Conditions: Glaucoma, Primary Open Angle Ocular Hypertension
Keywords: POAG OHT Primary open-angle glaucoma ocular hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
The study evaluated the safety and IOP-lowering effects of WB007 in adults with primary open-angle glaucoma or ocular hypertension in both eyes. This was a 2-part study. Part 1 was a 3-period dose escalation that evaluated 3 concentrations of WB007 ophthalmic solution following a single dose in one eye. Part 2 was a randomized, double-masked, parallel comparison that evaluated two concentrations of WB007 (selected based on Part 1 results) in both eyes compared with timolol 0.5% for 14 days.

Detailed description:

Arms:
arm 1: WB007 0.05%, single dose to study eye on Day 1 arm 2: WB007 0.15%, single dose to study eye on Day 1 arm 3: WB007 0.4%, single dose to study eye on Day 1 arm 4: WB007 0.15%, dosed twice daily for 14 days arm 5: WB007 0.4%, dosed twice daily for 14 days arm 6: Timolol 0.5%, dosed twice daily for 14 days.

Interventions: intervention 1: WB007 0.05% intervention 2: WB007 0.15% intervention 3: WB007 0.4% intervention 4: Timolol 0.5%
Intervention descriptions: intervention 1: WB007 Ophthalmic Solution 0.05% intervention 2: WB007 Ophthalmic Solution 0.15% intervention 3: WB007 Ophthalmic Solution 0.4% intervention 4: Timolol Maleate 0.5% Ophthalmic Solution

Protocol document:
Prot_000.pdf: 
Whitecap Biosciences 
Confidential 
 Protocol WB007-001_05 
 
1 
2021.01.30 
NCT#:  NCT04149899 
Whitecap Biosciences – CONFIDENTIAL 
This protocol contains confidential information intended solely for the recipient clinical 
investigator(s), IRBs/IECs, and regulatory agencies.  This protocol and all related study 
materials are the property of Whitecap Biosciences and must not be copied by or distributed 
by persons not involved in this clinical investigation without prior written consent from 
Whitecap Biosciences. 
STUDY TITLE 
A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with Primary Open-
Angle Glaucoma or Ocular Hypertension 
Protocol Number:   
WB007-001 
EudraCT Number: 
Not Applicable 
Phase: 
1/2 
Investigational Product: 
WB007 (also known as AGN-227535) 
Sponsor: 
Whitecap Biosciences 
6789 Quail Hill Pkwy Suite 719 
Irvine, CA 92603 
Medical Safety Physician  
Contact information: 
Robert David, MD 
robert.david@clindevop.com 
Tel:  +1.949.200.7988 
Emergency Telephone Number: 
(Dr. David) 
1-949-246-8368 
SAE Reporting: 
wb007@JANIX.com 
Whitecap Biosciences, LLC Signatory: 
Scott M Whitcup, MD 
Chief Executive Officer 
 
 
_____________________________  
____________ 
Scott M Whitcup, MD 
 
 
Date 
 
 


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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
STUDY LOCATION: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
Good Clinical Practices and all applicable laws and regulations. 
• Maintain all information supplied by Whitecap Biosciences in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Independent Ethics 
Committee (IEC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
RETURN TO WHITECAP BIOSCIENCES WITH ATTACHED PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
Protocol Synopsis ................................................................................................................................... 7 
1. 
Background and Rationale ...................................................................................................... 14 
1.1. 
Background ............................................................................................................................. 14 
1.2. 
Investigational Product ............................................................................................................ 14 
1.3. 
Summary of Nonclinical Studies ............................................................................................. 14 
1.4. 
Benefit/Risk Assessment ......................................................................................................... 16 
2. 
Study Purpose, Objectives, and Clinical Hypothesis(es) ........................................................ 16 
3. 
Study Design and Rationale .................................................................................................... 16 
3.1. 
Study Endpoints ...................................................................................................................... 18 
3.1.1. Primary Efficacy Endpoint(s) .................................................................................................. 18 
3.1.2. Secondary Efficacy Endpoint(s) .............................................................................................. 18 
3.2. 
Methods for Randomization, Stratification, Masking, and Minimization of Bias .................. 18 
3.2.1. Randomization and Stratification (Part 2 Only) ...................................................................... 18 
3.2.2. Masking ................................................................................................................................... 18 
3.2.3. Minimization of Bias ............................................................................................................... 19 
3.3. 
Treatment Stopping Rules and Discontinuation Criteria ......................................................... 19 
3.3.1. Treatment Stopping Rules ....................................................................................................... 19 
3.3.2. Discontinuation Criteria .......................................................................................................... 19 
3.4. 
Decision Making During Parts 1 and 2 ................................................................................... 20 
4. 
Study Population ..................................................................................................................... 20 
4.1. 
Inclusion Criteria ..................................................................................................................... 20 
4.2. 
Exclusion Criteria .................................................................................................................... 22 
4.3. 
Lifestyle Considerations .......................................................................................................... 24 
4.4. 
Screen Failures ........................................................................................................................ 25 
4.5. 
Rationale for Inclusion and Exclusion Criteria ....................................................................... 25 
5. 
Study Treatments ..................................................................................................................... 25 
5.1. 
Investigational Product ............................................................................................................ 25 
5.1.1. Preparation/Handling/Storage/Accountability ........................................................................ 26 
5.2. 
Study Treatment Administration ............................................................................................. 27 
5.2.1. Study Treatment Regimen and Dosing .................................................................................... 27 
5.2.2. Treatment Compliance ............................................................................................................ 28 
6. 
Concomitant Treatments and Medications .............................................................................. 28 
6.1. 
Prohibited Treatments and Medications .................................................................................. 28 
6.2. 
Washout/Waiting Period ......................................................................................................... 29 
6.2.1. Washout Period ....................................................................................................................... 29 


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6.2.2. Considerations During Washout Period .................................................................................. 30 
6.2.3. Waiting Period ......................................................................................................................... 30 
6.3. 
Permissible Medications and Treatments ................................................................................ 30 
6.4. 
Pregnancy and Contraception Considerations ......................................................................... 31 
6.4.1. Pregnancy Considerations ....................................................................................................... 31 
6.4.2. Acceptable Contraception ....................................................................................................... 31 
6.4.3. Procedures for Pregnancy Follow-up and Reporting .............................................................. 31 
7. 
Study Assessments .................................................................................................................. 32 
7.1. 
Demographics and Baseline Characteristics ........................................................................... 32 
7.2. 
Efficacy Assessments .............................................................................................................. 32 
7.3. 
Safety Assessments ................................................................................................................. 32 
7.4. 
Other Assessments .................................................................................................................. 33 
7.5. 
Methods of Data Collection .................................................................................................... 33 
8. 
Study Conduct ......................................................................................................................... 34 
8.1. 
Informed Consent .................................................................................................................... 35 
8.2. 
Subject Screening Visit /Screening Period (Days –50 to –4) .................................................. 35 
8.3. 
Subject Enrollment – Baseline Visit (Day -1) ......................................................................... 37 
8.3.1. Procedures Prior to Randomization (Part 2 only) .................................................................... 38 
8.3.2. Randomization Procedures (Part 2 only) ................................................................................. 38 
8.4. 
Study Visits and Procedures for Enrolled Subjects ................................................................. 38 
8.4.1. Part 1 - Study Visits and Procedures for Enrolled Subjects .................................................... 38 
8.4.2. Part 2 - Study Visits and Procedures for Enrolled Subjects .................................................... 40 
8.5. 
Unscheduled Visits and Associated Procedures ...................................................................... 42 
8.6. 
Instructions for Subjects .......................................................................................................... 42 
8.7. 
Safety Monitoring.................................................................................................................... 44 
8.7.1. Procedures for Collecting and Reporting Adverse Events ...................................................... 44 
8.7.2. Severity .................................................................................................................................... 45 
8.7.3. Relationship to Study Drug or Study Procedure ..................................................................... 45 
8.7.4. Procedures for Reporting a Serious Adverse Event ................................................................ 45 
8.8. 
Procedures for Stopping Study Treatment .............................................................................. 46 
8.9. 
Early Study Exit Procedures .................................................................................................... 46 
8.9.1. Subject Discontinuation/Withdrawal from the Study .............................................................. 46 
8.9.2. Lost to Follow Up.................................................................................................................... 47 
8.10. 
Procedures for Unmasking of Study Medication .................................................................... 48 
9. 
Statistical Procedures .............................................................................................................. 48 
9.1. 
Analysis Population(s) ............................................................................................................ 48 


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9.2. 
Sample Size Calculation .......................................................................................................... 49 
9.3. 
Methods of Analyses ............................................................................................................... 50 
9.3.2. Safety Analyses ....................................................................................................................... 51 
9.4. 
Other Analyses ........................................................................................................................ 52 
9.5. 
Subgroup Analyses .................................................................................................................. 52 
9.6. 
Interim Analyses...................................................................................................................... 52 
10. 
Supporting Documentation and Operational Considerations .................................................. 52 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations ...................................................... 52 
10.1.1. Regulatory and Ethical Considerations ................................................................................... 52 
10.1.2. Financial Disclosure ................................................................................................................ 53 
10.1.3. Informed Consent Process ....................................................................................................... 53 
10.1.4. Data Protection ........................................................................................................................ 54 
10.1.5. Coordinating Investigator ........................................................................................................ 54 
10.2. 
Protection of Human Subjects ................................................................................................. 54 
10.2.1. Subject Confidentiality ............................................................................................................ 54 
10.2.2. Subject Privacy ........................................................................................................................ 54 
10.2.3. Compliance with Informed Consent Regulations and Relevant Country Regulations ............ 55 
10.2.4. Compliance with IRB Regulations .......................................................................................... 56 
10.2.5. Compliance with Good Clinical Practice ................................................................................ 56 
10.3. 
Changes to the Protocol ........................................................................................................... 56 
10.4. 
Documentation ........................................................................................................................ 56 
10.4.1. Source Documents ................................................................................................................... 56 
10.4.2. Compliance with Electronic Records; Electronic Signatures Regulations .............................. 58 
10.4.3. Case Report Form Completion ................................................................................................ 58 
10.4.4. Data Quality Assurance ........................................................................................................... 58 
10.4.5. Study and Site Closure ............................................................................................................ 59 
10.4.6. Final Report by Investigator .................................................................................................... 59 
10.4.7. Retention of Documentation ................................................................................................... 59 
10.5. 
Monitoring by Whitecap Biosciences ..................................................................................... 60 
10.6. 
Publications ............................................................................................................................. 60 
11. 
References ............................................................................................................................... 61 
12. 
Attachments ............................................................................................................................. 62 
12.1. 
Glossary of Terms, Abbreviations and Definitions ................................................................. 62 
12.2. 
Examination Procedures, Tests, Equipment, and Techniques ................................................. 65 
12.2.1. Demographics and Baseline Characteristics ........................................................................... 65 
12.2.2. Ophthalmic Examination Procedures, Tests, Equipment, and Techniques ............................. 67 


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12.3. 
Other Study Supplies ............................................................................................................... 74 
12.4. 
List of Computerized Systems ................................................................................................ 74 
12.5. 
Protocol Amendments ............................................................................................................. 75 
12.5.1. Amendment 1 Summary .......................................................................................................... 75 
12.5.2. Amendment 2 Summary .......................................................................................................... 77 
12.5.3. Amendment 3 Summary .......................................................................................................... 78 
12.5.4. Amendment 4 Summary .......................................................................................................... 78 
12.5.5. Amendment 5 Summary .......................................................................................................... 79 
  
List of Tables 
Table 1 
Scheduled Visits and Procedures - Screening and Baseline (Parts 1 and 2)....................... 11 
Table 2 
Part 1 - Schedule of Visits and Procedures:  Days 1 and 2................................................. 12 
Table 3 
Part 2 - Schedule of Visits and Procedures:  Day 1 to Day 14/Exit ................................... 13 
Table 4 
Formulation Characteristics for AGN-227535/WB007  (Study Treatments 1-3) .............. 26 
Table 5 
Minimum Washout Period ................................................................................................. 29 
Table 6 
Power Calculations for Study Part 2 Tests of Treatment Differences ................................ 49 
Table 7 
Glossary of Terms and Abbreviations ................................................................................ 62 
Table 8 
Glossary of Definitions....................................................................................................... 64 
 
List of Figures 
Figure 1  Schematic of Study Design ................................................................................................ 10 
Figure 2  Part 1 Dose Escalation  ....................................................................................................... 10 
Figure 3  Part 2 Parallel Comparison ................................................................................................. 10 
 
 
 


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Protocol Synopsis 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Investigational Product:  WB007 (also known as AGN-227535) 
Phase:  1/2a 
Study Objectives:  The objective of this study is to assess the safety, ocular tolerability and 
IOP-lowering effects of AGN-227535 in adult subjects with bilateral primary open-angle 
glaucoma or ocular hypertension. 
Clinical Hypotheses:   
Parts 1/2:  
AGN-227535 has an acceptable safety and tolerability profile; 
Part 1: 
The safety profile allows for assessing AGN-227535 in Part 2; 
Part 2:   
At least 1 concentration of AGN-227535 demonstrates an IOP lowering effect. 
Type of Study:  Two-part, multi-centered [(Part 1- single-dose in one eye, open-labeled, 
dose-escalation), (Part 2 - multiple-dose, randomized, double-masked, active-controlled)], 
bilateral treatment.  
Study Population: Adult (at least 18 years of age) male or female subjects with primary 
open-angle glaucoma or ocular hypertension in each eye who are otherwise in generally good 
health.  Only one eye must meet all ocular entry criteria.   
Number of Subjects and Sites: Approximately 100 subjects will be screened to participate 
in the study (Part 1 – 25; Part 2 – 75).  An expected 95 subjects will be assigned to study 
treatment such that approximately 18 (Part 1) and 60 (Part 2) subjects complete the study at 
3-5 sites.  Subjects who do not complete the study may be replaced.   
Part 1: 
Approximately 6 subjects per dose-escalation cohort (up to 3). 
Part 2:  
Up to 2 investigational doses will be chosen based on results from Part 1.  
Approximately 24 subjects per AGN-227535 group and approximately 12 subjects 
for the timolol group will be given study treatment.   
Duration of Study Participation:   
Part 1: 
Up to 2 months from Screening through Day 2/Exit;   
Part 2: 
Up to 2.5 months from Screening through Day 14/Exit. 
Study Treatments:  AGN-227535 Ophthalmic Solution (Parts 1 and 2) and timolol 0.5% 
ophthalmic solution (as a control in Part 2 only) 
Part 1: 
Study Treatments 1-3:   AGN-227535 (0.05%; 0.15%; 0.40%);   
Part 2: 
Up to 2 AGN-227535 study treatments and Timolol 0.5% (Study Treatment 4). 
Dosage/Dose Regimen:   
Part 1: 
Subjects will be given 1 dose of study treatment to one eye in the morning 
(administered by site personnel). 


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Part 2: 
Subjects will dose study treatment every morning and every evening 
(approximately 12 hours apart) to each eye for up to 14 days.  Site personnel will 
administer the morning dose at study visits. 
Randomization/Stratification: 
Part 1: 
If only one eye qualifies, the study medication will be administered to that eye.  If 
both eyes qualify, the eye with the higher IOP at Baseline (Day -1) Hour 0 will be 
the study eye and will receive study medication.  If both eyes have the same IOP 
value at this timepoint, the right eye will be the study eye. 
Part 2: 
Part 2:  Subjects will be randomly assigned to 1 of up to 3 treatment arms (based 
on results from Part 1) in a 2(:2):1 allocation ratio to receive 1 of up to 2 AGN-
227535 concentrations or timolol 0.5% in each eye.  The randomization will be 
stratified by baseline IOP (IOP ≤ 25 mm Hg and > 25 mm Hg at Hour 0) and 
performed centrally (ie, across sites).  Randomization and stratification will be 
performed using the Interactive Web Response System (IWRS), a module within 
the electronic data capture (eDC) system. 
Visit Schedule:  
Part 1: 
Screening (days -50 to -4, including washout/waiting period as required); Baseline 
(Day -1), Day 1, Day 2/Exit 
Part 2: 
Screening (days -50 to -4, including washout/waiting period as required; Baseline 
(Day -1), Day 1, Day 4 and Day 14/Exit. 
Primary Efficacy Endpoint (Part 2 only):  Mean change from baseline in IOP 
Statistical Method for primary endpoint:   
In general, data will be summarized with descriptive statistics which will include sample 
size, mean, standard deviation, median, minimum and maximum for continuous variables 
and frequency and percentage for categorical variables. 
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events. The number and percentage of subjects with adverse event reports will 
be tabulated for all treatment-emergent adverse events (TEAEs) regardless of causality, 
treatment-related TEAEs, all serious TEAEs, treatment-related serious TEAEs, and all 
adverse events leading to premature discontinuation of study treatment.  
Analysis populations: Each population will be analyzed based on the treatment received. 
Part 1:  
The Safety population consisting of all treated subjects will be used for all 
analyses.  All safety and IOP-lowering effects tabulations will provide descriptive 
statistics by cohort. 
Part 2: 
The Safety population, as defined above, will be used for analyses of all Safety 
data. In addition to the Safety population two other populations are defined for 
analyses of Part 2 efficacy data: 


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The Modified Intent-to-treat (mITT) will consist of all randomized and treated subjects who 
provide IOP data at baseline and at least one post-baseline IOP assessment.  This population 
will be used for analyses of efficacy data.  
The Per-protocol (PP) population is a subset of the mITT population and will consist of 
subjects who did not have any major protocol violations deemed to have potential impact on 
the primary endpoint.  This population will be used to confirm the primary efficacy analysis. 
The primary efficacy endpoints are the Day 14/Exit mean IOP changes from Baseline (Day -
1) at each time-matched hour (0, 2, 4, 8) in the study eye.  The primary efficacy analysis will 
be within-group mean change from baseline IOP at hour 2, the time of peak effect of timolol.  
Between treatment group comparative analyses will be performed in the mITT population via 
analysis of covariance (ANCOVA) tests which will have treatment as the main effect and the 
baseline hour-matched IOP as the covariate in the model.  Pairwise treatment group 
comparisons will be performed for each individual dose of AGN-227535 ophthalmic solution 
versus timolol ophthalmic solution 0.5%.  Confidence intervals (95%) based on this 
ANCOVA model will be provided for the differences between treatment groups.  AGN-
227535 will be considered to be non-inferior to Timolol 0.5% if the upper limit of the 95% 
CI does not exceed 1.5 mm Hg at the majority of timepoints evaluated (ie, 3/4) at the Day 
14/Exit visit.  If AGN-227535 ophthalmic solution is determined to be non-inferior to 
Timolol ophthalmic solution 0.5%, a further attempt to show superiority of AGN-227535 
over Timolol will be made.  These analyses will also be performed on the PP population.  As 
this is an exploratory trial, all treatment comparisons will be made at the two-sided α = 0.05 
level without adjustment for multiple comparisons. 
Additional safety analyses will include evaluation of peak severity of macroscopic hyperemia 
and hyperemia as evaluated on biomicroscopy at each post-baseline visit (Days 4 and 14) and 
across all post-baseline time points. 
Sample Size Calculation:  For each cohort in Part 1 of the study a sample size of 6 patients 
will provide 83% power to detect a 3 mm Hg within-group change from pre-dose assuming a 
standard deviation of 2 and two-sided alpha = 0.05.  
Part 2 sample size will provide >90% power to detect within-group and between-group 
treatment differences of mean change from baseline of at least 3 mm Hg for the primary 
endpoint assuming a standard deviation of 2.5 with two-sided alpha = 0.05.  With a treatment 
group difference of -1 mmHg, the power ranged from 50% for a common SD of 3.5 to 78% 
for a common SD of 2.5 to conclude non-inferiority based on a 1.5 mmHg margin and a 1-
sided alpha = 0.025. 
Data Monitoring Committee:  No formal Data Monitoring Committee is planned.  Between 
dose-escalation groups in Part 1, all available data collected to date will be used to assist in 
decision making to continue to the next dose or to stop the study.  All data collected in Part 1 
will be used to select 1 or 2 concentrations of AGN-227535 to evaluate in Part 2.  The 
decision to proceed or to stop the study will be made by the Medical Monitor, the Head of 
Clinical and the Chief Executive Officer.  All decisions will be documented. 


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Figure 1  
Schematic of Study Design  
 
Figure 2  
Part 1 Dose Escalation  
Visit Flow 
 
Dose Escalation 
 
Figure 3  
Part 2 (Parallel Comparison) 
Visit Flow  


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Table 1 
Scheduled Visits and Procedures - Screening and Baseline (Parts 1 and 2) 
Assessment Visits (Visit Window ± Day) 
Screening 
Days -50 to -4 
Washout / Waiting Period (-50 to -4 Days) a 
Baseline 
(Day -1) 
Timepoint:  All examinations for all visits and timepoints should be performed in 
the order listed below from top to bottom (refer to Attachment 12.2 for details on 
how to perform procedures) 
Hour 
Hour 
Not Applicable 
0 
2 
4 
8 
Informed Consent/Authorization 
X 
 
 
 
 
Adverse Event Query 
X 
X 
 
 
 
(Part 2 only) Subject Comfort of Eye Drops Evaluation (for subjects on IOP 
lowering medications; evaluation to be administered by designated site 
personnel) 
X 
 
 
 
 
Concomitant Medications/Treatments 
X 
X 
 
 
 
Medical and Ophthalmic Histories 
X 
X 
 
 
 
Prior Medications/Treatments 
X 
X 
 
 
 
Physical Exam including height and weight 
X 
 
 
 
 
Respiration rate and temperature (seated) 
X 
X 
 
 
 
Postural (supine/standing) Blood Pressure & Heart Rate 
X 
Xb 
 
 
 
Non-fasting Laboratory assessments (CBC with differential, Blood Chemistries, 
Urinalysis) 
X 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
Urine Pregnancy Test (for females of childbearing potential) 
 
X 
 
 
 
Macroscopic (Gross) Hyperemia 
X 
X 
X 
X 
X 
Pupil Size (Part 2 only) 
 
X 
X 
 
 
Visual Acuity (using Manifest Refraction) 
X 
X 
 
 
 
Contrast Sensitivity (Part 2 only) 
 
X 
 
 
 
Slit-Lamp Biomicroscopic Examination 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP)c 
X 
X 
X 
X 
X 
Visual Fieldsd 
X 
X 
Fundus Exam (including cup/disc ratio) (post-pupil dilation) 
X 
 
 
 
 
NOTE:  CBC - Complete blood count; H = hour (hour 0 = 07:00 to 09:00 hours)  
a 
Washout / Waiting Period (Day -50 to Day -4).  For subjects taking IOP-lowering medications, the washout must be completed 
according to the schedule in Section 6.2.  For subjects who are not taking IOP-lowering medications, a 3-day waiting period from 
Screening to Baseline is required.  
b 
At Baseline, blood pressure and heart rate will be measured in the supine position only. 
c 
IOP should be measured before pupil dilation (as applicable)  
d 
Results of 2 reliable visual field (VF) examinations are required for eligibility.  See Section 4 for eligibility details, Sections 8.2 and 8.3 
for timing and Attachment 12.2 for methodology.  The same methodology and equipment should be used for all VF examinations.  
 


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Table 2 
Part 1 - Schedule of Visits and Procedures:  Days 1 and 2 
Outcome Assessment Visits (Visit window ± day) 
Day 1 
Day 2 
Timepoint:  All examinations for all visits and timepoints should be performed in the 
order listed below from top to bottom (refer to Attachment 12.2 for details on how to 
perform procedures) 
H0a 
30 
minutes 
post-1st 
dose 
H2 H
4 
H
8 
H0 
Adverse Event Query 
X 
<——————————> 
X 
Concomitant Medications/Treatments 
X 
 
 
 
 
X 
Postural (Supine/Standing) Blood Pressure & Heart Rate 
X 
 
X  
 
X 
Urine Pregnancy Test 
 
 
 
 
 
X 
Macroscopic (Gross) Hyperemia 
X 
X 
X 
X 
X 
X 
Visual Acuityb 
Xb 
 
 
 
 
Xb 
Slit-Lamp Biomicroscopic Examination 
X 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP)c  
X 
X 
X 
X 
X 
X 
Fundus Exam (including cup/disc ratio) (post-pupil dilation) 
 
 
 
 
 
X 
Confirm Inclusion / Exclusion criteria 
X 
 
 
 
 
 
Study Medication Assignment 
X 
 
 
 
 
 
Study medications administered at the site by site personnel  
X 
 
 
 
 
 
Collect subject EXIT status 
 
 
 
 
 
X 
NOTE:  H = hour (hour 0 = 07:00 to 09:00 hours) 
a 
Pre-dose  
b 
Manifest refraction performed at Baseline (Day -1) should be used at Days 1 and 2 to obtain a correction for visual acuity evaluation.  
Manifest refraction(s) may be repeated, if in the opinion of the investigator, it is necessary.  Visual acuity will be collected in Snellen-
equivalent units using a logarithmic (LogMar) visual acuity chart. 
c  
IOP should be measured before pupil dilation (as applicable) and at the same time (± 15 minutes) each day as the time established 
at baseline (day -1, hour 0, between 07:00 and 09:00 hours). 
 
 


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Table 3 
Part 2 - Schedule of Visits and Procedures:  Day 1 to Day 14/Exit 
Outcome Assessment Visits (Visit window ± day) 
Day 1 
(± 0 day) 
Days 4 (± 1 day) 
and 14 (± 2 days) 
Timepoint:  All examinations for all visits and timepoints should be 
performed in the order listed below from top to bottom (refer to 
Attachment 12.2 for details on how to perform procedures) 
H0 
30 
minutes 
post-1st 
dosea 
H2 H0 H2 H4 H8 
Text or phone call from site reminding subject to dose approximately 12 
hours prior to morning Hour 0 appointment 
 
X 
Adverse Event Query 
X  
 
X  
 
 
Subject Comfort of Eye Drops Evaluation (administered by designated site 
personnel) (Day 1 and Day 14/Exit only) 
 
X 
 
X  
 
 
Concomitant Medications/Treatments 
X  
 
X  
 
 
Postural (Supine/Standing) Blood Pressure & Heart Rate 
X  
X 
X 
X  
 
Non-fasting Laboratory assessments (CBC with differential, Blood 
Chemistries, Urinalysis) (Day 14/Exit only, following final dose) 
 
 
 
X 
Electrocardiogram (Day 14/Exit only) 
 
 
 
 
X 
 
 
Urine Pregnancy Test (Day 14/Exit only, following final dose) 
 
 
 
X 
Macroscopic (Gross) Hyperemia 
X 
X 
X 
X 
X 
X 
X 
Pupil Size (Day 14/Exit only)  
 
 
 
X 
X 
 
 
Visual Acuityb 
Xb  
 
Xb  
 
 
Contrast Sensitivity (Day 14/Exit only) 
 
 
 
X  
 
 
Slit-Lamp Biomicroscopic Examination 
X 
X 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP)c  
X 
X 
X 
X 
X 
X 
X 
Visual Fieldd (Day 14/Exit only) 
 
 
 
 
X 
Fundus Exam (incl. C/D ratio) (post-pupil dilation) (Day 14/Exit only) 
 
 
 
 
 
 
X 
Confirm Inclusion / Exclusion criteria 
X  
 
 
 
 
 
Randomize subject / Dispense study medication (for first dose)e 
X  
 
 
 
 
 
Study medication administered by site personnel 
X  
 
X  
 
 
Collect subject EXIT status (Day 14/Exit only) 
 
 
 
 
 
 
X 
NOTE:  C/D = cup/disc; H = hour (hour 0 = 07:00 to 09:00 hours)  
NOTE:  The night before postbaseline visits, evening dosing should occur approximately 12 hours (between 19:00 and 21:00 hours) prior 
to hour 0 of the subject’s next morning’s visit) 
a 
Subject Comfort of Eye Drops Evaluation will be performed within 30 minutes post-morning dose. 
b 
Manifest refraction performed at Baseline should be used at the days 1, 4 and 14 visits to obtain a correction for visual acuity 
evaluation.  Manifest refraction(s) may be repeated, if in the opinion of the investigator, it is necessary. 
c 
IOP should be measured before pupil dilation (as applicable) and at the same time (± 15 minutes) each day as the time established 
at baseline (day -1, hour 0, between 07:00 and 09:00 hours). 
d 
The same methodology and equipment should be used for examinations of VF performed throughout the study.  Visual Field 
evaluation can occur at any time after the Hour 2 examination and prior to pupil dilation for fundus examination at Hour 8. 
e 
Give a single bottle of study medication to subject at the end of the visit 


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1. 
Background and Rationale 
1.1. 
Background 
Ocular hypertension, or chronically elevated intraocular pressure (IOP), is a major risk factor 
for optic nerve injury and sight loss associated with glaucoma (AGIS, 2000; Heijl et al, 
2002); therefore, a primary goal of glaucoma management is to reduce IOP.  Brimonidine 
(ALPHAGAN®, ALPHAGAN® P) is a potent alpha2 adrenergic receptor full agonist that is 
used clinically for long-term management of increased IOP.  However, due to its relatively 
short duration of action, it is labelled in the United States for administration three times daily 
(TID).  An alpha-agonist with an improved pharmacokinetic profile could lead to higher 
therapeutic drug levels or decreased dosing which may provide an opportunity for better IOP 
management.  
Whitecap Biosciences plans to conduct an initial 2-part clinical study to evaluate the safety 
and IOP-lowering effects of AGN-227535 ophthalmic solution in adult patients with primary 
open-angle glaucoma (POAG) or ocular hypertension (OHT).  Part 1 will be an open-label, 
single-dose, dose-escalation assessment of up to 3 concentrations (0.05% 0.15%, 0.4%) of 
AGN-227535 administered unilaterally to assess initial safety, tolerability and IOP-lowering 
effects.  Results from Part 1 will determine concentration(s) to assess in Part 2.  In Part 2, up 
to 2 concentrations of AGN-227535 will be administered bilaterally, twice-daily for up to 14 
days and compared to timolol as the active control.  The non-clinical data package supports 
twice-daily dosing of AGN-227535 0.4% for up to 28 days in humans. 
1.2. 
Investigational Product  
AGN-227535 is a pivalate ester prodrug that undergoes enzymatic hydrolysis in the cornea to 
yield the active metabolite, AGN-222390.  Whereas AGN-227535 is only a weak alpha2 
agonist, AGN-222390 is a potent alpha2 adrenergic receptor pan-agonist that exhibits partial 
agonism at the alpha2A receptor AGN-222390 is also the 3-methyl hydroxylated metabolite 
of dexmedotomidine  a marketed drug used to produce short-term sedation of patients in the 
critical care setting.  
A detailed description of the chemistry, non-clinical pharmacology and toxicology of AGN-
227535 is provided in the Investigator’s Brochure.  
1.3. 
Summary of Nonclinical Studies  
Nonclinical studies have been conducted with AGN-227535 to assess pharmacology, 
pharmacokinetics and toxicology (both locally and systemically) from ocular and oral 


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administration using various models including in vitro, rat, rabbit, dog, and nonhuman 
primates.  The focus of the nonclinical testing strategy was 3-fold: to establish whether AGN-
227535 is differentiated from brimonidine relative to attributes that may form the basis for a 
better therapy for IOP management; to validate the conversion of the prodrug to the active 
metabolite and to enable the conduct of clinical testing of AGN-227535 with completion of 
the prerequisite IND-enabling toxicology studies.  
Below is a high-level summary of findings from the nonclinical studies: 
• AGN-227535 is a pivalate ester prodrug that is enzymatically hydrolyzed as it passes 
through the cornea to its active metabolite, AGN-222390; 
• AGN-222390 is a potent alpha2 receptor pan-agonist that exhibits partial agonism at the 
alpha2A receptor whereas its parent, AGN-227535, exhibits only weak activity;  
• AGN-222390 may offer advantages over brimonidine including less potential for receptor 
down regulation (tachyphylaxis) and a longer duration of IOP reduction; 
• Pharmacological and pharmacokinetic evidence indicate that AGN-222390 is the 
pharmacologically active moiety; 
• Ocular instillation of AGN-227535 is well tolerated at the proposed clinical 
concentrations and did not result in adverse morphological changes; 
• Systemic effects of AGN-227535 are largely the known pharmacologic effects of alpha2 
receptor agonists and include decreased intestinal motility, arterial hypotension, 
bradycardia, and sedation.  In some cases, these were transient. The pharmacologic 
systemic adverse effects are monitorable and reversible. At higher doses than the planned 
human equivalent starting dose, adverse cardiovascular effects and/or decreased GI 
motility were the likely cause(s) of death observed following oral administration in 
rats.  The lower systemic exposure achieved with topical ocular dosing suggests that 
cardiovascular effects are unlikely to occur with the topical dose (up to 0.4%) and dosing 
frequency (twice-daily) in this clinical study; 
• Morphological changes in the dog testes and epididymides were observed at the highest 
dose tested in a 14-day oral toxicity study but not in the 1-month oral toxicity study at 
equivalent or higher doses; 
• Overall, systemic effects of topically applied AGN-227535 at concentrations of up to 
0.4% dosed twice daily are not expected in humans given the administration of a 
relatively small administered dose and a much larger central volume compared to the 
toxicology species; 
• AGN-227535 and AGN-222390 are not mutagenic or clastogenic. 
Details of the non-clinical pharmacology, pharmacokinetics and toxicology of AGN-227535 
is provided in the Investigator’s Brochure. The non-clinical profile of AGN-227535 supports 


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the planned twice-daily dosing regimen of concentrations of up to 0.4% and the 2-week study 
duration in this clinical study.  This study will be conducted in compliance with the protocol, 
International Conference on Harmonization guidance and Good Clinical Practices.  
1.4. 
Benefit/Risk Assessment 
This is the first clinical study of AGN-227535 in humans; the potential benefits may be 
identifying an alpha-agonist with a longer duration of action and a better safety profile than 
currently available alpha-agonist treatments for IOP lowering.  Detailed information about 
the potential and/or known risks and potential adverse events of AGN-227535 may be found 
in the Investigator’s Brochure. 
2. 
Study Purpose, Objectives, and Clinical Hypothesis(es)   
Overall Study Purpose  
The purpose of this study is to assess initial ocular and systemic safety in humans of AGN-
227535 ophthalmic solution and to assess its potential to lower IOP in subjects with 
glaucoma or ocular hypertension.  
Study Objective(s) 
The objective of this study is to assess the safety, ocular tolerability and IOP-lowering effects 
of AGN-227535 in adult subjects with primary open-angle glaucoma or ocular hypertension. 
Clinical Hypotheses  
Parts 1/2: 
AGN-227535 has an acceptable safety and tolerability profile. 
Part 1: 
The IOP-lowering effects of at least 1 concentration of AGN-227535 are 
sufficient for evaluation to proceed to Part 2;  
Part 2: 
The IOP effects of at least 1 concentration of AGN-227535 demonstrate 
adequate IOP lowering; 
3. 
Study Design and Rationale 
Study Design Description:  This is a 2-part study designed to evaluate the safety, tolerability 
and IOP-lowering effects of AGN-227535 in subjects with primary open-angle glaucoma 
(POAG) or ocular hypertension (OHT).   Approximately 100 subjects are planned to be 
enrolled at up to approximately 5 study centers in the United States. 
In Part 1, an open-label dose-escalation of AGN-227535 0.05%, 0.15% and 0.4% is planned 
in order to assess initial safety, tolerability and IOP-lowering effects.  Approximately 6 
subjects will be exposed to a single dose (to one eye) at each concentration level.  Between 


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cohorts, all available data will be used to assess the appropriateness to pursue the next 
concentration.  Approximately 25 subjects will be screened so that 18 subjects complete the 
study.   
In Part 2, In addition to the primary analysis of the within-group mean IOP change from 
baseline, a parallel comparison of AGN-227535 with timolol 0.5% is planned.  Study 
treatments will be administered twice-daily for 14 days.  Up to 2 investigational doses will be 
chosen based on results from Part 1.  Subjects will be randomized in a 2(:2):1 ratio to receive 
one of up to two concentrations of AGN-227535 (based on results from Part 1) or timolol 
ophthalmic solution 0.5% and will be stratified based on IOP at Baseline, Hour 0 (≤ 25 mm 
Hg versus > 25 mm Hg).  Approximately 24 subjects per AGN-227535 group and 12 subjects 
for the timolol group will be given study treatment.  If 2 investigational doses are selected: 
approximately 75 subjects will be screened so that 60 subjects complete the study.  
For both Parts 1 and 2, potential subjects will be screened within the 50 days prior to 
initiation of treatment.  Thus, the total duration of study participation for each subject is up to 
2.5 months which includes 4 (Part 1) and 5 (Part 2) in-clinic visits.  The visit schedule 
requires day-long visits at some time points to perform sufficient clinical assessments.  The 
primary efficacy endpoint (Part 2) is IOP change from baseline at each time-matched hour at 
Day 14/Exit. 
Subject safety will be monitored throughout the study.  
Rationale for the Study Design:  Part 1 of this first in-human study will be conducted in a 
dose-escalation approach to assess the initial safety, tolerability and IOP-lowering effects of 
AGN-227535 following a single dose.  Part 2 will be conducted as a 14-day assessment of 
the safety, tolerability and IOP-lowering effects of AGN-227535 dosed bilaterally BID to 
evaluate the short-term potential to lower IOP with an acceptable safety/tolerability profile. 
Timolol, an accepted standard of care treatment, will be used as the control in Part 2. 
Rationale for Dose and Route of Administration:  Alpha-2 agonists are well-characterized.  
For  AGN-227535 approximately 44- to 714-fold safety margins were derived from the 
systemic, local (ocular), cardiovascular, and pulmonary toxicology studies in rats and/or dogs 
(Studies TX11082, TX11057, TX11154, and TX11120); these margins are considered to be 
sufficient to support the clinical starting dose of 0.05% AGN-227535 with up to BID bilateral 
administration in subjects with POAG or OHT.  As a topical eyedrop, the route of 
administration is considered appropriate. 


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 Rationale for Duration of Observation:  As the first-in-humans study, it is appropriate to 
take a measured approach with limited exposure to confirm the non-clinical results.  Alpha-
agonists are well-characterized in humans and based on results of Part 1, a planned 14-day 
assessment is appropriate. 
3.1. 
Study Endpoints 
3.1.1. 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is mean change from baseline in IOP at each time-matched 
hour of Day 14/Exit (Hours 0, 2, 4 and 8).   
3.1.2. 
Secondary Efficacy Endpoint(s) 
Mean IOP at Day 14/Exit.   
3.2. 
Methods for Randomization, Stratification, Masking, and 
Minimization of Bias  
3.2.1. 
Randomization and Stratification (Part 2 Only) 
Subjects will be randomly assigned to 1 of up to 3 treatment arms (based on results from Part 
1) in a 2(:2):1 allocation ratio to receive 1 of up to 2 AGN-227535 concentrations or timolol.   
To ensure balance of elements that could influence the IOP-lowering effects across treatment 
groups, the randomization will be stratified by baseline (Hour 0) IOP (≤25 mm Hg; >25 mm 
Hg). 
The randomization scheme will be prepared by Whitecap Biosciences Biostatistics or its’ 
designee. The IWRS, a module within eDC, will be used to confirm Baseline IOP eligibility 
and in Part 2 only, stratification and randomization of subjects.     
3.2.2. 
Masking 
Part 1: Subject treatment will not be masked.  If both eyes qualify, the eye with the higher 
IOP at Baseline (Day -1) Hour 0 will be the study eye and will receive study medication.  If 
both eyes have the same IOP value at this timepoint, the right eye will be the study eye.   
Part 2: Subject treatment will be double-masked; neither the investigator nor the staff or 
subject will be aware of treatment assignment.  All study treatments will be provided in 
similarly-appearing bottles with the same colored bottle caps and identical cartons to 
maintain masking of the study. 


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3.2.3. 
Minimization of Bias 
The study design is that of a well-controlled clinical trial that includes elements necessary for 
a valid ascertainment of the effectiveness of treatment.  Part 2 of the study is randomized and 
double-masked to minimize investigator and subject bias.  A parallel-group design eliminates 
possible confounding effects that are inherent in other study designs (eg, crossover).  The 
selection of subjects, study endpoints, and therapy are in general similar to studies that 
established the safety and efficacy of other IOP-lowering treatments of subjects with 
glaucoma or ocular hypertension.  Subjects who are chronically treated with ocular 
hypotensive medications will be required to undergo appropriate washout periods prior to 
study entry to eliminate residual effects of other active ocular hypotensive medications. 
3.3. 
Treatment Stopping Rules and Discontinuation Criteria  
3.3.1. 
Treatment Stopping Rules  
There are no specific treatment stopping rules.  On an ongoing basis, all available safety data 
will be reviewed by the sponsor.  If two or more adverse events of the same kind that are 
severe in nature and considered possibly study drug related occur, a decision will be made as 
to whether to stop enrollment of the cohort (Part 1 only), to add subjects to a lower 
concentration cohort (Part 1 only), to stop the study and exit all subjects, or to continue the 
study and proceed as planned (see Section 3.4 for details on decision making). 
3.3.2. 
Discontinuation Criteria 
Subject Discontinuation 
Whitecap Biosciences, or the investigator, may decide to discontinue subjects who are 
enrolled into the study but who had significant deviation from protocol-specified 
inclusion/exclusion criteria. 
If a subject meets any of the following criteria, s/he must be exited from the study (see Early 
Exit Procedures, Section 8.9).   
• The investigator or Whitecap Biosciences deems that it is unsafe for the subject to 
continue in the study; 
• Subject indicates that s/he no longer want to participate in the study. 
Subjects will be discontinued from the study under the following circumstances:  if a female 
subject becomes pregnant during the study, the investigator will notify Whitecap Biosciences 
immediately after the pregnancy is confirmed, the subject should not receive further study 
treatment and she must be exited from the study and the pregnancy followed to term (see 


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Section 8.9 for Early Exit Procedures and Section 6.4.3 for Procedures for Pregnancy 
Follow-up and Reporting). 
Subjects who are exited before completing the study may be replaced following consultation 
with sponsor. 
Study Discontinuation 
The study may be stopped at a study site at any time by the site investigator.  Whitecap 
Biosciences may stop the study (and/or the study site) for any reason with appropriate 
notification. 
3.4. 
Decision Making During Parts 1 and 2 
No formal Data Monitoring Committee will be established for this study.  Prior to each dose-
escalation step in Part 1, all available data will be reviewed to determine if the next dose 
should be assessed or if the study should be stopped.  If the study proceeds to Part 2, the 
determination of doses to evaluate will be based on an unmasked review of all available data 
from Part 1. 
All decisions to proceed or stop the study at any time will be made by a committee 
comprised of the Medical Monitor, the Head of Clinical and the Chief Executive Officer.  
Dose selection to be studied in Part 2 will be made by the same committee:  an unmasked 
review of all Part 1 safety, tolerability and IOP effect results will be performed to determine 
if Part 2 should be performed and if yes, which dose(s) should be assessed.  All decisions will 
be documented.   
4. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
The study population consists of adult subjects with POAG or OHT (but who are otherwise 
healthy).  Subject eligibility will be based on the entry criteria below.  
4.1. 
Inclusion Criteria 
The following are requirements for enrollment into the study:  
General: 
1. 
Male or female at least 18 years of age at the time of consent. 


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2. 
Female subjects must agree to use an acceptable method of contraception (see Section 
6.4 for pregnancy considerations and contraceptive requirements). 
Type of Participant and Disease Characteristics: 
3. 
Subject who: 
a. Is able and willing to follow study instructions and likely to complete all required 
study visits; 
b. Has chronic POAG or OHT in each eye and IOP is likely to be controlled on 
monotherapy; 
c. If on IOP-lowering medication, is willing to withhold his/her IOP-lowering 
treatments for the duration of the study and can do so without significant risk, in the 
opinion of the investigator; 
d. If on IOP-lowering medication, has been appropriately washed out of all IOP-
lowering medications prior to Baseline (Day - 1) (see Section 6.2); 
e. At Baseline (Day -1), meets the following criteria in at least 1 eye (and in the same 
eye for all hours indicated below):  
1. An IOP ≥ 24 mm Hg and ≤ 34 mm Hg at Hour 0; and  
2. An IOP ≥ 22 mm Hg and ≤ 34 mm Hg at Hours 2, 4 and 8. 
f. Has an IOP ≤ 34 mm Hg in the fellow eye at Baseline (Day-1) Hours 0, 2, 4 and 8 
g. Has a best-corrected visual acuity (BCVA) score equivalent (using a logarithmic 
(LogMar) visual acuity chart) to Snellen acuity of 20/100 or better in at least 1 eye 
and of 20/200 or better in the fellow eye, using a logarithmic visual acuity chart at 
Screening and Baseline (Day -1);  
h. Is in good general health [as determined by the investigator from medical history 
and physical examination findings, non-fasting blood analysis (complete blood 
count with differential, blood chemistry), urinalysis], and 12 lead-ECG results are 
within reference range or acceptable to the investigator prior to randomization.  
Note:  For the screening laboratory evaluation, subjects may have laboratory tests 
repeated once for reassessment at the discretion of the investigator prior to 
randomization. The investigator must review the screening results to confirm 
subject qualification for study entry. 
Informed Consent and Written Authorization 
4. 
Written informed consent of the subject has been obtained prior to any study-related 
procedures.  
5. 
Written documentation has been obtained in accordance with the relevant country and 
local privacy requirements, where applicable (eg, Written Authorization for Use and 
Release of Health and Research Study Information). 


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4.2. 
Exclusion Criteria 
If any of the following criteria are met, the subject is not eligible for participation in the 
study: 
Medical Conditions 
1. 
Uncontrolled systemic disease. 
2. 
History of orthostatic hypotension. 
3. 
Female who is pregnant, nursing, or planning a pregnancy, or female of childbearing 
potential not using a reliable means of contraception (see Section 6.4). 
4. 
Abnormal anatomy of nasolacrimal drainage system (eg, nasolacrimal duct obstruction). 
5. 
History of chronic alcohol consumption or drug addiction. 
6. 
Contraindications to topical beta-blocker therapy including bronchial asthma; a history 
of bronchial asthma; chronic obstructive pulmonary disease; second- or third-degree 
atrioventricular block; overt cardiac failure; cardiogenic shock. 
7. 
History of or current diagnosis of cardiac arrhythmia. 
8. 
Heart rate < 55 beats per minute while in a resting supine position. 
9. 
Blood pressure decrease from the supine measurements of at least 20 mm Hg (systolic) 
or of at least 10 mm Hg (diastolic) after 3 minutes of standing. 
10. Systolic blood pressure < 90 mm Hg while in a resting supine position. 
Ophthalmic History / Conditions 
11. Types of glaucoma other than chronic POAG (eg, uveitic; pigmentary; PXE, traumatic; 
angle-closure, including those who have had an iridectomy and/or iridotomy).  
12. Surgical intervention for glaucoma at any time or laser intervention for glaucoma within 
the 12 months prior to Screening.   
13. History of ocular neoplasia, uveitis, or herpetic ocular diseases. 
14. History (within 6 months prior to Baseline [Day -1]) of any intraocular or refractive 
surgery in either eye. 
15. Evidence of cataract surgery resulting in complications (eg, capsular rupture) in the 
study eye.   
16. History or evidence of severe ocular trauma in the study eye. 
17. Moderate or advanced findings of glaucoma on visual field examination; visual field 
loss which, in the opinion of the investigator, is functionally significant or shows 
evidence of progression (based on 2 visual field examinations) (see Sections 8.2 and 8.3 
for timing of visual field examination requirements).   


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Prior/Concomitant Therapy 
18. Current or anticipated use of any ocular medications (including periocular, intraocular, or 
sub-Tenon’s administration) or other medications (eg, oral) for ophthalmic indications 
outside of those of the study protocol from 2 months prior to Screening through Day 
2/Exit (Part 1) or Day 14/Exit (Part 2).  NOTE:  If required, IOP-lowering medications 
with shorter washout durations may be used during the washout period shown in Table 5. 
19. Introduction or anticipated alteration of existing chronic systemic medications that may 
have a substantial effect on IOP (eg, systemic beta-blockers, carbonic anhydrase 
inhibitors or cholinergic agonists) from 2 months prior to Screening through Day 
2/Exit (Part 1) or Day 14/Exit (Part 2). 
20. Current or anticipated use of oral, intramuscular, intravenous, intravitreal, periocular, or 
topical ophthalmic corticosteroids from 2 months prior to Screening through Day 
2/Exit (Part 1) or Day 14/Exit (Part 2) (see Sections 6.1 and 6.3). 
21. Treatment with any non-ocular alpha agonists, alpha antagonists (including medications 
for benign prostate hyperplasia), anticholinergics, sedative medications (including 
antihistamines, benzodiazepines, or opiate-type medications), or cold medications that 
could confound the study results within 2 weeks prior to Baseline (Day -1) or 
anticipated use during the study (see Sections 6.1 and 6.3). 
22. Use of adrenergic augmenting antidepressant drugs, monoamine oxidase inhibitors 
(MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic 
antidepressants (TCAs) within 30 days prior to Screening or anticipated use during 
the study (see Sections 6.1 and 6.3). 
23. Subject has a sleep disorder or has had excessive daytime somnolence within 30 days 
prior to Screening. 
24. Use of sedative-hypnotics or other agents (including over the counter) for insomnia 
within 10 days prior to Screening or anticipated use during the study (see Sections 
6.1 and 6.3). 
25. Consumption of alcohol-containing beverages or products within 72 hours prior to 
dosing on Day 1 or anticipated consumption within 72 hours prior to a study visit.  
26. Blood donation or equivalent blood loss of ≥450 mL within 90 days prior to Day 1. 
Prior/Concurrent Clinical Study Experience 
27. Previous randomization in Part 2 of this study. 
28. Concurrent enrollment in an investigational drug or device study or participation in such 
a study within the 30 days prior to Screening. 
Diagnostic Assessments 
29. Known allergy or hypersensitivity to the study medication or their components. 


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30. Known allergy, hypersensitivity or lack of efficacy with brimonidine (ALPHAGAN®, 
ALPHAGAN® P).  
31. Known allergy or contraindication to use of any diagnostic agents. 
32. Anticipated wearing of contact lenses in either eye during the study: 
o Use of rigid gas permeable (RGP) lenses or hard contact lenses should be 
discontinued at least 1 week prior to Baseline (Day -1); 
o Discontinue use of soft contact lenses at least 24 hours prior to Baseline (Day -1). 
33. The following ocular surface findings: 
o Ocular hyperemia in either eye, on either macroscopic or slit-lamp examination, 
greater than +1 (mild) at Screening or greater than or equal to +1 (mild) at Baseline 
(Day -1) at Hour 0, based on a bulbar hyperemia grading guide (standard 
photographs) provided by the sponsor; 
o Active ocular surface findings other than hyperemia in either eye, on either 
macroscopic or slit-lamp examination, greater than or equal to +0.5 (trace) at 
Baseline (Day -1) at Hour 0. 
34. Any ocular symptom at Baseline (Day -1) at Hour 0. 
35. Active ocular disease (eg, blepharitis, dry eye, ocular seasonal allergies) that would 
interfere with the interpretation of the study data in either eye. 
36. Corneal or other ocular abnormalities that would preclude accurate reading with an 
applanation tonometer (eg, corneal ectasias, corneal graft, significant corneal scarring). 
37. Contraindication to pupil dilation. 
Other Exclusions 
38. Anticipated need to participate in any activity that may cause irritation to the eye (eg, 
swimming, smoking) during the study. 
39. Anticipated need to engage in strenuous physical activity/exercise within 24 hours prior 
to a study visit, or to change an established exercise routine during the study. 
40. Subject has a condition or is in a situation which, in the investigator's opinion, may put 
the subject at significant risk, confound the study results, or interfere significantly with 
the subject's participation in the study. 
4.3. 
Lifestyle Considerations 
During the study, subjects will be advised to: 
• Refrain from activities that may cause irritation to the eye (eg, swimming or smoking); 


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• Refrain from engaging in strenuous physical activities/exercise within 24 hours prior to a 
study visit or changing established exercise routine during the study; subjects may 
participate in light recreational activities during the study (eg, watching television, 
reading); 
• Refrain from use of types of medications listed in exclusion criteria.  If used, document, 
in subject’s Source Document /Case Report Form; 
• Refrain from drinking more than ½ cup of liquid for one hour prior to IOP measurements 
on study visit days. 
4.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently entered into the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure reasons, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet certain eligibility criteria (eg, IOP) for participation in this study 
(screen failure) may be re-screened once.  Each case must be discussed with Whitecap 
Biosciences for re-screening consideration.  Re-screened subjects should be assigned the 
same participant number as for the initial screening. 
4.5. 
Rationale for Inclusion and Exclusion Criteria  
The inclusion criteria and exclusion criteria [11-17] are designed to enroll adult subjects with 
OHT or mild POAG, as these subjects will be unlikely to require other treatment 
interventions during the study. 
Exclusion criteria [18-26] are designed to exclude subjects whose study results could 
interfere with the interpretation of the efficacy results. Exclusion criteria [29-38] are designed 
to avoid including subjects with ocular conditions that may interfere with the interpretation 
of the study results. 
5. 
Study Treatments 
5.1. 
Investigational Product 
Investigational Product Description 
The following study treatments will be used in this study (Study treatments 1, 2 and 3).  For 
study purposes, these treatments are referred to as Investigational Products (IP).  AGN-


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227535/WB007 ophthalmic solutions at concentrations of 0.05%, 0.15% and 0.4% are the 
planned study treatments.   In Part 2, Timolol maleate ophthalmic solution 0.5% will be used 
as a control (Study treatment 4).  A description of the formulation characteristics for AGN-
227535/WB007 is given in Table 4. 
Table 4 
Formulation Characteristics for AGN-227535/WB007  
(Study Treatments 1-3) 
AGN-227535 Formulation Name 
Formulation 
Number 
Strength 
0.05% Ophthalmic Solution 
11024X 
0.05% w/v* 
0.15% Ophthalmic Solution 
10183X 
0.15% w/v 
0.4% Ophthalmic Solution 
10184X 
0.4% w/v 
*w/v = mass/volume 
 
 
The vehicle used for all AGN-227535 formulations include the following:  benzalkonium 
chloride (BAK) 0.02% w/v (200 ppm), Solutol®, edetate disodium, citric acid monohydrate, 
sodium phosphate dibasic heptahydrate, glycerin, hydrochloric acid, sodium hydroxide, and 
water for injection.   
Study Treatment #4 - Timolol maleate ophthalmic solution 0.5%:  contains timolol 0.5% 
(6.8 mg timolol maleate), mono basic and dibasic sodium phosphate, hydrochloric acid 
and/or sodium hydroxide to adjust pH, purified water and benzalkonium chloride 0.005%. 
5.1.1. 
Preparation/Handling/Storage/Accountability 
Investigational Product Storage 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported 
and resolved before use of the study medications.  Study product must be stored in a secure, 
environmentally controlled, and monitored (automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.   Study 
product must be stored in their original containers at room temperature (between 15ºC to 
25ºC; 59ºF to 77ºF) with a calibrated continuous temperature monitoring device.  Sites must 
report any temperature excursion to Whitecap Biosciences and avoid dispensing and/or 
administering the impacted study product, by isolating the product, until receiving further 
instructions from Whitecap Biosciences (see Study Reference Manual for more information). 


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Investigational Product Kit 
Each IP kit will contain a single bottle of study treatment (Part 1) and 2 bottles of study 
treatment (Part 2).  Each subject will be allocated 1 kit.  Additional kits will be provided to 
the site in the event of loss/damage.  In Part 2, each bottle of study treatment will be 
packaged in a unit carton.  Each IP kit will be stored in secondary packaging.  Clinical 
supplies for each subject will be labeled with a kit number associated with the subject 
randomization.   
To assign kits in Part 1, designated site personnel will pull a kit from the provided inventory 
for the given cohort.  To assign kits in Part 2, designated site personnel will use IWRS to 
obtain the specific kit number(s).  The site will receive the IWRS confirmation notification 
for transactions.  All notifications are to be maintained with the study source documents (see 
Study Reference Manual for more information). 
Appropriately qualified study site personnel will administer/dispense study medications as 
indicated in Section 8.4. 
Investigational Product Preparation  
Not applicable.  
Investigational Product Inventory  
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for investigational product accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused investigational product 
are provided in the Study Reference Manual. 
5.2. 
Study Treatment Administration 
5.2.1. 
Study Treatment Regimen and Dosing 
The principal investigator or delegated study personnel will instruct subjects on proper 
dosing techniques of ocular medications.  In Part 1 and on study visit days in Part 2, the 
morning dose of study medications will be administered by the site, and dosing will occur at 
approximately the same time of day (hour 0 between the hours of 07:00 and 09:00) for a 
given subject.  Also in Part 2, subjects will self-administer the study medication as follows:  
all other morning doses (between 07:00 and 09:00 hours) and all evening doses (between 
19:00 and 21:00 hours) at approximately the same time of day each morning and evening.  


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Study visits should be scheduled to occur approximately 12 hours following the evening dose 
the night before a study visit. 
5.2.2. 
Treatment Compliance  
The IP must be dispensed/ administered only to the study subject by appropriately qualified 
site personnel.  The IP is to be used in accordance with the protocol for subjects who are 
under the direct supervision of an investigator. 
Part 1:  The study treatment will be administered by site personnel.   
Part 2:  Subjects will be instructed on proper dosing techniques and site personnel will 
periodically remind subjects to take their treatments (via text message or phone call), 
(at a minimum, the night before a scheduled follow-up visit). 
6. 
Concomitant Treatments and Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving after study treatment dosing is 
initiated must be recorded along with: 
• Reason for use; 
• Dates of administration including start and end dates; 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
treatments and medications. 
6.1. 
Prohibited Treatments and Medications 
The decision to administer a prohibited treatment and/or medication is done with the safety 
of the study participant as the primary consideration.  When possible, Whitecap Biosciences 
should be notified before the prohibited treatment or medication is administered. 
The following medications, classes of medications, and treatment procedures are not 
permitted as concurrent therapy during the study: 
• Medication, conditions, or treatments that are contraindicated to brimonidine;  
• Treatment with any alpha agonists, alpha antagonists (including medications for benign 
prostate hyperplasia), anticholinergics, sedative medications (including antihistamines, 
benzodiazepines, or opiate-type medications), or cold medications;  


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• Use of adrenergic augmenting antidepressant drugs, MAOIs, SNRIs, or TCAs, or drugs;  
• Use of oral, intramuscular, intravenous, intravitreal, periocular, or topical ophthalmic 
corticosteroids.  NOTE:  intra-articular, inhaled, nasal, and dermal corticosteroids are 
permitted; 
• Use of sedative-hypnotics or other agents (including over the counter) for insomnia; 
• Use of any other ophthalmic topical medications or oral medications for ophthalmic 
indications.  NOTE: artificial tears are allowed during study (see Section 6.3 for 
acceptable usage); 
• Excessive consumption of alcohol or caffeine; 
• Wearing of contact lenses. 
6.2. 
Washout/Waiting Period 
The washout/waiting period between Screening and Baseline is 4 to 50 days.  The duration of 
this period is dependent upon whether a subject is taking IOP-lowering medications at 
Screening. 
6.2.1. 
Washout Period  
Eligible subjects who are being treated with IOP-lowering medication(s) in either eye will 
begin washout of these medication(s) following the screening visit.  The minimum washout 
period will be 4 days to 6 weeks depending on the washout schedule below (Table 5).  Note:  
The time from Screening to Baseline should not exceed 50 days.   
Table 5 
Minimum Washout Period 
Ophthalmic Medication(s) 
Minimum 
Carbonic anhydrase inhibitors (topical or systemic) (eg, acetazolamide [Diamox®], dorzolamide 
[eg, Trusopt®], brinzolamide [eg, Azopt®], methazolamide [eg, Neptazane]) 
4 days  
Sympathomimetics (eg, Dipivefrin, [PROPINE®]) or Epinephrine [eg, Epifrin®]) 
2 weeks 
Alpha-agonists (eg, brimonidine [ALPHAGAN® P], apraclonidine [Iopidine®]) 
2 weeks 
Beta-adrenergic blocking agents (eg, timolol [Timoptic®, Timoptic XE®], levobunolol 
[BETAGAN®], betaxolol [Betoptic®, Betoptic-S®], metipranolol [Opti-Pranolol®], carteolol 
[Ocupress®] and generics) 
4 weeks 
Fixed-combination therapy (eg, Cosopt®, COMBIGAN®) 
4 weeks 
Prostamides, prostaglandins, and prostaglandin analogs (eg, bimatoprost [LUMIGAN®], 
latanoprost [Xalatan®], travoprost [Travatan®], unoprostone [Rescula®], tafluprost [Taflotan®]) 
6 weeks 
Rho Kinase (ROCK) Inhibitors 
6 weeks 
 


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6.2.2. 
Considerations During Washout Period 
For a subject on IOP-lowering medication(s), to minimize the effect of the absence of IOP-
lowering therapy during the washout period, the investigator (at his/her discretion) may 
choose to modify a subject’s medication regimen to a medication with a shorter washout 
duration rather than stop all IOP-lowering medications at once (eg, while undergoing the 
washout of a prostaglandin analog [PGA] (6 weeks), a subject may be switched to a carbonic 
anhydrase inhibitor which has shorter washout duration (4 days) than the PGA).  The 
duration of the washout period must adhere to the requirements summarized in Table 5 based 
on the medications used at the time of Screening.  At the discretion of the investigator, for 
subjects undergoing a washout period, consideration should be given to interim safety 
evaluation of IOP at some time during the washout period. 
6.2.3. 
Waiting Period 
Subjects who are not taking any IOP-lowering medications at Screening must have a 
minimum of 3 days between the Screening and Baseline visits.  If a subject has taken 
IOP-lowering medications prior to the screening visit, then s/he must also adhere to the 
appropriate washout period (See Table 5). 
6.3. 
Permissible Medications and Treatments  
During the study, therapy considered necessary for the subject's welfare may be given at the 
discretion of the investigator.  If the permissibility of a specific medication/treatment is in 
question, please contact the Medical Safety Physician.   
Use of intra-articular, inhaled, nasal, and dermal corticosteroids are permitted. 
Use of artificial tears is permitted providing the artificial tear is not given within 30 minutes 
pre- or post-study treatment administration.  Use of artificial tears will be documented in the 
appropriate eCRF. 
Existing use of chronic systemic medications that may have a substantial effect on IOP (eg, 
systemic beta-blockers, carbonic anhydrase inhibitors cholinergic agonists) are allowed 
providing the dosage has been stable for at least 3 months prior to randomization and remains 
stable throughout the study.  


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6.4. 
Pregnancy and Contraception Considerations 
Definition of Female of Child-bearing Potential  
For purposes of this study, a female will be considered of childbearing potential unless she is 
permanently sterilized (ie, hysterectomy) or is naturally postmenopausal.  Natural menopause 
is defined as the permanent cessation of menstrual periods, determined retrospectively after a 
woman who is at least 40 years of age has experienced 12 months or more of amenorrhea 
without any other obvious pathological or physiological cause.  Female subjects who have 
had a hysterectomy or are naturally postmenopausal will not be required to perform a urine 
pregnancy test or to use contraceptives during the study. 
6.4.1. 
Pregnancy Considerations 
All female subjects who are of child-bearing potential will be advised to avoid pregnancy and 
are required to use methods of contraception considered acceptable to Whitecap Biosciences 
during the study.   
 For information about pregnancy reporting procedures, see Section 6.4.3. 
6.4.2. 
Acceptable Contraception 
The investigator will review the contraception requirements for the study with each subject.  
The following methods of contraception, if properly used, are considered acceptable for use 
to avoid pregnancy during this study:  hormonal contraceptives for females, (ie, oral, patch, 
injection, implant); sterilization (ie, bilateral salpingectomy, bilateral tubal ligation, 
vasectomy with the appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate); intrauterine devices/systems, sexual abstinence (when this is the lifestyle of 
the subject), and the following barrier methods (male condom with intravaginal spermicide, 
diaphragm or cervical cap with spermicide, vaginal contraceptive ring).  Note: spermicide 
alone is not an acceptable barrier method. 
6.4.3. 
Procedures for Pregnancy Follow-up and Reporting  
If a female subject becomes pregnant during the study (or within 30 days post-study exit), the 
investigator will notify Whitecap Biosciences (or designee) immediately after the pregnancy 
is confirmed.  The subject should not receive further study treatment and she must be exited 
from the study (see Section 8.9 for Early Study Exit Procedures).   
The investigator will (1) notify the subject’s physician that the subject was enrolled in the 
study and treated with an investigational drug AGN-227535 ophthalmic solution or with 
timolol ophthalmic solution, and (2) follow the progress of the pregnancy to term.  The 


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investigator must document the outcome of the pregnancy and provide a copy of the 
documentation to Whitecap Biosciences. 
7. 
Study Assessments  
This section provides a high-level summary of the study assessments to be performed.  For 
details as to when these assessments are performed, see Section 8.  For a description of study 
procedures, examination procedures, tests, equipment and techniques, see Attachment 12.2.  
For an explanation of terms and abbreviations, see Tables 6 and 7.   
7.1. 
Demographics and Baseline Characteristics 
• Age, race (including categories for ethnicity), sex, iris color; 
• Medical and ophthalmic histories; 
• Prior medications and treatments; 
• Physical Examination; 
• Ophthalmic Examination. 
7.2. 
Efficacy Assessments  
• IOP:  IOP will be measured using a Goldmann Applanation Tonometer (GAT) and a 2-
person reading method. 
7.3. 
Safety Assessments  
• Adverse Events:  Adverse events will be monitored throughout the study; 
• Physical Examination:  A physical examination including height and weight;  
• Respiratory rate and temperature in a resting seated position;    
• Postural (Supine and Standing) blood pressure and heart rate will be assessed at 
specified timepoints and visits; 
• Electrocardiogram (ECG):  A standard 12-lead ECG will be performed at the specified 
visits and timepoints.  ECGs will be collected as triplicate recordings (within 
approximately 1 minute apart) and reviewed by the investigator.  A consulting 
cardiologist will confirm the qualification of the subject prior to dosing of subject; 
• Non-Fasting Laboratory Tests:  Complete blood count with differential, blood 
biochemistry, and urinalysis will be measured; 
• Urine Pregnancy Test:  Female subjects of childbearing potential will have urine 
pregnancy tests performed; 


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• Macroscopic Hyperemia Evaluations:  Macroscopic bulbar conjunctival hyperemia will 
be graded by the investigator upon gross inspection and compared with standard images; 
• Pupil size:  Using the centimeter ruler on the near card, measure the subject's pupils to 
the nearest 0.5 mm in size.  The pupil gauge on the near card may also be used to 
estimate pupil diameter per investigator preference; 
• Visual Acuity:  Visual acuity (in Snellen equivalents) will be measured for each eye 
using a logarithmic visual acuity chart (4-meter distance).  Manifest refraction will be 
performed; 
• Contrast Sensitivity (Part 2 only):  Contrast sensitivity will be measured for each eye 
using a VectorVision CSV1000 at designated sites; 
• Slit-lamp Biomicroscopy:  Biomicroscopic examinations will be performed using a slit 
lamp through an undilated pupil.  The examinations will include evaluation of the 
condition of the conjunctiva, cornea, anterior chamber, iris/pupil, and lens.   The lens will 
also be evaluated following dilation for the cataract assessment; 
• Visual Field Examinations:  Visual field examinations (including historical tests used 
for screening) will be performed using Humphrey automated perimetry.  Acceptable test 
methods are the Humphrey 24-2 full-threshold or Swedish Interactive Threshold 
Algorithm (SITA) Standard tests.  The same test methodology will be used for all study-
related examinations for a given subject; 
• Dilated fundus exam:  Stereoscopic fundus assessments should be conducted through a 
dilated pupil.  The examination will include evaluation of the macula, optic nerve, 
vitreous, and retina.  The cup/disc (C/D) ratio will also be assessed using the Armaly 
Cup-Disc grading card. 
7.4. 
Other Assessments  
• Patient Comfort of Eye Drops Evaluation (questionnaire administered by designated 
site personnel) (Part 2 only):  Subjects are asked to rate the overall comfort of the eye 
drops.  
7.5. 
Methods of Data Collection 
This protocol will use electronic case report forms (eCRFs) with remote data capture through 
a qualified third-party vendor (iMednet).  Data entered into the eCRF will correspond to, and 
be supported by, source documentation maintained at the sites (See Section 10.4.1, for 
investigator responsibilities regarding source documentation requirements). The data will be 
entered on the eCRFs by appropriately trained personnel in a timely manner and on an 
ongoing basis. 


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IWRS will be used to manage study treatment inventory.  In Part 2 only, IWRS will also 
stratify and randomize subjects and assign study treatment kit numbers.  
A qualified third-party laboratory will be used for the analysis of blood and urine samples.  
Laboratory results will be provided to the sites by the vendor.  For statistical analysis 
purposes, laboratory data will be transferred to Whitecap Biosciences (or designee) at the end 
of each part of the study; detailed laboratory data will not be captured in EDC. 
8. 
Study Conduct 
This section provides a high-level summary of when during the study the procedures are to 
be performed.  Detailed information on the examination procedures, equipment, and 
techniques is presented in Attachment 12.2.  The procedures should be performed in the order 
as listed on the Schedule of Visits and Procedures (see Tables 1, 2 and 3).  The order of the 
following procedures (Medical and ophthalmic histories, Prior medications/treatments, 
concomitant medications/treatments) can be completed at any time during the study visit.  
For a glossary of terms and abbreviations, see Table 7; for a glossary of subject status 
definitions and other definitions, see Table 8.  For a list of other study supplies besides the IP, 
see Attachment 12.3. 
This study consists of the following scheduled visits: 
• Part 1 (4 visits):  Screening (Days -50 to -4); Baseline (Day -1); Days 1, 2/Exit; 
• Part 2 (5 visits):  Screening (Days -50 to -4); Baseline (Day -1); Days 1, 4, 14/Exit; 
designated site personnel will phone the subject on the evenings before Days 4 and 
14/Exit to remind subjects of dosing requirements (See Section 8.4.2 for details). 
Several visits (Part 1:  Baseline [Day -1], Day 1; Part 2:  Baseline [Day -1], Day 4, Day 
14/Exit) will consist of an 8-hour diurnal assessment. 
The following subsections provide details on the conduct of the study and list of procedures 
for each scheduled visit. Listed ocular procedures should be performed on both eyes.  The 
procedures are listed in the order in which they should be performed (unless otherwise 
specified. 
The Screening visit will occur between 4 and 50 days prior to Baseline (Day -1).  Final 
subject qualification for the study will be determined at Baseline (Day -1).  Subjects who 
qualify for the study will be considered eligible for study treatment administration and be 
assigned to one of the cohorts in a sequential manner (Part 1) or randomly assigned to one of 
the treatment groups (Part 2). 


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To minimize diurnal variation across study visits, particularly for IOP, the time of 
examinations for each subject’s post-screening study-related activities and examinations 
should remain consistent over the course of the study.  IOP measurements should be 
performed at approximately the same time each day based on the time of day established at 
the corresponding Baseline visit.  Hour 0 should occur between 0700 and 0900 hours.  At the 
Baseline visit, IOP measurements should occur 2, 4 and 8 hours from the time of the Hour 0 
IOP evaluation.  At post-Baseline visits, IOP measurements should be obtained as close as 
possible to the same time of day as the corresponding timepoint at Baseline. 
Evaluations should be performed in the order listed in the Schedule of Visits and Procedures 
(see Tables 1, 2 and 3).  Evaluations should be performed by the same evaluator throughout 
the study whenever possible.  If it is not possible to use the same evaluator to follow the 
subject, then evaluations should overlap (ie, examine the subject together and discuss 
findings) for at least one visit. 
If a female becomes pregnant during the study, the investigator will notify Whitecap 
Biosciences immediately after the pregnancy is confirmed and the subject will stop taking 
study treatment.  The subject will be discontinued from the study after appropriate safety 
follow-up. See Section 6.4.3 for Procedures for Pregnancy Follow-up and Reporting. 
8.1. 
Informed Consent  
The study will be discussed with potential subjects.  Those who are interested must give 
written informed consent prior to being subjected to any study-related procedures.  Written 
documentation will be obtained in accordance with relevant country requirements (ie, Written 
Authorization for Use and Release of Health and Research Study Information and local 
privacy requirements, where applicable.  See Section 10.1.3 for details on the Informed 
Consent process. 
After obtaining consent and authorization, potential subjects will undergo a series of 
preliminary screening procedures to assess qualification for the study.  At Screening, each 
subject will be assigned a subject number. 
8.2. 
Subject Screening Visit /Screening Period (Days –50 to –4) 
Subjects who provide informed consent will be assigned a subject identification number that 
will be used on all study documents.  For each subject, the start of the study is defined as the 
time the informed consent is signed.  Study-related procedures and data collection for study 
purposes may commence only after the informed consent has been obtained.  All subjects 
(Part 1 and Part 2) will undergo screening that includes procedures for initial qualification at 


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the Screening visit followed by a Screening period (washout/waiting period, see Section 6.2) 
for those who meet required Screening visit eligibility criteria (see Sections 4.1 and 4.2 for 
inclusion/exclusion criteria).  For subjects who screen fail, the reason for screen failure, as 
well as demographic and AE data will be collected and reported on the appropriate eCRF. 
Once informed consent has been provided, the following procedures should be performed in 
the order below:  
• Informed consent and authorization; 
• Query to screen for any recent event that could jeopardize the subject’s safety prior to 
further screening; 
• Subject comfort of eye drops evaluation (for IOP-lowering agent(s) subject is taking at 
Screening) (Part 2 only); 
• Medical and ophthalmic histories (including demographic data); 
• Prior medications and treatments (current as well as those that have been stopped within 
3 months prior to the Screening visit); 
• Physical exam (including height and weight); 
• Respiratory rate and temperature (seated); 
• Postural (supine/standing) blood pressure and heart rate; 
• Clinical laboratory evaluation (non-fasting), including CBC with differential, blood 
chemistries and urinalysis.  Note:  The Screening labs will be used to determine subject 
eligibility.  If repeat testing is required, a non-fasting sample should be drawn at least 3 
days prior to the scheduled Baseline visit to ensure results are available for review prior 
to randomization; 
• Macroscopic (gross) hyperemia evaluation; 
• Visual acuity (VA):  Manifest refraction required to obtain a correction for VA evaluation; 
• Slit-Lamp Biomicroscopy;  
• IOP (GAT); 
• Visual field:  May be performed up to 12 months prior to or at Screening using the 
protocol-required testing method.  For subjects requiring pupil dilation, the visual field 
should be performed after the IOP measurement or the next day.  The same test 
methodology should be used throughout the study for a given subject; 
• Fundus exam (including cup/disc ratio, post-pupil dilation); 
• Begin washout of all IOP-lowering medication (see Section 6.2); 
• Enter subject as "in Screening” in eDC; 


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• Preliminary determination of eligibility. 
Washout Period (Days –50 to –4) 
Eligible subject who are being treated with IOP-lowering medication(s) in either eye will 
enter the Screening Period and begin washout of these medication(s) following the Screening 
visit.  Details of the washout requirements and options to minimize the absence of treatment 
during washout can be found in Section 6.2 and Table 5.  The Baseline visit will occur 
following the completion of the washout period. 
Waiting Period (Days –4 to –1) 
There is a minimum of 3 days waiting between the Screening and Baseline visits for all 
subjects.  Additionally, for subjects who have taken IOP-lowering medications prior to/at the 
screening visit, then they must also adhere to the appropriate washout period (See Table 5). 
8.3. 
Subject Enrollment – Baseline Visit (Day -1) 
A subject is considered to be enrolled in the study when s/he has completed all screening and 
qualification procedures and meets all eligibility criteria at the Baseline (Day -1) visit based 
on the inclusion/exclusion criteria (see Section 4.1 and 4.2) and confirmed eligibility on the 
morning of Day 1 (Part 1) AND has been randomized at Day 1 (Part 2). 
Baseline - Hour 0: 
• Adverse event (AE) query 
• Medical and ophthalmic histories (including demographic data) 
• Prior medications and treatments (between Screening and Baseline) 
• Concomitant medications and treatments 
• Respiratory rate and temperature (seated) 
• Postural (supine) blood pressure and heart rate  
• 12 lead-ECG 
• Urine Pregnancy Test - Results of pregnancy tests (required for female subjects of 
childbearing potential only) must be obtained prior to treatment and must be negative for 
the subject to be eligible   
• Macroscopic (gross) hyperemia evaluation 
• Pupil Size using near card (Part 2 only) 
• Visual acuity (VA):  Manifest refraction required to obtain a correction for VA evaluation  
• Contrast Sensitivity (Part 2 only) 


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• Slit-Lamp Biomicroscopy 
• IOP (GAT) 
• Visual field:  The 2nd VF examination can be performed at any time prior to pupil 
dilation   
• Confirm 2 reliable fields are available and meet entry criteria.   
Baseline - Hours 2, 4, 8 
• Macroscopic (gross) hyperemia evaluation 
• Pupil Size using near card (Part 2, Hour 2 only) 
• Slit-Lamp Biomicroscopy 
• IOP (GAT) 
8.3.1. 
Procedures Prior to Randomization (Part 2 only) 
At the end of the Screening period, subjects will be assessed at the Baseline (Day -1) visit for 
eligibility.  Qualified subjects will return the morning of Day 1 where eligibility will be 
confirmed.  Eligible subjects may then be randomized. (Note:  Subjects who do not meet 
eligibility criteria at Baseline (Day -1) or confirmation of eligibility on Day 1 before dosing 
occurs will be exited from the study as screen failures).  
Only eligible subjects will be randomized. 
8.3.2. 
Randomization Procedures (Part 2 only) 
Prior to randomization of a subject, the site will be required to enter certain data into eDC. 
For IOP, each of the Baseline (Day -1) IOP measurements (either 2 or 3 per eye per hour) 
will need to be entered into IWRS, within eDC.  These measurements will be used to confirm 
that the subject meets IOP inclusion criterion numbers 3 e and f (see Section 4.1).  For 
confirmed qualified IOP, IWRS will assign a stratification code based on the IOP value(s) 
entered, randomize the subject and assign a study kit number.  The kit number corresponds to 
the assigned study treatment for the subject.  See Study Randomization Procedures in the 
IWRS section of the Study Reference Manual for detailed instructions on randomization 
procedures. 
8.4. 
Study Visits and Procedures for Enrolled Subjects  
8.4.1. 
Part 1 - Study Visits and Procedures for Enrolled Subjects  
See Table 2 for the Schedule of Visits and Procedures in Part 1.  Visits in Part 1 should occur 
on the designated day.  No windows will be allowed.   


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Part 1 - Day 1 (Hour 0, pre-1st dose) 
• Adverse event (AE) query 
• Concomitant medications and treatments 
• Postural (supine/standing) blood pressure and heart rate 
• Macroscopic (gross) hyperemia evaluation 
• Visual acuity (VA):  Manifest refraction performed at Baseline (Day -1) should be used 
for visual acuity evaluation.  Manifest refraction(s) may be repeated, if in the opinion of 
the investigator, it is necessary.   
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Confirm Inclusion/Exclusion Criteria are still met 
• Study medication assignment 
• Enter Treatment Assignment form in eDC  
• Site to administer study medication 
Part 1 - Day 1 (30 minutes post-dose) 
• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
Part 1 - Day 1 (Hour 2) 
• Postural (supine/standing) blood pressure and heart rate 
• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
Part 1 - Day 1 (Hours 4 and 8) 
• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
Part 1 - Day 2 (Hour 0) 
• Adverse event (AE) query 


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• Concomitant medications and treatments 
• Postural (supine/standing) blood pressure and heart rate 
• Urine pregnancy test (females of child-bearing potential only) 
• Macroscopic (gross) hyperemia evaluation 
• Visual acuity (VA):  Manifest refraction performed at Baseline (Day -1) should be used 
for visual acuity evaluation.  Manifest refraction(s) may be repeated, if in the opinion of 
the investigator, it is necessary.  
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Fundus exam (including cup/disc ratio, post-pupil dilation) 
Following the completion of the Day 2/Exit examination, the subject will exit the study. 
8.4.2. 
Part 2 - Study Visits and Procedures for Enrolled Subjects  
Visit windows will be applied in Part 2 only.  Visit windows of ±1 day will be allowed.  In 
Part 2, for each subject, the schedule of all post-baseline visits should be determined using 
the date of the Baseline visit. 
Part 2 - Day 1 (Hour 0, Pre-1st Dose) 
• Adverse event (AE) query 
• Concomitant medications and treatments 
• Postural (supine/standing) blood pressure and heart rate 
• Macroscopic (gross) hyperemia evaluation 
• Visual acuity (VA):  Manifest refraction performed at Baseline (Day -1) should be used 
for visual acuity evaluation.  Manifest refraction(s) may be repeated, if in the opinion of 
the investigator, it is necessary.  
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Confirm Inclusion/Exclusion Criteria still met 
• Randomize subject / obtain kit assignment / dispense a single bottle of study medication 
for first dose 
• Site to administer 1st dose of study medication to each eye 
Part 2 - Day 1 (30 minutes post-dose) (±5 minutes) 
• Subject Comfort of Eye Drop Evaluation 


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• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
Part 2 - Day 1 (Hour 2) (±10 minutes) 
• Postural (supine/standing) blood pressure and heart rate 
• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Review instillation technique and give study medication to the subject to take home  
Part 2 – Evening before Day 4 and Day 14/ Exit  
• On the evenings before Day 4 and Day 14/Exit, designated site personnel will remind 
subjects to dose their evening dose approximately 12 hours prior to their next morning 
Hour 0 timepoint and to not dose the following morning (study medications will be 
administered by designated site personnel at the end of the Hour 0 timepoint). 
Part 2 - Days 4 and 14/Exit (Hour 0) (±10 minutes) 
• Adverse event (AE) query 
• Concomitant medications and treatments 
• Postural (supine/standing) blood pressure and heart rate 
• Macroscopic (gross) hyperemia evaluation 
• Pupil Size using near card (Day 14/Exit only) 
• Visual acuity (VA):  Manifest refraction performed at Baseline (Day -1) should be used 
for visual acuity evaluation.  Manifest refraction(s) may be repeated, if in the opinion of 
the investigator, it is necessary.  
• Contrast sensitivity (Day 14/Exit only) 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Site to administer study medication at end of Hour 0 examination 
• Site to collect study medication following final dose (Day 14/Exit only) 
Part 2 - Day 14/Exit only, once final dose has been administered 
• Clinical laboratory evaluation (non-fasting)   


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• Urine pregnancy test (females of child-bearing potential only) 
Part 2 - Day 14/Exit only (30 minutes post-dose) (±5 minutes) 
• Subject Comfort of Eye Drops Evaluation (administered by designated site personnel) 
Part 2 - Days 4 and 14/Exit (Hour 2) (±10 minutes) 
• Postural (supine/standing) blood pressure and heart rate 
• ECG (Day 14/Exit only) 
• Macroscopic (gross) hyperemia evaluation 
• Pupil Size using near card (Day 14/Exit only) 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Visual Field (may occur at any time from Hour 2 prior to pupil dilation) (Day 14/Exit 
only) 
Part 2 - Days 4 and 14/Exit (Hours 4 and 8) (±10 minutes) 
• Macroscopic (gross) hyperemia evaluation 
• Slit-lamp biomicroscopy 
• IOP (GAT) 
• Fundus exam (including cup/disc ratio, post-pupil dilation) (Day 14/Exit, Hour 8 only) 
Following the completion of the Day 14/Exit examination, the subject will exit the study. 
8.5. 
Unscheduled Visits and Associated Procedures 
Additional examinations may be conducted as necessary to ensure the safety and well-being 
of subjects during the study period.  eCRFs should be completed for each unscheduled visit.  
For all parameters not measured, indicate “Not Done”. 
Subjects may experience adverse events that necessitate their returning for unscheduled 
visits.  The adverse event and all required information should be recorded on the appropriate 
eCRF and the subject’s record should include all relevant information.   
8.6. 
Instructions for Subjects  
The principal investigator or designated study personnel will instruct the subject on proper 
dosing techniques prior to dispensing the study treatment to the subject.  The sites will 
contact subjects routinely to remind them to administer their study treatment as instructed.  


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After each subject has signed the informed consent, s/he will be instructed as follows:  
• To provide a list of all medications (prescription, non-prescription, vitamins, herbal 
supplements), taken within the 3 months prior to Screening and those that will be 
continued during the study period, including the dose and the reason for taking the 
medication and a list of any non-medicinal treatments; 
• At Screening, subjects whose IOP is currently being treated with IOP-lowering 
medication(s) will be instructed by the site to stop taking the IOP-lowering meds 
(ie, begin the washout period) following the Screening visit.  The washout period will be 
a minimum of 4 days to 6 weeks depending on the schedule in Table 5.  Subjects may be 
instructed to return for a visit during the washout period so that the investigator may 
assess their IOP; 
• To return to the study site, at approximately the same time of day established at Baseline 
(Day -1); 
• To remain at the site to complete the remainder of the day’s study-related procedures as 
explained to them by the study site personnel; 
• To refrain from swimming and smoking, being exposed to smoke or other exposure that 
might cause eye irritation during the study; 
• To refrain from drinking more than ½ cup of liquid within 1 hour prior to IOP 
measurement; 
• To avoid discussing side effects (if any experienced) with other subjects in the trial; 
• If spectacles are worn for vision correction, subjects should remember to bring the 
spectacles each time they visit the doctor’s office; 
• Females of childbearing potential should be reminded that they are to maintain the agreed 
to contraception method throughout the study and notify the site in the event of a 
pregnancy, up to 30 days after exiting from the study (see Section 6.4.3); 
• Subjects should also be reminded to contact the study site if they are experiencing any 
difficulties during their study participation. 


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In Part 2 only, subjects will also be instructed as follows: 
• On proper dosing of ocular medications and to dose study medication as directed:  
administer one drop in each eye each evening (between 1900 and 2100 hours) starting the 
evening of Day 1 and each morning (between 0700 and 0900 hours) through the evening 
of Day 13. The final dose of study medication on the morning of Day 14/Exit will be 
administered by site personnel after the Hour 0 examination.  Subjects will be reminded 
to take their study medications approximately 12 hours before their Hour 0 appointments 
the evening prior to a post-baseline study visit and to not dose in the morning of Days 4 
and 14.  If desired, subjects will also be given the option for periodic (eg, daily) 
reminders from the Site to take their study medications each morning and evening; 
• On proper storage conditions for study medications.  The study medications should be 
kept in their unit carton (box).  Do not show the bottles to other subjects or study staff 
(except the individual who dispenses the study medication to the subject).  The study 
medications may be stored at room temperature during the study period (between 59°F 
and 77°F); 
• To bring all used and unused study medication to all visits and to remind subjects that all 
study medications will be collected by the site at the Day 14/Exit visit. 
8.7. 
Safety Monitoring  
Investigators are responsible for identifying, monitoring and reporting adverse events that 
occur throughout the study (from subject signing of informed consent through study exit).  
Any adverse event that is marked ‘ongoing’ at the exit visit should be followed-up as 
appropriate until the event is resolved or deemed chronic or stable by the Study Investigator.  
8.7.1. 
Procedures for Collecting and Reporting Adverse Events 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each subject a general, non-directed question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate eCRF. 
If, after obtaining the subject’s informed consent but prior to administration of study 
product/treatment, a medical condition is identified via a study entry protocol assessment or 
procedure (eg, screening ECG test) which, based on the Investigator’s judgment (and in 
consultation with the subject), is determined to be a pre-existing condition (ie, a condition 
existing prior to the time of the subject’s informed consent), it should be documented on the 


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appropriate eCRF.  Otherwise, the condition should be reported as a pre-treatment adverse 
event.  
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.   
8.7.2. 
Severity 
A clinical determination will be made of the intensity of an AE.  The severity assessment for 
an AE must be completed using the following definitions as guidelines: 
Mild 
Awareness of signs or symptoms, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or do usual activity 
Not Applicable 
In some cases, an AE may be an ‘all or nothing’ finding that cannot be 
graded (eg, death) 
8.7.3. 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an AE and the study drug 
or study procedure, as applicable.  A causal relationship is present if a determination is made 
that there is a reasonable possibility that the AE may have been caused by the study drug or 
study procedure. 
8.7.4. 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event must be immediately reported but no later than 24 hours after 
learning of the serious adverse event. The first report should be submitted even if the 
available information is minimal.  All subjects with a serious adverse event must be followed 
up and the outcomes reported.  The investigator must supply Whitecap Biosciences and the 
IRB/IEC with any additional requested information (eg, autopsy reports, discharge 
summaries).   
In the event of a serious adverse event, the investigator must: 
1. Notify Whitecap Biosciences (or designee) immediately by email using the Serious 
Adverse Event Form; phone numbers and relevant Whitecap Biosciences (or designee) 
personnel contacts are on the front page of this protocol. 


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2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject. 
3. Provide Whitecap Biosciences (or designee) with a complete, written description of the 
adverse event(s) on the Serious Adverse Event Form describing the event 
chronologically, including any treatment given (eg, medications administered, other 
treatments given) for the adverse event(s).  Summarize relevant clinical information 
about the event:  signs, symptoms, diagnosis, clinical course and relevant clinical 
laboratory tests, etc.  Include any additional or alternative explanation(s) for the 
causality which includes a statement as to whether the event was or was not related to 
the use of the investigational drug. 
4. Provide follow-up SAE reports to Whitecap Biosciences (or designee) as more 
information becomes available 
5. Promptly inform the governing IRB/IEC of the serious adverse event as required by the 
IRB/IEC, local regulations, and the governing health authorities. 
See Study Reference Manual for additional details. 
8.8. 
Procedures for Stopping Study Treatment  
Part 1- There are no specific procedures for stopping treatment. 
Part 2 - When the study treatment is stopped for an individual subject prior to the protocol 
defined duration for study treatment administration, the Day 14/Exit (Hour 0) procedures, at 
a minimum should be performed.  The reason that the study treatment is stopped should be 
documented on the appropriate eCRF. 
8.9. 
Early Study Exit Procedures 
8.9.1. 
Subject Discontinuation/Withdrawal from the Study 
• A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons;   
• If the subject withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent; 
• If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records; 
• A subject who is enrolled, but who had significant deviation from protocol-specified 
inclusion/exclusion criteria, may be discontinued from participation in the study; 


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• If a female becomes pregnant during the study, the investigator will notify Whitecap 
Biosciences immediately after the pregnancy is confirmed and the subject will stop taking 
study treatment.  The subject will be discontinued from the study after appropriate safety 
follow-up. See Section 6.4.3 for Procedures for Pregnancy Follow-up and Reporting; 
• Subjects who are exited before completing the study may be replaced. 
See Schedule of Visits and Procedures for specific data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  If a 
subject is discontinued prior to completing the study, the procedures outlined for the Day 
2/Exit visit (for Part 1) or the Day 14/Exit visit (Hour 0 timepoint at a minimum) for Part 2 
should be performed at the last visit attended. 
When a subject exits before completing the study, the reason for the early exit will be clearly 
documented on the appropriate eCRF. 
If the subject exits before completing the study, any serious adverse events or treatment-
related non-serious adverse events occurring within 14 days after the last dose of study 
treatment should be reported to the Site.   
8.9.2. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study; 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record; 
• Should the participant continue to be unreachable, he/she will be considered to be lost to 
follow up and exited from the study;  
• When a subject is lost to follow-up, the reason for the early exit will be clearly 
documented on the appropriate eCRF. 


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8.10. 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the subject, the investigator can 
unmask the subject’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, Whitecap Biosciences (or designee) 
should be notified prior to unmasking study medication.  The investigator should inform 
Whitecap Biosciences (or designee) of the unmasking if there is no notification prior to the 
unmasking.  
The treatment assignment for the subject can be determined by designated site personnel 
through the IWRS via password protected access.  The reason for breaking the code must be 
recorded in the subject’s source documents.  See Study Reference Manual for additional 
details. 
9. 
Statistical Procedures 
One database lock will occur when all subjects (both Part 1 and Part 2) have either completed 
the study or discontinued from the study prematurely, and all data queries have been 
resolved.  Randomization release will occur following the database lock.  A detailed 
statistical analysis plan (SAP) will be approved prior to database lock.  
9.1. 
Analysis Population(s) 
Each population will be analyzed based on the treatment received. 
Part 1:  The Safety population consisting of all treated subjects will be used for all analyses. 
Part 2: The following populations will be used for analysis:  
• The Safety population will consist of all treated subjects. All safety analyses will be 
performed using the safety population; 
• The Modified Intent-to-treat (mITT) will consist of all randomized and treated subjects 
who provide IOP data at baseline and at least one post-baseline IOP assessment.  This 
population will be used for analyses of efficacy data; 
• The Per-protocol (PP) population is a subset of the mITT population and will consist of 
subjects who did not have any major protocol violations deemed to have potential impact 
on the primary endpoint.  This population will be used to confirm the primary efficacy 
analysis and will be determined prior to database lock. 


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9.2. 
Sample Size Calculation 
For each cohort in Part 1 of the study a sample size of 6 patients will provide 83% power to 
detect a 3 mmHg within-group change from pre-dose assuming a standard deviation of 2 and 
two-sided alpha = 0.05, based on a one-sample t-test.  With larger standard deviations (≥2.5) 
the power to detect this difference is <66%. 
For Part 2, a sample size of 24 has > 90% power to detect a within-group mean changes from 
baseline IOP of 3 mm Hg, assuming a SD of 2.5 mm Hg.  Also, power calculations were 
performed for the comparison of each dose of AGN–227535 versus Timolol.  These 
calculations consider treatment differences (AGN–227535 minus Timolol) mean changes 
from baseline in study eye IOP in the mITT population at Day 14/Exit.  
The power to detect treatment group differences from -1 to -4 mm Hg with common standard 
deviations (SDs) ranging from 2.5 to 3.5, based on a two-sample t-test are shown in Table 6. 
Table 6 
Power Calculations for Study Part 2 Tests of Treatment Differences 
(AGN-227535 N = 24; Timolol N = 12; alpha = 0.05) 
Treatment Group 
Difference 
Common 
SD 
Power 
(%) 
-4 
2.5 
99 
3 
96 
3.5 
88 
-3 
2.5 
91 
3 
78 
3.5 
65 
-2 
2.5 
59 
3 
45  
3.5 
35 
-1 
≥2.0 
<20 
Additional sample size calculations were performed for tests of non-inferiority of either dose 
of AGN-227535 to Timolol.  These calculations considered a non-inferiority margin of 1.5 
mm Hg and one-sided α = 0.025.   With a treatment group difference of -1 mm Hg, the power 
ranged from 50% for a common SD of 3.5 to 78% for a common SD of 2.5. 
The calculation was based on the non-inferiority tests for the difference between two means 
using t-test as implemented in the commercial software PASS version 16.0.3 (2018). 


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9.3. 
Methods of Analyses 
In general, data will be summarized with descriptive statistics which will include sample 
size, mean, standard deviation, median, minimum and maximum for continuous variables 
and frequency and percentage for categorical variables.   
Part 1: All safety and IOP-lowering effects tabulations will provide descriptive statistics by 
cohort. 
Part 2: For continuous variables, treatment groups will be compared using analysis of 
variance covariance techniques or two-sample t-tests.  Nominal variables will be 
analyzed using Pearson's chi-square test or Fisher's exact test.  
Analyses performed for the mITT population will use the method of last observation carried 
forward (LOCF) to impute missing values.  No imputation for missing data will be 
performed for the PP or safety populations.   
As this is an exploratory trial, all treatment comparisons will be made at the two-sided α = 
0.05 level without adjustment for multiple comparisons.  
9.3.1 
Efficacy (Part 2) 
9.3.1.1. 
Primary Efficacy Endpoint(s) 
The primary response measure is IOP.  Two consecutive measurements of IOP will be taken 
for each eye, with the right eye measured first.  If the first two measurements of either eye 
differ by more than two mm Hg, a third measurement will be taken for the eye.  Depending 
on the number of measurements required and obtained, the IOP for a given eye will be 
represented by either the average or the median of the readings.  Details will be provided in 
the SAP.  
The change from baseline for each eye at each post-baseline assessment is calculated as the 
IOP at that assessment minus the IOP at the corresponding hour at baseline.  Efficacy will be 
evaluated in the study eye. The study eye is the eye that meets the inclusion/exclusion 
criteria.  If both eyes meet the criteria, the study eye will be the eye with the worse (highest) 
IOP at Day -1 Hour 0.  If both eyes have the same IOP value at this timepoint, the right eye 
will be the study eye. 
The primary efficacy endpoints are the Day 14/Exit mean IOP changes from Baseline (Day -
1) at each time-matched hour (0, 2, 4, 8). The primary hypothesis is that AGN-227535 
ophthalmic solution effectively lowers IOP.  The primary efficacy analysis is the within-


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group mean change from baseline at Hour 2, the time of peak efficacy of timolol.  This study 
will also assess if AGN-227535 is non-inferior to Timolol ophthalmic solution 0.5% with 
respect to change from baseline (follow-up minus baseline) in study eye IOP at each time-
matched hour evaluated (hours 0, 2 4, and 8) at Day 14/Exit in the mITT population.  The 
analyses will be performed via analysis of covariance (ANCOVA) which will have treatment 
as the main effect and the Baseline hour-matched IOP as the covariate in the model.  
Pairwise treatment group comparisons will be performed for each individual dose of AGN-
227535 versus timolol ophthalmic solution 0.5%. A 2-sided 95% confidence interval (CI) for 
the treatment difference (AGN-227535 Ophthalmic Solution minus Timolol ophthalmic 
solution 0.5%) will be constructed based on this ANOVA model for each AGN-227535 dose.  
AGN-227535 ophthalmic solution will be considered to be non-inferior to Timolol 
ophthalmic solution 0.5% if the upper limit of the 95% CI does not exceed 1.5 mmHg at the 
majority of timepoints evaluated (ie, 3/4) at the Day 14/Exit visit.  If AGN-227535 
ophthalmic solution is determined to be non-inferior to Timolol ophthalmic solution 0.5%, a 
further attempt to show superiority of AGN-227535 over Timolol will be made.   
Primary efficacy will be evaluated in the mITT population.  
9.3.1.2. 
Secondary Efficacy Endpoint(s) 
Mean IOP at Day 14/Exit. 
Mean IOP change from baseline at each time-matched hour via analysis of variance 
(ANOVA) which will have treatment and the Baseline IOP stratum (IOP ≤25 mm Hg and > 
25 mm Hg as the main effects in the model. 
9.3.2. 
 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to 
code adverse events. A detailed definition of treatment emergent adverse events (TEAEs) will 
be provided in the SAP. The number and percent of subjects with adverse event reports will 
be tabulated for all treatment emergent adverse events (TEAEs) regardless of causality, 
treatment-related TEAEs, all serious TEAEs, treatment-related serious TEAEs, and all 
adverse events leading to premature discontinuation of study treatment.  
For Part 2, analyses of macroscopic hyperemia and hyperemia as evaluated on 
biomicroscopy will include evaluation of peak severity at each post-baseline visit (Days 4 
and 14) and across all post-baseline time points.  


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Detailed methods for analyses of all safety variables will be provided in the SAP. 
9.4. 
Other Analyses 
The primary analysis (see Section 9.3.1.1) will be performed for the PP population. 
Additional planned analyses include treatment comparisons of: 
• Mean diurnal IOP (average of IOP measurements taken throughout the day) change from 
baseline.  The same methods as described in Section 9.3.1.1 will be used; 
• IOP values at each scheduled hour of Day 14/Exit.  Analyses will be performed using an 
ANCOVA model with treatment as the main effect and baseline IOP hour-matched IOP as 
the covariate;  
• Mean diurnal IOP at Day 14/Exit. Analyses will be performed using a two-way ANCOVA 
model with treatment as the main effect and baseline mean diurnal IOP as the covariate. 
Additional exploratory analyses may be described in the SAP.  
9.5. 
Subgroup Analyses 
For Part 2, descriptive statistics for the primary analyses will be provided by Baseline IOP 
stratum. Additional subgroup analyses may be specified in the SAP.   
9.6. 
Interim Analyses 
No interim statistical analysis is planned. 
10. 
Supporting Documentation and Operational Considerations 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines; 
• Applicable ICH Good Clinical Practice (GCP) Guidelines; 
• Applicable laws and regulations; 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated;  


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• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects;  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of US 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable 
local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study;  
• Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of US 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center;  
• The medical record/source document must include a statement that written informed 
consent was obtained before the subject was entered in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must also 
sign the ICF; 
• If the ICF is modified during the subject’s participation in the study, it may be required 
for the subject to be re-consented;  
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  


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10.1.4. 
Data Protection 
• Subjects will be assigned a unique identifier by the sponsor.  Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred;  
• The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to the subject;  
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
10.2. 
Protection of Human Subjects 
10.2.1. 
Subject Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents.  The subject's name may be 
disclosed to Whitecap Biosciences or the governing health authorities (eg, US FDA, 
Canadian Committee for Medicinal Products for Human Use [CHMP], US Pharmaceutical 
and Medical Devices Agency, Japan PMDA) if they inspect the study records.  Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information. 
10.2.2. 
Subject Privacy 
Written authorization and other documentation in accordance with the country and local 
privacy requirements (where applicable) is to be obtained from each subject prior to 
enrollment into the study, and/or from the subject's legally authorized representative in 
accordance with the applicable privacy requirements (eg, the Health Insurance Portability 
and Accountability Act Standards for Privacy of Individually Identifiable Health Information 
(“HIPAA”). 
In accordance with country-specific requirements, additional purposes of this study may 
include publishing of anonymized subject data from the study. 


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10.2.3. 
Compliance with Informed Consent Regulations and Relevant Country 
Regulations 
Following informed consent regulations (eg, US 21 CFR Part 50) Written informed consent 
is to be obtained from each subject prior to any study-related activities or procedures in the 
study, and/or from the subject's legally authorized representative.   
1. That the study involves research; 
2. The objectives of the study; 
3. The study procedures; 
4. The expected duration of the subject’s participation in the study; 
5. The approximate number of subjects involved in the study; 
6. The reasonably foreseeable risks or inconveniences to the subject; 
7. The alternative procedures or courses of treatments that may be available to the subject, 
and their important potential benefits and risks; 
8. The compensation and/or treatment available to the subject in the event of study-related 
injury; 
9. That the subject’s participation in the study is voluntary and that the subject may refuse to 
participate or withdraw from the study at any time, without penalty or loss of benefits to 
which the subject is otherwise entitled; 
10. That subject will be informed in a timely manner if information becomes available that 
may be relevant to the subject’s willingness to continue participation in the study; 
11. The foreseeable circumstances and/or reason under which the subject’s participation in 
the study may be terminated; 
12. That the monitors, auditors, the IRB, and the regulatory authorities may provide direct 
access to the subject’s original medical records.  In such cases, the confidentiality of the 
subject should be protected, and by signing and sealing an informed consent form, the 
subject is authorizing such access; 
13. If the results of the study are published, the subject’s identity will remain confidential; 
14. The anticipated expenses, if any, to the subject for participating in the study; 
15. The anticipated prorated payment, in any, to the subject for participating in the study; 
16. The name, title, and address of the investigator to contact; 
17. The person(s) to contact for further information regarding the clinical study and the rights 
of subjects, and whom to contact in the event of study-related injury; 


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18. The type of the IRB engaged in the assessment and deliberation about the acceptability of 
the study, items subject to the assessment of each IRB, and other IRB-related items 
relating to the study; 
19. The subject’s responsibilities. 
10.2.4. 
Compliance with IRB Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
regulations.  The investigator must obtain approval from a properly constituted IRB/IEC 
prior to initiating the study and reapproval or review at least annually.  Whitecap Biosciences 
is to be notified immediately if the responsible IRB has been disqualified or if proceedings 
leading to disqualification have begun.  Copies of all IRB correspondence with the 
investigator should be provided to Whitecap Biosciences. 
10.2.5. 
Compliance with Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.3. 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Whitecap Biosciences and prior review and documented approval/favorable 
opinion from the IRB/IEC of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects. 
10.4. 
Documentation 
10.4.1. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.  Data 
entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Source documents may include a subject's medical records, hospital charts, clinic charts, the 
investigator's subject study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator's copy of the eCRFs serves as part 
of the investigator's record of a subject's study-related data. 


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The following information should be entered into the subject's medical record /source notes: 
• Subject’s contact information; 
• The date that the subject entered the study, subject number and for Part 2, subject study 
treatment kit number;  
• Sites will receive the IWRS confirmation notification for each transaction.  All 
notifications are to be maintained with the study source documents; 
• The study title and/or the protocol number of the study and the name of Whitecap 
Biosciences; 
• A statement that informed consent was obtained including the date.  A statement that 
written authorization (HIPAA authorization; US sites only) and any local subject privacy 
required documentation for this study has been obtained (including the date) A statement 
that informed consent was obtained (including the date); 
• Reasons for screen failure;  
• Dates of all subject visits; 
• All prior and concurrent medications (see Table 7 for definitions and timeframes).  List 
all prescription and non-prescription medications being taken.  At each subsequent visit, 
changes to the list of medications should be recorded; 
• All prior and concurrent procedures and/or non-medication treatments (see Table 7 for 
definitions and timeframes).  List all procedure and non-medication treatments being 
taken.  At each subsequent visit, changes to the list of medications should be recorded; 
• Occurrence and status of any adverse events (including onset date, assessments of 
severity, seriousness, and relationship with study drug, treatment instigated (if any), 
action taken regarding study drug, outcome, and stop date); 
• The date the subject exited the study, and a notation as to whether the subject completed 
the study or reason for early exit; 
• The results of protocol-required laboratory tests performed by the site (ie, results of urine 
pregnancy tests, hematology including complete blood count and differential, blood 
chemistry panel and urinalysis); 
• Patient medical and surgical histories (including demographics); 
• Patient ophthalmic history (including iris color); 
• Results of physical examination performed by site (including height and weight); 
• For females, documentation of non-childbearing potential or results of pregnancy test and 
documentation of subject’s stated birth control method when applicable; 


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• Ophthalmic examination results of subject visits including all IOP measurements and 
times, macroscopic bulbar hyperemia evaluations, pupil size (Part 2 only), visual acuity, 
contrast sensitivity (Part 2 only), slit-lamp biomicroscopy, visual field and fundus exams;  
• Subject comfort of eye drop evaluations responses (Part 2 only); 
• Respiratory rate, and temperature measurements (seated); 
• Postural (supine/standing) blood pressure and heart rate; 
• Electrocardiogram findings;  
• Source notes should also include any subject counseling/education (when applicable) 
regarding contact lens usage, activities that would interfere with ocular surface 
evaluation, permissible mediations/treatments, prohibited medications/treatments, and 
timing in relation to scheduled study visits and study compliance including instruction 
provided to subject for administration and storage of study medication. 
10.4.2. 
Compliance with Electronic Records; Electronic Signatures Regulations 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature (US 21CFR Part 11).   
10.4.3. 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each subject’s 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally electronically sign the eCRFs to ensure that the observations and findings 
are recorded on the eCRFs correctly and completely.  A certified electronic copy of the 
eCRFs including data corrections will be provided to the site for archiving at the end of the 
study.  See Study Reference Manual for eCRF completion guidelines. 
10.4.4. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF;  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF;  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents;  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data;  


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• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.4.5. 
Study and Site Closure 
The sponsor reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of the sponsor.   
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines; 
• Inadequate recruitment of subjects by the investigator; 
• Discontinuation by the sponsor of further development of the study treatment.  
10.4.6. 
Final Report by Investigator 
An investigator's summary, in compliance with US 21 CFR Part 312.64(c),  will be provided 
to Whitecap Biosciences (or designee) within a short time after the completion of the study, 
or as designated by Whitecap Biosciences.  A summary of the study’s outcome is also to be 
provided to the responsible IRB and, if applicable, the investigator’s institution. 
10.4.7. 
Retention of Documentation 
All study-related correspondence, subject records, consent forms, subject privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of case report forms should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Whitecap Biosciences-
specific essential documents should 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 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Whitecap Biosciences. 


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Whitecap Biosciences requires that it be notified in writing if the investigator wishes to 
relinquish ownership of the data so that mutually agreed-upon arrangements can be made for 
transfer of ownership to a suitably qualified, responsible person. 
10.5. 
Monitoring by Whitecap Biosciences 
Authorized representatives of Whitecap Biosciences will monitor the study on a periodic 
basis.  The determination of the extent, frequency and nature of monitoring will be based on 
such as the objective, purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of Whitecap Biosciences or regulatory authority representatives 
will conduct on-site visits to review, audit and copy study-related documents.  These 
representatives will meet with the investigator(s) and appropriate staff at mutually convenient 
times to discuss study-related data and questions. 
10.6. 
Publications  
The results of this study may be published or presented at scientific meetings; the 
investigator shall agree to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results, in accordance 
with standard editorial and ethical practice.  Whitecap Biosciences, as the sponsor, has 
proprietary interest in this study and thus will be involved in reviewing, at a minimum, any 
abstract or manuscript prior to submission in order to allow the sponsor to protect proprietary 
information and to provide comments.  Authorship and manuscript composition will reflect 
joint cooperation between the investigator(s) and Whitecap Biosciences personnel.  
Authorship will be established prior to the writing of abstracts or manuscripts, will be 
determined by mutual agreement, and in line with International Committee of Medical 
Journal Editors authorship requirements. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study, except as agreed with Whitecap 
Biosciences.  


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11. 
References 
AGIS (The Advanced Glaucoma Intervention Study). The relationship between control of 
intraocular pressure and visual field deterioration. The AGIS Investigators. Am J 
Ophthalmol. 2000;130(4):429-440. 
Burke J, Schwartz M. Preclinical evaluation of brimonidine. Surv Ophthalmol. 1996;41 
Suppl 1:S9-18. 
Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, et al. Reduction of 
intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma 
Trial. Arch Ophthalmol. 2002;120(10):1268-1279. 
ICH M3 guidance and UK Clarification of Contraceptive Wording in Clinical Trials 
Conducted in the UK (21 May 2010).   
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group.  Standardization of uveitis nomenclature for reporting clinical data. Results 
of the First International Workshop. Am J Ophthalmol. 2005;140(3):509-516. 


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12. 
Attachments 
12.1. 
Glossary of Terms, Abbreviations and Definitions 
Table 7 
Glossary of Terms and Abbreviations 
Term/Abbreviation 
Definition 
ANOVA/ANCOVA 
Analysis of Variance/Analysis of Covariance 
BAK 
benzalkonium chloride 
BCVA 
best-corrected visual acuity 
BID 
twice daily 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
C/D 
cup/disc 
CRF/eCRF 
case report form/electronic case report form 
ECG 
electrocardiogram 
eDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GAT 
Goldmann Applanation Tonometer 
GCP 
Good Clinical Practices 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IETD 
investigator emergency treatment disclosure 
IOP 
intraocular pressure 
IP 
investigation product 
IRB 
Institutional Review Board 
IWRS 
Interactive web-response system 
LogMar 
logarithm of the minimum angle of resolution 
MAOI 
monoamine oxidase inhibitor 


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Term/Abbreviation Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mm Hg 
millimeters of mercury 
NOAEL 
no observed adverse effect level 
OHT 
ocular hypertension 
OU 
both eyes 
PGA 
prostaglandin analog 
POAG 
primary open angle glaucoma 
PP 
per protocol 
RGP 
rigid gas permeable 
SITA 
Swedish Interactive Thresholding Algorithm 
SNRI 
serotonin norepinephrine reuptake inhibitor 
TCA 
tricyclic antidepressant 
US 
United States 
 
 
 


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Table 8 
Glossary of Definitions 
Term 
Definition 
End of Study 
The date of the last visit of the last subject in the study 
Subject Status 
Subject status is defined below: 
Study entry 
A subject who has signed informed consent and has undergone at least 1 
screening procedure and been entered into IWRS 
In screening 
A subject who has is undergoing the screening process and has not yet qualified 
for study enrollment. 
Screen failure 
Subject who has signed informed consent, has undergone at least 1 screening 
procedure, but fails to qualify for study at any time prior to and up until the 
completion of the Baseline visit. 
Enrolled 
A subject who qualifies for study based on Inclusion and exclusion criteria (Parts 1 
and 2) (see Sections 4.1 and 4.2) AND is randomized (assigned a randomization 
number (Part 2). 
Subject completion 
A subject who has completed all phases of the study including the last scheduled 
procedure as shown in the Schedule of Visits and Procedures. 
“Should” vs “Must” 
Use of the word “should” means that it is suggested or recommended, but not 
required, whereas the use of the word “must” means that it is required. 
Concurrent Medication 
A medication that the study subject is taking at the time of enrollment or after 
Concurrent Treatment 
A procedure or other non-medication medical treatment that the study subject is 
receiving at the time of enrollment or after. 
eg, 
for example 
ie, 
in other words 
Prior Medication 
A medication taken by the study subject within time period specified in entry 
criteria prior to enrolling in the study.  Other prior medications within 3 months 
prior to enrolling into the study. 
Prior Treatment 
A procedure or other non-medication medical treatment received by the study 
subject within time period specified in entry criteria prior to enrolling in the study.  
Other prior treatments within 3 months prior to enrolling into the study. 
Study eye 
The designated eye for use in analysis of IOP effects will be based on the eye 
with the higher IOP at Day -1, Hour 0.  If both eyes qualify, the eye with the higher 
IOP at Baseline (Day -1) Hour 0 will be the study eye.  If both eyes have the same 
IOP value at this timepoint, the right eye will be the study eye. 
 
 


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12.2. 
Examination Procedures, Tests, Equipment, and Techniques  
Study evaluations should be performed by the same investigator or sub-investigator 
throughout the study whenever possible.  If it is not possible to use the same individual to 
follow the subject, then an attempt should be made to have visits overlap (examine the 
subject together and discuss findings) for at least one visit.  At designated study visits, 
physical examinations and the comfort of eye drop subject questionnaire should be conducted 
prior to other assessments or invasive procedures.  Data will be recorded on the appropriate 
eCRF. 
12.2.1. 
Demographics and Baseline Characteristics 
Demographic information including age, race (including limited ethnicity), gender and iris 
color are to be obtained at the screening visit. 
12.2.1.1. Medical and Ophthalmic Histories and Procedures 
Medical (relevant) and ophthalmic history (including the history of the current 
disease/disorder), any pertinent procedures that could potentially influence the safety of the 
subject and/or the outcome of the study and any information regarding underlying 
disease/disorders are to be obtained at Screening.  Data will be recorded on the appropriate 
eCRF.   
12.2.1.2. Physical Examination (Including Height and Weight) 
The subject will be examined for any detectable abnormalities of the following body 
systems:  general appearance; head, eyes, ears, nose and throat (HEENT); 
heart/cardiovascular; lungs; abdomen; neurologic; extremities; back; musculoskeletal; 
lymphatic and skin. 
Height will be measured (without shoes) in inches (in) or centimeters (cm).  Weight (without 
shoes) will be measured in pounds (lb) or kilograms (kg) using a scale.  Historical subject 
information and/or subject reports should not be used for the height and weight 
measurements. 
12.2.1.3. Respiratory Rate and Temperature 
Respiration rate will be measured after the subject has been in a resting state (seated) for at 
least 5 minutes.  Respiration rate will be counted for 30 seconds, multiplied by 2, and 
recorded as breaths per minute.  Temperature will be measured after the subject has been in 
a resting state (seated) for at least 5 minutes.  Temperature will be measured in Celsius (°C) 
or Fahrenheit (°F).  Oral, Skin or tympanic temperature methods of collection are acceptable. 


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12.2.1.4. Postural (Supine / Standing) Blood Pressure and Heart Rate  
Postural Systolic/diastolic blood pressure and heart rate will be measured after the subject 
has been in a resting state (supine) for at least 5 minutes and then again 3 minutes after 
standing.  Record the 2 measurements from the 2 positions (supine and standing).  Pulse will 
be counted for 30 seconds, multiplied by 2, and recorded in bpm. 
12.2.1.5. Urine Pregnancy Test 
Female subjects who are of child-bearing potential (see Section 6.4 for definition) will have a 
urine pregnancy test performed.  Pregnancy test kits will be provided by a qualified third-
party vendor (see Attachment 12.4) and will be administered according to the instructions 
provided with the tests. 
12.2.1.6. 12 lead-ECG 
Sites will receive training on the use of ECG equipment provided.   
[Triplicate] 12-lead ECG will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and [QTc] intervals.  At each time point, 
3 individual ECG tracings should be obtained as closely as possible in succession, but no 
more than 2 minutes apart. The full set of triplicates should be completed in less than 4 
minutes.  
12.2.1.7. Clinical Safety Laboratory Assessments (non-fasting) 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.  The laboratory reports must be filed with the source documents.   
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within [insert timeframe] after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified; 
• All protocol-required laboratory assessments (see below) must be conducted in 
accordance with the Laboratory Manual and the Schedule of Visits and Procedures;  


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Laboratory assessments will include blood chemistry panel, hematology including complete 
blood count with differential, urinalysis and urine pregnancy test for all females who are of 
child-bearing potential (See Section 6.4 for definition). 
The specific tests in these panels are: 
Complete Blood Count (with differential):  hematocrit, hemoglobin, red and white cell 
count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), red blood cell morphology, reticulocyte 
count, platelet count, neutrophils (bands and segments), lymphocytes, monocytes, 
eosinophils, and basophils. 
Chemistry Panel:  albumin/globulin (A/G ratio), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), albumin, alkaline 
phosphatase, bilirubin (total, direct, and indirect), blood urea nitrogen (BUN), 
BUN/creatinine ratio, calcium, magnesium, cholesterol, high-density lipoprotein (HDL), 
low-density lipoprotein (LDL), chloride, creatinine, globulin, hemoglobin A1c (HbA1c), 
lactic dehydrogenase (LDH), phosphorus, potassium, serum bicarbonate, total protein, 
sodium, triglycerides, uric acid, and creatine phosphokinase (CPK).   
Urinalysis:  A urine specimen will be collected and assessed for color (appearance), specific 
gravity, pH, glucose, protein, ketone, urobilinogen, nitrite, leukocyte esterase, occult blood, 
and bilirubin.  Microscopic analysis includes the following:  red blood cells per high power 
field (RBC/HPF), white blood cells per high power field (WBC/HPF), squamous epithelial 
cells; additional components, abnormal and/or atypical cells will also be reported if present.   
Urine pregnancy test:  All females who are of child-bearing potential are required to have 
urine pregnancy tests. 
Handling of Biological Specimens:  Samples of blood and urine for evaluation of 
hematology, chemistries and urinalysis will be analyzed at a centralized clinical laboratory 
with certification from a recognized accreditation agency (eg, College of American 
Pathology [CAP] or Clinical Laboratory Improvement Amendments [CLIA] certification).  
12.2.2. 
Ophthalmic Examination Procedures, Tests, Equipment, and Techniques  
Visits for ophthalmic examinations should be scheduled at approximately the same time of 
the day.  A gross general examination of the external eye and adnexa should be performed, 
and pathology described.  See the Schedule of Visits and Procedures (Tables 1, 2 and 3) for 
the order in which the procedures should be performed. 


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12.2.2.1. Subject Comfort of Eye Drops Evaluation (Questionnaire) (Part 2 only) 
Subjects will be asked questions by a designated clinical staff member at the site to assess the 
study medications by responding to a series of questions regarding their comfort of their IOP-
lowering medications.  Conduct these interviews in a quiet place with only the study 
participant and the interviewer present.  Please instruct each subject that his/her input is 
important.  Subjects should report on their experiences and impressions (ie, there are no 
“right” or “wrong” answers).  Begin with asking the subject about all of the symptoms s/he 
may be experiencing or overall comfort in the right eye and then when complete, ask about 
the symptoms of the left eye. 
Subjects will be asked questions by a clinical staff member at the site to assess the comfort of 
their eye drop medication(s) (for each eye): 
• (if applicable) the IOP-lowering medication they are taking prior to entry into the study 
(at Screening); 
• the study medication (at post-Baseline visits). 
Leading Question at Screening:  Thinking about your <appropriate> eye, how would you 
rate the overall comfort of your current glaucoma eye drops? 
Leading Question at Study Visits:  Thinking about your <appropriate> eye, how would you 
rate the overall comfort of the study eye drops? 
Using the Subject Comfort of Eye Drops Questionnaire on a 6-point scale, read to the subject 
each of the responses for the selection that best matches their experience:  Very comfortable, 
Comfortable, Slightly uncomfortable, Uncomfortable, Very Uncomfortable, Intolerable. 
12.2.2.2. Macroscopic Bulbar Conjunctival Hyperemia 
The macroscopic (gross) hyperemia grading should be completed prior to any other eye 
examinations.  Bulbar hyperemia will be graded by the Investigator upon gross inspection 
under consistent illumination by comparing the appearance of the bulbar conjunctiva to 
standard photographs.  
  0 
(None) 
= 
Normal. Vessels of bulbar conjunctiva easily observed 
+0.5 
(Trace) 
= 
Trace flush, reddish-pink color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
The gross macroscopic hyperemia evaluation should be performed by the same evaluator in 
the same facility with consistent lighting throughout the entire study, whenever possible.  


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12.2.2.3. Visual Acuity 
Manifest refraction will be performed at specified study visits (See the Schedule of Visits and 
Procedures Tables 1, 2, and 3 in the protocol synopsis and see Section 8) to obtain a 
correction for all visual acuity evaluations.  Visual acuity (in Snellen equivalents) will be 
measured for each eye using a logarithmic (LogMar) visual acuity chart for testing at 4 
meters.  Please refer to the Study Reference Manual for details on the procedures for 
measuring visual acuity. 
12.2.2.4. Pupil Size (Part 2 only) 
Pupil size for each eye will be measured using the centimeter ruler on the near card, measure 
the subject's undilated pupils to the nearest 0.5 mm in size.  The pupil gauge on the near card 
may be used instead per investigator preference.  The size of the pupil will be measured prior 
to biomicroscopy and IOP evaluations. 
12.2.2.5. Contrast Sensitivity (Part 2 only) 
Contrast Sensitivity will be measured using the VectorVision CSV-1000 test at four levels of 
contrast.  The test distance for the chart must be kept consistent throughout the study.  Do not 
set up chart in brightly lit room or sunlight.  Details for the operation of the equipment and 
the conduct of the test for each patient can be found in the Study Reference Manual. 
12.2.2.6. Biomicroscopic Examinations 
Findings other than those listed below should be recorded under “other” for the appropriate 
location of the finding.  Required dilated examinations are designated on the Schedule of 
Visits and Procedures. 
Eyelid/Eyelid Margins/Lashes 
Edema 
 
 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) 
= 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
Erythema 
 
 
  0 
(None) 
= 
No erythema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) flush reddish color  


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+1 
(Mild) 
= 
Localized, mild, flush reddish color 
+2 
(Moderate) 
= 
Diffuse reddish color encompassing the entire lid margin 
+3 
(Severe) 
= 
Deep diffuse reddish color of lid margins and superior and/or inferior 
eyelid 
Conjunctiva (Bulbar) 
Hyperemia 
 
 
 
  0 
(None) 
= 
No hyperemia 
+0.5 
(Trace) 
= 
Minimal (trace) flush, reddish color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
Edema 
 
 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) 
= 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
 
Cornea 
Edema 
 
 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) epithelial haze 
+1 
(Mild) 
= 
Dull glass appearance of epithelium that may include fine localized 
microcystic changes 
+2 
(Moderate) 
= 
Dull glass appearance of the epithelium with large number of cystic 
changes with or without stromal edema 
+3 
(Severe) 
= 
Epithelial bullae and/or stromal edema, localized or diffuse, with or 
without stromal striae 


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Superficial Punctate Keratopathy 
  0 
No superficial punctate keratopathy 
+0.5 
(Trace) 
 
 
+1 
(Mild) 
 
 
+2 
(Moderate) 
 
 
+3 
(Severe) 
 
 
Anterior Chamber 
For the measurements of cells and flare based on standardized uveitis nomenclature 
(SUN Working Group, 2005), the following settings should be used: 
1 x 1 mm slit  
High magnification 
Highest slit lamp voltage  
Low ambient lighting 
Illumination angle of 45 degrees 
Same grader and slit lamp whenever possible 
Cells 
  0 
= 
0 cells  
+0.5 
= 
1-5 cells (trace)  
+1 
= 
6-15 cells 
+2 
= 
16-25 cells 
+3 
= 
26-50 cells 
+4 
= 
>50 cells 
Flare 
  0 
= 
None: 
No flare seen 
+1 
= 
Faint:  
Faint flare seen 
+2 
= 
Moderate:   
Iris and lens details clear 
+3 
= 
Marked:   
Iris and lens details hazy 
+4 
= 
Intense:   
Fibrin or plastic aqueous 
 
Iris/Pupil 
The iris/pupil will be evaluated for pathology.  If pathology is present, it will be described. 
Iris Color (Screening only) 
Iris color will be recorded at Screening using the following classification:  blue, blue-gray, 
blue/gray-brown, gray, green, green-brown, hazel, brown, dark brown, or other (specify). 
12.2.2.7. Intraocular Pressure (IOP) (mm Hg)  
IOP should be measured only after the biomicroscopic exam is completed and must be 
measured prior to pupil dilation.  IOP measurements will be taken by two qualified 


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independent study site personnel using a Goldmann applanation tonometer (GAT) affixed to 
a slit lamp with the subject seated.  One person will adjust the dial in masked fashion while 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.  Tight fitting neckwear should be loosened.  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 mm Hg).  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 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.  For a given subject, the reader should not also be the person to 
dispense/administer/discuss study medications with the subject. 
At least two, and if necessary, three consecutive measurements will be taken to determine 
IOP in the manner described above.  If the first two measurements differ by 2 mm Hg or less, 
a third measurement is not required, and the two measurements will be recorded.  If the first 
two measurements differ by more than 2 mm Hg, a third measurement should be made, and 
all three measurements will be recorded. 
12.2.2.8. Visual Field 
Measure the subject’s pupils (to the nearest 0.5 mm).  If they are less than 3 mm in diameter, 
dilate them with 2.5% phenylephrine drops, unless contraindicated.  If the brow is heavy or 
the upper lid is drooping, tape accordingly.  Visual field results must be reliable (ie, ≤ 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 a Humphrey automated 
perimetry test (24-2) using the full threshold or SITA standard testing method).  The same 
test method (eg, SITA Standard 24-2) should be used for all visual fields for a given subject, 
including the historical visual field, if applicable.  Preferred equipment is the Humphrey 700 
Humphrey Field Analyzer (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 
(dB). 


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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. 
12.2.2.9. Other Ophthalmic Examinations 
Use biomicroscopic examination, indirect lenses, direct/indirect ophthalmoscopy, etc. as 
appropriate to visualize. 
Lens 
Lens Status 
Lens status will be assessed as phakic, pseudophakic, or aphakic.  The lens (including the 
posterior capsule for subjects who have undergone lens extraction) will also be evaluated for 
pathology.  If pathology is present, it will be described. 
Cataract Assessment (phakic eyes only) 
Under dilated examination, the presence and severity of nuclear, cortical and posterior 
subcapsular cataract lens opacities will be evaluated.  At the first dilated examination, each 
type of cataract, if present, will be graded using the scale below.  At the last follow-up dilated 
examination, each type of cataract will be assessed for change from baseline and if changed, 
the current severity will be graded using the scale below:  
  0 
= 
None 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
Vitreous 
The vitreous will be evaluated for pathology.  If pathology is present, it will be described.  
Note if the condition is not evaluable. 
Fundus 
The fundus (posterior pole; periphery, when dilated) will be evaluated for pathology.  If 
pathology is present, it will be described.  Note if the condition is not evaluable.  


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Optic Nerve 
The optic nerve will be evaluated for pathology.  If pathology is present, it will be described.  
Note if the condition is not evaluable.  
Cup/disc ratio will be reported using a 0.0 to 1.0 scale.  The Armaly chart provided by 
Whitecap Biosciences provides a pictorial scale of cup/disc ratio of 0.0 to 0.8.  Note if the 
condition is not evaluable. 
12.3. 
Other Study Supplies  
As needed, Whitecap Biosciences will provide logarithmic visual acuity charts as necessary, 
the Armaly chart (for measurement of cup/disc ratio), and the bulbar hyperemia grading 
guide (standard photographs).  In addition, ECG equipment will be provided to each site as 
needed.  Contrast sensitivity equipment will be provided to designated sites.  Study sites are 
to use their own equipment for all other examinations and measures. 
The kits for collection of non-fasting clinical laboratory analysis, as well as urine pregnancy 
test kits will be provided a qualified third-party vendor (see Attachment 12.4): 
• Laboratory kits (including pregnancy tests) for the collection and shipment of blood and 
urine samples. 
• Shipping materials for shipment of laboratory samples to the central laboratory. 
12.4. 
List of Computerized Systems 
Electronic Data Capture (EDC) 
This protocol will use eCRFs using remote eDC through a qualified third-party vendor.  The 
data will be entered on the eCRFs in a timely manner on an ongoing basis.  Data will be 
located in a study-specific clinical database.  Service Provider:  iMednet  Location:  Lowell, 
MA USA. 
Interactive Web-Based Response System (IWRS) 
The IWRS, a module of the eDC, will be used to confirm Baseline IOP eligibility and in Part 
2 only, stratification, randomization and medication kit numbers assignment.  The IWRS will 
also be used to manage study medication inventory.  Service Provider:  iMednet, Location:  
Lowell, MA USA. 
Clinical Laboratory Sample Analysis 
Analysis of laboratory samples:  blood chemistry panel, hematology including complete 
blood count with differential, urinalysis, and urine pregnancy tests for all females who are of 


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child-bearing potential will be performed by a qualified third-party vendor.  Service Provider:  
LabCorp; Location:  Burlington, North Carolina, USA. 
12.5. 
Protocol Amendments 
12.5.1. 
Amendment 1 Summary 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Protocol WB007-001_01 (Amendment 1);  Date of Amendment:  July 2019 
 
Section 
Revision 
Rationale 
Synopsis 
Study Population: Adult (at least 18 years of age) male 
or female subjects with primary open-angle glaucoma or 
ocular hypertension in each eye who are otherwise in 
generally good health.  Only one eye must meet all ocular 
entry criteria.  
Clarified that only one eye must 
meet all ocular entry criteria to 
participate in the study.  
 
Dosage/Dose Regimen (Part 2):  added “Site personnel 
will administer the morning dose at study visits.” 
Added emphasis here that site 
personnel will administer doses 
at study visits. 
Randomization/Stratification:  added “When both eyes 
qualify, the study eye will be defined using the 
Interactive Web Response System (IWRS), a module 
within the electronic data capture (eDC) system.” 
Clarified use of IWRS during 
randomization 
Synopsis, 
Sections 9.3.1.1 
and 9.4 
Primary analysis:  The primary analyses will be 
performed in the mITT population via analysis of 
covariance (ANCOVA) tests which will have treatment 
as the main effect and the baseline hour-matched IOP as 
the covariate in the model.   This approach will also be 
used  on “Other analyses” of IOP values at Day 14 and 
Mean Diurnal IOP at Day 14. 
Accepted FDA suggestion to 
change primary analysis.  
Original primary analysis will 
now be secondary.  Other 
Sections 3.2, 
5.1.1, 7.5, 8.3.2, 
12.4 
An interactive web response system (IWRS), a module 
within the Electronic Data Capture (eDC) system will be 
used to select study eye and manage the treatment 
assignment process, including subject randomization and 
stratification in Part 2. 
Clarified how IWRS will be 
used in this study 


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Section 
Revision 
Rationale 
Section 3.2.2. 
Part 2: Subject treatment will be double-masked; neither 
the investigator nor the staff or subject will be aware of 
treatment assignment.  All study treatments will be 
provided in similarly-appearing bottles and identical 
cartons to maintain masking of the study. 
The study treatments will not 
be in identical bottles, but in 
similar-appearing bottles with 
the same colored bottle caps.  
The bottles will be packaged in 
identical unit cartons.  
Tables 1, 2, 3; 
Section 7.3, 8.2, 
8.3, 8.4, 10.4.1, 
12.2.1.3, 12.2.1.4 
“Vital Signs” has been removed.  Respiration rate and 
temperature have been separated from “Postural blood 
pressure and heart rate”.   
Clarify seated vs. supine and 
standing measurements.  The 
use of the term “vital signs” 
became superfluous.  
Table 1 
Removed footnote d: 
 “At Day 1 Hour 0, if IOP has changed by more than 3 
mm Hg from Baseline (Day -1) Hour 0, the subject is not 
eligible.”  
Decision to simplify entry 
criteria and alignment between 
Parts 1 and 2. 
Table 3, Section 
8.4.2 
Subject Comfort of Eye Drops Evaluation (administered 
by designated site personnel) (Day 14/Exit only) 
Clarified that evaluation will be 
performed at Day 14 only (not 
Days 7 AND 14)  
Table 3, Section 
8.4.2 
Added footnote e to table:  “Give study medication to 
subject at the end of the visit” and clarified language in 
Section 8.4.2 
 
Clarify in Part 2 that subject 
will be given the study 
medication at the end of the 
Day 1 visit. 
4.2 
• Removed exclusion criterion #9 
• Removed exclusion criterion #10  
Original criteria 10, 11 and 12 
were sub-bullets of Criterion 
#9.  A formatting issue 
occurred which elevated criteria 
10, 11 and 12 to same level as 
9, rendering 9 unnecessary.   
Criterion #10 was a duplicate of 
criterion #2. 
4.2 
Exclusion #33 was modified to allow subjects with up to 
+1 (mild)  conjunctival hyperemia (rather than up to +0.5 
(trace) to screen for this study.    
Loosened the criterion to 
ensure efficient enrollment of 
this study population without 
jeopardizing the outcome of the 
study.   
Tables 1, 3; 
Sections 7.3, 8.3, 
10.4.1 
Pupil size will be measured before visual acuity 
Aligns with common practice 
8.4.1 
Part 1 – Day 1 (Hour 0):  added a bullet for study 
medication assignment 
 
8.4.2 
Added bullet to Part 2 – Evening before Day 7 and Day 
14 (Exit):  “Contact from site to remind subject to dose 
study medication approximately 12 hours prior to Hour 0 
appointment time.” 
Clarified in this section to align 
with Table 3 and Sections 
5.2.1, 8 and 8.6 
8.4.2 and 8.6 
Added bullet to Part 2 - Days 7 and 14/Exit (Hour 0) (±10 
minutes): “Site to collect study medication following 
final dose (Day 14/Exit only)” 
Clarified when study 
medications will be collected 
from the subject in Part 2.  


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Section 
Revision 
Rationale 
8.6 
Added to Subject Instructions:  “To avoid discussing side 
effects (if any experienced) with other subjects in the 
study” and in Part 2: 
“The study medications should be kept in their unit 
carton (box).  Do not show the bottles to other subjects or 
study staff (except the individual who dispenses the study 
medication to the subject.” 
To minimize bias 
9.3.1.2 
Moved analysis of variance to secondary efficacy 
endpoint 
To accommodate updated 
primary analysis. 
10.1.3 
Rephrased the 4th bullet: 
If the ICF is modified during the subject’s participation in 
the study, subjects must be re-consented to the most 
current version of the ICF(s).   
Previous wording was 
confusing. 
12.2.2.4 
Pupil Size methodology clarified to remove pupillometry 
and accept the use of a near card.  
Methodology section aligned 
with main body of protocol. 
12.2.2.7 
For a given subject, the reader should not also be the 
person to dispense/administer/discuss study medications 
with the subject. 
To minimize bias 
12.5.2. 
Amendment 2 Summary 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Protocol WB007-001_02 (Amendment 2);  Date of Amendment:  Sept 2019 
Section 
Revision 
Rationale 
4.1 
IOP in fellow eye at Baseline ≤ 34 mm Hg at Hour 4 
added. 
 Inadvertently omitted Hour 4. 
4.1, 7.3 and 
12.2.2.3, 12.3 
Visual Acuity (VA):  replaced testing distance of 3 
meters to 4 meters; removed distance from entry 
criterion; visual acuity charts will be provided to sites as 
necessary. 
Testing distance of 4 meters is 
a standard practice with 
logarithmic VA charts.  
 
Distance for VA testing is 
redundant in inclusion criterion. 
 
Logarithmic VA charts will be 
provided as necessary.  
8.2 
Clinical laboratory evaluation (non-fasting), “including 
CBC with differential, Blood Chemistries, Urinalysis” 
added. 
Clarified that both blood and 
urine specimens will be 
collected. 
8.4.2 
Part 2, Day 1, 30 minutes Subject Comfort of Eye Drop 
Evaluation was added 
Examination inadvertently 
omitted in the text. 
8.4.2 
Part 2, Days 7 and 14/Exit Hour 2 Visual Field 
examination is to be performed at Day 14/Exit only. 
Part 2, Days 7 and 14/Exit Hour 8 Fundus examination is 
to be performed at Day 14/Exit only. 
Clarified that these 2 
examinations are to be 
performed at Day 14/Exit only. 


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12.5.3. 
Amendment 3 Summary 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Protocol WB007-001_03 (Amendment 3);  Date of Amendment:  January 2020 
Section(s) 
Revision 
Rationale 
Synopsis, Table 3, 
Figure 3;  
Sections 8, 8.4.2, 
8.6, and 9.3.2 
Moved Day 7 to Day 4 
Assess potential to observe 
early steady state 
Synopsis, Table 3, 
Figure 3; Sections 
8 and 8.4.2 
Removed Day 2-3 required phone call 
Phone call now optional.  
Synopsis 
Schematic of study design for Part 2 modified duration of 
diurnal days from 12 to 8 hours 
Align with protocol text. 
8.3.2. 
Removed “Hour 0” from IOP required to enter into 
IWRS.  All Baseline IOP needs to be entered prior to 
randomization.  
Align with inclusion criteria 3e 
and 3f 
Table 3; Sections 
5.1.1 and 8.4.2 
IP kits for Part 2 will include 2 bottles, each in a unit 
carton.  Secondary packaging to group the bottles for 
each subject will also be used.  Only 1 bottle at a time is 
to be dispensed to a subject. 
If necessary (eg, lost or 
damaged bottle), a second 
bottle will be available to 
dispense. 
Table 8 
Updated definition of Concurrent medication and 
concurrent procedure to include during the study 
Clarified to include post-
enrollment additions 
12.5.4. 
Amendment 4 Summary 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Protocol WB007-001_04 (Amendment 4);  Date of Amendment:  September 2020 
Section(s) 
Revision 
Rationale 
4.1 
Exclusion 15: removed “evidence of unilateral cataract 
surgery” from the criterion.  The criterion now is: 
“Evidence of cataract surgery resulting in complications 
(eg, capsular rupture) in the study eye.” 
Loosened the criterion to 
ensure efficient enrollment of 
the study population without 
jeopardizing the outcome of the 
study.   
4.1 and 8.4.1 
Modified exclusion 27: “Previous participation in this 
study” to “Previous randomization in Part 2 of this 
study”. 
 
Part 1 Day 2 (Hour 0): removed statement not allowing 
participation in Part 2 for subjects who participated in 
Part 1. 
Allow for subjects who 
participated in Part 1of the 
study to participate in Part 2.  A 
subject who participates in both 
Parts 1 and 2 will be counted 
only once in the total number of 
participants of the study. 
 


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12.5.5. 
Amendment 5 Summary 
Study Title:  A Phase 1/2a Assessment of WB007 Ophthalmic Solution in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension 
Protocol WB007-001_05 (Amendment 5);  Date of Amendment:  January 2021 
Section(s) 
Revision 
Rationale 
Synopsis, 3.2.1, 
7.5, 8.3.2, Table 
8, 12.4. 
Further clarified wording on the role of the IWRS for 
selection of study eye.  
IWRS was used to confirm IOP 
eligibility.  Designation of the 
study eye was based on the 
algorithm pre-specified in the 
protocol in Section 9.3.1.1. 
Synopsis, 3, 
9.3.1.1, 
 
Clarified the wording for the primary efficacy analysis.  
The primary efficacy analysis is the within-group mean 
change from baseline at Hour 2, the time of peak efficacy 
of timolol. 
The protocol wording was 
clarified to align with the 
Statistical Analysis Plan (SAP).   
Synopsis, 9.2 
 
 
Clarified the sample size power calculation to include the 
power to detect within-group mean change from baseline 
of at least a 3 mm Hg for the primary endpoint assuming 
a standard deviation of 2.5 with two-sided alpha = 0.05.”  
 
In Section 9.2, deleted the last paragraph and replaced the 
3rd sentence under the table to align with the protocol 
synopsis. 
The protocol wording was 
clarified to align with the SAP.   
 

SAP_001.pdf: 
Whitecap Biosciences                                                                                                            Statistical Analysis Plan 
Protocol: WB007-001                                                                                                        Version Date: 02 Mar 2021 
                                                                                  CONFIDENTIAL                                                          Page 1 of 14 
 
STATISTICAL ANALYSIS PLAN 
 
WB007-001 
 
A Phase I/2a Assessment of WB007 Ophthalmic Solution in Subjects with Primary Open-Angle Glaucoma 
or Ocular Hypertension 
Prepared for: 
Whitecap Biosciences 
Version and Author details: 
Version Date: 
02 March 2021 
Version Number 
2.0 
Author: 
 
 
NCT#  NCT04149899


Whitecap Biosciences                                                                                                            Statistical Analysis Plan 
Protocol: WB007-001                                                                                                        Version Date: 02 Mar 2021 
                                                                                  CONFIDENTIAL                                                          Page 2 of 14 
 
SIGNATURES 
 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Statistical Consultant, Whitecap Biosciences 
 
Date 
 
 
 
 
 
 
 
 
 
Clinical Head, Whitecap Biosciences, LLC 
 
Date 
 
 
 
 


Whitecap Biosciences                                                                                                            Statistical Analysis Plan 
Protocol: WB007-001                                                                                                        Version Date: 02 Mar 2021 
                                                                                  CONFIDENTIAL                                                          Page 3 of 14 
 
Table of Contents 
1 
INTRODUCTION ................................................................................................................................... 4 
1.1 
Changes from Protocol ........................................................................................................................ 4 
2 
STUDY OBJECTIVES ............................................................................................................................. 4 
3 
STUDY DESIGN .................................................................................................................................... 4 
3.1 
Sample Size Considerations ................................................................................................................. 5 
3.2 
Randomization and Study Eye Assignment ............................................................................................ 6 
4 
ANALYSIS POPULATIONS .................................................................................................................... 6 
5 
STUDY VARIABLES AND COVARIATES ................................................................................................. 7 
5.1 
Primary Efficacy Endpoints (Part 2) ...................................................................................................... 7 
5.2 
Secondary and Other Efficacy Endpoints (Part 2) .................................................................................. 7 
5.3 
Subgroup Analyses (Part 2) ................................................................................................................. 7 
5.4 
Safety Endpoints ................................................................................................................................. 7 
6 
DATA CONVENTION ............................................................................................................................. 7 
6.1 
Missing Data ....................................................................................................................................... 8 
6.2 
Descriptive Statistics ........................................................................................................................... 8 
7 
DISPOSITION AND EXIT STATUS ........................................................................................................ 8 
7.1 
Subject Disposition .............................................................................................................................. 8 
7.2 
Extent of Study Drug Exposure ............................................................................................................ 8 
7.3 
Protocol Deviations ............................................................................................................................. 8 
7.4 
Screen Failures ................................................................................................................................... 9 
8 
BASELINE CHARACTERISTICS ............................................................................................................. 9 
8.1 
Demographics and Baseline/Screening Characteristics ........................................................................... 9 
8.2 
Prior and Concomitant Medications ...................................................................................................... 9 
8.3 
Medical History ................................................................................................................................... 9 
9 
EFFICACY ANALYSIS ........................................................................................................................... 9 
9.1 
Primary Efficacy Endpoint Analysis ....................................................................................................... 9 
9.2 
Secondary, Other and Subgroup Efficacy Endpoint Analyses ................................................................ 10 
9.2.1 
Secondary Efficacy Endpoint Analyses.......................................................................................... 10 
9.2.2 
Other Efficacy Analyses .............................................................................................................. 10 
9.3 
IOP Analysis of Non-Study Eye ........................................................................................................... 10 
9.4 
Interim Analysis ................................................................................................................................ 11 
10  SAFETY ANALYSIS ............................................................................................................................. 11 
10.1 
Safety Endpoint Analysis.................................................................................................................... 11 
10.1.1 
Adverse Events .......................................................................................................................... 11 
10.1.2 
Electrocardiogram (ECG) ............................................................................................................. 11 
10.1.3 
Biomicroscopy ............................................................................................................................ 11 
10.1.4 
Vital Signs .................................................................................................................................. 12 
10.1.5 
Best Corrected Visual Acuity (BCVA) ............................................................................................ 12 
10.1.6 
Other Safety Analysis.................................................................................................................. 12 
10.2 
Data Monitoring ................................................................................................................................ 12 
11  VALIDATION ...................................................................................................................................... 12 
12  GLOSSARY OF ABBREVIATIONS ........................................................................................................ 13 
13  VERSION HISTORY ............................................................................................................................ 14 
 


Whitecap Biosciences                                                                                                            Statistical Analysis Plan 
Protocol: WB007-001                                                                                                        Version Date: 02 Mar 2021 
 
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      Page 4 of 14 
 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Whitecap Biosciences Protocol WB007-001.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol amendment No. 5, dated 30 Jan 2021. The final approval 
of the SAP will occur prior to database lock.  
1.1 
Changes from Protocol 
The changes described in this section apply to Part 2 only.   
The per protocol analysis to confirm the primary efficacy analysis in section 9.1 of protocol will be performed 
on a post hoc basis only as needed; however, the specific criteria of protocol deviations deemed to have 
potential impact on the primary endpoint will be determined and the exclusion of data points will be identified 
prior to the database lock. 
The following secondary efficacy endpoint analysis will be performed on a post hoc basis as needed 
(protocol section 9.3.1.2): 
 
Mean IOP change from baseline at each time-matched hour at Day 14/Exit will be analyzed with 
a 2-way ANOVA method which will have treatment and the baseline IOP stratum (IOP ≤25 mm  
Hg and > 25 mm Hg) as the main effects in the model.   
 
The following subgroup analysis will be performed on a post hoc basis as needed (protocol section 9.5): 
 
Descriptive statistics for the primary analysis will also be provided by each Baseline IOP stratum. 
2 
STUDY OBJECTIVES 
The objective of this study is to assess the safety, ocular tolerability and IOP-lowering effects of WB007 
(also known as AGN-227535) in adult subjects with primary open-angle glaucoma or ocular hypertension. 
The clinical hypotheses for these studies are: 
Parts 1/2: AGN-227535 has an acceptable safety and tolerability profile. 
Part 1: The IOP-lowering effects of at least 1 concentration of AGN-227535 are sufficient for evaluation to 
proceed to Part 2. 
Part 2: The primary hypothesis is that AGN-227535 ophthalmic solution effectively lowers IOP.  Specifically, 
at least 1 concentration of AGN-227535 demonstrates an IOP lowering effect.  
3 
STUDY DESIGN 
This is a 2-part study designed to evaluate the safety, tolerability and IOP-lowering effects of AGN-227535 
in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Approximately 100 
subjects are planned to be enrolled at up to approximately 5 study centers in the United States.  
In Part 1, an open-label dose-escalation of AGN-227535 
 is planned in order to 
assess initial safety, tolerability and IOP-lowering effects. Approximately 6 subjects will be exposed to a 
single dose (to one eye) at each concentration level. Between cohorts, all available data will be used to 
assess the appropriateness to pursue the next concentration. Approximately 25 subjects will be screened 
so that 18 subjects complete the study. 


Whitecap Biosciences                                                                                                            Statistical Analysis Plan 
Protocol: WB007-001                                                                                                        Version Date: 02 Mar 2021 
 
CONFIDENTIAL 
      Page 5 of 14 
 
 
In Part 2, in addition to the primary analysis of the within-group mean IOP change from baseline, a parallel 
comparison of AGN-227535 with timolol 0.5% is planned. Study treatments will be administered twice-daily 
for 14 days. Up to 2 investigational doses will be chosen based on results from Part 1. Subjects will be 
randomized in a 2(:2):1 ratio to receive one of up to two concentrations of AGN-227535 (based on results 
from Part 1) or timolol ophthalmic solution 0.5% and will be stratified based on IOP at Baseline, Hour 0 (≤ 
25 mm Hg versus > 25 mm Hg). Approximately 24 subjects per AGN-227535 group and 12 subjects for the 
timolol group will be given study treatment. If 2 investigational doses are selected: approximately 75 
subjects will be screened so that 60 subjects complete the study. 
For both Parts 1 and 2, potential subjects will be screened within the 50 days prior to initiation of treatment. 
Thus, the total duration of study participation for each subject is up to 2.5 months which includes 4 (Part 1) 
and 6 (Part 2) in-clinic visits. The visit schedule requires day-long visits at some time points to perform 
sufficient clinical assessments. The primary efficacy endpoint (Part 2) is IOP change from baseline at each 
time-matched hour at Day 14/Exit. 
Part 2 of the study is designed as a parallel group comparison, randomized and double-masked to minimize 
investigator and subject bias, and eliminate possible confounding effects that are inherent in other study 
designs (e.g., crossover design). The selection of subjects, study endpoints, and therapy are in general 
similar to studies that established the safety and efficacy of other IOP-lowering treatments of subjects with 
glaucoma or ocular hypertension. Subjects who are chronically treated with ocular hypotensive medications 
will be required to undergo appropriate washout periods prior to study entry to eliminate residual effects of 
other active ocular hypotensive medications. 
Subject safety will be monitored throughout the study. 
3.1 
Sample Size Considerations 
For each cohort in Part 1 of the study a sample size of 6 patients will provide 83% power to detect a 3 mm 
Hg within group change from pre-dose assuming a standard deviation of 2 and two-sided alpha = 0.05, 
based on a one-sample t-test. With larger standard deviations (≥2.5) the power to detect this difference is 
<66%. 
For Part 2, the sample size will provide >90% power to detect within-group mean change from baseline of 
at least a 3 mm Hg for the primary endpoint assuming a standard deviation of 2.5 with two-sided alpha = 
0.05. In addition, power calculations were performed for the comparison of each dose of AGN–227535 
versus Timolol. These calculations consider treatment differences (AGN–227535 minus Timolol) mean 
changes from baseline in study eye IOP in the mITT population at Day 14/Exit. 
The power to detect treatment group differences from -1 to -4 mm Hg with common standard deviations 
(SDs) ranging from 2.5 to 3.5, based on a two-sample t-test are shown in the Table below. 


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Power Calculations for Study Part 2 Tests of Treatment Difference 
 
Additional sample size calculations were performed for tests of non-inferiority of either dose of AGN-227535 
to Timolol. These calculations considered a non-inferiority margin of 1.5 mm Hg and one-sided α = 0.025. 
With a treatment group difference of -1 mm Hg, the power ranged from 50% for a common SD of 3.5 to 
78% for a common SD of 2.5. 
The calculation was based on the non-inferiority tests for the difference between two means using t-test as 
implemented in the commercial software PASS version 16.0.3 (2018). 
3.2 
Randomization and Study Eye Assignment 
Part 1: No randomization is involved because all subjects in the same cohort receive the same treatment. 
If only one eye qualifies, the study medication will be administered to that eye. If both eyes qualify, the eye 
with the higher IOP at Baseline (Day -1) Hour 0 will be the study eye and will receive study medication. If 
both eyes have the same IOP value at this timepoint, the right eye will be the study eye. 
Part 2: Subjects will be randomly assigned to 1 of up to 3 treatment arms (based on results from Part 1) in 
a 2(:2):1 allocation ratio to receive 1 of up to 2 AGN-227535 concentrations or timolol. To ensure balance 
of elements that could influence the IOP-lowering effects across treatment groups, the randomization will 
be stratified by baseline (Hour 0) IOP (≤25 mm Hg; >25 mm Hg). The randomization scheme will be 
prepared by Whitecap Biosciences or its designee. The IWRS, a module within eDC, will be used to confirm 
Baseline IOP eligibility and perform stratification and randomization of subjects. Subject treatment will be 
double-masked; neither the investigator nor the staff or subject will be aware of treatment assignment. All 
study treatments will be provided in similarly-appearing bottles with the same-colored bottle caps and 
identical cartons to maintain masking of the study.  The study eye of each subject will be defined the same 
way as for the Part 1.   
4 
ANALYSIS POPULATIONS 
Each population will be analysed based on the treatment received. 
Part 1: The Safety population consisting of all treated subjects will be used for all analyses. 
Part 2: The following populations will be used for analysis: 


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 
The Safety population will consist of all treated subjects. All safety analyses will be performed using 
the safety population. 
 
The Modified Intent-to-treat (mITT) will consist of all randomized and treated subjects who provide 
IOP data at baseline and at least one post-baseline IOP assessment. This population will be used 
for analyses of efficacy data. 
 
The Per-Protocol (PP) population is a subset of the mITT population and consists of subjects and 
data points which did not have any protocol deviations deemed to have potential impact on the 
primary endpoint. The protocol instructs subjects to apply study treatment every morning and every 
evening approximately 12 hours apart each day. The 12-hour time window, if violated, may impact 
the Hour 0 IOP measurement on the following day. It is determined that the IOP measurement at 
Hour 0 on Day 4 or Day 14 visit will be excluded from the PP population if the duration between the 
time of evening dose on the day before and Hour 0 on the day of visit deviates from the 12-hour 
requirement by more than 1 hour (i.e., outside the [11 hours, 13 hours] window).   
5 
STUDY VARIABLES AND COVARIATES   
5.1 
Primary Efficacy Endpoints (Part 2) 
The primary response measure is IOP.  The mean hour-matching IOP change from baseline will be the 
primary efficacy endpoint.   
5.2 
Secondary and Other Efficacy Endpoints (Part 2) 
IOP values at each scheduled hour of Day 14/Exit. The mean IOP value will be the secondary efficacy 
endpoint. Also see section 1.1. 
5.3 
Subgroup Analyses (Part 2) 
Subgroup analysis for Part 2 of the study will be performed on post hoc basis as needed, including by 
baseline IOP stratum, by investigational site, and by prior medication category (e.g., Timolol users vs non-
users). Also, see section 1.1.  
5.4 
Safety Endpoints 
All safety analyses will be performed on the Safety Population. 
Safety and tolerability will be assessed by reporting of AEs, ECG, vital sign measurements, clinical 
laboratory results, BCVA, slit lamp biomicroscopy, macroscopic hyperemia, pupil size, visual fields, dilated 
fundus examination, and subject comfort.   
6 
DATA CONVENTION 
Statistical programming and analyses will be performed using SAS® Version 9.4 or higher.  Output will be 
provided in RTF and/or PDF format for tables, listings, and figures using landscape orientation.  All study 
data will be listed by study part subject, treatment, and visit (as applicable) based on all enrolled or safety 
subjects.  Subject data listings will be organized by study part, cohort treatment groups.   
One database lock will occur when all subjects (both Part 1 and Part 2) have either completed the study or 
discontinued from the study prematurely, and all data queries have been resolved. Randomization release 
will occur following the database lock.  
Change from baseline for all variables will be hour-matched. When there is no hour matched value (for 
example, cup-to-disc ratio), change from baseline will be calculated from post baseline values minus the 
baseline. 


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6.1 
Missing Data  
Unless otherwise stated, missing data will be handled using the following approach: 
 
Analyses performed for the mITT population will use the method of last observation carried forward 
(LOCF) to impute missing values. No imputation for missing data will be performed for the safety 
population. 
 
For start date, partial dates will have first day of the month imputed if day is missing, and January 
of that year will be imputed if month is missing. If both day and month are missing, January 01 will 
be imputed.  
 
For end date, partial dates will have last day of the month imputed if day is missing, and December 
of that year will be imputed if month is missing. If both day and month are missing, December 31 
will be imputed. An exception is that missing dates of prior and concomitant medications will not be 
imputed.   
 
Where severity or relationship is missing for adverse events, most conservative imputation will be 
made; in that a missing severity will be imputed as ‘severe’ and a missing relationship as ‘related’.  
6.2 
Descriptive Statistics   
Descriptive statistics will be provided in 3 areas: (1) demographics and baseline characteristics for Parts 1 
and 2, (2) IOP analyses as noted in Sections 5.1 and 5.2 for Part 2, and (3) adverse events analysis for 
Part 2.  
 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, standard 
deviation (SD), median, minimum and maximum. Categorical variables will be summarized using absolute 
and relative frequencies (i.e., counts and percentages). All data to be summarized will be presented by 
cohort treatment groups using appropriate descriptive statistics.  
 
Unscheduled data, such as information from unscheduled visits or investigator comments, will be included 
in the data listings.  In general, these data will be excluded from the summary tables unless otherwise 
specified.  
 
7 
DISPOSITION AND EXIT STATUS 
7.1 
Subject Disposition 
Subject disposition (completed, discontinued and reason for discontinuation) for Part 1 of the study will be 
listed for all treated subjects by cohort treatment groups. For Part 2 of the study, subject disposition will be 
listed for all randomized subjects by cohort treatment groups.  
7.2 
Extent of Study Drug Exposure 
Exposure to treatment group for Part 1 of the study will be listed for all treated subjects, and for Part 2 study, 
exposure to treatment group will also be listed for all randomized subjects.   
For Part 2 of the study, treatment compliance will be listed by cohort treatment groups. For this, duration of 
exposure will be calculated as date of last dose minus date of first dose plus 1.    
7.3 
Protocol Deviations 
A subject listing will be provided that includes the date of the deviation and the deviation description. 


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7.4 
Screen Failures 
The reason for screen failure for both Part 1 and 2 of the study will be listed. 
8 
BASELINE CHARACTERISTICS  
8.1 
Demographics and Baseline/Screening Characteristics 
All demographic and baseline data for Part 1 and 2 of the study will be summarized per treatment group 
and overall. These will be presented for the safety population, and will include age, race, sex, ethnicity, iris 
color, childbearing potential for female subjects, height, and weight. A listing for demographics and baseline 
characteristics for Part 1 and 2 of the study will be presented showing the above parameters.  
8.2 
Prior and Concomitant Medications 
Prior and concomitant medications will be presented for each subject coded per the World Health 
Organization (WHO) Anatomical Therapeutics Chemical (ATC) Drug dictionary. Prior medication are those 
medications that stopped prior to dosing. Concomitant medications are those medications that either started 
anytime from dosing onwards or continued once subject had been dosed with study medication. 
Medications with partial dates that do not allow determination of whether prior or concomitant will be 
considered concomitant.   
Prior and concomitant medications for Part 1 and 2 of the study will be listed separately. This listing will be 
presented for ocular and non-ocular prior and concomitant medications.   
8.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 22 
Subject listings of medical history will be generated separately for study part and for ocular and non-ocular 
data by System Organ Class (SOC) and Preferred Term (PT). 
9 
EFFICACY ANALYSIS  
Part 1: Listings will be provided for all IOP measurements of the study eye and non-study eye by cohort, 
visit, and hour.  
Part 2: Listings will be provided for all IOP measurements of the study eye and non-study eye by cohort, 
visit, and hour. Mean and/or median of the IOP measurements will also be presented along with hour-
matched change from baseline IOP values. 
Apart from listings, statistical analysis will be carried out for Part 2 of the study. Efficacy analyses are 
described in detail within this section. Analyses performed for the mITT population will use the method of 
last observation carried forward (LOCF) to impute missing values. Efficacy analyses will be presented for 
the study eye and non-study eye. The study eye would be considered the main analysis for each endpoint. 
For Part 2, the primary efficacy analysis is the within-group mean change from baseline at hour 2, the time 
of peak efficacy of timolol, on Day 14.  As this is an exploratory trial, all treatment comparisons will be made 
at the two-sided α = 0.05 level without adjustment for multiple comparisons. 
9.1 
Primary Efficacy Endpoint Analysis 
The primary response measure is IOP. Two consecutive measurements of IOP will be taken for each eye, 
with the right eye measured first. If the first two measurements of either eye differ by more than two mm 
Hg, a third measurement will be taken for the eye. Depending on the number of measurements required 
and obtained, the IOP for a given eye will be represented by either the average or the median of the 
readings.  


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Baseline is defined as the value of Day -1 prior to treatment. The change from baseline for each eye at 
each post-baseline assessment is calculated as the IOP at that assessment minus the IOP at the 
corresponding hour at baseline. The primary efficacy endpoint analysis will be evaluated in the study eye.  
The null hypothesis that the mean IOP hour-matching change from baseline is equal to 0 mm Hg will be 
tested and a corresponding 95% confidence interval will be calculated, based on the 1-sample t-test 
procedure at each hour on Days 4 and 14. The primary hypothesis is that at least one dose of AGN-227535 
ophthalmic solution has a statistically significant within-group mean IOP change from baseline at Hour 2 on 
Day 14/Exit in the mITT population.  
In addition, for exploratory purposes, each dose of AGN-227535 is hypothesized to be non-inferior to 
Timolol ophthalmic solution 0.5% with respect to change from baseline (follow-up minus baseline) in study 
eye IOP at each time-matched hour evaluated (hours 0, 2 4, and 8) on Day 4 and Day 14/Exit in the mITT 
population. The non-inferiority analyses will be performed via analysis of covariance (ANCOVA) which will 
have treatment as the main effect and the baseline hour-matched IOP as the covariate in the model. When 
there is no hour-matched baseline value (for example, 30 min post-dose), change from baseline will be 
calculated from baseline hour 0.  
Pairwise treatment group comparisons will be performed for each individual dose of AGN- 227535 versus 
timolol ophthalmic solution 0.5%. A 2-sided 95% confidence interval (CI) for the treatment difference (AGN-
227535 Ophthalmic Solution minus Timolol ophthalmic solution 0.5%) will be constructed based on this 
ANCOVA model for each AGN-227535 dose. 
 If AGN-227535 
ophthalmic solution is determined to be non-inferior to Timolol ophthalmic solution 0.5%, further, an attempt 
to show superiority of AGN-227535 over Timolol will be made.  
 
 
 
9.2 
Secondary, Other and Subgroup Efficacy Endpoint Analyses 
9.2.1 Secondary Efficacy Endpoint Analyses 
The mean IOP values will be analyzed similarly as the mean IOP change from baseline as described in 
section 9.1. That is, summary statistics (N, mean, SD, min and max) of IOP values at each scheduled hour 
of each visit. Also, analyses of IOP values will be performed using an ANCOVA model with treatment as 
main effect and hour-matched baseline IOP as covariate 
9.2.2 Other Efficacy Analyses  
For each visit at Baseline, Day 4 and Day 14, a mean diurnal IOP value will be calculated for each subject 
by taking the average of the IOP value at all hours (0, 2, 4, and 8).  The change from baseline mean diurnal 
IOP value will be analyzed by the ANCOVA model similarly as the primary efficacy endpoint analysis 
(section 9.1).  In addition, the mean diurnal IOP value will be analyzed by the ANCOVA model similarly as 
the secondary efficacy endpoint analysis (section 9.2.1). 
  
9.3 
IOP Analysis of Non-Study Eye 
Summary statistics of IOP values of non-study eyes will be provided by Day and Hour for each treatment 
group. Efficacy analysis (sections 9.1, 9.2.1 and 9.2.2) will also be carried out for non-study eye.   


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9.4 
Interim Analysis 
No interim statistical analysis is planned. 
10  SAFETY ANALYSIS 
Listings will be presented for all of the safety parameters (section 5.4) for Part 1 and 2 of the study, with the 
exception of adverse events, which will be summarized as described below.  For slit-lamp biomicroscope 
and visual acuity parameters, potentially clinically significant findings will be flagged according to pre-
defined criteria in the listings.  
10.1 Safety Endpoint Analysis 
10.1.1 Adverse Events 
All adverse events (AEs) reported during the study will be recorded and coded using MedDRA version 20.1 
terminology. An AE will be considered as treatment-emergent if it has an onset during the treatment period 
or is pre-existing and worsens after the first dose of study medication is administered. Subjects may have 
more than one AE per System Organ Class (SOC) and Preferred Term (PT). At each level of subject 
summarization, a subject will be counted once if they reported one or more events and will be reported with 
the highest severity. In cases where severity or relationship is missing, the most conservative approach will 
be taken (i.e., highest severity and assumed to be related). 
For Part 2 of the study, the number, and percent of subjects with adverse events will be tabulated by PT 
using counts and percentages by treatment groups. This summary will include all treatment emergent 
adverse events (TEAEs) regardless of causality, treatment-related TEAEs, all serious AEs, treatment-
related serious AEs, and all adverse events leading to premature discontinuation of study treatment. A 
separate summary will also be produced for TEAEs by SOC and PT. For Part 1 of the study, no summary 
presentation of adverse events will be carried out.  
Both parts of the study will present a listing of TEAEs by SOC and PT showing adverse events location 
(OD, OS or non-ocular), severity, relationship, discontinuation details, and action taken. Also, listing for 
serious adverse events, and adverse events leading to discontinuation will be generated for both parts of 
the study.   
10.1.2 Electrocardiogram (ECG) 
For Part 1 of the study, baseline ECG parameters (Heart rate, PR Interval, QRS Duration, QT Interval, and 
QTc Interval) along with interpretation whether the subject’s ECG is normal or abnormal will be listed by 
cohort treatment groups.  
For Part 2 of the study, ECG parameters from baseline and post-baseline visits will be listed by cohort 
treatment groups. Change from baseline will also be presented in the listing.  
10.1.3 Biomicroscopy 
Slit-lamp biomicroscopy will be listed for Part 1 and 2 of the study by cohort treatment groups. Parameters 
with positive (no zeros or missing) findings will be presented. At any timepoint, a parameter will be omitted 
if there is no positive finding on either eye. Potentially clinically significant findings will also be flagged on 
the following category: 
 
Hour-matched change from baseline is of ≥2 grade worsening 
The biomicroscopy Case Report Form (CRF) includes multiple categories, each of which includes multiple 
parameters to be evaluated. If the CRF’s leading question “Were there any biomicroscopic findings? 


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(Yes/No)” is answered “No”, then all parameters in all categories are to be treated as zero score or negative 
grade, even though they will show as “missing” in the database. If the CRF’s leading question is answered 
“Yes”, then the leading question of each category “Were there any /category/ findings (Yes/No)?” must be 
answered.  If the category’s leading question is answered “No”, then all parameters in the category are to 
be treated as zero score or negative grade, even though they will show as “missing” in the database. Thus, 
a parameter with a “missing” value in the database will be treated as either zero score or negative grade 
under either of the two conditions below: 
1. When the CRF’s leading question about any biomicroscopic findings is answered “No”. 
2. When the CRF’s leading question about any biomicroscopic findings is answered “Yes” and 
the category’s leading question about any findings is answered “No”.  
10.1.4 Vital Signs 
For Part 1 and 2 of the study, vital signs will be listed by cohort treatment groups, visit, hour and 
measurement position (supine or standing). Change from baseline and change from supine to standing 
will be presented in the listing.  
10.1.5 Best Corrected Visual Acuity (BCVA) 
BCVA will be listed by cohort treatment groups and visit for both Snellen Equivalent and logMar 
measurements under standard lighting condition (both Part 1 and 2) and low luminance condition (Part 2 
only).  Potentially clinically significant findings under the standard lighting condition will be flagged according 
to the following category: 
 
Change from baseline is ≥ 15 letters improvement or worsening (logMar)  
 
10.1.6 Other Safety Analysis  
A number of safety measures, for example: Clinical Laboratory Test, Urine Pregnancy Test, Physical 
Examination, Visual Fields, Macroscopic Hyperemia, Dilated Fundus Examination, Pupil Size, and Subject 
Comfort will only be presented in the listing.  
10.2 Data Monitoring  
No formal Data Monitoring Committee is planned. Between dose-escalation groups in Part 1, all available 
data collected to date will be used to assist in decision making to continue to the next dose or to stop the 
study. All data collected in Part 1 will be used to select 1 or 2 concentrations of AGN-227535 to evaluate in 
Part 2. The decision to proceed or to stop the study will be made by the Medical Monitor, the Head of 
Clinical and the Chief Executive Officer. All decisions will be documented.  If needed, IOP summary data 
as described in Section 9 and data listings or tabulations of non-IOP data for Part 1 will be provided for the 
decision-making purpose.   
11 VALIDATION 
Derived datasets will be independently reprogrammed by a second programmer. The separate datasets 
produced by the two programmers must match 100%. Tables and listings will be independently 
reprogrammed by a second programmer for numeric results. Statisticians will be involved in the process of 
programming and validating tables that include inferential statistical results.  
 
 


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12 GLOSSARY OF ABBREVIATIONS 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutics Chemical 
BCVA 
Best Corrected Visual Acuity 
bpm 
Beats Per Minute 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
IOP 
Intra-ocular Pressure 
IWRS 
Interactive web-response system 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mm Hg 
Millimeters of mercury 
mITT 
Modified Intent-to-Treat 
OD 
Right Eye 
OHT 
Ocular Hypertension 
OS 
Left Eye 
POAG 
Primary Open Angle Glaucoma 
PP 
Per Protocol 
PR 
Pulse Rate 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 
 


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13 VERSION HISTORY 
 
Version 
Date
Details
1.0 
18 Feb 2021
SAP Approval 
2.0 
02 Mar 2021 
 
Section 13 added 
 
Table of Contents 
Refreshed