio
of means, and that each t-test is made at the 5.0% level. Assuming
approximately 27% subjects do not qualify for PP population; minimum
330 subjects will be enrolled in each group to demonstrate
bioequivalence of two diclofenac formulations.
Thus this study will need to randomize 990 subjects (330 in each
treatment group) with OA of the knee, to get an evaluable data of at least
900 subjects in a 1:1:1 ratio at baseline visit to the 3 treatment groups,
Vehicle of Diclofenac Sodium Topical Gel, Diclofenac Test and
Diclofenac Reference formulation.
Data Analysis and Statistical Considerations
The descriptive statistics for continuous variables will be presented with
number (n) of non-missing observations, mean, standard deviation (SD),
median, and minimum and maximum (range). For categorical data, the
descriptive statistics will be presented with number of exposed subjects
and number (n) with percentage of observations in various categories of
the endpoint, where percentage will be based on the exposed subjects.
Descriptive analyses will also include graphical presentation of data,
wherever appropriate. Individual data listings will also be provided.
Statistical
Methodology
Analysis populations
The following are the 3 analysis populations: per-protocol (PP),
modified intent-to-treat (mITT), and safety population.
Confidential
PP population: includes all randomized subjects who meet all

inclusion / exclusion criteria, are compliant with the assigned
study treatment (used at least 75% and no more than 125% of
study treatment doses), returns to the study site for visit 5 / week
4 within the specified window ( 4 days) or discontinues from
the study as a treatment failure, and do not have any protocol
violations. The PP population will be used for the bioequivalence
evaluation of test versus reference. Subjects who will be
discontinued early from the study due to lack of treatment effect
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will be included in the PP population, using last observation

carried forward (LOCF)
mITT population: includes all randomized subjects who meet
all inclusion / exclusion criteria, receive study treatment, and
return for at least one post-baseline visit.
mITT population will be used to compare both test and reference
products to vehicle, as a test of study sensitivity. Subjects who
discontinue early for other reasons will be excluded from the PP
population but will be included in the mITT population using
LOCF.
Safety population: includes all randomized subjects who receive
study treatment
Primary efficacy analysis
To establish bioequivalence for the primary endpoint, 90% confidence
interval (CI) for the test / reference ratio of mean change from baseline
to week 4 must be contained within [0.80, 1.25] for a continuous
variable, using the PP population.
Where T = mean of test product and R = mean of reference product
Typically, we reject H0 with type I error = 0.05 (two 1-sided tests), if
90% CI for the ratio of means between test and reference products (T /
R) is contained within the interval [1, 2], where 1 = 0.80 and 2 =
1.25.
Rejection of the null hypothesis H0 supports the conclusion of
equivalence of the two products. Similarly, superiority of test and
reference over vehicle will be tested with a 1-sided test using type 1
error of 0.05.
The primary efficacy data will be calculated using sample number,
mean, SD, minimum, maximum and 90% CI.
change in WOMAC pain score from baseline to week 4 with the use of
treatment as factors and baseline values as covariates.
Comparison to baseline analysis of treatment effects with relevant test
will be described in a statistical analysis plan.
Secondary efficacy analysis
change in POM (using VAS score) and PGA (using Likert scale) from
Confidential
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baseline to week 4 with the use of treatment as factors and baseline

values as covariates.
As a parameter for determining adequate study sensitivity, both test
product and reference should be statistically superior to vehicle (p <
0.05, two-sided) for the primary endpoint using the mITT study
population and LOCF.
Safety analyses
All safety endpoints will be analyzed based on descriptive statistics as
described above for continuous and categorical variables.
The AEs will be coded by system organ classification (SOC) and
preferred term (PT) using the latest version of Medical Dictionary for
Drug Regulatory Affairs.
All AEs will be listed and categorized before dosing and after dosing.
All AEs which occur after the first dose of the study medication will be
categorized as treatment emergent AEs i.e. AEs with onset date on or
after the first dose of the study medication. The AEs will be tabulated
and summarized for each treatment group. All AEs will be collected,
evaluated, and tabulated by SOC, PT, date of onset, description,
relationship to study medication, seriousness, severity, action taken,
outcome, and date of resolution for each treatment group.
Actual visit wise summary and Change values from baseline to week 4
for other safety measures like physical examination, vital signs, different
lab parameters [hematology and biochemistry] will also be summarized
as per standard convention. The descriptive statistics for continuous
variables will be presented with number (n) of non-missing
observations, mean, SD, median, and minimum and maximum (range).
For categorical data, the descriptive statistics will be presented with
number of exposed patients and number (n) with percentage of
observations in various categories of the endpoint, where percentage will
be based on the exposed patients. Shift table for change from baseline to
week 4 in categorical response will also be prepared where needed.
Ethical Aspects
Confidential
The study will be conducted in compliance with International

Conference on Harmonization-Good Clinical Practice Guidelines, the
Helsinki Declaration, 21 Code of Federal Regulations (CFR) 320.38,
320.63, and 320.36, 21 CFR 58, ICH E6, and local regulatory
requirement (Indian Good Clinical Practice, Schedule Y, and Indian
Council of Medical Research). This protocol and any amendments will
be submitted to an Institutional Ethics Committee, in agreement with
local regulations, for formal approval of the study conduct.
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TABLE OF CONTENTS
1
CONTACT DETAILS .................................................................................................. 2
2
INTRODUCTION....................................................................................................... 21
2.1
Background ................................................................................................................... 21
2.2
Name and Description of Investigational Product(s) .................................................... 22
2.3
Indication ...................................................................................................................... 22
2.4
Non-Clinical Studies ..................................................................................................... 22
2.5
Clinical Data to Date ..................................................................................................... 23
2.6
Adverse Reactions ........................................................................................................ 24
2.7
Risks and Benefits for Study Subjects ......................................................................... 25
2.8
Rationale for the Current Study .................................................................................... 26
2.9
Compliance Statement .................................................................................................. 26
2.10
Description of the Study Population ............................................................................. 26
3
4
4.1
STUDY OBJECTIVE ................................................................................................. 26

STUDY DESIGN ......................................................................................................... 26
Efficacy Endpoints ........................................................................................................ 26
4.1.1 Primary Efficacy Endpoint ........................................................................................... 26

4.1.2 Secondary Efficacy Endpoints ...................................................................................... 27
4.2
Safety Endpoints ........................................................................................................... 27
4.3
Description of Type and Design of Study..................................................................... 27
4.3.1 Description of the Sequence and Duration of Events during Study ............................. 30
4.3.1.1 Visit 1 (Day -21 to Day -15 / Week -3 / Screening Visit) ................................ 30
4.3.1.2 Visit 2 (Day -14 to Day -1 / Week -2 / Eligibility Visit / Run-in Period) ........ 31
4.3.1.3 Visit 3 (Day 0 / Week 0 / Baseline Visit) ......................................................... 31
4.3.1.4 Visit 4 (Day 14 4 / Week 2 / Interim Visit) ................................................... 32
4.3.1.5 Visit 5 (Day 28 4 / Week 4 / End of Study) ................................................... 34
4.3.2 Unscheduled Visits ....................................................................................................... 35
4.4
Measures Taken to Avoid Bias ..................................................................................... 35
4.4.1 Randomization .............................................................................................................. 35

4.4.2 Blinding......................................................................................................................... 35
4.5
Accountability Procedures for the Investigational Product .......................................... 36
4.6
Maintenance of Study Treatment Randomization Codes and Procedures for

Breaking Codes ............................................................................................................. 36
4.6.1 Emergency Unblinding of an Individual Subject.......................................................... 36

Confidential
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4.7
Identification of Any Data to be Directly Recorded on Case Report Forms ................ 36
5
5.1
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................... 36

Inclusion Criteria .......................................................................................................... 36
5.2
Exclusion Criteria ......................................................................................................... 37
5.3
Subject Withdrawal Criteria ......................................................................................... 38
6
6.1
TREATMENT OF SUBJECTS ................................................................................. 39

Investigational Medicinal Product ................................................................................ 39
6.2
Dosage Regimen ........................................................................................................... 39
6.2.1 Dispensing (Labeling) and Compliance........................................................................ 40

6.2.2 Storage Condition ......................................................................................................... 40
6.3
Handling of Study Medication ...................................................................................... 40
6.4
Retention of Study Medication Samples....................................................................... 41
6.5
Medication(s) / Treatment(s) Permitted and Not Permitted Before and / or During

the Study ....................................................................................................................... 41
6.5.1 Medication(s) / Treatment(s) Permitted ........................................................................ 41

6.5.2 Medications / Treatment(s) Not Permitted ................................................................... 41
6.5.3 Procedure(s) for Monitoring Subject Compliance ........................................................ 42
7
7.1
STUDY ASSESSMENTS ........................................................................................... 42

Efficacy Assessments.................................................................................................... 42
8
8.1
ASSESSMENT OF SAFETY ..................................................................................... 43

Adverse Events ............................................................................................................. 43
8.1.1 Definition of Adverse Event ......................................................................................... 43

8.1.2 Serious Adverse Event .................................................................................................. 44
8.1.3 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters ..... 44
8.1.4 Documentation and Reporting of Serious Adverse Events........................................... 44
Illnesses ......................................................................................................................... 45
8.1.5.1 Eliciting, Documentation and Reporting of Adverse Events ........................... 45
8.1.6 Rating of Adverse Events ............................................................................................. 46
8.2
Emergency Contact ....................................................................................................... 48
8.3
Physical Examination.................................................................................................... 48
8.4
Vital Signs ..................................................................................................................... 48
8.5
Laboratory Evaluations ................................................................................................. 49
8.6
12 Lead Electrocardiogram ........................................................................................... 49
Confidential
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9
9.1
STATISTICS ............................................................................................................... 49
Statistical Method ......................................................................................................... 49
9.1.1 Demographic and Other Baseline Characteristics ........................................................ 50

9.1.2 Decoding of Randomization ......................................................................................... 50
9.1.3 Primary Analysis (Efficacy Analysis): ......................................................................... 50
9.1.4 Secondary Analysis (Efficacy Analysis): ..................................................................... 51
9.1.5 Safety Analysis ............................................................................................................. 51
9.2
Sample Size................................................................................................................... 51
9.3
Level of Significance .................................................................................................... 52
9.4
Study Termination Criteria ........................................................................................... 52
9.4.1 Withdrawal Criteria ...................................................................................................... 52

9.4.2 Withdrawn Subject Data Collection ............................................................................. 53
9.4.3 Replacement of Subjects ............................................................................................... 53
9.5
Missing Data ................................................................................................................. 53
9.6
Procedures for Reporting Deviations from Original Statistical Plan ............................ 53
9.7
Study Population ........................................................................................................... 54
10
10.1
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS .................................... 54

Monitoring .................................................................................................................... 54
10.2
Documentation at the Study Site................................................................................... 54
10.3
Subject's Data and Data Protection ............................................................................... 55
10.4
Data Management and Analysis ................................................................................... 55
10.5
Amendments to the Protocol ......................................................................................... 55
11
11.1
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 56

Audit ............................................................................................................................. 56
12
12.1
ETHICS ....................................................................................................................... 56
Institutional Ethics Committee or Institutional Review Board ..................................... 56
12.2
Ethical Conduct of the Study ........................................................................................ 56
12.3
Subject Information and Consent.................................................................................. 56
13
14
15
16
17
18
DATA HANDLING AND RECORD KEEPING ..................................................... 57

FINANCING AND INSURANCE ............................................................................. 57
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ........................... 57
PUBLICATION POLICY .......................................................................................... 58
REFERENCES ............................................................................................................ 58
APPENDICES ............................................................................................................. 60
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LIST OF TABLES:
Table 1: Summary of Clinical Studies on Diclofenac Sodium Topical Gel 1%,
Diclofenac Sodium Topical Solution 1.5% and Oral Diclofenac 50 mg: ..................24
Table 2: Study flow chart .........................................................................................................29
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LIST OF ABBREVIATIONS
ACE
Angiotensin Converting Enzyme
ACR
American College of Rheumatology
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BA
Bioavailability
BE
Bioequivalence
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
COX-2
Cyclooxygenase-2
CRF
Case Report Form
CRO
Contract Research Organisation
CSR
Clinical Study Report
CT
Clinical Trial
DCGI
Drugs Controller General of India
DSG
Diclofenac Sodium Gel
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
EOS
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
GGT
Gamma Glutaryl Transpeptidase
GI
Gastrointestinal
Hb
Hemoglobin
HBsAg
Hepatitis B Virus
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HCT
Hematocrit
HCV
Hepatitis C Virus
HEENT
Head-Eyes-Ear-Nose-Throat
HIV
Human Immunodeficiency Virus
ICF
Informed Consent Form
ICH-GCP
International Conference on Harmonization-Good Clinical Practice
IEC
Institutional Ethics Committee
IP
Investigational Product
IWRS
Interactive Web Response System
LAR
Legally Acceptable Representative
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Drug Regulatory Affairs
mITT
Modified Intent-to-Treat
NSAID
Non-steroidal anti-Inflammatory Drugs
OA
Osteoarthritis
OARSI
Osteoarthritis Research Society International
PGA
Patient Global Assessment
POM
Pain on Movement
PP
Per Protocol
PT
Preferred Term
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
VAS
WBC
White Blood Cells
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index
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INTRODUCTION
2.1
Background
Osteoarthritis (OA) is a highly prevalent chronic joint disease characterized by cartilage loss,
synovial inflammation, and bone remodeling. Occurring most frequent in the knee, the
prevalence of OA in this joint increases with age from approximately 1% in people aged 25-34
years to > 30% in people aged 75 years. Radiographic evidence of knee OA is present in 37%
of US adults aged 60 years. Signs and symptoms of OA include joint pain, stiffness, restricted
motion, and crepitus (creaking or crackling) on motion. OA is associated with substantial
disability and diminished productivity (Baraf et al, 2011).
Currently recommended non-pharmacological and pharmacological treatment of OA aims to
control pain and physical dysfunction while avoiding therapeutic adverse effects. Non-steroidal
anti-inflammatory drugs (NSAIDs) are commonly used for the management of OA and are
effective in relieving the pain and physical dysfunction. However, their use is associated with
deleterious gastrointestinal (GI) effects, ranging from mild heartburn and bloating to serious
ulceration, perforation, obstruction, and bleeding, and with hepatic and renal toxic effects. The
newer cyclooxygenase-2 (COX-2) selective NSAIDs reported efficacious results with
diminished risk of GI toxicity. However, their reported safety profile came under scrutiny with
suggestion of other serious harmful effects, including increased incidence of thrombotic
cardiovascular events (Tugwell P et al, 2015). These risks increase with dose and duration of
treatment and patients age (Baraf et al, 2011).
International guidelines on OA care recommend the use of topical NSAIDs as an alternative to
oral NSAIDs (Baraf et al, 2011). Also, the OA Research Society International guidelines
recommended topical NSAIDs as a first-line therapy for patients with OA and it was observed
that the topical NSAIDs had an equivalent efficacy and a lower frequency of adverse events
(AEs) compared with oral NSAIDs. The lower systemic availability of the topical NSAIDs
compared with oral NSAIDs may be the basis of lower frequency of AEs seen with topical
NSAIDs as compared to oral NSAIDs (Peniston et al, 2012 and Roth et al, 2012).
Topical NSAIDs are a relatively new option in the US for the relief of OA pain with the first
receiving US Food and Drug Administration (FDA) approval in 2007 (diclofenac sodium 1% gel
[DSG]; Voltaren Gel; Novartis Consumer Health, Inc., Parsippany, NJ). Topical NSAIDs are a
first-line alternative for knee OA with equivalent efficacy compared to oral NSAIDs and have a,
lower NSAID exposure (Baraf et al, 2010). Topical diclofenac is effectively absorbed in the knee
and hand; however, the plasma concentrations remain very low (Argoff et al, 2011). Therapeutic
doses of DSG (16 g / day; contains 160 mg of diclofenac sodium) applied to one knee produced
peak plasma diclofenac levels approximately 150-fold lower than therapeutic doses of oral
diclofenac (150 mg / day). NSAIDs applied topically could achieve therapeutic concentration in
the tissues proximal to the application site with only low, relatively safe serum concentrations
and may mitigate the risk of drug-drug interactions. This would avoid adverse GI events,
eliminate first pass metabolism, and reduce the risk of AEs related to high serum concentration
often needed for efficacy with systemic dosage forms (Peniston et al, 2013, Heyneman et al,
2000).
Diclofenac sodium is an NSAID with anti-inflammatory, anti-nociception, and antipyretic effects
and has been in widespread therapeutic use for approximately 30 years (Gan, 2010; Zacher et al,
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2008; Scholer et al, 1986). Diclofenac sodium inhibits the enzyme, COX-2, an early component
in the arachidonic acid cascade. By inhibiting COX-2, diclofenac prevents the formation of
thromboxanes, prostaglandins, and prostacyclin. Diclofenac also inhibits the production of
leukotrienes by decreasing arachidonic acid release and increasing its uptake. Diclofenac is
among the most effective inhibitors of prostaglandin E2 (PGE2) production and has been
reported to be 3 to 1000 times more potent on a molar basis compared with other NSAIDs in its
ability to inhibit COX-2 activity (Gan, 2010). Pharmacokinetic evidence indicates that DSG 1%
is the lowest effective dose of NSAID to achieve effective relief. In 2012, Peniston et al. reported
DSG 1% to be efficacious for the relief of OA pain in the hand and knee (Peniston et al, 2012).
2.2
Name and Description of Investigational Product(s)
Synonym
: DSG 1%
Active substance
: Diclofenac sodium
IUPAC / Chemical name
: 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid,
monosodium salt
Molecular formula
: C14H10Cl2NNaO2
Molecular weight
: 318.14
Manufactured by
: Cipla Limited
Specific storage conditions
: Store at 25C (77F); excursions permitted to 15-30C

(59-86F).
Keep from freezing
2.3
Indication
The intended usage of the product is for the relief of the pain of osteoarthritis of joints amenable
to topical treatment, such as the knees and those of the hands.
The intended usage of the medication in the study is treatment for the relief of the pain of OA of
knee.
2.4
Non-Clinical Studies
The following is the non-clinical data of Voltaren Gel.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent
for 2 years at doses up to 2 mg / kg / day resulted in no significant increase in tumor incidence
corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat,
respectively) of the maximum human topical dose of Voltaren Gel (based on bioavailability and
body surface area comparison).
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In a dermal carcinogenicity study conducted in albino mice, daily topical application of a DSG
product for two years at concentration up to 0.035% diclofenac sodium (a 29 - fold lower
diclofenac sodium concentration than present in Voltaren Gel) did not increase neoplasm
incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of a
DSG product at doses up to 0.035% diclofenac sodium (a 29 - fold lower diclofenac sodium
concentration than present in Voltaren Gel) resulted in an earlier median time of onset of
tumors.
Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests, including
bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal
aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal
aberration assay of bone marrow cells.
Diclofenac did not affect male or female fertility in rats at doses up to 4 mg / kg / day which
induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than
the maximum human topical dose of Voltaren Gel (based on bioavailability and body surface
area comparison) (Voltaren Gel Package Insert, Novartis Consumer Health, Inc., NJ, 2014).
2.5
Clinical Data to Date
Oral NSAIDs used for the treatment of OA have dose-related risks for GI, cardiovascular and
renal systems, particularly in the elderly patients. Hence, topical NSAIDs may provide an
alternative to oral NSAIDs to relieve pain from OA as it mitigates the above risk due to its
reduced systemic exposure (Baraf et al, 2010; 2011).
Various studies reported DSG to be effective and well tolerated in patients with symptomatic OA
in knee. Table 1 summarizes the details of the previous published reports on topical DSG 1% and
1.5%.
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Table 1: Summary of Clinical Studies on Diclofenac Sodium Topical Gel 1%, Diclofenac
Sodium Topical Solution 1.5% and Oral Diclofenac 50 mg:
Drug
Duration
of
treatment
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
12 weeks
(4 times
daily)
Current
status
(Reference)
Completed
(Argoff et al.,
2011)
Completed
(Baraf et al.,
2010)
Completed
(Peniston et
al., 2013)
Completed
(Peniston et
al., 2012)
n=622
12 weeks
(3 times
daily)
Completed
(Tugwell et
al.,2015)
Pooled data
n=1426
12 weeks
(4 times
daily)
Completed
(Baraf et al.,
2011)
Sample Size
Study
Indication
Treatment groups
Long-term
safety and
tolerability
OA of knee
1% DSG and 1%
vehicle gel
Pooled data
n=1426
DSG
Safety and
efficacy
OA of knee
1% DSG and 1%
vehicle gel
n=420
DSG
Post-hoc
analysis
OA of knee
1% DSG and 1%
vehicle gel
n=254
DSG
Long-term
safety
OA of knee
1% DSG and placebo
n=583
Topical
Diclofenac
Solution
Equivalence
Study
OA of knee
1.5% Topical
Diclofenac Solution
and Oral Diclofenac
(50 mg)
DSG
Safety and
efficacy
OA of knee
1% DSG and 1%
vehicle gel
2.6
Adverse Reactions
DSG
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
During clinical development, 913 patients were exposed to Voltaren Gel in randomized,
double-blind, multicenter, vehicle-controlled, parallel-group study in OA of the superficial joints
of the extremities. Of these, 513 patients received Voltaren Gel for knee OA and 400 were
treated for hand OA. Additionally, 583 patients were exposed to Voltaren Gel in an
uncontrolled, open-label, long-term safety trial in knee OA. Of these, 355 patients were treated
for OA of 1 knee and 228 were treated for OA of both knees. Duration of exposure ranged from
8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety
trial.
Short-Term Placebo-Controlled Trials: Adverse reactions observed in at least 1% of patients
treated with Voltaren Gel: Non-serious adverse reactions, application site reactions, were
reported during the short-term placebo-controlled studies comparing Voltaren Gel and placebo
(vehicle gel) over study periods ranging from 8 to 12 weeks (16 g per day). These were the only
adverse reactions that occurred in > 1% of the treated patients with a greater frequency in the
Voltaren Gel group (7%) than the placebo group (2%).
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Application site dermatitis was the most frequent type of application site reaction and was
reported by 4% of patients treated with Voltaren Gel compared to 1% of placebo patients.
In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for
patients treated with Voltaren Gel and 3% for patients in the placebo group. Application site
reactions, including application site dermatitis was the most frequent reason for treatment
discontinuation
Long-Term Open-Label Safety Trial:
In the open-label, long-term safety study, distribution of adverse reactions was similar to that in
the placebo-controlled studies. In this study, patients were treated for up to 1 year with Voltaren
Gel up to 32 g per day and application site dermatitis was observed in 11% of the patients.
Adverse reactions that led to discontinuation of the study drug were experienced in 12% of the
patients. The most common adverse reaction that led to discontinuation of the study was
application site dermatitis, which was experienced by 6% of patients (Voltaren Gel Package
Insert, Novartis Consumer Health, Inc., Parsippany, 2014).
2.7
Risks and Benefits for Study Subjects
Topical NSAIDs are a first-line alternative for knee OA with equivalent efficacy compared to
oral NSAIDs and have a lower NSAID exposure (Baraf et al, 2010). Topical diclofenac is
effectively absorbed in the knee and hand; however, the plasma concentrations remain very low
(Argoff et al, 2011). Therapeutic doses of DSG (16 g / day; contains 160 mg of diclofenac
sodium) applied to one knee produced peak plasma diclofenac levels approximately 150-fold
lower than therapeutic doses of oral diclofenac (150 mg / day). NSAIDs applied topically could
achieve therapeutic concentration in the tissues proximal to the application site with only low,
relatively safe serum concentrations and may mitigate the risk of drug-drug interactions. This
would avoid adverse GI events, eliminate first pass metabolism, and reduce the risk of AEs
related to high serum concentration often needed for efficacy with systemic dosage forms
(Peniston et al, 2013, Heyneman et al, 2000).
Various studies have reported 1% DSG topical gel to be safe and effective in subjects with OA
Table 1 of the knee.
In this study, the participants will receive multiple doses of either test, reference or vehicle
product as per randomization. As reported in various clinical trials the study subjects may
experience some adverse events during the study. Most common adverse reactions (incidence >
2% of patients treated with DSG, 1% and greater than placebo) were application site reactions,
including dermatitis.
NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) events including bleeding,
ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal.
Elevations of one or more liver tests may occur during therapy with diclofenac sodium.
Anaphylactoid reactions may occur in patients with the aspirin triad or in patients without prior
exposure to DSG 1%. NSAIDs can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can
be fatal. (Voltaren Gel Package Insert, Novartis Consumer Health, Inc., Parsippany, 2014).
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2.8
Rationale for the Current Study
The study medication in the present study is a gel formulation that contains the diclofenac
sodium as its active ingredient. Various studies have reported 1% DSG topical gel to be safe and
effective in patients of OA (Table 1). In addition, peak plasma diclofenac levels were
approximately 150-fold lower in patients treated with topical diclofenac sodium (16 g / day;
contains 160 mg of diclofenac sodium) compared to therapeutic doses of oral diclofenac (150 mg
/ day).
In this multi-center, randomized, double-blind, vehicle-controlled, parallel-group study, clinical
efficacy, safety, and tolerability of DSG 1% of Cipla Ltd., India will be compared to Voltaren
Gel (a Diclofenac Sodium Topical Gel 1%) of Endo Pharmaceuticals Inc., USA in subjects with
OA of the knee.
2.9
Compliance Statement
The study protocol, amendments to the protocol (if applicable), informed consent form (ICF),
and consent form updates (if applicable) will be submitted to the Drug Controller General of
India (DCGI), which is constituted according to local law to obtain approval before initiation of
the study and as applicable thereafter. The study will only be initiated after receipt of the
approval from the DCGI. The study will be carried out in conformity with International
Conference on Harmonization-Good Clinical Practice (ICH-GCP), the Helsinki Declaration, 21
Code of Federal Regulations (CFR) 320.38, 320.63, and 320.36, 21 CFR 58, ICH E6, and local
regulatory requirement (Indian Good Clinical Practice, Schedule Y, and Indian Council of
Medical Research) and applicable regulatory requirements. Subject confidentiality will be
maintained during all audits.
2.10 Description of the Study Population
Male or non-pregnant female aged 35 years with a clinical diagnosis of OA of the knee
according to the American College of Rheumatology (ACR) criteria at screening will be enrolled
in the study.
3
STUDY OBJECTIVE
To compare clinical efficacy, safety and tolerability of generic Diclofenac Sodium Topical Gel
1% of Cipla Ltd., India with Voltaren Gel (a Diclofenac Sodium Topical Gel 1%) of Endo
Pharmaceuticals Inc., USA and Vehicle of Diclofenac Sodium Topical Gel 1% (manufactured by
Cipla Ltd., India) in subjects with OA of the knee.
4
STUDY DESIGN
4.1
Efficacy Endpoints
4.1.1 Primary Efficacy Endpoint

The primary efficacy endpoint of the study is:
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Mean change in the Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) pain score in target knee from baseline to week 4
4.1.2 Secondary Efficacy Endpoints

4.2
Mean change in pain on movement (POM) on a Visual Analog Scale (VAS) for target
knee from baseline to week 4
Mean change in patient global assessment (PGA) score from baseline to week 4
Safety Endpoints
4.3
Proportion of subjects with AEs and serious adverse events (SAEs)

Change in, physical examination, vital signs, and clinical laboratory tests (hematology
and biochemistry parameters), from baseline to week 4
Description of Type and Design of Study
This is a prospective, randomized, double blind, vehicle-controlled, parallel-group,

bioequivalence (BE) study with clinical endpoints to be performed at approximately 23 study
centers across India. A minimum of 990 subjects (330 in each treatment group) with OA of the
knee will be randomized (considering 10% drop outs) to get an evaluable data of at least 900 in a
The total study duration for the subjects will be approximately 7 weeks, including 4 weeks of
treatment.
Visit 1: Screening visit (day-21 to day -15 / week -3)

Visit 2: Eligibility visit / Run-in period (day -14 to day -1 / week -2)
In order to qualify for participation in the study, the subject must present with a clinical
diagnosis of OA of the knee according to the ACR criteria [i.e. Pain in the knee and presence of
at least 3 of the following ACR criteria: age 50 years; stiffness lasting for < 30 min; bony
tenderness; crepitus; bony enlargement; no palpable warmth], including:
Symptoms for at least 6 months prior to screening, and

Knee (not referred) pain for 15 days of the preceding month (periarticular knee pain due
to OA and not due to other conditions such as bursitis, tendonitis, etc.), and
The pain in the target knee required the use of NSAIDs or acetaminophen / paracetamol
(topical or oral treatments)
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The eligible subjects will enter a washout period (run-in period) of 7 days or 5 plasma
elimination half-lives of the discontinued medication (whichever is longer) during which other
topical products applied to knees, including corticosteroids, pain medications, anticoagulants,
At baseline, subjects will be randomized to 1 of the 3 treatment groups and 4 g of either generic
Diclofenac Sodium topical gel 1%, or reference product, or vehicle will be applied to the target
knee. Study medications will be applied to the target knee 4 times daily for 4 weeks. The subject
should not take shower / bathe for at least 1 h after the application but should wash the hands
after use. Both efficacy and safety assessments will be done during the study (Table 2). Subjects
will be permitted to use acetaminophen / paracetamol (up to 4 g / day) as a rescue therapy for
Subject diaries will be dispensed to subjects at baseline. During the study, subjects will be
required to use subject diaries in order to record the date and time of study treatments, any
missed treatments, use of acetaminophen / paracetamol (rescue medication), use of concomitant
medications, and AE(s) experienced or intolerability to study medication. These subject diaries
will be reviewed at visits 4 and 5 and collected from the subjects at visit 5 (day 28 4 / week 4).
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Table 2: Study flow chart

Parameters
Visit
Day / Week
Informed Consent
Screening
Visit
1
Day -21 to
Day -15 /
Week -3
X
Inclusion/Exclusion Criteria
Medical/Surgical History
Subject Demographics
Prior Medication History

X-ray of Target Knee
Laboratory Testsb
12 Lead ECG
Vital Signs
Urine Pregnancy Test
Efficacy Assessments:
X
X
X
X
X
X
X
Eligibility Visit /
Run-in period
2
Day -14 to Day -1 /
Week -2
Baseline
/random
ization
visit
3
Treatment Phase
Interim Visit
End of
Study Visit
5a
Day 0
Day 14 ( 4) /
Week 2
Day 28 ( 4) /
Week 4
X
X
X
X
X
X
X
WOMAC pain score, POM using

VAS Score; PGA using Likert
scale
Randomization
Dispensing of Study
Medicationc
Collect Study Medication
Dispense Rescue
Medications
Dispense Subject Diaryd
Review Subject Diaryd
Collect Subject Diaryd
Concomitant Medication
AE/SAE Recordinge
Accountability &
Compliance Check of Study
Drugs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
aIf
the subjects participation is prematurely terminated at any point during the course of the study, the EOS visit assessments
(week 4) will be performed during that visit.
bLaboratory tests, including hematology tests (HCT, RBC, Hb, platelets, WBC with differential blood count) and biochemistry
tests (ALT, AST, GGT, total bilirubin, creatinine, urea, sodium, potassium, calcium, phosphorus & bicarbonate, FPG) will be
evaluated at visits 1, 3, and 5.
Serology tests, including evaluation of HIV antibody (I and II), HBsAg and HCV antibodies will be done at screening visit 1.
cStudy medication will be dispensed at baseline and visit 4.
dSubject diary will be dispensed at baseline, the diary will be reviewed at visits 4 and 5 and collected at visit 5.
eAE reporting will begin from the time of signing the informed consent form until visit 5.
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4.3.1 Description of the Sequence and Duration of Events during Study

4.3.1.1 Visit 1 (Day -21 to Day -15 / Week -3 / Screening Visit)
Subjects will sign the ICF. Once informed consent is obtained, the subject will be
enrolled in the study. Audio-video recording of the process will be done.
Inclusion and exclusion criteria will be checked
Recording of medical / surgical history
Collection of demographic information (age [years], height [cm] and weight [Kg])
Recording of prior medication history
X-ray of target knee
Laboratory tests
o Hematology: haematocrit (HCT), red blood cells (RBC), hemoglobin (Hb), platelet,
white blood cells (WBC),with differential blood count
o Biochemistry: Alanine aminotransferase (ALT), aspartate aminotransferase (AST),
gamma glutaryl transpeptidase (GGT), total bilirubin, creatinine, urea, sodium,
potassium, calcium, phosphorus, bicarbonate, and fasting plasma glucose (FPG)
o Serology
Human Immunodeficiency Virus (HIV) antibody (I and II)
Hepatitis B Virus surface antigen (HBsAg)
12-Lead ECG
o Head-eyes-ear-nose-throat (HEENT)
o Nervous system
o Urogenital system
BP (Blood Pressure) [mm / Hg], and body temperature [C]). Subjects must remain in a
seated position for 5 min before vital signs are obtained
Urine pregnancy test (UPT)
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Recording of AE / SAE
4.3.1.2 Visit 2 (Day -14 to Day -1 / Week -2 / Eligibility Visit / Run-in Period)
o HEENT
o Nervous system
o Urogenital system
4.3.1.3 Visit 3 (Day 0 / Week 0 / Baseline Visit)

Subjects will be evaluated for Inclusion/Exclusion criteria, including assessment of the

subjects OA after discontinuing all pain medication for at least 7 days:
o Subject must have at least moderate POM for target knee, defined as a baseline score
of 50mm on a 0-100 mm VAS immediately prior to randomization, and
o A baseline WOMAC pain subscale of at least 9 immediately prior to randomization.
Laboratory tests
o Hematology: HCT, RBC, Hb, platelet, WBC, including differential count
o Biochemistry: ALT, AST, GGT, total bilirubin, creatinine, urea, sodium, potassium,
calcium, phosphorus, bicarbonate, and FPG
o HEENT
o Nervous system
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o Urogenital system
o WOMAC pain score
Subject randomization in 1:1:1 ratio to either of the 3 treatment groups.

o Subjects will be provided with 3 tubes of study medication (each tube will contain
100 g of study medication) sufficient to last for 14 days, study duration of 2 weeks
treatment of the target knee. The study medication will be supplied along with
dosing card to standardize the amount of study medication applied to the target knee
Dispensing of subject diary
o Subjects will be provided with a subject diary and instructions on how and when to
complete the subject diary. The subjects will record all the treatments administered,
including date and time, and any treatments missed. In addition, will record all the
AEs experienced, use of concomitant medication, and rescue medication, including
date and time. Subjects will also be instructed to call the study site if they experience
any severe intolerability (i.e., local skin reactions) to study medication.
Subjects will be provided with rescue medication paracetamol / acetaminophen and

instructed to record the date, time and quantity of paracetamol / acetaminophen used.
Subjects will be instructed that they cannot use more than 4 grams per day
Accountability of study medication
o Subjects will be instructed to bring all the study medication (used tubes, unused or
partially used) at the next study visit and should not throw any study medication.
Total amount of tubes dispensed to a subject will be recorded
4.3.1.4 Visit 4 (Day 14 4 / Week 2 / Interim Visit)

o HEENT
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o Nervous system
o Urogenital system
o WOMAC pain score
Collection of study medication
All the used tubes will be collected from a subject and will be instructed to bring
used, unused, and partially used tubes at the next visit for accountability purpose.
Additional rescue medication will be dispensed to the subjects based on the
requirement
o Subjects will be provided with 2 new tubes of study medication (each tube will
contain 100 g of study medication) along with the partially used tube from baseline,
sufficient to last for 14 days, study duration of 2 weeks treatment of the target knee.
The study medication will be supplied along with dosing card to standardize the
amount of study medication applied to the target knee
o In case an additional tube is to be dispensed to the subject so as to suffice the dosing
for 14 days, the reason for the same will be recorded and the tube will be dispensed
on receiving the details from IWRS
Dispense additional rescue medication, paracetamol / acetaminophen (if required).
Subject will be instructed to record the date, time and quantity of paracetamol /
acetaminophen used. Subjects will be instructed that they cannot use more than 4 grams
per day
Subject diary will be reviewed
o

number of used tubes returned). A subject is said to be 100% compliant to the study
medication if he / she applies 224 g of the study medication and have a partially used
tube containing 76 g of the gel [300 g-224g = 76g]). This partially used tube will be
returned to the subject by the site personnel. Subjects will be considered compliant with
the assigned study treatment if they have used at least 75% and no more than 125% of the
study treatment doses
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4.3.1.5 Visit 5 (Day 28 4 / Week 4 / End of Study)

Laboratory tests
o Hematology: HCT, RBC, Hb, platelet, WBC, with differential count
o Biochemistry: ALT, AST, and GGT, Total bilirubin, Creatinine, Urea, Sodium,
potassium, calcium, phosphorus, bicarbonate, FPG
o UPT
12-Lead ECG
o HEENT
o Nervous system
o Urogenital system
5 min before vital signs are obtained.
o WOMAC pain score
Collection of used, unused, or partially used study medication

Collect and review subject diary

study medication and should have any partially used tube [in case no additional tube was
dispensed]. Subjects will be considered compliant with the assigned study treatment if
they have used at least 75% and no more than 125% of the study treatment doses
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4.3.2 Unscheduled Visits

An unscheduled visit is defined as any visit that occurs outside the schedule of visits. Data
collected during the unscheduled visit will be recorded on the electronic case report form (eCRF)
document with the Unscheduled visit ID box marked but will not be included in the analysis. If
the unscheduled visit results in premature termination / withdrawal, then all the procedures
enlisted under Visit 5 will be performed.
4.4
Measures Taken to Avoid Bias
All subjects and investigators will be masked to the treatment assigned until completion of the
trial to minimise any subject- or investigator-induced bias in the outcome measures.
4.4.1 Randomization
Approximately 990 subjects (330 in each treatment group) with OA of the knee will be
randomized (considering 10% drop outs) to get an evaluable data of at least 900 subjects in a

Block randomization will be used for subject randomization into the 3 treatment groups. The
randomization list will be prepared by JSS Medical Research India (JSS India) using a validated
computer program, statistical analysis system (SAS) for Windows version 9.3 / Proc PLAN
(SAS Institute Inc., Cary, NC, USA). An interactive web response system (IWRS) method
containing randomization codes will be used to randomize the eligible subject to the treatment
groups.
4.4.2 Blinding
This will be a double blinded and randomized study. The packaging of the test, reference, and
vehicle will be similar in appearance so that the subject and all relevant personnel involved with
the conduct and interpretation of the study (including investigator, investigational site personnel,
and the sponsor, CRO study team or designees staff) will be blinded to the treatment allocation.
Final randomization list will be kept strictly confidential, filed securely by the independent
biostatistician, and accessible only to authorized persons per sponsor (or designee) standard
operating procedures until completion of the study.
A treating physician may request unblinding of study medication on an individual subject, if it is
essential for the clinical management of the subjects health, to ensure safety. If a treating
physician requires unblinding of study medication on a subject, e.g. for management of SAE, the
request will be made telephonically to the JSS India medical monitor/sponsor, followed by a
written request. Upon receipt of such request, the identity of the treating physician as well as the
subjects identifiers will be confirmed by JSS India medical monitor/sponsor before actual
unblinding of subjects treatment assignment by the investigator. The date and reason for
unblinding has to be documented in the source document (medical record) and CRF,
accordingly. The JSS India medical monitor or designee is required to contact and inform the
sponsor regarding unblinding of the subjects treatment.
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Any accidental unblinding will be recorded as a protocol deviation and the subjects continuation
or discontinuation from the study will be decided after discussion with JSS India and sponsors
medical monitors. In case there is any need to open the investigator blinding of trial medication
for clinical management of subjects health during the trial or in case of occurrence of a SAE
subject will be withdrawn from the trial.
4.5
Accountability Procedures for the Investigational Product
A study medication accountability log will be maintained by the study staff. This record will
document receipt, dispensing, and return of tubes containing study medication. Accountability
will be performed by reviewing the accountability records and by checking the randomization
number entered in the eCRF. After visit 5 EOS, all used and unused tubes containing study
medication will be shipped to third party for storage or destruction as per sponsors
communication.
4.6
Maintenance of Study Treatment Randomization Codes and Procedures for Breaking

Codes
A central randomization schedule will be generated by the study biostatistician. Subjects will be
randomized 1:1:1 to 1 of the 3 treatment groups. Randomization will be performed with a
computer program generated randomization schedule assigning the subjects in the sequence of
their appearance to treatment groups.
4.6.1 Emergency Unblinding of an Individual Subject
If it is medically imperative to know which study treatment the subject is receiving, emergency
unblinding will be done through IWRS. The investigator or his / her designee will unblind the
code when medically needed, without identifying other subjects treatment. Every attempt must
be made to contact the sponsor before the code is unblinded. The person who unblinds the
randomization code must record the date, time and the reason for emergency unblinding in the
subjects medical record / study documents / eCRF. In such cases, the subject will be
discontinued from the study.
Treatment failures and withdrawn subjects will not be re-randomized and will not be reentered
into the study. A subject may be designated a treatment failure by the investigator if, in the
investigators opinion, the subject has failed to show sufficient benefit from treatment over a
reasonable period of compliant (applied at least 75% of doses of study medication) exposure to
justify continuation in the study.
4.7
Identification of Any Data to be Directly Recorded on Case Report Forms
Not applicable since eCRF will be used in the study.

5
SELECTION AND WITHDRAWAL OF SUBJECTS
5.1
Inclusion Criteria
A subject will be eligible for inclusion in the study if he / she fulfills the following criteria:
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1. Male or non-pregnant female aged 35 years with a clinical diagnosis of OA of the knee
according to the ACR criteria,:
a. Pain in the knee and presence of at least 3 of the following ACR criteria: age 50
years; stiffness lasting for < 30 min; bony tenderness; crepitus; bony enlargement; no
palpable warmth, and including:
ii. Knee (not referred) pain for 15 days of the preceding month (periarticular knee
pain due to OA and not due to other conditions such as bursitis, tendonitis, etc.),
and
iii. The pain in the target knee required the use of NSAIDs or acetaminophen /
paracetamol (topical or oral treatments)
2. Had an X-ray of the target knee, taken no more than 1 year before baseline, showing
evidence of OA with Kellgren-Lawrence grade 1-3 disease
3. After discontinuing all pain medications for at least 7 days, had at least moderate POM
for target knee, defined as a baseline score of 50 mm on a 0-100 mm VAS immediately
prior to randomization, and a baseline WOMAC pain subscale of at least 9 immediately
prior to randomization
4. Able to tolerate rescue medication (i.e., acetaminophen / paracetamol)
5. Subjects willing to refrain from using any other OA treatment during the 4-week
treatment period, other than the study treatment, and rescue medication
6. Subjects willing to give written informed consent and provide audio-visual recording of
the consent process
8. Not pregnant / not planning to be pregnant/ not a lactating female. Women of
childbearing potential and male subjects were included in the study if they are willing to
use an appropriate method of contraception
5.2
Exclusion Criteria
A subject will not be considered eligible for inclusion in this study if he / she meets any of the
following criteria:
1. X-ray showing evidence of OA with Kellgren-Lawrence grade 4 disease
2. History of OA pain in the contralateral knee requiring medication within 1 year prior to
screening
3. After discontinuing all pain medications for at least 7 days, had a baseline score of 20
mm on a 0-100 mm VAS for the contralateral knee immediately prior to randomization
4. History of secondary OA, rheumatoid arthritis, chronic inflammatory disease (e.g.,
colitis) or fibromyalgia.
5. History of asthma, hypertension, myocardial infarction, thrombotic events, stroke,
congestive heart failure, impaired renal function or liver disease
6. History of GI bleeding or peptic ulcer disease
8. Elevated transaminases at screening (i.e., AST or ALT more than 2 times the upper limit
of normal at screening visit)
9. Use of anticoagulants, ACE-inhibitors, cyclosporine, diuretics, lithium, or methotrexate
within the past 30 days prior to entry into the study
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10. Concomitant acetyl salicylic acid therapy other than a stable low dose used for cardiac
prophylaxis (max 162 mg daily) taken for at least 3 months prior to enrolment and
maintained throughout the duration of the study
14. Any other acute or chronic illness that in the opinion of the investigator could
compromise the integrity of the study data or place the subject at risk by participating in
the study
15. Receipt of any drug as a part of a research within 30 days prior to screening
18. Subjects who are alcohol or drug dependent i.e. substance of abuse
19. Subjects having clinically significant liver, kidney, or cardiac dysfunction
20. Subjects having history of hypersensitivity reactions to DSG or any of its excipients
21. A positive serology test result for HIV antibody (I & II), HBsAg, and / or HCV
antibodies
5.3
Subject Withdrawal Criteria
Subjects will have the right to withdraw from the study at any time and for any reason without
prejudice to her / his future medical care by the physician or at the institution. The investigator
can withdraw subjects from the study in the following situations: in the event of intercurrent
illness, AEs, treatment failure, and protocol violation.
Withdrawal of consent means that the subject does not wish to or is unable to continue further
study participation. The investigator will discuss with the subject the most appropriate way to
withdraw to ensure the subjects health. For a subject prematurely discontinuing from the study,
besides scheduled study assessments for that visit, the investigator will perform all EOS
assessments at that visit itself.
The reasons for subject withdrawal from the study may include:
Lost to follow-up
Subject non-compliance / significant protocol deviation
Any AE or SAE
As per investigators discretion, continuation in the study would be detrimental to the
subjects well being
Any other reason
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TREATMENT OF SUBJECTS
6.1
Investigational Medicinal Product
The three treatments in this study will be as follows:

Test Product: The test product is generic Diclofenac Sodium Topical Gel 1%. It is
manufactured by Cipla Ltd, India and is available in the form of a topical gel containing 1% of
diclofenac sodium. Each subject will apply approximately 4 g dose of the gel on the target knee 4
times daily for 4 weeks.
Vehicle: Manufactured by Cipla Limited, India in the form of a topical gel. Each subject will
apply approximately 4 g dose of the gel on the target knee 4 times daily for 4 weeks.
Reference Product: The reference product is Voltaren gel (diclofenac sodium topical gel 1%).
It is manufactured by: Novartis Consumer Health, Inc., USA OR Novartis Pharma Produktions
GmbH, Germany and marketed by Endo Pharmaceuticals, Inc., USA. It is available in the form
of a topical gel containing 1% of diclofenac sodium. Each subject will apply approximately 4 g
dose of the gel on the target knee 4 times daily for 4 weeks.
The assigned study medications (gel tubes) will be labelled. Each label will clearly disclose the
protocol number, subject randomization number, subject initials, directions for use, storage
statement, caution statement, and sponsors name.
All the tubes of study medication will be of the similar size, shape, cap configuration, color and
will be labelled in a similar manner in order to maintain blinding.
Each subject will be assigned study medication at the time of randomization (visit 3 / Day 0).
Study medication will be dispensed at baseline (Day 0) and visit 4 (Day 14 / Week 2). Subject
will be provided with 3 tubes (1 tube = 100 g of study medication), adequate enough to last for
14 days, 2-week treatment period. At week 2 (visit 4 / Day 14), subjects will be provided with 2
new tubes of study medication (each tube will contain 100 g of study medication) along with the
partially used tube from baseline, sufficient to last for 14 days (2 weeks treatment of the target
knee). In case an additional tube is to be dispensed to the subject so as to suffice the dosing for
14 days, the reason for the same will be recorded and the tube will be dispensed on receiving the
details from IWRS.
6.2
Dosage Regimen
The dosage regimen in this study is that approved for the reference product. Each randomized
subject will receive study medication at visit 3 / baseline. Subjects will be instructed to apply 4 g
of study medication on the target treated knee 4 times daily for 4 weeks. Each treatment should
be applied laterally, medially, anteriorly, immediately proximal and to 4 inches (10 cm) distal
to the knee. Subjects will be provided with detailed application instructions along with a dosing
card to standardize the amount applied. For this purpose, subjects will place the dosing card on a
flat surface so that they can read the print. The treatment gel should be squeezed onto the dosing
card evenly upto the 4 g line, making sure the gel covers the entire 4 g area of the dosing card.
The subjects will have to apply their knee using the dosing card. Study medication should be
applied to the affected knee area and gently rubbed the skin using hands. The target treatment
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area should not be occluded. The date and time of application will be recorded in the subject
diary. After using the dosing card, it should be rinsed, and dried until next use.
6.2.1 Dispensing (Labeling) and Compliance
The investigational product (IP) will be dispensed by the unblinded pharmacist to the
investigator or designee as per the randomization list provided by the unblinded biostatistician.
Access to the dispensed IP must be provided only to the investigator or designee or pharmacist.
All the test, reference, and vehicle products will have a similar packaging in terms of size, shape,
cap configuration and color to maintain blinding.
The label on each tube will have the following information:
Study Identification Code
Batch/ Code Number
Expiry Date
Storage instructions
Site Number
Subject Number
The statement For Clinical Study Use Only
6.2.2 Storage Condition
The tube must be stored at 20C to 25C (68F to 77F). Keep from freezing. Store the dosing
card with DSG.
6.3
Handling of Study Medication
The study medication will be supplied in 100 g tubes provided by the sponsor. The blinded tubes
will be labeled and packaged by a third party vendor so that neither the subject, the investigator,
and nor the sponsor can identify the treatment. Study medication will be packaged for individual
subjects with each receiving three 100 g tubes at baseline and two 100 g new tubes along with
partially used tube from baseline at visit 4, In case an additional tube is to be dispensed to the
subject so as to suffice the dosing for 14 days, the reason for the same will be recorded and the
tube will be dispensed on receiving the details from IWRS.
All study medication will be dispensed by a qualified study personnel designated by the
investigator. Study medication used to conduct this study will be maintained under adequate
security by the investigator. Study medications will be stored at 25C (77F); excursions
permitted to 15-30C (59-86F) and kept from freezing in a secured area. Documentation of
appropriate daily (when study site is open) study medication storage temperature must be
maintained throughout the study. The investigator will not supply study medications to any
person not enrolled in this study, or to any physician or scientist except those named as subinvestigators.
Subjects will be instructed to return both used and unused tubes of study medication at visit 4 /
Interim visit (week 2) and at visit 5 (week 4). All the used and unused tubes of study medication
will be collected at visit 5 / EOS for study medication inventory. The study site personnel will
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keep a running inventory of the study medication dispensed and the number of tubes (used,
unused, and partially used) that are returned. Forms will be provided to the investigator to
document all the medication received, all study medication dispensed by the site, and study
medication used by each subject. The dispensing and return of study medication at subsequent
study visits will also be recorded in the drug dispensing log. At the conclusion of the study, all
unused, partially used, and empty tubes will be inventoried by the monitor and returned to
sponsor.
6.4
Retention of Study Medication Samples
Each study site where study medication is dispensed to at least 1 subject will be required to
randomly select 1 block (containing 3 consecutively numbered subject boxes) of study
medication from initial shipment to be maintained as retain samples. The investigator will
maintain one randomly selected block of study medication for each additional shipment of study
medication received or as per the specification in the IMP shipment document. As per the 21
CFR 320.38 and 320.63 and the guidance Handling and retention of bioavailability and BE
Testing Samples, Each reserve sample shall be stored under conditions consistent with the
product labeling [25C (77F); excursions permitted to 15-30C (59-86F)] and in an area
segregated from the area where testing is conducted and with access limited to authorized
personnel. Retain samples shall be stored for a period of at least 5 years following the date on
which the application or supplemental application is approved, or, if such application or
supplemental application is not approved, at least 5 years following the date of completion of the
study in which the sample from which the reserve sample was obtained was used. Retention
samples should not be returned to the sponsor at any time.
6.5
Medication(s) / Treatment(s) Permitted and Not Permitted Before and / or During the
Study
6.5.1 Medication(s) / Treatment(s) Permitted

Generally, subjects will be allowed to continue taking stable (non-analgesic) medications that
would not interfere with the metabolism of diclofenac sodium.
Physical therapy will be permitted if started at least 1 month before screening but could not be
initiated or changed during the study. Similarly, exercise regimens and the application of heat or
cold compressions could not be started, discontinued or changed during the study.
Rescue Medications
The use of acetaminophen / paracetamol (upto 4 g per day) will be permitted as rescue therapy
for residual knee or other body pain throughout the study. Rescue medication will be recorded in
the subject diary.
6.5.2 Medications / Treatment(s) Not Permitted
The prescription and over-the-counter drug products that are prohibited during the study include:
Any other tropical products applied to the knees
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ACE-inhibitors, anticoagulants, cyclosporine, diuretics, lithium, methotrexate, oral

NSAIDs, aspirin [except for cardiac prophylaxis (max 162 mg daily) taken for at least 3
months prior to enrolment and maintained throughout the duration of the study]
Systemic corticosteroids or immunosuppressive drugs
Pain medication other than acetaminophen / paracetamol
Subjects will be instructed not to use moisturizers, sunscreen, creams, lotions, powders, avoid
exposure to sunlight and sunlamps, not use any type of bandage or occlusive dressing or heating
pad on the treatment area, not allow the gel to come in contact with the eyes or mucous
membranes, and not apply the gel to open skin wounds, infections, inflammations, or exfoliative
dermatitis on the treatment area (target knee) for the entire study duration.
6.5.3 Procedure(s) for Monitoring Subject Compliance
Treatment compliance will be monitored by reviewing the subject diaries and the total number of
applications and missed applications. Subjects are to apply 16 g (4 g four times daily) of the
assigned study medication to the target treated knee for 4 weeks. At visits 4 and 5, the subject
diary will be reviewed and the used and unused tubes will be collected at visit 5. Subjects who
applied too much or too little medication will be reinstructed on proper dosing. Subjects will be
considered compliant with the assigned study treatment if they use at least 75% and no more than
125% of study treatment doses.
The date of the first application, the date of the last application, the total number of applications,
and the total number of missed applications will be recorded by the study coordinator on the
subjects eCRF. At visit 5, subject diary will be kept at the study center as a part of the source
documentation records. Rescue medication consumption will also be monitored by reviewing the
diaries. The investigator is responsible for the accountability of study drug, reconciliation, and
for recording maintenance throughout the course of the study in accordance with all applicable
regulatory requirements.
7
STUDY ASSESSMENTS
7.1
The enrolled subjects will be assessed for OA after discontinuing all pain medication for at least
7 days (subject must have at least moderate POM for target knee, defined as a baseline score of
50 mm on a 0-100 mm VAS immediately prior to randomization, and a baseline WOMAC pain
score of at least 9 immediately prior to randomization). Any existing conditions in that area will
be noted with respect to how they might affect the application of the study medication. The
efficacy assessments will be conducted at visits 3-5.
The WOMAC pain score (pain score = 0 to 20) and PGA of target knee OA will be done by
using a 5-point Likert scale (i.e., 0 = none; 1 = mild, 2 = moderate, 3 = severe, 4 = extreme).
The following 5 questions pertain to the amount of pain the subject is currently experiencing in
the target knee when:
Q1 Walking on a flat surface (S1)
Q2 Going up or down stairs (S2)
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Q3 At night while in bed (S3)

Q4 Sitting or lying (S4)
Q5 Standing upright (S5)
POM is evaluated using VAS. It is a continuous scale, usually 100 mm in length, anchored by 2
verbal descriptors, one for each symptom extreme (no pain and worst pain imaginable).
Subjects are asked to rate their pain by placing a mark on the line corresponding to their current
level of pain. The distance along the line from the no pain marker is then measured with a ruler
giving a pain score out of 10.
Source: Huskisson EC. Measurement of pain. Lancet. 1974 Nov 9; 2 (7889): 1127-31
PGA will be evaluated at visits 3-5, where the subject will give a global self-assessment of target
knee OA condition using 5-point Likert scale (0 = very well, 1 = well, 2 = fair, 3 = poor, 4 = very
poor) to rate his / her OA, and will be recorded on the eCRF.
8
ASSESSMENT OF SAFETY
8.1
Adverse Events
8.1.1 Definition of Adverse Event

An AE is defined in the ICH-GCP as any untoward medical occurrence in a subject or clinical
investigation subject administered a pharmaceutical product and which does not necessarily have
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a IP, whether or not
considered related to the IP (ICH E6:1.2).
All abnormal laboratory findings should be classified as clinically significant or nonclinically significant by investigator as per his clinical judgment. Only clinically significant
abnormal laboratory values should be considered as an AE.
Worsening of a pre-existing medical condition should be considered as an AE if there is either an
increase in severity, frequency, or duration of the condition or an association with significantly
worse outcomes.
Pre-existing conditions that have not worsened are not considered AEs.
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8.1.2 Serious Adverse Event

A SAE is any untoward medical occurrence that at any dose fulfills one or more of the
following:
results in death
is life-threatening*
requires in subject hospitalisation or prolongation of existing hospitalisation
results in persistent or significant disability / incapacity
is a congenital anomaly / birth defect
is an important medical event: important medical event in the definition of serious
refers to those events which may not be immediately life-threatening, or result in death,
or hospitalization, but from medical and scientific judgment may jeopardize the subject
and / or may require medical or surgical intervention to prevent one of the other
outcomes listed above. Examples of such events are intensive treatment in an emergency
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not
result in hospitalization
*NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the
subject was at risk of death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe.
Hospitalization is to be considered only hospital stay for 24 hours. The following

hospitalizations should not be reported as SAEs:
Hospitalization or prolongation of hospitalization needed for procedures required by the
clinical trial protocol
Hospitalization or prolongation of hospitalization as part of a routine procedure followed
by the center
Hospitalization for a survey visit, annual physicals, or social reasons
Elective (pre-planned) hospitalizations for a pre-existing condition that had not worsened
from baseline (e.g. elective or scheduled surgery arranged prior to start of the study)
Admissions not associated with an AE (e.g. social hospitalization for purposes of respite care)
8.1.3 Methods and Timing for Assessing, Recording and Analyzing Safety Parameters
All AEs will be collected on eCRFs from the time the subject signs the ICF until study exit. Any
SAE that is ongoing at the time the subject exits the study must be followed until the event is
resolved or there is a satisfactory explanation which meets one of the following outcomes:
Resolved (With residual effects or without residual effects)

Death
Unknown (Despite adequate follow-up)
8.1.4 Documentation and Reporting of Serious Adverse Events

All SAEs will be recorded from the time a subject signs the ICF till the end of the study.
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All SAEs, regardless of causal relationship will be reported by the site to sponsor /
designee, Licensing Authority i.e. the DCGI, and institutional ethics committee (IEC) of
the site within 24 hours of occurrence through the initial SAE form.
Follow-up information on an existing SAE that is fatal or life-threatening will be reported
by the investigator after the initial report. Where appropriate, hospitalisation or autopsy
reports will be made available. All SAEs will be followed up until resolution (i.e.,
asymptomatic, stabilisation or death)
The investigator and sponsor / sponsor designee will prepare and submit a detailed
analysed report of all the SAEs to the Head of the Institution where the trial is being
conducted, to the Chairman of the IEC that accorded approval for conduct of the trial and
the Licensing Authority within 14 days. This notification will be as per the Appendix XI
of Schedule Y
If the SAE resolves after the submission of the 14 day analysed report, the investigator
will prepare and submit a second analysed report upon resolution of the SAE.
Report serious adverse events by phone and facsimile to:
Sponsor Details

Email: dhiraj.abhyankar@cipla.com
Regulatory Authority
Central Drugs Standard Control Organization

Directorate General of Health Services
Ministry of Health and Family Welfare
Government of India
FDA Bhavan, ITO, Kotla Road,
New Delhi -110002
Phone: 91-11-23236975 / 23236971
Fax: 91-11-23236973
E-mail:- dci@nb.nic.in
Illnesses
8.1.5.1 Eliciting, Documentation and Reporting of Adverse Events
Information on AE will be derived by questioning the subjects in general terms (e.g. "How do
you feel? or How have you been feeling since the last questioning? respectively), by subjects'
spontaneous reports, or by observation.
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AEs will be documented on the source documents and eCRFs. Trained monitors will check the
entries in the source documents. The AE will be transcribed to the AE eCRF-pages. The
following information will be given for each AE:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Description of the AE (verbatim term / diagnosis)

Date of onset
Date of resolution
Severity (mild, moderate, severe)
Causality or relationship to the study medication
Seriousness
Action taken (with regard to study medication)
Other action (to treat the event)
Outcome
8.1.6 Rating of Adverse Events

The investigator should describe an AE regarding severity, relatedness, and outcome of every
AE:
Severity will be described as follows:
Mild: The AE does not interfere in a significant manner with the subjects normal
functioning level, but may be an annoyance
Moderate: The AE produces some impairment of functioning but is not hazardous to

health, but is uncomfortable and / or an embarrassment
Severe: The AE produces significant impairment of functioning or incapacitation and is a

hazard to the subject
The duration of the event will be described by the start date and end date.
The causal relationship of the event to use of the IP is described in terms of related or not related
to the IP, wherein related AEs includes Certain, Probable and Possible and not related
includes Unlikely and Unassessable
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Causality term
Certain
Assessment criteria
Probable
Possible
Unlikely
Unassessable
Event or laboratory test abnormality, with plausible

Cannot be explained by disease or other drugs
Response to withdrawal plausible
(pharmacologically, pathologically)
Event definitive pharmacologically or
phenomenologically (i.e. an objective and specific
medical disorder or a recognized pharmacological
phenomenon)
Rechallenge satisfactory, if necessary
Unlikely to be attributed to disease or other drugs
Response to withdrawal clinically reasonable
Rechallenge not required
Could also be explained by disease or other drugs
Information on drug withdrawal may be lacking or
unclear
Event or laboratory test abnormality, with a time to
drug intake that makes a relationship improbable (but
not impossible)
Disease or other drugs provide plausible explanations
Report suggesting an adverse reaction
Cannot be judged because information is insufficient
or contradictory
Data cannot be supplemented or verified
The outcome of all AEs will be reported based on the following definitions, independent of
whether they are serious or non-serious AEs, their severity, or their relationship to the IP:
Recovered: Fully recovered, or by medical or surgical treatment the condition has

returned to the level observed at the first study related activity after the subject signed the
informed consent
Recovering: The condition is improving and the subject is expected to recover from the
event. This term should only be used when the subject has completed the study
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Recovered with sequelae: As a result of the AE, the subject suffered persistent and
significant disability / incapacity (e.g. became blind, deaf, paralyzed)
Not recovered
Fatal
Unknown: This term should only be used in cases where the subject is lost to follow-up
Each AE will be followed to satisfactory clinical resolution. An IP-related event (adverse drug
reaction) is an AE that is judged by the investigator or the sponsor / sponsors designee to be
either certainly related, probably related or possibly related to the study IP.
8.2
Emergency Contact
In case of any emergency, contact:

Address: Plot 12/2, 6th Floor, Vatika Mindscapes Tower- B, Sarai Khwaja Metro Station, NH-2
Mathura Road, Sector 27 D, Faridabad, Haryana- 121003, India
Ph: +91 11 129 6613500
Fax:-+ 91 11 129 6613520
Email ID: safety@jssresearch.com
8.3
A physical examination will be performed at all study visits. The physical examination will
consist of examination of the following body systems:
HEENT
8.4
Cardiovascular system
Respiratory system
Nervous system
Gastrointestinal system
Musculo-skeletal system
Urogenital system
Others, if required
Vital Signs
Vital signs (pulse rate [beats / min], respiratory rate [breaths / min], systolic and diastolic BP
[mm / Hg], and body temperature [C]) will be recorded at each study visit, after the subject has
rested in a seated position for at least 5 min.
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8.5
Laboratory Evaluations
Blood and urine samples will be collected for laboratory evaluations at visit 1, 3, and 5. All the
laboratory assessments (serology, hematology, biochemistry, and UPT) will be carried out in
central / local laboratory of the respective study sites. The following are the laboratory tests:
Hematology
o HCT
o RBC
o Hb
o Platelets
o WBC with differential blood count
Biochemistry
o ALT, AST, and GGT

o Total bilirubin
o Creatinine
o Urea
o Sodium, potassium, calcium, phosphorus, bicarbonate
o FPG
Urinalysis
o Urine pregnancy test*- All female subjects of childbearing potential will undergo a
UPT at visits 1 and 5.
Serology*
o HIV antibody (I and II)
o HBsAg
o HCV antibodies
*Serology and Urine pregnancy tests are the eligibility tests.
8.6
12 Lead Electrocardiogram
12 Lead ECG will be evaluated at Screening and EOS visit.

9
STATISTICS
9.1
Statistical Method
All the statistical tests will be carried out as two-sided on 5% level of significance unless
otherwise stated. The descriptive statistics for continuous variables will be presented with
number (n) of non-missing observations, mean, standard deviation (SD), median, and minimum
and maximum (range). For categorical data, the descriptive statistics will be presented with
number of exposed subjects and number (n) with percentage of observations in various
categories of the endpoint, where percentage will be based on the exposed subjects. Descriptive
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analyses will also include graphical presentations of data wherever appropriate. Individual data
listings will also be provided.
A detailed statistical analysis plan (SAP) will be finalized providing detailed methods for the
analyses outlined below before the database is locked and prior to analysis of the study being
carried out. Any deviations from the analyses described below will be included in the SAP.
9.1.1 Demographic and Other Baseline Characteristics
Demographic variables and subject characteristics will be summarized descriptively by treatment
assignment and overall. Demographic variables will include age, weight and height. Variables
that are measured on a continuous scale, such as the age of the subject at the time of enrollment,
the number of non-missing observations (n), mean, median, SD, minimum, and maximum will
be tabulated by treatment assignment and overall for the randomized population. Variables that
are measured on a categorical scale will be summarized using frequencies and percentages by
treatment assignment and overall for the safety population.
9.1.2 Decoding of Randomization
The study blind may be broken in case of an emergency when the information of the treatment
assigned is essential for medical management of the subject. The investigator must notify the
sponsor within 24 hours after determining that it is necessary to unblind the treatment
assignment. The investigator must also indicate in source documents and in the eCRF that the
blind was broken and provide the date, time, and reason for breaking the blind. Any AE or SAE
that requires breaking the blind must be recorded and reported as specified in this protocol.
9.1.3 Primary Analysis (Efficacy Analysis):
To establish bioequivalence for the primary endpoint, 90% confidence interval (CI) for the test /
reference ratio of mean change from baseline to week 4 must be contained within [0.80, 1.25] for
a continuous variable, using the per-protocol (PP) population.
Where T = mean of test treatment and R = mean of reference product
Typically, we reject H0 with type I error = 0.05 (two 1-sided tests), if 90% CI for the ratio of
means between test and reference products (T / R) is contained within the interval [1, 2],
where 1 = 0.80 and 2 = 1.25.
Rejection of the null hypothesis H0 supports the conclusion of equivalence of the two products.
Similarly, superiority of test and reference over vehicle will be tested with a 1-sided test using
type 1 error of 0.05.
The primary efficacy data will be calculated using sample number, mean, SD, minimum,
maximum and 90% CI.
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A general linear regression model will be used to compare the average change in WOMAC pain
score from baseline to week 4 with the use of treatment as factors and baseline values as
covariates.
Comparison to baseline analysis of treatment effects with relevant test will be described in a
statistical analysis plan.
9.1.4 Secondary Analysis (Efficacy Analysis):
A general linear regression model will be used to compare the average change in POM (using
VAS score) and PGA (using Likert scale) from baseline to week 4 with the use of treatment as
factors and baseline values as covariates.
As a parameter for determining adequate study sensitivity, both test product and reference should
be statistically superior to vehicle (p < 0.05, two-sided) for the primary endpoint using the
modified intent-to-treat (mITT) study population and last observation carried forward (LOCF).
9.1.5 Safety Analysis
All safety endpoints will be analyzed based on descriptive statistics as described above for
continuous and categorical variables.
The AEs will be coded by system organ classification (SOC) and preferred term (PT) using the
latest version of Medical Dictionary for Drug Regulatory Affairs.
All AEs will be listed and categorized before dosing and after dosing. All AEs which occur after
the first dose of the study medication will be categorized as treatment emergent AEs i.e. AEs
with onset date on or after the first dose of the study medication. The AEs will be tabulated and
summarized for each treatment group. All AEs will be collected, evaluated and tabulated by
SOC, PT, date of onset, description, relationship to study medication, seriousness, severity,
action taken, outcome, and date of resolution for each treatment group.
Actual visit wise summary and Change values from baseline to week 4 for other safety measures
like physical examination, vital signs, different lab parameters [hematology and biochemistry]
will also be summarized as per standard convention. The descriptive statistics for continuous
variables will be presented with number (n) of non-missing observations, mean, SD, median, and
minimum and maximum (range). For categorical data, the descriptive statistics will be presented
with number of exposed patients and number (n) with percentage of observations in various
categories of the endpoint, where percentage will be based on the exposed patients. Shift table
for change from baseline to week 4 in categorical response will also be prepared where needed.
9.2
Sample Size
A sample size of 300 in each group will have at least 80% power to detect a difference in means
of 1.1 (change in WOMAC pain score from baseline to final) between active treatment (5.8) and
control- vehicle arm (4.7) assuming that the common SD is 4.54 using a two group t-test with a
0.05 two-sided significance level (assuming both active treatment groups are compared with
vehicle at 0.05 level of significance and no multiplicity adjustment is performed). Assuming
approximately 10% subjects will not qualify for mITT population, 330 subjects will be needed to
be enrolled in each group to demonstrate superiority of both active treatments over vehicle.
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When the sample size in each group is 240, a two-group design will have 85% power to reject
both the null hypotheses; the 1st hypothesis is that the ratio of the test mean to the reference mean
is below 0.800 and the 2nd null hypothesis is that the ratio of test mean to the reference mean is
above 1.250; the test and reference mean are not equivalent, in favour of the alternative
hypothesis that the means of the two groups are equivalent, assuming that the expected ratio of
means is 1.0, the coefficient of variation for the standard is approximately 0.78, that data will be
analyzed in the original scale using Sasabuchi t-tests for the ratio of means, and that each t-test is
made at the 5.0% level. Assuming approximately 27% subjects do not qualify for PP population;
minimum 330 subjects will be enrolled in each group to demonstrate bioequivalence of two
diclofenac formulations.
Thus this study will need to randomize 990 subjects (330 in each treatment group) with OA of
the knee, to get an evaluable data of at least 900 subjects in a 1:1:1 ratio at baseline visit to the 3
treatment groups, Vehicle of Diclofenac Sodium Topical Gel, Diclofenac Test and Diclofenac
Reference formulation.
9.3
Level of Significance
The data will be summarized descriptively including the sample number, mean, SD, minimum,
median, maximum, and the 95% CI. Applicable comparative tests will have 0.05 significance
level.
9.4
Study Termination Criteria
9.4.1 Withdrawal Criteria

Subjects may be withdrawn from the study (i.e. in these withdrawn subjects, IP will not be
further administered and any study procedures will not be carried out but they will be included in
the safety analyses) for the following reasons:
Lost to follow-up
Subject non-compliance/significant protocol deviation
Any AE or SAE
subjects well being
Any other reason
In all cases, the reason for and date of withdrawal must be recorded in eCRF and in the subjects
medical records. The subject must be followed up to establish whether the reason was an AE,
and, if so, this must be reported in accordance with the procedures in Section 8.
The investigator must make every effort to contact subject who are lost to follow-up. Attempts to
contact such subject must be documented in the subjects records (e.g., dates and times of
attempted telephone contact).
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Any subject may be withdrawn from the study at the discretion of the investigator. The subject is
also free to terminate his / her participation at any time. An EOS visit will then be organized.
9.4.2 Withdrawn Subject Data Collection
The principal investigator and / or other investigator involved in the study will document the
reason for the subject withdrawal as follows:
Lost to follow-up: Subject who leaves the study unnotified or do not attend the study visit
or cannot be contacted by phone. Repeated efforts should be made to locate and recall
them if possible and to determine their health status at a minimum
Significant protocol deviation/violation: Non follow-up for safety or efficacy procedures
required for the study, or repeated missing of study medication doses. Protocol violation
will be considered when the subject is not included as per protocol-defined eligibility
criteria
Subject non-compliance: Repeated missing of study medication doses or any other
procedures in the study which would affect study objectives or subjects safety
AE or SAE: An AE form must be completed. All subjects irrespective of the time of
drop-out will be considered for safety analysis. Clinically significant abnormal value not
explained by a laboratory error or being not a known or abnormal value commonly
observed in this type of population will also be considered as an AE or SAE, and
recorded on AE form as applicable
Requirement of prohibited concomitant medication: Concomitant medication page of
eCRF must be completed
subjects well being
Any, other reason: If no above mentioned reasons are applicable, then please specify
other reason
9.4.3 Replacement of Subjects

Subjects will not be replaced.
9.5
Missing Data
Missing data points will be dealt using appropriate statistical techniques, depending on the nature
of the data.
9.6
Procedures for Reporting Deviations from Original Statistical Plan
Any post-hoc, or unplanned, analyses not identified in SAP will be clearly identified in the
respective clinical study report (CSR).
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9.7
Study Population
The following are the 3 analysis populations: PP, mITT, and safety population.
10
PP population: includes all randomized subjects who meet all inclusion / exclusion
criteria, are compliant with the assigned study treatment (used at least 75% and no more
than 125% of study treatment doses), returns to the study site for visit 5 / week 4 within
the specified window ( 4 days) or discontinues from the study as a treatment failure, and
do not have any protocol violations. The PP population will be used for the
bioequivalence evaluation of test versus reference. Subjects who will be discontinued
early from the study due to lack of treatment effect will be included in the PP population,
using LOCF.
mITT population: includes all randomized subjects who meet all inclusion / exclusion
criteria, receive study treatment, and return for at least one post-baseline visit. mITT
population will be used to compare both test and reference products to vehicle, as a test
of study sensitivity. Subjects who discontinue early for other reasons will be excluded
from the PP population but will be included in the mITT population using LOCF.
Safety population: includes all randomized subjects who receive study treatment
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS
10.1 Monitoring
In accordance with applicable regulations and ICH-GCP guidelines, sponsor or its designees
monitors will contact the site prior to the start of the study to review with the site staff the
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and
sponsor's requirements. When reviewing the data collection procedures, the discussion will also
include identification, agreement, and documentation of data items for which the eCRF will
serve as the source document.
Sponsor and or its designee will monitor the study for protocol compliance verifying the
following, but not limited to:
Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol and any other
study agreements, ICH-GCP guidelines, and all applicable regulatory requirements
Data reported is authentic, accurate, and complete
The investigator agrees to allow the monitor direct access to all relevant documents for the
purpose of verification of available data.
10.2 Documentation at the Study Site
All data related to the study will be documented in the eCRF. This eCRF is developed to record
the data requested by the protocol. The investigator will ensure the accuracy, completeness,
legibility, and timeliness of the data recorded in the eCRF. At the beginning of the study, a site
master file will be established at the investigational site. The investigator will maintain the study
documents as specified in the ICH-GCP and as required by the applicable regulatory
requirements. The investigator will take measures to prevent accidental or premature destruction
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of these documents. Prior to the start of the study, a signature and delegation list will be
completed showing the signatures and hand-written initials of all who are authorized to entry
data or make corrections in the eCRF. The investigator will permit study-related monitoring,
audits, and regulatory inspection, providing direct access to source data / documents.
10.3 Subject's Data and Data Protection
To protect the subject's identity, subject initials and a subject number will be assigned by the
investigator to each study subject and used in lieu of the subject's name when the investigator
reports AEs and / or other study-related data. Personal information will be treated as confidential
but may need to be reviewed by authorized representatives of the sponsor (monitor and auditor,
respectively) and regulatory authorities. The subject's consent for direct access to his original
medical records for data verification purposes has to be obtained prior to a subject's participation
in the study.
The investigator must maintain a list of names and identifying information (e.g. initials, date of
birth, subject identification code and date of study entry) of all subjects enrolled in the study. The
investigator will keep the subject identification code list in the site master file.
10.4 Data Management and Analysis
Data management based on GCP refers to the activities defined for achieving routines for
entering subject information in a database in an efficient and error-free manner.
Data management routines include procedures for handling the eCRFs, database set up and
handling, data entry and verification, data validation, and documentation of activities performed,
including information on discrepancies in the procedure.
All of the AEs, including SAEs reported in the study will be entered in the study database. The
initial notification of SAEs will also be entered into the safety database for coding, medical
evaluation, and notification to regulatory authorities according to national regulatory
requirements. Before database lock, SAE reconciliation will be performed between the safety
and study databases.
Data will be entered and verified in a validated database. Data will be validated continuously by
running logic checks and manual reviews. For any discrepancies identified in study database,
queries will be generated in clinical data management system for resolution. When the data have
been entered, verified, and validated, the database will be locked for analysis.
10.5 Amendments to the Protocol
The investigator will not implement any deviation from, or changes to the protocol without
agreement by sponsor and prior review and documented approval / favorable opinion from the
IEC of an amendment, except where necessary to eliminate immediate hazards to study subject
or when the changes involve only logistical or administrative aspects of the study (e.g. change in
monitor(s), change in telephone numbers).
All changes or deviations of the trial must be confirmed in writing. Amendment(s) will be signed
off in the same way as the protocol and submitted to the applicable authorities and IEC.
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11
QUALITY CONTROL AND QUALITY ASSURANCE
11.1 Audit
To ensure compliance with ICH-GCP guidelines and all applicable regulatory requirements, the
sponsor may conduct a quality assurance audit following intimation and appointment. Regulatory
agencies may also conduct a regulatory inspection of this study. Such audits / inspections can
occur at any time during or after completion of the study. If an audit or inspection occurs, the
investigator and institution agree to allow the auditor / inspector direct access to all relevant
documents and to allocate his / her time and the time of his / her staff to the auditor / inspector to
discuss findings and any relevant issues.
12
ETHICS
Before initiation of the study, sponsor will seek permission from the regulatory authorities for
conducting the study. All documents required by the appropriate authorities will be submitted.
Any notification / submission will be dated and contain sufficient information to identify the
protocol.
12.1 Institutional Ethics Committee or Institutional Review Board
The study protocol, amendments to the protocol (if applicable), IP information, ICF, and consent
form updates (if applicable) will be submitted to the IEC, which is constituted according to local
law to obtain approval before initiation of the study. This study will be initiated after the protocol
is reviewed and approved by the concerned IEC. The approval should be kept on file in the site
master file with a copy in the trial master file. The investigator will report promptly to the IEC
new information that may adversely affect the safety of the subjects or the conduct of the trial.
The present study will be registered on Clinical Trials Registry-India (www.ctri.nic.in).
12.2 Ethical Conduct of the Study
The study will be conducted in compliance with International Conference on HarmonizationGood Clinical Practice Guidelines, the Helsinki Declaration, 21 CFR 320.38, 320.63, and
320.36, 21 CFR 58, ICH E6, and local regulatory requirement (Indian Good Clinical Practice,
Schedule Y, and Indian Council of Medical Research). This protocol and any amendments will
be submitted to an IEC, in agreement with local regulations, for formal approval of the study
conduct.
12.3 Subject Information and Consent
Subject will be screened and included in the study only after giving them adequate and
appropriate information, and obtaining a written informed consent which will be audio-visually
recorded. The subject will be given sufficient time to consider the studys implications before
deciding to participate. The subject will be provided with a copy of the signed ICF. The
confidentiality of the subjects records will be maintained.
Should there be any amendments to the protocol, such that would directly affect the subjects
participation in the study e.g., a change in any procedure, the ICF will be amended to incorporate
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this modification and the subject must agree to sign this amended form indicating that they reconsent to continue their participation in the study.
The investigator is responsible for obtaining the subjects freely given written consent. The
consent form must be signed by the subject or legally acceptable representative and the
investigator-designated research professional obtaining the consent.
13
DATA HANDLING AND RECORD KEEPING
The investigator must maintain all documentation relating to this study. Essential documents (as
defined in the ICH-GCP) and all raw data generated in connection with this study, together with
a copy of this protocol, signed ICDs and the final report will be archived for at least 5-years as
per the ICH guideline for good clinical practice.. These documents must be retained for a longer
period, however, if required by the applicable regulatory requirement(s) or if needed by sponsor.
In any case, all study records such as but not limited to eCRF, regulatory documents, subject
identification code list, subject files, and other source data that support eCRFs must be retained
for at least 5-years after the completion or discontinuation of the study The investigator must
notify sponsor or its designee of any changes in the archival arrangements, including, but not
limited to, archival at an off-site facility, transfer of ownership of the records in the event the
investigator leaves the site. These documents must be retained for a longer period, however, if
required by the applicable regulatory requirement(s) or if needed by sponsor.
Sponsor will notify the investigator in writing when the study-related records are no longer
needed.
14
FINANCING AND INSURANCE
Cipla Limited is the sponsor of this study and all agreements between the investigator and
sponsor or its designee will be signed prior to inclusion of the first subject in the clinical study.
The agreement must clearly state the rights and obligations of the parties concerned and include
a detailed financial settlement.
Every subject participating in the study will be insured in accordance with the local legal
requirements against study related injuries to the subject, which may occur during the study.
Excluded from this, however, are injuries to health and deteriorations of illnesses already
present, which would have occurred or continued to exist even if the subject had not taken part in
this clinical study. Any injury to health, which might have occurred as a result of participation in
the clinical study, must be reported by the investigator.
The sponsor is self-insured which covers product liability and subject injuries.
15
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS
A CSR, according to the ICH Guideline for Structure and Content of CSRs, will be prepared by
JSS India, in close collaboration with sponsor upon full completion of the study. The final report
will be compiled and sent as per e-CTD (Module 5) format. All copies of supplementary
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documents such as approved final version of protocol along with all appendices, IEC approval
letter, List of IEC members, CVs of investigators, all patient CRFs, adverse event form (if any),
Investigational Medicinal Product accountability records, Randomization list, Summary report of
statistical analysis, Protocol deviations, Demographics and Baseline characteristics and Safety
data will be submitted to sponsor with the final study report. It shall contain particularly Study
Protocol, Clinical data and Statistical Report.
16
PUBLICATION POLICY
This CSR, as well as any discovery and improvement related to IP, shall be the property of the
sponsor.
Neither the complete nor any part of the results of the study carried out under this protocol, nor
any of the information provided by the sponsor for the purposes of performing the study, will be
published or passed on to any third party without the consent of sponsor. Any investigator
involved with this study is obligated to provide the sponsor with complete test results and all data
derived from the study.
The investigator agrees to keep strictly confidential all unpublished information and results
concerning this study. Unpublished information must not be published or disclosed without
sponsors prior written approval.
17
REFERENCES
Argoff CE, and Gloth MF (2011). Topical nonsteroidal anti-inflammatory drugs for
management of osteoarthritis in long-term care patients. Therapeutics and Clinical Risk
Management 7:393-399.
Efficay of Topical Diclofenac Sodium Gel for Knee Osteoarthritis in Elderly and
Younger Patients. Pooled Data from Three Randomized, Double-Blind, Parallel-Group,
Placebo-Controlled, MultiCentre Trials. Drugs Aging 28 (1):27-40.
Efficay of Topical Diclofenac Sodium 1% Gel in Knee Osteoarthritis: A Randomized
Controlled Trial. The Physician and Sports Medicine. 1SSN-0091-3847 38 (2):19-28.
Draft
Guidance
on
Diclofenac
Sodium,
Recommended
Mar
2011.
http://www.fda.gov./downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm244644.pdf
Guidance for Industry Handling and Retention of BA and BE Testing Samples. US FDA
May2004.
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126836.pdf
http://www.fizjoterapeutom.pl/attachments/article/348/2008-4404b1-05-WOMACQuestionnaire.pdf
Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med
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Res Opin. 2010; 26(7): 1715-31

Heyneman CA et al.Oral versus Topical NSAIDs in Rheumatic Diseases (2000);
60(3):555-574
Huskisson EC. Measurement of pain. Lancet. 1974 Nov 9; 2 (7889): 1127-31
Peniston JH, Gold MS, Wieman MS and Alwine LK (2012). Long-term tolerability of
diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities.
Peniston JH, Gold MS, Wieman MS and Alwine LK (2013). Tolerability of diclofenac
sodium 1% gel with concomitant medications known to interact with diclofenac.
Roth SH, and Fuller P (2012). Pooled safety analysis of diclofenac topical solution 1.5%
(w/w) in the treatment of osteoarthritis in patients aged 75 years or older. Clinical
Interventions in Aging 7:127-137.
Scholer DW, Ku EC, Boettcher I, Schweizer A. Pharmacology of diclofenac sodium. Am
J Med. 1986; 80(4B): 34-8
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
http://www.performanceptpc.com/paperwork/womac.pdf
Tugwell PS, Wells GA, and Shainhouse ZJ (2015). Equivalence study of a topical
diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment
of osteoarthritis of the knee: a randomized controlled trial. The Journal of Rheumatology
31 (10):2002-2012.
Voltaren Gel Package Insert, Novartis Consumer Health, Inc., Parsippany, 2014
WOMAC Osteoarthritis Index LK3.1 (IK).
Zacher J, Altman R, Bellamy N, Brhlmann P, Da Silva J, Huskisson E, Taylor RS.
Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr
Med Res Opin.2008; 24(4): 925-50
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18
APPENDICES
Appendix 1:
WOMAC Questionnaire
Appendix 2:
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Appendix 1: WOMAC Pain Score

Instructions to Patients
WOMAC Pain Score questions will be asked in the following format. Please mark your
answers by putting X in one of the boxes
Examples:
1. If you put your X in the box on the far left as shown below,
none
mild
moderate
severe
extreme
then you are indicating that you feel no pain

2. If you put your X in the box on the far right as shown below,
none
mild
moderate
severe
extreme
then you are indicating that you feel extreme pain

3. Please note that:
a. the further to the right you place your X, the more pain you feel
b. the further to the left you place your X, the less pain you feel
c. please do not place X, outside any of the boxes
You will be asked to indicate on this type of scale the amount of pain you have felt during
the last 48 hours.
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WOMAC PAIN SCORE

Think about the pain you felt during the last 48 hours caused by osteoarthritis in your
target knee
Please mark your answers with an X
QUESTION: How much pain you have had.
1. when walking on a flat surface?
none
mild
moderate
severe
extreme
severe
extreme
2. when going up or down the stairs?

none
mild
moderate
3. at night while in bed? (that is pain that disturbs your sleep)

none
mild
moderate
severe
extreme
moderate
severe
extreme
moderate
severe
extreme
4. while sitting or lying down?

none
mild
5. while standing?
none
mild
Study Co-ordinators Use

PAIN 1
PAIN 2
PAIN 3
PAIN 4
PAIN 5
Confidential
Page 62 of 63
158 of 167

Version: 1.1
Date: 26 Feb 2016
Appendix 2: Visual Analogue Scale

Pain on movement (POM) is evaluated using Visual Analogue Scale (VAS). It is a subjective
measure of pain. It is a continuous scale, usually 100 mm in length, anchored by 2 verbal
descriptors, one for each symptom extreme (no pain and worst pain imaginable). Subjects are
asked to rate their pain by placing a mark on the line corresponding to their current level of pain.
The distance along the line from the no pain marker is then measured with a ruler giving a pain
score out of 10.
Interpretation of Score
The score can be used as a baseline assessment of pain with follow-up measures providing an
indication of whether pain is reducing. The scores can also be used to evaluate treatment
effectiveness
Confidential
Page 63 of 63
159 of 167
Protocol Number:
CIP-DSG-01
Document:
Summary of changes for Amendment 1
Date of document:
26 February 2016
Clinical Study Protocol Amendment 1

A Prospective, Multi-Center, Randomized, Double-Blind, VehicleControlled, Parallel-Group Bioequivalence Study with Clinical Endpoints
Comparing Generic Diclofenac Sodium Topical Gel 1% of Cipla Limited,
India to Voltaren Gel (a Diclofenac Sodium Topical Gel 1%) of Endo
Pharmaceuticals Inc., USA in Subjects with Osteoarthritis of the Knee
Original protocol:
Protocol amendment 1:
Version 1.0, 18 June 2015

Version 1.1, 26 February 2016
Confidential
This protocol is a confidential document owned by Cipla Limited. Any unpublished information
contained in it may not be disclosed to a third party without prior written approval of Cipla Limited.
However, the document may be disclosed to an Institutional Ethics Committee or a statutory regulatory
authority under a similar condition of confidentiality.
Confidential and Proprietary
Page 1 of 5
160 of 167
Protocol Number:
CIP-DSG-01
Document:
Date of document:
26 February 2016
The modifications applied to the clinical study protocol amendment 1 are tabulated below as
follows:
Original text: The text in the original protocol version 1.0, dated 18 June 2015
Amended text: The text in the original protocol version 1.1, dated 26 February 2016
Rationale: Administrative changes and correction in typo errors
Modification 1: Administrative Changes

Original text (page 1 and page 2)
Amended text (page 1 and page 2)
Contract Research Organization (Address)
Contract Research Organization (Address)

Max House, 1, Dr. Jha Marg, Okhla
Phase III
JSS Medical Research India Limited

6th Floor Vatika Mindspaces Tower-B,
Plot 12/2, Sector 27D,
Faridabad-121003, India
Original text (page 2)
Amended text (page 2)
Contract research organization Details
Contract research organization
Name: Max Neeman International

Address: Max House, 1, Dr. Jha Marg,
Okhla Phase III, New Delhi 110020, India
Phone: +91 11 40772100
Fax: +91 11 4054 8168
Name: JSS Medical Research India Limited

Address: Plot 12/2, 6th Floor, Vatika
Mindscapes Tower- B, Sarai Khwaja Metro
Station, NH-2, Mathura Road Sector 27 D,
Faridabad, Haryana- 121003, India
Phone: +91 0129 6613500
Fax: +91 0129 6613520
Original text (Version No./Date)
Amended text (Version No./Date)
1.0/18 June 2015
1.1/26 February 2016
Original text: (Sections 4.4.1, 4.4.2 and 15)
Amended text: (Sections 4.4.1, 4.4.2 and

15)
JSS Medical Research India and JSS India
in the sections 4.4.1 Randomization, 4.4.2
Blinding, and 15 Study reports and
supplementary documents respectively
Max Neeman International and MNI in the

sections 4.4.1 Randomization, 4.4.2
Blinding, and 15 Study reports and
supplementary documents respectively
Page 2 of 5
Protocol Number:
CIP-DSG-01
Document:
Date of document:
26 February 2016
Original text (page 3)

Preparation and Approval of the Protocol
Amended text (page 3)

Preparation and Approval of the Protocol
E-mail:
Medical
Urmila.Jetley@maxneema
Writing
responsible n.com
person
Medical
Address: E-mail:
Writing
Urmila.Gupta@jssresearch
responsible .com
person
Biostatistic Name: Santosh Kumar
Biostatistic Name: Santosh Kumar

ian
Address: Max Neeman
International, Max
House,1, Dr. Jha Marg,
Okhla Phase III, New
Delhi - 110020, India
Phone: 011- 40772100 Ext:
2751
E-mail:
Santosh.Kumar@maxneem
an.com
ian
Address: JSS Medical

Research India Ltd, Plot
12/2, 6th Floor, Vatika
Mindscapes Tower- B,
Sarai Khwaja Metro
Station, NH-2, Mathura
Road Sector 27 D,
Faridabad, Haryana121003, India
Phone: 0129- 6613500
Ext: 1117
E-mail:
Santosh1.kumar@jssresear
ch.com
Rationale: Change in Email ID of the medical writing responsible person and contact
details of biostatistician.
Modification 2: Section 8.2 Emergency Contact
In case of any emergency, following personal
should be contacted:
Name: Dr Subhranshu Nayak (Medical
Monitor)
Address: MNI, Max House, 1st Floor 1, Dr.
Jha Marg, Okhla Phase-III, New Delhi110020
Ph: 011-40772100; Extn: 2745
Fax:-+91.11.41001945
Email ID:
Subhranshu.Nayak@maxneeman.com
Mobile: +91-9643430098
In case of any emergency, contact:

Address: JSS Medical Research India Ltd
Plot 12/2, 6th Floor, Vatika Mindscapes,
Tower- B Sarai Khwaja Metro Station, NH2, Mathura Road, Sector 27 D, Faridabad,
Haryana- 121003, India
Phone: +91 0129 6613500;
Fax:-+91 0129 6613520
Rationale: Administrative Changes
Page 3 of 5
Protocol Number:
CIP-DSG-01
Document:
Date of document:
26 February 2016
Modification 3: Section 8.1.4 Documentation and Reporting of Serious Adverse Events

Sponsor Details:
Dr. Sachin Naik
Mobile Number: (0)8879935397
Email: sachin.naik@cipla.com
Sponsor Details:
Email: dhiraj.abhyankar@cipla.com
Rationale: Administrative Changes
Page 4 of 5
Protocol Number:
CIP-DSG-01
Document:
Date of document:
26 February 2016
Modification 4: Section 13 Data Handling and Record Keeping; Section 4.3.1.5: Visit
5 (Day 28 4 / Week 4 / End of Study); Section 8.5: Laboratory investigations
Original text (Section 13 Data Handling Amended text (Section 13 Data Handling
and Record Keeping; Section 4.3.1.5: and Record Keeping; Section 4.3.1.5: Visit 5
Visit 5 (Day 28 4 / Week 4 / End of (Day 28 4 / Week 4 / End of Study);
Study); Section 8.5: Laboratory Section 8.5: Laboratory investigations)
investigations)
Section 13 Data Handling and Record
Section 13 Data Handling and Record Keeping: (15 years to 5 years)
Keeping:
Essential documents (as defined in the Essential documents (as defined in the ICHICH-GCP) and all raw data generated in GCP) and all raw data generated in connection
connection with this study, together with a with this study, together with a copy of this
copy of this protocol, signed ICDs and the protocol, signed ICDs and the final report will
final report will be archived for at least 15 be archived for at least 5 years as per the ICH
years as per the ICH guideline for good guideline for good clinical practice.
clinical practice.
Section 4.3.1.5: Visit 5 (Day 28 4 / Week 4
/ End of Study): (Deleted not)
Section 4.3.1.5: Visit 5 (Day 28 4 /
Week 4 / End of Study):
Accountability of study medications with the
Accountability of study medications with help of subject dairies (by counting the number
the help of subject dairies (by counting the of used tubes returned). From week 2 to week
number of used tubes returned). From week 4, a subject must use 224 g of the study
2 to week 4, a subject must use 224 g of the medication and should have a partially used
study medication and should not have any tube [in case no additional tube was
partially used tube [in case no additional dispensed].
tube was dispensed].
Section 8.5: Laboratory investigations:

All the laboratory assessments (serology,
hematology, biochemistry, and UPT) will
be carried out in local laboratories of the
respective study sites.

(Addition of Central Lab):
All the laboratory assessments (serology,
hematology, biochemistry, and UPT) will be
carried out in central/local laboratory for the
study
Rationale: Typo errors were rectified
Page 5 of 5

Current Version Number: 1.0
Previous Version Number: Nil
Date: 29 December 2015
PROTOCOL CLARIFICATION FORM
Protocol: CIP-DSG-01
Version 1.0, dated 18th Jun, 2015
A Prospective, Multi-Center, Randomized, Double-Blind, Vehicle-Controlled,

Parallel-Group Bioequivalence Study with Clinical Endpoints Comparing Generic
Diclofenac Sodium Topical Gel 1% of Cipla Limited, India to Voltaren Gel (a
Diclofenac Sodium Topical Gel 1%) of Endo Pharmaceuticals Inc., USA in Subjects
with Osteoarthritis of the Knee
Page 1 of 3
165 of 167

Sr. No.
1.
2.
3.
CLARIFICATION
Typo errors or any clarifications from the Protocol have been explained in the
below mentioned sections
Section 13: Data Handling and Record Keeping:
Essential documents (as defined in the ICH-GCP) and all raw data generated in
connection with this study, together with a copy of this protocol, signed ICDs and the
final report will be archived for at least 15 years as per the ICH guideline for good
clinical practice.
Corrective action: Typo error - archival for 15 years changed to archival for 5
years
Essential documents (as defined in the ICH-GCP) and all raw data generated in
connection with this study, together with a copy of this protocol, signed ICDs and the
final report will be archived for at least 5 years as per the ICH guideline for good clinical
practice.
Section 4.3.1.5: Visit 5 (Day 28 4 / Week 4 / End of Study):
study medication and should not have any partially used tube [in case no additional tube
was dispensed].
Corrective action: Typo error Deleted not
study medication and should have a partially used tube [in case no additional tube was
dispensed].
Justification for prohibiting the use of ACE inhibitors:
a. NSAIDs may diminish the antihypertensive effect of angiotensin converting
enzyme (ACE) inhibitors. This interaction should be given consideration in
patients taking NSAIDs concomitantly with ACE-inhibitors.
b. Long-term administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. Renal toxicity has also been seen in patients in whom renal
prostaglandins have a compensatory role in the maintenance of renal perfusion.
In these patients, administration of an NSAID may cause a dose-dependent
reduction in prostaglandin formation and, secondarily, in renal blood flow,
which may precipitate overt renal decompensation. Patients at greatest risk of
this reaction are those with impaired renal function, heart failure, liver
dysfunction, those taking diuretics and ACE-inhibitors, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
Page 2 of 3

4.
5.
6.
Possible drug-drug interactions:

The possible drug-drug interactions with topical diclofenac sodium gel are seen with
following drugs:
Aspirin, anticoagulants (warfarin), ACE inhibitors, diuretics, lithium, methotrexate,
cyclosporine (renal prostaglandins), oral NSAIDs (oral diclofenac sodium or aspirin),
topical treatments (topical medications, sunscreens, lotions, moisturizers, and cosmetics,
on the same skin site)
All the laboratory assessments (serology, hematology, biochemistry, and UPT) will be
carried out in local laboratories of the respective study sites.
Corrective adion: Addition of "Central" Lab
All the laboratory assessments (serology, hematology, biochemistry, and UPT) will be
carried out in Central/Local laboratory for the study
Clarification for the washout period:
As per Protocol visit 2: Eligibility visit/Run-In period (day -14 to day -1/week-2)
This is to clarify that based on the enclosed list of medications, at Visit 2, there will be
a run-in period of 2: 7 days [maximum of up to 14 days for patients on Pyrazolone

derivatives (long half-life of approximately 13 days)]. Subjects who are not on
7.
Pyrazolonc derivatives will be enrolled into the study after 7111 day of wash out period
and the visit will be considered as Visit 3: Baseline/ randomization visit (day 0)
Clarification for the exclusion criteria no.ll:
This is to clarify that the criteria should be evaluated at baseline visit [Visit 3] and the
subjects will be excluded if they apply any other topical products other than the
investigational medicinal product to the target site from Visit 2 till the end of study.
Prepared by:
Reviewed &
Approved by:
Dr. Urmila Jetley

Senior Medical Writer
Name and Designation
Head- Clinical Research &
Development
Name and Designation
41-t.tl<..Lv
~\ \tl.. ,~01 ~
- (f
\J
Signaturc'-llnd Date
0~~
Sign ature and Date
Page 3 of3
04- _1'/.:<.c.JI~

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Cipla Limited

Protocol No: CIP_DSG_01

Protocol and Protocol Amendments

Protocol Number: CIP-DSG-01

CLINICAL STUDY PROTOCOL

Version 1.0 / 18 Jun 2015

Clinical Trial Phase:

Max Neeman International

Diclofenac Sodium Topical Gel 1%

Protocol Number: CIP-DSG-01

Dr. Dhiraj Abhyankar

Clinical Research Organization

Max Neeman International

Protocol Author [Medical writer]

Dr. Urmila Jetley

Mr. Santosh Kumar

Investigator Responsible for

This information is documented separately in the

Clinical Laboratory and other

This information is documented separately in the

Protocol Number: CIP-DSG-01

Protocol Number: CIP-DSG-01

CRO Approv'a l Page

Date: 18 Jun 2015

Date: 18 Jun 2015

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of investigators and all other pertinent requirements of the International

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