CLINICAL THERAPEUTICSWOL. 22, NO.

12,200O

Comparison of the Clinical Efficacy and Comfort of

Olopatadine Hydrochloride 0.1% Ophthalmic Solution
and Nedocromil Sodium 2% Ophthalmic Solution in the
Human Conjunctival Allergen Challenge Model

Salim Butrus, MD,’ Jack K Greiner, OD, DO, PhD,2

Marino Discepola, MD,j and Ira Finegold, MD, MS4
‘Washington Hospital Centev, George Washington University, and Department of
Ophthalmology, Georgetown University School of Medicine, Washington, DC, 2Schepens
Eye Research Institute, and Department of Ophthalmology, Harvard Medical School,
Boston, Massachusetts, 3Department of Ophthalmology, McGill Medical School, McGill
University, Montreal, Quebec, Canada, and 4Division of Allergy and Immunology, Beth
Israel Medical Centel; New York, New York

ABSTRACT

Background: Mast cell stabilizers, such as the ocular antiallergic agent nedocromil
sodium 2% ophthalmic solution, are not rapid acting and often require a loading period
of 22 weeks for maximal efficacy. Olopatadine hydrochloride 0.1% ophthalmic solution
is a member of a new class of topical antiallergic agents that have combined antihista-
minic and mast cell-stabilizing properties.
Objective: The purpose of this study was to compare the clinical efficacy and comfort
of olopatadine with those of nedocromil in the conjunctival allergen challenge model.
Methods: This was a single-center, 3-visit, randomized, double-masked, contralaterally
controlled study. Seventy-five subjects with a history of allergic conjunctivitis were
screened, and the 52 who responded to conjunctival allergen challenge at visits 1 and 2
were randomized by eye to receive olopatadine, nedocromil, or placebo (a “natural tears”
lubricant eye drop). Because nedocromil may require a 2-week loading period for maxi-
mal efficacy, the eyes assigned to that agent received nedocromil for 14 days (between
visits 2 and 3), whereas the eyes assigned to olopatadine or placebo received placebo dur-
ing this period. Throughout the loading phase, subjects instilled 1 drop of the assigned
masked medication in each eye twice daily. At the assessment visit (visit 3), subjects re-
ceived 1 drop of masked olopatadine, nedocromil, or placebo in each eye and were asked
to rate the comfort of each drop on a scale from 0 to 8. Fifteen minutes after instillation
of medication, subjects were challenged with the allergen concentration that had elicited

Accepted for publication October 5, 2000.

Printed in the USA. Reproduction in whole or part is not permitted.

1462 0149.2918/00/$19.00
S. BUTRUS ET AL.
a positive conjunctival allergic response
at the previous visits. Subjects then scored
their itching on a scale from 0 to 4 at 3,
5, and 10 minutes after challenge. Mean
itching scores for all eyes were compared
by treatment. Paired t tests were per-
formed on the mean itching and ocular
comfort scores at each time point. At the
end of the study, subjects were asked
which treatment they preferred in terms
of comfort and efficacy.
Results: Forty-nine subjects completed
the study. Forty eyes received olopatadine,
36 received nedocromil, and 22 received
placebo. Olopatadine was clinically and
statistically superior to nedocromil at re-
ducing itching in the conjunctival allergen
challenge model (mean unit difference:
-1.60 at 3 minutes, -1.68 at 5 minutes,
-1.19 at 10 minutes; P < 0.001). One drop
of olopatadine was more efficacious than
29 drops of nedocromil. Olopatadine-
treated eyes were rated as being signifi-
cantly more comfortable than nedocromil-
treated eyes (0.73 vs 1.55; P = 0.034). Of
the 14 subjects treated with olopatadine
and nedocromil who stated a preference,
10 (7 1%) were more satisfied with olopata-
dine than with nedocromil.
Conclusion: In the conjunctival aller-
gen challenge model, olopatadine was
more efficacious and comfortable than ne-
docromil in reducing the itching associ-
ated with allergic conjunctivitis.
Key words: olopatadine, nedocromil,
conjunctival allergen challenge, ocular al-
lergy. (Clin Ther: 2000;22: 1462-1472)
INTRODUCTION
Seasonal allergic conjunctivitis affects
20% of the world’s population, ’ often act-
ing in conjunction with rhinitis. In the
search for better therapies, our under-
standing of ocular allergy and the mecha-
nisms behind it has grown considerably.
The focus is now on the primary role of
histamine and H, receptors,24 on the cen-
tral role of the mast cell536 and its media-
tors (eg, vasoactive amines and cyto-
kines),’ and on the importance of T-helper,
lymphocytes in modulating the entire oc-
ular allergic reaction.* The significance of
histaminase in stabilizing the allergic re-
action has also been claritied.9.‘0
First-generation topical antihistamines
such as pheniramine maleate and antazo-
line phosphate are effective in reducing
itching and redness, the primary symp-
tom and sign, respectively, of allergic
conjunctivitis.“,‘* However, the efficacy
of these agents, although rapid in onset,
is short-lived; they provide relief for -2
hours. ’ ’
Another class of ocular antiallergic
agents, the mast cell stabilizers, act by in-
hibiting the release of allergic mediators
from mast cells through an unknown
mechanism. These agents do not provide
rapid relief of signs and symptoms during
an allergic reaction’” and often require a
loading period of s2 weeks for maximal
efficacy. I4 Nedocromil sodium 2%* is a
mast cell stabilizer approved in 1999 by
the US Food and Drug Administration
(FDA) for the treatment of itching associ-
ated with allergic conjunctivitis. Its rec-
ommended dosage is 1 or 2 drops twice
daily.‘” Unlike topical antihistamines,
which are used as needed, nedocromil is
continued throughout the allergy season,
even when symptoms are absent.
A new class of topical antiallergic agents
has been developed with combined anti-
histaminic and mast cell-stabilizing prop-
-Trademark: Alocril’” (United States) and Tilavist@
(Canada) (Allergan, Inc, Irvine, California).
1463
 CLINICAL THERAPEUTIC!9

Visit 1 Visit 2
j sti%z
1 Visit 3
I
Nedocromil Nedocromil
28 drops 1 drop

Drug
assessment:
Placebo Olopatadine
Antigen Drop comfort,
Antigen 28 drops 1 drop
determination itching, subject
confirmation satisfaction
and titration
Placebo
1 Drop
+
i 15 minutes
1Cday BID loading dose
J before
challenge

Day 0 Day 7 Day 21

Figure 1. Study design.

erties. Olopatadine hydrochloride 0.1%” is
the first member of this class to be ap-
proved by the FDA. I6 It has the character-
istics of its class, blocking the histamine
H, receptor immediately after instillation
(rapid onset of action) and attenuating the
release of allergic mediators from the mast
cell (prolonged treatment effect).” It has
been shown to reduce all signs and symp-
toms of allergic conjunctivitis, including
itching, redness, chemosis, tearing, and lid
edema.i5,i8 There is also evidence that this
agent may be effective in allergic sinusitis
and rhinitis,i7 presumably by draining from
the conjunctival sac through the lacrimal
drainage system and into the inferior
turbinate.
This study compared the efficacy and
comfort of olopatadine and nedocromil for
the inhibition of ocular itching in the con-
junctival allergen challenge model.i8 Be-
cause nedocromil is indicated for ocular
itching only whereas olopatadine has re-
cently received an expanded indication for
‘“Trademark: PatanolO (Alcon Laboratories,
Worth, Texas).
all signs and symptoms of allergic con-
junctivitis,i3-i5,i8 this study focused on the
indication shared by the 2 medications.
SUBJECTS AND METHODS
This was a single-center, randomized,
double-masked, contralaterally controlled
allergen challenge study. The randomiza-
tion of study medications for assessment
of the efficacy of the active agents was
performed according to FDA guidelines.19
The protocol was reviewed and approved
by the Western Institutional Review Board,
and written informed consent was obtained
from all subjects. The study consisted of 3
visits, as detailed in the following sections
and illustrated in Figure 1.
Visit I: Baseline Screening visit
At visit 1, medical and medication histo-
ries and demographic data were recorded
(Table I). Visual acuity was measured. A
baseline slit-lamp examination was per-
Inc. Fort formed to rule out any ocular-surface anom-
aly that would interfere with study assess-

1464
S. BUTRUS ET AL.

Table I. Subjects’ demographic characteristics.

Olopatadine Nedocromil Placebo

(n = 20) (n = 18) (n= 11)

Sex, no. (%)

Female 12 (60) 11 (61) 8 (76)
Male 8 (40) 7 (39) 3 (24)
Age (y), mean 44.2 42.0 47.5
Race, no. (%)*
White 19 (98) 18 (100) IO (96)
Black 1 (2) 0 (0) I (4)
No. of eyes 40 36 22
Iris color, no. (%)I
Blue 16 (40) I8 (50) 8 (36)
Brown I5 (38) 7 (19) 8 (36)
Hazel 5 (13) 6 (17) 5 (23)
4 (IO) 5 (14) 1 (5)

*In the olapatadine group, white subjects accounted for 39 eyes and black subjects for I eye; in the placebo
group, white subjects accounted for 21 eyes and black subjects for I eye.
+Percentages may exceed 100 due to rounding error.

ments. A urine pregnancy test (Contrast@ ical antiallergic medication (pheniramine

human chorionic gonadotropin, Genzyme,
San Carlos, California) was given to all
women of childbearing potential.
Bilateral conjunctival allergen chal-
lengel was performed with cat dander/
hair, ragweed, or dust mites in phosphate-
buffered saline. The allergen used for con-
junctival challenge was chosen based on
the results of skin testing. One 25-PL drop
of allergen solution at the lowest concen-
tration was instilled into the inferior cul-
de-sac of each eye. After 10 minutes, if
the reaction was not sufficient (defined as
itching graded a2 in both eyes), the aller-
gen concentration was increased every 10
minutes until an adequate reaction oc-
curred. Ocular itching was graded using a
standardized scale from 0 (no itching) to 4
(severe itching). I8 Subjects who did not
react were excluded from the study. If nec-
essary, 1 drop of a currently marketed top-
maleate 0.3%/naphazoline hydrochloride
0.025% ophthalmic solution) was admin-
istered at the end of the visit to relieve any
immediate discomfort caused by the aller-
gic reaction. No data were collected on
how many subjects used relief drops.
Visit 2: Confirmatory Visit
At visit 2, medical and medication his-
tories were updated and visual acuity
measured. A slit-lamp examination was
performed. One drop of allergen solution
at the concentration that had elicited a
positive conjunctival allergic response at
visit 1 was instilled bilaterally. Subjects
were asked to grade their ocular itching
3, 5, and 10 minutes after challenge on
the 5-point itching scale.‘*
All subjects who reacted positively
(itching graded ~2 in both eyes) were

1465

randomized by eye to receive 1 of 3
masked study medications: olopatadine,
nedocromil, or placebo (a “natural tears”
lubricant eye drop). Subjects were dis-
pensed 2 bottles labeled “right eye” and
“left eye” and were instructed to instill 1
drop from the right-eye bottle into the
right eye and 1 drop from the left-eye
bottle into the left eye twice a day for the
next 14 days.
This 14-day period was incorporated
into the study design to ensure that the
eyes assigned to nedocromil would re-
ceive a loading dose and the active med-
ications would have an equal opportunity
to demonstrate maximal efficacy. During
this loading phase, the eyes assigned to
olopatadine or placebo received 2 weeks
of placebo. If necessary, 1 drop of a cur-
rently marketed topical antiallergy med-
ication could be administered bilaterally
at the end of the visit to relieve any im-
mediate discomfort. No data were col-
lected on how many subjects used relief
drops.
?+sit 3: Eflcacy and Comfort
Assessment
At visit 3, medical and medication his-
tories were updated and visual acuity mea-
sured. A slit-lamp examination was per-
formed. Subjects were administered
drop of masked study medication from
the right-eye bottle into the right eye and
1 drop from the left-eye bottle into the
left eye. Immediately after instillation of
medication, subjects were asked to till out
an eye drop comfort assessment for each
eye on a scale from 0 to 8 (from greater
to lesser comfort). Fifteen minutes after
instillation of medication, subjects were
challenged bilaterally with 1 drop of al-
lergen solution at the concentration that
1466
CLINICAL THERAPEUTICSa
had elicited a positive response at visits 1
and 2.
Subjects were asked to grade their oc-
ular itching 3, 5, and 10 minutes after al-
lergen challenge. After all itching assess-
ments were completed, each subject was
asked which treated eye was more satis-
factory in terms of efficacy and overall
comfort. If necessary, 1 drop of a cur-
rently marketed topical antiallergy med-
ication was administered bilaterally at the
end of the visit to relieve any immediate
discomfort. No data were collected on
how many subjects used relief drops.
Statistical Analysis
Data from all subjects who completed
the study were included in the comfort
and efficacy analyses. Mean itching scores
at visit 3 were compared between treat-
ments. Also compared between treatments
were mean ocular comfort scores at visit
3 immediately after instillation of drops.
Paired t tests were performed on the mean
itching and ocular comfort score compar-
isons at each time point. Two-sided statis-
tical tests were used, with statistical sig-
nificance set at P < 0.05.
RESULTS
1
Patient Disposition
Seventy-five subjects were screened, 52
subjects were enrolled, and 49 subjects com-
pleted the study. The treatment assignments
of these 49 were as follows: 8 received
olopatadine-placebo, 6 nedocromil-placebo,
9 olopatadine-olopatadine, 8 nedocromil-
nedocromil, 4 placebo-placebo, and 14
olopatadine-nedocromiil. Thus, total treated
eyes were as follows: 40 olopatadine, 36 ne-
docromil, and 22 placebo. There were no
S. BUTRUS ET AL.
significant between-group differences in
sex, age, race, or iris color (Table I).
Three subjects were discontinued from
the study because they did not return for
visit 3. One of these subjects had been
randomized to olopatadine-nedocromil,
and the other 2 had been randomized to
placebo-placebo.
Two adverse events were reported in
the course of the study. One subject re-
ported a sprained left thigh at visit 3. An-
other subject, who had been randomized
to nedocromil-nedocromil, reported a
stinging sensation in the right eye after in-
stillation of study medication.
Efficacy Assessment
Table II summarizes the mean difference
scores between treatments. Figure 2 shows
mean itching scores for the treated eyes
during the confirmatory (visit 2) and as-
sessment (visit 3) visits. No significant
between-group differences were observed
at the confirmatory visit. At the assessment
visit, olopatadine produced superior relief
from itching at all time points compared
with nedocromil and placebo, both statisti-
Table II. Mean difference between scores for itching 3, 5, and 10 minutes after conjuncti-
val allergen challenge.
Mean Difference (SD)
Time After Olopatadine
Challenge Versus
(min) Placebo
3 -2.16*+ (0.98)
5 -2.15*+ (1.04)
10 -I .59*+ (1.05)
*P < 0.05 versus placebo.
‘Clinically significant (>I-unit difference in itching) versus placebo.
+Both statistically (P < 0.05) and clinically (>l-unit difference in itching) significant
cally (P < 0.001) and clinically (>l-unit
difference). Olopatadine-treated eyes (n =
40) had itching scores >2 units lower than
eyes receiving placebo (n = 22), a clini-
cally and statistically significant difference
(P < 0.001). In the olopatadine-nedocromil
comparison, olopatadine had itching scores
2 1 unit lower than those of nedocromil; all
differences were clinically and statistically
significant at all time points (P < 0.001).
The comparison between nedocromil-
treated eyes (n = 36) and eyes receiving
placebo (n = 22) exhibited a much smaller
treatment effect than did the olopatadine-
placebo comparison. No clinically signif-
icant differences were observed between
eyes receiving nedocromil and placebo.
However, a statistically significant differ-
ence in favor of nedocromil in relief of
itching was seen at 3 minutes (P = 0.045).
Comfort Assessment
When the comfort level of each eye was
graded immediately after drug instillation,
olopatadine-treated eyes were statistically
significantly more comfortable than those
treated with nedocromil(O.73 vs 1.55; P =
Nedocromil Olopatadine
Versus Versus
Placebo Nedocromil
-0.56* (0.95) -1.601 (0.82)
-0.37 (1 .OO) -1.68$ (0.92)
-0.40 (1.11) -1.19’(1.08)
versus nedocromil.
1467
 CLINICAL THERAPEUTICF

A
+ Placebo
A n Nedocromil

1
3.5 Olopatadine

3.0-

a, 2.5-

$
(o 2.0-
P
E
g 1.5-
C
z
= l.O-

3 5 10
Time After Challenge (min)

3.0-
4

2 25- *
8 .

g 2.0-
.$

2 1.5-

:
= l.O-
t t
t .
,
0.5-

0 I I I
3 5 10
Time After Challenge (min)

Figure 2. Mean itching scores (Spoint scale, from 0 = no itching to 4 = severe itching)
for eyes treated with olopatadine compared with those receiving nedocromil or
placebo at 3, 5, and 10 minutes after conjunctival allergen challenge at (A) the
confirmatory visit (visit 2) and (B) the assessment visit (visit 3). At visit 3, al-
lergen challenge was conducted 15 minutes after drug instillation. *P < 0.045
versus olopatadine; +P < 0.001 versus nedocromil and placebo.

1468
S. BUTRUS ET AL.

4.0,

3.5-

$ 3.0-
”
z 2.5- *
P
E 2.0-
6
c 1.5-
:
2 l.O-

0.5-

0 ,
Olopatadine Nedocromil Placebo

Figure 3. Mean comfort scores (S-point scale, from 0 = more comfort to 8 = less comfort)
immediately after instillation of olopatadine, nedocromil, or placebo. *P = 0.034
versus nedocromil.

0.034). Olopatadine-treated eyes were as of olopatadine was more effective than

comfortable as eyes receiving placebo nedocromil given twice daily over a 14-
(Figure 3). This assessment was performed day loading period for the relief of itch-
before allergen challenge. ing, nedocromil’s only approved indica-
tion. These results support previous
research demonstrating the superior eff-
Overall Satisfaction
cacy of olopatadine.‘7+‘8~2~23
At the end of the study, after the break- Olopatadine is a potent selective Hi-
ing of the randomization code, only data receptor antagonist. The inhibition con-
from the 14 subjects who had received stant for the Hi-binding affinity of
olopatadine in 1 eye and nedocromil in olopatadine is 36 nmol/L,24 and its me-
the other were included in the assess- dian effective dose for the prevention of
ment of overall satisfaction (both com- histamine-induced vascular permeability
fort and efficacy) with the 2 treatments. in the conjunctiva of guinea pigs has
Ten of the 14 subjects (71%) preferred been shown to be 0.002%.25 In addition
olopatadine for overall efficacy and com- to its antihistaminic properties, olopata-
fort, and the remaining 4 (29%) had no dine inhibits the release of histamine and
preference. other allergic mediators from the con-
junctival mast cell, a result of its mast
cell-stabilizing properties.26,27 A study
DISCUSSION
in human conjunctival mast cells demon-
In the conjunctival allergen challenge strated that olopatadine produced greater
model, olopatadine was clinically and sta- inhibition of histamine release after im-
tistically superior to both nedocromil and munologic challenge than did the mast
placebo in inhibiting the itching associ- cell stabilizers cromolyn, nedocromil,
ated with allergic conjunctivitis. One drop and pemirolast.28

1469

In contrast, nedocromil’s exact mecha-
nism of action is not known. It has been
hypothesized that the drug stabilizes the
membranes of mast cells, preventing de-
granulation. Nedocromil was originally
used as a mast cell stabilizer in the treat-
ment of respiratory conditions such as
asthma. There are 2 types of mast cells in
the human body, those containing the en-
zymes tryptase and chymase, and those
containing only tryptase. The latter are
present in lung and upper respiratory tract
tissue, whereas the former are found in the
conjunctiva and skin. There is evidence
that mast cell stabilizers such as nedocromil
are more effective in stabilizing mast cells
containing tryptase and chymase than those
containing only tryptase.28,2g
When used to treat upper respiratory
conditions, nedocromil can require a ~2-
week loading period to show efficacy.30,31
A loading period may also be necessary
before clinically relevant results are seen
in the treatment of itching associated with
allergic conjunctivitis.
Olopatadine was found to be associated
with greater comfort than nedocromil in
this study. This is of clinical relevance,
because there is a link between drop com-
fort and compliance.32 With nedocromil,
which requires dosing throughout the al-
lergy season to maintain efficacy, compli-
ance is crucial.
CONCLUSIONS
Olopatadine was more efficacious and
comfortable than nedocromil in relieving
the itching associated with allergic con-
junctivitis. Subjects expressed greater
overall satisfaction with olopatadine. Cli-
nicians should consider these results when
choosing an antiallergic medication for
patients with allergic conjunctivitis.
1470
CLINICAL THERAPEUTICS’
ACKNOWLEDGMENT
This paper was supported by an unre-
stricted grant from Alcon Laboratories,
Inc, Fort Worth, Texas. Dr. Greiner was
compensated for his role as principal
investigator.
Address correspondence to: Salim
Butrus, MD, 650 Pennsylvania Avenue
SE, Washington, DC 20003.
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