Clinical trial NCT02558400
Conditions: Open-angle Glaucoma Ocular Hypertension
Sponsor: Aerie Pharmaceuticals
Start date: 2015-09-18; Completion date: 2017-06-30
Enrollment: 718 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate ocular hypotensive efficacy and safety of PG324 Ophthalmic Solution compared to Netarsudil (AR-13324) Ophthalmic Solution and Latanoprost Ophthalmic Solution.

Following completion of the Month 12 study visit procedures, subjects will be offered the opportunity to participate in a 2-month observational (i.e., non-interventional) trial extension.

Detailed description:

Arms: arm 1: Fixed combination of netarsudil 0.02%, latanoprost 0.005% ophthalmic solution arm 2: Netarsudil 0.02% ophthalmic solution arm 3: Latanoprost 0.005% ophthalmic solution
Interventions: intervention 1: PG324 Ophthalmic Solution 0.02%/0.005% intervention 2: Netarsudil (AR-13324) Ophthalmic Solution 0.02% intervention 3: Latanoprost Ophthalmic Solution 0.005%
Intervention descriptions: intervention 1: 1 drop once daily (QD), in the evening (PM) in both eyes (OU) intervention 2: 1 drop once daily (QD), in the evening (PM) in both eyes (OU) intervention 3: 1 drop once daily (QD), in the evening (PM) in both eyes (OU)

Protocol documents:
Prot_000.pdf: 
 
 
 
 A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group 
12-month study assessing the safety and 
ocular hypotensive efficacy of PG324 
Ophthalmic Solution compared to AR-13324 
Ophthalmic Solution, 0.02% and Latanoprost 
Ophthalmic Solution, 0.005% in subjects with 
elevated intraocular pressure  
 
 
 
NCT02558400 
 
 
12June2017 
 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS301, Amendment 4 
Aerie Pharmaceuticals, Inc. 
Confidential 
Page 1 of 123 
Clinical Study Protocol: PG324-CS301 
Study Title: 
A prospective, double-masked, randomized, multi-center, 
active-controlled, parallel-group 12-month study assessing the safety 
and ocular hypotensive efficacy of PG324 Ophthalmic Solution 
compared to AR-13324 Ophthalmic Solution, 0.02% and Latanoprost 
Ophthalmic Solution, 0.005% in subjects with elevated intraocular 
pressure 
Study Number: 
PG324-CS301 
Study Phase: 
3 
Product Name: 
PG324 (AR-13324, 0.02% and latanoprost, 0.005%) Ophthalmic 
Solution 
Indication: 
Reduction of intraocular pressure in subjects with open-angle glaucoma 
or ocular hypertension 
Investigators: 
Multi-center 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Sponsor Contact: 
135 US Highway 206, Suite 15 
Bedminster, NJ 07921 
(908) 470-4320 
Medical Monitor: Richard A. Lewis, M.D. 
Date 
Original Protocol (Rev 0): 
10 June 2015 
Amendment 1 (Rev 1): 
24 June 2015 
Amendment 2 (Rev 2): 
Amendment 3 (Rev 3): 
Amendment 4 (Rev 4): 
12 April 2016 
05 January 2017 
12 June 2017 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals®, Inc.’s (Aerie) information that is 
confidential, a trade secret and/or proprietary in nature.  It is loaned to you for your 
confidential use on behalf of Aerie and is not to be photocopied, disclosed or transmitted to 
any other person or party who is not covered by a Confidential Disclosure Agreement with 
Aerie.  As the Principal Investigator you are responsible for the safekeeping and return of this 
document to Aerie upon request.  You will be sent updated information and/or amendments 
as they become available. 






















































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4.
Known hypersensitivity to any component of the formulation, to latanoprost, or to topical anesthetic
5.
Previous glaucoma intraocular surgery, including SLT or ALT in either eye
6.
Refractive surgery in either eye (eg, radial keratotomy, PRK, LASIK, corneal cross-linking, etc.)
7.
Ocular trauma within the six months prior to screening, or ocular surgery or non-refractive laser treatment
within the three months prior to screening
8.
Recent or current evidence of ocular infection or inflammation in either eye.  Current evidence of clinically
significant blepharitis, keratitis, or conjunctivitis.  Additionally, current evidence or history of herpes
simplex or zoster keratitis in either eye at screening is excluded.
9.
Used ocular medication in either eye of any kind within 30 days of screening and throughout the study,
with the exception of a) ocular hypotensive medications (which must be washed out according to the
provided schedule), b) lid scrubs (which may be used prior to, but not after screening), c) lubricating drops
for dry eye (which may be used throughout the study), or d) non-corticosteroid or non-vasoconstrictor
containing allergy drops and allergy drops that do not have a redness reliever effect as prescribed by the
Investigator
10. Mean central corneal thickness greater than 620 μm at screening
11. Any abnormality preventing reliable applanation tonometry of either eye (eg, keratoconus, etc.)
Systemic:
12. Clinically significant abnormalities in laboratory tests at screening
13. Clinically significant systemic disease (eg, uncontrolled diabetes, myasthenia gravis, hepatic, renal,
endocrine or cardiovascular disorders) which might interfere with the study
14. Participation in any investigational study within 60 days prior to screening
15. Systemic medication that could have a substantial effect on IOP within 30 days prior to screening, or
anticipated during the study, including any corticosteroid-containing drug regardless of route of
administration.
16. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a
medically acceptable form of birth control.  An adult woman is considered to be of childbearing potential
unless she is one year post-menopausal or three months post-surgical sterilization.  All females of
childbearing potential must have a negative urine pregnancy test result at the screening examination and
must not intend to become pregnant during the study.
Study Population: 
A total of approximately 690 subjects will be enrolled in this study at approximately 60 clinical sites, 
comprising a total of approximately 230 subjects per treatment arm for each of 3 treatment arms.  Subjects who 
are enrolled in this study will be those at least 18 years of age with diagnosed open angle glaucoma (OAG) or 
ocular hypertension (OHT), each of whom meets all inclusion criteria and none of the exclusion criteria. 
Investigational Products, Dose, and Mode of Administration: 
•
PG324 Ophthalmic Solution, 1 drop QD (PM), OU
•
AR-13324 Ophthalmic Solution, 0.02%, 1 drop QD (PM), OU
•
Latanoprost Ophthalmic Solution, 0.005%, 1 drop QD (PM), OU
Duration of Treatment:  Subjects will dose for approximately 365 days 
Efficacy Assessments:  
The primary efficacy variable will be: 
•
IOP measurements at 8:00, 10:00, and 16:00 hours at Week 2 (Day 15), Week 6 (Day 43), and Month 3
(Day 90) by Goldmann Applanation Tonometry
The primary efficacy outcome will be the comparison of PG324 Ophthalmic Solution relative to each of its 
active components, AR-13324, 0.02% and latanoprost, 0.005%, for: 






PG324 Ophthalmic Solution 
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TABLE OF CONTENTS 
SYNOPSIS ........................................................................................................................26 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................35 
1. 
INTRODUCTION ....................................................................................................37 
1.1 
Investigational Product .......................................................................................37 
1.2 
Findings from Nonclinical and Clinical Studies ................................................38 
1.3 
Risks and Benefits to Human Subjects ..............................................................38 
2. 
STUDY OBJECTIVES ............................................................................................38 
2.1 
Primary Objectives ..............................................................................................38 
2.2 
Secondary Objectives...........................................................................................39 
3. 
INVESTIGATIONAL PLAN ..................................................................................39 
3.1 
Overall Study Design and Plan ...........................................................................39 
3.2 
Rationale for Study Design and Control Group ...............................................41 
3.3 
Expected Duration of Subject Participation......................................................41 
4. 
STUDY POPULATION SELECTION ...................................................................41 
4.1 
Study Population ..................................................................................................41 
4.2 
Inclusion Criteria .................................................................................................41 
4.3 
Exclusion Criteria ................................................................................................42 
4.4 
Subject Enrollment ..............................................................................................44 
5. 
STUDY TREATMENTS ..........................................................................................44 
5.1 
Description of Treatments ...................................................................................44 
5.1.1 
Investigational Product .................................................................................44 
5.1.2 
Comparator Products ....................................................................................44 
5.2 
Treatments Administered ...................................................................................44 
5.3 
Selection and Timing of Dose for Each Subject ................................................45 
5.4 
Method of Assigning Subjects to Treatment Groups .......................................45 
5.5 
Masking .................................................................................................................45 
5.6 
Concomitant Therapy ..........................................................................................46 
5.7 
Restrictions ...........................................................................................................47 
5.7.1 
Prior Therapy .................................................................................................47 
5.7.2 
Fluid and Food Intake ...................................................................................47 
5.7.3 
Subject Activity Restrictions .........................................................................48 
5.8 
Treatment Compliance ........................................................................................48 
5.9 
Packaging and Labeling ......................................................................................48 
5.10 
Storage and Accountability .................................................................................49 
5.11 
Investigational Product Accountability at Study Site.......................................49 
5.11.1 
Receipt and Disposition of Study Medication .............................................49 
5.11.2 
Return of Study Medication ..........................................................................49 
6. 
STUDY PROCEDURES ..........................................................................................50 
6.1 
Informed Consent ................................................................................................50 
6.2 
Demographics and Medical History ...................................................................50 
6.3 
Dispensing Investigational Product ....................................................................50 
6.4 
Appropriateness of Measurements .....................................................................51 


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6.5 
Efficacy Assessments ...........................................................................................51 
6.5.1 
Specification of the Efficacy Parameters .....................................................51 
6.5.2 
Method and Timing for Assessing Efficacy Parameters ............................52 
6.6 
Assessment of Safety ............................................................................................52 
6.7 
Vital Signs .............................................................................................................53 
6.7.1 
Heart Rate.......................................................................................................53 
6.7.2 
Blood Pressure ................................................................................................53 
6.8 
Clinical Laboratory Tests....................................................................................53 
6.8.1 
Laboratory Parameters .................................................................................53 
6.8.2 
Pregnancy Testing ..........................................................................................53 
6.9 
Adverse Event Assessments and Ocular Safety ................................................53 
6.9.1 
Performing Adverse Events Assessments ....................................................53 
6.9.2 
Adverse Event Definitions .............................................................................54 
6.9.3 
Timing for Reporting of Adverse Events .....................................................55 
6.9.4 
Severity............................................................................................................56 
6.9.5 
Relationship ....................................................................................................57 
6.9.6 
Expectedness ...................................................................................................57 
6.9.7 
Clinical Significance.......................................................................................58 
6.9.8 
Clinical Laboratory Adverse Events ............................................................58 
6.9.9 
Serious Adverse Events (SAEs) or Serious Suspected Adverse 
Reactions .........................................................................................................58 
6.9.9.1 
Reporting Serious Adverse Events .........................................................58 
6.9.10 
Serious Unexpected Suspected Adverse Reactions (SUSARs) ...................59 
6.9.10.1 
Reporting Serious Unexpected Suspected Adverse Reactions .............59 
6.9.11 
Follow-up of Subjects after Adverse Events ................................................60 
6.10 
Comfort Test.........................................................................................................60 
6.11 
Best Corrected Visual Acuity (BCVA) ...............................................................60 
6.12 
Pupil Size...............................................................................................................60 
6.13 
Biomicroscopy ......................................................................................................60 
6.14 
Gonioscopy/Pachymetry ......................................................................................60 
6.15 
Visual Field Testing .............................................................................................61 
6.16 
Dilated Ophthalmoscopy .....................................................................................61 
6.17 
Removal of Subjects from the Study or Investigational Product ....................61 
6.17.1 
Completed subject ..........................................................................................61 
6.17.2 
Non-completing subject .................................................................................61 
6.17.3 
Actions after Discontinuation .......................................................................62 
6.17.4 
Discontinuation of the Entire Study .............................................................62 
6.17.5 
Completed study.............................................................................................62 
7. 
STUDY ACTIVITIES ..............................................................................................63 
7.1 
Study Visits ...........................................................................................................63 
7.1.1 
Visit 1 (Screening Visit) .................................................................................63 
7.1.1.1 
Evaluation of eye-drop instillation performance ..................................63 
7.1.1.2 
Washout ....................................................................................................64 
7.1.2 
Visit 2 (Qualifying Visit #1, for 08:00 hours IOP measurement) ..............64 
7.1.3 
Visit 3.0 (Qualifying Visit #2 [Day 1] for IOP measurement at 08:00 
hours) ..............................................................................................................65 




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9.5 
Procedure for Accounting for Missing, Unused, or Spurious Data ................86 
9.6 
Procedure for Reporting Deviations from the Statistical Plan ........................86 
9.7 
Data Listings .........................................................................................................86 
10. ADMINISTRATIVE CONSIDERATIONS ...........................................................86 
10.1 
GCP compliance ...................................................................................................86 
10.2 
Amendments to the Protocol ...............................................................................87 
10.3 
Investigators and Study Administrative Structure ...........................................87 
10.4 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval.....................................................................................................87 
10.5 
Ethical Conduct of the Study ..............................................................................88 
10.6 
Subject Information and Consent ......................................................................88 
10.7 
Subject Confidentiality ........................................................................................88 
10.8 
Study Monitoring .................................................................................................89 
10.9 
Case Report Forms and Study Records .............................................................90 
10.10 Protocol Deviations ..............................................................................................91 
10.11 Access to Source Documentation ........................................................................91 
10.12 Data Generation and Analysis ............................................................................92 
10.13 Retention of Data .................................................................................................92 
10.14 Financial Disclosure .............................................................................................92 
10.15 Publication and Disclosure Policy ......................................................................92 
11. REFERENCES .........................................................................................................94 
11.1 
Published References ...........................................................................................94 
11.2 
Internal References ..............................................................................................95 
 
LIST OF TABLES 
Table 1 
Ocular Hypotensive Medication Washout Period ................................47 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Visits and Examinations .....................................................96 
 
 
Appendix 3 
Marketed Product Information: Latanoprost Ophthalmic Solution, 
0.005%.....................................................................................................105 
Appendix 4 
Sponsor’s Obligations ............................................................................115 
Appendix 5 
Investigator’s Obligations .....................................................................116 
Appendix 6 
Declaration of Helsinki ..........................................................................119 
Appendix 7 
Sample SAS Code ...................................................................................122 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Argon laser trabeculoplasty 
BCVA 
Best corrected visual acuity 
BOCF 
Baseline observation carried forward 
BP 
Blood Pressure 
C 
Centigrade 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CRO 
Contract research organization 
CV 
Curriculum vitae 
DHHS 
Department of Health and Human Services 
EDC 
Electronic data capture 
eCRF 
electronic case report form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
F 
Fahrenheit 
FAX 
Facsimile communication 
FDA 
Food and Drug Administration  
FDC 
Fixed dose combination 
FP 
Prostaglandin F2α 
GCP 
Good clinical practice 
hCG 
human chorionic gonadotropin 
hr 
Hour 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web-based response system 
kg 
Kilogram 
L 
Liter 
LASIK 
Laser-assisted in-situ keratomileusis 


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LOCF 
Last observation carried forward 
logMAR 
Logarithm of the minimum angle resolvable 
M.D. 
Medical doctor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters Mercury 
mOsmol 
milliOsmoles 
OAG 
Open angle glaucoma 
OHT 
Ocular hypertension 
OTC 
Over-the-counter 
OU 
Both eyes 
pH 
−log10 [hydrogen ion concentration in moles/liter] 
PM 
Post meridian (ie, after noon) 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
PT 
Preferred term 
QD 
Once daily 
ROCK 
Rho kinase 
Rx 
Prescription 
SAE 
Serious Adverse Event 
SITA 
Swedish interactive threshold algorithm 
SLT 
Selective laser trabeculoplasty 
SOC 
System/Organ/Class 
SSAR 
Serious Suspected Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
US 
United States 
 
 
 
 












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1. Must be 18 years of age or older 
2. Diagnosis of open angle glaucoma (OAG) or ocular hypertension (OHT) in both eyes 
(OAG in one eye and OHT in the fellow eye is acceptable) 
3. Unmedicated (post-washout) IOP > 20 mmHg and < 36 mmHg in both eyes at 2 
qualification visits at 08:00 hour, 2-7 days apart.  At the second qualification visit, have 
IOP > 17 mmHg and < 36 mmHg in both eyes at 10:00 and 16:00 hours.  Both eyes must 
qualify at all qualification visit time points.  Note: For purposes of determining 
eligibility of subjects to be enrolled, any non-integral mean IOP number should not 
be rounded.    
4. Best corrected visual acuity +1.0 logMAR or better by ETDRS in each eye 
(equivalent to 20/200 or better Snellen visual acuity in each eye) 
5. Be able and willing to give signed informed consent and follow study instructions 
4.3 
Exclusion Criteria 
Individuals with the following characteristics will be excluded from the study: 
Ophthalmic: 
1. Clinically significant ocular disease (eg corneal edema, uveitis, severe 
keratoconjunctivitis sicca) which might interfere with interpretation of the study 
efficacy endpoints or with safety assessments, including subjects with glaucomatous 
damage so severe that washout of ocular hypotensive medications (if needed) for up 
to 1 month is not judged safe as it would put the subject at risk for further vision loss  
2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle 
closure glaucoma, or narrow angles (i.e., Grade 2 or less [Shaffer scale]; extreme 
narrow angle with complete or partial closure). Note: Previous laser peripheral 
iridotomy is NOT acceptable 
3. Intraocular pressure ≥ 36 mmHg (unmedicated) in either eyes at any time point 
(individuals who are excluded for this criterion are not allowed to attempt 
requalification), or use of more than two ocular hypotensive medications within 
30 days of screening.  Note: fixed dose combination medications, for the purpose of 
this exclusion criterion, count as one medication 
4. Known hypersensitivity to any component of the formulation, to latanoprost, or to 
topical anesthetic 
5. Previous glaucoma intraocular surgery, including SLT or ALT in either eye  
6. Refractive surgery in either eye (eg, radial keratotomy, PRK, LASIK, corneal 
cross-linking, etc.) 


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7. Ocular trauma in either eye within the six months prior to screening, or ocular surgery 
or non-refractive laser treatment within the three months prior to screening 
8. Recent or current evidence of ocular infection or inflammation in either eye.  
Current evidence of clinically significant blepharitis, keratitis or conjunctivitis.  
Additionally, current evidence or history of herpes simplex or zoster keratitis in 
either eye at screening is excluded.  
9. Used ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications 
(which must be washed out according to the provided schedule), b) lid scrubs 
(which may be used prior to, but not after screening), c) lubricating drops for dry eye 
(which may be used throughout the study), or d) non-corticosteroid or non-
vasoconstrictor-containing allergy drops and allergy drops that do not have a redness 
reliever effect as prescribed by the Investigator 
10. Mean central corneal thickness greater than 620 μm in either eye at screening 
11. Any abnormality preventing reliable applanation tonometry of either eye 
(eg, keratoconus, etc.) 
 
Systemic: 
12. Clinically significant abnormalities in laboratory tests at screening 
13. Clinically significant systemic disease (eg, uncontrolled diabetes, myasthenia gravis, 
hepatic, renal, endocrine or cardiovascular disorders) which might interfere with the 
study 
14. Participation in any investigational study within 60 days prior to screening  
15. Systemic medication that could have a substantial effect on IOP within 30 days prior 
to screening, or anticipated during the study, including any corticosteroid-containing 
drug regardless of route of administration. 
16. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or 
not using a medically acceptable form of birth control.  An adult woman is considered 
to be of childbearing potential unless she is one year post-menopausal or three 
months post-surgical sterilization.  All females of childbearing potential must have a 
negative urine pregnancy test result at the screening examination and must not intend 
to become pregnant during the study. 


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4.4 
Subject Enrollment 
Enrollment numbers are higher in this study (230 subjects per arm) than statistically required 
for demonstrating efficacy at 90% power, accounting for an estimated 15% discontinuation 
rate over the course of the first 3 months of the study.  
5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Investigational Product 
• PG324 Ophthalmic Solution is a sterile, isotonic, buffered aqueous solution 
containing AR-13324 (0.02%), latanoprost (0.005%), boric acid, mannitol, water for 
injection, and preserved with benzalkonium chloride (0.02%).  The product 
formulation is adjusted to approximately pH 5.  
5.1.2 
Comparator Products 
• Latanoprost Ophthalmic Solution, 0.005% is a sterile, isotonic, buffered aqueous 
solution of latanoprost with a pH of approximately 6.7 and an osmolality of 
approximately 267 mOsmol/kg. Each mL of Latanoprost Ophthalmic Solution, 
0.005% contains 50 micrograms of latanoprost.  Benzalkonium chloride, 0.02% is 
added as a preservative. The inactive ingredients are sodium chloride, sodium 
dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and 
water for injection. 
• AR-13324 Ophthalmic Solution is a sterile, isotonic, buffered aqueous solution 
containing AR-13324 (0.02%), boric acid, mannitol, water for injection, and 
preserved with benzalkonium chloride (0.015%).  The product formulation is adjusted 
to approximately pH 5. 
5.2 
Treatments Administered  
There will be 3 treatments in this study:  
• PG324 (AR-13324, 0.02% and latanoprost, 0.005%) Ophthalmic Solution  
• AR-13324 Ophthalmic Solution, 0.02% 
• Latanoprost Ophthalmic Solution, 0.005%  
Subjects will be assigned according to a computer-generated randomization list in a 1:1:1 
ratio to PG324 Ophthalmic Solution, AR-13324 Ophthalmic Solution, 0.02%, or Latanoprost 
Ophthalmic Solution, 0.005% (stratified by investigative site and by maximum baseline IOP 
[< 25 mmHg vs ≥ 25 mmHg]).  Subjects will instill 1 drop of study drug into each eye, one 
time per day in the evening, at approximately 24 hour intervals; all treatments will be OU.  
Doses will be self-administered by the study subjects.  For subjects deemed unable to 


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self-administer the doses, a caregiver will be asked to administer the medication. All subjects 
will administer study treatment for approximately 365 days. 
5.3 
Selection and Timing of Dose for Each Subject 
The dose of PG324 selected for this study is based upon the positive outcomes seen for 
PG324 in the PG324-CS201 clinical study.  Each investigational product is being dosed 
QD OU (in the evening between 20:00 and 22:00 hours) in this study to allow for estimated 
peak and trough levels of both AR-13324 and latanoprost to be present in ocular tissue at the 
observation times selected in the clinic for the following morning and the subsequent 
afternoon.  The treatment period is selected on the basis of nonclinical safety studies and 
regulatory requirements for pivotal studies of ophthalmic glaucoma medications.  
5.4 
Method of Assigning Subjects to Treatment Groups 
A randomization code for allocating the treatments will be prepared by an independent 
biostatistician who is not involved in the day-to-day conduct of the study.  Subjects will be 
randomized using an IWRS in a 1:1:1 ratio to receive PG324 Ophthalmic Solution, 
AR-13324 Ophthalmic Solution, 0.02%, or Latanoprost Ophthalmic Solution, 0.005%.   
5.5 
Masking 
An independent person at the site not responsible for performing any of the study procedures 
is assigned to dispense, collect, and store investigational product while maintaining the 
masking of the study. 
Study related site personnel will be cautioned that any used or unused subject kits are not to 
be opened at the clinical site by the site staff involved in efficacy or safety measurements.   
Treatment assignments will be masked to the Investigator, the clinical study team 
(Sponsor, personnel involved in day to day study management, Data Managers, and 
Statisticians), and the subjects prior to all subjects completing 3 months of treatment.  
Treatment assignment(s) will be unmasked and made available to the Investigator and the 
Sponsor’s Medical Monitor during this period only in case of medical emergency or 
occurrence of adverse events that in the opinion of the investigator warrant unmasking.  
In the absence of medical need, the randomization code/treatment assignment(s) will not be 
available to the above study personnel until after the study is completed and the database is 
locked.  
If the Investigator feels it is necessary to unmask a subject’s treatment assignment after an 
emergency situation, the Investigator should promptly contact the Sponsor’s Medical 
Monitor or designee.  A decision will be made as to whether or not the treatment for the 
subject should be unmasked, preferably after consultation with the Sponsor’s Medical 
Monitor or designee.  The treatment assignment will be revealed on a subject-by-subject 
basis, thus leaving the masking on remaining subjects intact.   


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In an emergency situation in which treatment of an adverse event requires immediate 
unmasking, and the Investigator is unable to promptly contact the Sponsor’s Medical 
Monitor, the Investigator may unmask the treatment.  The masked portion of the kit label 
may be revealed for the treatment assignment.  In the case of such unmasking in an 
emergency situation, the Investigator should contact the Sponsor immediately thereafter and 
document the unmasking in writing, recording the date, time, and reason for unmasking the 
study drug treatment in the source documentation.  Individual unmasking by the Investigator 
will normally result in withdrawal of the subject from the study and should only be 
performed for the specific subject requiring unmasking in their treatment group.   
5.6 
Concomitant Therapy 
Intermittent use of over-the-counter (OTC) artificial tear lubricant products is acceptable, 
with a minimum of 10 minutes between use of OTC products and study medication.  
However, concurrent therapy with any form of ocular hypotensive medications 
(prescription or over-the-counter) is not allowed during the study.  Subjects who are not 
taking any concomitant disallowed ocular medication or who do not require washout of 
ocular hypotensive medication can return as soon as clinical chemistry and hematology 
results are received for Qualification Visit #1 (see Section 7.1.2 of this protocol for more 
details). 
Disallowed concomitant ocular medications for enrolled subjects include: 
• Miotics  
• Epinephrine-related compounds  
• Carbonic anhydrase inhibitors (ocular or systemic)  
• α-adrenoceptor agonists  
• β- adrenoceptor antagonists 
• Muscarinic agonists (eg, pilocarpine)  
• Prostaglandin analogues other than that contained in the provided investigational 
product 
Systemic therapy with agents that could have an effect on IOP is to be consistent in dose, 
regimen and agent within the 30 days prior to screening and throughout the study, except for 
corticosteroid-containing drugs.  For example, a subject can be treated with a systemic β-
adrenoceptor antagonist as long as the particular agent and its dose and regimen had been 
consistent for the 30 days prior to screening, and there is no reason to believe that alteration 
would be necessary at some point later during the study.  Subjects should be cautioned to 
avoid use of alcohol or the use of drugs such as marijuana during the study visit days.   


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Any corticosteroid-containing systemic drug is disallowed during the study regardless of 
route of administration.    
Contact lens wear during the study is acceptable.  However, subjects must remove their 
contact lenses at least 30 minutes before instillation of study medication, and not place them 
in their eye(s) until 30 minutes after instillation.   
Use of all medications should be documented on the appropriate CRF.  Investigators are 
encouraged to contact the Sponsor for any questions regarding allowed medications.  
Judgment of continued study participation by the subject, and inclusion of this subject’s 
subsequent visits in the safety and efficacy analysis will be made by the Sponsor.   
All medications which the subject has taken within 30 days prior to screening and during the 
study will be recorded in the CRF.  The name of the drug, dose, route of administration, 
duration of treatment and indication will be recorded for each medication.  For combination 
products (eg, Contac®), the brand name is required.  For non-combination products, the 
generic name is desired.  The use of routine ophthalmic diagnostic pharmaceutical agents 
(eg, fluorescein and local anesthetic) will be allowed, and individual documentation not 
required.  Any change in dosing parameters should also be recorded in the CRF.   
5.7 
Restrictions 
5.7.1 
Prior Therapy 
Individuals currently using ocular hypotensive medications must undergo a minimum 
washout period as specified in Table 1.  If washout is to be extended beyond 6 weeks 
(42 days) for logistical or other reasons, the Sponsor should be contacted.  If subjects need to 
washout of a hypotensive medication, they are not allowed to use a washout medication of 
shorter required washout time (including Azopt) than for the original hypotensive 
medication. 
Table 1 
Ocular Hypotensive Medication Washout Period 
Medication class 
Minimum washout 
period 
Prostaglandins 
4 weeks 
β-adrenoceptor antagonists 
4 weeks 
Adrenergic agonists (including α-agonists such as brimonidine 
and apraclonidine) 
2 weeks 
Muscarinic agonists (eg, pilocarpine), Carbonic anhydrase 
inhibitors (topical or oral) 
5 days 
Hughes 2005 
5.7.2 
Fluid and Food Intake 
There are no general restrictions on fluid or food intake for subjects participating in this 
study.  




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Ophthalmic Solution, 0.005% will be removed and replaced with an investigational label 
which will be similar in appearance for all treatment groups.   
Upon dispensing of a clinical trial material packer or kit to a subject, a portion of the kit label 
will be affixed to the designated study drug kit label log which will be part of the study files 
at the individual study site for this study. 
5.10 
Storage and Accountability  
The investigational products should be stored refrigerated (2°C to 8°C/36°F to 46°F) until 
provided to the subject.  The subject should be instructed that, once an investigational 
product bottle is opened, the product may be kept refrigerated or at room temperature 
(up to 25°C/77°F) while continuing to store the bottle in the carton.  Do not freeze the 
product and protect from light.  Prior to dispensing to the subject, all investigational material 
must be stored in a secure location at the recommended long-term storage condition 
(2°C to 8°C) with strictly limited access documented by signature of authorized persons who 
may dispense investigational product. Temporary temperature excursions up to 30°C are 
permissible. 
5.11 
Investigational Product Accountability at Study Site   
5.11.1 
Receipt and Disposition of Study Medication 
Investigational product will be shipped to the Investigator’s site from a central depot.  
A study staff member at the Investigator’s site who is not involved in conducting any 
efficacy or safety procedures will verify study medication shipment records by comparing the 
shipping documentation accompanying the study medication to the study medication actually 
received at the Investigator’s site.  If a discrepancy is noted, the appropriate individual at the 
Sponsor or designee must be notified immediately.  The responsible person for dispensing 
study medication at the Investigator’s institution is the only site staff member that can 
distribute investigational product and also has sole responsibility to account for all returned 
used, partially used and unused bottles and kits of investigational products.  The 
investigational product(s) must not be used outside this protocol.  A Drug Accountability Log 
will be kept at the clinical site.  
5.11.2 
Return of Study Medication 
When the study is completed or is terminated by the Sponsor, all study material including 
used and unused study medication kits will be returned to the Sponsor or their designee.  
All study medication accounting procedures must be completed before the study is 
considered to be concluded.  The responsible person at the Investigator’s institution has the 
sole responsibility to account for all used, partially used and unused bottles of investigational 
products.  This site staff member at the Investigator’s institution will complete a study drug 
returns form or equivalent that will be signed by the Investigator or designee prior to 
returning the used and unused study medication kits and bottles to the Sponsor or their 
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Study staff responsible for dispensing investigational product will be listed on the Delegation 
of Responsibilities log.  When a subject meets all criteria for selection and has completed all 
screening assessments, the subject will be assigned to a treatment according to the interactive 
web-based response system (IWRS).  The responsible study staff will account for all used 
and unused investigation product packers and their kit contents by maintaining an 
investigational product accountability log.   
6.4 
Appropriateness of Measurements 
The ophthalmic and systemic measures used in this study are consistent with standard of 
care.  In particular, intraocular pressure (IOP) as measured by Goldmann applanation 
tonometry, the primary efficacy assessment in this study, is accepted worldwide as a standard 
for testing of pharmacologically active agents intended to reduce IOP. 
6.5 
Efficacy Assessments 
6.5.1 
Specification of the Efficacy Parameters  
The primary efficacy outcome will be the comparison of PG324 Ophthalmic Solution relative 
to each of its active components, AR-13324, 0.02% and latanoprost, 0.005%, for the mean 
IOP within a treatment group at 08:00, 10:00, and 16:00 hrs at the Week 2, Week 6, and 
Month 3 study visits.  A description of the method for measuring IOP to be used in this study 
is contained in Appendix 2.  Study visits at Month 6, Month 9, and Month 12 will focus 
primarily on safety and will include measurement of IOP at 08:00, 10:00 and 16:00 hrs. 
Secondary efficacy outcomes will include a summary of the following comparisons of 
PG324 Ophthalmic Solution relative to each of its active components (AR-13324, 0.02% and 
latanoprost, 0.005%) for: 
• Mean IOP within a treatment group at each post-treatment time point  
• Mean diurnal IOP within a treatment group at each post-treatment visit 
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point  
• Mean change from baseline in diurnal IOP at each post-treatment visit  
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment 
time point 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit  
• Percentages of subjects achieving pre-specified mean, mean change, and percent 
mean change diurnal IOP levels  
Other secondary efficacy analyses will be carried out as described in the study Statistical 
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All treatment-emergent adverse events occurring during the study, regardless of the 
assumption of causal relationship, must be documented on the respective CRF.  
Adverse events should be documented from the time the subject receives the first dose of 
Investigational Product until the subject’s participation in the study has been completed.  
If a subject has an ongoing adverse event at the time of study completion, the ongoing 
adverse event must be followed-up and provided appropriate medical care until the event has 
resolved or stabilized.   
Documentation of adverse events/adverse reactions includes start date and stop date, severity, 
action(s) taken, seriousness and outcome.   
6.9.2 
Adverse Event Definitions 
The following definitions of terms apply to this section: 
• Adverse event: any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.   
• Life-threatening adverse event or life-threatening suspected adverse reaction: an 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the Investigator or Sponsor, its occurrence places the subject or subject 
at immediate risk of death.  It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.   
• Serious adverse event (SAE) or serious suspected adverse reaction (SSAR):  an 
adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes: Death, 
a life-threatening or sight-threatening adverse event, in subject hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in subject hospitalization, or the development of drug 
dependency or drug abuse. 
• Suspected adverse reaction: any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.   


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• Unexpected adverse event or unexpected suspected adverse reaction:  an adverse 
event or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in 
the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or, if an Investigator’s Brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the 
Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigator’s Brochure listed only cerebral 
vascular accidents.  “Unexpected,” as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the Investigator’s 
Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Note: Any medical condition present prior to administration of the masked study medication 
which remains unchanged or improved should not be recorded as an adverse event at 
subsequent visits. 
Note: If an event occurs during the washout period, prior to subject enrollment and the 
commencement of study medication, it should be recorded as part of the Medical History and 
not as an adverse event.  As noted in Section 7.1.2, any change in their Visit 1 (screening) 
health status should be recorded on the Medical History page of the CRF (eg, the subject has 
been diagnosed with cancer). 
Note: In the present study, Investigators are asked to use the verbatim term “conjunctival 
hyperemia” on the study AE form to describe observations of conjunctival redness if the 
ocular redness observation is increased from Visit 1 (Screening) observations.  Investigators 
are also asked to note all observations of conjunctival hyperemia on the biomicroscopy CRF 
as well as on the study AE form. 
6.9.3 
Timing for Reporting of Adverse Events 
The AEs occurring during the study must be documented, regardless of the assumption of a 
causal relationship.  AEs should be documented from the time the subject receives the first 
dose of investigational product until subject participation in the study has been completed.  
If a subject has one or more ongoing AEs at the time of study completion, the subject must 
be followed and provided appropriate medical care until the sign(s) and/or symptoms(s) of 
the AE have remitted or stabilized in the opinion of the Investigator. 
When recording an AE, the following information should be provided on the study AE CRF: 
1. Action Taken with Study Drug:  
• None 


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• Investigational Product Discontinued 
• Investigational Product Interrupted 
2. Other Action Taken:  
• None 
• Non-Drug Therapy 
• New OTC or Rx Drug Added 
• Hospitalized less than 24 hours 
• Hospitalized greater than or equal to 24 hours 
3. Outcome of an adverse event is to be coded as: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/Lost to follow-up 
6.9.4 
Severity 
Severity of an adverse event is defined as a qualitative assessment of the level of discomfort 
or the degree of intensity of an adverse event as determined by the Investigator or reported to 
him/her by the subject.  The assessment of severity is made irrespective of study medication 
relationship or seriousness of the event and should be evaluated according to the following 
scale: 
• 1 = Mild: present and noticeable, but not distressing, and no disruption of normal 
daily activities 
• 2 = Moderate:  bothersome, discomfort sufficient to possibly reduce or affect normal 
daily activity 
• 3 = Severe: incapacitating, with inability to work or perform normal daily activity 


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A change in severity for a reported AE will require a stop date for the previous severity and a 
new start and stop date for the new severity.  For example, a change in severity may go from 
mild to severe, or from severe to moderate.  In either case, the start and stop dates should be 
recorded.   
Please note: a severe AE is not the same as a serious AE.  Seriousness of an AE (NOT 
severity) serves as a guide for defining regulatory reporting obligations (see Section 6.9.9 for 
further information on serious AEs [SAEs]). 
6.9.5 
Relationship 
The study medication relationship for each adverse event/adverse reaction should be 
determined by the Investigator using these explanations: 
•
Not Related: The event is clearly related to other factors such as subject’s clinical
condition, therapeutic interventions, concomitant disease or therapy administered to
the subject and does not follow a known response pattern to the product.
•
Unlikely Related: The event is most probably caused by other etiologies such as
participant’s underlying condition, therapeutic intervention, or concomitant therapy;
or the delay between administration and the onset of the AE is incompatible with a
causal relationship. Therefore, there is not a reasonable possibility that the AE was
caused by the study medication.
•
Possibly Related:  The event follows a reasonable, temporal sequence from the time
of study medication administration and/or follows a known response pattern to the
study medication, but could have been produced by other factors such as the subject’s
clinical state, therapeutic interventions or concomitant therapy administered to the
subject.
•
Related:  The event follows a reasonable, temporal sequence from the time of study
medication administration and/or follows a known response pattern to the study
medication and cannot be reasonably explained by other factors such as subject’s
clinical state, therapeutic interventions or concomitant therapy administered to the
subject, and either occurs immediately following study medication administration, or
improves on stopping the study medication, or reappears on repeat exposure, or there
is a positive reaction at the application site.
6.9.6 
Expectedness 
For AR-13324, the most frequently reported AE in 3 Phase 2 studies (AR-13324-CS201, 
AR-13324-CS202, and PG324-CS201) has been conjunctival hyperemia.  Other AEs seen in 
greater frequency with AR-13324 than in active control treatment arms in these studies 
include instillation site erythema or pain, conjunctival hemorrhage, blurred vision, eye 
irritation, increased lacrimation, and foreign body sensation. 


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The most common AEs seen with Latanoprost Ophthalmic Solution, 0.005% in clinical trials 
as reported in the latanoprost prescribing information (Appendix 3) include conjunctival 
hyperemia, eyelash changes, increased iris pigmentation, eyelid skin darkening, macular 
edema (including cystoid macular edema), and intraocular inflammation (iritis/uveitis). 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with this class of 
drugs or as anticipated from the pharmacological properties of AR-13324 or latanoprost, and 
are not specifically mentioned as occurring with the investigational product.  The AEs that 
are both unexpected and serious should be reported in an expedited fashion to the Sponsor 
(see Section 6.9.10 for further details). 
6.9.7 
Clinical Significance 
Determination of whether a finding is clinically significant will be made by the Principal 
Investigator or the Sub-Investigator and will be documented on the CRF. 
6.9.8 
Clinical Laboratory Adverse Events 
Clinical laboratory values (other than pregnancy tests results) that are noted as abnormal and 
clinically significant at study exit and that are changes from Visit 1 (screening) values will be 
documented as AEs. 
6.9.9 
Serious Adverse Events (SAEs) or Serious Suspected Adverse Reactions  
6.9.9.1 
Reporting Serious Adverse Events 
An investigator must immediately report any SAE or SSAR (see Section 6.9.2 for 
definitions) to the Sponsor or Rho Product Safety, the Sponsor CRO representative, whether 
or not the SAE or SSAR is considered drug-related, including those listed in the protocol or 
Investigator’s Brochure.  The investigator report must include an assessment of whether there 
is a reasonable possibility that the drug caused the event.  The Investigator must report any 
SAE or SSAR that occurs during the study for a subject or any SAE or SSAR that occurs 
within 4 weeks (ie, 30 days) after the last administration of IP. Study endpoints that are 
serious adverse events (eg, all-cause mortality) must be reported in accordance with the 
protocol unless there is evidence suggesting a causal relationship between the drug and the 
event (eg, death from anaphylaxis).  In that case, the Investigator must immediately report 
the event to the Sponsor.  The investigator must record non-serious adverse events and report 
them to the Sponsor according to the timetable for reporting specified in the protocol.  In 
case of incomplete information, the Investigator must provide follow-up information as soon 
as possible, again using the SAE report form.   
In addition, in the case of immediately life-threatening AEs or AEs with fatal outcome, or 
adverse events that are serious, unexpected (ie, not in the Investigator’s Brochure) and 




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6.9.11 
Follow-up of Subjects after Adverse Events 
If an adverse event/adverse reaction occurs, the Investigator will institute support and/or 
treatment as deemed appropriate.  If a non-serious adverse event/adverse reaction is 
unresolved at the time of the last visit, efforts will be made to follow up until the adverse 
event/adverse reaction is resolved or stabilized, the subject is lost to follow-up, or there is 
other resolution to the event.  
6.10 
Comfort Test 
Individuals will be asked “Did you experience any discomfort when placing the drops in your 
eyes?”  This will refer to the study medication use the previous evening.  The response will 
be scored as None, Mild, Moderate or Severe. 
6.11 
Best Corrected Visual Acuity (BCVA) 
Best corrected visual acuity (BCVA) will be taken at visits as a measure of ocular function 
and will be measured at screening and frequently throughout the study. Visual acuity will be 
measured using ETDRS charts or their equivalents.  Accepted charts are those designed 
according to the principles described by Ferris and coworkers (Ferris 1982) and supported by 
the guidelines from the Eye Care Technology Forum (Ferris 1996). 
See Appendix 2 for details of the procedures to be followed when determining BCVA.   
6.12 
Pupil Size 
Pupil size will be measured prior to dilation with a ruler to the nearest 0.5 mm in ambient 
room light. 
6.13 
Biomicroscopy 
Biomicroscopic examination of the eyelids, conjunctiva, cornea, anterior chamber, lens, iris, 
and pupil of both lenses will be carried out at every study visit for both eyes of subjects.  
Normal or abnormal status of these ocular tissues will be graded as described in Appendix 2.  
6.14 
Gonioscopy/Pachymetry 
Gonioscopy will be used to confirm the iridocorneal angle is open and to what extent. 
Eligible subjects must have an angle grading of 3 or 4 (Shaffer grading scale: Kolker 1976) 
for participation in the study.  Pachymetry will be used to measure the thickness of the 
central cornea.  Both of these assessments will be done in order to determine the eligibility of 
a subject to be enrolled in this study.  Further information on these procedures is found in 
Appendix 2. 




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• Adverse Events (adverse events including, in the opinion of the investigator, 
clinically relevant laboratory abnormalities and intercurrent diseases reported by the 
subject or observed by the investigator with documentation on the CRF)   
• Withdrawal of consent 
• Non-compliance (eg, use of disallowed medication and/or non-adherence to 
scheduled follow-up visits) 
• Lost to follow-up 
• Lack of efficacy (as demonstrated by IOP measurements and investigator decision 
that there is a risk of additional glaucomatous damage if the subject continues in the 
study)   
• Disallowed concurrent medication 
• Investigator decision 
• Protocol violation 
• Death 
• Other 
6.17.3 
Actions after Discontinuation 
All subjects who discontinue Investigational Product due to a report of an AE must be 
followed-up and provided appropriate medical care until their signs and symptoms have 
remitted or stabilized or until clinically significant abnormal laboratory findings have 
returned to acceptable or pre-study limits. 
For the subject who chooses to withdraw consent or who is discontinued for non-compliance, 
every possible effort should be made by the Investigator to assure there is an exit visit that 
includes all examinations listed for Visit 9.0 (Day 365) and dilated ophthalmoscopy.   
6.17.4 
Discontinuation of the Entire Study  
The entire study may be discontinued at a given site (by the Investigator or the Sponsor) or 
for all sites (by the Sponsor).  Prompt, written notice of reasonable cause to all other relevant 
parties (Sponsor or Investigator) is required.  Prompt notice to the IRB/IEC and to regulatory 
authorities is also required. 
6.17.5 
Completed study 
The study is completed when the planned enrollment has been completed, and all enrolled 
subjects have completed the study.  The Sponsor or their designated representative(s) will be 


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in communication with investigational sites regarding completion of enrollment and the in-
life portion of the study.   
7. STUDY ACTIVITIES 
The schedule of study visits and procedures is shown in Appendix 1. 
7.1 
Study Visits  
7.1.1 
Visit 1 (Screening Visit) 
This visit may occur at any time of the day.  Individuals who are potential subjects will arrive 
at the Investigator’s office at any time point during the day.   
A member of the Investigator’s staff will interview the individual as to their qualifications for 
participation in the study.  Individuals will be asked to review the informed consent, discuss 
issues as needed, and to sign the form.  Significant medical and ophthalmic history including 
systemic and ocular medication use will be taken, and demographic measures recorded 
(see Section 6.2).  An examination will be conducted, including measurement of heart rate 
and blood pressure, a urine pregnancy test (for females of childbearing potential), collection 
of a blood sample for clinical laboratory assessments, and an ophthalmic examination to 
include symptoms, best corrected visual acuity (BCVA), intraocular pressure (before pupil 
dilation), biomicroscopy, gonioscopy, central corneal thickness by ultrasound pachymetry, 
visual field testing, and dilated ophthalmoscopy.  Gonioscopy and visual fields may be taken 
up to three months (ie, within 90 days) prior to randomization.  If assessment of visual fields 
requires dilation due to subject small pupils, visual field testing should not take place within 
48 hours of Visit 2 (Qualification Visit #1).  
Pachymetry must be taken at screening Visit 1 or within one week of Visit 1.  The results of 
blood work should be reviewed after this study visit in order to determine eligibility of the 
subject prior to undertaking the examination at Visit 2 (Qualification Visit #1).  For subjects 
who are unable or unwilling to have blood drawn for clinical labs at Visit 1 (screening), the 
blood sample may be drawn at Visit 2 (Qualification Visit #1) so long as the results of the 
clinical labs are available for that subject prior to Visit 3 (Qualification Visit #2). 
All females of childbearing potential must have a negative urine pregnancy test result at the 
screening examination and must not intend to become pregnant during the study. 
The Investigator will evaluate the results of these examinations for possible enrollment of the 
individual into the study.  All individuals who are qualified for enrollment at this study visit 
should undergo a washout period (if needed) as noted in Section 5.7.1 and will be asked to 
return for Visit 2 (Qualification Visit #1).  
7.1.1.1 
Evaluation of eye-drop instillation performance 
Subjects (or a legally authorized representative for subjects deemed unable to 
self-administer) will be provided a bottle of commercially available, multi-dose, 


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non-medicated artificial tears in a room with access to water and soap.  Medication instiller 
will be asked to instill a drop of the artificial tear in each eye under the observation of a 
member of the investigator’s staff.  The staff will observe the subject or representative to 
assure that they instill one drop of the artificial tear into each eye, without touching the tip of 
the bottle to their eye or face (Stone 2009).  The staff member may work with the individual 
to improve their delivery technique to meet this standard.  If the instiller (or representative) 
cannot demonstrate proper delivery of the eye drop, or if staff member feels that the 
individual will be unable to do so consistently, then the subject will be excluded from further 
study participation.   
7.1.1.2 
Washout 
As noted in Section 5.7.1., a washout period is required for individuals currently using ocular 
hypotensive medications.  The Investigator is encouraged to have interim visits during the 
washout period for intraocular pressure measurement for individuals to whom the washout 
period may be a risk for further glaucomatous progression.  
7.1.2 
Visit 2 (Qualifying Visit #1, for 08:00 hours IOP measurement) 
After the washout, if required, individuals will return to the Investigator’s office in the early 
morning.  For individuals not requiring washout of ocular hypotensive medication, this visit 
should take place at least one day and no later than approximately 28 days subsequent to the 
screening visit.  The subject will be questioned regarding any changes in their health or 
concomitant medication use.  Any change in the individual’s Visit 1 health status or use of 
concomitant medications should be recorded on the Medical History page of the CRF 
(eg, the subject has been diagnosed with cancer).  Inclusion/exclusion criteria will be 
reviewed again for the qualified individual, and the subject’s heart rate and blood pressure 
will be measured.  Results of the clinical laboratory tests from Visit 1 need to be available, 
and reviewed by the Investigator. For subjects who were unable or unwilling to have blood 
drawn for clinical labs at Visit 1, the blood sample may be drawn at Visit 2 
(Qualification Visit #1) so long as the results of the clinical labs are available for that subject 
prior to Visit 3 (Qualification Visit #2). 
The following procedures then will be performed: 
• Symptomatology: Individuals will be asked “How are you feeling?”  
• Best corrected visual acuity 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to 
08:30 hours) 
o IOP measurements:  Unmedicated (post-washout) IOP > 20 mmHg and 
< 36 mmHg in both eyes at this qualification visit at 08:00 hour is required. This 
is the first of four qualifying IOPs for randomization.  Individuals who do 


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NOT meet this requirement may return for up to 2 additional (unscheduled) 
qualification visits within 1 week of failing this qualification visit.  Individuals 
returning at an unscheduled visit within 1 week are required to only re-measure 
IOP in both eyes.  Individuals who screen fail due to IOP being ≥ 36 mmHg in 
either eye at this study visit or at an unscheduled visit within 1 week of the 
original visit MAY NOT return for additional qualification visits and are to be 
exited from the study. 
Qualified individuals who have met all criteria at this study visit will be scheduled to return 
2-7 days later for the second qualification visit.   
7.1.3 
Visit 3.0 (Qualifying Visit #2 [Day 1] for IOP measurement at 08:00 hours) 
Within 2 to 7 days after Visit 2, individuals will return to the Investigator’s office for the next 
08:00 hour IOP measurement.  The results of the clinical laboratory tests from Visit 1 or 
Visit 2 need to be available, and reviewed by the Investigator.  In order for the individual to 
be enrolled at a subsequent visit, the tests CANNOT be indicative of any clinically 
significant disease in the opinion of the Investigator.  The subject will be questioned 
regarding any changes in their health or concomitant medication use.  Any change in the 
individual’s health relative to their Visit 1 (screening) or Visit 2 health status and 
concomitant medication use should be recorded on the Medical History page of the CRF 
(eg, the subject has been diagnosed with cancer).  Inclusion/exclusion criteria will be 
reviewed again for the qualified individual.   
The following procedures will be performed: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Heart rate and blood pressure 
• Best corrected visual acuity 
• A non-dilated eye examination will be performed, including pupil size, IOP and 
biomicroscopy   
o IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to 
08:30 hours) 
o IOP measurements:  Unmedicated (post-washout) IOP > 20 mmHg and 
< 36 mmHg in both eyes at this study visit at 08:00 hour is required.  This is the 
second of four qualifying IOPs for randomization.   
Qualified individuals will continue with the measurements of IOP at 10:00 hours and 
16:00 hours on the day of this study visit.  Individuals who do NOT meet the above IOP 
requirement may return for up to 2 additional (unscheduled) qualification visits within 
1 week of failing this qualification visit.  Individuals returning at an unscheduled visit within 
1 week are required to only re-measure IOP in both eyes.  Upon return for an unscheduled 


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qualification visit, such individuals’ IOP measurements would need to qualify at each of 
08:00, 10:00 and 16:00 hours.  Individuals who screen fail due to IOP being ≥ 36 mmHg in 
either eye (exclusion criterion) at any of these time points at this study visit or at an 
unscheduled visit within 1 week of the original visit MAY NOT return for additional 
qualification visits and are to be exited from the study. 
Individuals are allowed to leave the Investigator’s office on the day of this study visit 
between assessments, and eat and drink with no restrictions.  However, individuals are not to 
consume alcohol or engage in strenuous exercise.  
7.1.4 
Visit 3.1 (Day 1, for IOP measurement at 10:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual.  
Qualified individuals will be examined.  Each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy  
o IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to 
10:30 hours) 
 
At this and any other in-office visit, any subject complaining of visual function issues 
will have visual function assessed as judged appropriate by the Investigator.   
For further participation in the study, unmedicated IOP at this time (10:00 hours, Day 1) 
must be > 17 mmHg and < 36  mmHg in both eyes.  This is the third of four qualifying 
IOPs for randomization.   
Qualified individuals will continue with the qualification visit.  Individuals who do NOT 
meet this requirement may return for up to 2 additional unscheduled qualification visits 
within 1 week of failing this qualification visit.  Individuals returning at an unscheduled visit 
within 1 week are required to only re-measure IOP in both eyes.  Upon return, such 
individuals would need to qualify at 08:00, 10:00 and 16:00 hours.  Individuals who screen 
fail due to IOP being ≥ 36 mmHg in either eye (exclusion criterion) at any of these time 
points at this study visit or at an unscheduled visit within 1 week of the original visit MAY 
NOT return for additional qualification visits and are to be exited from the study. 
Individuals are allowed to leave the Investigator’s office on the day of this study visit 
between assessments, and eat and drink without restrictions.  However, individuals are not to 
consume alcohol or engage in strenuous exercise. 
7.1.5 
Visit 3.2 (Day 1, for IOP measurement at 16:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual.   
Qualified individuals will be examined.  Each examination will include: 


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• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to 
16:30 hours) 
For further participation in the study, unmedicated IOP for a subject must be > 17 mmHg and 
< 36 mmHg in both eyes at this time (16:00 hours, Day 1).  This is the fourth of four 
qualifying IOPs for randomization.   
Individuals who do NOT meet this requirement may return for up to 2 additional 
unscheduled qualification visits within 1 week of failing the first qualification visit.  
Individuals returning at an unscheduled visit within 1 week are required to only re-measure 
IOP in both eyes.  Upon return, such individuals would need to qualify at 08:00, 10:00 and 
16:00 hours.  Individuals who screen fail due to IOP being ≥ 36 mmHg in either eye 
(exclusion criterion) at any of these time points at this study visit or at an unscheduled visit 
within 1 week of the original visit MAY NOT return for additional qualification visits and 
are to be exited from the study. 
As noted in Section 4.2, subjects must qualify in both eyes based upon IOP and ocular 
history.  For a subject who qualifies, the study eye will be the eye with the higher IOP at 
08:00 hours on Visit 3.  If both eyes have the same IOP at 08:00 hours on Visit 3, then the 
right eye will be the study eye.  In each subject, BOTH eyes will be treated.   
At this point, eligible subjects will be enrolled and assigned to an investigational product 
through an IWRS system according to a computer-generated randomization list.  The first kit 
removed from an investigational product packer assigned through the IWRS system to the 
eligible subject will be dispensed unopened to the subject, along with written storage 
instructions.   
Subjects will be:  
• Instructed to self-administer their masked medication at home between 20:00-22:00 
hours (8 PM and 10 PM) beginning with the evening dose on that day   
• Instructed to return to the office with their study medication at Week 2 (Day 15)   
7.1.6 
Visit 4.0 (Week 2 [Day 15], for IOP measurement at 08:00 hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure 


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• Symptomatology:  Individuals will be asked “How are you feeling”? 
• Recording of any AEs 
• Comfort Test: Individuals will be asked “Did you experience any discomfort when 
placing the drops in your eyes?” 
• Best corrected visual acuity  
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy  
o IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to 
08:30 hours) 
 
• Collect study medication from the subject. 
After randomization, any new or worsening of symptoms beyond those collected at the 
baseline visit are to be entered as adverse events. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.7 
Visit 4.1 (Week 2 [Day 15], for IOP measurement at 10:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to 
10:30 hours) 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.8 
Visit 4.2 (Week 2 [Day 15], for IOP measurement at 16:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 


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o IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to 
16:30 hours) 
 
Subjects will be: 
• Instructed to continue to self-administer their masked medication at home between 
20:00 - 22:00 hours (8 PM and 10 PM, beginning with the evening dose on that day).   
• They also will be instructed to return to the office with their study medication at 
Week 6 (Day 43)  
One subject kit from the originally assigned subject packer will be dispensed to the subject, 
along with storage instructions. 
7.1.9 
Visit 5.0 (Week 6 [Day 43], for IOP measurement at 08:00 hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• Comfort Test: Individuals will be asked “Did you experience any discomfort when 
placing the drops in your eyes?” 
• Best corrected visual acuity  
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to 
08:30 hours) 
• Collect study medication from the subject 
After randomization, any new or worsening of symptoms beyond those collected at the 
baseline visit are to be entered as adverse events. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 


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7.1.10 
Visit 5.1 (Week 6 [Day 43], for IOP measurement at 10:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to 
10:30 hours) 
 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.11 
Visit 5.2 (Week 6 [Day 43], for IOP measurement at 16:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy 
o IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to 
16:30 hours) 
Subjects will be: 
• Instructed to continue to self-administer their masked medication at home between 
20:00 - 22:00 hours (8 PM and 10 PM, beginning with the evening dose on that day)   
• Instructed to return to the office with their study medication on Month 3 (Day 90)   
• Two subject kits from the originally assigned subject packer for this subject will be 
dispensed to the subject, along with storage instructions 
7.1.12 
Visit 6.0 (Month 3 [Day 90], for IOP measurement at 08:00 hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure 
• Urine Pregnancy Test (female subjects of childbearing potential; as applicable)  


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Blood samples will be taken for clinical chemistry and hematology (see Appendix 1). 
Note that these samples may be taken at any time of the day
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
Recording of any AEs
•
Comfort Test: Individuals will be asked “Did you experience any discomfort when
placing the drops in your eyes?”
•
Best corrected visual acuity
•
A non-dilated eye examination will be performed, including pupil size, IOP
measurements and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to
08:30 hours)
•
Pachymetry at the study visit or within one week of the study visit
•
Visual fields (Note: may be assessed up to one week prior to this visit, or later in the
morning or afternoon of this series of Day 90 visits so long as it occurs after IOP
measurement at that visit). See Appendix 2 for further details when dilation is
required due to subject small pupils
•
Collect study medication from the subject.
After randomization, any new or worsening of symptoms beyond those collected at baseline 
are to be entered as adverse events. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.13 
Visit 6.1 (Month 3 [Day 90], for IOP measurement at 10:00 hours) 
Subjects will be examined and each examination will include: 
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
A non-dilated eye examination will be performed, including IOP and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to
10:30 hours)


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Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.14 
Visit 6.2 (Month 3 [Day 90], for IOP measurement at 16:00 hours) 
Subjects will be examined and each examination will include: 
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
A non-dilated eye examination will be performed, including IOP and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to
16:30 hours)
•
A dilated ophthalmoscopy examination (including cup-disc ratio)
Subjects will be: 
•
Instructed to continue to self-administer their masked medication at home between
20:00 - 22:00 hours (8 PM and 10 PM, beginning with the evening dose on that day)
•
Instructed to return to the office with their study medication on Month 6 (Day 180)
•
A new packer containing 3 kits will be dispensed to the subject, along with storage
instructions
7.1.15 
Visit 7.0 (Month 6 [Day 180], for IOP and safety measurements at 08:00 
hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
•
Heart rate and blood pressure
•
Urine Pregnancy Test (female subjects of childbearing potential; as applicable)
•
Blood samples will be taken for clinical chemistry and hematology (see Appendix 1). 
Note that these samples may be taken at any time of the day
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
Recording of any AEs


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•
Comfort Test: Individuals will be asked “Did you experience any discomfort when
placing the drops in your eyes?”
•
Best corrected visual acuity
•
A non-dilated eye examination will be performed, including pupil size, IOP and
biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to
08:30 hours)
•
Pachymetry at the study visit or within one week of the study visit
•
Visual fields (Note: may be assessed up to one week prior to this visit, or later in the
morning or afternoon of this series of Day 180 visits so long as it occurs after IOP
measurement at that visit). See Appendix 2 for further details when dilation is
required due to subject small pupils
•
Collect study medication from the subject.
After randomization, any new or worsening of symptoms beyond those collected at baseline 
are to be entered as adverse events. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.16 
Visit 7.1 (Month 6 [Day 180], for IOP and safety measurements at 10:00 
hours) 
Subjects will be examined and each examination will include: 
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
A non-dilated eye examination will be performed, including IOP and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to
10:30 hours)
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.17 
Visit 7.2 (Month 6 [Day 180}, for IOP and safety measurements at 16:00 
hours) 
Subjects will be examined and each examination will include: 


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•
Symptomatology: Individuals will be asked “How are you feeling?”
•
A non-dilated eye examination will be performed, including IOP and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to
16:30 hours)
•
A dilated ophthalmoscopy examination (including cup-disc ratio)
Subjects will be: 
•
Instructed to continue to self-administer their masked medication at home between
20:00 - 22:00 hours (8 PM and 10 PM, beginning with the evening dose on that day)
•
Instructed to return to the office with their study medication on Month 9 (Day 270)
•
A new packer containing 3 kits will be dispensed to the subject, along with storage
instructions
7.1.18 
Visit 8.0 (Month 9 [Day 270], for IOP and safety measurements at 08:00 
hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
•
Heart rate and blood pressure
•
Urine Pregnancy Test (female subjects of childbearing potential; as applicable)
•
Symptomatology: Individuals will be asked “How are you feeling?”
•
Recording of any AEs
•
Comfort Test: Individuals will be asked “Did you experience any discomfort when
placing the drops in your eyes?”
•
Best corrected visual acuity
•
A non-dilated eye examination will be performed, including IOP and biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to
08:30 hours)
•
Collect study medication from the subject.


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After randomization, any new or worsening of symptoms beyond those collected at baseline 
are to be entered as adverse events. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.19 
Visit 8.1 (Month 9 [Day 270], for IOP and safety measurements at 10:00 
hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• IOP measurement 
o IOP must be measured within 30 minutes of the nominal time (ie, 09:30 to 
10:30 hours) 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
7.1.20 
Visit 8.2 (Month 9 [Day 270], for IOP and safety measurements at 16:00 
hours) 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• IOP measurement 
o IOP must be measured within 30 minutes of the nominal time (ie, 15:30 to 
16:30 hours) 
Subjects will be: 
• Instructed to continue to self-administer their masked medication at home between 
20:00 - 22:00 hours (8 PM and 10 PM, beginning with the evening dose on that day)   
• Instructed to return to the office with their study medication on Month12 (Day 365)   
• A new packer containing 3 kits will be dispensed to the subject, along with storage 
instructions 


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7.1.21 
Visit 9.0 (Month 12 [Day 365], for IOP and safety measurements at 08:00 
hours) 
Subjects will return to the Investigator’s office with their study medication.  The subject will 
be questioned about any missed doses and any changes in their health or concomitant 
medication use.  
Subjects will be examined and each examination will include: 
•
Heart rate and blood pressure
•
Urine Pregnancy Test (female subjects of childbearing potential; as applicable)
•
Blood samples will be taken for clinical chemistry and hematology (see Appendix 1). 
Note that these samples may be taken at any time of the day
•
Symptomatology: Individuals will be asked "How are you feeling?"
•
Recording of any AEs
•
Comfort Test: Individuals will be asked "Did you experience any discomfort when
placing the drops in your eyes?"
•
Best corrected visual acuity
•
A non-dilated eye examination will be performed, including pupil size, IOP and
biomicroscopy
o
IOP must be measured within 30 minutes of the nominal time (ie, 07:30 to
08:30 hours)
•
Visual fields (Note: may be assessed up to one week prior to this visit, or later in the
morning or afternoon of this series of Day 365 visits so long as it occurs after IOP
measurement at that visit). See Appendix 2 for further details when dilation is
required due to subject small pupils
•
Collect study medication from the subject.
After randomization, any new or worsening of symptoms beyond those collected at baseline 
are to be entered as adverse events. 
Subjects are allowed to leave the Investigator's office on the day of this study visit between 
assessments, and eat and drink without restrictions.  However, individuals are not to consume 
alcohol or engage in strenuous exercise. 








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•
H02:  The difference between study eyes treated with PG324 Ophthalmic Solution and
study eyes treated with AR-13324 Ophthalmic Solution, 0.02%
(PG324 − AR-13324), in mean IOP at the following time points: 08:00, 10:00, and
16:00 hours at the Week 2, Week 6, and Month 3 Visits, is ≥ 0 mmHg for at least one
time point over all visits.
•
H12:  The difference between study eyes treated with PG324 Ophthalmic Solution and
study eyes treated with AR-13324 Ophthalmic Solution, 0.02%
(PG324 − AR-13324), in mean IOP at the following time points: 08:00, 10:00, and
16:00 hours at the Week 2, Week 6, and Month 3 Visits, is < 0 mmHg for all time
points over all visits.
The study will be considered a success if both H01 and H02 are rejected. 
9.2 
Sample Size Considerations 
Efficacy: 
One-hundred ninety six (196) subjects per arm completing 3 months of treatment yields at 
least 90% power to conclude statistical superiority of PG324 to latanoprost and >99% power 
to conclude statistical superiority of PG324 to AR-13324 at all nine time points assuming a 
two-sided alpha = 0.05, a true mean difference of 1.5 mmHg (to latanoprost) and 2.0 mmHg 
(to AR-13324), a common standard deviation of 3.5 mmHg at each time point, and 
independence among time points.  Power increases as the correlation among time points 
increases.  Therefore, 196 subjects per arm yield at least 90% power to conclude superiority 
to both controls over all nine time points.   
9.3 
Analysis Populations  
Randomized Population: The randomized population will include all subjects who were 
randomized to treatment.  Baseline variables and demographic characteristics will be 
summarized for this population. 
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects 
who have received at least one dose of study medication.  This population will be the primary 
population for efficacy analyses and will be used to summarize all efficacy variables and will 
summarize subjects as randomized. 
Per-protocol population (PP): The PP population is a subset of the ITT population, which 
will include those subjects (and their visits) who do not have major protocol violations likely 
to seriously affect the primary outcome of the study as judged by a masked evaluation prior 
to the unmasking of the study treatment.  This population will be the secondary population 
for efficacy analyses and will be used to summarize a subset of efficacy variables.  If the PP 
and ITT populations are exactly the same, then additional efficacy analyses on the PP 
population will not be performed.  The PP population will summarize subjects as treated. 


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Safety Population: The safety population will include all randomized subjects who have 
received at least one dose of study medication.  This population will be used to summarize 
safety variables and will summarize subjects as treated.   
9.4 
Statistical Methods to be Employed 
9.4.1 
General Considerations 
All continuous study assessments will be summarized by treatment and time point 
(as applicable) using descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum).  All categorical study assessments will be summarized by treatment and time 
point (as applicable) using frequency counts and percentages.   
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 
0.05 significance level.  When applicable, two-sided 95% confidence intervals will be 
reported.  All p-values will be displayed to four decimal places, with p-values less than 
0.0001 presented as '<0.0001' and p-values greater than 0.9999 presented as ‘>0.9999’.  
Differences between PG324 and each comparator (latanoprost and AR-13324) will be 
calculated as PG324 – comparator.   
All study data will be listed by treatment, subject and time point (as applicable).  
For diurnally-adjusted IOP, baseline will refer to the time-relevant measure at Visit 3.0 
through 3.2 (eg, IOP at 08:00 hours at Visit 3.0 will be the baseline for 08:00 hours at 
Visit 4.0, Visit 5.0, and Visit 6.0; IOP at 10:00 hours at Visit 3.1 will be the baseline for 
10:00 hours at Visit 4.1, Visit 5.1, and Visit 6.1; etc.).  For all other variables, baseline is 
defined as the last measurement prior to the first dose of study medication.  
The unit of analysis for efficacy will be the study eye.  For a subject who qualifies, the study 
eye will be the eye with the higher IOP at 08:00 hours on Visit 3.  If both eyes have the same 
IOP at 08:00 hours on Visit 3, then the right eye will be the study eye. 
Data collected during the observation extension visits may be summarized separately from 
the data collected during the main portion of the study. 
Statistical methods will be more fully described in separate document(s) (ie, the Statistical 
Analysis Plan).   
9.4.2 
Interim Analyses 
When all subjects have completed three months of treatment, the Sponsor will unmask the 
study to analyze the 3 month efficacy and safety data.  This is the time for primary efficacy 
analysis of the study.  Efforts will be made to keep the Investigators, site staff, and subjects 
masked as to individual subject assignments, as the subjects continue to be evaluated for 
safety for the following 9 months. The Sponsor will conduct an additional data base lock and 
unmask the study when all subjects have completed their 12 month visit. This is the time for 
primary analysis of the 12 month safety data. Interim analyses will be conducted so as to 




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Percentages of subjects achieving pre-specified mean, mean change, and percent
mean change diurnal IOP levels
Other secondary efficacy analyses will be conducted as described in the study Statistical 
Analysis Plan.  Note that each subject will have one eye designated as the study eye.  
Only the study eyes will be evaluated for the primary efficacy measure or for selected 
secondary efficacy measures; however, both eyes will be treated.   Qualifying fellow eyes 
will be evaluated separately for the primary analysis of the primary efficacy measure.    
The primary analysis of the primary outcome will employ a linear model with mean IOP at 
the given visit (Week 2, Week 6, and Month 3) and time point (08:00, 10:00, and 
16:00 hours) as the response, baseline IOP as a covariate, and treatment as a main effect 
factor, using the intent to treat population with multiple imputation techniques 
(eg, Monte Carlo Markov Chain) used to impute missing data.  Each time point within each 
visit will be modeled separately.  The least squares mean differences (test – control) between 
PG324 Ophthalmic Solution and each of Latanoprost Ophthalmic Solution, 0.005% and 
AR-13324 Ophthalmic Solution, 0.02% will be presented as well as 2-sided p-values and 
95% confidence intervals. For a given comparator (latanoprost and AR-13324), if the p-value 
is P < 0.05 and the point estimate < 0 for all time points at the Week 2, Week 6, and Month 3 
Visits, then the corresponding null hypothesis will be rejected in favor of the alternative 
hypothesis and PG324 will be considered to be superior to the comparator.  Results will be 
presented in both tabular and graphical form. 
Analyses will be performed primarily on the ITT population using multiple imputation 
techniques to impute missing data and secondarily using: observed data only, last observation 
carried forward (LOCF) where LOCF will be performed using time-relevant measures; and 
baseline observation carried forward (BOCF) using time-relevant measures to determine the 
robustness of results.  Additionally, the above analyses will be repeated on the PP population 
to determine robustness of results.  Additional imputation techniques may be designated in 
the formal statistical analysis plan.  Sample SAS code to demonstrate the methodology that 
will be used for data imputation can be found in Appendix 7. 
Secondary analyses of the primary endpoint will be completed using individual two-sample 
t-tests and 95% t-distribution confidence intervals for each comparison (PG324 vs 
latanoprost and AR-13324) at each time point (08:00, 10:00, and 16:00 at the Week 2, 
Week 6, and Month 3 Visits) using the ITT population. Similar analyses will be completed 
on the secondary endpoints: mean IOP measure at each time point and visit and mean diurnal 
IOP and change from baseline diurnal IOP measures.  Models adjusting for baseline will only 
be performed on the mean IOP response variable as inference is identical between this 
response and the change from baseline IOP response variable in such a model. 
Additionally, for the mean IOP values at each time point, mixed model repeated measures 
will be run with baseline as the covariate; treatment, visit, time point, treatment by visit, 
treatment by time point, visit by time point, and treatment by visit by time point as the fixed 
effect factors; and subject as the random effect, repeated measure.  An unstructured 
covariance structure will be used to model the within subject, between visit and time point 






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presented separately for ocular and non-ocular AEs.  These summaries will also be presented 
for relation to Investigational Product and by severity.  Fisher’s exact test will be used to test 
the difference in proportions of subjects with each AE between treatment groups 
(SOC and PT).   
9.5 
Procedure for Accounting for Missing, Unused, or Spurious Data   
Analyses will be performed primarily on observed data only (without imputation) and 
secondarily using: last observation carried forward (LOCF) where LOCF will be performed 
using time-relevant measures (ie, from the same time point of the most recent visit with a 
non-missing value); BOCF using time-relevant measures; and using multiple imputation 
methods to determine the robustness of results.  Any missing, unused, or spurious data will 
be noted in the final statistical report. 
9.6 
Procedure for Reporting Deviations from the Statistical Plan   
Any deviations from the statistical plan will be described and a justification given in the final 
statistical report. 
9.7 
Data Listings   
Data listings will be prepared for all data on the database. 
10. ADMINISTRATIVE CONSIDERATIONS
10.1 
GCP compliance 
The proposed study is subject to all applicable governmental rules and regulations 
concerning the conduct of clinical trials on human subjects.  This includes, but is not 
necessarily limited to:  
•
Approval of properly constituted Institutional Review Boards
•
Helsinki Declaration (See Appendix 6)
•
U.S. FDA Law
•
ICH GCP guidelines
•
Obtaining prospective informed consent
•
Monitoring of the conduct of the study
•
Completeness of the Case Report Forms by the Sponsor or its designee(s)
•
Appropriate record retention by the Investigator.
Protocol change or amendment procedures, applicable IRB requirements, 
Investigator/Sponsor obligations, and study monitoring procedures are detailed in 
Section 10.2 through Section 10.8 of this protocol.  






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agencies) may be granted direct access to the study subject’s original medical and study 
records for verification of the data or clinical study procedures. Access to this information 
will be permitted to representatives of the aforementioned organizations to the extent 
permitted by law.  
A report of this study’s results may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but subject identities will 
not be disclosed in these documents. 
10.8 
Study Monitoring 
Clinical research associates hired or contracted by the Sponsor will be responsible for 
monitoring the study sites and study activities.  They will contact and visit the Investigator 
regularly.  The actual frequency of monitoring visits depends on subject enrollment and on 
study site performance.  Among others, the following items will be reviewed: 
•
Study progress
•
Compliance with the protocol
•
Completion of CRFs
•
Dispensing, storage, and accountability of IP, including intentional or inadvertent
unmasking of IP
•
Source data verification
•
AE and SAE reporting
•
Essential documents contained within the regulatory binder
For source data verification (ie, comparison of CRF entries with subject records), data will be 
100% source verified and will include as a minimum:  
•
Subject identification
•
Informed consent (procedure, signature, and date)
•
Selection criteria
•
Primary efficacy and safety parameters (ie, AEs)
Member(s) of the Sponsor or their designee will meet with the Investigator prior to the 
initiation of the study in order to assess the adequacy of the Investigator's subject population, 
facilities, and equipment, and to familiarize the Investigator with the protocol. 


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A member of the Sponsor or their designee in the role of Study Monitor will subsequently 
meet with the Investigator after several of the subjects have initiated the study in order to 
ensure that the subjects are being properly selected, that adequate supplies for the study have 
been provided and that the assignment of medication is properly recorded. In addition, the 
Study Monitor will verify that the Investigator follows the approved protocol and all 
approved amendments, if any, by reviewing the Investigator’s regulatory documents, source 
documents, Informed Consent Forms, and Case Report Forms of study subjects. 
The Study Monitor will meet with the Investigator when all subjects have completed the 
Final Visit of the study, in order to collect the Case Report Forms, unused study medications, 
and unused supplies and materials. 
Interim monitoring visits and telephone consultations will be done by the Study Monitor as 
necessary, to ensure the proper progression and documentation of the study. 
10.9 
Case Report Forms and Study Records 
The initial point of entry of study data should be the subject source documentation.  The 
location and nature of the source documentation for all data collected in the study will be 
identified in the study files at the investigator’s site.  In cases where no source documents 
will be used (ie, data will be recorded directly onto the case report form (CRF) without first 
being recorded on another document, such as a flowsheet, laboratory report, or other typical 
form of data reporting for later transcription to the CRF), the original data will be included in 
the CRF.  
Source document information should be legible. Recorded data should only be corrected by 
drawing a single line through the incorrect entry and writing the revision next to the 
corrected data. The person who has made the correction should place his or her initials as 
well as the date of the correction next to the correction. Data may not be obliterated by 
erasure, redaction, or with correction fluid. 
Study data will be transcribed and recorded via an electronic data capture (EDC) system as 
electronic CRFs (eCRFs). Security and authorization procedures consistent with the EDC 
system must be used. At each subject visit, the appropriate eCRFs must be completed.  
Whenever an eCRF is used, be sure to provide all information requested including subject 
identification number and initials, name or number of Investigator, date(s), etc.  
All applicable questions should be answered and all data requested should be provided.  
Those areas that require a response but are not filled in correctly are considered incomplete 
or erroneous entries, and will have to be corrected.   
Each authorized study staff member will receive a unique access account in order to use the 
EDC system. Access accounts will not be shared among study staff. Authorized users will 
make entries and/or changes to eCRFs via a secure internet access. Each completed set of 
eCRFs will be reviewed by the Investigator who will then electronically sign and date the 
eCRF confirming that data for the subjects are complete and accurate. 


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The study records must include a copy of each Investigator's CV and medical license, 
completed, FDA Form 1572 or statement of Investigator, each eCRF, subject charts/source 
documents, Investigator’s Brochure, protocol, protocol amendments, correspondence with 
the Sponsor and the IRB/IEC, IP storage, receipts, returns and dispensing records, Delegation 
of Responsibilities Log, site training records, records of site monitoring, any unmasking 
documentation, AE and SAE reporting, IRB/IEC approvals, advertisements, written 
information provided to subjects, and subject completed ICFs. If the Investigator moves, 
withdraws from an investigation, or retires, the responsibility for maintaining the records 
may be transferred to another person (eg, Sponsor, other Investigator) who will accept the 
responsibility. Notice of this transfer, including written acceptance, must be made to and 
agreed upon by the Sponsor. 
10.10 Protocol Deviations 
A protocol deviation occurs when there is non-adherence to study procedures or schedules 
which does not involve inclusion/exclusion criteria or the primary efficacy endpoint and 
which does not place the subject at any added risk or affect the data quality or study outcome. 
Examples of deviations include common out of window visits or timed procedures, a missed 
procedure, etc. Sites will record protocol deviations in the study records. To the extent 
possible, sites will make their best efforts to quickly remedy deviations. 
The site will contact the Sponsor for clarification of inclusion/exclusion criteria as needed 
prior to enrollment of a study subject. The Sponsor will document clarification requests and 
responses. If a potential subject does not meet all inclusion and exclusion criteria during 
screening, that subject may not be enrolled in the study. 
The site will notify the Sponsor or their representative and IRB/IEC within 10 days of 
becoming aware of any significant protocol deviation. Typically, significant protocol 
deviation include significant deviations from the inclusion and exclusion criteria that may 
impact interpretation or the quality of efficacy information or the safety of a subject, 
concomitant medication restrictions, or any other protocol requirement that results in a 
significant added risk to the subject or has an impact on the quality of the data collected or 
the outcome of the study. 
The Sponsor will review, designate, and/or approve all protocol deviations prior to database 
lock. 
10.11 Access to Source Documentation 
Monitors, auditors, and other authorized representatives of the Sponsor, the governing 
IRB(s)/IEC(s), the FDA, the DHHS, other domestic government agencies, and other foreign 
regulatory agencies will be granted direct access to the study subject’s original medical and 
study records for verification of the data and/or clinical study procedures. Access to this 
information will be permitted to representatives of the aforementioned organizations to the 
extent permitted by law. 


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10.12 Data Generation and Analysis 
After data have been entered into the study EDC system database, a system of computerized 
data validation checks will be implemented and applied to the database.  Query reports 
pertaining to data omissions and discrepancies will be forwarded to the clinical Investigator 
and the Sponsor for resolution.  Where required, the Investigator will be asked for 
supplementary information through a query.  The study EDC system database will be 
updated by the clinical investigator or their staff, in accordance with the resolved query 
reports.  All changes to the study database will be documented.   
Once the eCRFs are monitored in the EDC system, the data management CRO and the 
Sponsor will further check the eCRFs for completeness and plausibility of the data. The data 
management CRO will use quality systems in order to verify accurate and complete data 
entry, including additional checks of the data once entered in a database 
(eg, range checks, cross checks and other edit checks).  
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting ICH and US Food and Drug Administration (FDA) guidelines for the 
handling and analysis of data for clinical trials.  Data will be checked per the data 
management CRO’s SOPs. The database then will be locked and a biostatistician will 
complete the analyses of the data in accordance with the Statistical Analysis Plan. 
10.13 Retention of Data 
Archived versions of the EDC system database will be saved by the Sponsor consistent with 
ICH Good Clinical Practices Guidelines.  The Sponsor will notify the investigator when 
documents should be returned.   
The Investigator’s site and the study clinical laboratory will retain all records related to the 
study in compliance with ICH Good Clinical Practices Guidelines and 21 CFR 312.57(c)  
(see Appendix 5 for additional investigator obligations).  
10.14 Financial Disclosure 
The Principal Investigator and Sub-investigators (as listed on Form FDA 1572) will provide 
financial disclosure information prior to participation in the study. The Principal Investigator 
and any Sub-investigators will notify the Sponsor promptly of any required revision to their 
financial disclosure status during the term of this study, annually, or at the end of the study 
(if applicable). The Principal Investigator and Sub-investigators will provide updated 
financial disclosure information upon the Sponsor’s written request following completion of 
the study. 
10.15 Publication and Disclosure Policy 
Aerie Pharmaceuticals, as the Sponsor, has proprietary interest in the study. Authorship and 
manuscript composition will reflect joint cooperation between multiple investigators and 
sites and Aerie Pharmaceuticals personnel.  As this study involves multiple centers, no 


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individual publications will be allowed prior to completion of the final report of the 
multicenter study except as agreed with Aerie Pharmaceuticals. 


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11. REFERENCES
11.1 
Published References 
1.
Chen J, Runyan SA, Robinson MR.  Novel ocular antihypertensive compounds in
clinical trials. Clin Ophthalmol 2011; 5:667-77.
2.
Collaborative Normal-Tension Glaucoma Study Group.  The effectiveness of
intraocular pressure reduction in the treatment of normal-tension glaucoma.  Am J
Ophthalmol 1998; 126:498-505.
3.
Ferris FL and Bailey I.  Standardizing the measurement of visual acuity for clinical
research studies.  Ophthalmol 1996; 103:181-82.
4.
Ferris FL, Kassoff, A, Bresnick GH, et al.  New visual acuity charts for clinical
research.  Am J Ophthalmol 1982; 94:91-6.
5.
Heijl A, Leske MC, Bengtsson B, et al.  Reduction of intraocular pressure and
glaucoma progression: results from the Early Manifest Glaucoma Trial.  Arch
Ophthalmol 2002; 120: 1268-79.
6.
Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-
masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5%
ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol
0.5% dosed concomitantly in subjects with open angle glaucoma or ocular
hypertension. J Glaucoma 2005;14:392-9.
7.
Jabs DA, Nussenblatt RB, Rosenbaum JT.  Standardization of uveitis nomenclature
for reporting clinical data. Results of the First International Workshop.  Am J
Ophthalmol 2005; 140:509-16.
8.
Kass MA, Gordon MO, Gao F, et al. Delaying Treatment of Ocular Hypertension:
The Ocular Hypertension Treatment Study. Arch Ophthalmol 2010;128:276-87.
9.
Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure in Dutch
Belted rabbits. J Ocul Pharmacol Ther 2015; 31(3):146-51.
10.
Kolker AE, Hetherington J Jr, eds.  Becker and Shaffer’s diagnosis and therapy of the
glaucomas, 5th ed.  St Louis: CV Mosby, 1976.
11.
Kopczynski CC and Epstein DL.  Emerging Trabecular Outflow Drugs. J Ocul
Pharmacol Ther 2014; 30:85-7.
12.
Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5%
timolol fixed-combination therapy vs. monotherapy with timolol or brimonidine in
patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch
Ophthalmol 2006;124:1230-8.
13.
Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop
instillation in glaucoma patients. Arch Ophthalmol 2009;127:732-6.


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14.
The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The
relationship between control of intraocular pressure and visual field deterioration. Am
J Ophthalmol 2000;130:429-40.
15.
Wang R-F, Williamson JE, Kopczynski C, et al. Effect of 0.04% AR-13324, a ROCK
and Norepinephrine Transporter Inhibitor, on Aqueous Humor Dynamics in
Normotensive Monkey Eyes. J Glaucoma, 2015; 24:51-4.
16.
Wang SK and Chang RT.  An emerging treatment option for glaucoma: Rho kinase
inhibitors.  Clin Ophthalmol 2014; 8:883-90.
17.
Williams RD, Novack GD, Van Haarlem T, et al.  Ocular hypotensive effect of the
rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension.
Am J Ophthalmol 2011; 152:834-41.
11.2 
Internal References 
1.
Aerie Pharmaceuticals, Inc., AR-13324 Investigator’s Brochure, 2017.
2.
AR-13324-CS101 Clinical Study Report: An Open-Label Study Assessing the Ocular
and Systemic Safety and Systemic Absorption of AR-13324 Ophthalmic Solution,
0.02% in Healthy Volunteers (2014).
3.
AR-13324-CS201 Clinical Study Report: A Phase 2, double-masked, randomized,
placebo-controlled, dose-response study assessing the safety and ocular hypotensive
efficacy of three doses of AR-13324 Ophthalmic Solution in patients with elevated
intraocular pressure (2012).
4.
AR-13324-CS202 Clinical Study Report: A phase 2, double-masked, randomized,
multi-center, active-controlled, dose-response parallel-group study comparing the
safety and ocular hypotensive efficacy of AR-13324 to latanoprost in patients with
elevated intraocular pressure (2013).
5.
PG324-CS201 Clinical Study Report: A double-masked, randomized, controlled
study assessing the safety and ocular hypotensive efficacy of PG324 Ophthalmic
Solution, 0.01% and PG324 Ophthalmic Solution, 0.02%, compared to AR-13324
Ophthalmic Solution, 0.02% and Latanoprost Ophthalmic Solution, 0.005% in
patients with elevated intraocular pressure (2014).
6.
AR-13324-CS301 Clinical Study Report: A double-masked, randomized, multi-
center, active-controlled, parallel, 3-month study assessing the safety and ocular
hypotensive efficacy of AR-13324 Ophthalmic Solution, 0.02% compared to timolol
maleate ophthalmic solution, 0.5% in patients with elevated intraocular pressure
(2016)


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Appendix 1 
Schedule of Visits and Examinations 
Day/Week/Month 
Scree
n 
Qual 
#1 
Qual. #2 
D1 
Post D1 Treatment Period Assessments 
Observational 
Period 
W2 
(Day 15±3) 
W6 
(Day 43±3) 
M3, M6 
(Day 90±3, Day 
180±7) 
M9 
(Day 270±7) 
M12 
(Day 365±7) 
M13 
(D395±
7) 
M14 
(D425±
7) 
Visit 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
4.2 
5.0 
5.
1 
5.2 
6.0, 
7.0 
6.1, 
7.1 
6.2, 
7.2 
8.0 
8.1 
8.2 
9.0 
9.1 
9.2 
10 
11 
Hour (XY = XY:00) 
 
08 
08 
10 
16 
08 
10 
16 
08 
10 
16 
08 
10 
16 
08 
10 
16 
08 
10 
16 
08 
08 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Washout1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic Hist. 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
HR/BP 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 Urine Pregnancy Test2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Clinical Labs (Chem/Hem) 
 X3 
 
 
 
 
 
 
 
 
 
 
X 
 
 
  
 
 
X 
 
 
 
 
Symptoms/AEs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Comfort Test5 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Visual Acuity (ETDRS) 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Pupil size 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
IOP 
X 
X6 
X6 
X6 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
Gonioscopy7/ Pachymetry8 
G/P 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
 
 
 
 
 
Visual Field9 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X11 
 
X 
 
X 
Eye-Drop Instillation Eval. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Meds Dispensed 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Collect Study Meds 
 
 
 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
 
Study Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
X13 
Abbreviations:  D, day; W, week; M, month; Med/Ophthalmic Hist, Medical/Ophthalmic History; HR/BP, heart rate/blood pressure; Clin Labs, 
Clinical Labs (Chemistry/Hematology); G, gonioscopy; P, pachymetry; AE, adverse event; ETDRS, early treatment diabetic retinopathy study; IOP, intraocular pressure 
 


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Appendix 1 
Schedule of Visits and Examinations (cont’d) 
1 Subjects currently using ocular hypotensive medications must undergo a minimum washout period (Table 1 for details). 
2 Urine pregnancy test for women of childbearing potential is required. 
3 For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 (screening), the blood sample may be drawn at Visit 2 (Qualification  Visit #1) 
so long as the results of the clinical labs are available for that subject prior to Visit 3 (Qualification Visit #2). 
4 Ocular symptoms: Subjects will be queried at each visit “How are you feeling?” and treatment emergent AEs beginning at Visit 3 (Qualification Visit #2) will be 
documented on the AE form. Additional symptoms reported after screening and before randomization will be documented on the medical history form. 
5 Comfort test: At 08:00 hour for study drug visits, subjects will be queried “Did you experience any discomfort when placing the drops in your eyes?” 
6 Individuals returning at an unscheduled visit within 1 week are required to only remeasure IOP in both eyes (Section 7.1.2 to Section 7.1.5). 
7 Gonioscopy evaluation up to 3 months prior to randomization is acceptable. 
8 Pachymetry within one week of study visit is acceptable. 
9 Entry visual field evaluation up to 3 months prior to randomization is acceptable.  Visual field collection must meet the requirement for automated threshold visual 
field assessment (eg, 30-2 or 24-2 Humphrey) and reliability. 
10 Collect used kit(s) dispensed during the previous visit. 
11 Ophthalmoscopy (dilated) at Visit 9.0 at 08:00: this assessment should be performed for all non-completing subjects during the exit visit. 
12 Informed consent must be completed by the subjects before entering the extension visits. 
13 Month 12 visit completed for the treatment period. Month 14 visit completed for the subjects entering the extension visits of the study.  
 
















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Appendix 3 
Marketed Product Information: Latanoprost Ophthalmic Solution, 
0.005% 
The following is taken from the most recent package insert as of the date of this protocol for 
latanoprost ophthalmic solution 0.005% as marketed by Bausch & Lomb. 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LATANOPROST safely 
and effectively. See full prescribing information for LATANOPROST. 
LATANOPROST (latanoprost ophthalmic solution) 0.005% 
Initial U.S. Approval: 1996 
------------------INDICATIONS AND USAGE------------------- 
Latanoprost is a prostaglandin F2α analogue indicated for the reduction of elevated 
intraocular pressure in patients with open-angle glaucoma or ocular hypertension. (1) 
 
--------------DOSAGE AND ADMINISTRATION---------------- 
One drop in the affected eye(s) once daily in the evening. (2) 
 
------------ DOSAGE FORMS AND STRENGTHS-------------- 
Ophthalmic solution containing 50 mcg/mL latanoprost (0.005%). (3) 
 
--------------------CONTRAINDICATIONS---------------------- 
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in 
this product. (4) 
-------------WARNINGS AND PRECAUTIONS---------------- 
• Pigmentation: pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. 
Iris pigmentation likely to be permanent. (5.1) 
• Eyelash Changes: gradual change to eyelashes including increased length, thickness and 
number of lashes. Usually reversible. (5.2) 
 
--------------------ADVERSE REACTIONS---------------------- 
Most common adverse reactions (≥4%) from clinical trials are blurred vision, burning and 
stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of 
the iris, punctate epithelial keratopathy, and upper respiratory tract infection/cold/flu. (6). 
To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb at 1-800-
323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
 
--------------------DRUG INTERACTIONS---------------------- 
In vitro studies have shown that precipitation occurs when eye drops containing thimerosal 
are mixed with Latanoprost.  If such drugs are used, they should be administered at least 
5 minutes apart. (7) 
See 17 for PATIENT COUNSELING INFORMATION 
Revised: 02/2015 


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FULL PRESCRIBING INFORMATION: CONTENTS* 
1          INDICATIONS AND USAGE 
2          DOSAGE AND ADMINISTRATION 
3          DOSAGE FORMS AND STRENGTHS 
4          CONTRAINDICATIONS 
5          WARNINGS AND PRECAUTIONS 
5.1        Pigmentation 
5.2       Eyelash Changes 
5.3        Intraocular Inflammation 
5.4        Macular Edema 
5.5        Herpetic Keratitis 
5.6        Bacterial Keratitis 
5.7        Use with Contact Lenses 
6          ADVERSE REACTIONS 
6.1       Clinical Trials Experience 
6.2        Postmarketing Experience 
7          DRUG INTERACTIONS 
8          USE IN SPECIFIC POPULATIONS 
8.1        Pregnancy 
8.3        Nursing Mothers 
8.4        Pediatric Use 
8.5        Geriatric Use 
10        OVERDOSAGE 
11        DESCRIPTION 
12        CLINICAL PHARMACOLOGY 
12.1      Mechanism of Action 
12.2      Pharmacodynamics 
12.3      Pharmacokinetics 
13        NONCLINICAL TOXICOLOGY 
13.1      Carcinogenesis, Mutagenesis, Impairment of Fertility 
14        CLINICAL STUDIES 
14.1     Elevated Baseline IOP 
14.2      Progression of Increased Iris Pigmentation 
16        HOW SUPPLIED/STORAGE AND HANDLING 
17        PATIENT COUNSELING INFORMATION 
17.1      Potential for Pigmentation 
17.2      Potential for Eyelash Changes 
17.3      Handling the Container 
17.4      When to Seek Physician Advice 
17.5      Use with Contact Lenses 
17.6      Use with Other Ophthalmic Drugs 
*Sections or subsections omitted from the full prescribing information are not listed. 


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FULL PRESCRIBING INFORMATION 
1 INDICATIONS AND USAGE 
Latanoprost Sterile Ophthalmic Solution is indicated for the reduction of elevated intraocular 
pressure in patients with open-angle glaucoma or ocular hypertension. 
2 DOSAGE AND ADMINISTRATION 
The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one 
dose is missed, treatment should continue with the next dose as normal.   
The dosage of latanoprost ophthalmic solution should not exceed once daily; the combined 
use of two or more prostaglandins, or prostaglandin analogs including latanoprost is not 
recommended. It has been shown that administration of these prostaglandin drug products 
more than once daily may decrease the intraocular pressure (IOP) lowering effect or cause 
paradoxical elevations in IOP.   
Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum 
effect is reached after 8 to 12 hours.   
Latanoprost ophthalmic solution may be used concomitantly with other topical ophthalmic 
drug products to lower IOP.  If more than one topical ophthalmic drug is being used, the 
drugs should be administered at least five (5) minutes apart.  Contact lenses should be 
removed prior to the administration of latanoprost ophthalmic solution, and may be 
reinserted 15 minutes after administration. 
3 DOSAGE FORMS AND STRENGTHS 
Sterile ophthalmic solution containing 50 mcg/mL latanoprost. 
4 CONTRAINDICATIONS 
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in 
this product. 
5 WARNINGS AND PRECAUTIONS 
5.1 Pigmentation 
Latanoprost has been reported to cause changes to pigmented tissues. The most frequently 
reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and 
eyelashes. Pigmentation is expected to increase as long as latanoprost is administered. 
The pigmentation change is due to increased melanin content in the melanocytes rather than 
to an increase in the number of melanocytes. After discontinuation of latanoprost, 
pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue 
and eyelash changes have been reported to be reversible in some patients. Patients who 
receive treatment should be informed of the possibility of increased pigmentation. Beyond 5 
years the effects of increased pigmentation are not known [see Clinical Studies (14.2)]. 
Iris color change may not be noticeable for several months to years. Typically, the brown 
pigmentation around the pupil spreads concentrically towards the periphery of the iris and 


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the entire iris or parts of the iris become more brownish.  Neither nevi nor freckles of the iris 
appear to be affected by treatment. While treatment with latanoprost can be continued in 
patients who develop noticeably increased iris pigmentation, these patients should be 
examined regularly [see Patient Counseling Information (17.1)]. 
5.2 Eyelash Changes 
Latanoprost may gradually change eyelashes and vellus hair in the treated eye; these changes 
include increased length, thickness, pigmentation, the number of lashes or hairs, and 
misdirected growth of eyelashes. Eyelash changes are usually reversible upon 
discontinuation of treatment [see Patient Counseling Information (17.2)]. 
5.3 Intraocular Inflammation 
Latanoprost should be used with caution in patients with a history of intraocular 
inflammation (iritis/uveitis) and should generally not be used in patients with active 
intraocular inflammation because inflammation may be exacerbated. 
5.4 Macular Edema 
Macular edema, including cystoid macular edema, has been reported during treatment with 
latanoprost. Latanoprost ophthalmic solution should be used with caution in aphakic 
patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with 
known risk factors for macular edema. 
5.5 Herpetic Keratitis 
Reactivation of Herpes Simplex keratitis has been reported during treatment with latanoprost 
ophthalmic solution.  Latanoprost should be used with caution in patients with a history of 
herpetic keratitis. Latanoprost should be avoided in cases of active herpes simplex keratitis 
because inflammation may be exacerbated. 
5.6 Bacterial Keratitis 
There have been reports of bacterial keratitis associated with the use of multiple-dose 
containers of topical ophthalmic products. These containers had been inadvertently 
contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption 
of the ocular epithelial surface [see Patient Counseling Information (17.3)]. 
5.7 Use with Contact Lenses 
Contact lenses should be removed prior to the administration of latanoprost ophthalmic 
solution, and may be reinserted 15 minutes after administration. 
6 ADVERSE REACTIONS 
The following adverse reactions were reported in postmarketing experience and are discussed 
in greater detail in other sections of the label: 
• Iris pigmentation changes [see Warnings and Precautions (5.1)] 
• Eyelid skin darkening [see Warnings and Precautions (5.1)] 
• Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [see   
Warnings and Precautions (5.2)] 
• Intraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)] 


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• Macular edema, including cystoid macular edema [see Warnings and Precautions (5.4)] 
6.1 Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, the adverse reaction 
rates observed in the clinical studies of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in clinical practice. 
Latanoprost was studied in three multicenter, randomized, controlled clinical trials. Patients 
received 50 mcg/mL latanoprost once daily or 5 mg/mL active-comparator (timolol) 
twice daily. The patient population studied had a mean age of 65±10 years. Seven percent of 
patients withdrew before the 6-month endpoint. 
Table 1: Ocular Adverse Reactions and ocular signs/symptoms reported by 5–15% of 
patients receiving Latanoprost 
Symptom/Finding 
Adverse Reactions (incidence (%) 
Latanoprost 
(n = 460) 
Timolol 
(n = 369) 
Foreign body sensation 
13 
8 
Punctate epithelial 
keratopathy 
10 
9 
Stinging 
9 
12 
Conjunctival hyperemia 
8 
3 
Blurred vision 
8 
8 
Itching 
8 
8 
Burning 
7 
8 
Increased pigmentation of 
the iris 
7 
0 
Less than 1% of the patients treated with latanoprost required discontinuation of therapy 
because of intolerance to conjunctival hyperemia. 
6.2 Postmarketing Experience 
The following reactions have been identified during postmarketing use of latanoprost in 
clinical practice. Because they are reported voluntarily from a population of unknown size, 
estimates of frequency cannot be made. The reactions, which have been chosen for inclusion 
due to either their seriousness, frequency of reporting, possible causal connection to 
latanoprost, or a combination of these factors, include: 
Nervous System Disorders: dizziness, headache, and toxic epidermal necrolysis 
Eye Disorders: eyelash and vellus hair changes (increased length, thickness, pigmentation, 
and number); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); 
macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting 
in eye irritation; periorbital and lid changes resulting in deepening of the eyelid sulcus. 
Respiratory, Thoracic and Mediastinal Disorders: asthma and exacerbation of asthma; 
dyspnea 


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Skin and Subcutaneous Tissue Disorders: eyelid skin darkening Infections and Infestations: 
Herpes keratitis 
Table 2: Adverse Reactions that were reported in 1–5% of patients receiving 
Latanoprost 
 
Adverse Reactions (incidence (%)) 
Latanoprost 
(n = 460) 
Timolol 
(n = 369) 
Ocular Events/Signs and 
Symptoms 
 
 
Excessive tearing 
4 
6 
Lid discomfort/pain 
4 
2 
Dry eye 
3 
3 
Eye pain 
3 
3 
Lid crusting 
3 
3 
Lid erythema 
3 
2 
Photophobia 
2 
1 
Lid edema 
1 
3 
Systemic Events 
 
 
Upper respiratory tract 
infection/cold/flu 
3 
3 
Muscle/joint/back pain 
1 
0.5 
Rash/allergic skin reaction 
1 
0.3 
7 DRUG INTERACTIONS 
In vitro studies have shown that precipitation occurs when eye drops containing thimerosal 
are mixed with latanoprost.  If such drugs are used, they should be administered at least five 
(5) minutes apart.  
The combined use of two or more prostaglandins, or prostaglandin analogs including 
latanoprost is not recommended. It has been shown that administration of these prostaglandin 
drug products more than once daily may decrease the IOP lowering effect or cause 
paradoxical elevations in IOP. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Teratogenic Effects: Pregnancy Category C. 


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Reproduction studies have been performed in rats and rabbits.  In rabbits, an incidence of 4 
of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum 
human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the 
maximum human dose. 
There are no adequate and well-controlled studies in pregnant women. Latanoprost should be 
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
8.3 Nursing Mothers 
It is not known whether this drug or its metabolites are excreted in human milk. Because 
many drugs are excreted in human milk, caution should be exercised when latanoprost is 
administered to a nursing woman. 
8.4 Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
8.5 Geriatric Use 
No overall differences in safety or effectiveness have been observed between elderly and 
younger patients. 
10 OVERDOSAGE 
Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma 
concentrations 200 times higher than during clinical treatment and no adverse reactions were 
observed.  Intravenous dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, 
fatigue, hot flushes, nausea, and sweating.  If overdosage with latanoprost occurs, treatment 
should be symptomatic. 
11 DESCRIPTION 
Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-
7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-
heptenoate. Its molecular formula is C26H40O5 and its chemical structure is: 
 
 
 
Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely 
soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically 
insoluble in water. 
Latanoprost ophthalmic solution 0.005% is supplied as a sterile, isotonic, buffered aqueous 
solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 


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267 mOsmol/kg.  Each mL of Latanoprost ophthalmic solution contains 50 micrograms of 
latanoprost.  Benzalkonium chloride, 0.02% is added as a preservative.  The inactive 
ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium 
hydrogen phosphate anhydrous, and water for injection.  One drop contains approximately 
1.5 mcg of latanoprost. 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the 
intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals 
and man suggest that the main mechanism of action is increased uveoscleral outflow. 
Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the 
level of IOP, the greater the likelihood of optic nerve damage and visual field loss. 
12.2 Pharmacodynamics 
Reduction of the IOP in man starts about 3–4 hours after administration and maximum effect 
is reached after 8–12 hours. IOP reduction is present for at least 24 hours. 
12.3 Pharmacokinetics 
Absorption 
Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed 
to the acid form to become biologically active. 
Distribution 
The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be 
measured in aqueous humor during the first 4 hours, and in plasma only during the first 
hour after local administration. Studies in man indicate that the peak concentration in the 
aqueous humor is reached about two hours after topical administration. 
Metabolism 
Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the 
biologically active acid. The active acid of latanoprost reaching the systemic circulation 
is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via 
fatty acid β-oxidation. 
Excretion 
The elimination of the acid of latanoprost from human plasma is rapid (t1/2 = 17 min) after 
both intravenous and topical administration. Systemic clearance is approximately 
7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the 
kidneys. Approximately 88% and 98% of the administered dose are recovered in the urine 
after topical and intravenous dosing, respectively. 


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13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at 
doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum 
human dose) for up to 20 and 24 months, respectively. 
Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus 
tests. Chromosome aberrations were observed in vitro with human lymphocytes.  Additional 
in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative. 
Latanoprost has not been found to have any effect on male or female fertility in animal 
studies. 
14 CLINICAL STUDIES 
14.1 Elevated Baseline IOP 
Patients with mean baseline IOP of 24 – 25 mmHg who were treated for 6 months in multi-
center, randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP 
reduction with latanoprost 0.005% dosed once daily was equivalent to the effect of timolol 
0.5% dosed twice daily. 
14.2 Progression of Increased Iris Pigmentation 
A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to 
evaluate the progression of increased iris pigmentation with continuous use of latanoprost 
once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was 
based on observed-cases population of the 380 patients who continued in the extension 
phase.  Results showed that the onset of noticeable increased iris pigmentation occurred 
within the first year of treatment for the majority of the patients who developed noticeable 
increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation 
throughout the five years of the study. Observation of increased iris pigmentation did not 
affect the incidence, nature, or severity of adverse events (other than increased iris 
pigmentation) recorded in the study.  IOP reduction was similar regardless of the 
development of increased iris pigmentation during the study. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Latanoprost ophthalmic solution is a clear, isotonic, buffered, preserved colorless solution of 
latanoprost 0.005% (50 mcg/mL).  It is supplied as a 2.5 mL solution in a 4 mL clear low 
density polyethylene bottle with a low density polyethylene dropper tip, and a turquoise high 
density polypropylene screw cap, and a clear PVC film with a single perforation. 
2.5 mL fill, 0.005% (50 mcg/mL): Package of 1 bottle: 
NDC 24208-463-25 
Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 
46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 
40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be 
stored at room temperature up to 25°C (77°F) for 6 weeks. 


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17 PATIENT COUNSELING INFORMATION 
17.1 Potential for Pigmentation 
Advise patients about the potential for increased brown pigmentation of the iris, which may 
be permanent. Inform patients about the possibility of eyelid skin darkening, which may be 
reversible after discontinuation of Latanoprost ophthalmic solution [see Warnings and 
Precautions (5.1)]. 
17.2 Potential for Eyelash Changes 
Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during 
treatment with Latanoprost ophthalmic solution. These changes may result in a disparity 
between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or 
direction of eyelash growth.  Eyelash changes are usually reversible upon discontinuation 
of treatment. 
17.3 Handling the Container 
Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or 
surrounding structures because this could cause the tip to become contaminated by 
common bacteria known to cause ocular infections. Serious damage to the eye and 
subsequent loss of vision may result from using contaminated solutions [see Warnings and 
Precautions (5.6)]. 
17.4 When to Seek Physician Advice 
Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or 
infection) or have ocular surgery, or develop any ocular reactions, particularly conjunctivitis 
and eyelid reactions, they should immediately seek their physician’s advice concerning the 
continued use of the multiple-dose container. 
17.5 Use with Contact Lenses 
Advise patients that Latanoprost ophthalmic solution contains benzalkonium chloride, which 
may be absorbed by contact lenses. Contact lenses should be removed prior to administration 
of the solution. Lenses may be reinserted 15 minutes following administration of Latanoprost 
ophthalmic solution. 
17.6 Use with Other Ophthalmic Drugs 
If more than one topical ophthalmic drug is being used, the drugs should be administered at 
least five (5) minutes apart. 
Manufactured By: 
Bausch & Lomb Incorporated 
Tampa, Florida 33637 
©Bausch & Lomb Incorporated 
 
 
 
9144705 (folded) 
Revised: February 2015 
 
 
 
 
9144805 (flat) 
 
 


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Appendix 4 
Sponsor’s Obligations 
Aerie Pharmaceuticals, Inc. is committed to: 
1. Complying with the local health authority regulations for the conduct of clinical research 
studies. 
2. Informing the Investigator of any new information about the investigational product that 
may affect the subject's welfare or may influence the subject's decision to continue 
participation in the study. 
3. In the event of a serious adverse experience, whether related to the use of the study 
medication or device or not, or the death of a subject, the Sponsor is responsible for 
notifying the regulatory authority(ies) immediately (see Section 6.9, Adverse events).  
4. When the study is terminated the Sponsor should promptly inform the regulatory 
authority(ies) of the termination and the reason(s) for it. The IRB should also be informed 
promptly and provide the reason(s) for the termination by the Sponsor as specified by the 
applicable regulatory requirement(s).  
5. Providing to the Investigator the most up-to-date editions of the Clinical Investigator’s 
Brochure (for the investigational product), the protocol, Serious Adverse Experience 
forms, and a full set of Case Report Forms for each subject entered into the study to 
document the study evaluation parameters. 
6. Providing study medications suitably masked/blinded, coded and packaged for use with 
subjects entered into the study. 
7. Providing statistical and report writing resources to complete appropriate reporting of 
study results. 
8. Ensuring equity considerations among all Investigators in multicenter studies, including 
all matters of publications and meeting presentations, etc. (where applicable). 
9. Prepare an FDA Form No. 3454 (Certification: Financial Interests and Arrangements of 
Clinical Investigators) or 3455 (Disclosure: Financial Interests and Arrangements of 
Clinical Investigators) or Sponsor’s equivalent.


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Appendix 5 
Investigator’s Obligations 
The Investigator is obligated to: 
1. In the event of a serious adverse experience, whether related to the use of the study 
medication or device or not, or the death of a subject, the Investigator is responsible for 
notifying the Sponsor Safety Officer immediately (see Section 6.9, Adverse events). 
The Investigator must also notify the Sponsor Representative and the Institutional 
Review Board (IRB) to which he/she is responsible. 
2. Prior to initiating the study, sign and return to the Sponsor Representative, the relevant 
form (Statement of Investigator form provided by the Sponsor for studies involving 
non-significant risk devices, or OTC drugs; or an FDA No. 1572 is required for IND 
Phase I, II, III and IV studies). Each sub-Investigator who will assist in the study is to be 
identified in the required form. The current curriculum vitae (signed and dated) of the 
principal Investigator and of each sub-Investigator named in the Statement of Investigator 
form or 1572 form is to accompany the form.  
3. Cooperate with the Sponsor on the preparation of an FDA Form No. 3454 
(Certification: Financial Interests and Arrangements of Clinical Investigators) or 3455 
(Disclosure: Financial Interests and Arrangements of Clinical Investigators).  
4. Obtain and submit to the Sponsor a copy of his/her IRB approval of the protocol prior to 
initiating the study. 
5. Obtain signed informed consent from each subject or his/her legal guardian prior to 
acceptance of the subject into the study. 
6. Read, and agree to adhere to the study protocol prior to the initiation of the study. 
Deviations from the study protocol are not to be implemented without the prior written 
approval of the Sponsor and IRB, unless protection of the safety and welfare of study 
subjects requires prompt action. During the study, if the Investigator feels that in his/her 
clinical judgment, it is necessary to promptly terminate one or more subjects from the 
study, or to promptly implement reasonable alternatives to, or deviations from the 
protocol in consideration of the safety of study subjects, the Sponsor is to be notified of 
these terminations, alternatives, and deviations, and the reasons for such changes are to 
be documented in the study records. The Investigator is to also notify his/her IRB of any 
such changes. 
7. Accurately record, at the Investigator’s site, all required data on each subject's electronic 
Case Report Form.  
 
8. Replace subjects consistent with the directions in Section 4.4. 
 
 


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9. Keep accurate records of the number of study medication or device units received from 
the Sponsor and dispensed or administered to each subject during the study, and return 
any unused study medication or devices to the Sponsor at the completion of the study. 
Before returning the study medications or devices to the Sponsor, a detailed inventory 
should be recorded and placed in the Investigator’s file. 
10. Assure that Investigational Products will be dispensed or administered only to subjects 
under his/her personal supervision, or under the supervision of authorized sub-
Investigators responsible to him/her. 
11. Allow a representative of the Sponsor and/or representatives of health regulatory 
agencies to inspect all Case Report Forms and corresponding portions of each study 
subject's source documentation (ie, original office, hospital, and laboratory records) 
at mutually convenient times at regular intervals during the study, and upon request after 
the study has been completed. The purpose of these on-site monitoring visits is to provide 
the Sponsor the opportunity to evaluate the progress of the study, document compliance 
with the protocol and with regulatory requirements, verify the accuracy and completeness 
of subject electronic Case Report Forms, resolve any apparent discrepancies or 
inconsistencies in the study records, and account for all investigational supplies. 
12. Provide the governing IRB with a brief (ie, one to three pages) Investigator's summary 
within 90 working days of the study completion.  
13. Complete the study within the time limits agreed upon with the Sponsor prior to the 
initiation of the study. 
14. Maintenance of records 
a. Disposition of drug. An investigator is required to maintain adequate records 
of the disposition of the drug, including dates, quantity, and use by subjects. 
If the investigation is terminated, suspended, discontinued, or completed, the 
investigator shall return the unused supplies of the drug to the Sponsor, or 
otherwise provide for disposition of the unused supplies of the drug under 
21 CFR 312.59. 
 
b. Case histories. An investigator is required to prepare and maintain adequate 
and accurate case histories that record all observations and other data pertinent 
to the investigation on each individual administered the investigational drug or 
employed as a control in the investigation. Case histories include the case 
report forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of 
the physician, the individual's hospital chart(s), and the nurses' notes. The case 
history for each individual shall document that informed consent was obtained 
prior to participation in the study. 
 
c. Record retention. An investigator shall retain records required to be 
maintained under this part for a period of 2 years following the date a 


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marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is 
not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. 
 
These documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
If for any reason the Investigator withdraws from the responsibility of maintaining the study 
records for the required period of time, custody of the records may be transferred to any other 
person who will accept responsibility for the records. The Sponsor is to be notified in writing 
of any such transfer. 


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Appendix 6 
Declaration of Helsinki 
Recommendations Guiding Medical Doctors in Biomedical Research Involving Human 
Subjects 
I. BASIC PRINCIPLES 
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
2. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted to 
a specially appointed independent committee for consideration, comment and guidance. 
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human subject must always rest with a medically qualified 
person and never rest with the subject of the research, even though the subject has given 
his or her consent. 
4. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
5. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society. 
6. The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
7. Doctors should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable. 
Doctors should cease any investigation if the hazards are found to outweigh the potential 
benefits. 
8. In publication of the results of his or her research, the doctor is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to 


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abstain from participation in the study and that he or she is free to withdraw his or her 
consent to participation at any time. The doctor should then obtain the subject's given 
informed consent, preferably in writing. 
10. When obtaining informed consent for the research project the doctor should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case, the informed consent should be obtained by a doctor 
who is not engaged in the investigation and who is completely independent of this official 
relationship. 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation. 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(CLINICAL RESEARCH) 
13. In the treatment of the sick person, the doctor must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing 
health or alleviating suffering. 
14. The potential benefits, hazards and discomforts of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
15. In any medical study, all subjects - including those of a control group, if any, should be 
assured of the best proven diagnostic and therapeutic methods. 
16. The refusal of the subject to participate in a study must never interfere with the 
doctor-subject relationship. 
17. If the doctor considers it essential not to obtain informed consent, the specific reasons for 
this proposal should be stated in the experimental protocol for transmission to the 
independent committee. 
18. The doctor can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the subject. 
 
 


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III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECT (NONCLINICAL BIOMEDICAL RESEARCH) 
19. In the purely scientific application of medical research carried out on a human being, it is 
the duty of the doctor to remain the protector of the life and health of that person on 
whom biomedical research is being carried out. 
20. The subjects should be volunteers - either healthy person or subjects for whom the 
experimental design is not related to the subject's illness. 
21. The Investigator or the team should discontinue the research if in his/her or their 
judgment it may, if continued, be harmful to the individual.  
22. In research on man, the interest of science and society should never take precedence over 
consideration related to the well-being of the subject.


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Aerie Pharmaceuticals, Inc. 
 
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Appendix 7 
Sample SAS Code 
The following SAS code will be used for multiple imputations using the Monte-Carlo 
Markov Chain method, where a separate model will be fit for each time point at each visit. 
proc mi data = indata seed = 48669 out = outdata1; 
     mcmc initial = em; 
     var trt01pn baseline IOP; 
run; 
 
where 
- 
indata is the name of the input dataset 
- 
outdata1 is the name of the output dataset 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
baseline captures the baseline IOP for the given time point 
- 
IOP is the name of the IOP measure. 
Five complete data sets will be generated from the above code. Each complete data set will 
be used to analyze this primary efficacy endpoint separately using analysis of variance. Then, 
the SAS procedure MIANALYZE will be used to analyze the results from the 5 complete 
data sets to generate a combined inference. The following SAS code will be used: 
 
ods output diffs = outdata2; 
proc mixed data= outdata1; 
 
by _IMPUTATION_; 
 
class trt01pn; 
 
model IOP = trt01pn baseline; 
 
lsmeans trt01pn / cl pdiff; 
run; 
 
proc sort data= outdata2; 
 
by trt01pn _trt01pn; 
run; 
 
ods output ParameterEstimates = outdata3; 
proc mianalyze data= outdata2 alpha = 0.05; 
 
by trt01pn _trt01pn; 
 
class trt01pn _trt01pn; 
 
modeleffects estimate; 
 
stderr;  


PG324 Ophthalmic Solution 
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Aerie Pharmaceuticals, Inc. 
 
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run; 
where 
- 
outdata1 is the name of the input dataset from Proc MI 
- 
_IMPUTATION_ is the imputation number 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
IOP is the name of the IOP measure 
- 
baseline captures the baseline IOP for the given time point 
- 
outdata2 is the name of the output dataset that contains the statistical results of the 
difference between treatment groups  
- 
outdata3 is the name of the output dataset that contains summary and inferential 
statistics. 
 

SAP_001.pdf: 
 
 
 
 
A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group 
12-month study assessing the safety and 
ocular hypotensive efficacy of PG324 
Ophthalmic Solution compared to AR-13324 
Ophthalmic Solution, 0.02% and Latanoprost 
Ophthalmic Solution, 0.005% in subjects with 
elevated intraocular pressure 
 
 
NCT02558400 
 
 
20July2016 
 


Aerie Pharmaceuticals, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. PG324-CS301 
 
20 July 2016 
Version 1.0 
 
Page 1 of 38 
 
STATISTICAL ANALYSIS PLAN 
Version 1.0 
20 July 2016  
 
 
 
 
 
 
 A prospective, double-masked, randomized, multi-center, active-controlled, 
parallel, 12-month study assessing the safety and ocular hypotensive efficacy 
of PG324 Ophthalmic Solution compared to AR-13324 Ophthalmic Solution, 
0.02% and Latanoprost Ophthalmic Solution, 0.005% in subjects with 
elevated intraocular pressure 
 
 
PROTOCOL NUMBER PG324-CS301 
 
 
 
SPONSORED BY 
 
Aerie Pharmaceuticals, Inc. 
135 US Highway 206, Suite 15 
Bedminster, NJ 07921 
Telephone: (908) 470-4320 
Fax: (908) 325-0266 
 
 
PREPARED BY 
 
 
 
 
 
 
 
 
 
 
This document contains Aerie Pharmaceuticals, Inc. (Aerie) information that is confidential, a trade secret and/or 
proprietary in nature.  It is loaned to you for your confidential use on behalf of Aerie and is not to be photocopied, 
disclosed or transmitted to any other person or party who is not covered by a Confidential Disclosure Agreement 
with Aerie.   


Aerie Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
Protocol No. PG324-CS301 
 
20 July 2016 
Version 1.0 
 
Page 2 of 38 
DOCUMENT VERSION CONTROL 
 
Version Number 
Date 
Comments/Changes 
0.1 
1.0 
February 5, 2016 
20 July, 2016 
Draft 
Final 
 
 
 
 
 




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Statistical Analysis Plan 
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20 July 2016 
Version 1.0 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 6 
1. 
PURPOSE OF THE ANALYSES ......................................................................................... 7 
2. 
PROTOCOL SUMMARY ..................................................................................................... 8 
2.1 Study Objectives .............................................................................................................. 8 
2.2 Overall Study Design and Plan ........................................................................................ 8 
2.3 Study Population ............................................................................................................ 11 
2.4 Treatment Regimens ...................................................................................................... 11 
2.5 Treatment Group Assignments or Randomization ......................................................... 11 
2.6 Sample Size Determination ............................................................................................ 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..................................... 13 
4. 
ANALYSIS POPULATIONS .............................................................................................. 14 
4.1 Randomized Population ................................................................................................. 14 
4.2 Intent-to-Treat Population (ITT) .................................................................................... 14 
4.3 Per-protocol Population (PP) ......................................................................................... 14 
4.4 Safety Population ........................................................................................................... 14 
5. 
STUDY SUBJECTS ............................................................................................................. 15 
5.1 Disposition of Subjects ................................................................................................... 15 
5.2 Protocol Deviations ........................................................................................................ 15 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................... 16 
6.1 Demographics and Baseline Characteristics .................................................................. 16 
6.2 Prior and Concomitant Medications ............................................................................... 16 
6.3 Medical and Ocular History ........................................................................................... 17 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ................................................ 18 
8. 
EFFICACY EVALUATION ............................................................................................... 19 
8.1 Overview of Efficacy Analysis Issues ............................................................................ 19 
8.1.1 
Handling of Dropouts or Missing Data ............................................................. 19 
8.1.2 
Multicenter Studies ........................................................................................... 19 
8.1.3 
Assessment Time Windows .............................................................................. 19 
8.2 Efficacy Variables and Primary Hypotheses .................................................................. 19 
8.3 Analysis Methods ........................................................................................................... 21 
8.3.1 
Primary Efficacy Analyses ................................................................................ 23 
8.3.2 
Secondary Efficacy Analyses ............................................................................ 24 
8.4 Examination of Subgroups ............................................................................................. 25 
9. 
SAFETY EVALUATION .................................................................................................... 27 
9.1 Overview of Safety Analysis Methods ........................................................................... 27 
9.2 Extent of Exposure ......................................................................................................... 27 
9.3 Adverse Events ............................................................................................................... 27 
9.4 Deaths, Serious Adverse Events, and Other Significant Adverse Events ...................... 28 
9.5 Clinical Laboratory Evaluation ...................................................................................... 29 
9.6 Vital Signs, Ophthalmic Exam Findings, and Other Safety Outcomes .......................... 29 
9.6.1 
Vital Signs ......................................................................................................... 29 
9.6.2 
Intraocular Pressure ........................................................................................... 29 
9.6.3 
Visual Acuity .................................................................................................... 29 


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9.6.4 
Dilated Ophthalmoscopy and Cup-to-Disc Ratio .............................................. 29 
9.6.5 
Biomicroscopy .................................................................................................. 30 
9.6.6 
Comfort Test (Ocular Tolerability) ................................................................... 30 
9.6.7 
Pupil Size .......................................................................................................... 30 
9.6.8 
Visual Field Examination, Pachymetry, and Gonioscopy ................................. 31 
10. PHARMACOKINETIC EVALUATION .......................................................................... 32 
11. OTHER ANALYSES ........................................................................................................... 33 
12. INTERIM ANALYSES AND DATA MONITORING ..................................................... 34 
13. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................... 35 
14. REFERENCES ..................................................................................................................... 36 
15. APPENDICES ...................................................................................................................... 37 
16. ATTACHMENTS ................................................................................................................ 38 
 


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Statistical Analysis Plan 
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20 July 2016 
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Page 6 of 38 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
AR-13324 
Analysis of Variance 
AR-13324 (Netarsudil Ophthalmic Solution) 0.02% 
BCVA 
Best Corrected Visual Acuity 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS Mean 
Least Squares Mean 
ITT 
Intent-to-treat 
MMRM 
Mixed Model Repeated Measures 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
OU 
Both eyes 
PP 
Per-Protocol 
QD 
Once-daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
 
 
SE 
Standard Error 
TEAE 
Treatment Emergent Adverse Event 
VF 
Visual Fields 
 
 
 


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1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is being developed after review of the Aerie Pharmaceuticals, 
Inc., protocol number PG324-CS301 (Amendment 2, dated 12 April 2016) but before any 
analyses of the data.  The SAP contains detailed information to aid in the performance of the 
statistical analysis and reporting of the study data for use in the final clinical study report (CSR).  
This SAP is being written with due consideration of the recommendations outlined in the most 
recent International Conference on Harmonization (ICH) E9 Guideline entitled: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled: Structure and 
Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and 
safety assessments that will be evaluated.  This SAP provides details of the specific statistical 
methods that will be used.  If additional analyses are required to supplement the planned analyses 
described in this SAP, they may be completed and will be identified in the CSR. 
 


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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
The primary objectives of this study are to evaluate: 
 The ocular hypotensive efficacy of PG324 Ophthalmic Solution, QD relative to each of 
its active components, Netarsudil 0.02%, QD and Latanoprost 0.005%, QD at 8:00, 
10:00, and 16:00 hours at Week 2, Week 6, and Month 3   
 The ocular and systemic safety of PG324 Ophthalmic Solution during a 12-month 
treatment period 
 
The secondary objectives of this study are to evaluate:  
 Mean IOP within a treatment group at each post-treatment time point 
 Mean diurnal IOP within a treatment group at each post-treatment visit 
 Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
 Mean change from baseline in diurnal IOP at each post-treatment visit 
 Mean percent change from diurnally adjusted baseline IOP at each post-treatment time 
point 
 Mean percent change from baseline in diurnal IOP at each post-treatment visit 
 Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in diurnal IOP levels 
 
2.2 
Overall Study Design and Plan 
This is a phase 3, double-masked, randomized, multi-center, active-controlled, parallel-group, 
12-month study assessing the safety and ocular hypotensive efficacy of PG324 Ophthalmic 
Solution compared to each of its active components, Netarsudil 0.02% and Latanoprost 0.005% 
in subjects with elevated intraocular pressure. All investigational products will be dosed QD 
(PM). A total of approximately 690 subjects will be enrolled in this study at approximately 60 
clinical sites, all in United States, comprising a total of approximately 230 subjects per treatment 
arm for each of 3 treatment arms. Subjects who are enrolled in this study will be those at least 18 
years of age with diagnosed open angle glaucoma (OAG) or ocular hypertension (OHT), each of 
whom meets all inclusion criteria and none of the exclusion criteria.  
There will be a total of 9 visits designated as V1 – V9. For visits 3, 4, 5, 6, 7, 8, and 9, the 
subjects will be evaluated at multiple time points (08:00, 10:00, and 16:00 hours) within the visit 
day. These time points will be designated as visit x.0, x.1, and x.2 respectively. The total 
treatment period is 365 days, starting at Visit 3 (Day 1), and there are follow-up visits at Week 2, 
Week 6, and Months 3, 6, 9, and 12. 
At Screening (Visit 1), an examination will be conducted, including measurements of heart rate 
and blood pressure (vital signs), urine pregnancy test (for women of child bearing potential), and 
an ophthalmic examination (to include ocular symptoms, best corrected visual acuity (BCVA), 
central corneal thickness by ultrasound pachymetry (may be taken within 1 week of Visit 1), 
intraocular pressure (IOP; before pupil dilation), biomicroscopy, and dilated ophthalmoscopy).  
Visual fields and gonioscopy may be taken up to three months prior to randomization (Visit 3). 
Subject symptoms will be queried and blood samples will be taken for clinical chemistry and 


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20 July 2016 
Version 1.0 
 
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hematology.  All individuals who are qualified for enrollment will have their current ocular 
hypotensive therapy reviewed to determine the appropriate washout period, prior to Visit 2, as 
specified in Section 5.7.1 of the protocol.    
At Visit 2 (Qualification #1, Day -2 to -7, 08:00 hours), potential study subjects will again be 
questioned with respect to changes in their health (to be recorded as medical history) and 
concomitant medication use.  Study inclusion/exclusion criteria will be reassessed to confirm 
eligibility. BCVA, vital signs, IOP, and biomicroscopy assessments will again be performed.  
The potential subject must have a post-washout IOP > 20 mmHg and < 36 mmHg in both eyes to 
qualify for further participation.  This is the first of four qualifying IOPs for randomization 
Qualified subjects will return for Visit 3 (Qualification #2, Baseline, Day 1) 2 to 7 days after 
Visit 2 at 3 time points. At Visit 3.0 (08:00 hours), testing will include recording 
symptomatology, vital signs, BCVA, IOP, biomicroscopy, and pupil size assessments.  Any 
symptoms reported at this visit should be entered into medical history. The potential subject must 
have a post-washout IOP > 20 mmHg and < 36 mmHg in both eyes to qualify for further 
participation. This is the second of four qualifying IOPs for randomization.    
Qualifying subjects will return for two additional visits on this day (Visit 3.1 at 10:00 hours and 
Visit 3.2 at 16:00 hours) during which symptomatology, IOP, and biomicroscopy assessments 
will be performed.  The subject must have an IOP of > 17 mmHg and < 36 mmHg in both eyes 
to continue to be qualified.  These are the third and the fourth of four qualifying IOPs for 
randomization.   
In summary, the following IOP criteria must be met at the qualifying visits in both eyes for the 
subject to qualify for the study: 
Visit, Day, Time 
IOP Requirement 
(mmHg) 
Visit 2, Day-2 to -7, 8:00 
hours 
> 20 & < 36 
Visit 3.0, Day 1, 8:00 hours 
> 20 & < 36 
Visit 3.1, Day 1, 10:00 hours 
> 17 & < 36 
Visit 3.2, Day 1, 16:00 hours 
> 17 & < 36 
Subjects qualify in both eyes based upon IOP and ocular history.  
For each qualification visit, individuals who don’t meet the IOP requirement may return for up to 
2 additional unscheduled qualification visits within 1 week of failing the specific qualification 
visit. Individuals returning at an unscheduled visit within 1 week are required to only re-measure 
IOP in both eyes. Upon return, such individuals would need to qualify at 08:00, 10:00 and16:00 
hours to continue the study.  


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For a subject who qualifies, the study eye will be the eye with the higher IOP at 08:00 hours on 
Visit 3. If both eyes have the same IOP at 08:00 hours on Visit 3, then the right eye will be the 
study eye. In each subject, both eyes will be treated. 
 
At this point, eligible subjects will be enrolled and assigned to an investigational product through 
an IWRS system according to a computer-generated randomization list. The first kit removed 
from an investigational product packer assigned through the IWRS system to the eligible subject 
will be dispensed unopened to the subject, along with written storage instructions. 
 
Subjects will be: 
 
 Instructed to self-administer their masked medication at home between 20:00-22:00 hours 
(8 PM - 10 PM) beginning with the evening dose on that day 
Subjects will return for post-treatment Visits 4.0, 4.1, and 4.2 (Week 2 [Day 15]; 08:00, 10:00, 
and 16:00 hours), Visits 5.0, 5.1, and 5.2 (Week 6 [Day 43]; 08:00, 10:00, and 16:00 hours), 
Visits 6.0, 6.1, and 6.2 (Month 3 [Day 90]; 08:00, 10:00, and 16:00 hours), Visits 7.0, 7.1, and 
7.2 (Month 6 [Day 180]; 08:00, 10:00, and 16:00 hours), Visits 8.0, 8.1, and 8.2 (Month 9 [Day 
270]; 08:00, 10:00, and 16:00 hours), and Visits 9.0, 9.1, and 9.2 (Month 12 [Day 365]; 08:00, 
10:00, and 16:00 hours).  Symptomatology and non-dilated eye examinations including IOP and 
biomicroscopy will be conducted at all of these visits (except biomicroscopy at Visits 8.1, 8.2, 
9.1, and 9.2).  Vital signs, comfort test, and BCVA will also be conducted at the 08:00 hour 
visits. Any symptoms reported, or clinical signs observed which have worsened, either from 
baseline or from previous visits at these post-dose visits, will be recorded as treatment emergent 
adverse events (TEAEs). 
Other tests will be performed in addition to those mentioned in the previous paragraph: 
1. At Visit 6.0 (Month 3 [Day 90], 08:00 hours), a urine pregnancy test will be performed, 
and visual fields, pachymetry, and pupil size will be measured.  Blood will be drawn for 
clinical chemistry and hematology labs as well. A dilated ophthalmoscopy will be 
performed at Visit 6.2 (Month 3 [Day 90], 16:00 hours).   
2. At Visit 7.0 (Month 6 [Day 180], 08:00 hours), a urine pregnancy test will be performed, 
and visual fields, pachymetry, and pupil size will be measured.  Blood will be drawn for 
clinical chemistry and hematology labs as well. A dilated ophthalmoscopy will be 
performed at Visit 7.2 (Month 6 [Day 180], 16:00 hours).   
3. At Visit 8.0 (Month 9 [Day 270], 08:00 hours), a urine pregnancy test will be performed.   
4. At Visit 9.0 (Month 12 [Day 365], 08:00 hours), a urine pregnancy test will be 
performed, and visual fields and pupil size will be measured.  Blood will be drawn for 
clinical chemistry and hematology labs as well. A dilated ophthalmoscopy will be 
performed at Visit 9.2 (Month 12 [Day 365], 16:00 hours).  Dilated ophthalmoscopy at 
Visit 9.0 should be performed for all non-completing subjects during the exit visit. 
A study schedule of events table is presented in Appendix 1. 


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2.3 
Study Population 
The study population includes subjects aged 18 years or older with a diagnosis of OAG or OHT.  
Subjects must have an unmedicated (post-washout) IOP > 20 and < 36 mmHg at 2 eligibility 
visits (08:00 hour), 2-7 days apart and > 17 and < 36 mmHg at 10:00 and 16:00 hours at the 
second qualification visit in both eyes.   Corrected visual acuity in each eye must be +1.0 
logMAR or better by early treatment of diabetic retinopathy study (ETDRS). The subject must 
also be willing to give signed inform consent and follow study instructions.  The specific 
inclusion and exclusion criteria can be found in Sections 4.2 and 4.3 of the study protocol. 
2.4 
Treatment Regimens 
There will be 3 treatments in this study: 
 PG324 (Netarsudil 0.02% and latanoprost 0.005%) Ophthalmic Solution, QD  
 Netarsudil Ophthalmic Solution 0.02%, QD 
 Latanoprost Ophthalmic Solution 0.005%, QD  
 
Each investigational product is being dosed QD OU (in the evening between 20:00 and 22:00 
hours) 
Subjects will be instructed to self-administer their masked medication once a day (QD) in the 
evening between 20:00 – 22:00 hours (8pm - 10pm). All treatments will be dosed in both eyes 
(OU). The treatment period will be 365 days.   
2.5 
Treatment Group Assignments or Randomization 
A randomization code for allocating the treatments was prepared by an independent 
biostatistician, who was not involved in the day-to-day conduct of the study, and provided in 
confidence to the VP of Manufacturing at Aerie, the clinical supply company chosen by Aerie, 
and the Interactive Web Response (IWR) system personnel.  At Visit 3.2 (Day 1), qualified 
subjects will be randomized in a 1:1:1 ratio to receive PG324 Ophthalmic Solution, Netarsudil 
Ophthalmic Solution 0.02%, or Latanoprost Ophthalmic Solution 0.005% (stratified by 
investigative site and by maximum baseline IOP [< 25 mmHg vs ≥ 25 mmHg]).  Treatment 
assignments were masked to the Investigator, the Sponsor team members involved in the day-to-
day oversight of the clinical study and employees of the CRO administrating the study for the 
Sponsor, and the study subjects.  At the end of the study, the randomized treatment assignments 
will be presented in a data listing. 
2.6 
Sample Size Determination 
One-hundred ninety six (196) subjects per arm completing 3 months of treatment yields at least 
90% power to conclude statistical superiority of PG324 to latanoprost and > 99% power to 
conclude statistical superiority of PG324 to Netarsudil at all nine time points assuming a two-
sided alpha = 0.05, a true mean difference of 1.5 mmHg (to latanoprost) and 2.0 mmHg (to 
Netarsudil), a common standard deviation of 3.5 mmHg at each time point, and independence 
among time points.  Power increases as the correlation among time points increases.  Therefore, 


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196 subjects per arm yields at least 90% power to conclude superiority to both controls over all 
nine time points. 
 
 
 
 


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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study.  Departures from these general policies may be given in the specific detailed 
sections of this SAP.  When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies. 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using descriptive statistics (n, mean, median, standard deviation (SD), minimum, and maximum).  
All categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and percentages.   
All study data will be listed by treatment, subject, visit, and time point (as applicable).  
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 0.05 significance 
level. When applicable, two-sided 95% confidence intervals will be reported.  All p-values will 
be displayed to four decimal places, with p-values less than 0.0001 presented as '<0.0001' and p-
values greater than 0.9999 presented as ‘>0.9999’.  Differences between PG324 and each 
comparator (latanoprost and Netarsudil) will be calculated as PG324 – comparator. 
For diurnally adjusted IOP, baseline will refer to the time-relevant measure at Visits 3.0 through 
3.2 (e.g. IOP at 08:00 hours at Visit 3.0 will be the baseline for 08:00 hours at Visits 4.0, 5.0, and 
6.0, etc.; IOP at 10:00 hours at Visit 3.1 will be the baseline for 10:00 hours at Visits 4.1, 5.1, 
and 6.1, etc.).  For mean diurnal IOP, baseline will refer to the mean diurnal IOP at Visit 3.  For 
all other variables, baseline is defined as the last measurement prior to the first dose of study 
medication. Change from baseline will be calculated as follow-up visit – baseline visit. 
All study data will be listed by subject, treatment, and time point (as applicable).  In the listings, 
individual subjects will be identified by a combination of site number and subject number, e.g., 
XXX-YYY, where XXX is the site number and YYY is the subject number.  
All data analysis will be performed by 
 after the study is 
completed and the database has been locked and released for un-masking.  Statistical 
programming and analyses will be performed using SAS Version 9.2 or higher.  Output will be 
provided in rtf format for tables and pdf format for tables, listings, and figures.   


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4. 
ANALYSIS POPULATIONS 
4.1 
Randomized Population 
The randomized population will include all subjects who were randomized to treatment.  
Baseline variables and demographic characteristics will be summarized for this population. 
 
4.2 
Intent-to-Treat Population (ITT) 
The ITT population will include all randomized subjects who have received at least one dose of 
study medication.  This population will be the primary population for efficacy analyses and will 
be used to summarize all efficacy variables and will summarize subjects as randomized. 
 
4.3 
Per-protocol Population (PP) 
The PP population is a subset of the ITT population, which will include those subjects (and their 
visits) who do not have major protocol violations likely to seriously affect the primary outcome 
of the study as judged by a masked evaluation prior to the unmasking of the study treatment.  
This population will be the secondary population for efficacy analyses and will be used to 
summarize a subset of efficacy variables.  If the PP and ITT populations are exactly the same, 
then additional efficacy analyses on the PP population will not be performed.  The PP population 
will summarize subjects as treated.  
 
4.4 
Safety Population 
The safety population will include all randomized subjects who have received at least one dose 
of study medication.  This population will be used to summarize safety variables and will 
summarize subjects as treated. 


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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Subject randomization, analysis populations, study completion, and withdrawal from the study 
will be summarized and listed for all randomized subjects.  The summary table will include the 
numbers of subjects randomized and included in the analysis populations by randomized 
treatment group for the ITT population and by actual treatment group for the PP and Safety 
populations.  It will also include the numbers of subjects who completed and discontinued from 
the study.  The reasons for subject discontinuation and test agent discontinuation will be 
summarized for the applicable subjects.  Reasons for subject discontinuation will include adverse 
event (AE), withdrawal of consent, non-compliance lost to follow-up, lack of efficacy, 
disallowed concurrent medication, investigator decision, protocol violation, death, and an “other” 
category for reasons other than those previously listed.  
By-subject listings will include randomization information, actual treatment assigned, first and 
last dose dates, exposure, study eye, and analysis population inclusion.  For subjects who 
prematurely discontinue following randomization, an additional by-subject listing will be 
provided that shows treatment assignment, gender, age, date of last visit, date of last dose, 
treatment duration at time of discontinuation, study day of discontinuation, and reason for 
discontinuation.  Study day of discontinuation will be calculated as (date of discontinuation – 
date of Visit 3 date +1).  Note that date of first dose is not collected, but will be assumed to be 
the Visit 3 date.  Treatment duration will be calculated as the (Date of Last Dose – Visit 3 Date + 
1). 
5.2 
Protocol Deviations 
Protocol deviations will be evaluated for all subjects in the safety population. Major protocol 
violations will be judged by a masked evaluation and summarized in writing prior to the 
unmasking of the study treatment, for the purpose of selecting the PP population. All subjects 
having a protocol deviation will be identified in a subject data listing.  The number of subjects 
with protocol deviations and level of deviations (major or minor) will be summarized by 
treatment group and severity of the deviation along with the disposition data. 
Concomitant medications used during the study will be reviewed by study staff to identify 
deviations associated with the use of prohibited medications during the double-masked treatment 
period.  Concomitant medications will be coded by medication class and preferred drug name 
using the World Health Organization Drug (WHO Drug) Dictionary (Version: March 2014).  
Procedural deviations will be determined from administrative requirements and any other 
comments recorded on the CRF or supporting documentation. 
Failure to meet all Protocol Inclusion Criteria or meeting any Exclusion Criterion will also be 
considered for categorization as a major Protocol Deviation.  Inclusion and Exclusion Criteria 
will be presented in a by-subject listing. 


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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group and listed for 
the randomized population.  Demographic parameters will include gender, iris color, age in years 
at signing of informed consent form (ICF), race, ethnicity, prior hypotensive therapy, and time 
on current hypotensive therapy.  Baseline characteristics will include study eye diagnosis of 
OHT or OAG, length of time since study eye diagnosis of OHT or OAG, study eye IOP at 
screening, and study eye mean diurnal IOP at baseline. Additionally, means for both the study 
eye and the fellow eye will be summarized separately for the baseline ocular measurements of 
deviation in visual fields, central corneal thickness, and cup to disc ratio.   
Age will be reported in years and calculated in SAS using the formula:  
Age = Floor ((ICFDT – DOB) / 365.25) 
where ICFDT is the date the subject signed the informed consent, DOB is the subject’s date of 
birth, and Floor takes the integer part of the result. 
Tests of differences between the treatment groups will be performed for both demographic and 
baseline characteristics.  Categorical responses will be tested using Fisher’s exact tests.  
Continuous measures will be tested using an analysis of variance model with treatment as the 
only explanatory variable. 
6.2 
Prior and Concomitant Medications 
All medications which the subject has taken within 30 days prior to randomization and during 
the study will be recorded on the CRF. The name of the drug, dose, route of administration, 
duration of treatment, and indication will be recorded for each medication. For combination 
products (e.g., Contac®), the brand name is required. For non-combination products, the generic 
name is desired.  The use of routine ophthalmic diagnostic pharmaceutical agents (e.g., 
fluorescein and local anesthetic) will be allowed, and individual documentation not required. 
Any change in dosing parameters should also be recorded on the CRF. 
All prior and concomitant medications will be coded to preferred drug names and therapeutic 
drug class using the WHO Drug Dictionary (Version: March 2014).  Use of concomitant 
medications will be summarized for each therapeutic drug class and each preferred drug name by 
treatment group.  Subjects will be counted only once under each therapeutic drug class and 
preferred term for which they have used at least one concomitant medication. All prior and 
concomitant medication data will also be listed. 
The class of prior hypotensive therapy, summarized on the baseline characteristic table and listed 
on the washout medication listing, will also be derived from the coded medication data. Classes 
include the following: Prostaglandins, -adrenoceptor antagonists, adrenergic agonists (including 
-agonists such as brimonidine and apraclonidine), Muscarinic agonists (e.g., pilocarpine), and 
Carbonic anhydrase inhibitors (topical or oral). For the summary table, categories will be: 
combination therapy, prostaglandins (monotherapy), other (monotherapy), and no prior therapy.  


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Additionally, the following two classes will be summarized: prior prostaglandin therapy and no 
prior prostaglandin therapy.   
6.3 
Medical and Ocular History 
A medical and ocular history will be collected at screening, including diagnosis, start date, and 
stop date (as applicable) or ongoing. For ocular history, the applicable eye(s) will be noted. Any 
change in the individual’s baseline health status that occur after screening and prior to first dose 
of study medication should be reported as medical history events.   
Ocular surgery and laser procedures will also be collected at screening including the procedure 
description, procedure date, and affected eye(s). 
All medical history and ocular surgery/laser procedures data will be presented in a by-subject 
listing.  Medical and ocular history will be coded to preferred terms and system organ class using 
the MedDRA Dictionary (Version: 19.0).  Medical and ocular histories will be summarized for 
each system organ class and each preferred term by treatment group.  Subjects will be counted 
only once under each system organ class and preferred term for which they have at least one 
medical/ocular history.  
Study eye diagnosis will be derived from the coded ocular history data.  The preferred terms of 
“Ocular hypertension” and “Open angle glaucoma” will be matched to the study eye selection 
page of the CRF.  Analyses based on study diagnosis will use this definition. 


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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
All subjects will be instructed to follow once a day dosing regimen in the evening between 20:00 
– 22:00 hours (8pm - 10pm). All treatments will be dosed in both eyes (OU). 
 
 


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8. 
EFFICACY EVALUATION 
8.1 
Overview of Efficacy Analysis Issues 
8.1.1 Handling of Dropouts or Missing Data 
Any missing, unused, or spurious data will be noted in the final statistical report.  Analyses will 
be performed primarily on the intent to treat population with multiple imputation techniques (eg, 
Monte Carlo Markov Chain) used to impute missing data and secondarily using: observed data 
only, last observation carried forward (LOCF) where LOCF will be performed using time-
relevant measures (i.e. from the same time point of the most recent visit with a non-missing 
value); and baseline observation carried forward (BOCF) using time-relevant measures to 
determine the robustness of results. 
 
8.1.2 Multicenter Studies 
This study will have approximately 60 different sites enrolling and treating subjects.  The 
homogeneity of treatment effect across investigative sites will be examined by a model 
containing the additional factors of investigative site and its interaction with treatment for the 
primary IOP efficacy endpoint.  
8.1.3 Assessment Time Windows 
In general, it is intended that all safety and efficacy data (with some exceptions) will be 
summarized at each time point collected regardless of assessment time windows.  Because 
subjects may have an early termination visit at any time or may have unscheduled visits, the 
following conventions will be implemented. 
For all safety data, the visit date or start date (e.g., adverse events) will be used to calculate study 
day, defined as the number of days from the day of first dose. The day of first dose (Visit 3) is 
considered study day 1, so study day will be computed as (date of data – Visit 3 + 1).  Study day 
will be presented in listings for medical history, concomitant medications, and adverse events.   
In all by-visit safety assessments, end of study visits and early termination visits will be 
combined in order to present all data available for each subject; early termination visits will not 
be windowed into the nearest fitting study visit.  Each subject will have one end of study visit.  
For efficacy outcomes, early termination data will not be combined with end of study visit 
information as the timing of the outcome measure is integral to the analysis. Instead, the efficacy 
outcome will be windowed into the nearest study visit, where each follow-up visit through 
Month 3 has a ± 3 day window.  Subsequent visits have a ± 7 day window. 
8.2 
Efficacy Variables and Primary Hypotheses 
1. 
The primary efficacy outcome will be the comparison of PG324 Ophthalmic Solution 
relative to each of its active components (Netarsudil 0.02% and latanoprost 0.005%) for: 
 Mean IOP within a treatment group at 08:00, 10:00, and 16:00 hours at the Week 2, 
Week 6, and Month 3 study visits 


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2. 
Secondary efficacy endpoints will include the comparison of PG324 Ophthalmic Solution 
relative to each of its active components (Netarsudil 0.02% and latanoprost 0.005%) for:  
 Mean IOP within a treatment group at each post-treatment time point 
 Mean diurnal IOP within a treatment group at each post-treatment visit 
 Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
 Mean change from baseline in diurnal IOP at each post-treatment visit 
 Mean percent change from diurnally adjusted baseline IOP at each post-treatment 
time point 
 Mean percent change from baseline in diurnal IOP at each post-treatment visit  
 Percentages of subjects achieving pre-specified mean, mean change, and percent 
mean change diurnal IOP levels at each post-treatment time point: 
o Diurnal mean IOP of ≤22, ≤21, ≤20, ≤19, ≤18, ≤17, ≤16, ≤15, ≤14 
o IOP reduction from baseline of ≥2, ≥4, ≥6,  ≥8, ≥10, ≥12 (IOP reduction at a 
visit from baseline was calculated as IOP [baseline] - IOP [visit], using mean 
[integral or non-integral] IOP values) 
o IOP percent reduction from baseline of ≥5, ≥10, ≥15, ≥20, ≥25, ≥30, ≥35, ≥40 
(IOP percent reduction at a visit from baseline was calculated as [IOP 
reduction from baseline / IOP (baseline)] * 100%) 
3. 
The primary hypotheses are: 
 H01: The difference between study eyes treated with PG324 Ophthalmic Solution and 
study eyes treated with latanoprost Ophthalmic Solution 0.005% (PG324 - latanoprost), 
in mean IOP at the following time points: 08:00, 10:00, and 16:00 hours at the Week 2, 
Week 6, and Month 3 Visits, is ≥ 0 mmHg for at least one time point over all visits 
 
 H11: The difference between study eyes treated with PG324 Ophthalmic Solution and 
study eyes treated with latanoprost Ophthalmic Solution 0.005% (PG324 − latanoprost), 
in mean IOP at the following time points: 08:00, 10:00, and 16:00 hours at the Week 2, 
Week 6, and Month 3 Visits, is < 0 mmHg for all time points over all visits. 
 
 H02: The difference between study eyes treated with PG324 Ophthalmic Solution and 
study eyes treated with Netarsudil Ophthalmic Solution 0.02% (PG324 − Netarsudil), in 
mean IOP at the following time points: 08:00, 10:00, and 16:00 hours at the Week 2, 
Week 6, and Month 3 Visits, is ≥ 0 mmHg for at least one time point over all visits. 
 
 H12: The difference between study eyes treated with PG324 Ophthalmic Solution and 
study eyes treated with Netarsudil Ophthalmic Solution 0.02% (PG324 − Netarsudil), in 
mean IOP at the following time points: 08:00, 10:00, and 16:00 hours at the Week 2, 
Week 6, and Month 3 Visits, is < 0 mmHg for all time points over all visits. 
The study will be considered a success if both H01 and H02 are rejected.  


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8.3 
Analysis Methods 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using descriptive statistics (n, mean, median, SD, minimum, and maximum).  All categorical 
study assessments will be summarized by treatment and time point (as applicable) using 
frequency counts and percentages.  All statistical tests will be performed at a 2-sided 5% 
significance level. For the IOP measurements, 2-sided tests and 2-sided 95% confidence intervals 
will be reported. 
Mean diurnal IOP values will be constructed by averaging the three IOP measurements on each 
of Week 2, Week 6, and Months 3, 6, 9, and 12.  Mean diurnal baseline IOP will be constructed 
as the average of the three Day 1 IOP measurements.  Mean change from mean baseline diurnal 
IOP will be created by taking the average of the three time points on each of Week 2, Week 6, 
and Months 3, 6, 9, and 12 and subtracting the mean baseline diurnal IOP measurement. 
For diurnally adjusted IOP measures, baseline will refer to the time-relevant measure at Visits 
3.0 through 3.2 (e.g., IOP at 08:00 hours at Visit 3.0 will be the baseline for 08:00 hours at Visits 
4.0, 5.0, 6.0, 7.0, 8.0 and 9.0; IOP at 10:00 hours at Visit 3.1 will be the baseline for 10:00 hours 
at Visits 4.1, 5.1, 6.1, 7.1, 8.1 and 9.1). For mean diurnal IOP, baseline will refer to the mean 
diurnal IOP at Visit 3.  For all other variables, baseline is defined as the last measurement prior 
to the first dose of study medication. Change from baseline will be calculated as follow-up visit – 
baseline visit. 
Percent change from diurnally adjusted baseline IOP will be determined by dividing the change 
from diurnally adjusted baseline by the corresponding baseline IOP value, such that a negative 
change from baseline will produce a negative percent change from baseline. 
All primary and secondary efficacy variables, along with the planned analysis methods for those 
variables, are given in Table 8-1.  These analyses will be performed for the ITT population for 
all efficacy variables and PP population for selected efficacy variables. The ITT population will 
be used for all efficacy subgroup analyses.  Note that each subject will have one eye designated 
as the study eye.  Only study eyes will be evaluated for all of the efficacy measures; however, 
both eyes will be treated.  Fellow eyes will be evaluated separately for the primary analysis of 
the primary efficacy measure. 
 
 
 
 


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Table 8-1   Summary of Efficacy Variables and Analysis Methods 
 
 
Two 
Sample  
T-testa  
ANCOVAb 
MMRMc  
 
Fisher’s 
Exact 
Testd  
Analysis 
Population 
Missing Data 
Imputation 
Primary Analysis 
 
 
 
 
 
 
Mean IOP at each time point at 
Week 2, Week 6, and Month 3 
 
X 
 
 
ITT 
MCMC  
 
Secondary Analyses 
 
 
 
 
 
 
Mean IOP at each time point at 
Week 2, Week 6, and Month 3 
X 
 
 
 
ITT 
MCMC 
X 
X 
 
 
PP 
MCMC, LOCF, 
BOCF, 
Observed data  
X 
X 
 
 
ITT 
LOCF, 
BOCF 
X 
X 
X 
 
ITT 
Observed data 
Mean IOP at each time point at 
Months 6, 9, and 12 and;  
Mean diurnal IOP at each post-
treatment time point 
X 
X 
 
 
ITT 
MCMC 
LOCF, 
Observed data 
Mean change from diurnally 
adjusted baseline IOP at each 
post-treatment time point  
X 
 
 
 
ITT 
MCMC 
LOCF, 
Observed data 
Mean change from baseline in 
diurnal IOP at each post-
treatment time point 
X 
 
 
 
ITT 
MCMC 
LOCF, 
Observed data 
Mean percent change from 
diurnally adjusted baseline IOP 
at each post-treatment time 
point  
X 
 
 
 
ITT 
Observed data 
Percentages of subjects 
achieving pre-specified mean, 
mean change, and percent 
mean change diurnal IOP 
levels 
 
 
 
X 
ITT, PP 
Observed data 
a Two Sample T-test comparing actual mean IOP value at each time point between PG324 and each comparator (latanoprost and 
Netarsudil). 
b ANCOVA model including treatment as the main effect and baseline as the covariate. Individual models will be fit for each visit 
and time point. 
c Mixed Model Repeated Measures analysis including treatment as the main effect, and baseline IOP, visit, time point, 
treatment*visit, treatment*time point, visit*time point, and treatment*visit*time point as model terms.  Repeated measures will be 
used to account for the correlation among measures within a subject.  The model will include all post-dose visits and time points. 
d Fisher’s exact test comparing the incidence in each category at each time point between PG324 and each comparator (latanoprost 
and Netarsudil). 
 


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8.3.1 Primary Efficacy Analyses 
The primary analysis of the primary outcome will employ a linear model with mean IOP at the 
given visit (Week 2, Week 6, and Month 3) and time point (08:00, 10:00, and 16:00 hours) as the 
response, baseline IOP as a covariate, and treatment as a main effect factor, using the intent to 
treat population with multiple imputation techniques (eg, Monte Carlo Markov Chain) used to 
impute missing data. Each time point within each visit will be modeled separately. The least 
squares mean differences (PG324 – comparator) between PG324 Ophthalmic Solution and each 
of Latanoprost Ophthalmic Solution 0.005% and Netarsudil Ophthalmic Solution 0.02% will be 
tested. The 2-sided p-values and associated 95% confidence intervals will be presented. For a 
given comparator (latanoprost and Netarsudil), if the p-value is < 0.05 and the point estimate < 0 
for all time points at the Week 2, Week 6, and Month 3 Visits, then the corresponding null 
hypothesis will be rejected in favor of the alternative hypothesis and PG324 will be considered to 
be superior to the comparator. 
 
The following SAS code will be used for multiple imputations using the Monte-Carlo Markov 
Chain method, where a separate model will be fit for each time point at each visit. 
 
proc mi data = indata seed = 48669 out = outdata1; 
   mcmc initial = em; 
   var trt01pn baseline IOP; 
run; 
where 
- 
indata is the name of the input dataset 
- 
outdata is the name of the output dataset 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
baseline captures the baseline IOP for the given time point 
- 
IOP is the name of the IOP measure. 
 
Five complete data sets will be generated from the above code. Each complete data set will be 
used to analyze this primary efficacy endpoint separately using analysis of variance. Then, the 
SAS procedure MIANALYZE will be used to analyze the results from the 5 complete data 
sets to generate a combined inference. The following SAS code will be used: 
 
ods output diffs = outdata2; 
proc mixed data = outdata1; 
  class trt01pn; 
  model IOP=trt01pn baseline; 
  lsmeans trt01pn / cl pdiff; 
  by _Imputation_; 
run; 
 
proc sort data=outdata2; 
 by trt01pn _trt01pn; 
run; 
 


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ods output ParameterEstimates = outdata3; 
proc mianalyze data = outdata2 alpha = 0.05; 
   by trt01pn _trt01pn; 
    class trt01pn _trt01pn; 
    modeleffects estimate; 
    stderr stderr; 
run; 
where 
- 
IOP is the name of the IOP measure 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
outdata2 is the name of the output dataset that contains the statistical results of the 
differences between treatment groups 
- 
outdata3 is the name of the output dataset that contains summary and inferential 
statistics. 
 
8.3.2 Secondary Efficacy Analyses 
The secondary efficacy analyses will include repeating the primary efficacy analysis on all 
subjects and additional analyses of the primary efficacy endpoint as well as other analyses of the 
secondary endpoints, as outlined below.  
The primary efficacy analysis will be repeated on the ITT population using observed data only, 
last observation carried forward (LOCF) where LOCF will be performed using time-relevant 
measures; and baseline observation carried forward (BOCF) using time-relevant measures to 
determine the robustness of results. Additionally, the above analyses will be repeated on the PP 
population to determine robustness of results.  
Secondary analyses of the primary endpoint will be completed using individual two-sample  
t-tests and 95% t-distribution confidence intervals for each comparison (PG324 vs latanoprost 
and Netarsudil) at each time point (08:00, 10:00, and 16:00 at the Week 2, Week 6 and Month 3 
Visits) using the ITT and PP populations. Similar analyses will be completed on the secondary 
endpoints: mean IOP measure at each time point at Month 6, Month 9, and Month 12 visits and 
mean diurnal IOP and change from baseline diurnal IOP measures based on the ITT population. 
Models adjusting for baseline will only be performed on the mean IOP response variable as 
inference is identical between this response and the change from baseline IOP response variable 
in such a model based on the ITT population. 
 
Additionally, for the mean IOP values at each time point, mixed model repeated measures will 
be run with baseline as the covariate; treatment, visit, time point, treatment by visit, treatment by 
time point, visit by time point, and treatment by visit by time point as the fixed effect factors; and 
subject as the random effect, repeated measure. An unstructured covariance structure will be 
used to model the within subject, between visit and time point variances. This allows for 
different variances and covariances within and between time points and visits. The treatment by 
visit, treatment by time point, visit by time point, and treatment by visit by time point 
interactions allow for a different rate of change in IOP in the different treatment arms among 


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visits and time points. This model will be run including the Week 2, Week 6, and Month 3 visits 
based on the ITT population. 
 
Percent change from diurnally adjusted baseline IOP at each time point will be analyzed using 
two-sample t-tests, between PG324 and each comparator, at each time point and visit, including 
two-sample t-tests and 95% t-distribution confidence intervals on the difference (PG324 – 
comparator). The analysis will be based on ITT population. 
 
Analyses of IOP will also include summarizing the number and percentage of study eyes 
achieving mean diurnal IOP reduction from baseline of ≥ 4 to ≥ 12 mmHg in 2 mmHg 
increments and percent reduction from baseline of ≥ 5% to ≥ 40% in 5% increments at Week 2, 
Week 6, and Month 3. Additionally, the number and percentage of study eyes attaining a mean 
diurnal IOP of ≤ 22 to ≤ 14 mmHg in 1 mmHg increments will be summarized at Week 2, Week 
6, Month 3, Month 6, Month 9, and Month 12. Fisher’s exact test (2-sided p-values) will be used 
to test the pair wise differences between treatment groups for each category at each visit. These 
analyses will be presented for both the ITT and PP populations with observed data only. 
 
8.4 
Examination of Subgroups 
Subgroup analyses based upon pre-study characteristics include: 
 Age: <65 years, ≥65 years 
 Gender: Male, Female 
 Race: Caucasian, Other  
 Iris Color: Blue/Grey/Green, Brown/Black, Hazel 
 Randomization stratum of baseline IOP value: <25 mmHg, ≥25 mmHg 
 Maximum baseline IOP value: <23 mmHg, <27 mmHg, <30 mmHg, <32 mmHg 
 Prior hypotensive medication experience category 1: Combination Therapy, 
Prostaglandin (monotherapy), Other (monotherapy), No Prior Therapy 
 Prior hypotensive medication experience category 2: Prior Prostaglandin, No Prior 
Prostaglandin 
For each subgroup, except those defined by unmedicated baseline IOP, IOP will be compared at 
each post-dose time point between treatment groups (using an ANCOVA model with treatment 
as the main effect, baseline IOP and subgroup as covariates, and the interaction of treatment by 
subgroup.  The least squares mean differences (test – control) between PG324 Ophthalmic 
Solution and each of Latanoprost Ophthalmic Solution 0.005% and Netarsudil Ophthalmic 
Solution 0.02% will be tested. P-values for testing the treatment difference and the interaction of 
treatment by subgroup will be presented. These subgroup examinations are based on the ITT 
population and use observed data only. 
An analysis of investigative site will also be included as a subgroup analysis.  The homogeneity 
of treatment effect across investigative sites will be examined using a similar model as the above 
subgroup analyses.  Sites with fewer than nine subjects will be pooled together for the analysis.  
Results will be presented in tabular form. This analysis is based on the ITT population and use 
observed data only. 


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 Statistical inference will not be made on any subgroups with fewer than nine subjects. 
Subgroup analyses based upon maximum unmedicated baseline IOP in the study eye additionally 
will be completed for maximum baseline IOP <23 mmHg, <27 mmHg, <30 mmHg, <32 mmHg 
and <25 mmHg. The analysis of these IOP subgroups will be completed using only the primary 
endpoint analysis strategy. 
 


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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
The assessment of safety and tolerability is the secondary objective of this study.  All safety 
analyses will be carried out using the Safety Population and will include the study eye and fellow 
eye separately, where applicable. All tabular summaries will be provided primarily for all 
subjects  
The assessment of safety will be evaluated by: 
 Adverse events 
 Comfort test (ocular tolerability) 
 Heart rate and blood pressure  
 Biomicroscopy of anterior segment including evaluation of cornea, conjunctiva and 
anterior chamber.  (Fluorescein staining to be used.) 
 Dilated ophthalmoscopy 
 Best Corrected ETDRS Visual Acuity  
 Pupil size 
 Visual fields 
 Pachymetry (screening only) 
 IOP 
 Clinical chemistry and hematology laboratory findings 
All safety variables will be descriptively summarized by treatment group at each assessment time 
and for relevant changes from baseline. 
For complete inclusion of subjects who withdraw from the study early, the End of Study visit for 
safety outcomes will be defined as either Visit 9 or Early Discontinuation.   
For the first interim analysis, the Month 3 visit for safety outcomes will be defined as either Visit 
3 or Early Discontinuation.   
9.2 
Extent of Exposure 
Summary statistics will be presented for treatment exposure.  Note that date of first dose is not 
collected, but will be assumed to be the Visit 3 date. Treatment exposure will be defined as the 
number of days that the subject was exposed to study treatment as calculated using the formula:  
Treatment exposure = Date of Last Dose – Visit 3 Date + 1.  
9.3 
Adverse Events 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. All AEs occurring during the study (i.e. once 
the subject has received one dose of study drug) will be defined as treatment emergent adverse 
events (TEAEs) and must be documented, regardless of the assumption of causal relationship, on 


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the respective AE CRF. All adverse events should be documented from the time the subject 
receives the first dose of study drug until the subject’s participation in the study has been 
completed. If a subject has ongoing AEs at the time of study completion, the ongoing AEs must 
be followed-up and provided appropriate medical care until the event has resolved or stabilized. 
Documentation of AEs includes onset date, severity, action(s) taken, study medication 
relationship, outcome, resolution date, and seriousness. 
Verbatim descriptions of AEs will be mapped to MedDRA (version: 19.0) thesaurus terms and 
be presented in a data listing. Treatment emergent AEs, those that occur after the first dose of 
study medication, will be summarized by treatment group using frequencies and proportions for 
each system organ class (SOC) and preferred term (PT) within each SOC. A separate summary 
will be presented for AEs that are related to the study drug (marked as “possibly related” or 
“related” in the CRF). For these summaries, Fisher’s exact tests will be used to test the difference 
in proportions of subjects with each AE between treatment groups, SOC, and PT. Another table 
will be presented summarizing AEs by maximum severity. Additional summaries will be 
presented for serious AEs and AEs leading to test article discontinuation.  
An overall summary table will be developed to report the number of events and the incidence of 
subjects having at least one event in the following categories:  
 TEAEs 
 Serious TEAEs (SAEs) 
 Treatment-Related TEAEs (reported as possibly related or related to the study drug) 
 Treatment-Related SAEs 
 TEAEs by severity 
 TEAEs leading to study drug discontinuation 
 TEAEs resulting in death 
While the overall summary of TEAEs will present both the number of TEAEs and the incidence 
of TEAEs, the other summaries will only report the incidence of TEAEs.  When reporting the 
number of TEAEs, if the same TEAE occurs for a subject on multiple occasions the event will be 
counted once for each occurrence.  When reporting the incidence, a subject will only be counted 
once if they ever experience an event within the SOC and ever experience the individual PT.  
Summaries will be performed using the actual treatment received.   
9.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events 
An adverse event is considered “serious” if, in the view of either the Investigator or Sponsor, it 
results in any of the following outcomes: Death, a life-threatening or sight-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Serious adverse events and deaths will be listed and 
summarized separately for the Safety population.  


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9.5 
Clinical Laboratory Evaluation 
Clinical laboratory results, including clinical chemistry and hematology, will be presented in data 
listings.  Abnormal results, those above or below the normal range, will be flagged with "H" 
(high), “HP” (high panic), "L" (low) or “LP” (low panic) based on the laboratory ranges 
provided by the lab and included in the listings.  Descriptive statistics will be used to summarize 
continuous measures and will be presented in tabular form including change from baseline to the 
Months 3, 6 and 12 visits.  Shifts from baseline to the Months 3, 6 and 12 visits will also be 
presented in tabular form for clinical chemistries and hematology parameters by treatment group 
and laboratory domain. Summary tables also will be presented for the number of subjects with 
abnormal values within each laboratory parameter at the end of the study. Clinical laboratory 
results, including clinical chemistry, hematology, and urine pregnancy test will also be listed by 
subject. 
9.6 
Vital Signs, Ophthalmic Exam Findings, and Other Safety Outcomes 
9.6.1 Vital Signs 
Heart rate and blood pressure will be listed by treatment group, subject, and visit including 
observed values and changes from baseline.  Measurements and change from baseline 
measurements will be summarized by treatment group and visit.  Paired t-tests will be used to 
test within treatment group changes from baseline in vital sign parameters.  Two-sided 95% CIs 
will be provided. 
 
9.6.2 Intraocular Pressure 
Intraocular pressure will be presented in data listings. Intraocular pressure data will be 
summarized at each visit and time point using continuous summaries, including change from 
baseline, for both the study eye and the fellow eye.  
9.6.3 Visual Acuity 
Visual acuity scores will be presented in data listings. Subjects who lost three or more lines will 
be presented in an additional listing. Visual acuity data will be summarized at each visit using 
continuous summaries, including change from baseline, for both the study eye and the fellow 
eye. Additionally, discrete summaries of the worst change from baseline will be presented for 
both the study eye and the fellow eye with the following groupings based on the logMAR scores: 
0 or less, >0 to +0.09, +0.10 to +0.19, +0.20 to 0.29, +0.30 or more.   
9.6.4 Dilated Ophthalmoscopy and Cup-to-Disc Ratio 
Dilated ophthalmoscopy and cup-to-disc ratio results from Screening and Months 3, 6, and 12 
will be presented in data listings. A separate listing will be created for those subjects with a 
criterion change, defined as a change from “Normal” to “Abnormal” or a change from 
“Abnormal – Not Clinically Significant” to “Abnormal – Clinically Significant”. Frequencies 
and percentages of normal, abnormal ophthalmoscopy results will be created for the following 
fields: Retina, Macula, Choroid, Optic Nerve, and Vitreous Humor. Abnormal results will further 


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be broken down by clinical significance.  A shift table of study eye and fellow eye 
ophthalmoscopy results will also be presented by treatment group.   
Vertical cup-to-disc ratio at Screening will be summarized for the study eye and for the fellow 
eye by treatment group in the baseline characteristics table. Additionally, vertical cup-to-disc 
ratio will be summarized at follow-up visits and change from baseline to follow-up visits using 
continuous summary statistics.  A listing of subjects with increases of ≥ 0.2 in either eye at end 
of study will be presented. 
9.6.5 Biomicroscopy 
Biomicroscopy results will be listed for both eyes at each visit. A separate listing will be 
presented for subjects with a criterion change, defined as a +1 unit increase from baseline.  
Summaries of biomicroscopy results will also be presented for study eyes and fellow eyes by 
treatment group, visit, and time point in tabular form.   
A summary table of the number and percentage of subjects with at least a +1 unit increase in 
score from baseline will be presented by region, finding, time point and eye (study eye and 
fellow eye). In addition to each time point, there will be summaries for “At the Final Visit” and 
“At Any Visit”.  
Additionally, for Conjunctival Hyperemia, the proportion of subjects with a one severity grade 
increase from baseline will be compared between Day 15 and Day 90 at each time point within a 
treatment arm using McNemar’s test. Another summary table will be presented with the number 
and percentage of subjects who had a finding judged to be clinically significant by region, 
finding, time point and eye (study eye and fellow eye). Fisher’s exact tests will be used to 
compare incidence between treatment groups in both tables.  Additionally Conjunctival 
Hyperemia will be presented using continuous summary statistics for each visit, for the change 
from baseline to each post-baseline visit, and for the change from Day 15 to Day 90 visit (which 
will use time-specific differences [e.g. 08:00 at Day 90 – 08:00 at Day 15]).  Differences 
between treatment groups will be tested using two-sample t-tests as well as Wilcoxon rank sum 
tests. 
9.6.6 Comfort Test (Ocular Tolerability) 
Ocular discomfort after instillation of study drug will be collected at Week 2, Week 6, and 
Months 3, 6, 9, and 12, using the following categories: None, Mild, Moderate, and Severe. 
Discrete summaries of the discomfort categories will be provided for each visit, including the 
number and percentage of subjects with Moderate or Severe discomfort.  Fisher’s exact test will 
be used to compare the incidence of Moderate or Severe discomfort between treatment groups. 
 
9.6.7 Pupil Size 
Pupil size (mm) will be measured at Day 1 (baseline) and Months 3, and 12 and listed for each 
subject.  Pupil size will be summarized using continuous summary statistics for the Day 1 
(baseline), Month 3, and Month 12 visits as well as change from Day 1 (baseline) to Month 3, 
and Month 12 by treatment group for the study eye and fellow eye separately. 


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9.6.8 Visual Field Examination, Pachymetry, and Gonioscopy  
Visual field examination results will be collected at Screening and Months 3, 6 and 12 and listed 
for each subject.  Visual field mean deviation (dB) will be summarized using continuous 
summary statistics for the Screening and Months 3, 6 and 12 visits as well as change from 
Screening to Months 3, 6 and 12 by treatment group for the study eye and fellow eye separately. 
 
Central corneal thickness, collected at Screening and Months 3 and 6 will be listed for each 
subject. Central corneal thickness will be summarized using continuous summary statistics for 
the Screening and Months 3 and 6 visits as well as change from Screening to Months 3 and 6 by 
treatment group for the study eye and fellow eye separately. The study eye and fellow eye means 
at screening will also be summarized by treatment group and included with baseline 
characteristics.  
  
Gonioscopy will be collected at screening for each eye and listed for each subject.  Possible 
values will be Open Angle, Narrow Angle, and Closed Angle. 
 
 
 


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10. 
PHARMACOKINETIC EVALUATION 
Not applicable. 


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11. 
OTHER ANALYSES 
Any additional analyses conducted will be considered exploratory and enumerated in the CSR. 
 


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12. 
INTERIM ANALYSES AND DATA MONITORING 
When all subjects have completed three months of treatment, the Sponsor biostatistical 
representative will unmask the study to analyze the 3-month efficacy and safety data.  No other 
study personnel other than the statistician, SAS programmers, VP Clinical Research and Medical 
Director, Chief Scientific Officer and Information Systems Manager will be unmasked to the 
individual subject treatment assignments and demographic information to perform the 3-month 
efficacy and safety data analysis and further exploratory data analysis as necessary. This is the 
primary efficacy analysis of the study and therefore no alpha adjustment for this interim analysis 
will be implemented. The interim analysis will be completed at an overall 2-sided alpha of 5%, 
with each of the pairwise comparisons of PG-324 to comparators.  For the efficacy interim 
analyses, analyses will be limited to data available through 3 months of treatment.  Additionally, 
key adverse event summaries will be limited to data available through 3 months.   
 
 
 


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13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
No changes to the analyses that are planned in the protocol. 
  
 


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14. 
REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration.  Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9) 
 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: 
Food and Drug Administration.  Federal Register Vol. 61, July 17, 1996, page 37320. (E3) 
 
 
 


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15. 
APPENDICES 
Table 15.1: Schedule of Visits and Procedures 
 
Screen 
Qual. 
#1 
Qual. #2 
Post D1 Treatment Period Assessments 
Day/Week/Month 
-- 
-- 
D1 
W2 (Day 15±3)  
W6 (Day 43±3) 
M3, M6 (Day 90±3, 
Day 180±7) 
M9 (Day 270±7) 
M12 (Day 365±7) 
Visit 
1 
2 
3 0 
3 1 
3 2 
4 0 
4 1 
4 2 
5 0 
5 1 
5 2 
6 0 
7 0 
6 1 
7 1 
6 2 
7 2 
8 0 
8 1 
8 2 
9 0 
9 1 
9 2 
Hour 
-- 
08:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00  
10:00 
16:00 
08:00 
10:00 
16:00 
08:00  
10:00  
16:00  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Washout1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic Hist  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Rx 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HR/BP 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Clinical Labs (chem/hem ) 
X3 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Symptoms/AEs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comfort test5 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Visual Acuity (ETDRS) 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pupil size 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
IOP 
X 
X6 
X6 
X6 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Gonioscopy7/ 
G/P 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual field9 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X11 
 
X 
Eye-Drop Instillation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
Dose 
(pt 
self-
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Study meds dispensed 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Study meds collected 
 
 
 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
Study completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
                                                 
1 Subjects currently using ocular hypotensive medications must undergo a minimum washout period  
2 Urine pregnancy test for women of childbearing potential. 
3 For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 (screening), the blood sample may be drawn at Visit 2 (Qualification Visit #1) so long as the results of the 
clinical labs are available for that subject prior to Visit 3 (Qualification Visit #2).   
4 Ocular symptoms: Subjects will be queried at each visit “How are you feeling?” and treatment emergent AE’s beginning at Visit 3 (Qualification Visit #2) will be documented on the AE form. 
Additional symptoms reported after screening and before randomization will be documented on the medical history form.   
5 Comfort test: At 08:00 hours for on study drug visits, subjects will be queried “Did you experience any discomfort when placing the drops in your eyes?” 
6 Individuals returning at an unscheduled visit within 1 week are required to only re-measure IOP in both eyes 
7 Gonioscopy evaluation up to three months prior to randomization is acceptable.  
8 Pachymetry within one week of screening is acceptable. 
9 Entry visual field evaluation up to 3 months prior to randomization is acceptable. Visual field collection must meet the requirement for automated threshold visual field assessment (eg, 30-2 or 24-2 
Humphrey) and reliability. 
10 Collect used kit(s) dispensed during the previous visit at 08:00 hours (after the AM dosing). 
11 Ophthalmoscopy (dilated) at Visit 9.0 at 08:00: this assessment should be performed for all non-completing subjects during the exit visit. 


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16. 
ATTACHMENTS 
 
PG324-CS301 Listing Shells 
 
PG324-CS301 Table Shells