Clinical trial NCT04024072
Conditions: Glaucoma, Open-Angle Ocular Hypertension
Sponsor: Padagis LLC
Start date: 2019-06-24; Completion date: 2020-04-30
Enrollment: 495 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the safety and efficacy of Perrigo's product to an FDA approved product in the treatment of Primary Open Angle Glaucoma or Ocular Hypertension in Both Eyes.

Detailed description:

Arms: arm 1: Test product arm 2: Azopt ophthalmic suspension
Interventions: intervention 1: Brinzolamide 1% ophthalmic suspension intervention 2: Azopt 1% Ophthalmic Suspension
Intervention descriptions: intervention 1: Test product intervention 2: Reference product

Protocol documents:
Prot_000.pdf: 
NCT04024072 
07-01-2019


 Page 1 of 60 
A Multi-Center, Randomized, Double-Masked, Active Controlled, Parallel 
Group Bioequivalence Study with Clinical Endpoint Comparing Brinzolamide 
Ophthalmic Suspension 1% of Perrigo Pharma International DAC to Azopt® 
(brinzolamide ophthalmic suspension) 1% of Novartis Pharmaceuticals 
Corporation in the Treatment of Primary Open Angle Glaucoma or Ocular 
Hypertension in Both Eyes 
Protocol No: PRG-NY-19-001 
Confidential 
The confidential information provided in this document is for use by parties directly 
involved in this investigation.  By accepting this document, you agree that the information 
contained herein will not be disclosed to any person not directly involved in this 
investigation without written authorization from Perrigo New York Inc.  






Protocol No: PRG-NY-19-001     
 
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1. 
BACKGROUND .................................................................................... 9 
2. 
STUDY OBJECTIVE ............................................................................... 9 
2.1. 
Endpoint ............................................................................................................... 9 
2.2. 
Safety ................................................................................................................... 9 
3. 
STUDY DESIGN .................................................................................. 10 
3.1. 
Patient Population ............................................................................................. 10 
4. 
STUDY SUBJECT SELECTION ............................................................... 11 
4.1. 
Inclusion Criteria ................................................................................................ 11 
4.2. 
Exclusion Criteria................................................................................................ 13 
4.3. 
Prohibited Medications and Activities ............................................................... 15 
4.4. 
Precautions ........................................................................................................ 19 
5. 
STUDY PROCEDURES ......................................................................... 20 
5.1. 
Study Medication Masking ................................................................................ 20 
5.2. 
Dosing Regimen Overview ................................................................................. 21 
5.3. 
Subject Screening and Informed Consent ......................................................... 22 
5.4. 
Assignment of Subject Number ......................................................................... 22 
5.5. 
Medical History .................................................................................................. 22 
5.6. 
Ocular History .................................................................................................... 22 
5.7. 
Prior and Concomitant Medications .................................................................. 23 
5.8. 
Vital Signs ........................................................................................................... 23 
5.9. 
Pregnancy Test ................................................................................................... 23 
5.10. 
External Eye Exam .............................................................................................. 23 
5.11. 
Iris Color ............................................................................................................. 23 
5.12. 
Intraocular Pressure (IOP) Measurement .......................................................... 24 
 
 
 
 
 
 
 
 
 
 
 
 
5.19. 
Study Medication Dispensing, Dosing and Diary Cards. .................................... 27 
5.20. 
Schedule of Assessments By Visit ...................................................................... 29 
5.21. 
Schedule of Assessments ................................................................................... 33 
5.22. 
Screen Failures ................................................................................................... 35 
5.23. 
Protocol Deviations and Violations .................................................................... 35 
5.24. 
Subject Treatment Compliance ......................................................................... 35 
5.25. 
Reasons for Discontinuation/Withdrawal ......................................................... 36 
5.26. 
Procedures for Early Termination ...................................................................... 36 
6. 
STUDY MEDICATION AND SUPPLIES .................................................. 37 
6.1. 
Study Medication ............................................................................................... 37 
6.2. 
Randomization Code .......................................................................................... 37 


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6.3. 
Packaging and labels .......................................................................................... 37 
6.4. 
Procedure for Breaking the Blind....................................................................... 38 
6.5. 
Retention Samples ............................................................................................. 39 
6.6. 
Storage and Test Article Accountability ............................................................. 39 
7. 
ADVERSE REACTIONS ........................................................................ 40 
7.1. 
Departure From the Protocol For Individual Subjects ....................................... 40 
7.2. 
Definitions .......................................................................................................... 40 
7.3. 
Eliciting and Reporting of Adverse Events ......................................................... 42 
7.4. 
Expedited Reporting Responsibilities of the Study Center ................................ 42 
7.5. 
Submitting an Expedited Safety Report to the IRB ............................................ 43 
7.6. 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies .... 44 
7.7. 
Pregnancy ........................................................................................................... 45 
7.8. 
Post Study Events ............................................................................................... 46 
8. 
STATISTICAL ANALYSIS ...................................................................... 46 
8.1. 
Statistical Analysis Plan ...................................................................................... 46 
8.2. 
Analysis Populations .......................................................................................... 46 
8.3. 
Planned Analysis ................................................................................................ 47 
8.4. 
Sample Size ........................................................................................................ 47 
8.5. 
Efficacy Measures and Analysis ......................................................................... 48 
8.6. 
Safety Analysis ................................................................................................... 49 
9. 
CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES .................. 49 
9.1. 
Subject Confidentiality ....................................................................................... 50 
10. 
CONDUCT OF STUDY ......................................................................... 50 
10.1. 
Completion of Study .......................................................................................... 50 
10.2. 
Protocol Amendments ....................................................................................... 51 
11. 
RECORDS MANAGEMENT.................................................................. 51 
11.1. 
Data Collection ................................................................................................... 51 
11.2. 
Source Documents ............................................................................................. 52 
11.3. 
File Management at the Study Site ................................................................... 52 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................. 53 
12.1. 
Monitoring ......................................................................................................... 53 
12.2. 
Auditing .............................................................................................................. 53 
13. 
ETHICS AND RESPONSIBILITY ............................................................ 53 
14. 
USE OF INFORMATION AND PUBLICATION ........................................ 53 
15. 
APPENDICES ...................................................................................... 56 
15.1. 
Appendix A: Study Personnel Contacts .............................................................. 56 
15.2. 
Appendix B:   Subject Instructions ..................................................................... 57 
16. 
REFERENCES ...................................................................................... 60 


Protocol No: PRG-NY-19-001     
 
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Synopsis 
 
Title 
A Multi-Center, Randomized, Double-Masked, Active Controlled, Parallel Group 
Bioequivalence Study with Clinical Endpoint Comparing Brinzolamide Ophthalmic 
Suspension 1% of Perrigo Pharma International DAC to Azopt® (brinzolamide 
ophthalmic suspension) 1% of Novartis Pharmaceuticals Corporation in the 
Treatment of Primary Open Angle Glaucoma or Ocular Hypertension in Both Eyes  
Protocol No.  
PRG-NY-19-001 
Study 
Medication 
Test  
Product: 
Brinzolamide Ophthalmic Suspension, 1% 
 
Reference  
Listed  
Drug: 
Azopt® (brinzolamide ophthalmic suspension), 1% 
Novartis Pharmaceuticals Corporation 
Study 
Objectives 
To demonstrate bioequivalence of brinzolamide ophthalmic suspension 1% (Perrigo 
Pharma International DAC) to Azopt® (brinzolamide ophthalmic suspension) 1% 
(Novartis Pharmaceutical Corporation) by comparing their efficacy and safety in the 
treatment of subjects with Primary Open Angle Glaucoma (POAG) or Ocular 
Hypertension (OH) in both eyes. 
Study Design 
Double-masked, randomized, multi-center, active-controlled, parallel-group, 
bioequivalence study with clinical endpoint.  
Study 
Population 
Approximately 
 subjects will be enrolled 
 to obtain 
approximately 
 per protocol subjects.  All efforts will be made so that the study 
population will consist of subjects with light colored iris and dark colored iris similar 
in proportion to the U. S. population.  
Dosing  
The study consists of a six-week treatment (42 ± 4 days) period.  
 
At Baseline/Visit 2, eligible subjects will be randomized in a double-masked manner, 
 to either the test product or reference product.  Subjects will apply one 
drop of either test product or reference product in both eyes three times daily at 
approximately 08:00 am, 04:00 pm and 10:00 pm for six weeks (42 ± 4 days) 
Study Visits 
Clinical Evaluations will be performed at: 
1. Visit 1/Screening  
2. Visit 2/Day 0 (Baseline)  
3. Visit 3/Week 2/Day 14 (±4 days) 
4. Visit 4/Week 6/Day 42 (±4 days) (End of Study) 


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Title 
A Multi-Center, Randomized, Double-Masked, Active Controlled, Parallel Group 
Bioequivalence Study with Clinical Endpoint Comparing Brinzolamide Ophthalmic 
Suspension 1% of Perrigo Pharma International DAC to Azopt® (brinzolamide 
ophthalmic suspension) 1% of Novartis Pharmaceuticals Corporation in the 
Treatment of Primary Open Angle Glaucoma or Ocular Hypertension in Both Eyes  
Evaluations 
• Intraocular pressure
  
• 
  
 
  
 
  
 
  
 
  
 
 
  
• Vital signs  
• Adverse events  
Primary 
Endpoint 
The primary efficacy endpoint is mean change from baseline in IOP of both eyes at 
four time points, i.e., at approximately 8:00 a.m. (hour 0; before the morning drop) 
and approximately 10:00 a.m. (hour 2) on Day 14 (Week 2) and Day 42 (Week 6) 
visits. 
Safety 
The incidence of all adverse events reported during the study will be summarized by 
treatment group. Test and reference product will be compared for safety by 
analyzing nature, severity and frequency of treatment emergent adverse events.  
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
 
 
CMH 
Cochran–Mantel–Haenszel test 
CAI 
Carbonic Anhydrous Inhibitor 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
dB 
Decibel 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
 
 
DCF 
Data Correction Form 
FDA 
US Food and Drug Administration 
 
 
GCP  
Good Clinical Practices 
hr 
Hour 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IU 
International Unit 
IUD 
Intra-Uterine Device 
LogMar 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minutes 
NSAID 
Non-Steroidal Anti-Inflammatory Drug  
OH 
Ocular Hypertension 
OTC 
Over the counter 
POAG 
Primary Open Angle Glaucoma 
PI 
Principal Investigator 
PP 
Per-protocol (population) 
RLD 
Reference Listed Drug 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SITA 
Swedish Interactive Testing Algorithm 
Sub-I  
Sub-Investigator 
UPT 
Urine Pregnancy Test  


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1.  BACKGROUND 
 
 
   
 
 
 
 
  
  
 
 
2. STUDY OBJECTIVE 
The objective of the study is to demonstrate bioequivalence of brinzolamide ophthalmic 
suspension 1% (Perrigo Pharma International DAC) to Azopt® (brinzolamide ophthalmic 
suspension) 1% (Novartis Pharmaceutical Corporation) by comparing their efficacy and safety 
in the treatment of subjects with Primary Open Angle Glaucoma (POAG) or Ocular Hypertension 
(OH) in both eyes. 
 
2.1. 
Endpoint  
The primary efficacy endpoint is mean change from baseline in IOP of both eyes at four time 
points, i.e., at approximately 8:00 a.m. (hour 0; before the morning drop) and approximately 
10:00 a.m. (hour 2) on Day 14 (Week 2) and Day 42 (Week 6) visits. 
 
2.2. 
Safety 
Safety of the test and reference products will be compared by evaluating the nature, severity 
and frequency of their adverse event profiles.  All adverse events that occur during the study 
will be recorded whether or not they are considered to be related to the study medication. The 
report of AEs should include date of onset, description of the AE, severity, relation to study 
medication, action taken, outcome and date of resolution.  Comparisons between the 
treatment groups will be made by tabulating the frequency of subjects with one or more 
adverse events (classified into MedDRA terms) during the study. Pearson’s Chi-Square test or 
Fisher’s Exact test, whichever is most appropriate, will be used to compare the proportion of 
subjects in each treatment group with any adverse event.  The adverse events reported by at 
least five percent of the subjects in any treatment group will be summarized descriptively. 
 


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3. STUDY DESIGN  
The study will be conducted as a multi-center, double-masked, randomized, active-controlled, 
parallel-group study, comparing the test product, brinzolamide ophthalmic suspension 1%, to 
the reference product, Azopt® (brinzolamide) ophthalmic suspension 1%, in subjects diagnosed 
with open angle glaucoma or ocular hypertension in both eyes. 
 
Eligible subjects will be randomized in a double-masked manner, 
 to either the 
test product or reference product.  The study consists of a run-in phase and a six-week 
treatment (42 ± 4 days) period. 
 
Screening and run-in phase: 
 
 
 
   
 
Randomization and double-masked treatment phase: 
 
. 
 
 
3.1. 
Patient Population 
subjects will be enrolled 
 to obtain approximately 
 per protocol subjects. 
 
 
  
 
 
     
   
     


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4. STUDY SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
 
1. Subjects 18 years or older must sign an Institutional Review Board (IRB) approved written 
informed consent prior to any study related procedures being performed. 
 
 
 
 
 
 
2. Male or non-pregnant females aged at least 18 years. 
3. Subjects with Primary Open Angle Glaucoma (POAG) or Ocular Hypertension (OH) in both 
eyes.  
4. 
 
 
 
5. 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  




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4.2. 
Exclusion Criteria 
1. Females who are pregnant, breast feeding, or planning a pregnancy during the study. 
2. Females of childbearing potential who do not agree to use an adequate form of 
contraception (Section 5.9).  
3. Known or suspected substance abuse (e.g., alcohol, marijuana, etc.) and/or any other 
medical or psychological condition(s) that in the investigator’s opinion precludes study 
enrollment. 
4. 
 
 
7. 
 
 
. 
8. Current disease or in the opinion of the investigator have a history of significant ocular 
disease, 
 within three months prior to 
baseline.    
9. 
  
 
  
 
 
 
 
  
 
  
 
 
16. 
 
. 
17. Contraindication to brinzolamide or sulfonamide or known hypersensitivity to any 
component of the study medication or sulfonamide therapy.   
18. 
 
 
 
 
 
  
 
 
 
 
 
 
 


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30. Participation (randomized) in any clinical study involving an investigational product, agent 
and/or device in the thirty (30) days prior to the Screening Visit. 
31. 
 
 
  
33. Subject who in the opinion of the investigator, is unlikely to be able to follow the 
restrictions of the protocol and complete the study. 
34. Have a condition/circumstance which, in the Investigator's opinion, may put the subject at 
a significant risk, may confound study results, and/or may interfere significantly with the 
subject's participation in the study. 
 


 
                                                                         Page 15 of 60 
 
 
4.3. 
Prohibited Medications and Activities 
 
The following medications and procedures are prohibited as outlined below.  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4. 
Precautions 
The precautions below are to be discussed with and followed by subjects during this study. 
 
Hygiene: Subjects must wash their hands prior to and after applying the study medication. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 


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5. STUDY PROCEDURES 
5.1. 
Study Medication Masking 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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5.2. 
Dosing Regimen Overview 
Eligible subjects 
 
 will return for baseline assessments at Visit 2/Day 0.  Subjects who meet the 
inclusion criteria and do not meet any of the exclusion criteria at Visit 2 will be randomized  
 to either the test or reference product for six (6) weeks (42+ 4 days) of treatment. 
During the treatment phase, subjects will apply one drop of the study medication in each eye 
three (3) times daily at approximately 8:00 am, 4:00 pm and 10:00 pm. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 


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Study medication compliance will be assessed following review of subject diaries.   
 
5.3. 
Subject Screening and Informed Consent 
The study personnel will review the IRB approved informed consent form with each subject, 
give the subject an opportunity to have all questions answered, and ensure that the consent 
form is executed prior to any study related procedures being performed.  Subjects 18 years or 
older must sign an Institutional Review Board (IRB) approved written informed consent. 
 
 
 
 
 
  
 
5.4. 
Assignment of Subject Number 
Once potential subjects sign the informed consent document, they will be given a Screening 
Number. 
 
 
 
 
At Visit 2/ Day 0, subjects that qualify for the randomized treatment phase of the study will be 
dispensed a kit which will identify their Subject Number. 
 
   
 
5.5. 
Medical History 
A demographic profile and complete medical history will be recorded prior to dispensing study 
medication.  The medical history will include a complete review of all current diseases and their 
respective treatments.   
 
5.6. 
Ocular History 
 A complete ocular and surgical history will be recorded prior to starting study medication.  
The ocular history will include a complete review of all prior and current ocular diseases and 
their respective treatments.  


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5.7. 
Prior and Concomitant Medications 
Concomitant medications and any medications taken 
 prior to signing informed 
consent will be recorded as prior/concomitant medications (using their generic name, if known) 
with the corresponding indication.
 
 
The medications to be recorded will include 
prescription and over-the-counter (OTC) medications and dietary supplements. All medications 
taken on either a regular or “prn” basis, including vitamins, should be recorded on this page 
prior to starting the study medication. An update of medication taken by the subject during the 
study is to be recorded at each study visit. 
 
5.8. 
Vital Signs 
 
Vital signs will be obtained at all visits.  Sitting blood pressure and sitting heart rate (after resting 
for 5 minutes), and temperature will be obtained.   
 
5.9. 
Pregnancy Test 
A urine pregnancy test will be conducted on women of child bearing potential at Visit 1, Visit 2 
(Day 0) and Visit 4/Day 42 (±4 days), and if warranted at an unscheduled visit. An investigator 
may repeat the pregnancy test anytime during the study visit if there is any suspicion or 
possibility that the subject may be pregnant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.10. External Eye Exam 
External eye exam will be performed at Visit 1.  
 
 
 
5.11. Iris Color  
At Screening/Visit 1, the Investigator will classify the color of the iris
 
 
s Light Iris, 
 Dark Iris. 




Protocol No: PRG-NY-19-001     
 
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hypertension during the study should be discontinued and provided with effective or 
alternative treatment. 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The time the IOP was measured and the time the dose was instilled will be recorded. 
 
 
  
 
 
 
   


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5.19. Study Medication Dispensing, Dosing and Diary Cards.  
Baseline 
Visit 2/Day 0 
 
At baseline, Visit 2/Day 0, upon meeting the study entry criteria and being randomized, the 
investigator 
 assign a kit (not previously assigned) to 
the subject. 
  
 
 
 


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Week 2: 
 Visit 3/Day 14 (+4 days)  
 
At Visit 3, the subjects will return with the used bottle and completed diaries. 
 
 
 
 
 
 
 
  
 
 
  
 
Week 6:   
Visit 4/Day 42 (+ 4 days) 
 
At Visit 4, the subjects will return with the used bottle(s) and completed diaries.  
 
 


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5.20. Schedule of Assessments By Visit 
 
Visit 1 Screening 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
Visit 2/Day 0, Baseline 
 
All assessments will be performed on the same day.   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Visit 3/Day 14 (± 4 days) or Week 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Visit 4/Day 42 (± 4 Days) or Week 6.  End of Study/Early Termination  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Unscheduled Visits 
An unscheduled visit is allowed at any time if in the investigator’s opinion it is warranted due 
an AE or safety concern. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 




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5.22. Screen Failures  
Screen failures are not included in any data analyses. A screen failure is a subject who received 
information about the study, including signing an informed consent/assent, and possibly 
underwent some study-related procedures but was not enrolled, dispensed study medication, 
nor applied the investigational product. 
 
 
 
 
5.23. Protocol Deviations and Violations 
This study will be conducted as described in this protocol except for an emergency in which the 
protection, safety, and well-being of the subject requires immediate intervention, based on the 
judgment of the investigator or a responsible, appropriately trained and credentialed 
professional(s) designated by the investigator. In the event of a significant deviation from the 
protocol due to an emergency, accident or mistake, the investigator or designee must contact 
Perrigo /CRO contacts at the earliest possible time. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
5.24. Subject Treatment Compliance  
Compliance will be verified by use of diary cards in which subject will record daily all missed 
or completed applications.  Subjects will be considered compliant if they apply at least 
 
and not more than 
 
 and do not miss 
 consecutive days 
 of 
study medication for either eye 
 
 


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5.25. Reasons for Discontinuation/Withdrawal 
The reasons for withdrawal from this study may include but are not limited to:  
 
1. The subject withdraws his or her consent for any reason. 
2. In the opinion of the investigator, the IOP is not adequately controlled for a subject’s 
current ocular condition or the subject’s condition has worsened to the degree that the 
investigator feels it is unsafe for the subject to continue in the study or requires an 
alternative therapy.  
3. Adverse event  
4. Study treatment is unmasked by either the subject or study staff 
 
  
5. The subject is lost to follow-up.  The investigator will document efforts to attempt to 
reach the subject (at least twice by telephone and via certified letter) before considering 
that subject lost to follow-up.  
6. The subject becomes pregnant during the study. 
7. Investigator discretion (e.g. non-compliant to study protocol requirements or subject is 
deceptive with information provided.)  
8. Subject did not meet or no longer meets the entry criteria 
9. Other 
 
5.26. Procedures for Early Termination 
If a subject withdraws or is removed from the study for any reason, Early Termination 
Visit/Visit 4 procedures will be completed. Reason for withdrawal, date of the 
discontinuation, and date of the last dose of study medication should be recorded in the 
source and eCRF.  
 
If a subject discontinues from the study at any time due to an adverse event, the reason for 
discontinuation, the nature of the event and its clinical course must be fully documented.  For 
such a subject, the investigator must strive to follow the subject until the adverse event has 
resolved, become clinically insignificant, is stabilized, or the subject is lost to follow-up.  
 
After a subject has been discontinued, he/she will not be allowed to re-enroll in the study at 
any facility. Study medication assigned to the withdrawn subject may not be re-assigned to 
another subject. 
 
 


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6. STUDY MEDICATION AND SUPPLIES 
6.1. 
Study Medication  
The study medication supplied by Perrigo will consist of: 
 
Test Product:   
 
 
Brinzolamide Ophthalmic suspension 1%, 10 mg/ml, 10 ml per bottle 
 
 
Reference Listed Drug:    
Azopt® (Brinzolamide Ophthalmic suspension) 1%, 10 mg/ml, 10 ml per bottle 
Novartis Pharmaceutical Corporation  
Distributed by Alcon 
 
 
  
 
6.2. 
Randomization Code  
Randomization will be performed by a third party vendor according to a computer-generated 
randomization schematic 
 where each Kit Number will be assigned one of two 
treatment assignments. An independent clinical packaging vendor will generate and hold the 
randomization codes throughout the study until formally released after database lock.  
 
6.3. 
Packaging and labels 
Both products are provided in 10 ml plastic dispenser bottles with a dispensing tip and cap. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4. 
Procedure for Breaking the Blind 
The investigator and the study staff performing the efficacy and safety assessments will be 
masked to the subject’s treatment assignment. In the event of an emergency, the specific 
subject treatment may be identified by removing the overlay of the blinded label for each 
subject at each investigator site, which is attached to the study medication log; however, every 
effort should be made to maintain the blind. The investigator must not scratch off the 


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occluding layer of the label unless absolutely necessary to provide medical treatment to a 
subject in an emergency situation only and should seek prior authorization by Perrigo or 
designee when possible.  The reason for breaking the blind must be clearly documented in the 
source documentation and eCRF and the subject must be discontinued from the study. Perrigo 
must be notified immediately upon all unblinding situations.  
 
 
6.5. 
Retention Samples 
Each investigational site where study medication is dispensed to at least one subject will be 
required to randomly select 
 retain 
(reserve) samples.  The investigator will maintain 
 randomly selected blocks of study 
medication for each shipment of study medication received.  As per the Code of Federal 
Regulations Part 21, Section 320.38(e), “Each reserve sample shall be stored under conditions 
consistent with product labeling and in an area segregated from the area where testing is 
conducted and with access limited to authorized personnel even after the study has concluded. 
Each reserve sample shall be retained for a period of at least 5 years following the date on 
which the application or supplemental application is approved, or, if such application or 
supplemental application is not approved, at least 5 years following the date of completion of 
the bioavailability study in which the sample from which the reserve sample was obtained was 
used.” The investigator will store the retain sample study medication until such time as 
notification is received from Perrigo that the samples are no longer required. 
 
6.6. 
Storage and Test Article Accountability 
The investigator should ensure that the study medication is stored under adequate security 
and regularly monitored and recorded and at temperature of 4°-30oC (39o-86oF).   
 
The investigator will not supply study medication to any person not enrolled in this study, or to 
any physician or scientist except those named as sub-investigators. 
 
The third party dispenser and study monitor (CRA) will perform drug accountability and 
reconciliation tasks. A running inventory of dispensed study medication will be kept that will 
include kit number, the date each bottle of study medication was dispensed, and date returned.  
A study medication accountability form will be provided to the investigator to document all 
medication bottles received and used by each subject.   
 
At the conclusion of the study all returned unused, partially used, and empty bottles will be 
inventoried by the CRA and/or third party dispenser and returned to Perrigo’s designee for 
destruction.  
 
 


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7. ADVERSE REACTIONS 
The potential adverse reactions of brinzolamide ophthalmic suspension 1% are anticipated to 
be like those observed for AZOPT (brinzolamide ophthalmic suspension) 1%. 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 and tearing potential adverse reactions of brinzolamide ophthalmic suspension 
1% are anticipated to be like those observed for AZOPT (brinzolamide ophthalmic suspension) 
1%. Adverse reactions related to treatment with AZOPT (brinzolamide ophthalmic 
suspension) 1%, include blurred vision and bitter, sour or unusual taste blepharitis, 
dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular 
discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis. 
 
7.1. 
Departure From the Protocol For Individual Subjects 
When an emergency occurs requiring a subject departure from the protocol, departure will 
be only for that subject. In such circumstances, the investigator or other physicians in 
attendance will contact the Medical Monitor or Perrigo by telephone and follow-up with a 
written description as soon as possible. The overseeing IRB should also be notified in 
accordance with the IRB’s guidelines.  
 
7.2. 
Definitions 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
a medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (for 
example, an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to this medicinal product. 
 
A serious adverse event (SAE) is an adverse event that results in any of the following outcomes: 
o death 
o life-threatening event (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death 
o requires in-subject hospitalization or prolongs hospitalization 
o a persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
o congenital anomaly/birth defect 


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o Other adverse events that may be considered serious based upon appropriate 
medical judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
 
Immediately Reportable Adverse Events (IRAE): Any serious AE or any AE that necessitates 
discontinuation of study medication, including pregnancy. 
 
Unexpected Adverse Event:  An unexpected event is any adverse drug experience, the 
specificity or severity of which is not consistent with the current approved product labeling 
(package insert) for the study medication, the Investigator’s Brochure, or as described in the 
clinical protocol and consent materials.    
 
Intensity of Adverse Events: 
 
 The maximum intensity of an AE during a day should be recorded on the CRF. If the intensity 
of an AE changes over a number of days, then separate entries should be made having 
distinct onset dates for the changes in severity. 
 
Mild - AEs are usually transient, requiring no special treatment, and do not interfere 
with subject’s daily activities. 
 
Moderate - AEs typically introduce a low level of inconvenience or concern to the 
subject and may interfere with daily activities but are usually ameliorated by simple 
therapeutic measures. 
 
Severe - AEs interrupt a subject’s usual daily activity and traditionally require systemic 
drug therapy or other treatment. 
 
Causal Relationship to Study Medication  
 
The following criteria should be used in assessing the apparent causal relationship of an AE to 
study medication.  
 
Definitely- The AE follows a reasonable temporal sequence from study medication 
administration abates upon discontinuation of the study medication (dechallenge) 
is confirmed by reappearance of the reaction on repeat exposure 
 
Probably - The AE follows a reasonable temporal sequence from study medication 
administration abates upon discontinuation of the study medication (dechallenge) 
cannot be reasonably explained by the known characteristics of the subject’s state. 
 
Possible - The AE follows a reasonable temporal sequence from study medication 
administration but that could readily be produced by a number of other factors. 


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Unlikely - The AE follows a reasonable temporal sequence from study medication 
administration could have been produced by either the subject’s clinical state or by 
study medication administration. 
 
Not related - The AE does not have a reasonable temporal association with the 
administration of study medication has some other obvious explanation for the event. 
 
7.3. 
Eliciting and Reporting of Adverse Events 
The investigator will periodically assess subjects for the occurrence of adverse events.
 
 
 
All adverse events (as defined in Section 7.2), either 
observed by the investigator or one of his/her medical collaborators, or reported by the 
participant spontaneously, or in response to direct questioning, will be reported and 
documented in the source document and the study reporting forms. When reporting an 
adverse event, the investigator must assign a severity grade to each event and declare an 
opinion on the relatedness of the event to the study medication or procedure. Serious or 
unexpected adverse events must be reported 
 within 24 hours of when the 
investigator first learns of the occurrence of the event.  
 
Adverse events will be documented in the source document and recorded in a timely manner 
on the eCRFs. Adverse events that are identified at the last assessment visit (or the early 
termination visit) must be recorded on the AE eCRF with the status of the AE noted.  
 
Adverse event reporting begins from the signing of informed consent. Adverse events should 
be followed until resolved or 30 days after the final study treatment. In any case, serious 
adverse events that are not resolved or considered to be chronic within 30 days of the final 
study treatment must be followed by the investigator until they become resolved or are 
considered to be chronic (stabilized for at least 30 days). All events that are ongoing at this time 
will be recorded as ongoing on the eCRF. 
 
7.4. 
Expedited Reporting Responsibilities of the Study Center 
For any serious or unexpected adverse event, 
 must be notified within 24 hours of when 
the investigator first learns of the occurrence of the event. Expedited reporting requirements 
for serious adverse events are described below. Adequate information must be collected with 
supporting documentation to complete a standard report for submission to Perrigo. The 
adverse event term on the AE eCRF and the SAE report should agree exactly. Special attention 
should be given to recording hospitalizations and concomitant medications.   
 
Subjects with unresolved adverse event(s) or serious adverse event(s) should be followed by 
the investigator until the events are resolved, events determined to be chronic, or the subject 
is lost to follow-up. Resolution means the subject has returned to the baseline state of health, 
or the investigator does not expect any further improvement or worsening of the adverse 


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event. The investigator should continue to report any significant follow-up information to the 
sponsor up to the point that the event has resolved. Any serious adverse event reported by the 
subject to the investigator that occurs within 30 days after the last assessment and is 
determined by the investigator to be reasonably associated with the use of the study 
medication, should be reported to the sponsor within 24 hours of when the investigator first 
learns of the occurrence of the event.   
 
When reporting an SAE, the investigator (or designated study staff) will promptly report any 
serious adverse event or pregnancy by telephone 
 or by 
 immediately after the investigator becomes aware of the event. An SAE 
form should be completed and sent by fax, email, or overnight courier 
 within 24 
hours of knowledge of the event by the site. In many cases, only preliminary information will 
be available. Appropriate follow-up information should be sought (hospital discharge 
summaries, operative reports, etc.) and a follow-up SAE report form submitted. A designation 
of causality from the study medication should always be included with a follow-up report. 
Assess and report the causality of the event. 
 
7.5. 
Submitting an Expedited Safety Report to the IRB 
 supporting documentation for the reported event, the Medical 
Monitor, in conjunction with Perrigo, will determine if the safety report is eligible for expedited 
review. 
 the initial event and will notify the sponsor that an event has been 
reported within 1 business day after initial receipt. 
 the review of the 
event. This form, as well as other supporting documentation, will be forwarded 
 
 for review. 
 finalize the report and distribute it to the sponsor 
within 1 day (one) after initial receipt. When expedited safety reporting to regulatory 
authorities is indeed required, the investigator should review and update any newly available 
materials at once. Follow-up queries may be sent to the study center to further clarify the 
event. 
 
Each expedited safety report will routinely include a brief cover memorandum, the completed 
report, and any additional pertinent information recommended by 
Perrigo, or the 
study Medical Monitor. Once the report is assembled, the Principal Investigator must submit 
the expedited safety report to the IRB within the required reporting timeframe. Follow-up 
reports should be submitted when requested or when pertinent information becomes 
available.  
 
When a Principal Investigator receives an expedited safety report from 
 the sponsor 
detailing adverse events occurring at other study centers under this protocol, it must be 
promptly submitted to the study center’s IRB. The Principal Investigator must retain a copy of 
such reports as submitted to his/her IRB in the site’s study Regulatory Binder.  
 
 
 


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7.6. 
SAE & AEs Requiring Discontinuation of Study Drug, including Pregnancies 
ANY SAE THAT OCCURS AFTER A SUBJECT HAS ENTERED THE STUDY, WHETHER OR NOT 
RELATED TO STUDY MEDICATION, MUST BE REPORTED 
 IMMEDIATELY (WITHIN 24 
HOURS) VIA TELEPHONE OR FACSIMILE. IF INITIALLY REPORTED VIA TELEPHONE, THIS MUST 
BE FOLLOWED-UP BY A FACSIMILE OF THE WRITTEN SAE REPORT WITHIN 24 HOURS OF THE 
CALL 
 
 
Non-serious events that require discontinuation of study medication (including laboratory 
abnormalities) should be reported 
 immediately and within 1 working day. 
Subjects who discontinue due to experiencing adverse events should be followed clinically 
until their health has returned to baseline status or until all parameters have returned to 
normal. It is expected that the investigator will provide or arrange appropriate supportive 
care for the subject. 
 
A subject who experiences a severe adverse event related to study drug will be discontinued 
from the study. 
 
The notification about any serious adverse event should be directed to: 
 
 
 
 
 
 
CRO will forward to: 
  
 
 
 
 
 
 
 
 
        
 
               
 
 
 
 
 
 
 
 
 
 
 
 


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7.7. 
Pregnancy 
At the time some Principal Investigator or site personnel becomes aware that a study 
participant became pregnant following study participation, the Principal Investigator or 
designee will report the pregnancy immediately by phone and/or by faxing a completed 
Pregnancy Report to CRO within one working day of being notified of the pregnancy report. 
 
The report will include the following elements: 
• Participant (mother’s) coded study identifier; 
• Date of participant’s last menstrual period; 
• Total accumulated dose of study treatment administered to date; 
• Date of study medication administration. 
 
The investigator will follow the subject until completion of the pregnancy and must assess the 
outcome in the shortest possible time but not more than 30 days within completion of the 
pregnancy. 
 
Upon delivery, miscarriage or abortion, the Principal Investigator or designee must forward a 
follow-up Pregnancy Report with any relevant information on the present condition of the fetus 
 including: 
• Mother’s coded study identifier(s); 
• Gestational age at delivery, miscarriage or abortion; 
• Birth weight, gender, length and head circumference, if available; 
• Apgar scores recorded after birth, if available; 
• Any abnormalities. 
 
If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is 
to be documented], stillbirth, neonatal death, or congenital anomaly), the investigator will 
report the event by phone and by faxing a completed SAE report form to CRO within one 
working day of being notified of the pregnancy report. 
 
If the study is completed before the outcome of the pregnancy is known, CRO will assume the 
responsibility for following up on the pregnancy.   CRO will contact the Investigator or Study 
coordinator on or around the potential expected date of delivery to follow-up on the 
outcome of pregnancy and will also check on the status of the infant 8 weeks post-delivery.  
Upon awareness of the pregnancy outcome and known status of the infant following 8 weeks  
 
 


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of delivery, the investigator will complete the applicable pregnancy report forms and fax 
 
 within 1 day of being notified. 
 
7.8. 
Post Study Events 
Non-serious Adverse Events 
Adverse events that are identified at the last assessment visit (or the early termination visit) 
must be recorded on the AE eCRF with the status of the AE noted. These adverse events must 
be followed by the investigator until the events are resolved, events determined to be chronic 
or the subject is lost to follow-up. Resolution means the subject has returned to the baseline 
state of health or the investigator does not expect any further improvement or worsening of 
the adverse event. 
 
Serious Adverse Events 
Serious adverse events that are identified on the last assessment visit (or the early termination 
visit) must be recorded on the AE eCRF page and reported to Perrigo according to the 
procedures outlined above. Subjects with unresolved previously reported serious adverse 
events, or any new serious adverse events identified on the last assessment visit, should be 
followed by the investigator until the events are resolved, or the subject is lost to follow-up. 
Resolution means the subject has returned to the baseline state of health or the investigator 
does not expect any further improvement or worsening of the adverse event. The investigator 
should continue to report any significant follow-up information to Perrigo up to the point that 
the event has resolved. Any serious adverse event reported by the subject to the investigator 
that occurs after the last assessment and is determined by the investigator to be reasonably 
associated with the use of the study drug, should be reported to Perrigo. 
 
8. Statistical Analysis   
8.1. 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be prepared separately from this protocol to describe the 
statistical methods, models, hypotheses and subject populations to be analyzed.  The SAP will 
be completed and approved before locking the database and unmasking the study. 
All statistical tests will be 2-sided with a significance level alpha=0.05.  Data will be 
summarized using descriptive statistics (number of subjects [n], mean, standard deviation 
[SD], median, minimum, and maximum) for continuous variables and frequency and 
percentage for discrete variables.  Subject listings of all data from the eCRFs as well as any 
derived variables will be presented. 
 
8.2. 
Analysis Populations 
The following populations are defined for analyses: 
 
• The Safety Population 
 
The safety population includes all randomized subjects who receive study product. 
 


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• Per Protocol (PP) Population: 
 
The accepted PP population used for BE evaluation includes all randomized subjects 
who: 
• meet all inclusion/exclusion criteria,  
• received and used study medication 
• 
 
 
 
 
• complete IOP evaluations for both eyes at Visit 3/Day 14 (week 2) and Visit 
4/Day 42 (week 6) within the designated visit window (i.e. +/- 4 days for each 
visit),  
• have no significant protocol violations that could have interfered with the 
administration of the treatment or the precise evaluation of treatment 
efficacy.  
 
 
 
 
 
 
8.3. 
Planned Analysis 
The safety analysis will be performed for the safety subjects while the efficacy analysis will be 
conducted on the PP population. 
 
8.4. 
Sample Size  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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8.6. 
Safety Analysis 
The frequency and percent of subjects with adverse events will be summarized by MedDRA 
system organ class and preferred term and by severity and relationship to study drug for all 
two treatment groups.  
 
 comparable safety of the Test and Reference 
treatments will be evaluated by statistical comparison of the proportion of subjects who 
reported any adverse events.  Safety comparisons will be performed on the safety population. 
 
9. CONSENT/ASSENT CONSIDERATIONS AND PROCEDURES 
It will be made clear to the subject that, for the purposes of the study, they are consenting only 
for ophthalmic application of the test or reference product.  Investigators may discuss the 
availability of the study and the possibility for entry with a potential subject without first 
obtaining consent/assent. However, informed consent/assent must be obtained and 
documented prior to initiation of any procedures that are performed solely for the purpose of 
determining eligibility for research, including withdrawal from current medication(s).  When 
this is done in anticipation of, or in preparation for, the research, it is considered to be part of 
the research. 
 
The study must be approved in writing by an appropriate IRB as defined by FDA regulations.  A 
copy of the Letter of Approval from the IRB, which also contains specific identification of the 
documents approved, must be received by Perrigo prior to study commencement. 
 
Periodic status reports must be submitted to the IRB at least annually as required by the site’s 
IRB, as well as notification of completion of the study. A copy of all reports submitted to the 
IRB by the sites must be sent to Perrigo. 
 
The investigator(s) has both ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the protocol.  This shall be 
delivered in the form of a written informed consent/assent form, which shall be approved by 
the same Institutional Review Board (IRB) responsible for approval of this protocol. Each 
informed consent/assent form shall include the elements required by FDA regulations in 21 CFR 
Part 50.  The investigator agrees to obtain approval from Perrigo of any written informed 
consent/assent form used in the study, preferably prior to submission to the IRB. 
 
Once the appropriate essential information has been provided to the subject and fully 
explained by the investigators (or a qualified delegated designee) the subject  has had the 
opportunity to have all questions answered, and it is felt that the subject understands the 
implications of participating, the IRB-approved written informed consent/assent form shall be 
signed by the subject (or their parent/legally authorized representative) and the person 


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obtaining consent/assent (investigator or designee).  The subject shall be given a copy of the 
signed informed consent/assent form and the investigator shall keep the original on file. 
 
If the subject fails to meet the inclusion/exclusion criteria at the conclusion of the screening 
phase, the subject will be withdrawn from study participation.  In the event that the subject is 
re-screened for study participation 30 days or more beyond the initial screening, a new 
informed consent/assent form must be signed. 
 
9.1. 
Subject Confidentiality 
All participants are concerned for the individual subject’s privacy and, therefore, all subject 
data will be identified only by a subject identification number and subject initials. However, in 
compliance with federal guidelines regarding the monitoring of clinical studies and in 
fulfillment of his/her obligations to Perrigo, it is required that the investigator permit the study 
monitor, any Perrigo authorized representative, and/or FDA representatives to review that 
portion of the subject’s medical record that is directly related to the study.  This shall include 
all study relevant documentation including but not limited to subject medical histories to verify 
eligibility, laboratory test results to verify transcription accuracy, admission/discharge 
summaries for hospital stays occurring while the subject is enrolled in the study and autopsy 
reports for deaths occurring during the study. 
 
As part of the required content of informed consent, the subject must be informed that his/her 
medical chart may be reviewed by Perrigo or their authorized representative, or a 
representative of the FDA.  Should access to the medical record require a separate waiver or 
authorization, it is the investigator’s responsibility to obtain such permission from the subject 
in writing 
 
To preserve the subject's confidentiality, the data collected will be available only to the 
investigators of the study, their support staff, Perrigo or their authorized representative and 
possibly the FDA. 
 
All reports and communications relating to the subject in the study will identify each subject 
only by the subject’s initials and by the Subject Number. The investigator agrees to furnish 
Perrigo with complete subject identification.  
 
10. CONDUCT OF STUDY 
The investigational site is to maintain complete documentation of all subject procedures and 
when they occur. 
 
10.1. Completion of Study 
The investigational site will complete the study and complete all documentation required in 
satisfactory compliance with the protocol. 
It is agreed that, the investigator or Perrigo may terminate this study before completion and 
shall provide written notice of such termination.   


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10.2. Protocol Amendments 
The Investigator will not make any changes to this protocol nor intentionally deviate from this 
protocol without prior written consent from Perrigo and subsequent approval by the IRB.  Any 
permanent change to the protocol, whether it is an overall change or a change for specific study 
center(s), must be handled as a protocol amendment. 
 
When in the judgment of the reviewing IRB, the investigators and/or Perrigo, the amendment 
to the protocol substantially alters the study design and/or increases the potential risk to the 
subject, the currently approved written informed consent form will require similar 
modification.  In such cases, additional informed consent will be obtained from subjects 
enrolled in the study before expecting continued participation. 
 
11. RECORDS MANAGEMENT 
11.1. Data Collection 
Database set-up will be performed 
 using an appropriate fully validated, 21 CFR 
Part 11 compliant Electronic Data Capture (EDC) system. eCRFs will be provided to each site 
via a secured web link. All applicable study data collected on each subject will be recorded by 
approved site personnel into the eCRF.  Only authorized site personnel will be able to 
enter/modify/correct data to the eCRF. 
 
Approved staff at the CRO will verify all data entered into eCRFs for completeness and accuracy 
with reference to the source documents and records and will issue data queries to correct 
missing data or discrepancies found against the source within the EDC system. 
 
Data validation will consist of automated and manual edit checks that are created directly into 
EDC. Automated edit checks will be executed on all data points defined and documented by 
the study team and data management. Study metrics will be reported from the EDC system. 
After all data have been verified by approved staff at the CRO, an Investigator or Sub-
Investigator (listed on Form FDA 1572) is required to review and approve all eCRFs prior to 
database lock and breaking of the blind.  
Quality assurance verification via a 10% database audit of eCRF data will be conducted before 
the treatment assignment code is broken. 
 
During each subject’s visit to the clinic, a designee participating in the study will record progress 
notes to document all significant observations.  At a minimum, these notes will contain the 
following information about the following procedure at the visits they occur: 
 
a) Documentation of the informed consent process (when obtained) 
b) The date of the visit and the corresponding Visit or Week in the study schedule; 
c) General subject status remarks, including any significant medical findings.  The severity, 
frequency, and duration of any adverse events and the investigator's assessment of 
relationship to study medication must also be recorded. 


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d) Any changes in concomitant medications or dosages; 
e) A general reference to the procedures completed; and 
f) The signature (or initials) and date of all clinicians who made an entry in the progress 
notes. 
 
In addition, any contact with the subject via telephone or other means that provides significant 
clinical information will also be documented in the progress notes as described above. 
 
Any changes to information in the study progress notes and other source documents, will be 
entered in black or blue ink, initialed and dated by the authorized person making the 
correction/addition.  Changes will be made by striking a single line through erroneous data, and 
clearly entering the correct data.  (e.g., wrong data right data).  Entries may not be erased or 
masked with white-out fluid.  If the reason for the change is not apparent, a brief explanation 
for the change will be written adjacent to the change by the clinician. 
 
For transmission to Perrigo, information from the study progress notes and other source 
documents will be entered into the database.  The database also contains a complete audit trail 
to capture all regulatory components of data corrections (e.g. initial entry, new value, initials 
and date of the change). 
 
11.2. Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation.  Source documents will include, but are not limited to, progress notes and 
screening logs.  All source documents pertaining to this study will be maintained by the 
investigators and made available for inspection by authorized persons.  The original signed 
informed consent form for each participating subject shall be filed with records kept by the 
investigators and a copy given to the subject. 
 
11.3. File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the International Conference on Harmonization (ICH) Guideline 
for Good Clinical Practices (GCP). 
 
Records Retention at the Study Site 
FDA regulations require all investigators participating in clinical drug studies to maintain 
detailed clinical data for one of the following periods: 
 
a) A period of at least two years following the date on which a New Drug Application is 
approved by the FDA; 
b) A period of two years after Perrigo notifies the investigator that no further 
application is to be filed with the FDA. 
 
The investigator must not dispose of any records relevant to this study without either (1) 
written permission from Perrigo or (2) providing an opportunity for Perrigo to collect such 


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records.  The investigator shall take responsibility for maintaining adequate and accurate 
electronic or hard copy source documents of all observations and data generated during this 
study, including any data correction forms (DCFs) received from CRO.  Such documentation is 
subject to inspection by Perrigo and the FDA. 
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
12.1. Monitoring 
Perrigo has ethical, legal and scientific obligations to carefully follow this study in a detailed 
and orderly manner in accordance with established research principles and FDA regulations.  
All medical records (source documents) of the subjects participating in this study must be 
presented for review and verification of eCRFs. 
 
12.2. Auditing 
Perrigo (or representative) may conduct audits at the study center(s).  Audits will include, but 
are not be limited to drug supply, presence of required documents, the informed consent 
process, and comparison of case report forms with source documents.  The investigator agrees 
to participate with audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study. The 
investigator should contact Perrigo immediately if notified of such an audit and must fully 
cooperate with the audits conducted at a reasonable time in a reasonable manner. 
 
13. ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the United States Food and 
Drug Administration (FDA) regulations, any other countries regulations, and ICH GCP 
Guidelines. 
 
14. USE OF INFORMATION AND PUBLICATION 
All information supplied by Perrigo in connection with this study and not previously published, 
is considered confidential information.  This information includes, but is not limited to, data, 
materials (i.e. the clinical protocol, case report forms), equipment, experience (whether of a 
scientific, technical, engineering, operational, or commercial nature), designs, specifications, 
know-how, product uses, processes, formulae, costs, financial data, marketing plans and direct 
selling systems, customer lists and technical and commercial information relating to customers 
or business projections used by Perrigo in its business. Any data, inventions, or discoveries 
collected or developed, as a result of this study is considered confidential. This confidential 
information shall remain the sole property of Perrigo, shall not be disclosed to any 
unauthorized person or used in any unauthorized manner without written consent of Perrigo, 
and shall not be used except in the performance of the study.  As such, confidential study-
related information should not be included on the curriculum vitae of any participating 
investigator or study staff. 
 


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The information developed during the course of this clinical study is also considered 
confidential and will be used by Perrigo in connection with the development of the drug.  The 
information may be disclosed as deemed necessary by Perrigo to allow the use of the 
information derived from this clinical study, the investigator is obliged to provide Perrigo with 
complete test results and all data developed in the study. The information obtained during this 
study may be made available to other investigators who are conducting similar studies. 
 
The investigator shall not make any publication related to this study without the express 
written permission of Perrigo.
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR AGREEMENT 
 
PROTOCOL NUMBER:    PRG-NY-19-001 
 
PROTOCOL TITLE: 
 
 
A Multi-Center, Randomized, Double-Masked, Active Controlled, 
Parallel Group Bioequivalence Study with Clinical Endpoint Comparing 
Brinzolamide Ophthalmic Suspension 1% of Perrigo Pharma 
International DAC to Azopt® (brinzolamide ophthalmic suspension) 
1% of Novartis Pharmaceuticals Corporation in the Treatment of 
Primary Open Angle Glaucoma or Ocular Hypertension in Both Eyes.  
 
 
I have carefully read the foregoing protocol and agree that it contains all the necessary 
information for conducting this study safely.  I will conduct this study in strict accordance with 
this protocol, ICH Guidelines for Good Clinical Practices, the Code of Federal Regulations, the 
Health Insurance Portability and Accountability Act (HIPAA) and any local regulatory 
requirements and will attempt to complete the study within the time designated.  I will provide 
access to copies of the protocol and all other information relating to pre-clinical and prior 
clinical experience submitted by Perrigo to all personnel responsible to me who participate in 
the study.  I will discuss this information with them to assure that they are adequately informed 
regarding the drug and conduct of the study.  I agree to keep records on all subject information 
in accordance with FDA regulations. 
 
 
 
 
 
 
 
   Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
   Principal Investigator’s Signature 
 
 
 
 
________________________________________________ 
 
   Date 
 
 




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15.2. Appendix B:   Subject Instructions 
 
SUBJECT INSTRUCTIONS 
Perrigo Study # PRG-NY-19-001  
 
Check Visit Dispensed:     Visit 2:  
       Visit 3:    
  Unscheduled visit:  
   Date: ________ 
 
SUBJECT INITIALS: ___  ___ ___     SITE NUMBER ____   ____         SUBJECT NUMBER:    ___    ___    ___    ___ 
 
 STORAGE AND HANDLING 
 
STORE THE STUDY MEDICATION AT 4O- 30OC (39O-86OF).  DO NOT FREEZE, AVOID HIGH TEMPERATURE BY NOT 
LEAVING IN YOUR CAR.   
 
 
 
  
  
 
  
 
 
 
   
 
 
 
  
 
  
 
 


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Protocol No: PRG-NY-19-001     
 
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APPOINTMENT  
 
 
You are scheduled to return at: 
 
_______________________AT ______________________   Visit 3, Treatment Week 2    
DATE 
   TIME  
 
Reminder:    
Don’t forget to instill the evening dose the evening before your study visit at about 10:00 pm.     
Do not instill the morning dose of study medication on the day of your study visit. 
 
 
___________________        AT_________________________  Visit 4, Treatment Week 6 
DATE 
 
 
             TIME 
 
ALL APPOINTMENTS ARE IMPORTANT! IF YOU NEED TO RE-SCHEDULE YOUR APPOINTMENT, PLEASE CALL YOUR 
STUDY DOCTOR’S OFFICE IMMEDIATELY. 
 
____________________________________________________________________________  
NAME AND TELEPHONE NUMBER OF STUDY COORDINATOR/STUDY SITE 
 


Protocol No: PRG-NY-19-001     
 
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16. References 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
NCT04024072 
07-01-2019




Table of Contents 
1 
Purpose of Statistical Analysis Plan ........................................................................................................ 4 
2 
Study Objectives ....................................................................................................................................... 4 
3 
Study Design and Sample Size ................................................................................................................ 4 
3.1 
Study Design ..................................................................................................................................................... 4 
3.2 
Sample Size ....................................................................................................................................................... 5 
4 
Analysis Populations ................................................................................................................................ 5 
5 
Planned Analyses ...................................................................................................................................... 6 
5.1 
Methodological Considerations ........................................................................................................................ 6 
5.2 
Handling of Dropouts or Missing Data ............................................................................................................. 7 
5.3 
Demographics and Baseline Characteristics ..................................................................................................... 7 
5.4 
Subject Disposition ........................................................................................................................................... 8 
5.5 
Protocol Deviation ............................................................................................................................................ 8 
5.6 
Study Drug Exposure and Compliance ............................................................................................................. 8 
5.7 
Efficacy  Analyses ............................................................................................................................................ 9 
5.7.1 
Primary Endpoint ................................................................................................................................. 9 
5.7.2 
Comparison to Historic Data .............................................................................................................. 10 
5.8 
Safety Variables and Analyses ........................................................................................................................ 11 
6 
Appendices .............................................................................................................................................. 11 
6.1 
Handling of Missing or Incomplete Dates for Adverse Events and Concomitant Medications ...................... 11 
6.2 
Summary of Assessments ............................................................................................................................... 12 
7 
Tables and Listings ................................................................................................................................. 15 
Table 14.1.1 - Subject Disposition .......................................................................................................................... 17 
Table 14.1.2 - Subject Population (General) ........................................................................................................... 18 
Table 14.1.3 - Subject Enrollment by Study Site .................................................................................................... 19 
Table 14.1.4.1 - Demographic Characteristics  Safety Population .......................................................................... 20 
Table 14.1.4.2 - Demographic Characteristics  Per-Protocol Population ................................................................ 21 
Table 14.1.5.1- Baseline Vital Signs  Safety Population ......................................................................................... 22 
Table 14.1.5.2- Baseline Vital Signs  Per-Protocol Population ............................................................................... 23 
Table 14.1.6.1- Intraocular Pressure (IOP) Measurement at Baseline  Safety Population ...................................... 24 
Table 14.1.6.2- Intraocular Pressure (IOP) Measurement at Baseline  Per-Protocol Population ............................ 25 
Table 14.1.6.3- Baseline Mean IOP: Comparison with Historical Data* Intent-to-Treat Population ..................... 26 
Table 14.1.7 – Days of Exposure and Medication Compliance Rate  Safety Population ........................................ 27 
Table 14.2.1.1- Primary Efficacy Analysis: Mean Change from Baseline in IOP of Both Eyes  Per-Protocol 
Population ............................................................................................................................................................ 29 
Table 14.2.1.2- Mean IOP and Mean Change from Baseline IOP at /Week 2 and Week 6: A Comparison with 
Historical Data* ................................................................................................................................................... 30 
Intent-to-Treat Population ....................................................................................................................................... 30 
Table 14.3.2.1 - Overall Summary of Treatment Emergent Adverse Events (TEAEs)  Safety Population ............ 31 




List of Abbreviations  
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
 
 
BE 
Bioequivalence 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel Test 
IOP 
Intraocular Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
OH 
Ocular Hypertension 
PD 
Protocol Deviation 
POAG 
Primary Open Angle Glaucoma 
PP 
Per-Protocol (Population) 
PV 
Protocol Violation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
WHO Drug 
World Health Organization Drug Dictionary