Clinical trial NCT05022004
Conditions: Primary Open Angle Glaucoma Ocular Hypertension
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2021-12-20; Completion date: 2023-01-06
Enrollment: 599 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, Investigator-masked, multi-center, parallel group, therapeutic equivalence study with clinical endpoint.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Brinzolamide ophthalmic suspension intervention 2: Azopt®
Intervention descriptions: intervention 1: dose: one drop of study medication; frequency: three times a day; route of administration: Topical ocular administration; duration of therapy: 6 weeks intervention 2: dose: one drop of study medication; frequency: three times a day; route of administration: Topical ocular administration; duration of therapy: 6 weeks

Protocol documents:
Prot_000.pdf: 
Official title: Therapeutic Equivalence Study of Generic Brinzolamide 1% Ophthalmic 
suspension Compared to Reference Listed Drug Azopt® (Brinzolamide) Ophthalmic 
Suspension 1% in Subjects With Primary Open Angle Glaucoma or Ocular Hypertension. 
Document: Clinical Study Protocol 
NCT number: NCT05022004 
Document date: 12-May-2021 




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1.0 
PROTOCOL SYNOPSIS  
Name of Sponsor: Sun Pharmaceutical Industries Ltd. (SPIL). 
Name of Investigational Product: Brinzolamide ophthalmic suspension USP 1% 
Name of Active Ingredient: Brinzolamide ophthalmic suspension 
Name of Reference Listed Drug: AZOPT® 
Title of Trial: A Therapeutic equivalence Study of Generic Brinzolamide 1% Ophthalmic 
Suspension Compared to Reference Listed Drug Azopt® (Brinzolamide) Ophthalmic 
Suspension 1% in Subjects with Primary Open Angle Glaucoma or Ocular Hypertension. 
Phase of Development: Therapeutic equivalence study 
Trial Centers: Multicenter  
Objectives:  
Primary Objective:  
To evaluate the efficacy of three times daily (TID) dosing of SPIL’s Brinzolamide ophthalmic 
suspension USP 1% compared with Azopt® 1% in subjects with open-angle glaucoma or 
ocular hypertension. 
Secondary Objectives: 
To evaluate the safety of TID dosing of SPIL’s Brinzolamide ophthalmic suspension USP 1% 
compared with Azopt® 1% in subjects with open-angle glaucoma or ocular hypertension. 
Study Endpoints:  
Primary Efficacy Endpoint: 
Mean difference in IOP of both eyes between the 2 treatment groups at the following time 
points: approximately 8:00 AM. (hour 0; before the morning drop) and 10:00 AM. (hour 2) 
at Day 14 (Week 2) and Day 42 (Week 6) visits.  
Secondary Efficacy Endpoint: 
Change from baseline in IOP of both eyes between the 2 treatment groups at 4 time points, 
i.e., at approximately 8:00 AM. (hour 0; before the morning drop) and 10:00 AM. (hour 2) at 
the Day 14 (Week 2) and Day 42 (Week 6) visits. 
Safety:  
Incidence and severity of adverse events (AEs) 
Study Design: This is a randomized, Investigator-masked, multi-center, parallel group, 
therapeutic equivalence study with clinical endpoint. 
Duration of Treatment : 6 weeks  
Total duration: 6 weeks of Screening; 6 weeks of treatment period, and 1 week of telephonic 
follow-up 






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x Ocular safety assessments: BSCVA, slit lamp biomicroscopy, intraocular pressure, 
dilated ophthalmoscopy, including recording cup/disc ratio. 
 
Sample size and statistical approach to primary analysis 
An equivalence test of means using 2 one-sided tests on data from a parallel-group design 
with sample sizes of 266 in the SPIL’s Brinzolamide ophthalmic suspension 1% and 266 in 
Azopt® 1% achieves 90% power at an α = 0.05 significance level when the true difference 
between the means is 0, the standard deviation is 3.5, and the 95% equivalence limits are -
1.0 and 1.0. Considering the possibility of 20% of subjects not being evaluable either due to 
dropping out of the study or having major protocol violations, approximately 333 subjects 
will be enrolled in each treatment group for a total of 666 subjects in the study.  
Efficacy analyses: The primary analyses will be completed by constructing two-sided 95% 
confidence intervals of the treatment difference (test – reference) for mean IOP of both eyes 
(continuous variable) at all 4 follow-up points i.e., at approximately 8:00 AM. (hour 0; before 
the morning drop) and 10:00 AM. (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) 
visits. This mean IOP must be within ± 1.5 mm Hg using the per protocol (PP) population 
for all time points measured and within ± 1.0 mm Hg using the PP population for the 
majority of time points measured. 
Safety analyses: The primary safety analysis will summarize ocular (in both eyes) and 
non-ocular AEs for all treated subjects using discrete summaries at the subject level by 
Medical Dictionary for Regulatory Activities (MedDRA®) system organ class (SOC) and 
preferred term (PT) for each treatment group. A treatment emergent adverse event (TEAE) 
will be defined as occurring after the first dose of study medication for the period. 
Treatment-related ocular and non-ocular TEAEs will be summarized similarly. Ocular and 
non-ocular TEAEs will also be summarized by severity. 
 
 




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TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS ..................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................7 
LIST OF TABLES .......................................................................................................................10 
LIST OF ABBREVIATIONS .....................................................................................................11 
2.0 
KEY ROLES ....................................................................................................................13 
2.1 
Emergency Contacts ..............................................................................................14 
2.2 
For Questions on Eligibility and the Protocol........................................................14 
3.0 
BACKGROUND INFORMATION ...............................................................................15 
3.1 
Introduction ............................................................................................................15 
3.2 
Investigational Product ..........................................................................................15 
3.2.1 
Name and Description ...........................................................................16 
3.2.2 
Non-clinical Data ..................................................................................16 
3.2.3 
Clinical Data .........................................................................................16 
3.2.3.1 
Pharmacokinetics: ..........................................................................16 
3.2.3.2 
Pharmacodynamics: .......................................................................17 
3.2.3.3 
Safety: ............................................................................................17 
3.3 
Rationale ................................................................................................................17 
3.3.1 
Rationale for the Trial and Selected Subject Population: .....................17 
3.3.2 
Rationale for Dose Selection .................................................................18 
3.3.3 
Rationale for the Use of Comparator ....................................................18 
3.3.4 
Rationale for Study Endpoints ..............................................................18 
3.4 
Compliance Statement for Study Conduct in Accordance with Protocol, GCP 
and Applicable Regulatory Requirements .............................................................18 
4.0 
STUDY OBJECTIVES ....................................................................................................19 
4.1 
Primary Objective (s) .............................................................................................19 
4.2 
Secondary Objective (s) .........................................................................................19 
5.0 
SELECTION OF SUBJECTS ........................................................................................19 
5.1 
Description of the Study Population ......................................................................19 
5.2 
Inclusion criteria ....................................................................................................19 
5.3 
Exclusion criteria ...................................................................................................20 
6.0 
STUDY DESIGN ..............................................................................................................21 
6.1 
Description of Type and Design of Study ..............................................................21 
6.2 
General Instructions for Study Visits .....................................................................21 
6.3 
Schedule of Assessments .......................................................................................21 


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6.3.1 
Visit 1 Screening Visit (-42 days to Day -1) .........................................21 
6.3.2 
Visit 2 (Day 0) Baseline/Randomization ..............................................23 
6.3.3 
Visit 3 -Week 2 ± 4 days .......................................................................24 
6.3.4 
End of treatment/Visit 4 (Week 6 ± 4 days) .........................................24 
6.3.5 
End of Study Visit 5: Telephonic Visit (Week 7 ± 4 days) ..................24 
6.3.6 
Early Discontinuation (ED) Visit ..........................................................24 
6.3.7 
Unscheduled Visits ...............................................................................25 
6.3.8 
COVID 19 restrictions ..........................................................................25 
6.4 
Measures Taken to Avoid Bias ..............................................................................26 
6.4.1 
Subject Number .....................................................................................26 
6.4.2 
Randomization ......................................................................................26 
6.5 
Withdrawal and Replacement Rules ......................................................................27 
6.5.1 
Lost to Follow-Up .................................................................................27 
6.5.2 
Discontinued due to Adverse Event ......................................................27 
6.5.3 
Replacement of Subjects .......................................................................27 
6.5.4 
Premature Discontinuation of the Complete Study ...............................27 
6.6 
The Identification of Any Data to be Recorded Directly in the eCRF ..................28 
7.0 
TREATMENT OF SUBJECTS ......................................................................................28 
7.1 
Investigational Medicinal Products ........................................................................28 
7.1.1 
Study Medication ..................................................................................28 
7.1.2 
Handling Requirements of the Investigational Product ........................28 
7.1.3 
Dispensing (Labeling and Packaging) and Compliance .......................29 
7.1.4 
Investigational Product Numbering ......................................................29 
7.1.5 
Accountability Procedures for the Investigational Product ..................29 
7.2 
Dosage and Dosage Regimen ................................................................................30 
7.2.1 
General Dosing Instructions ..................................................................30 
7.3 
Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or 
During the Study ....................................................................................................30 
7.4 
Procedure(s) for Monitoring Subject Compliance .................................................31 
8.0 
ASSESSMENT OF EFFICACY .....................................................................................32 
9.0 
ASSESSMENT OF SAFETY ..........................................................................................32 
9.1 
Description of Safety Parameters ...........................................................................32 
9.2 
Definitions of Adverse Events ...............................................................................32 
9.2.1 
Adverse Event .......................................................................................32 
9.2.2 
Serious Adverse Event ..........................................................................33 
9.3 
Pregnancy ...............................................................................................................33 




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13.1 
Ethics Committee (EC) or Institutional Review Board (IRB) ...............................45 
13.2 
Ethical Conduct of the Study .................................................................................45 
13.3 
Subject Information and Consent...........................................................................45 
14.0 
DATA HANDLING AND RECORD KEEPING ..........................................................46 
15.0 
FINANCING AND INSURANCE ..................................................................................46 
16.0 
PUBLICATION POLICY ...............................................................................................46 
17.0 
REFERENCES .................................................................................................................47 
18.0 
APPENDICES ..................................................................................................................48 
 
 
LIST OF TABLES 
Table 1-1 
Schedule of Assessments ..................................................................... 6 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BSCVA 
Best Spectacle Corrected Visual Acuity 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment Diabetic  Retinopathy Study 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice  
HRT 
Hormonal Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of technical requirements for 
pharmaceuticals for human use 
IEC 
Independent Ethics Committee 
IMP / IP 
Investigational Medicinal Product/Investigational Product 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
LOCF 
Last Observation Carried Forward 
logMAR 
logarithm of the Minimum Angle of Resolution 
MAO 
Monoamine Oxidase Inhibitor 
MedDRA 
Medical Dictionary of Regulatory Affairs 
MMRM 
Mixed Model Of Repeated Measures 
NCT 
Non contact tonometer 
OPD 
(in-)office physician dispensing 
OU 
Both eyes 
POC 
Proof-of-concept 
PP 
Per Protocol 
PT 
Preferred Term 
RLD 
Reference Listed Drug 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
 
 
SPIL 
Sun Pharmaceutical Industries Ltd 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


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TOST 
Two one-sided tests 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Three Times Daily 
 
 
 






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3.0 
BACKGROUND INFORMATION  
3.1 Introduction 
Glaucoma is collection of disorders characterized by a slow and progressive degeneration of retinal 
ganglion cells and their axons, resulting in a distinct appearance of the optic disc and a concomitant 
pattern of visual field loss. (1) In 2010, 60.5 million people were estimated to be suffering from 
glaucoma worldwide, with a predicted increase to 79.6 million by 2020. It is a leading cause of 
blindness in the United States of America (USA), affecting 1% to 2% of individuals aged 60 and 
over. (2) In India, the estimated number of cases of glaucoma is 12 million, around one fifth of the 
global burden of glaucoma. (3, 4) 
There are several recognized risk factors of glaucoma including an increased intraocular pressure 
(IOP), aging, family history, high myopia, systemic hypertension, cardiovascular disease, migraine 
headaches, peripheral vasospasm, and prior nerve damage. Elevated IOP is the only proven 
treatable risk factor in multiple forms of glaucoma. Increased IOP of greater than 21 mm Hg has 
traditionally been suspected to cause glaucoma, the higher the IOP, the greater the likelihood of 
optic nerve damage and visual field loss. With IOP > 30 mmHg, the potential risk for vision loss 
is 40 times greater compared to an IOP of 15 mm Hg. As IOP has been shown in several large-
scale National Eye Institute-sponsored studies to be a major factor in the pathogenesis of the 
progression of glaucoma, pharmacologic reduction of IOP is today the mainstay of treatment for 
this condition. (5, 6, 7)  
Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It 
catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of 
carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active 
being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other 
tissues. Inhibition of CA in the ciliary processes of the eye decreases aqueous humor secretion, 
presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and 
fluid transport. The result is a reduction in IOP. 
Azopt® 1% (brinzolamide ophthalmic suspension) of Alcon Laboratories Inc, initially approved in 
1998 is a carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure 
in patients with ocular hypertension or open-angle glaucoma. Sun Pharma Industries limited 
(SPIL) is developing a Q1/Q2 formulation to US reference listed drug (RLD) Azopt, and in 10mL 
and 15 mL packs. Sun Pharmaceutical Industries Ltd’s Brinzolamide ophthalmic suspension USP 
1% contains brinzolamide, an inhibitor of CA-II. Following topical ocular administration, 
brinzolamide inhibits aqueous humor formation and reduces elevated IOP.  
3.2 Investigational Product 
IMP: Brinzolamide ophthalmic suspension USP 1% w/v; 
RLD: Azopt® 1% (brinzolamide ophthalmic suspension) 
 


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3.2.1 
Name and Description  
Sun Pharmaceutical Industries Ltd’s Brinzolamide ophthalmic suspension USP 1% w/v contains 
 formulated for multidose topical ophthalmic use.  
 
  
It is a white powder, which is insoluble in water, very soluble in methanol and soluble in ethanol. 
SPIL’s Brinzolamide ophthalmic suspension USP 1% w/v is supplied as a sterile, suspension of 
brinzolamide USP which has been formulated to be readily suspended and slow settling, following 
shaking. It has a pH of approximately 7.5 and an osmolality of 300 mOsm/kg.  
Each mL of SPIL’s Brinzolamide ophthalmic suspension USP 1% w/v contains:  
Active ingredient: brinzolamide USP 10 mg.  
Preservative: benzalkonium chloride solution NF (50%) 0.02 mg 
Inactive ingredients: mannitol USP, carbomer homopolymer type B NF, tyloxapol USP, edetate 
disodium dihydrate USP, sodium chloride USP, water for Injection USP, and  hydrochloric acid 
NF and /or sodium hydroxide NF to adjust pH. 
Full name of IMP: Brinzolamide ophthalmic suspension USP 1% w/v, 10 ml 
Full name of RLD: Azopt® (brinzolamide) 1%, 10 ml 
3.2.2 
Non-clinical Data 
No non-clinical studies have been conducted with SPIL’s Brinzolamide ophthalmic suspension 
USP 1%. 
3.2.3 
Clinical Data  
No clinical studies have been conducted with SPIL’s Brinzolamide ophthalmic suspension USP 
1%. All the following data here is from the studies done with RLD AZOPT brinzolamide 
ophthalmic suspension 1%. (7) 
3.2.3.1 Pharmacokinetics: 
Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. 
Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits a 
long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl 
brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds 
mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and 


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N-desethyl brinzolamide concentrations are low and generally below assay quantitation limits. An 
oral pharmacokinetic study was conducted in which healthy volunteers received 1 mg capsule of 
brinzolamide twice per day for up to 32 weeks. This regimen approximates the amount of drug 
delivered by topical ocular administration of Azopt® (brinzolamide ophthalmic suspension) 1% 
dosed to both eyes three times per day and simulates systemic drug and metabolite concentrations 
similar to those achieved with long-term topical dosing. Red blood cell CA activity was measured 
to assess the degree of systemic CA inhibition. Brinzolamide saturation of RBC CA-II was 
achieved within 4 weeks (RBC concentrations of approximately 20 mcM). N-desethyl 
brinzolamide accumulated in RBCs to steady-state within 20 to 28 weeks reaching concentrations 
ranging from 6 to30 mcM. The inhibition of CA-II activity at steady-state was approximately 70 
to 75%, which is below the degree of inhibition expected to have a pharmacological effect on renal 
function or respiration in healthy subjects. 
3.2.3.2 Pharmacodynamics: 
In 2, 3-month clinical studies, Azopt® (brinzolamide ophthalmic suspension) 1% dosed three times 
daily (TID) in subjects with elevated IOP, produced significant reductions in IOPs (4 to 5 mmHg). 
These IOP reductions are equivalent to the reductions observed with TRUSOPT* (dorzolamide 
hydrochloride ophthalmic solution) 2% dosed TID in the same studies. 
3.2.3.3 Safety: 
In clinical studies of AZOPT (brinzolamide ophthalmic suspension) 1%, the most frequently 
reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or 
unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry 
eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular 
keratitis, ocular pain, ocular pruritus and rhinitis. The following adverse reactions were reported 
at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, 
diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, 
keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing, and 
urticaria. 
3.3 
Rationale  
The Office of Generic Drugs (OGD) of the US Food and Drug Administration (FDA), recommends 
conducting a BE study with a clinical endpoint in the treatment of open angle glaucoma and ocular 
hypertension comparing the test product to the RLD, each applied as 1 drop in both eyes TID at 
approximately 8:00 AM, 4:00 PM, and 10:00 PM for 42 days (6 weeks) 
3.3.1 Rationale for the Trial and Selected Subject Population: 
The subjects population for the study are males and females with chronic open angle glaucoma or 
ocular hypertension in both eyes, this is in accordance with the OGD Draft Guidance on 
Brinzolamide (Recommended Apr 2014; Revised Dec 2014, Mar 2015). (9)  


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3.3.2 Rationale for Dose Selection 
The dose of the study medication either SPIL’s  Brinzolamide ophthalmic suspension USP 1% or 
Azopt® is 1 drop in both eyes TID at approximately 8:00 AM., 4:00 PM., and 10:00 PM for 42 days 
(6 weeks). This is as per the dosing schedule of the RLD Azopt®. 
3.3.3 
Rationale for the Use of Comparator 
The comparator chosen is the RLD Azopt® (brinzolamide ophthalmic suspension 1%), this is in 
accordance with the Office of Generic Drugs (OGD) Draft Guidance on Brinzolamide 
(Recommended Apr 2014; Revised Dec 2014, Mar 2015). (9) 
3.3.4 
Rationale for Study Endpoints 
The primary efficacy endpoint is mean difference in IOP of both eyes between the 2 treatment 
groups at 4 time points, i.e., at approximately 8:00 AM. (hour 0; before the morning drop) and 
10:00 AM (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) visits. This is in accordance with 
the OGD Draft Guidance on brinzolamide (Recommended Apr 2014; Revised Dec 2014, Mar 
2015). (9) 
3.4 Compliance Statement for Study Conduct in Accordance with Protocol, GCP and 
Applicable Regulatory Requirements 
The study protocol, amendments to the protocol, Investigator’s Brochure (IB), subject recruitment 
procedures (e.g., advertisements), the subjects’ information and informed consent form (ICF) as 
well as consent form updates (if applicable), written information to be provided to the subjects, 
available safety information, information about payment and compensation available to subjects, 
the Investigator’s current curriculum vitae and/or other documentation evidencing qualifications, 
and any other documents will be submitted to the Institutional Review Board (IRB)/Ethics 
Committee (EC), which is constituted according to local law to obtain approval before initiation 
of the study and as applicable thereafter. 
The study will only be initiated after receipt of the approval from the IRB or EC and/or regulatory 
authority. The Investigator will report promptly to the IRB/EC new information that may adversely 
affect the safety of the subjects or the conduct of the study. 
The PI (Principal Investigator) will follow the protocol in conformity with Good Clinical Practice 
(GCP) described in Guideline E6 of the ICH (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use) and applicable regulatory requirements before 
admission into the study, the written ICF must be signed and personally dated by the subject and 
by the PI or designee who conducted the informed consent discussion. 
In obtaining and documenting informed consents, the PI must comply with the applicable 
regulatory requirement(s), and must adhere to GCP. The PI must inform the subject of all pertinent 
aspects of the study including the written information approved/favorably assessed by the IRB/EC. 






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 Subjects currently in another clinical trial 
6.0 
STUDY DESIGN 
This is a randomized, Investigator-masked, multi-center, parallel Group, therapeutic equivalence  
study with clinical endpoint. 
6.1 Description of Type and Design of Study  
Treatment period will consist of TID dosing for 6 weeks. Subjects who are chronically treated with 
ocular hypotensive medications are required to undergo appropriate washout periods prior to study 
entry to minimize any residual effects of other active ocular hypotensive medications. 
6.2 General Instructions for Study Visits 
The Schedules of Assessments (Table 1-1) provides an overview of the timing of each visit, with 
allowed time window for the visit, along with events to occur at each visit. Individual trial 
procedures are described below, though efficacy assessments are described in more detail in 
assessment section and safety assessments and AE reporting is described in more detail in safety 
assessment section. The Sponsor or Contract Research Organization (CRO) will be notified 
immediately of any critical deviation from study procedures. All protocol deviations will be 
routinely examined by the Sponsor and CRO. 
6.3 Schedule of Assessments  
6.3.1 
Visit 1 Screening Visit (-42 days to Day -1) 
Screening Assessments 
Informed consent: Prior to any changes in a subject’s medical treatment and/or study visit 
procedures, the study will be discussed with each subject, and subjects wishing to participate must 
give written informed consent. The informed consent process will be captured in the subject’s 
source documentation.  
Demographic data and medical/surgical/medication/ocular history: Collect and record 
demographic data (age/date of birth, gender, and iris colour), medical and surgical history, any 
medications and any underlying condition(s). Current underlying conditions, including those that 
began within the last 30 days, which may have been resolved before screening, must be recorded. 
Record any medications the subject is taking, as well as those the subject may have taken but 
discontinued within the thirty days prior to screening.  
Urine pregnancy test (if applicable): Women of childbearing potential must have a negative urine 
pregnancy test to continue in the study and must agree to use an adequate method of contraception 
as per Investigator’s discretion in order to be enrolled. 


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NOTE: If a female becomes pregnant during the study, then the Investigator will notify the CRO 
within 24 hours of knowledge of the pregnancy and the subject should be withdrawn from the 
study. The CRO will notify 
 within 1 business day of knowledge of the pregnancy. The 
Investigator shall request from the subject and/or the subject’s physician copies of all related 
medical reports during the pregnancy and shall document the outcome of the pregnancy. The 
Investigator will retain these reports together with the subject’s source documents and will provide 
a copy of all documentation to the CRO. 
Examination procedures: The sequence of procedures will be in the following order: BSCVA, 
corneal pachymetry, slit lamp biomicroscopy, IOP measurement by Goldmann Tonometer and 
Gonioscopy. After this, pupil dilation is performed followed by fundus ophthalmoscopy. 
The following tests may be performed at any time during the visits: Heart rate and blood pressure, 
urine pregnancy test, and automated perimetry 
BSCVA: Subjects must have a score of 0.8 logMAR or better in each eye in order to qualify (see 
Appendix 1). 
Heart rate: Heart rate will be measured and recorded after the subject has been sitting for at least 
5 minutes. 
Blood pressure: Blood pressure will be measured and recorded after the subject has been sitting 
for at least 5 minutes.   
Automated perimetry (if applicable: required only if there is no data within the past 6 months): 
Automated perimetry procedures are outlined in Appendix 1. 
Slit lamp biomicroscopy: A slit lamp exam will be performed to exclude subjects with disallowed 
ocular conditions (see Appendix 1). 
Intraocular pressure (Goldmann applanation tonometry): IOP measurements will be taken using 
a Goldmann applanation tonometer. IOP will be measured at least twice in each eye with the right 
eye measured first. If the difference of the first 2 measurements is ≤ 1 mm Hg, the average of these 
2 measurements will be used as the IOP data for this eye. If the difference is > 1 mm Hg, a third 
measurement will be taken, and the median of these 3 measurements will be used as the IOP data 
for this eye (see Appendix 1). 
Corneal pachymetry for central corneal thickness: (If applicable: required only if there is no data 
in subject’s file within past 30 days). Corneal thickness will be measured using an ultrasound 
pachymeter. Subjects will be excluded in corneal thickness is > 600 μm (see Appendix 1). 
Gonioscopy: To examine iridocorneal angles (open, closed, or partially closed); the procedure will 
be conducted per the investigator’s standard of practice with grading based on the Shaffer scale 
(see Appendix 1). 


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Dilated ophthalmoscopy including C/D ratio: A dilated ophthalmoscopy will be performed by the 
investigator to evaluate the presence or absence of clinically significant fundus abnormalities, 
vitreous pathology (see Appendix 1).  
Discontinuation of current IOP lowering medications, if any 
Evaluation of inclusion and exclusion criteria 
AE assessment (reported, elicited, observed) 
x Telephonic follow up: to be scheduled during screening period at 2 weeks from date of 
signing consent form for subjects if both of the following conditions are met:Screening 
period is > 3 weeks, and  
x ocular hypotensive medication(s) were changed specifically for study purpose 
The Investigator will assess if the subject has any features of raised IOP.  Accordingly, an 
unscheduled site visit may be required as per PI discretion, if the subject is having clinical 
suspicion of raised IOP. If the IOP is found to be significantly raised (e.g.  > 34 mm Hg in either 
eye), then the subject will be considered a screen failure and the appropriate medical management 
performed as per PI discretion.  
Schedule for Visit 2 
6.3.2 
Visit 2 (Day 0) Baseline/Randomization 
x Confirmation of subject eligibility and reassessment of inclusion/exclusion after  washout 
x Randomization 
x Concomitant medications (systemic and ophthalmic) 
x Adverse event assessment (reported, elicited, observed) 
x Urine pregnancy test (if applicable) 
x Heart rate and blood pressure 
x BSCVA 
x Slit lamp biomicroscopy 
x Intraocular pressure 8:00 AM ± 30 min: by Goldmann  applanation tonometer (this will be the 
qualifying IOP for enrollment) 
x Dispensation of study medication and study medication compliance diary after IOP reading. 
x Intraocular pressure at 10:00 AM ± 30 min: by Goldmann  applanation tonometer  
x Subjects will be instructed to use their assigned study medication at home starting the next day. 
Subjects will be instructed to shake the bottle well and then instill study medication into the 
inferior cul-de-sac of both eyes (OU) at 8.00 AM. (±60 minutes), 4.00 PM. (±60 minutes) and 
10.00 PM. (±60 minutes). 
x Schedule next visit - subjects will be instructed to come for the next visit without instilling the 
morning dose on the visit date 


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6.3.3 Visit 3 -Week 2 ± 4 days 
x Concomitant medications (systemic and ophthalmic) 
x Adverse event assessment (reported, elicited, observed) 
x Heart rate, Blood pressure 
x BSCVA 
x Slit lamp biomicroscopy 
x Intraocular pressure at 8:00 AM ± 30 min and at 10:00 AM ± 30 min by Goldmann applanation 
tonometer. 
x In house study medication instillation (8:00 AM ± 30 min dose) after IOP reading.Review 
compliance diary 
x Dispensation of study medication and study medication compliance diary after IOP reading. 
x Subjects will be instructed to continue their assigned medication as per the dosage 
x Schedule next visit -subjects will be instructed to come for the next visit without instilling the 
morning dose on the visit date 
6.3.4 
End of treatment/Visit 4 (Week 6 ± 4 days) 
x Concomitant medications  
x AE assessment (reported, elicited, observed) 
x Urine pregnancy test (if applicable) 
x Review study medication compliance diary  
x Collect the study medication and medication dairy 
x Heart rate and blood pressure 
x BSCVA 
x Slit lamp biomicroscopy 
x Intraocular pressure at 08:00 AM ± 30 min and at 10:00 AM ± 30 min by Goldmann 
applanation 
x In house study medication instillation (8:00 AM ± 30 min dose) after IOP reading 
x Dilated ophthalmoscopy 
x Study exit 
 
6.3.5 
End of Study Visit 5: Telephonic Visit (Week 7 ± 4 days) 
A telephonic call will be done from the study site personnel to the subject after at least 1 week ± 
2 days of end of treatment visit 4 (Week 6 ± 2 days). This is to ensure the overall well being of the 
subject. 
6.3.6 
Early Discontinuation (ED) Visit  
An Early Discontinuation (ED) Visit will occur if a subject requests to withdraw from the study 
or is asked to withdraw by an Investigator (withdrawal rules). Document reason of subject’s 
termination from study participation, record timing subject took dose of study drug prior day and 
on day of visit and perform all procedures that are applicable for Visit 4 /End of Treatment Visit 
(Week 6±2 days). 


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Subjects whose condition worsens (e.g., IOP ≥ 36 mm Hg in either eye) and require alternate or 
supplemental therapy for the treatment of their chronic open angle glaucoma or ocular 
hypertension during the study should be discontinued, excluded from the per protocol (PP) 
population analysis, and provided with effective treatment. 
6.3.7 
Unscheduled Visits 
An unscheduled visit is defined as any visit to the Investigator site outside of the protocol-specified 
time points due to safety reasons or when a repeated measurement is required (e.g., obvious 
measurement errors, confirmation of out-of-range results), or if a test is missed at a visit and needs 
to be performed, or for dispensing study drug to the subject, where the subject is seen by study 
personnel. 
All unscheduled visits and assessments performed during the visits will be recorded in the subject’s 
source documents and electronic Case Report Form (eCRF). During any unscheduled visits the 
Investigator will record any AEs and concomitant medications as well as performing any 
assessments or collecting samples deemed necessary at the discretion of the Investigator. 
6.3.8 
COVID 19 restrictions  
Wherever possible, subjects will visit the site for their routine visit. However if this is not possible 
due to COVID19 restrictions, the best possible efforts shall be made to capture the safety data 
virtually. Considering the study design, it is difficult to capture the efficacy data virtually. If 
necessary, site will also consider if visits can be rescheduled and postponed without impact after 
discussion with the CRO and Sponsor. 
Access to clinical trial medication (study medication): Sponsor through sites will try to make 
provision for study medication to be delivered to subject’s residence after obtaining a verbal 
consent from subject wherever feasible.  
Patient assessments:  Necessary subject assessments will be collected as per protocol, except if 
not possible due to restrictions. In this case, AEs can be collected virtually. If necessary, the 
Sponsor will also approve the nurse/ site staff visiting the subject’s residence for collecting other 
assessments if feasible and necessary. 
In the situation where none of the above can be done, the subject visit shall be recorded as missed 
and protocol deviation shall be captured. 
Clinical trial monitoring: Sponsor shall encourage the monitoring of clinical trial data remotely 
either through webex or video call. The source data verification of the data reviewed remotely 
shall be completed onsite, when the situation normalize. All above changes shall be documented 
in the Study Monitoring Plan. 


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6.4 Measures Taken to Avoid Bias 
6.4.1 
Subject Number 
Subjects will be allotted a unique subject number at time of consent. The subject number will 
appear on all study documents relating to that subject and will be cross-referenced by the subject’s 
year of birth. 
6.4.2 
Randomization 
A computer generated randomization scheme will be produced by the CRO. Randomization will 
be 1:1 to each group. Approximately 666 subjects (333 per treatment arm) will be randomized in 
this study. Since the study will be conducted in Russia and India, 466 subjects will be recruited in 
Russia and 200 subjects will be recruited in India. 
Masking: This is an evaluator-masked study. The Investigator, masked to treatment assignment, 
will perform all ophthalmic examinations. An unmasked study coordinator may perform study 
procedures other than ophthalmic/clinical examination, or treatment of the subjects. The 
Investigator will be responsible for deciding the type of medical care a subject will get; 
identifying the kinds of work a subject can safely perform while in the study, and assessment of 
safety. In order to maintain masking, the unmasked site personnel will dispense IP on Visit 2, 3, 
and 4 in a room separate from the evaluating Investigator and the subjects will be asked not to 
discuss the treatment received with the Investigator in order to maintain Investigator-masking.  
The blinding code will be stored in the Interactive Web Response System (IWRS) system, 
available only to parties independent of study conduct.  
To minimize bias, test and reference bottles will be packed in an identical box with similar label. 
An unmasked site personnel will instill the in-office physician dispensing (OPD) doses in a room 
separate from the evaluating Investigator in order to maintain Investigator-masking. In order to 
maintain masking, the Investigator will not personally retrieve/review the study medication 
diary; only designated study personnel will collect and review the diary at each visit to ensure 
treatment compliance. 
The code will be broken when the database is cleaned and locked. Prior to the final unblinding, a 
review to identify the per-protocol population will be undertaken. After database lock, 
unblinding will be performed by matching the randomization codes to the data in the database 
and the results will be analyzed. 
The treatment code may be revealed on an individual basis in the case of SAE or a safety 
emergency for which the Investigator must know the identity of the study medication to initiate 
appropriate treatment. The Investigator will use the IWRS to unblind the subject. Only PI or 
appropriately delegated sub-Investigator will be given necessary access to open the blind for an 
individual subject. If the blind is broken, the site must inform the medical monitor or designee 
and report the reason for unblinding. Date, time, and reason for unblinding, with Investigator’s 
signature, must be recorded. All serious SAEs will be evaluated for causality by the Investigator 
or designee. A designated member of the Sponsor’s safety team will be un-blinded for any SAE 
that needs unblinding for regulatory reporting purpose or for the subjects safety. 




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1. If the Investigator terminates or suspends a trial without prior agreement of the Sponsor, 
the 
Investigator 
should 
inform 
the 
institution 
where 
applicable, 
and 
the 
Investigator/institution should promptly inform the sponsor and the IRB/EC, and should 
provide the Sponsor and the IRB/EC a detailed written explanation of the termination or 
suspension. 
2. The Sponsor may discontinue entire study at any time, for business, ethical or scientific 
reasons. If the Sponsor terminates or suspends the trial, the Investigator should promptly 
inform the institution where applicable and the Investigator/institution should promptly 
inform the IRB/EC and provide the IRB/EC a detailed written explanation of the 
termination or suspension. 
3. If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the 
Investigator should inform the institution where applicable and the Investigator/institution 
should promptly notify the sponsor and provide the sponsor with a detailed written 
explanation of the termination or suspension. 
6.6 The Identification of Any Data to be Recorded Directly in the eCRF 
No data will be directly recorded in eCRF. Subjects’ information will be documented on source 
documents and then transferred to the individual eCRFs. The original reports, e.g., laboratory 
reports, will be kept at the study site. The date and time of report will be transcribed to specific 
sections in the eCRFs. Electronically generated data like laboratory results, etc could be directly 
integrated with or transferred to the clinical database.  
7.0 
TREATMENT OF SUBJECTS 
7.1 Investigational Medicinal Products 
7.1.1 
Study Medication 
SPIL’s Brinzolamide ophthalmic suspension USP 1% w/v, 10mL 
Azopt® 1% brinzolamide ophthalmic suspension (Alcon Laboratories, Inc), 10mL 
7.1.2 
Handling Requirements of the Investigational Product 
The Sponsor will be permitted upon request to audit the supplies, storage, dispensing procedures 
and records provided that the blind of the study is not compromised. 
Subjects will be instructed to store study medication/IP at room temperature 20° to 25°C, not to 
freeze and to protect from light (direct light, sunlight). Study medications will be permitted with 
temperature excursion of 15° to 30° C. Subjects will be dispensed their assigned study medication 
at Visit 2 and Visit 3. 


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7.1.3 
Dispensing (Labeling and Packaging) and Compliance 
The study drug will be supplied to the study centers by a CRO appointed by the Sponsor. The 
IWRS supports drug supply process. Individual subject treatments will be dispensed by the study 
center pharmacist/appropriately qualified designee in bottles. All clinical study material will be 
packaged and labelled to comply with applicable regulations. The study drug will be clearly 
labelled according to local requirements regarding use for clinical study investigation only. For 
further details see the IP Manual. 
The following information will be given on the label statement: 
x Sponsor name, address, and manufactured by 
x Protocol number 
x Study medication/IP name 
x Study medication/IP number 
x Volume of content 
x Batch number 
x Manufacturing/expiry date (as per local regulatory requirement) 
x Storage conditions 
x Re-test date 
x Do not use after 
x Subject number 
x Investigator’s name 
x Investigator’s contact number  
x Study site number 
x For ophthalmic topical use only 
Any additional information required as per the local regulatory requirements 
7.1.4 
Investigational Product Numbering 
Each study medication container will be uniquely numbered. The study medication number(s) 
will be recorded in the source documents. 
7.1.5 
Accountability Procedures for the Investigational Product 
The Sponsor will supply sufficient quantities of the study drug to allow completion of this study, 
in an appropriate package deemed to maintain the integrity of the products. In accordance with 
GCP, the study site will account for all supplies of study medication. The supplies will be stored 


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as per label instructions until dispensed, in a pharmacy accessible only to pharmacist or authorized 
person. Details of receipt, storage, assembly, dispensing, and return will be recorded. All unused 
supplies of study drug will either be destroyed by a designated vendor or will be returned to the 
study Sponsor at the end of the study in accordance with instructions by the Sponsor.  
7.2 Dosage and Dosage Regimen 
7.2.1 
General Dosing Instructions 
Subjects will be instructed to shake the study medication bottle well before use and to instill 1 
drop of study medication into the inferior cul-de-sac of each eye TID at 8.00 AM. (±60 minutes), 
4.00 PM. (±60 minutes) and 10.00 PM. (±60 minutes). Subjects will be instructed not to dose at 
home prior to their study visits on Week 2 and Week 6. 
7.3 Medication(s)/Treatment(s) Permitted and Not Permitted Before and/or During the 
Study 
Concomitant medications are any medications taken by the subject other than the assigned study 
drug, these will be recorded in the source document as concomitant medications. 
Any medications (other than those excluded by the inclusion/exclusion criteria) that are 
considered mandatory for the subjects’ welfare and that are not anticipated by the Investigator to 
be likely to interfere with the efficacy assessments, may be given at the discretion of the 
Investigator. 
Medications other than those specifically excluded in this study may be administered for 
management of concomitant illness, AEs, or symptoms associated with study medications may 
be administered. 
7.3.1 Prohibited medications include the following: 
a. Ocular hypotensive drug product other than a study treatment, e.g., acetazolamide 
(Diamox®), betaxolol (Betoptic®, Betopic-S®), betaxolol and pilocarpine (Betoptic® Pilo), 
bimatoprost (Lumigan®), brimonidine tartrate (Alphagan®, Alphagan® P), brimonidine 
tartrate and brinzolamide (Simbrinza®), brimonidine tartrate and timolol maleate 
(Combigan®), carbachol (Miostat®), carteolol (Ocupress®), dorzolamide hydrochloride 
(Trusopt®), dorzolamide hydrochloride and timolol maleate (Cosopt®), epinephrine 
(Epifrin®), latanoprost (Xalatan®), levobetaxolol (Betaxon®), levobunolol (Akbeta®, 
Betagan®), mannitol (Osmitrol®), metipranolol (OptiPranolol®), pilocarpine (Isopto® 
Carpine, Pilopine HS®), tafluprost (Zioptan™), timolol (Betimol®, Istalol®, Timoptic®, 
Timoptic XE®), travoprost (Travatan®, Travatan Z®) 
b. Ophthalmic over-the-counter or prescription product, other than study treatment and the 
occasional use of artificial tears 
c. Oral carbonic anhydrase inhibitor 
d. High-dose salicylate therapy 


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e. Topical or systemic corticosteroid 
f. Topical ophthalmic corticosteroid 
g. Intraocular corticosteroid implant 
h. Intravitreal or subtenon injection of ophthalmic corticosteroid 
i. Systemic beta-adrenergic blocking drug product 
j. Change in concurrent treatment or initiation of treatment with agents potentially 
affecting IOP, e.g., antihypertensive medication 
k. Contact lenses 
All concomitant medications must be appropriately recorded in the source documents and 
described in the eCRF. 
7.4 Procedure(s) for Monitoring Subject Compliance 
Study medication will be dispensed by the site personnel. Dispensation will be documented in the 
drug accountability log or equivalent document. Subjects will be instructed to bring their dosing 
diary and used and unused medication bottle at the time of visit, they will be instructed to record 
in a dosing diary the date and time at which they took the study drug.  
Compliance to study medication will be determined by subject self-report as recorded in subject 
diaries. Missing diary data may be collected by subject questioning. At Week 4 ± 2 days, the site 
personnel shall call the subject to remind them to continue dosing. This is simply a measure to 
enhance compliance to the study medication. 
 
 


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8.0 
ASSESSMENT OF EFFICACY 
As per the OGD guidance, primary efficacy endpoint is the mean difference in IOP of both eyes 
between the 2 treatment groups at 4 time points, i.e., at approximately 8:00 a.m. (hour 0; before 
the morning drop) and 10:00 a.m. (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) visits 
This will be done by measuring IOP at 08:00 AM ± 30 min and at 10:00 AM ± 30 min using 
Goldmann applanation tonometer at the baseline visit (Visit 2) and at the Day 14 (Week 2) and 
Day 42 (Week 6) visits. 
The secondary efficacy endpoint is change from baseline in IOP of both eyes between the 2 
treatment groups at 4 time points, i.e., at approximately 8:00 AM (hour 0; before the morning drop) 
and 10:00 AM (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) visits. 
9.0 
ASSESSMENT OF SAFETY 
9.1 Description of Safety Parameters 
The following ocular safety assessments will be done during the study as per the Schedule of 
Assessments  
The order of assessment will be the following: 
1. BSCVA 
2. Slit lamp biomicroscopy 
3. Goldmann tonometry 
4. Dilated ophthalmoscopy, including recording cup/disc ratio 
 
9.2 Definitions of Adverse Events 
9.2.1 
Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a drug 
and does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study medication (investigational), whether or not 
related to the study medication (investigational). 
Untoward medical experience occurring during medication-free pre-treatment periods does not 
meet the above-mentioned definition of an AE. Nevertheless, they have to be documented in the 
same way as AE. Each subject will be queried generally for the occurrence of adverse experiences 
prior to study medication administration and throughout the subject’s participation in the study. 
During and following a subject's participation in this study, the Investigator has to ensure that 
adequate medical care is provided to a subject for any AE, including clinically significant 
laboratory values. The subject will be treated and/or followed up until the symptom(s) return to 
normal, as judged by the Investigator. 


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9.2.2 
Serious Adverse Event 
A SAE is any untoward medical occurrence that, at any dose 
x Results in death 
x Is life-threatening 
x Requires in-subject hospitalization or prolongation of existing hospitalization* 
x Results in persistent or significant disability/incapacity 
x Is a congenital anomaly/birth defect 
x Important medical event: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered as SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.), 
convulsions that do not result in hospitalization, or the development of drug dependency 
or drug abuse. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event, which, 
hypothetically, might have caused death if it were more severe. 
*A planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health or if the hospitalization is clearly not 
associated with an AE (e.g., hospitalization due to social / logistic reason) are not to be considered 
as SAEs. 
9.3 Pregnancy 
Women of childbearing potential must agree to the use of a reliable method of contraception (e.g., 
total abstinence, intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], oral, transdermal, injected or implanted non- or hormonal contraceptive), 
throughout the study. A sterile sexual partner is not considered an adequate form of birth control. 
Subjects on hormonal contraceptives must have been on the same hormonal contraceptive for at 
least 1 month before the Screening and continue throughout the duration of the study. 
A female is considered of childbearing potential if she has had her first menses and she is either: 
a. not postmenopausal for at least 12 consecutive months prior to enrollment; or 
b. not surgically sterilized by bilateral tubal ligation, or bilateral oophorectomy, or 
hysterectomy 
c. Male subjects with partners of childbearing potential who are not using birth control as 
described above must use a barrier method of contraception (e.g., condom) if not surgically 
sterile (i.e., vasectomy). 


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Male subjects enrolled in the study will be instructed to avoid passage of semen to their partner by 
using an acceptable contraceptive method to avoid fathering a child. If a female subject becomes 
pregnant during the study, the pregnancy will be recorded as a significant medical event and 
reported per SAE reporting procedures and the subject will be withdrawn from the study 
immediately. If a female partner of a male subject becomes pregnant during the study, the medical 
event will be recorded appropriately with the ‘Pregnancy Reporting Form’ and submitted to the 
Sponsor’s safety physician/CRO. All pregnancies shall be followed every 3-months until outcome 
and up to one month post delivery to assess the functional status of the child. If any SAE occurs 
during pregnancy then it will be reported using SAE forms. Any congenital abnormalities or birth 
defects in the newborn will be followed 3-months post delivery.  
9.4 Eliciting, Documentation and Reporting of Adverse Events 
Information on AEs will be derived by questioning the subjects in general terms (e.g., "How do 
you feel?” or “How have you been feeling since the last questioning?” respectively), by subjects' 
spontaneous reports, or by observation. 
Adverse events will be documented on the source document. Trained monitors will check the 
entries on the source document. The AE will be transcribed to the AE eCRF-sections. The 
following information will be given for each AE: description of the AE, start date, stop date, 
severity, pattern, action taken, outcome, seriousness, dose of study drug, and relationship to the 
study medications. The dose of study medication assigned to an AE will be the dose the subject 
was assigned to take on the date the subject reported the AE first began.   
The AE/SAE collection period for safety surveillance begins when the subject signs the ICF and 
continues until the end of treatment visit or until the last dose of study medication for subjects with 
early discontinuation. Adverse events with an onset before the subject receives first dose of the 
study medication will be categorized as non-treatment emergent AEs (non-TEAEs). Adverse 
events with an onset after at least 1 dose of study medication is received will be reported as TEAEs. 
Safety reporting is inline with the local regulatory requirements in which the study will be 
conducted. 
9.5 Causality of Adverse Events 
The relationship of AEs to study medication will be assessed by the Investigator, and will be a 
clinical decision based on all available information. Following definitions shall be used for 
assessment of causality. 
Category  
Definition 
Unrelated 
Those adverse events (AEs) which, after thorough assessment, are clearly due to extraneous 
causes (disease, environment, etc.) 
Related 
The causal relation between the study medication and event cannot be excluded 
 
The Investigator should consider the following, for causality assessment:  
• Time relationship between study medication intake and event’s onset  


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• Dechallenge  
• Rechallenge  
• Medical history  
• Study treatment  
• Mechanism of action of study medication  
• Concomitant medications in use 
• Lack of efficacy/worsening of existing condition  
• Erroneous treatment with study medication or concomitant medication  
• Protocol-related procedure.  
 
9.6 Assessment of severity, outcome and expectedness of Adverse Events 
The severity of an AE will be characterized as: 
x Mild: AE which is easily tolerated 
x Moderate: AE sufficiently discomforting to interfere with daily activity. 
x Severe: AE, which prevents normal daily activities. 
x Life-threatening: The subject is at risk of death due to the AE as it occurred. This does not 
refer to an event that hypothetically might have caused death if it were more severe. 
x Death: Death related to AE 
Event outcome or time last follow-up is recorded is categorized as “fatal”, “resolved”, “resolved 
with sequelae”, “resolving”, “not resolved”, or “unknown”. 
Action taken with respect to study drug is categorized as “none”, “study medication discontinued 
/ withdrawn”, “study medication discontinued and restarted”, “required concomitant medication”, 
“required procedure”, or “other”. 
Assessment of Expectedness will be determined by the version of the IB effective at the time of 
onset of the adverse event. 
9.7 Documentation and Reporting of Immediately Reportable Adverse Events 
All SAEs must be reported according to ICH GCP or local regulations, applying the regulation 
with the stricter requirements. The report will contain as much available information concerning 
the SAE to enable the Sponsor’s safety physician/CRO to file a report, which satisfies regulatory 
reporting requirements. The SAE report will be notified by Investigator within 24 hours of his / 
her awareness to the Sponsor’s safety physician/CRO. These timelines apply to initial reports of 
SAEs and to all follow-up reports. 
All AEs/SAEs will be recorded on the AE/SAE Report Form in the eCRF and source documents. 
As much information as possible should be supplied at the time of the initial report with at least 
the following information using SAE Report Form: 
x Name, address, and telephone number of the reporting Investigator 
x Investigational product(s) (study medication) 


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x Protocol number 
x Subject identification number, initials, sex and date of birth 
x Description of the AE, reason considered serious, measures taken and outcome (if 
resolved) 
x Likelihood of drug causation of the AE assessed by the Investigator. 
x Additional follow-up information should be completed on an SAE follow-up form with a 
copy sent to the Sponsor’s safety physician/CRO. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone. 
In these cases, a written report must be sent immediately thereafter by email to the Sponsor’s safety 
physician/CRO. 
Relevant pages from the source document and eCRF may be provided in parallel (e.g., medical 
history, and concomitant drugs). Additional documents may be provided by the Investigator, if 
available (e.g., laboratory results, hospital report, and autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in the 
eCRF. 
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, and other records where needed) or to any question the 
Sponsor’s safety physician/CRO may have on the SAE. This is necessary to ensure prompt 
assessment of the event by the Sponsor’s safety physician to allow the Sponsor to meet strict 
regulatory timelines associated with expedited safety reporting obligations. 
Requests for follow-up will usually be made via the Sponsor’s safety physician/CRO. 
9.7.1 
Serious Adverse Events/Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
Reporting 
to 
Regulatory 
Authorities/EC/IRBs/Participating 
Investigators 
The applicable Regulatory Authorities shall be notified by Sponsor Safety Physician/CRO of any 
SAE/SUSAR, as per local Regulatory Authorities guidelines and timeframe specified as per local 
regulation.  
All participating Investigators, EC/IRB and other stakeholders shall be notified of any 
SAE/SUSAR by CRO as per local regulatory requirement. 
For any SAE, the Investigator must notify the contact person listed below immediately: 
 
 
The Investigator is obligated to pursue and provide information to Sponsor and the responsible 
CRO on all SAEs in accordance with the timeframes for reporting specified above. In addition, an 
Investigator may be requested by Sponsor and the responsible CRO to obtain specific additional 






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10.1 
Study Population 
10.1.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population consists of all subjects who are randomized into the study. 
All data will be included and no subjects will be excluded because of protocol violations.  The ITT 
population will summarize subjects as randomized and will be used for confirmatory analyses. 
10.1.2 
Per Protocol Population 
The PP  population includes all randomized subjects who meet all inclusion/exclusion criteria, and 
complete evaluations at week 2, week 6 (with compliance between 75 to 125%) with no protocol 
violations that would affect the treatment evaluation. The PP population will be considered the 
primary analysis population for the study and will summarize subjects as treated. 
10.1.3 
Safety Population 
The safety population includes all subjects who receive at least 1 dose of study medication. The 
safety population will be used to summarize safety variables and will summarize subjects as 
treated. 
10.2 
Study Endpoints 
10.2.1 
Primary Efficacy End point: 
Mean difference in IOP of both eyes between the two treatment groups at four time points, i.e., at 
approximately 8:00 a.m. (hour 0; before the morning drop) and 10:00 a.m. (2 hours) at the Day 
14 (Week 2) and Day 42 (Week 6) visits. 
10.2.2 
Secondary Efficacy endpoint: 
Change from baseline in IOP of both eyes between the 2 treatment groups at 4 time points, i.e., at 
approximately 8:00 a.m. (hour 0; before the morning drop) and 10:00 a.m. (hour 2) at the Day 14 
(Week 2) and Day 42 (Week 6) visits. 
 
10.2.3 
Safety: 
x Incidence and severity of AEs 
x BSCVA 
x Slit lamp Biomicroscopy 
x Tonometry 
x Dilated fundus exam, including Cup/Disc ratio 
 
10.3 
Efficacy Analysis 
The accepted PP population used for BE evaluation includes all randomized subjects who meet all 
inclusion/exclusion criteria, instill a pre-specified proportion of the scheduled doses (i.e., 
compliance between 75 to 125%) of the assigned product for the specified duration of the study, 


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and complete evaluations at Day 14 (Week 2) and Day 42 (Week 6) with no protocol violations 
that would affect the treatment evaluation. 
Subjects whose condition worsens (e.g., IOP ≥ 36 mm Hg in either eye) and require alternate or 
supplemental therapy for the treatment of their chronic open angle glaucoma or ocular 
hypertension during the study should be discontinued, excluded from the PP population analysis, 
and provided with effective treatment. 
Analysis will be done in both eyes. The primary analyses will be completed by constructing two-
sided 95% confidence intervals of the treatment difference (test – reference) for mean IOP of both 
eyes (continuous variable) at all four follow-up points (i.e., at approximately 8:00 a.m. [hour 0; 
before the morning drop] and 10:00 a.m. [hour 2] at the Day 14 [Week 2] and Day 42 [Week 6]) 
visits. This mean IOP must be within ± 1.5 mm Hg using the PP population for all time points 
measured and within ± 1.0 mm Hg using the PP population for the majority of time points 
measured. Additional details of the statistical approach considering country wise analysis will be 
provided in the SAP.  
For change from baseline IOP, baseline will refer to the time-matched measure at Visit 2. For all 
other variables, baseline is defined as the last measurement prior to the first dose of study 
medication. Change from baseline will be calculated as visit – baseline. The p-values for testing 
equivalence of these time-matched means between treatment groups will be generated using the 
TOST (two one-sided tests) procedure at each of the equivalence limits (-1.0, 1.0) and (-1.5, 1.5). 
In addition to these individual confidence intervals, a mixed effects repeated measures model, with 
random effect for subject, covariate for baseline IOP, and fixed effects for treatment and day/time 
(within subject repeated measures) will be fitted to the data.  Appropriate covariance structure will 
be used to model the within subject, between time point variances.  Individual and simultaneous 
confidence intervals will then be constructed based on this MMRM model at each of the time 
points.  The 95% simultaneous confidence intervals will use the Tukey-Kramer method to adjust 
for multiple comparisons across all 4 time points.   
The analyses of the efficacy variable will be completed on observed data only (without 
imputation). To check robustness of results, sensitivity analyses of the primary efficacy data will 
include using: a multiple imputation technique to impute missing data. 
For the multiple imputation approach, the multiple imputation technique proposed by Rubin (1987) 
replaces each missing value with a set of plausible values and these imputed data sets are then 
analyzed by using standard procedures for complete data and combining the results from these 
analyses. A Markov chain Monte Carlo (MCMC) method, which can be implemented within SAS 
software that assumes multivariate normality, will be used for imputation. 
10.4 
Safety Analysis 
The safety population includes all randomized subjects who receive study product. 


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The primary safety analysis will summarize ocular (in both the eyes) and non-ocular AEs for all 
treated subjects using discrete summaries at the subject level by Medical Dictionary for Regulatory 
Activities (MedDRA®), SOC, and PT for each treatment group. A TEAE will be defined as 
occurring after the first dose of study medication for the period. Treatment-related ocular and non-
ocular TEAEs will be summarized similarly. Ocular and non-ocular TEAEs will also be 
summarized by severity. For safety summaries the unit of analyses will be both eyes for ocular 
measures and will be the subject for non-ocular safety measures as well as all AEs. 
Ocular safety assessments include: 
a. Biomicroscopy: Slit lamp biomicroscopy will be performed at every visit during the study 
to observe the overall health of the eye, including the lid/lashes, conjunctiva, cornea 
anterior chamber, iris and lens. Any observations at the screening visit should be recorded 
as ocular medical history, and any new or worsened observations may be recorded as AEs 
b. Dilated ophthalmoscopy (Visits 1 and Visit 4) items to be observed are retina, macula, 
choroids, optic nerve, and optic disc pallor examination measures will be summarized at 
each visit using discrete summary statistics. 
c. Visual acuity: Data will be summarized at each visit, using continuous and discrete 
summaries, including change from baseline in the number of lines and the proportion of 
subjects with a worsening of ≥ 3 lines from baseline. 
Heart rate and blood pressure: Data will be summarized using continuous summary statistics 
(mean, standard deviation, minimum, median, and maximum) by visit including change from 
baseline summaries. 
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation of study 
drugs, will be listed. Adverse events will also be summarized by actual dose at time of onset of the 
AE to account for possible dose reductions over the course of the study. 
10.5 
Sample Size 
An equivalence test of means using two one-sided tests on data from a parallel-group design with 
sample sizes of 266 in the SPIL’s Brinzolamide ophthalmic suspension 1% and 266 in Azopt® 1% 
achieves 90% power at an α = 0.05 significance level when the true difference between the means 
is 0, the standard deviation is 3.5, and the 95% equivalence limits are -1.0 and 1.0. 
Considering the possibility of 20% of subjects not being evaluable either due to dropping out of 
the study or having major protocol violations, approximately 333 subjects will be enrolled in each 
treatment group for a total of 666 subjects in the study.  
 
11.0 
STUDY MANAGEMENT 
11.1 
Monitoring 
Onsite monitoring will be performed during the study. The monitor will ensure that the study is 
conducted, recorded and reported in accordance with the protocol, standard operating procedure 


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(SOP), GCP, and the applicable regulatory requirements. The monitor will check the accuracy and 
completeness of the eCRF entries, source documents, and other study-related records against each 
other. The monitor will follow written SOPs as well as those procedures that are specified by CRO 
for monitoring a specific study. The monitor will record the date of each visit together with a 
summary of the status and progress of the study. Proposed actions will be confirmed with the 
Investigator in writing. 
The Investigator will provide direct access to source data/documents for study related monitoring. 
It is important that the Investigator and/or other staff are available at these visits. The Investigator 
should maintain source documents such as laboratory reports, history and physical examination 
reports, etc., for possible review. 
11.2 
Documentation at the Study Site 
Data relating to the study will be documented in the source documents and eCRFs. The Investigator 
will ensure the accuracy, completeness, legibility, and timeliness of the data recorded in the source 
documents and eCRFs. Any change or correction to a source document or eCRF will be dated, 
initialed, and explained (if necessary) and will not obscure the original entry. 
At the beginning of the study, a site master file will be established at the investigational site. The 
Investigator will maintain the study documents as specified in the ICH Guideline of GCP and as 
required by the applicable regulatory requirements. The Investigator will take measures to prevent 
accidental or premature destruction of these documents. The Investigator will permit study-related 
monitoring, audits, and IRB/EC or regulatory inspection, providing direct access to source data or 
documents. 
Prior to the start of the study, a signature and delegation log will be completed showing the 
signatures and hand-written initials of all study staff. This log allows the PI to delegate study tasks 
to individual members of his/her team, identifies site staff participating in the study and the 
start/stop times of their participation, and provides a handwriting sample for all site staff 
participating in the study. 
11.3 
Retention Samples 
The clinical investigator or designee should randomly select sufficient test article and reference 
standard to conduct the study from the supplies received from the sponsor and/or drug 
manufacturer, and retain the remaining study samples as study reserves.  
The testing facility or the pharmacy of the testing facility should retain the reserve samples. 
If the testing facility does not have adequate storage, or goes out of business, the reserve samples 
can be transferred to an independent third party with an adequate facility for storage under 
conditions consistent with product labeling. 
 


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11.4 
Subject Data and Data Protection 
To protect the subject's identity, a subject number will be assigned by the Investigator to each 
study subject and used in lieu of the subject's name when the Investigator reports AEs and/or other 
study-related data. Personal information will be treated as confidential but may need to be 
reviewed by authorized representatives of CRO/Sponsor (if applicable) (monitor and auditor), 
IRB/EC and regulatory authorities. The subject's consent for direct access to his/her original 
medical records for data verification purposes has to be obtained prior to a subject's participation 
in the study. 
The Investigator must maintain a list of names and identifying information (e.g. initials, date of 
birth, subject identification code and date of study randomization) of all subjects enrolled in the 
study. The Investigator will keep the subject identification code list in the site master file. 
11.5 
Data Management  
A Code of Federal Regulations (CFR) Title 21 Part 11-compliance Electronic Data Capture (EDC) 
system will be used for this study. The eCRFs will be produced for each subject. The majority of 
study data collected on the source documents will be entered by the study center staff or directly 
captured from devices and submitted to the database. Data will be available for Sponsor review 
via predefined reports extracted from the database at agreed intervals. The eCRFs must be kept in 
order and up-to-date so that they reflect the latest observations on the enrolled subjects. 
All source documents will be retained. Photocopies of completed source documents will be 
provided only if essential (i.e., for regulatory purposes) at the request of the Sponsor. 
Safety laboratory data are managed and stored within the appropriate system and the date and time 
of sampling will be recorded in the eCRF. Safety laboratory data will be integrated or transferred 
with the consolidated clinical data before database lock. 
The informed consent will be kept with a copy of the completed source documents in the 
appropriate file folder provided, or a note to indicate where the records can be located. All records 
should be kept in conformance to applicable national laws and regulations. 
Validity and consistency of data will be checked by employing pre-programmed data validation 
rules that will be applied to the data extracted from the EDC system during the course of the study. 
The data management team will raise queries in the EDC system to resolve discrepancies. The 
Investigator must verify that all data entries in the eCRFs are accurate and correct per the source 
document. After completion of the study and when all collected data is validated, the database will 
be locked, pursuant to the prior approval by the Sponsor. Final data will be extracted from the 
EDC system and delivered to the Sponsor in form of SAS® datasets. A portable document format 
copy of the eCRF will be produced for each study subject and included in the final delivery. 
All eCRF entries, corrections, and alterations must be made by the Investigator or other, 
authorized, study center staff and only by individuals who have received training on the EDC 


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system. Study center staff may be allowed access to the system only after the relevant training is 
completed. Training must be documented and a log of all EDC users and their rights within the 
system be maintained. 
Adverse events will be coded using the current MedDRA thesaurus and concomitant medications 
will be coded using World Health Organization’s Drug Dictionary. 
The EDC system will keep track of all data entry, alterations and query resolution in an audit trail. 
The audit trail will form an integral part of the database and will be archived alongside with the 
data. 
Details of the data management process including the data to be entered of the screening failure 
subjects will included in the data management plan. 
11.6 
Compliance with Protocol 
The investigator or institution should conduct the trial in compliance with the protocol agreed to 
by the Sponsor and, if required, by the regulatory authority(ies) and which was given 
approval/favorable opinion by the IRB/EC. 
The Investigator will not implement any deviation from, or changes to the protocol without 
agreement by Sponsor and prior review and documented approval/favorable opinion from the 
IRB/EC of an amendment, except where necessary to eliminate immediate hazards to study subject 
or when the changes involve only logistical or administrative aspects of the study (e.g., change in 
monitor(s), change in telephone numbers). 
11.7 
Amendments to the Protocol 
All changes or deviations of the trial must be confirmed in writing. The amendments to protocol 
will be made jointly between the CRO (if applicable), the Sponsor and Investigator(s). Protocol 
amendment(s) will be signed off in the same way as the protocol.  
11.8 
Investigator Responsibilities 
11.8.1 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor 
or designee, and given approval/favorable opinion by the IRB and the appropriate regulatory 
authorities. The Investigator will sign this protocol to confirm agreement (see PI Signature Page). 
11.8.2 
Protocol Deviations 
The Investigator should not implement any deviation from, or change to the protocol without prior 
agreement with the Sponsor or designee. When immediate deviation from the protocol is required 
to eliminate an immediate hazard(s) to subjects, the Investigator will contact Sponsor or designee, 
if circumstances permit, to discuss the planned course of action. Any departures from the protocol 


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must be fully documented and submitted to the IRB in accordance with the IRB’s reporting 
requirements. 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance and quality control systems are implemented and maintained using written SOPs 
to ensure that the study is conducted and data are generated, documented (recorded) and reported 
in compliance with the protocol, GCP, and the applicable regulatory requirement(s). Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly. 
12.1 
Audit 
Sponsor or designee may conduct an internal or external audit. In such an instance, the auditor will 
be allowed direct access to the source medical records, the pharmacy, the eCRFs, and the Site’s 
master file for the study. In addition, the regulatory authorities may also request an audit. 
13.0 
ETHICS 
Before initiation of the study, Sponsor will seek permission from the regulatory authorities and EC 
for conducting the study. All documents required by the appropriate authorities will be submitted. 
Any notification/submission will be dated and contain sufficient information to identify the 
protocol. 
13.1 
Ethics Committee (EC) or Institutional Review Board (IRB) 
This study will be initiated after the protocol is reviewed and approved by the concerned IRB or 
EC. All documents required by the appropriate authorities will be submitted. Any 
notifications/submission will be dated and contain sufficient information to identify the protocol.  
13.2 
Ethical Conduct of the Study 
This study will be carried out in conformity with GCP described in Guideline E6 of the ICH. This 
study will also be carried out in conformity with the laws, rules, and regulations prevailing in the 
state and country of the study site. 
13.3 
Subject Information and Consent 
Subject will be screened and included in the study only after giving them adequate and appropriate 
information, and obtaining a written informed consent. The subject will be given sufficient time 
to consider the study’s implications before deciding to participate. The subject will be provided 
with a copy of the signed ICF. The confidentiality of the subject’s records will be maintained. If 
there is any major amendment in the protocol affecting the subject’s participation in the study e.g., 
a change in any procedure, the ICF will be amended to incorporate this modification and previously 
consented subjects will sign an amended consent form (when relevant). The Investigator is 
responsible for obtaining the subject’s freely given written consent. 


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14.0 
DATA HANDLING AND RECORD KEEPING 
The Investigator must maintain all documentation relating to this study. Essential documents (as 
defined in the ICH Guideline of GCP) must be retained until at least 2-years after the last approval 
of a marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2-years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents must be 
retained for a longer period, however, if required by the applicable regulatory requirement(s) or if 
needed by Sponsor. 
In any case, all study records such as but not limited to CRFs, regulatory documents, the subject 
identification code list, subject files and other source data that support CRFs must be retained for 
at least 15-years after the completion or discontinuation of the study. If the Investigator retires, 
relocates or for other reasons withdraws from the responsibility of keeping the study records, 
custody must be transferred and Sponsor notified in writing. Sponsor will notify the Investigator 
in writing when the study-related records are no longer needed. 
15.0 
FINANCING AND INSURANCE 
The Sponsor is covered by a liability insurance that also covers liability towards subjects in clinical 
trials. Sponsor is covered by a General and Products liability insurance that includes clinical trials. 
16.0 
PUBLICATION POLICY 
The CRO and Investigator agree to keep strictly confidential all unpublished information and 
results concerning this study. Any publication or disclosure by the investigator contrary to the 
provisions of this section or without prior written consent of Sponsor shall be void-ab-initio. 
Sponsor reserves all the rights to declare any of its data confidential or of business importance and 
will provide it only to the regulatory authorities of concern on request/demand. 
 
 


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17.0 
REFERENCES 
1. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004 May 
22;363(9422):1711-720. 
2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 
2020. Br J Ophthalmol 2006 Mar;90(3):262-267. 
3. Saxena R, Singh D, Vashist P. Glaucoma: An emerging peril. Indian J Community Med 
2013;38:135-7 
4. Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. 
Global data on visual impairment in the year 2002. Bull World Health Organ 2004 
Nov;82(11):844-851. 
5. Friedman DS, Wilson MR, Liebmann JM, Fechtner RD, Weinreb RN. An evidence-based 
assessment of risk factors for the progression of ocular hypertension and glaucoma. Am J 
Ophthalmol 2004 Sep;138(3 Suppl):S19-S31. 
6. Spry PG, Sparrow JM, Diamond JP, Harris HS. Risk factors for progressive visual field 
loss in primary open angle glaucoma. Eye (Lond) 2005 Jun;19(6):643-51. 
7. Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. N Engl J 
Med 2009 Mar 12;360(11):1113-24. 
8. Kooner KS, AlBdoor M, Cho BJ, Adams-Huet B. Risk factors for progression to 
blindness in high tension primary open angle glaucoma: Comparison of blind and 
nonblind subjects. Clin Ophthalmol 2008 Dec;2(4):757-62. 
9. Draft Guidance on Brinzolamide Recommended Apr 2014; Revised Dec 2014, Mar 2015 
https://www.accessdata.fda.gov/drugsatfda_docs/psg/Brinzolamide_opht_susp_1_20816_
RV03-15.pdf 
 
 


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18.0 
APPENDICES   
Appendix 1: Examination Procedures, Tests, Equipment and Techniques 
Urine Pregnancy Tests (If applicable) 
Standard dipstick-based urine pregnancy tests will be administered to subjects that are of child 
bearing potential to assess pregnancy status. Child bearing potential is defined as any female who 
has had her first menses, not had a hysterectomy or bilateral tubal ligation, and has not been post-
menopausal for at least 12 consecutive months. Pregnancy is not to be considered an AE, but it is 
an important medical event that must be followed up as described in Section 9.3.  
Best Spectacle Corrected Visual Acuity (BSCVA) Procedures (Each Eye) 
LogMAR Visual Acuity must be assessed using an Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart and as indicated in the study flowchart in Appendix 1. The procedure used will be 
consistent with the recommendations provided for using the ETDRS eye chart. Visual acuity 
should be evaluated at the beginning of each visit in the study (ie, prior to slit lamp examination). 
Visual acuity testing should be done with best (most recent) correction. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", e.g., 
from Prevent Blindness) wall charts are used, the subject viewing distance should be exactly 
10 feet (or as specified by the manufacturer). In all cases, for purposes of standardizing the testing 
conditions during the study, all sites must use only the 'R' charts, and the right eye should be tested 
first. For reflectance (wall) charts, the chart should be placed frontally and well-illuminated. 
 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at the 
top of the chart. The subject should be told that the chart has letters only, no numbers. If the subject 
reads a number, he or she should be reminded that the chart contains no numbers, and the examiner 
should then request a letter in lieu of the number. The subject should be asked to read slowly, so 
as to achieve the best identification of each letter. He/she is not to proceed to the next letter until 
he/she has given a definite response. 
If the subject changes a response (e.g., 'that was a "C" not an "O"') before he has read aloud the 
next letter, then the change must be accepted. If the subject changes a response having read the 
next letter, then the change is not to be accepted. The examiner should never point to the chart or 
to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject says he 
or she cannot read a letter, he or she should be encouraged to guess. If the subject identifies a letter 
as one of two letters, he or she should be asked to choose one letter and, if necessary, to guess. 
When it becomes evident that no further meaningful readings can be made, despite encouragement 
to read or guess, the examiner should stop the test for that eye. However, all letters on the last line 


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should be attempted as letter difficulties vary and the last may be the only one read correctly. The 
number of letters missed or read incorrectly should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To this 
value will be added the number "N × 0.02" where 'N' represents the total number of letters missed 
up to and included in the last line read. This total sum represents the logMAR visual acuity for that 
eye. 
For example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as well as 0.1) 
= 4 
N × T (T=0.02) 
= 0.08 
Base logMAR + (N × T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of visual acuity during the study, 
all visual acuity assessments at a single site must be consistently done using the same lighting 
conditions and same correction if possible during the entire study. If the same correction cannot 
be used (ie, a subject forgets his glasses), the reason for the change in correction should be 
documented. 
Gonioscopy (Both eyes) 
Gonioscopy will be graded with the Shaffer scale: 
Shaffer Scale 
Classification 
Finding 
Angle width (degree) 
Grade 4 
Ciliary body is visible 
35-45 
Grade 3 
Scleral spur is visible 
20-35 
Grade 2 
Only trabecular meshwork is visible 
20 
Grade 1 
Only Schwalbe’s line is visible 
≤10 
Grade 0 
Angle is closed 
0 
 
 
 


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Automated Perimetry 
(Each Eye, if applicable: required only if there is no data within the past 6 months) 
Automated perimetry will be performed as indicated in the study flowchart in Appendix 1. If the 
brow is heavy or the upper lid is drooping, tape accordingly. Visual field results must be reliable 
(i.e., ≤ 33% fixation losses, false positive or false negative errors) or the field should be repeated 
within two weeks. Visual field examinations will be performed using an automated perimetry test 
preferably Humphrey automated perimeter (full threshold 24-2 program or SITA standard). 
Preferred equipment is the Humphrey 700 HFA-2 series machines (eg, 740 or 750). Visual fields 
will be reported as normal or abnormal and the mean deviation will also be recorded in decibels.  
Begin by testing the right eye. Adjust the chin rest and the table height as needed to achieve proper 
alignment as well as to maintain the subject in a comfortable seated position throughout the test. 
It is permissible to encourage the subject occasionally if the subject seems to be fatigued or losing 
concentration, and to allow the subject to pause and rest if necessary. The subject should also be 
informed that a good time to blink is when the response button is pushed so as not to affect the 
results of the test.  
Slit Lamp Biomicroscopy (Each Eye) 
Biomicroscopy will be performed using a slit lamp. Magnification will be consistent with standard 
clinical practice at every visit. The subject will be seated. 
This will be done to observe the overall health of the eye, including the lid/lashes, conjunctiva, 
cornea anterior chamber, iris, and lens. Any observations at the screening visit will be recorded as 
ocular medical history, and any new or worsened observations may be recorded as AEs. 
Observations will be graded as Normal or Abnormal. Abnormal findings which are clinically 
significant will be described. 
Goldmann Applanation Tonometry (Each Eye) 
The time of tonometry will be recorded on the source document for all visits. Measurements will 
be taken by two qualified independent study site personnel using a Goldmann applanation 
tonometer affixed to a slit lamp with the subject seated. One person will adjust the dial in masked 
fashion and a second person will read and record the value. The subject and slit lamp should be 
adjusted so that the subject’s head is firmly positioned on the chin rest and against the forehead 
rest without leaning forward or straining. Both eyes will be tested, with the right eye preceding the 
left eye. Each IOP measurement is to be recorded. 
One person (“the measurer”) looks through the binocular viewer of the slit lamp at low power.  
The tension knob is pre-set at a low pressure value (4 to 6 mmHg). The measurer follows the image 
of the fluorescein-stained semicircles while he/she slowly rotates the tension knob until the inner 
borders of the fluorescein rings touch each other at the midpoint of their pulsation in response to 


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the cardiac cycle. When this image is reached, the measurer takes his/her fingers off the tension 
knob and the second person (“the reader”) records the IOP reading along with the date and time of 
day in the source document, thus maintaining a masked IOP reading. 
At least two, and if necessary, three consecutive measurements will be taken to determine IOP in 
the manner described above. After first measurement remove applanator (prism) from the corneal 
surface, reset the dial to low number, reapply applanator and re-measure. 
If the first two measurements differ by 1 mmHg or less, a third measurement is not required, the 
two measurements will be recorded and the mean IOP of the two measurements will be recorded 
and used in the analysis. If the first 2 measurements differ by more than 1 mmHg, a third 
measurement should be made, all 3 measurements will be recorded and the median IOP of the 
three measurements will be recorded and used in the analysis. 
Corneal Pachymetry 
(Each Eye, if applicable: required only if there is no data in the subject’s file within past 30 
days) 
Central corneal thickness measurements of each eye will be performed using an ultrasonic 
pachymeter and as indicated in the study flowchart in Appendix 1. Measurements will be made 
before IOP is taken. For ultrasound probes, the Probe Quality Factor must be greater than or equal 
to 85%. With the subject seated and visualizing a consistent fixation target, position the probe tip 
on the cornea, perpendicular to the corneal surface, on the visual axis (ie, centered on the pupil). 
Once the probe tip is positioned properly, take a measurement. A total of 3 acceptable 
measurements, as described above, should be made for each eye, and the 3 measurements will be 
recorded in microns. 
Dilated Ophthalmoscopy (Each Eye) 
Dilated exam will be performed after tonometry. The examination will not be performed until the 
subject’s eyes are deemed sufficiently dilated in the opinion of the investigator. The investigator 
will note any findings present and whether or not the findings are clinically significant or not 
clinically significant.  Findings which are clinically significant will be described. The following 
will be examined:  
x Vitreous 
x Retina 
x Macula 
x Choroid 
x Optic Nerve 
x Cup-to-Disc Ratio (may be assessed using slit lamp following dilation) 
 
 
 


Protocol: BRIN-20-01 
 
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Brinzolamide ophthalmic suspension 1% 
 
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Additional Study Supplies: 
x Urine pregnancy test 
x Study medication dosing  diary 
x Fluorescein and anesthetic for IOP measurement  
x Dilating drop(s) for ophthalmoscopy exam 
x Anesthetic for gonioscopy  
x Lubricating gel for gonioscopy (if applicable)  
 
 


Protocol: BRIN-20-01 
 
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Appendix 2 
Contraceptive Guidance 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
Note: Documentation can come from the study center personnel’s: review of the subject’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Contraception Guidance 
Male subjects 
x Male subjects with female partners of childbearing potential are eligible to participate if 
they agree to ONE of the following during the Clinical Investigational Plan-defined time 
frame in Section 5.3 
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
o Agree to use a male condom plus partner use of a contraceptive method with a 
failure rate of <1% per year as described below when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 


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x Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during study period (until Visit 5). 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
Oral. 
Intravaginal.  
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
Oral. 
Injectable. 
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
Intrauterine device (IUD). 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
subject.  
NOTES:  
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
Pregnancy Testing: 
x WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test at screening and at Visit 2 and Visit 4. 
 

SAP_001.pdf: 
Official title: Therapeutic Equivalence Study of Generic Brinzolamide 1% Ophthalmic 
suspension Compared to Reference Listed Drug Azopt® (Brinzolamide) Ophthalmic 
Suspension 1% in Subjects With Primary Open Angle Glaucoma or Ocular Hypertension. 
Document: Statistical Analysis Plan (SAP) 
NCT number: NCT05022004 
Document date: 20 Sep 2023 


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Statistical Analysis Plan
Study Title:
A Therapeutic equivalence Study of Generic Brinzolamide 1% 
Ophthalmic Suspension Compared to Reference Listed Drug Azopt® 
(Brinzolamide) Ophthalmic Suspension 1% in Subjects with Primary 
Open Angle Glaucoma or Ocular Hypertension.
Sponsor Identification:
Sun Pharmaceutical Industries Ltd
Phase:
Phase 3
Sponsor Study Number:
BRIN-20-01


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1
Table of Contents
1
Table of Contents......................................................................................................................2
2
Signatures.................................................................................................................................5
3
Document History .....................................................................................................................6
4
Abbreviations ............................................................................................................................7
5
Introduction ...............................................................................................................................8
6
Study Objectives.......................................................................................................................8
6.1.1
Primary Objectives .......................................................................................................8
6.1.2
Secondary Objectives......................................................................................................8
7
Study Design.............................................................................................................................8
7.1
Overview ..........................................................................................................................8
7.1.1
Study Design..................................................................................................................8
7.1.2
Treatment Groups .........................................................................................................11
7.2
Study Endpoints .............................................................................................................11
7.2.1
Primary Efficacy Endpoint ............................................................................................11
7.2.2
Secondary Efficacy End point ....................................................................................11
7.2.3
Safety Assessments...................................................................................................11
8
General Statistical Considerations..........................................................................................12
8.1
Descriptive Statistics ......................................................................................................12
8.2
Analysis Population........................................................................................................13
8.3
Definitions.......................................................................................................................13
8.4
Protocol Violation/Deviation ...........................................................................................14
8.5
Data Handling.................................................................................................................14
8.5.1
Imputation of Missing data ............................................................................................14
8.6
Sample Size Calculation ................................................................................................15
8.7
Interim Analysis..............................................................................................................15
8.8
Statistical Software.........................................................................................................16
9
Statistical Analyses.................................................................................................................16
9.1
Subject Disposition.........................................................................................................16
9.2
Demographic Data and Baseline Characteristics ..........................................................16
9.3
Medical History...............................................................................................................16
9.4
Prior and concomitant medication..................................................................................16
9.5
Protocol Deviation ..........................................................................................................17
9.6
Efficacy Analysis ............................................................................................................17
9.6.1
Primary Efficacy Endpoint ............................................................................................17
9.6.2
Secondary Efficacy Endpoints ...................................................................................18
9.6.3
Safety Analysis...........................................................................................................19
9.7
Data Manipulation and Subgroup Analyses...................................................................21
10
Deviation from the Study Protocol ..........................................................................................21


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11
Database Lock and Unblinding...............................................................................................21
12
References..............................................................................................................................21








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4
Abbreviations
ABBREVIATION
DEFINITION
AE
Adverse Event
BSCVA 
Best-Spectacle Corrected Visual Acuity
CI 
Confidence Interval
eCRF 
Electronic Case Report Form
IOP 
Intraocular Pressure
ITT 
Intent-To-Treat
MedDRA 
Medical Dictionary of Regulatory Affairs
MMRM 
Mixed Model Of Repeated Measures
PP 
Per Protocol
PT 
Preferred Term
SAE 
Serious Adverse Event
SAF
Safety Analysis Population
SAP 
Statistical Analysis Plan
SOC 
system organ class
SPIL
Sun Pharmaceutical Industries Ltd
TOST 
Two one-sided tests
TEAE 
Treatment-Emergent Adverse Event
TID 
Three Times Daily
w/v
Weight per Volume








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7.1.2
Treatment Groups
Approximately 666 subjects (333 per treatment arm) will be randomized in this study in a 1:1 treatment allocation ratio. 
The study will be conducted in Russia and India, out of 666 subjects466 subjects will be recruited in Russia and 200 
subjects will be recruited in India.
IMP: Brinzolamide ophthalmic suspension USP 1% w/v, 10mL.
RLD: Azopt® 1% (brinzolamide ophthalmic suspension), 10mL.
7.2 Study Endpoints
7.2.1
Primary Efficacy Endpoint
Primary endpoint of this study is to assess the mean difference in IOP of both eyes between the two treatment groups 
dosed in each eye TID  approximately at 8.00 AM. (±60 minutes), 4.00 PM. (±60 minutes) and 10.00 PM. (±60 minutes)
and sample collected at four time points, i.e., at approximately 8:00 a.m. (hour 0; before the morning drop) and 10:00 
a m. (2 hours) at the Day 14 (Week 2) and Day 42 (Week 6) visits. 
7.2.2
Secondary Efficacy End point
Change from baseline in IOP of both eyes between the 2 treatment groups at 4 time points, i.e., at approximately 8:00 
a m. (hour 0; before the morning drop) and 10:00 a.m. (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) visits.
7.2.3
Safety Assessments
x
Incidence and severity of AEs
x
BSCVA
x
Slit lamp Biomicroscopy
x
Tonometry
x
Dilated fundus exam, including Cup/Disc ratio 


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8
General Statistical Considerations 
8.1 Descriptive Statistics 
The following descriptive statistics will be calculated for continuous data and for categorical data:
Summary statistics are displayed with the following digits: 
Description
Characteristic
Number of
decimal places
Count
n
0
Count corresponding to the number of patients for a group
N
0
Mean
Mean
As in source + 1
Standard Deviation
SD
Mean+1
Minimum
Min 
As in source
Median
Median
As in source + 1
Maximum
Max
As in source
Percentage relative to N #
%
1
Confidence Interval
CI
Respective Estimate+2
1st Quartile / 3rd Quartile
Q1/Q3
As in source + 1
# Number of decimal places can be more than one, if necessary. All table percentages should be rounded to one decimal
place if not stated otherwise. 
All data will be presented in the subject data listings. 
If either table or listing does not include any observation, then the following placeholder will be used: “NO DATA 
CONTRIBUTED TO THIS TABLE / LISTING”.


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8.2 Analysis Population
Analysis Population
Definition
All Screened Population
All patients who have signed the informed consent form
Intent-to-Treat Population
The Intent-to-Treat (ITT) population consists of all subjects who are 
randomized into the study. and ITT based analysis will be used as
confirmatory analyses
Per Protocol Population
The PP population includes all randomized subjects who meet all 
inclusion/exclusion criteria, and complete evaluations at week 2, week 6 
(with compliance between 75 to 125%) with no major protocol deviations
that would affect the treatment evaluation (primary endpoint). The PP 
population will be considered the primary analysis population for the study 
and will summarize subjects as treated.
Safety Population
The safety population includes all subjects who receive at least 1 dose of 
study medication. The safety population will be used to summarize safety 
variables and will summarize subjects as treated.
Note: As there are multiple examples of violations to GCP and ALCOA principles, all the data reported from Site # 122
is not reliable. Hence, based on the clinical investigation report dated 13 Sep 2023, it has been agreed to remove all the 
20-subject data from the efficacy analysis These 20 subjects will be included in the safety analysis of the study data.
However, safety data will be presented with and without subjects from Site #122.
8.3 Definitions
In the following table, the definitions and calculation of derived variables are summarized.
Variable / Term
Definition / Way of calculation
Treatment Start Date
Date of dose administration on Day 
Treatment End Date
Date of Last Study Medication Taken in EoS page in CRF
Duration of exposure
Treatment end date- treatment start date + 1
Treatment Emergent AE (TEAE)
An AE will be considered as treatment-emergent if the time of onset is on or 
after the time of the first study drug administration or any AE that exist prior 
to first dose and if it increased in severity during the study
IOP
IOP will be measured at least twice in each eye with the right eye measured 
first. If the difference of the first 2 measurements is ≤ 1 mm Hg, the average 
of these 2 measurements will be used as the IOP data for this eye. If the 
difference is > 1 mm Hg, a third measurement will be taken, and the median 
of these 3 measurements will be used as the IOP data for this eye.


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Variable / Term
Definition / Way of calculation
Masking
In order to maintain the double-blind nature of the study, all study-related 
individuals, including the subjects, ancillary study site staff, clinical 
monitor(s), Investigator, Sponsor, and CRO staff, will remain blinded to the 
administered treatment.
8.4 Protocol Violation/Deviation
The relevant protocol violations/deviations have to be defined by a systematic data review prior to database closure. For 
this purpose, protocol violations that occurred during the study such as violations of inclusion/exclusion criteria or 
forbidden concomitant medications or patient non-compliance will be assessed as ‘major’ or ‘minor’ depending on their 
potential to interfere with the objectives of the study. Listings will be prepared to show the eligibility of all patients. 
Comprehensive justification for the classification of a protocol violation/deviation as “major” will be given in the 
integrated clinical study report.
A separate Protocol deviation listing will be prepared for the patients who discontinued the study or could not able to 
continue the study treatment or could not visit the study center or any procedure could not be performed.
8.5 Data Handling 
8.5.1
Imputation of Missing data
Efficacy:
The analyses of the efficacy variable IOP) will be completed on observed data only (without imputation). 
Safety:
To handle missing or partial AE and concomitant medication dates, the following rules will be applied.
For partial start dates:
The below table will illustrate how the imputation to be performed for unknown date/month/year.
DD
MM
YYYY
Imputation
Known
Known
Unknown
Do not impute the date but assign a missing value.
Known
Unknown
Known
a. If the year matches the year of the dose date, then impute the 
month and day of the dose date.
b. Otherwise, assign “January.”
Unknown
Known
Known
a. If the month and year match the month and year of the first 
dose date, then impute the day of the dose date.
b. Otherwise, assign “01.”
For partial end dates:
The below table will illustrate how the imputation to be performed for unknown date/month/year.


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DD
MM
YYYY
Imputation
Known
Known
Unknown
Do not impute the date but assign a missing value.
Known
Unknown
Known
Assign month as “December.”
Unknown
Known
Known
Assign last day of the month
After implementing the rules above, to determine whether AEs (or medications) with missing start or stop dates are 
pretreatment or on/after treatment, the following strategy will be used:
1. If the start date and stop date are both missing, then the most conservative approach is taken, and the AE (or medication) 
is considered to be treatment emergent (or concomitant medication).
2. If the start date is missing but the stop date is not missing and is on or after the day of study dose administration, then 
the most conservative approach is taken, and the AE (or medication) is considered to be treatment emergent (or 
concomitant medication).
3. If the start date is missing but the stop date is not missing and is before the day of study dose and after the date of 
signed informed consent, then the AE (or medication) is considered to be before treatment (or prior medication).
4. If the start date is not missing but the stop date is missing, then the most conservative approach is taken, and medication 
is considered to be concomitant while the AE is defined by start date.
If the Adverse Event Relationship flag is missing, the relationship for adverse event will be imputed and will be considered 
as related. If the Adverse Event Severity flag is missing, the severity will be imputed with the maximum severity will be 
considered as severity.
8.6 Sample Size Calculation
An equivalence test of means using two one-sided tests on data from a parallel-group design with sample sizes of 266 in 
the SPIL’s Brinzolamide ophthalmic suspension 1% and 266 in Azopt® 1% achieves 90% power at an α = 0.05 
significance level when the true difference between the means is 0, the standard deviation is 3.5, and the 95% equivalence 
limits are -1.0 and 1.0.
Considering the possibility of 20% of subjects not being evaluable either due to dropping out of the study or having major 
protocol violations, approximately 333 subjects will be enrolled in each treatment group for a total of 666 subjects in the 
study.
8.7 Interim Analysis
There is no interim analysis planned for the study.


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8.8 Statistical Software
All statistical analyses will be performed with SAS®, Version 9.4 or later. 
9
Statistical Analyses
9.1
Subject Disposition
Subject disposition will be tabulated with number and percentages of patient’s screened, screen failed, randomized, dosed, 
completed the study according to the protocol or discontinued the study prematurely. The patients who prematurely 
discontinued the study and the reasons for their discontinuation will be presented. The disposition table will be 
summarized using “Screened population” by treatment group.
9.2
Demographic Data and Baseline Characteristics
The demographic data and baseline characteristics will be summarized using descriptive statistics or by frequency and 
percentage for the applicable parameters using SAF Population by treatment group.
x
Age 
x
Gender
x
Race
x
Ethnicity
x
Iris color 
x
Childbearing potential
x
Best Spectacle-Corrected Visual Acuity Score (Left / Right Eye)
9.3 Medical History 
All general medical history conditions and concomitant diseases will be coded using MedDRA version 24.0. General 
medical history conditions and concomitant diseases will be summarized by system organ class, preferred term and by
treatment group using SAF population. The version of the utilized dictionary will be presented as part of the provided 
tables and listings. Listing of medical history will be provided.
9.4 Prior and concomitant medication
Prior and concomitant medications will be assessed at screening, while concomitant medications will be assessed at each 
subsequent study visit. Medications will be coded using WHODG MAR 1, 2021.
Medication will be classified as prior, if the end date is known and is prior to the first use of the study medication. 
Medications that are ongoing or ended after the first use of the study medication will be classified as concomitant. If the 
end date of the medication is unknown, it will also be considered as concomitant. Handling of missing date explained in 
section (Imputation of missing data section 8.5).


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Prior and concomitant medications will be separately summarized by ATC class (the highest available level), preferred 
name and treatment group for the safety population. Listings will be presented for prior and concomitant medications.
9.5 Protocol Deviation
Protocol deviations will be summarized by Number of patients with protocol deviations (Major/).  Protocol deviations 
will also be summarized by Number of patients with Major/Minor Protocol Deviations by its category and treatment using 
SAF population. 
Table and Listings will be presented for all the protocol deviations and separate table and listings.
9.6 Efficacy Analysis
  Primary and secondary efficacy endpoint will be analysed using the PP population.
9.6.1
Primary Efficacy Endpoint
Mean difference in IOP of both eyes between the two treatment groups at four time points, i.e., at approximately 8:00 
a m. (hour 0; before the morning drop) and 10:00 a.m. (2 hours) at the Day 14 (Week 2) and Day 42 (Week 6) visits
IOP measurements will be taken using a Goldmann applanation tonometer. IOP will be measured at least twice in each 
eye with the right eye measured first. If the difference of the first 2 measurements is ≤ 1 mm Hg, the average of these 2 
measurements will be used as the IOP data for this eye. If the difference is > 1 mm Hg, a third measurement will be taken, 
and the median of these 3 measurements will be used as the IOP data for this eye.
Two-sample 95% CIs around the difference in the mean IOP (both eyes) at each timepoints i.e., at approximately 8:00 
a m. [hour 0; before the morning drop] and 10:00 a.m. [hour 2] at the Day 14 [Week 2] and Day 42 [Week 6]) visits will 
be constructed using a two-sample t-distribution.
The hypotheses for a two-sample equivalence test are: 
Ho: μ <ϴL or μ >ϴU
H1: ϴL≤ μ ≥ ϴU
Where,
μ: Difference in mean IOP between treatment groups within study period
ϴL: -1.5mm Hg and (-1.0mm Hg)
ϴU: 1.5mm Hg and (1.0mm Hg)


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The overall p-value of the equivalence test will be reported, which is the larger of the two p-values of the tests L and U. 
Rejection of H0 in favour of H1 at significance level α occurs if and only if the 100 (1-2α) % confidence interval for μ is 
contained within (-1.5, 1.5) and (-1.0, 1.0). Two sample t-test also assumes equality of variances in the treatment groups, 
hence depending on the results from Levene’s test, CI, and p-values from Equal (Pooled) or Unequal (Satterthwaite) 
variance will be reported. 
This analysis also will be tested for ITT population to check the robustness of the result.
9.6.2
Secondary Efficacy Endpoints
Change from baseline in IOP of both eyes between the 2 treatment groups at 4 time points, i.e., at approximately 8:00 
AM. (hour 0; before the morning drop) and 10:00 AM. (hour 2) at the Day 14 (Week 2) and Day 42 (Week 6) visits.
For change from baseline IOP, baseline will refer to the time-matched measure at Visit 2. Change from baseline will be 
calculated as visit x – baseline. The overall p-value of the equivalence test will be reported, which is the larger of the two 
p-values of the tests L and U. Rejection of H0 in favour of H1 at significance level α occurs if and only if the 100 (1-2α) 
% confidence interval for μ is contained within (-1.5, 1.5) and (-1.0, 1.0). Two sample t-test also assumes equality of 
variances in the treatment groups, hence depending on the results from Levene’s test, CI and p-values from Equal (Pooled) 
or Unequal (Satterthwaite) variance will be reported. This mean IOP must be within ± 1.5 mm Hg using the PP population 
for all time points measured and within ± 1.0 mm Hg using the PP population for the majority of time points measured.
This analysis also will be tested for ITT population to check the robustness of the result.
In addition to these individual confidence intervals, a mixed effects repeated measures model, with random effect for 
subject, covariate for baseline IOP, and fixed effects for treatment and day/time (within subject repeated measures) will 
be fitted to the data. Appropriate covariance structure will be used to model the within subject, between time point 
variances with order of treatment Visit treatment*visit and baseline as covariate. Individual and simultaneous confidence 
intervals will then be constructed based on this MMRM model at each of the time points. The 95% simultaneous 
confidence intervals will use the Tukey-Kramer method to adjust for multiple comparisons across all 4 time points. Above 
mentioned analysis will be performed on PP and ITT population.


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9.6.3
Safety Analysis
The safety population includes all randomized subjects who receive study product
9.6.3.1
Adverse Events
The primary safety analysis will summarize ocular (in both the eyes) and non-ocular AEs for all treated subjects using 
discrete summaries at the subject level by Medical Dictionary for Regulatory Activities (MedDRA®), SOC, and PT for 
each treatment group. A TEAE will be defined as occurring after the first dose of study medication for the period. 
Treatment-related ocular and non-ocular TEAEs will be summarized similarly. Ocular and non-ocular TEAEs will also 
be summarized by severity. For safety summaries the unit of analyses will be both eyes for ocular measures and will be 
the subject for non-ocular safety measures as well as all AEs.
An AE will be considered as treatment-emergent if the time of onset is on or after the time of the first study drug 
administration or any AE that exist prior to first dose and if it increased in severity during the study period. Handling of 
missing data and date are explained in section 8.5 (Imputation of missing data).
An overall summary table, which summarizes, the number and percentages of patients with adverse events, serious 
adverse events, adverse events leading to death, adverse events related to study drug, Study Drug Discontinued 
Permanently due to adverse event and adverse events by severity categories will be provided by treatment groups.
Patients experiencing any treatment emerging adverse events will be summarized by Preferred Term (PT), SOC and 
treatment group. The number and percentage of patients with at least one TEAE, SAE, permanently discontinued study
treatment (IP) due to AE, AE leading to Death, AE by relationship and TEAEs of severe intensity will be summarized by 
system organ class, preferred term and treatment group.
Furthermore, listings of SAEs and AEs that lead to study withdrawal will be provided. 
AEs Tables by primary system organ class, preferred term and treatment group will be sorted in descending order of 
counts.
A patient experiencing the same AE multiple times will be counted only once for that preferred term. Similarly, if a 
patient experiences multiple AEs within the same system organ class that patient will be counted only once in that system 
organ class. Maximum severity will be considered if a patient has multiple severity reported for same AE. In summaries 
by relationship, if a subject has the same AE on multiple occasions, the closest relationship to study drug, will be used 
for summary.
9.6.3.2
Vital Signs
The actual and change from baseline of Heart rate and blood pressure will be summarized descriptively using SAF 
population and treatment group. In addition, number and percentage of patients reaching ‘Normal’, ‘Abnormal CS’ and 
‘Abnormal NCS’ results for vital signs parameters will be summarized by treatment group and visit using SAF population.
Data listings will be presented for vital signs parameters.


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9.6.3.3
Best spectacle-corrected visual acuity (BSCVA)
The actual and change from baseline of Base logMAR, Number of letters missed and Visual Acuity Testing for each eye
will be summarized descriptively using SAF population and treatment group. 
Data listings will be presented for best spectacle-corrected visual acuity (BSCVA)
9.6.3.4
Corneal pachymetry (CP)
Corneal pachymetry data will be summarized descriptively using the SAF population and treatment group. 
Data listings will be presented for Corneal pachymetry (CP).
9.6.3.5
Slit-lamp biomicroscopy (SLIT)
Slit-lamp biomicroscopy (SLIT) will be summarized by frequencies and percentages using the SAF population and 
treatment group by each visit.
Listing will be provided for the Slit-lamp biomicroscopy (SLIT)
9.6.3.6
Gonioscopy (GONI)
Gonioscopy (GONI) will be summarized by frequencies and percentages using the SAF population and treatment group.
Listing will be provided for the Gonioscopy (GONI)
9.6.3.7
Dilated ophthalmoscopy, including C/D ratio (DO)
Dilated ophthalmoscopy, including C/D ratio (DO) will be summarized by frequencies and percentages using the SAF 
population and treatment group by visit.
Listing will be provided for the Dilated ophthalmoscopy, including C/D ratio (DO)
9.6.3.8
Automated Perimetry (AP)
Automated Perimetry (AP) will be summarized by frequencies and percentages using the SAF population and treatment 
group.
Listing will be provided for the Automated Perimetry (AP)
9.6.3.9
Discontinue current IOP-lowering Medication (DIOPM)
Discontinue current IOP-lowering Medication (DIOPM) will be summarized using frequency and percentage using the 
SAF population and treatment group.


Statistical Analysis Plan
Sponsor: Sun Pharmaceutical Industries Ltd
Date: 20 Sep 2023
 This is a controlled version of the document, unauthorized use, print or 
reproduction is termed as uncontrolled.
Page 21 of 21
Confidential
9.6.3.10 Dispense study medication and compliance diary (DSMCD)
Dispense study medication and compliance diary (DSMCD) will be summarized using frequency and percentage using 
the SAF population and treatment group and visit.
Listing will be provided for the Dispense study medication and compliance diary (DSMCD)
9.6.3.11 Urine pregnancy test
Listing will be provided for the Urine pregnancy test.
9.7 Data Manipulation and Subgroup Analyses
Not Applicable.
10 Deviation from the Study Protocol
Not Applicable.
11 Database Lock and Unblinding
The SAP will be finalized prior to database lock. After the data cleaning process is finalized according to the data 
management plan (DMP) and the assignment of patients to the analysis sets is agreed and signed by the sponsor, the study 
database will be locked. 
12 References
Not Applicable