Clinical trial NCT04357795
Conditions: Dry Eye Disease
Keywords: Keratoconjunctivitis Sicca KCS Dry eye
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2020-06-29; Completion date: 2022-06-24
Enrollment: 135 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 4, multicenter, single arm, 12 week study in subjects with dry eye disease, which is inadequately controlled by cyclosporine 0.05% ophthalmic emulsion.

Detailed description:
This is a phase 4, multicenter, open-label, single-arm, 12-week study of subjects with dry eye disease that is inadequately controlled by cyclosporine (CsA) 0.05% ophthalmic emulsion. Subject enrollment will be classified by evidence of dry eye disease (ie, signs, symptoms, or both signs and symptoms). Treatment will be one drop of CsA 0.09% ophthalmic solution (Cequa) in each eye twice daily (BID) for 12 weeks. The study hypothesis is that CsA 0.09% ophthalmic solution will show improved clinical benefit in subjects whose dry eye signs and/or symptoms are inadequately controlled while on CsA.

Arms: arm 1: None
Interventions: intervention 1: CequaTM (Cyclosporine 0.09%) ophthalmic solution
Intervention descriptions: intervention 1: One drop CequaTM (Cyclosporine 0.09%) ophthalmic solution in each eye twice daily, approximately 12 hours apart.

Protocol documents:
Prot_000.pdf: 
Official Title: Effect of Cequa™ in Subjects with Dry Eye Disease That Is 
Currently Inadequately Controlled While on Cyclosporine 0.05% Ophthalmic 
Emulsion 
Document: Clinical Study Protocol 
NCT number: NCT04357795 
Date: 11-Dec-2019


Effect of Cequa TM in Subjects With Dry Eye Disease That 
Is Currently Inadequately Controlled While on 
Cyclosporine 0.05% Ophthalmic Emulsion 
Protocol Number: OTX101-2019-001 
Sponsor: Sun Pharma Global FZE 
Version Number: 1.0 
11 December 2019 
Statement of Compliance: 
The trial will be conducted in accordance with International Conference on Harmonisation (ICH) 
Good 
Clinical Practice (GCP), and applicable United States (US) Code of Federal Regulations (CFR). The 
Principal Investigator will assure that no deviation from, or changes to, the protocol will take 
place without prior agreement from the Sponsor and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have GCP training. 
The study is conducted also under the Declaration of Helsinki. The protocol, informed consent 
form(s) [ICF(s)], recruitment materials, and all participant materials will be submitted to the IRB 
for review and approval. Approval of both the protocol and the consent form must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the 
consent form will be IRB approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent using a previously 
approved consent form. 
Protocol Summary: 
SYNOPSIS 
Title: Effect of Cequa TM in Subjects With Dry Eye Disease That Is Currently Inadequately 
Controlled While on Cyclosporine 0.05% Ophthalmic Emulsion 
Study Description: 
Objectives: 
This is a phase 4, multicenter, open-label, single-arm, 12-week study of subjects with dry eye 
disease (DED) that is inadequately controlled by cyclosporine (CsA) 0.05% ophthalmic emulsion. 
Treatment will be one drop of CsA 0.09% ophthalmic solution (Cequa) in each eye twice daily 
(BID) for 12 weeks. The study hypothesis is that CsA 0.09% ophthalmic solution will show 
improved clinical benefit in subjects whose dry eye signs and/or symptoms are inadequately 
controlled while on CsA 0.05% ophthalmic emulsion.  


Primary: to evaluate improvement in the signs and/or symptoms of DED following use of CsA 
0.09% ophthalmic solution in subjects whose DED is inadequately controlled by CsA 0.05% 
ophthalmic emulsion. 
Secondary: to evaluate changes in additional signs and symptoms over the 12-week course of 
Cequa therapy. 
 
Statistical Analyses: 
Neither masking nor randomization will be employed for operation of this study; this is an 
open-label study 
• Primary efficacy endpoints will be analyzed using descriptive statistics and restricted 
maximum likelihood repeated measures mixed model (REMLMMRM) models. 
• Multiplicity adjustments of observed significance levels for primary efficacy endpoints will be 
presented. 
 
Study Population: 
Subjects will have DED that is not adequately controlled (ie, still symptomatic and/or still 
exhibiting signs of disease) by current treatment with CsA 0.05% ophthalmic emulsion. Eligible 
subjects must have been taking CsA 0.05% ophthalmic emulsion treatment for at least 3 
months prior to the Screening/Baseline visit. However, subjects who have failed prior 
treatment with CsA 0.05% ophthalmic emulsion will be excluded from the study. 
 
Inclusion/Exclusion Criteria: 
Inclusion Criteria: 
1. Male or female subjects with a history of bilateral dry eye disease for a period of at least 
3 months. 
2. Aged of at least 18 years. 
3. Subjects with total corneal fluorescein staining ≥6 or corneal fluorescein staining in an 
individual zone ≥2 as per National Eye Institute Grading Scale. 
4. Subjects with modified symptom assessment in dry eye global symptom score, ≥40 using 
visual analogue scale. 
5. Subjects with best-corrected visual acuity 20/200 or better in both eyes at the 
Screening/Baseline visit 
Exclusion Criteria: 
1. Subjects who have used cyclosporine 0.05% ophthalmic emulsion in both eyes for less 
than 3 months prior to the Screening/Baseline visit. 
2. Subjects with history of treatment failure with cyclosporine 0.05% ophthalmic emulsion. 
3. Subjects who have active seasonal and/or perennial allergic conjunctivitis in either eye. 
4. Subjects who had already Use initiated any systemic or topical ocular medication. 
 
 


Justification of Dose: 
Cyclosporine 0.09% ophthalmic solution (Cequa) is approved by the FDA to increase tear 
production in patients with KCS (Cequa prescribing information, 2018). It is to be dosed as 1 
drop BID (approximately 12 hours apart) into each eye. Therefore, the dosing in the current 
phase 4 study will match the approved dosing regimen. 
 
Overall Design: 
This is a phase 4, multicenter, open-label, single-arm, 12-week study of subjects with DED that 
is inadequately controlled by CsA 0.05% ophthalmic emulsion. Study subjects will be male or 
female, at least 18 years of age, with a history and clinical diagnosis of bilateral DED for a period 
of at least 3 months, corrected BCVA of 20/200 or better in both eyes at the Screening/Baseline 
visit, and a willingness to discontinue use of all dry eye therapy, aside from continuing any 
existing ATP use. In addition, subjects must have total CFS ~6 (or CFS ~2 in an individual zone) 
and/or a modified SAnDE score ~40.  
At the Screening/Baseline visit, sites will obtain signed informed consent, 
medical/ocular/concomitant medication histories, and demographics, perform a urine 
pregnancy test (for women of childbearing potential only), conduct screening ophthalmic 
examinations, and review inclusion/exclusion criteria. Site staff will dispense study medication, 
provide appropriate instructions for use, and supervise administration of first dose. All enrolled 
subjects will self-administer 1 drop of CsA 0.09% ophthalmic solution in each eye BID for 12 
weeks. Subjects will return at Weeks 4, 8, and 12. In addition, at the Week 12 visit, sites will 
perform a urine pregnancy test (for women of childbearing potential only), and subjects will 
answer a treatment preference question. At each visit, concomitant medications will be 
updated, adverse events (AEs) will be collected, the subject's daily diary on the frequency of 
ATP and CsA 0.09% ophthalmic solution use will be examined, subjects will answer a 
compliance question, and actual daily use entered into electronic data capture (EDC). 
 
Study Record Retention: 
Investigators should retain study-related records at the site for a minimum of 5 years after 
study closeout. 
 
 

SAP_001.pdf: 
Official Title: Effect of Cequa™ in Subjects with Dry Eye Disease That Is 
Currently Inadequately Controlled While on Cyclosporine 0.05% Ophthalmic 
Emulsion 
Document: Statistical Analysis Plan (SAP) 
NCT number: NCT04357795 
Date: 25‐Jan‐2023 


Statistical Analysis Plan 
 
Effect of Cequa® in Subjects with Dry Eye Disease That Is Currently 
Inadequately Controlled While on Cyclosporine 0.05% Ophthalmic 
Emulsion 
 
Study Phase Phase IV 
Product Name: Cequa® 
Study/Protocol Number: OTX101-2019-001 
Formulation: Cyclosporine 0.09% ophthalmic emulsion 
Sponsor: Sun Pharmaceuticals Industries, Ltd. 
Date: 25 JAN 2023 
 
This document presents the statistical analysis plan (SAP) for Sun Pharma Industries Ltd., 
Protocol No. OTX101-2019-001, Effect of Cequa® in Subjects with Dry Eye Disease That Is 
Currently Inadequately Controlled While on Cyclosporine 0.05% Ophthalmic Emulsion. 
Dry eye disease is a common, multifactorial, ophthalmologic disorder of the tears and ocular 
surface characterized by symptoms of burning, stinging, itching, grittiness, scratchiness, foreign 
body sensation, dryness, stickiness, and tired eye sensation. The onset of symptoms is usually 
gradual, bilateral, and chronic. Symptoms typically become more bothersome later in the day 
and are intensified by various environmental factors. 
The goal of this study is to evaluate the clinical benefits of switching to CsA 0.09% ophthalmic 
solution in subjects whose DED is inadequately controlled while on CsA 0.05% ophthalmic 
emulsion. This analysis plan is based on the final protocol (Version 1.0) dated 11 FEB 2020. The 
SAP provides the description of the analyses for the Final Analysis. 
Study Objectives: 
This study will be carried out with the intention to answer specific questions relating to clinical 
performance, efficacy and safety (i.e. residual risks) of the study medication when used in 
accordance with its approved labelling.  
 
1: Primary Objective 
The primary objective of this study is to evaluate improvements in the signs and/or symptoms 
of DED following the use of CEQ in subjects whose DED is inadequately controlled by 
cyclosporine 0.05% ophthalmic emulsion. 
 
2: Secondary Objective 


The secondary objective of this study is to evaluate changes in additional signs and/or 
symptoms over the 12-week course of CEQ therapy. 
 
The primary endpoint is as follows: 
-the mean CFB in total CFS and the mean CFB in modified SAnDE score at Week 12 for all 
patients 
 
The secondary endpoints are as follows: 
- Mean CFB in total conjunctival staining score at Week 12 
- Mean CFB in central corneal staining score at Week 12 
- Mean CFB in tear osmolarity at Week 12 
- Mean CFB in frequency of ATP use at Week 12 
- Mean CFB in unanaesthetized Schirmer’s score at Week 12 
- Percentage (%) of subjects who prefer study treatment over prior treatment at Week 
12 
 
Overall Study Design 
This is an open-label, multisite, single-arm, phase IV clinical study that will evaluate the efficacy 
of Cequa™ cyclosporine 0.09% ophthalmic emulsion in patients with DED that is not well 
controlled by cyclosporine 0.05% ophthalmic emulsion. Subjects will be enrolled in up to 10 
clinical sites throughout the United States. Informed consent will be obtained prior to any study 
specific procedure is performed. 
Subjects who withdraw or are withdrawn/discontinued from the study after they have signed 
the informed consent and received the study treatment will not be replaced. This is an 
Electronic Data Capture (EDC) study utilizing web-based electronic case report forms. The study 
is designed using Celes web-based EDC system. KCT Data Management, Inc. will manage the 
EDC system according to their standard operating procedures throughout the study. 
 
Analysis Populations: 
Two analysis populations will be defined for this study: Safety (SAF) and Intent-to-Treat 
(ITT). The determination of which subjects will be included in each population will be made 
prior to locking the final database. All efficacy variables will be analyzed using the ITT set of 
subjects, and all safety variables will be analyzed using the SAF set of subjects.  
 
Safety Analysis Population: 
All patients who receive at least 1 dose of the study medication will be included in the SAF 
population. No subjects (or data) will be excluded because of protocol deviations that occur 
during the study. 
 


 
 
Intent-to-Treat Population: 
The Intent-to-Treat (ITT) population will be comprised of all subjects who receive at least 1 dose 
of the study medication and have at least 1 post-baseline assessment. Following the ITT 
principle, subjects will be analyzed irrespective of dosing compliance or any deviations in the 
study medication received. 
 
Efficacy Analyses: 
The efficacy analysis will be performed after all subjects have completed Week 12 or 
discontinued prior to Week 12, and after the study database has been cleaned, verified, and 
locked. All efficacy analyses will be performed using the ITT population. All analyses will be 
implemented using SAS® version 9.4 or later (SAS Institute,Inc., Cary, NC). 
 
Statistical Methodology: 
Summary statistics will be presented for continuous variables with descriptive statistics, 
including n, mean, standard deviation (SD), median, minimum, and maximum. For categorical 
variables including binary variables, frequency counts and percentages will be presented. P-
values will be computed for each analysis group separately. In addition, 95% 2-sided confidence 
intervals (CIs) will be presented, where relevant. In case of percentages, the CI will be 
computed using the Clopper-Pearson method. The CI will be computed for continuous variables 
using t-test analysis. Summary statistics will be displayed by baseline groups. 
 
Demographics and Baseline Characteristics: 
Demographics will be presented in a summary table and in a by-subject listing, including age, 
gender, race, iris color, and ethnicity. Baseline characteristics, presented in a summary table 
and in a by-subject listing. 
 
Prior Medical, Ocular and Treatment History: 
All medical and ophthalmic histories reported at the screening and baseline visits will have their 
verbatim term mapped to their corresponding thesaurus terms using version 25.1 of the 
Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary. 
 
Efficacy Analysis: 
Primary Efficacy Analysis 
The primary efficacy endpoint parameters for the study are the mean CFB in total CFS and the 
mean CFB in modified SAnDE score at Week 12. Significance will be set at p<0.05 for the 
analysis of all groups and endpoints. 


 
 
Secondary Efficacy Analysis: 
Same as primary 
 
Safety Analyses: 
All safety analyses will be performed using the SAF population. No imputation of missing data 
will be performed. Safety analyses will be presented in summary tables and in by-subject 
listings. 
 
Compliance: 
Drug accountability data was assessed at each visit and used for further patient counselling but 
was not collected for analysis. 
 
Adverse Events: 
Adverse events will be coded according the MedDRA version that will be available at the time of 
the data cut-off. A treatment emergent AE (TEAE) is defined as an AE starting on or after the 
day of treatment. A serious AE (SAE) that is ongoing at the time of completion or 
discontinuation from the study will be followed until stabilization or resolution of the event.