Appendix to:

Network Meta-analysis of Antiepileptic Drugs in Focal Drug-resistant

Epilepsy

Contents
Appendix S1. Suggested range of average target dose of antiepileptic drugs..............2
Appendix S2: Characteristics in RCTs of Included Studies.............................................3
..................................................................................................................................................4
Appendix S3: Risk of bias summary....................................................................................6
Appendix S4: Comparisons of the efficacy (responder rate) and acceptability (dropout
rate) of the 16 new antiepileptic drugs and placebo........................................................10
Appendix S5: Treatment ranking and surface under the cumulative ranking curves
(SUCRA) for each primary outcome..................................................................................12
Appendix S1. Suggested range of average target dose of antiepileptic drugs

Drug Suggested range of average target dose (mg/day)

Brivaracetam 100-200
Carisbamate 300-1200
Eslicarbazepine acetate 800-1200
Ezogabine/retigabine 400-1200
Gabapentin 900-3600
Lacosamide 400-600
Lamotrigine 100-400
Levetiracetam 1000-3000
Oxcarbazepine 800-2400
Perampanel 4-12
Pregabalin 150-600
Remacemide hydrochloride 800-1200
Rufinamide 800-3200
Topiramate 100-400
Vigabatrin 500-3000
Zonisamide 200-600

Revised. Refer to BMJ. 2014;348:g254

Appendix S2: Characteristics in RCTs of Included Studies
 Mean Seizure
No. of No. of Dose Age in
Multi/ Size Conflict Age No. of frequenc Length of No. of
Recruitin Trial Diagnos Patient concomit Seizure arms Treatme Sponsor (min- % years,
Study Year Single (%Femal of Funds range previous y trial randomis
g area design e criteria status ant type included nt ed max, Female mean
centre e) interest (year) failed (monthly (weeks) ed
AEDs in NMA daily) (SD)
AEDs )
double- Gabapen
blinded,p tin * 12 1200 mg 52 * *
272 Focal (GBP)
Anhut 1994 America Multi lacebo- NA * 1981 * 12~67 ＞1 1~2 ＞10 2
(44.2) Seizure
controlle
d Placebo * 12 * 109 * *
double- 38.1
blinded,p Placebo * 12 * 96 43.7
multinati 287 Focal (12.4)
Arroyo 2004 Multi lacebo- NA * 1981 * 17~73 ＞1 1~3 ＞19 2
onal (49.5) Seizure Pregabal 36.4
controlle * 12 600 mg 92 48.9
d in (PGB) (10.5)
Pregabal 300~600 39.8(11.
double- * 17 152 48.7
in (PGB) mg 2)
blinded,p
multinati 433 Pfizer Focal 39.1(11.
Baulac 2010 Multi lacebo- Yes 2010 * 16~82 ≥3 1~3 ≥4 3 Placebo * 17 * 141 60.7
onal (51.5) Inc. Seizure 2)
controlle Lamotra
d 300~400 39.4(11.
gine * 17 141 45.4
mg 4)
double- (LTG)
Levetirac
1000~30
Ben- blinded,p etam * 12 181 52 37 (12)
Focal 00 mg
Menache 2000 Europe Multi lacebo- 286 (52) NA * 1981 * 16~70 ≥1 2~5 ＞6 2 (LEV)
Seizure
m controlle Placebo * 12 * 105 51 36 (12)
d
OSCIEN 38.9
double- CES, Placebo * 12 * 97 52
( 11.11)
Ben- blinded,p Inc.,
multinati 418 Focal SCHWA
Menache 2007 Multi lacebo- NA Researc 1981 * 18~68 ≥2 1~2 ≥4 2 Lacosam
onal (54.3) Seizure RZBIOS 39.4
m controlle h ide 12 600 mg 106 58
d Triangle CIENCE ( 10.53)
(LCM)
Park, S, Inc
36.7
double- Placebo * 14 * 100 48
(12.2)
Ben- blinded,p
multinati Focal Eslicarb
Menache 2010 Multi lacebo- 393 (51) NA * 1981 * 18~69 ＞1 1~4 ＞14 2 BIAL—
onal Seizure azepine 36.9
m controlle Portela & 14 1200 mg 97 46.9
d acetate (11.6)
Co., SA
(ESL)
blinded,c Lamotra
rossover Focal gine * 12 300 mg 20 * *
Beran 1998 Australia Multi 41 (48.8) NA * 1981 * 17~63 ＞1 1~3 ＞28 2
(LTG)
,placebo- Seizure
controlle Placebo * 12 300 mg 21 * *
double- 39.6
blinded,p Placebo * 12 * 98 49
America, Focal (11.8)
Beydoun 2005 Multi lacebo- 312 (50) NA * 1981 * 17~82 ＞1 1~4 ＞20 2
Canada Seizure Pregabal 39.1
controlle * 12 600 mg 111 48.6
d in (PGB) (12.0)
double- Rufinami
36.4
blinded,p de * 12 1600 mg 176 52.3
America, 356 Focal (14.77)
Biton 2011 * lacebo- NA Eisai Inc. 1981 inpatient 12~77 ＞1 1~3 ≥3 2 (RUF)
Canada (53.1) Seizure 38.1
controlle Placebo * 12 * 181 53.9
d (14.84)
double- Brivarac
UCB 38.9
blinded,p etam 12 50 mg 101 49.5
multinati 396 UCB Focal Pharma (12.3)
Biton 2014 Multi lacebo- NA 1981 * 16~70 ＞1 1~5 ＞8 2 (BRV)
onal (50.8） Pharma Seizure 37.5
controlle Placebo * 12 * 98 56.1
d (12.6)
double- Zonisami
blinded,p * 12 400 mg 73 41 35 (11)
Focal de (ZNS)
Brodie 2004 UK * lacebo- 144 NA * 1981 * 18~59 ≥1 1~5 ＞4 2
Seizure
controlle Placebo * 12 * 71 41 34 (12)
double-
d
blinded,p Placebo * 24 * 120 43.3 36.5
multinati Focal
Brodie 2005 Multi 349(49) NA * 1981 * 12~77 ≥1 1~4 ＞8 2
onal Seizure
 Johnson
& Mean Seizure
No. of No. of Dose Age in
Multi/ Size Conflict Johnson Age No. of frequenc Length of No. of
Recruitin Trial Pharmac Diagnos Patient concomit Seizure arms Treatme Sponsor (min- % years,
Study Year Single (%Femal of Funds range previous y trial randomis
g area design
double- eutical e criteria status ant type included nt ed max, Female mean
centre e) interest (year) failed (monthly (weeks) ed
blind, Researc AEDs in NMA Carisba daily) (SD)
AEDs )
20 parallel,
double- h& Focal mate * 14 1200 mg 182 49 37 (12.5)
Halford 2011 Multi 547 Yes 1981 * ≥16 ≥1 1~3 4~100 2
countries placebo-
blind, Develop Seizure (CRS)
Placebo
Topiram * 14 * 185 52 37 (12.2)
controlle ment, 12~30
Kälviäine parallel, 17.7~71. Focal ate * 22 77 44 36.4
1998 UK Multi d 154 * *
L.L.C., 1981 * 1~15 1~3 ≥3 2 mg
n placebo- 3 Seizure (TPM)
Placebo * 22 * 77 39 36
controlle Raritan,
double- New 39.8
d Placebo * 12 * 263 47
blind, Jersey, (12.5)
multinati parallel, UCB
U.S.A. Focal
Klein 2015 Multi 768 Yes 1981 * 16~80 1~5 1~3 ≥4 2
onal placebo- Pharma Seizure Brivarac
controlle 39.8
etam * 12 200 mg 251 60
d (12.8)
(BRV)
Topiram
double- 50~600 29.6
Korean ate * 18 91 48
blind, mg (7.8)
Topiram (TPM)
parallel, Focal
ate 1999 Korea Single 177 (46) * * 1981 * 16~65 1~2 * ≥2 2
placebo- Seizure
Study 29.8
controlle Placebo * 18 * 86 44
Group (8.7)
d
double-
blind, 33.4
Placebo * 19 * 185 49
multinati parallel, Focal (12.6)
Krauss 2012a Multi 712 (50) * Eisai Inc. 1981 * ≥12 ≥2 1~3 ＞5 2 Perampa
onal placebo- Seizure 34.6
controlle nel * 19 8 mg 169 54
double- (12.8)
d (PER)
blind, 38.1
Placebo * 12 * 51 55
multinati parallel, Focal (11.6)
Krauss 2012b1 Multi 153 Yes Eisai Inc. 2010 * 18~70 ≥3 1~3 ≥4 2 Perampa
onal placebo- Seizure 42.5
controlle nel * 12 1~4 mg 51 57
double- (12.1)
d (PER)
Perampa
blind, 40.7
nel * 16 2~12 mg 38 53
multinati parallel, Focal (12.0)
Krauss 2012b2 Multi 48 Yes Eisai Inc. 2010 * 18~70 ≥3 1~3 ＞3 2 (PER)
onal placebo- Seizure 45.5
controlle Placebo * 16 * 10 50
double- (12.1)
d Pregabal 150~600 33.3
blind, * 12 119 56
parallel, Pfizer Focal in (PGB) mg (9.7)
Lee 2009 Korea Multi 178 (92) NA 1981 * ≥18 ≥1 1~4 * 2
placebo- Inc. Seizure 35.1
controlle Placebo * 12 * 59 42
(8.8)
d
Retigabi
double- ne/ezoga
blind, bine * 16 900 mg 24 42 35
multinati parallel, GlaxoS Focal (RTG/EZ
Lim 2016 Multi 75 (40) yes 2010 * 18~70 ≥2 ≥1 ≥2 2
onal placebo- mithKline Seizure G)
controlle
d Placebo * 16 * 25 40 31
Gabapen
900~360
double- tin * 24 50 55 34.5
Lindberg multinati Focal 0 mg
2000 Multi blind, 102 (50) * * 1981 * 12~75 1~2 * ≥2 2 (GBP)
er onal Seizure Vigabatri 1000~40
parallel * 24 52 56 33
n (VGB) 00 mg
Eisai Co.
Ltd,
Tokyo,
Zonisami Japan 100~400 36.83
16 53 45
de (ZNS) Shenzhe mg (10.77)
double- n Zifu
blind, Co. Ltd,
parallel, 104 Focal China
Lu 2011 China Single NA NA 1981 * 18~70 1~2 1~2 ≥1 2 Eisai Co.
placebo- (41.3) Seizure
controlle Ltd,
d Tokyo,
Japan 29.81
Placebo 16 * 51 37
Shenzhe (8.24)
n Zifu
Co. Ltd,
double- GlaxoS China
Lamotra
blind, mithKline GlaxoS 25~500 35.8
gine 19 116 53
multinati parallel, Researc Focal mithKline mg (12.7)
Naritoku 2007 Multi 243 * 1981 * ＞12 1~2 * ≥4 2 (LTG) GlaxoS
onal placebo- h and Seizure 37.5
Placebo mithKline 19 * 120 47
controlle Develop (14.4)
,
UCB,
d ment
Levetirac Inc. and
33.97
etam UCB 12 1000 mg 79 34.2
(13.41)
(LEV) Pharma,
SA
Appendix S3: Risk of bias summary

Risk of bias assessments were followed according to the recommended approach for
assessing risk of bias in studies included in Cochrane reviews 1. Specific bias domains have
been addressed in this tool including methods for generating the random sequence, allocation
concealment, blinding of participants and investigators, blinding of outcome assessment,
incompleteness of outcome data, selective outcome reporting. The adjudication for the risk of
bias for each item within each study is done by answering pre-specified questions about the
methods reported by each study in relation to the risk domain. The conclusion of risk of bias
for each item is classified to either low risk of bias, unclear risk of bias or high risk of bias. In
overall, the study is at risk of bias from selective reporting domain when the data for seizure
frequency or drop out number were not reported.

Blinding of
Random Blinding of
Allocation participants Selective
sequence outcome Incomplete
concealmen and reporting
NO. Study Year generation assessment outcome data Other bias
t (selection personnel (reporting
(selection (detection (attrition bias)
bias) (performanc bias)
bias) bias)
e bias)

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Low risk of Low risk of
1 Anhut 1994
bias bias bias bias of bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
2 Arroyo 2004
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
3 Baulac 2010
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Low risk of Low risk of
4 Ben-Menachem 2000
bias bias bias bias of bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
5 Ben-Menachem 2007
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
6 Ben-Menachem 2010
bias bias bias bias bias bias bias

Unclear risk of Unclear risk Unclear risk Low risk of Unclear risk Unclear risk Low risk of
7 Beran 1998
bias of bias of bias bias of bias of bias bias

Unclear risk of Unclear risk Low risk of Low risk of Low risk of Low risk of Low risk of
8 Beydoun 2005
bias of bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Unclear risk Low risk of
9 Biton 2011
bias bias bias bias bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
10 Biton 2014
bias bias bias bias bias bias bias
 Unclear risk of Low risk of Unclear risk Low risk of Unclear risk Low risk of Low risk of
11 Brodie 2004
bias bias of bias bias of bias bias bias

Unclear risk of Unclear risk Unclear risk Low risk of Low risk of Unclear risk Low risk of
12 Brodie 2005
bias of bias of bias bias bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
13 Brodie 2009
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
14 Brodie 2010
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
15 Bruni 2000
bias bias bias bias of bias of bias bias

Low risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
16 Cereghino 2000
bias bias bias bias of bias of bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
17 Chadwick 2002
bias bias bias bias of bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
18 Chung 2010
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
19 Cramer 2000
bias bias bias bias of bias of bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
20 Elger 2007
bias bias bias bias of bias of bias bias

Low risk of Low risk of Low risk of Low risk of Unclear risk Unclear risk Low risk of
21 Elger 2009
bias bias bias bias of bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
22 Elger 2010
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
23 Faught 1996
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
24 Faught 2008
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
25 French 2003
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
26 French 2011
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
27 French 2012
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
28 French 2013
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
29 French 2014
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
30 Gil-Nagel 2009
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
31 Halász 2009
bias bias bias bias bias bias bias
 Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
32 Halford 2011
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
33 Kälviäinen 1998
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Unclear risk Low risk of Low risk of
34 Klein 2015
bias bias bias bias of bias bias bias

Korean Topiramate Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
35 1999
Study Group bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
36 Krauss 2012a
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
37 Krauss 2012b1
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
38 Krauss 2012b2
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
39 Lee 2009
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
40 Lim 2016
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
41 Lindberger 2000
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
42 Lu 2011
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
43 Naritoku 2007
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
44 Peltola 2009
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
45 Porter 2007
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
46 Ryvlin 2014
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
47 Sackellares 2004
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Unclear risk Low risk of
48 Schmidt 1993
bias bias bias bias bias of bias bias

Unclear risk of Unclear risk Unclear risk Unclear risk Low risk of Unclear risk Low risk of
49 Sethi 2002
bias of bias of bias of bias bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
50 Shorvon 2000
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Unclear risk Low risk of
51 Sivenius 1991
bias bias bias bias bias of bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
52 Sperling 2010a
bias bias bias bias bias bias bias
 Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
53 Sperling 2010b
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
54 Sperling 2015
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
55 Tsai 2006
bias bias bias bias bias bias bias

UK Gabapentin Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
56 1990
Study Group bias bias bias bias bias bias bias

US Gabapentin Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
57 1993
Study Group bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
58 Wu 2009
bias bias bias bias bias bias bias

Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
59 Xiao 2009
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
60 Yamauchi 2006
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
61 Yen 2000
bias bias bias bias bias bias bias

Unclear risk of Low risk of Low risk of Low risk of Low risk of Low risk of Low risk of
62 Zaccara 2014
bias bias bias bias bias bias bias

Reference
1. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for
assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
Appendix S4: Comparisons of the efficacy (responder rate) and acceptability (dropout rate) of the 16 new antiepileptic drugs and

placebo.

Comparisons of the efficacy (responder rate, bottom left, green cells) and acceptability (dropout rate, upright, orange cells) of the 16 new antiepileptic drugs
and placebo. The drugs are reported in alphabetical order. The results are the ORs (95% CrIs) in the column-defined treatment compared with the row-
defined treatment. For efficacy, ORs higher than 1 favor column-defined treatment. For acceptability, ORs lower than 1 favor row-defined treatment. The
results are statistically significant when the 95% credible intervals (95% CrIs) for the OR do not cross 1; significant results are in bold text. To obtain ORs for
comparison in the opposite direction, reciprocals should be taken. *Significant results. ORs indicate odds ratios; CrIs, credible interval; BRV, brivaracetam;
CRS, carisbamate; ESL, eslicarbazepine acetate; EZG/RTG, ezogabine/retigabine; GBP, gabapentin; LCM, lacosamide; LTG, lamotrigine; LEV, levetiracetam;
OXC, oxcarbazepine; PER, perampanel; PGB, pregabalin; RMC, remacemide hydrochloride; RUF, rufinamide; TPM, topiramate; VGB, vigabatrin; ZNS,
zonisamide.
Appendix S5: Treatment ranking and surface under the cumulative ranking curves (SUCRA) for each primary outcome

Appendix 5.1 Response rate—Treatment ranking graph

Appendix 5.2 Response rate—SUCRA
Appendix 5.3 Seizure-free rate—Treatment ranking graph
Appendix 5.4 Seizure-free rate—SUCRA
Appendix 5.5 Dropout rate—Treatment ranking graph
Appendix 5.6 Dropout rate—SUCRA