Litegrast Ophthalmic Solution 5.

0% for
Treatment of Dry Eye Disease
Results of the OPUS-1 Phase 3 Study
John D. Sheppard, MD, MMSc,1 Gail L. Torkildsen, MD,2 John D. Lonsdale, MD,3
Francis A. DAmbrosio, Jr., MD,4 Eugene B. McLaurin, MD,5 Richard A. Eiferman, MD,6
Kathryn S. Kennedy, PhD, MSE,7 Charles P. Semba, MD,8 for the OPUS-1 Study Group*
Purpose: To assess the efcacy and safety of litegrast ophthalmic solution 5.0% compared with placebo in
subjects with dry eye disease.
Design: Prospective, randomized, double-masked, placebo-controlled, parallel arm, multicenter clinical trial.
Participants: A total of 588 adult subjects with dry eye disease.
Methods: Eligible subjects were randomized 1:1 to receive topically administered litegrast (5.0%) or
placebo (vehicle) twice daily for 84 days after a 14-day open-label placebo run-in period. After enrollment (day 0),
subjects were evaluated at days 14, 42, and 84. Key objective (uorescein and lissamine staining scores
[Ora scales]) and subjective (Ocular Surface Disease Index [OSDI], 7-item visual analog scale, and ocular
discomfort score [Ora scale]) measures were assessed at all visits.
Main Outcome Measures: The primary objective efcacy measure (sign) was mean change from baseline
inferior corneal staining score (ICSS) at day 84. The co-primary subjective efcacy measure (symptom) was the
mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index (VROSDI). Supportive measures included corneal uorescein scores (superior, central, total region) and conjunctival
lissamine scores (nasal, temporal, total region) and symptom scores at day 84.
Results: The study met the primary objective efcacy ICSS end point in demonstrating superiority of litegrast compared with placebo (P 0.0007). Litegrast signicantly reduced corneal uorescein staining (superior,
P 0.0392; total cornea, P 0.0148) and conjunctival lissamine staining (nasal, P 0.0039; total conjunctiva,
P 0.0086) at day 84 versus placebo. Signicant (P < 0.05) improvements in nasal and total lissamine scores
were observed at day 14 and maintained through day 84. The study did not meet the co-primary subjective VROSDI measure (P 0.7894). However, signicant improvements were observed at day 84 in ocular discomfort
(P 0.0273) and eye dryness (P 0.0291), the most common and severe symptoms reported at baseline in both
groups. There were no unanticipated or serious ocular adverse events (AEs). The most frequent reported ocular
AEs were transient intermittent instillation site symptoms (irritation, discomfort) primarily on the initial litegrast
dose at day 0.
Conclusions: Litegrast ophthalmic solution 5.0% signicantly reduced corneal uorescein and conjunctival
lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when
administered twice daily over 84 days. Ophthalmology 2014;121:475-483 2014 by the American Academy of
Ophthalmology.
*Group members listed online in Appendix 1 (available at http://aaojournal.org).

Dry eye is a complex disorder of the ocular surface characterized by symptoms of discomfort, decreased tear
quality, and chronic inammation affecting an estimated
25 million patients in the United States alone.1,2 Over the
past decade, signicant progress has been made in understanding the inammatory nature of dry eye disease through
advancements in animal models and clinical biomarkers.3,4
Although the cause of dry eye is multifactorial, a common
pathway is the establishment of a proinammatory state
leading to activation of T-cellemediated immune responses,
cytokine release, and hyperosmolar tears.5,6 The resulting
 2014 by the American Academy of Ophthalmology
Published by Elsevier Inc.

inammatory milieu stimulates corneal neural bers resulting in sensations of ocular discomfort and dryness.
Activation and homing of lymphocytes to the ocular
surface are central to the chronic inammatory process and
inuenced by the binding of the T-cell integrin, lymphocyte
function antigen-1 (LFA-1; CD11a/CD18; aLb2), to its
cognate ligand, intercellular adhesion molecule-1 (ICAM-1;
CD54) expressed on the cell surface of inamed epithelium.7
The LFA-1/ICAM-1 binding promotes T-cell activation
(immunologic synapse), adhesion, migration, and cytokine
release.8 Lymphocytic inltrates of CD3 T cells and CD4
ISSN 0161-6420/14/$ - see front matter
http://dx.doi.org/10.1016/j.ophtha.2013.09.015

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Ophthalmology Volume 121, Number 2, February 2014

T-helper cells have been observed in conjunctival and
lacrimal tissue obtained by incisional biopsy in patients
with and without Sjgrens dry eye.9 Increased expression
of ICAM-1 is demonstrated at both the mRNA and protein
levels in conjunctival epithelial/lacrimal acinar cells in
patients with dry eye,10 along with elevated levels of
inammatory T-cellemediated cytokines in the tear lm.11
Litegrast (formerly SAR 1118) is a small molecule
LFA-1 antagonist currently under development in the
United States as a topical therapy for dry eye disease and
represents a rst-in-class integrin anti-inammatory specifically engineered for ophthalmic use.12 Litegrast is an
ICAM-1 decoy and prevents binding of LFA-1 to native
ICAM-1 expressed on the surface of inamed epithelial,
endothelial, and antigen presenting cells. We hypothesize
that inhibition of the LFA-1/ICAM-1 interaction may be an
appropriate pharmacologic target for breaking the constant
cycle of T-cellemediated inammation associated with dry
eye.13 The anti-inammatory effects of LFA-1 inhibition
have been biologically validated in experimental models of
chronic inammation, including uveitis, diabetic retinopathy, and keratoconjunctivitis.14e16
A prior phase 2 study in a population with dry eye
comparing litegrast (0.1%, 1.0%, 5.0%) with placebo
(vehicle) demonstrated statistically signicant dose responses
(P < 0.05) in reduction of corneal uorescein staining and
symptom parameters, including the visual-related function
subscale of the Ocular Surface Disease Index (VR-OSDI
[questions 6e9]) and dose-related trends in reducing
discomfort and dryness when administered twice daily for 84
days (12 weeks).17 The purpose of this study was to conrm
therapeutic clinical responses by conducting a pivotal phase 3
registrational study comparing litegrast ophthalmic solution
5.0% with placebo in a larger population with dry eye.

Methods
Study Design
This was a phase 3 randomized, prospective, double-masked,
placebo-controlled, parallel-arm design study with block enrollment conducted at 13 sites in the United States. All subjects were
informed of risks and benets of study participation, and written
informed consent was obtained before subject enrollment in
compliance with the institutional review board (Alpha Institutional
Review Board, San Clemente, CA). The study was conducted in
accordance with the Health Insurance Portability and Accountability Act of 1996 and the Declaration of Helsinki of 1996, and
registered at ClinicalTrials.gov: NCT 01421498 (http://clinicaltrials.gov, accessed June 4, 2013).
The study was approximately 100 days in duration and consisted of 3 periods: screening (day 14 to 0), treatment (day
0e84), and a follow-up (day 85 or 86) telephone safety interview 1
to 2 days after the last dose of study treatment. A total of 5 study
visits were scheduled: 2 during screening (visits 1 and 2) and 3
during treatment (visits 3, 4, and 5).
The study used methods similar to the previously described
phase 2 study with the exception that the use of a controlled
adverse environment (CAE) was limited only to screening at visits
1 and 2.17 Study investigators consisted of board-certied
ophthalmologists with corneal fellowship training and optometrists. Pre-study preparation included a training meeting for

476

investigators to review study procedures and to train on the use of

standardized grading scales for objective measures of uorescein
and lissamine staining procedures developed by the contract
research organization (Ora, Inc, Andover, MA).

Study Protocol
Screening and Eligibility. At visit 1 (day 14), after written
informed consent, subjects underwent data collection by study
personnel that included demographic data, medical and medication
history, urine pregnancy testing (as appropriate), and initial
inclusion and exclusion criteria evaluation. A summary of scheduled assessments and study visits is provided in Table 1. Inclusion
criteria included adult subjects aged 18 years, established history
of bilateral dry eye disease, use or desire to use articial tear
substitutes within the past 6 months, presence of conjunctival
redness in any eye, corneal uorescein staining score of 2.0
point in any eld (Ora scale [0e4 points; 0 none to 4
conuent]) in any eye, unanesthetized Schirmer tear test (STT;
mm/5 minutes) of 1 and 10 in any eye, and best-corrected
visual acuity of 0.7 logarithm of the minimum angle of resolution (Early Treatment Diabetic Retinopathy Study chart) in both
eyes. Exclusion criteria included known contraindications or
hypersensitivity to the study drug or its components, active ocular
inammation (including active lid margin disease, as evaluated by
the investigator using slit-lamp examination with standard clinical
magnication and illumination with the patient seated), active
ocular infection, any ocular surgery within the past 12 months
including laser-assisted in situ keratomileusis, the need for contact
lens use during the study, and pregnancy. Prohibited medications
during the study included topical cyclosporine (discontinued >6
weeks before visit 1) or use of any other ophthalmic medication
(e.g., glaucoma medication, topical anti-inammatory eye drops)
for the duration of the study. Subjects actively taking articial tears
had to discontinue use 72 hours before visit 1.
If subjects met initial screening requirements, additional
assessments of symptoms and signs were conducted before and
after 90-minute exposure to acute environmental stress using the
CAE (Ora, Inc) model.18 The CAE exacerbates signs and
symptoms of dry eye disease using standardized temperature,
humidity, air-ow, ambient lighting, and visual-tasking. To
enrich the study population, enrolled subjects had to exhibit
evidence of a dynamic response to the CAE as demonstrated by
exacerbation in inferior corneal uorescein staining (Ora scale) and
ocular discomfort score (ODS; Ora scale [0e4 points; 0 none,
4 severe]); those subjects with xed uorescein staining or
ocular discomfort symptoms despite CAE exposure were excluded.
Fluorescein staining was assessed pre-CAE and post-CAE; ODS
was assessed pre-CAE, every 5 minutes intra-CAE, and post-CAE
(Table 1).
The designated study eye had to demonstrate the following
criteria at visits 1 and 2: (1) STT (mm/5 minutes) 1 and 10 (preCAE), (2) 1.0 point increase in inferior corneal staining (postCAE minus pre-CAE value), and (3) ODS 3.0 points at 2
consecutive time points intra-CAE (or ODS 4.0 points at 2
consecutive time points if the subject reported a baseline pre-CAE
score of 3.0 points). If both eyes met these requirements at visit 2,
the worst eye was designated the eligible study eye; if both eyes
were equal, the right eye was considered the eligible study eye.
All subjects having a positive screening response and meeting all
other eligibility criteria after visit 1 (day 14) were initiated on
self-administered open-label placebo (vehicle) twice daily
(morning and evening) for 14 days until visit 2 (day 0). At visit 2,
the sequence of pre-CAE, CAE, and post-CAE assessments were
repeated similar to visit 1. The eligible study eye identied at visit
1 had to meet the same qualication criteria at visit 2. All subjects

Sheppard et al

Litegrast for Dry Eye Disease

Table 1. Schedule of Events in a Phase 3 Study of Litegrast 5.0% versus Placebo for Dry Eye Disease
Visit 1 Day L142

Informed consent
Demographic data/medical history
Inclusion/exclusion criteria
Enrollment and randomization
Subjective measures
ODS
OSDI
VAS
Objective measures
Best-corrected visual acuity
Slit-lamp biomicroscopy
Conjunctival redness score
Corneal staining (uorescein)
Conjunctival staining (lissamine green)
STT (without anesthesia)
Dilated fundoscopy
Study therapy
Study drug administration
Placebo dispensation (open-label)
AE assessment
Study exit*

Visit 2 Day 0

Pree
CAE

PostCAE

X
X
X

X
X

X
X
X

X
X
X
X
X
X
X
X
X

Day L13 Preto L1

CAE

X
X
X
X
X
X

X
X
X
X

Post- Days Visit 3

Days
Visit 4
Days
Visit 5
CAE 1e13 Day 142 15e41 Day 424 43e83 Day 846

X
X
X
X

X
X
X

X
X
X

X
X
X

X
X
X
X
X
X

X
X
X
X
X
X

X
X
X
X
X
X

X
X

X
X

X
X

AE adverse event; CAE controlled adverse environment; ODS ocular discomfort score; OSDI Ocular Surface Disease Index; STT Schirmer tear
test; VAS visual analogue scale.
*Study exit was preceded by a telephone follow-up 1 to 2 days after the last administered dose on visit 5.

meeting the study eligibility criteria were randomized 1:1 to 1 of 2

treatment arms (placebo, 5.0% litegrast) and instructed to instill
1 drop per eye twice daily (morning and evening) for the entire
84-day study treatment period. Subjects were dispensed sufcient
study treatment until the next scheduled study visit. Subjects
returned to the clinical site at day 14 (visit 3), day 42 (visit 4), and
day 84 (visit 5) for scheduled study assessments. A stratication
scheme was used to ensure balance at study baseline on the basis of
use of articial tears within 30 days of the rst screening visit and
severity of inferior corneal staining at study baseline.
Concomitant Medications. No supplemental articial tears or
rescue therapy for the management of dry eye disease were allowed
during the course of the study. Systemically delivered steroids,
immunosuppressants, and immunomodulators were prohibited.
Study Masking. The treating physician, study and site personnel, and subjects were masked to the treatment assignment.
Packaging of study drug and vehicle (placebo) was identical and
contained in low-density polyethylene unit dose vials in numbered
study kits that contained the appropriate supply of assigned study
treatment until the next scheduled study visit. Both study drug and
vehicle were sterile, unpreserved, and colorless aqueous solutions.
Subjects were randomized and assigned study kits with the use of an
Integrated Web Response System. An unmasked independent statistician generated the subject randomization and randomized kit lists.

Outcome Measures
Efcacy. Objective and subjective measures were collected at all
study visits, including screening. Objective assessments included
corneal uorescein score (inferior, superior, central regions) and
conjunctival lissamine staining score (nasal and temporal regions)
and STT. Both uorescein and lissamine scoring used the Ora scale
for each region (0e4 points; 0 none to 4 conuent).

Subjective assessments used 2 types of patient-reported outcome

inventories: (1) spontaneous subject-reported assessments and (2)
recall-based questionnaires. The spontaneous instruments ask
subjects to evaluate symptomatology to specic prompted terms at
the time of the study visit and included a 7-item visual analogue
scale (VAS; 100-point scale; 0 no discomfort, 100 maximal
discomfort; dryness, burning/stinging, photophobia, foreign body
sensation, blurred vision, itching, and pain) and ODS (Ora scale).
The 7-item VAS scores were collected before CAE exposure in the
screening period and at all study visits during treatment. The recallbased inventory was the Ocular Surface Disease Index (OSDI) and
asks subjects to recall various symptom parameters experienced in
the previous week.19 The OSDI consists of 12 questions in 3
subscales (symptoms [questions 1e5], visual-related function
(VR-OSDI [questions 6e9]), and environmental triggers
[questions 10e12]) and was obtained before CAE exposure
during screening and at all treatment study visits. The subscales
were mean composite scores for the included questions (0e4
points; 0 none of the time, 4 all of the time), whereas the
total OSDI score is calculated on a scale of 0 to 100, with larger
scores relating to greater severity.
The primary objective efcacy end point (sign) in the study eye
was the inferior corneal staining score, mean change from
baseline to day 84. The primary subjective end point (efcacy) was
the VR-OSDI subscale score, mean change from baseline to day
84. Supportive objective end points included corneal uorescein
scores (superior, central, total), conjunctival lissamine scores
(nasal, temporal, total), and STT. Supportive subjective end points
included the 7-item VAS, ODS, and total OSDI score.
Safety. Safety assessments and recording of adverse events
(AEs) were conducted at all study visits and included best-corrected
visual acuity, slit-lamp examination, corneal sensitivity, and dilated
fundoscopy. All AEs were classied according to the Medical

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Ophthalmology Volume 121, Number 2, February 2014

Dictionary for Regulatory Activities (MedDRA version 14.1,
MedDRA MSSO, McLean, VA).

Table 2. Subject Disposition and Demographics in a Phase 3

Study of Litegrast 5.0% versus Placebo for Dry Eye Disease

Statistical Methods
The primary efcacy outcome measures were the mean change
from baseline to day 84 (week 12) in the inferior corneal uorescein staining score in the designated study eye and the VR-OSDI
subscale. The primary analyses of the primary end points used
a 2-sample t test comparing litegrast with placebo in the intent-totreat population with last observation carried forward using visit 2
data (pre-CAE; day 0) as the study baseline. P values presented are
the nominal unadjusted values derived from the 2-sided t test
unless otherwise noted. Supportive analyses included Wilcoxon
rank-sum test and analysis of covariance at visit 5. Analyses of
proportions were conducted using the Fisher exact test. A 2-sided t
test with a P value 0.050 was considered statistically signicant.
For the primary ocular sign, on the basis of the results of the
phase 2 study,17 it was reasonable to expect a 0.30 unit difference
in litegrast (5.0%) and placebo in the mean change from baseline
to day 84 in inferior corneal staining, with a common standard
deviation of 0.95 units. For the primary ocular symptom, on the
basis of the results of the phase 2 study, it was reasonable to
expect a 0.30 unit difference in litegrast (5.0%) and placebo in
the mean change from baseline to day 84 in the VR-OSDI, with
a common standard deviation of 0.95 units. Under these assumptions, a sample size of 294 per group would yield approximately
95% power to show a statistical difference at the a 0.050 level
under a 2-sample t test for each end point.

Results
Subject Disposition
The study screened 1016 adult subjects to achieve an enrolled
population of 588 adult subjects (Table 2). The rst subject was
enrolled in September 2011, and the last subject was evaluated
in April 2012. A total of 565 subjects completed the study
(96.1%), and 23 subjects (N 11 and N 12 for placebo and
litegrast, respectively) were withdrawn.

Analysis population, N (%)

Enrolled population
Safety population
Enrolled population who
completed study
Withdrawals, N (%)
AE
Lost to follow-up
Noncompliance
Did not meet
inclusion/exclusion
Pregnancy
Age
Mean yrs (SD)
Range (yrs; min, max)
Gender, N (%)
Male
Female
Race, N (%)
White
Black
Asian
Other
Iris color, N (%)
Blue
Brown
Hazel
Green
Gray
Other
Ocular medical history, N (%)*
Dry eye
Cataract
Active use of articial tears
within 30 days
Pinguecula
Vitreous detachment
Arcus lipoides

Placebo
(N [ 295)

5.0% LIF
(N [ 293)

295 (100%)
295 (100%)
284 (96.3%)

293 (100%)
293 (100%)
281 (95.9%)

3
2
2
3

(1.0%)
(0.7%)
(0.7%)
(1.0%)

10 (3.4%)
0
0
2 (0.7%)

1 (0.3%)

61.1 (11.8)
24e85

60.2 (12.2)
20e91

78 (26.4%)
217 (73.6%)

64 (21.8%)
229 (78.2%)

276
11
2
6

(93.6%)
(3.7%)
(0.7%)
(2.0%)

270
16
3
4

(92.2%)
(5.5%)
(1.0%)
(1.3%)

198
193
141
54
4

(33.6%)
(32.7%)
(23.9%)
(9.2%)
(0.7%)
0

211
226
104
36
2
1

(36.0%)
(38.6%)
(17.7%)
(6.1%)
(0.3%)
(0.2%)

295 (100%)
161 (54.6%)
129 (43.4%)

293 (100%)
147 (50.2%)
128 (43.4%)

58 (19.7%)
71 (24.1%)
35 (11.9%)

60 (20.5%)
42 (14.3%)
29 (9.9%)

Subject Demographics
The demographic characteristics are presented in Table 2. There
was overall balance with regard to age, gender, race, iris color,
and medical history, with no statistically signicant differences
between the demographic variables measured.

Efcacy Analysis
Primary Efcacy. At baseline, the mean values for inferior corneal
staining were 1.84 and 1.82 for litegrast and placebo, respectively, with no statistically signicant difference between groups.
Litegrast demonstrated superiority compared with placebo (P
0.0007) in reduction of inferior corneal staining at day 84 (Fig 1).
Supportive analyses were highly signicant in favor of litegrast
(P 0.0007 Wilcoxon rank-sum, P 0.0004 analysis of covariance). The proportion of subjects demonstrating 1.0-point
reduction in inferior corneal staining score was 22.2% for litegrast (N 65) versus 13.9% for placebo (N 41) (P 0.010
Fisher exact test).
At baseline, the mean values for the VR-OSDI were 0.86 and
0.93 for litegrast and placebo, respectively, with no statistically
signicant difference between groups. The mean change from
baseline to day 84 analysis showed no difference in reduction in
the VR-OSDI comparing litegrast with placebo (P 0.7894).

478

AE adverse event; LIF litegrast; SD standard deviation.

*Reported in 10% of subjects.

Corneal Staining. At baseline, the mean values for the superior

(1.79 placebo, 1.82 litegrast), central (1.22 placebo, 1.18 litegrast), and total corneal staining regions (4.83 placebo, 4.84 litegrast) showed no statistically signicant differences between
groups. Litegrast demonstrated superiority compared with
placebo, mean change from baseline to day 84, in total corneal score
(P 0.0148; sum of the inferior, superior, and central regions) and
superior corneal region (P 0.0392); no statistical signicance was
observed for the central corneal region (P 0.7346) (Fig 1).
Lissamine Staining. At baseline, the mean values for nasal
(1.90 placebo, 2.05 litegrast), temporal (1.68 placebo, 1.71 litegrast), and total conjunctival staining (3.58 placebo, 3.74 litegrast) showed no statistically signicant differences between
groups. Litegrast demonstrated superiority compared with
placebo, mean change from baseline to day 84, in the nasal (P
0.0039) and total lissamine score (P 0.0086); no statistical
signicance was observed for the temporal region (P 0.1066).
The nasal eld demonstrated statistically signicant differences as
early as day 14 (P 0.0032) with benet maintained through day

Sheppard et al

Litegrast for Dry Eye Disease

Figure 1. Corneal uorescein staining score in a study of litegrast compared

with placebo for dry eye disease. Results for the inferior, superior, central, and
total corneal regions (Ora scale) using mean change from baseline to day 84
analysis (*2-sided t test). LIF litegrast; ODS ocular discomfort score;
SE standard error.

84 (Fig 2). Likewise, the total conjunctival region (sum of the nasal
and temporal regions) was signicant at day 14 (P 0.0149) with
duration of benet through day 84 (P 0.0086). The proportion of
subjects demonstrating 1.0-point reduction in nasal lissamine
staining was 24.6% (N 72) for litegrast versus 15.6% for
placebo (N 46) (P 0.0074 Fisher exact test).

Schirmer Tear Test. At baseline, the mean values for STT

(mm/5 minutes) were 4.7 and 4.9 for placebo and litegrast,
respectively, with no statistically signicant difference between
groups. Both treatment groups demonstrated a slight increase
overall at day 84 (6.3 placebo, 6.6 litegrast), but no statistically
signicant differences were observed at any study visit.
Visual Analogue Scale. The mean baseline values for the
treatment and placebo groups are shown in Table 3. No statistically
signicant differences were observed at baseline for any symptom
parameter. Litegrast demonstrated signicant reduction in the
mean eye dryness score at day 42 (P 0.0441) with benet
maintained through day 84 compared with placebo (P 0.0291).
All other symptom parameters demonstrated general improvement;
however, no statistically signicant differences were observed for
burning/stinging, itching, foreign body sensation, blurred vision,
and pain at any follow-up study visit.
Ocular Discomfort Score. At baseline, the mean values for the
ODS were 1.8 and 1.7 for placebo and litegrast, respectively, with no
statistically signicant difference between groups. Litegrast demonstrated a signicant reduction in the mean ODS at day 84 compared with
placebo (P 0.0273) (Fig 3). No statistically signicant differences
were observed between the 2 treatment groups at day 14 or 42.
Ocular Surface Disease Index Score. At baseline, the mean
values were as follows: symptoms (1.01 placebo, 0.97 litegrast),
environmental triggers (1.63 placebo, 1.59 litegrast), and total
score (27.04 placebo, 26.03 litegrast). No statistically signicant
differences were observed at baseline or at any follow-up study
visit for any OSDI parameter.

Safety Analysis
All 588 subjects enrolled in the study received at least 1 dose of
study medication and comprise the safety population.
Ocular Adverse Events. There were no unanticipated ocular
AEs or any serious adverse events (SAEs). The most common

Figure 2. Conjunctival lissamine staining score in a study of litegrast compared with placebo for dry eye disease. Results for nasal and total conjunctival
regions (Ora scale) using mean change from baseline analysis (*2-sided t test, xWilcoxon rank-sum test). LIF litegrast; SE standard error.

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Ophthalmology Volume 121, Number 2, February 2014

Table 3. Mean Visual Analogue Scale Scores (0e100 points) at
Baseline (Day 0) in a Phase 3 Study of Litegrast 5.0% versus
Placebo for Dry Eye Disease

Eye dryness
Photophobia
Burning/stinging
Itching
Foreign body sensation
Blurred vision
Pain
LIF litegrast.

Placebo (N [ 295)

5.0% LIF (N [ 293)

41.6
23.7
20.9
22.2
20.3
16.7
8.6

40.2
23.6
21.2
21.4
19.9
18.3
8.8

ocular AEs were intermittent administrative site symptoms (e.g.,

irritation, discomfort) primarily on the initial instilled dose at day 0
on exit from the CAE (Table 4). The number of new administrative
site AEs decreased rapidly after day 0. Overall, the majority of AEs
were transient and mild to moderate in severity (Table 4).
Nonocular Adverse Events. The most commonly reported
nonocular AE was dysgeusia (taste) in 13% of subjects in the
litegrast group and none reported in the placebo group. Seven
subjects (2 in the placebo group, 5 in the litegrast group) experienced SAEs, all nonocular, and none were reported as drug
related. The SAEs were consistent with medical complications in
an older population (upper abdominal pain, noncardiac chest pain,
infectious peritonitis, humeral fracture, presyncopal episode,
herniated cervical disk, and prostate cancer).
Other Safety Assessments. No signicant changes were
observed during the course of the study in best-corrected visual
acuity, slit-lamp examination, intraocular pressure, corneal sensitivity, or dilated fundoscopy examination.

Discussion
The OPUS-1 was a phase 3 multicenter, randomized,
prospective, double-masked, placebo-controlled study that
compared the efcacy and safety of litegrast ophthalmic

solution 5.0% with placebo in subjects with dry eye treated

twice daily over an 84-day period. The purpose was to
conrm ndings of improvement in signs and symptoms
observed in a previous phase 2 dose-ranging study. The
results from OPUS-1 showed improvements of dry eye signs
and symptoms with litegrast administration in patients who
had bilateral dry eye disease and baseline evidence of corneal
staining and symptoms of ocular discomfort.
For the primary objective efcacy variable of inferior
corneal uorescein staining, the study demonstrated superiority of litegrast 5.0% in reducing ocular surface
epithelial lesions compared with placebo. These ndings
were supported by statistically signicant improvements
observed in the superior and total corneal regions after
84 days of treatment. Furthermore, benets in corneal
uorescein staining were supported by improvements in
conjunctival lissamine staining in the nasal and total
conjunctival regions with statistical signicance observed as
early as day 14 and benet maintained through day 84. To
our knowledge, this is the rst phase 3 registrational study in
dry eye disease to demonstrate statistical superiority for an
investigational agent in both uorescein and lissamine
staining parameters compared with vehicle, key clinical
markers in evaluating ocular surface health in dry eye disease.20e22 The study provides evidence that use of litegrast, a topically administered LFA-1 inhibitor, can reduce
inammatory changes of the ocular surface associated with
dry eye disease as early as week 2 when administered twice
daily over a 12-week treatment period.
Signicant improvements (P < 0.05) in subjective measures of ocular discomfort and eye dryness were consistent
with observed dose responses in phase 2; however, the
current study was not able to replicate improvements in the
VR-OSDI parameters with statistical signicance. A current
dilemma in dry eye studies is the lack of a standardized,
validated dry eye patientereported outcome instrument.

Figure 3. Key symptom scores in a study of litegrast compared with placebo for dry eye disease. The ocular discomfort zone (Ora scale; left) and Eye Dryness
score (visual analog scale, right) at all visits (*2-sided t test). LIF litegrast; SE standard error.

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Litegrast for Dry Eye Disease

Table 4. Safety Summary in a Phase 3 Study of Litegrast 5.0%

versus Placebo for Dry Eye Disease
Subjects (%)/No. of Ocular
Adverse Events

Subjects with 1 ocular AE

Administrative site
Condition*
Instillation site irritation
Instillation site pain
Instillation site reaction
Instillation site pruritus
Day of reported
Administrative site
Events
Day 0 (post-CAE)
Day 1
Days 2e10
Days 11e14
Days 15e42
Days 43e84
Eye disordery
Visual acuity reduced
Eye pain
Lacrimation increased
Eye pruritus
Ocular hyperemia
Ocular AE by severity
Mild
Moderate
Severe
Withdrawals due to AEs
Ocular pain
Punctate keratitis
Instillation site
irritation/reaction
Retinal detachment
Periocular dermatitis
Nonocular SAE
Relapse of multiple
sclerosis

Placebo
(N 295)

5.0% LIF
(N 293)

73 (25%)/113

172 (59%)/302

12
11
2
6

(4%)/12
(4%)/11
(1%)/2
(2%)/6

69
63
50
19

(24%)/70
(22%)/63
(17%)/52
(7%)/19

16
2
5
1
5
1

(5%)/18
(1%)/2
(2%)/7
(0.5%)/1
(2%)/5
(0.5%)/1

113
16
6
8
5
2

(39%)/152
(5%)/30
(2%)/6
(3%)/13
(2%)/5
(1%)/2

13
5
1
2
4

(4%)/15
(2%)/6
(0.5%)/1
(1%)/2
(1.5%)/4

12
6
7
5
7

(4%)/15
(2%)/6
(2%)/7
(2%)/5
(2%)/7

69 (23%)/100
8 (3%)/13
0

164 (56%)/272
21 (7%)/29
1 (0.5%)/1

1 (0.5%)/1
1 (0.5%)/1
0

1 (0.5%)/1
0
3 (1%)/3

0
0
1 (0.5%)/1
0

1
1
2
1

(0.5%)/1
(0.5%)/1
(1%)/2
(0.5%)/1

AE adverse event; CAE controlled adverse environment; LIF litegrast; SAE serious adverse event.
*Instillation site events occurring 2% in any group.
y
Events occurring 2% in any group.

Although several instruments have been proposed, no existing method has been validated in the approval of a dry eye
pharmaceutical in the United States or Europe. The issue is
confounded by the low correlation between dry eye signs and
symptoms,23 high placebo responses, and statistical oor and
ceiling effects that readily explain inconclusive ndings.24
The average baseline total OSDI score was approximately
26 points (0e100) across both arms, indicating a moderate
level of symptomatic dry eye disease overall.19 However,
no minimal VR-OSDI severity score was specied as part
of the eligibility requirement, and a oor effect was observed
whereby the observed baseline data for the VR-OSDI end
point was near normal (0 points). The oor effect combined
with a greater than anticipated placebo response signicantly
impaired the ability of the VR-OSDI instrument to detect
a patient-reported drug response.

Spontaneous patient-reported symptom instruments may

offer an advantage over the recall-based OSDI question
naire. First, spontaneous instruments do not require the
subject to recall the complex perceptions of his/her disease
status over the prior weekda particularly challenging task
given the waxing and waning nature of the symptoms.
Second, in this study, the index terms of ocular discomfort
and eye dryness demonstrated sufcient symptom severity at
baseline to allow detection of a response (no oor/ceiling
effect). Last, the index terms of ocular discomfort and eye
dryness have a high degree of clinical relevance. These were
the 2 most commonly reported symptoms at baseline in both
frequency and severity in phase 2 and OPUS-1 and are
consistent with reported observations in other multicenter
dry eye symptom studies in patients with and without Sjrens syndrome.23,25,26
Litegrast demonstrated evidence of reduced ocular
surface inammation as early as day 14 as measured by lissamine. The relatively rapid onset of action may be attributable
to broad inhibition of inammatory cytokines associated with
dry eye and maintenance of sustained inhibitory concentrations of drug in the tear lm up to 24 hours after a single dose.
Preclinical studies with 1 mM solutions of litegrast demonstrated rapid and potent inhibition of cytokine secretion from
inamed leukocytes linked to dry eye disease, including
interferon-g, tumor necrosis factor-a, macrophage inammatory protein-1a, interleukin (IL)-1a, IL-1b, IL-2, IL-4,
and IL-10.16 Ocular pharmacokinetic studies of topically
administered litegrast in normal human volunteers have
demonstrated that drug concentrations 1 mM are sustained
in the tear lm 24 hours after a single drop of 5.0%
litegrast.27 Formulation of litegrast as a 5.0% ophthalmic
solution, in contrast with emulsions or suspensions, allows
sustained drug bioavailability directly in the aqueous tear
lm, ocular surface, and surrounding periocular tissue.
Providing a sustained therapeutic drug concentration in the
tear lm may be an essential pharmacokinetic feature for
dry eye disease because the majority (>99%) of topically
administered drugs are normally cleared from the ocular
surface within the rst 30 to 60 minutes after administration
because of normal tear turnover.12
Litegrast ophthalmic solution 5.0% administered twice
daily for 12 weeks appeared safe and well tolerated. Of note,
there were no unanticipated AEs, including no evidence of
localized or systemic infections. The most commonly reported ocular AEs for litegrast were intermittent administrative site conditions of transient discomfort and irritation
primarily on the initial instilled dose at day 0. A long-term
safety study (SONATA, Safety Study of Litegrast to Treat
Dry Eye; NCT01636206. http://clinicaltrials.gov, accessed
October 17, 2013) is currently under way and will evaluate
the safety and tolerability of litegrast when administered
for up to 1 year in duration in a double-masked study versus
placebo (vehicle).

Study Limitations
Limitations of this study include a relatively short treatment
period (12 weeks), no allowance for concomitant therapy
(e.g., adjunctive use of articial tears or cyclosporine

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Ophthalmology Volume 121, Number 2, February 2014

emulsion), selection of only aqueous decient subjects for
study, and the need for conrmatory replication of these
phase 3 study results. The long-term safety study
(SONATA) will evaluate the use of litegrast ophthalmic
solution 5.0% compared with placebo when used twice daily
for 1 year and will allow the use of concomitant therapy,
such as articial tears and low-potency topical steroids.
The decision to exclude patients with active lid margin
disease was to avoid potential confounding results introduced by subjects requiring additional medications and lid
hygiene procedures that could interfere with study parameters. Patients with a history of blepharitis or nonactive lid
disease were allowed to enroll in the study. Although we
did not specically include patients with active lid-margin
disease, there may still be a role for litegrast in ameliorating the inammatory component of this disorder, but
further studies are warranted to test this hypothesis. Last, the
ability to replicate the observed improvements in signs and
symptoms in OPUS-1 using litegrast will be required for
registration. Historically, demonstrating evidence of replication has been the most difcult challenge in dry eye drugdevelopment programs, particularly with a priori sign and
symptom end points. A second conrmatory pivotal study
(OPUS-2) is ongoing.
In conclusion, this phase 3 registrational study of the novel
integrin antagonist litegrast has shown its ability to improve
ocular surface epithelial health and associated symptoms,
thereby demonstrating its potential as a relatively fast-acting
second-generation agent for the treatment of dry eye disease.

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Sheppard et al

Litegrast for Dry Eye Disease

Footnotes and Financial Disclosures

Originally received: April 6, 2013.
Final revision: August 14, 2013.
Accepted: September 12, 2013.
Available online: November 27, 2013.

Manuscript no. 2013-566.

Virginia Eye Consultants and Eastern Virginia Medical School, Norfolk,

Virginia.

Andover Eye Associates, Andover, Massachusetts.

Central Maine Eye Care, Lewiston, Maine.

DAmbrosio Eye Care, Lancaster, Massachusetts.

Total Eye Care, Memphis, Tennessee.

University of Louisville, Louisville, Kentucky.

Independent Biostatistical Consultants, Tempe, Arizona.

SARcode Bioscience, Inc, Brisbane, California.

*Members of the OPUS-1 Study Group are listed online in Appendix 1

(available at http://aaojournal.org).
Presented at: the 116th Annual Meeting of the American Academy of
Ophthalmology, November 12, 2012, Chicago, Illinois.

Financial Disclosure(s):
The author(s) have made the following disclosure(s): J.D.S. is a consultant
to Alcon, Abbott Laboratories, Allergan, Bausch & Lomb, EyeGate, Lux
Biosciences, Merck, NiCox, Lacrisciences, Ocucure, Omeros, EyeRx
Research, Provision Network, SARcode Bioscience, Science Based Health,
and Tear Lab. K.S.K. is a consultant to SARcode Bioscience, Inc, a wholly
owned subsidiary of Shire Plc. C.P.S. is an employee of SARcode
Bioscience, Inc, a wholly owned subsidiary of Shire Plc. The Ocular
Surface Disease Index is copyrighted by Allergan, Inc, Irvine, California.
The Ora uorescein scales, lissamine green scales, and ocular discomfort
scale are copyrighted by Ora, Inc, Andover, Massachusetts. The Ora
Controlled Adverse Environment is a trademark of Ora, Inc.
The study was sponsored by SARcode Bioscience, Inc, Brisbane, CA.
SARcode Bioscience, Inc, is a wholly owned subsidiary of Shire Plc.
SARcode Bioscience participated in the design of the study, conducting the
study, data collection, data management, data analysis, interpretation of the
data, and manuscript preparation, review, and approval.
Correspondence:
Charles P. Semba, MD, SARcode Bioscience, Inc., 1000 Marina Blvd.,
Suite 250, Brisbane, CA 94005. E-mail: csemba@shire.com.

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