Clinical trial NCT04620135
Conditions: Primary Open Angle Glaucoma Ocular Hypertension
Keywords: Glaucoma, Primary Open-Angle Glaucoma Ocular Hypertension
Sponsor: Aerie Pharmaceuticals
Start date: 2020-11-30; Completion date: 2021-07-30
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 3 Study Comparing the Efficacy and Safety of Netarsudil Ophthalmic Solution 0.02% QD to Ripasudil Hydrochloride Hydrate Ophthalmic Solution 0.4% BID, for Treatment of Primary Open-Angle Glaucoma or Ocular Hypertension Over A 4-Week Period.

Detailed description:

Arms: arm 1: 1 drop netarsudil 0.02% in the evening and 1 drop netarsudil vehicle in the morning in each eye. arm 2: 1 drop ripasudil twice daily in the morning and evening in each eye.
Interventions: intervention 1: Netarsudil ophthalmic solution 0.02% intervention 2: Ripasudil hydrochloride hydrate ophthalmic solution 0.4%
Intervention descriptions: intervention 1: Topical sterile ophthalmic solution Other Name: Rhopressa® intervention 2: Other Name: Glanatec®

Protocol documents:
Prot_002.pdf: 
 
Title: ClinicalTrials.gov Results Submission - 
Cover Page (Redacted Documents) 
 
Form No.: FM-CL-0024  
Ver.: 1.0 
 
Associated Document No.: SOP-CL-000021 
 
Page 1 of 1 
 
Efficacy and Safety Study of Netarsudil 0.02% Ophthalmic 
Solution Compared to Ripasudil Hydrochloride Hydrate 0.4% 
Ophthalmic Solution in Japanese Subjects With Primary Open 
Angle Glaucoma or Ocular Hypertension 
NCT04620135 
Amendment 1 (Rev 1) dated 11 January 2021 
 
 


 
 
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Clinical Study Protocol: AR-13324-CS305, Amendment 1 
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Clinical Study Protocol 
Study Title: 
A single-masked, randomized, multi-center, parallel-group, 4-week 
study evaluating the efficacy and safety of once daily netarsudil 
ophthalmic solution 0.02% compared to twice daily ripasudil 
hydrochloride hydrate ophthalmic solution 0.4% in Japanese subjects 
with primary open angle glaucoma (POAG) or ocular hypertension 
(OHT) 
Study Number: 
AR-13324-CS305 
Study Phase: 
Phase 3 
Product Name: 
Netarsudil Ophthalmic Solution 0.02%  
Indication: 
Reduction of elevated intraocular pressure (IOP) in subjects with 
primary open-angle glaucoma (POAG) or ocular hypertension 
(OHT) 
Investigators: 
Multicenter 
Sponsor: 
Aerie Pharmaceuticals Ireland Limited 
Sponsor Contact: 
 
 
Medical Monitor: 
  
 
ClinicalTrials.gov 
Identifier: 
NCT04620135 
 
 
Date 
Original Protocol (Rev 0): 
Amendment 1 (Rev 1): 
29 July 2020 
11 January 2021 
 
 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals Ireland Ltd (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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Clinical Study Protocol: AR-13324-CS305, Amendment 1 
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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: A single-masked, randomized, multi-center, parallel-group, 4-week study evaluating 
the efficacy and safety of once daily netarsudil ophthalmic solution 0.02% compared to twice daily 
ripasudil hydrochloride hydrate ophthalmic solution 0.4% in Japanese subjects with primary open 
angle glaucoma (POAG) or ocular hypertension (OHT) 
 
Study No: AR-13324-CS305 
Original Protocol Date: 29 July 2020 
Protocol Version No: Rev 1 
Protocol Version Date: 11 January 2021 
 
Role 
Contact information 
Clinical Operations 
 
 
  
 
 
 
______________________ 
Signature 
 
Date 
Aerie Management and Sponsor 
Safety Officer 
 
 
 
 
 
 
 
 
______________________ 
Signature 
 
Date 
DocuSign Envelope ID: 385F8B03-8EE6-4AB4-88AB-D251C5722E44


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Medical Monitor  
 
 
 
 
 
Biostatistics and Data Management 
 
 
 
 
  
 
 
  
 


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SYNOPSIS 
Sponsor: Aerie Pharmaceuticals Ireland Ltd. 
Name of Finished Product: Netarsudil ophthalmic solution 0.02% 
Name of Active Ingredients: Netarsudil 
Study Title:  
A single-masked, randomized, multi-center, parallel-group, 4-week study evaluating the efficacy and safety 
of once daily netarsudil ophthalmic solution 0.02% compared to twice daily ripasudil hydrochloride hydrate 
ophthalmic solution 0.4% in Japanese subjects with primary open angle glaucoma (POAG) or ocular 
hypertension (OHT) 
Study Number: AR-13324-CS305 
Study Phase: Phase 3 
Primary Objective(s): 
The objective of this study is to evaluate the ocular hypotensive efficacy and safety of netarsudil ophthalmic 
solution 0.02% QD compared to the active comparator, ripasudil hydrochloride hydrate ophthalmic solution 
0.4% BID, over a 4-week period (superiority study). 
Study Design: 
This will be a prospective, single-masked, randomized, multi-center, parallel-group, 4-week study evaluating 
the efficacy and safety of once daily (QD) netarsudil ophthalmic solution 0.02% compared to twice daily 
(BID) ripasudil hydrochloride hydrate ophthalmic solution 0.4% in Japanese subjects with primary open 
angle glaucoma (POAG) or ocular hypertension (OHT) in Japan. 
Netarsudil ophthalmic solution, 0.02% will be dosed QD (21:00) while ripasudil hydrochloride hydrate 
ophthalmic solution, 0.4% will be dosed BID (9:00/21:00). In order to be adequately masked, subjects dosing 
with netarsudil ophthalmic solution 0.02% (21:00) also will dose with netarsudil ophthalmic solution, 
Vehicle QD (9:00). 
Subjects eligible to be enrolled in this study will be subjects with diagnosis of either POAG or OHT. 
Approximately 240 subjects will be enrolled in this study. Subjects who agree to participate in this study and 
are enrolled will attend a total of up to 6 study visits: Screening Visit, Qualification Visit #1, Qualification 
Visit #2/Day 1 (baseline), Week 1 (Day 8), Week 2 (Day 15), and Week 4 (Day 29). 
Subjects will be required to washout of their pre-study ocular hypotensive medication for a prescribed period 
(i.e., 5 days to 6 weeks, depending on the medication) prior to attending Qualification Visit #1. Subjects 
eligible to be enrolled in this study must meet all inclusion criteria and none of the exclusion criteria at each 
of the Screening Visit and Qualification Visits #1 and #2. Subjects will receive a baseline eye examination 
including intraocular pressure (IOP) measurements at the Screening Visit and Qualification Visits #1 and #2 
and undergo additional testing at Qualification Visit #2. If deemed eligible, subjects will be enrolled at 
Qualification Visit #2 and assigned to either the netarsudil group or ripasudil group in a 1:1 ratio according 
to a computer-generated randomization list. Randomization will take place using Interactive Web Response 
System (IWRS) methodology and will stratify subjects by site.  
Randomized subjects will dose the assigned study drug in both eyes BID in the morning (9:00 ± 1 hour) and 
in the evening (21:00 ± 1hour) beginning on Day 1 and up to and including the evening prior to the final visit 
at Visit 6 (Week 4). Procedures conducted at each of study Visits 4-6 will include safety measures and 
efficacy measurements, including IOP assessments. At Visits 4-6 (Weeks 1, 2, and 4, respectively), IOP will 
be assessed at pre-dose, 2 hours and 7 hours post-dose of the dose in the morning. Following completion of 
the Visit 6 (Week 4) study visit procedures, subjects will exit the study. For subjects who discontinue early, 
every possible effort will be made to assure there is a final visit that includes all examinations listed for Visit 
6.0 (Week 4) and dilated ophthalmoscopy. 
Study Population:  
A total of approximately 240 subjects will be enrolled in this study at approximately 28 clinical sites, 
comprising a total of 120 subjects per treatment arm for each of two treatment arms. Subjects will be at least 
20 years of age with diagnosed POAG or OHT, each of whom meets all inclusion criteria and none of the 
exclusion criteria. 
 


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Inclusion Criteria: 
Subjects have to meet all of the following criteria at screening and qualification visits to enter into the study: 
1. 20 years of age or older  
2. Diagnosis of POAG or OHT in both eyes (POAG in one eye and OHT in the fellow eye is acceptable) 
3. Medicated intraocular pressure (IOP) ≥ 14 mmHg in at least one eye and < 30 mmHg in both eyes at 
screening visit (this also applies to treatment naive subjects) 
4. For POAG eyes, unmedicated (post washout) IOP ≥ 15 mmHg and < 35 mmHg in the study eye at 
2 qualification visits (09:00 hour), 2-7 days apart. At second qualification visit IOP ≥ 15 mmHg and 
< 35 mmHg at 11:00 and 16:00 hours (in the same eye). 
5. For OHT eyes, unmedicated (post washout) IOP ≥ 22 mmHg and < 35 mmHg in the study eye at 
2 qualification visits (09:00 hour), 2-7 days apart. At second qualification visit IOP ≥ 22 mmHg and 
< 35 mmHg at 11:00 and 16:00 hours (in the same eye). 
6. Best-corrected visual acuity (BCVA) +0.7 log MAR or better (20/100 Snellen or better or 0.20 or 
better in decimal unit) in each eye 
7. Willingness and ability to give signed informed consent and follow study instructions 
Exclusion Criteria: 
Subjects meeting any of the following criteria during screening or qualification evaluations (e.g., at the time 
of randomization) will be excluded from entry into the study: 
Ophthalmic: 
1. Clinically significant ocular disease (e.g., corneal edema, uveitis, or 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 for up to a maximum of 8 weeks is not judged safe as it would put the subject at risk for 
further vision loss  
2. Retinal diseases that may progress during the study period (e.g., Macular edema, retinal detachment, 
diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, pathological myopia) 
3. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure glaucoma, 
or narrow angles (i.e., Shaffer Grade 2 or less). Note: Previous laser peripheral iridotomy is NOT 
acceptable 
4. Ocular hyperemia score of moderate (+ 2) or severe (+3) at Qualification Visit #2 
5. Previous glaucoma intraocular surgery, including selective laser trabeculoplasty (SLT) or argon laser 
trabeculoplasty (ALT) in either eye 
6. Refractive surgery in either eye (e.g., radial keratotomy, photorefractive keratectomy [PRK], 
laser-assisted in situ keratomileusis [LASIK], corneal cross-linking) 
7. Ocular trauma within the 6 months prior to screening, or ocular surgery or non-refractive laser 
treatment within the 3 months prior to screening 
8. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of 
clinically significant blepharitis, conjunctivitis, keratitis, or a history of herpes simplex or zoster 
keratitis in either eye at screening 
9. Any corneal disease or condition in either eye that in the Investigator’s opinion, may confound 
assessment of the cornea 
10. Current evidence of corneal deposits or cornea verticillata in either eye 
11. Planned use of any prohibited concomitant medications in either eye during the study 
12. Mean central corneal thickness greater than 620 μm in either eye at screening 
13. Any abnormality preventing reliable Goldmann applanation tonometry of either eye 
(e.g., keratoconus) 
14. Known hypersensitivity to any component of netarsudil ophthalmic solution 0.02%, ripasudil 
hydrochloride hydrate ophthalmic solution 0.4%, or to topical anesthetic. 
15. Cannot demonstrate proper delivery of the eye drop, or in the Investigator or Co-investigator’s 
opinion, unable to deliver the eye drop consistently 


 
 
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Systemic: 
16. Clinically significant systemic disease which might interfere with the study or place the subject at risk 
17. Participation in any investigational study within 30 days prior to screening 
18. 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 
19. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a 
medically acceptable form of birth control. Acceptable birth control includes: condoms plus 
intrauterine devices or condoms plus oral hormonal contraceptives, double barrier methods 
(e.g., condoms with spermicidal gel plus diaphragms). Birth control must be continued for at least 
30 days after the last dose of the study drug. An adult woman is considered to be of childbearing 
potential unless she is 1 year post-menopausal or 3 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 drug, Dose, and Mode of Administration: 
 
Netarsudil ophthalmic solution Vehicle, 1 drop QD (9:00), in both eyes (OU) 
 
Netarsudil ophthalmic solution 0.02%, 1 drop QD (21:00), OU 
 
Ripasudil hydrochloride hydrate ophthalmic solution 0.4%, 1 drop BID (9:00/21:00), OU 
Duration of Treatment: 
Dosing will continue daily for approximately 28 days continuously. 
Efficacy Assessments: 
The primary efficacy endpoint will be mean diurnal IOP at Week 4 (Day 29) for netarsudil ophthalmic 
solution 0.02% relative to ripasudil hydrochloride hydrate ophthalmic solution 0.4% by Goldmann 
Applanation Tonometry. Superiority of netarsudil ophthalmic solution 0.02% QD to ripasudil hydrochloride 
hydrate ophthalmic solution 0.4% BID in the study eye is tested. 
Secondary efficacy endpoints will be comparison of netarsudil ophthalmic solution 0.02% QD relative to 
ripasudil hydrochloride hydrate ophthalmic solution 0.4% BID for: 
 
Mean diurnal IOP at Weeks 1 and 2 (Days 8 and 15, respectively) 
 
Mean change from baseline in mean diurnal IOP at each post-treatment visit 
 
Mean percent change from baseline in mean diurnal IOP at each post-treatment visit 
 
Mean IOP at each post-treatment time point  
 
Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
 
Mean percent change from diurnally adjusted baseline IOP at each post-treatment time point 
 
Percentages of subjects achieving pre-specified mean, mean change, and percent mean change in 
mean diurnal IOP levels 
Other secondary efficacy analyses may be carried out as described in the study Statistical Analysis Plan. 
Safety Assessments: 
Primary safety assessments: 
 
Ophthalmic and systemic adverse events (AEs) 
 
BCVA 
 
Objective findings of biomicroscopic examinations (i.e., anterior segment examinations including 
evaluation of cornea, conjunctiva, lids, and lens) 
 
Dilated ophthalmoscopy, including vertical cup-disc ratio measurements 
Additional safety assessments: 
 
Systemic safety assessments as measured by heart rate and blood pressure 
 
Pregnancy testing (for women of childbearing potential) 


 
 
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Statistical Methods: 
Summaries will be presented by treatment, visit, and time point (as applicable). Continuous and ordinal study 
assessments will be summarized using descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum).  Discrete study assessments will be summarized using frequency counts and percentages.   
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 0.05 significance level.   
Hypotheses: 
H0: The difference in mean diurnal IOP in study eyes treated with netarsudil QD versus study eyes treated 
with ripasudil BID (netarsudil QD – ripasudil BID) at Week 4 = 0. 
H1: The difference in mean diurnal IOP in study eyes treated with netarsudil QD versus study eyes treated 
with ripasudil BID (netarsudil QD – ripasudil BID) at Week 4 ≠ 0. 
Sample Size: 
Ninety three (93) subjects (study eyes) per treatment group are required to have 90% power (1-β) to reject 
H0 in favor of H1 at a two-sided significance level of 5%, assuming that a difference of the change from 
baseline in mean diurnal IOP between netarsudil and ripasudil (netarsudil QD – ripasudil BID) in the present 
study is -1.1 mmHg with a common standard deviation of 2.3.  The target sample size is set to 120 per 
treatment group to allow for withdrawals and dropouts.  Note that change from baseline values from historic 
studies are being used as estimates from which to calculate sample size for a non-change from baseline 
primary endpoint due to the change from baseline estimates for standard deviation better reflecting the 
standard deviation obtained from the primary analysis strategy within this study. 
Primary Efficacy Population and Analysis: 
The intent-to-treat (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. 
The primary analysis of the primary endpoint will employ a linear model with mean diurnal IOP at Week 4 
as the response, baseline mean diurnal IOP as a covariate, and treatment as a main effect factor, using the 
ITT population with Monte Carlo Markov Chain multiple imputation techniques used to impute missing data 
as defined in the intercurrent event strategy within the body of the protocol.  The least squares mean 
difference (netarsudil QD – ripasudil BID) will be presented as well as the 2-sided p-value and 95% 
confidence interval (CI). Inference will be made on the 2-sided p value. Superiority of netarsudil QD over 
ripasudil BID will be concluded if the 2-sided p-value, for testing the difference (netarsudil QD – ripasudil 
BID) to 0, ≤ 0.05 and the point estimate of the difference < 0. 
Date of Original Approved Protocol (Rev 0): 29 July 2020 
Date of Most Recent Protocol Amendment (Rev 1): 11 January 2021 
 


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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................12 
1. 
INTRODUCTION ....................................................................................................14 
1.1 
Investigational Product .......................................................................................14 
1.2 
Findings from Non-Clinical and Clinical Studies .............................................16 
1.3 
Risks and Benefits to Human Subjects ..............................................................16 
2. 
STUDY OBJECTIVES ............................................................................................18 
2.1 
Primary Objective(s) ...........................................................................................18 
3. 
INVESTIGATIONAL PLAN ..................................................................................18 
3.1 
Overall Study Design and Plan ...........................................................................19 
3.2 
Rationale for Study Design and Control Group ...............................................19 
3.3 
Expected Duration of Subject Participation ......................................................20 
4. 
STUDY POPULATION SELECTION ...................................................................21 
4.1 
Study Population ..................................................................................................21 
4.2 
Inclusion Criteria .................................................................................................21 
4.3 
Exclusion Criteria ................................................................................................22 
5. 
STUDY TREATMENTS ..........................................................................................24 
5.1 
Description of Treatments ...................................................................................24 
5.1.1 
Study Drug ......................................................................................................24 
5.1.2 
Vehicle or Control Drug ................................................................................24 
5.2 
Treatments Administered ...................................................................................24 
5.3 
Selection and Timing of Dose for Each Patient .................................................24 
5.4 
Method of Assigning Patients to Treatment Groups ........................................25 
5.5 
Masking .................................................................................................................25 
5.6 
Concomitant Therapy ..........................................................................................26 
5.7 
Restrictions ...........................................................................................................27 
5.7.1 
Prior Therapy/Washout Period ....................................................................27 
5.7.2 
Fluid and Food Intake ...................................................................................27 
5.7.3 
Subject Activity Restrictions .........................................................................27 
5.8 
Treatment Compliance ........................................................................................28 
5.9 
Packaging and Labeling ......................................................................................28 
5.10 
Storage and Accountability .................................................................................28 
5.11 
Study drug Retention at Study Site ....................................................................29 
5.11.1 
Receipt and Disposition of Study Medication .............................................29 
5.11.2 
Return of Study Medication ..........................................................................29 
6. 
STUDY PROCEDURES ..........................................................................................30 
6.1 
Informed Consent ................................................................................................30 
6.2 
Demographics and Medical History ...................................................................30 
6.3 
Concomitant Medication Assessments ...............................................................30 
6.4 
Ophthalmic Assessment.......................................................................................31 
6.5 
Vital Signs .............................................................................................................31 
6.6 
Pregnancy testing (for women of childbearing potential) ................................31 
6.7 
Study Eye Selection Process ................................................................................31 


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6.8 
Dispensing Study Drug ........................................................................................32 
6.9 
Efficacy Assessments ...........................................................................................32 
6.9.1 
Specification of the Efficacy Parameters .....................................................32 
6.9.2 
Method and Timing for Assessing, Recording, and Analyzing of 
Efficacy Parameters .......................................................................................32 
6.9.3 
Intraocular Pressure ......................................................................................33 
6.10 
Safety Assessments ...............................................................................................33 
6.10.1 
Best-Corrected Visual Acuity (BCVA) ........................................................33 
6.10.2 
Biomicroscopy ................................................................................................34 
6.10.2.1 
Corneal Deposit Grading under Biomicroscopy ...................................34 
6.10.3 
Gonioscopy/Pachymetry ................................................................................34 
6.10.4 
Visual Field Testing .......................................................................................34 
6.10.5 
Dilated Ophthalmoscopy ...............................................................................34 
6.11 
Adverse Events Assessments ...............................................................................35 
6.11.1 
Performing Adverse Event (AE) Assessments ............................................35 
6.11.2 
Adverse Event Definition ..............................................................................35 
6.11.3 
Timing for Reporting of Adverse Events .....................................................36 
6.11.4 
Severity............................................................................................................37 
6.11.5 
Relationship ....................................................................................................38 
6.11.6 
Expectedness ...................................................................................................38 
6.11.7 
Serious Adverse Events (SAEs), Suspected Serious Adverse Reactions 
(SSARs), Suspected Unexpected Serious Adverse Reactions (SUSARs) ..39 
6.11.7.1 
Reporting SAEs or SSARs ......................................................................39 
6.11.7.2 
Reporting SUSARs ..................................................................................39 
6.11.7.3 
Safety Reporting Contact Information ..................................................39 
6.12 
Pregnancy Reporting ...........................................................................................40 
6.13 
Removal of Subjects from the Study or Study Treatment ...............................40 
6.13.1 
Completed Subject .........................................................................................40 
6.13.2 
Non-completing Subject ................................................................................40 
6.13.3 
Actions after Discontinuation .......................................................................41 
6.13.4 
Discontinuation of the Entire Study .............................................................41 
6.13.5 
Completed Study ............................................................................................41 
6.14 
Appropriateness of Measurements .....................................................................41 
7. 
STUDY ACTIVITIES ..............................................................................................42 
7.1 
Visit 1 (Screening) ................................................................................................42 
7.1.1 
Evaluation of Eye-Drop Instillation Performance ......................................43 
7.1.2 
Washout ..........................................................................................................43 
7.2 
Visit 2 (Qualification Visit #1, for IOP and safety measurements at 09:00 
hours) ....................................................................................................................43 
7.3 
Treatment Period .................................................................................................44 
7.3.1 
Visit 3.0 (Qualification Visit #2, Day 1, for IOP and safety 
measurements at 09:00 hours) ......................................................................44 
7.3.2 
Visit 3.1 (Day 1, for IOP and safety measurements at 11:00 hours) .........45 
7.3.3 
Visit 3.2 (Day 1, for IOP and safety measurements at 16:00 hours) .........45 


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7.3.4 
Visit 4.0 (Week 1 [Day 8], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................47 
7.3.5 
Visit 4.1 (Week 1 [Day 8], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................47 
7.3.6 
Visit 4.2 (Week 1 [Day 8], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................47 
7.3.7 
Visit 5.0 (Week 2 [Day 15], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................48 
7.3.8 
Visit 5.1 (Week 2 [Day 15], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................49 
7.3.9 
Visit 5.2 (Week 2 [Day 15], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................49 
7.3.10 
Visit 6.0 (Week 4 [Day 29], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................49 
7.3.11 
Visit 6.1 (Week 4 [Day 29], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................50 
7.3.12 
Visit 6.2 (Week 4 [Day 29], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................50 
7.4 
Unscheduled Visits ...............................................................................................51 
8. 
QUALITY CONTROL AND ASSURANCE .........................................................51 
9. 
PLANNED STATISTICAL METHODS ................................................................51 
9.1 
General Considerations .......................................................................................51 
9.2 
Hypotheses ............................................................................................................52 
9.3 
Adjustments for Multiplicity ..............................................................................52 
9.4 
Determination of Sample Size .............................................................................52 
9.5 
Analysis Populations ............................................................................................53 
9.5.1 
Intent-to-Treat (ITT) Population .................................................................53 
9.5.2 
Per Protocol (PP) Population ........................................................................53 
9.5.3 
Safety Population ...........................................................................................53 
9.6 
Demographics and Baseline Characteristics .....................................................53 
9.7 
Primary Efficacy ..................................................................................................53 
9.7.1 
Primary Efficacy Endpoint(s) .......................................................................53 
9.7.2 
Primary Efficacy Analyses ............................................................................54 
9.8 
Secondary Efficacy...............................................................................................54 
9.8.1 
Secondary Efficacy Endpoints ......................................................................54 
9.8.2 
Secondary Efficacy Analyses ........................................................................55 
9.9 
Safety .....................................................................................................................56 
9.9.1 
Safety Endpoints ............................................................................................56 
9.9.2 
Safety Analyses ...............................................................................................57 
9.10 
Other Assessments or Analyses ..........................................................................57 
9.11 
Interim Analysis ...................................................................................................57 
10. ADMINISTRATIVE CONSIDERATIONS ...........................................................58 
10.1 
Investigators and Study Administrative Structure ...........................................58 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .....58 
10.3 
Ethical Conduct of the Study ..............................................................................58 


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10.4 
Subject Information and Consent ......................................................................58 
10.5 
Subject Confidentiality ........................................................................................59 
10.6 
Study Monitoring .................................................................................................59 
10.7 
Case Report Forms and Study Records .............................................................60 
10.8 
Protocol Deviations ..............................................................................................60 
10.9 
Access to Source Documentation ........................................................................61 
10.10 Data Generation and Analysis ............................................................................61 
10.11 Retention of Data .................................................................................................61 
10.12 Financial Disclosure .............................................................................................62 
10.13 Publication and Disclosure Policy ......................................................................62 
11. REFERENCES .........................................................................................................63 
11.1 
External References .............................................................................................63 
11.2 
Internal References ..............................................................................................64 
 
TABLE OF TABLES 
Table 1 
Ocular Hypotensive Medication Washout Period ................................27 
 
TABLE OF FIGURES 
Figure 1 
Study Design .............................................................................................18 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Visits and Procedures ..........................................................66 
Appendix 2 
Sponsor’s Obligations ..............................................................................68 
Appendix 3 
Investigator’s Obligations .......................................................................69 
Appendix 4 
Declaration of Helsinki ............................................................................71 
Appendix 5 
Study Monitoring .....................................................................................74 
Appendix 6 
Sample SAS Code .....................................................................................75 
Appendix 7 
Protocol Amendment ...............................................................................78 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Argon Laser Trabeculoplasty 
AM 
Morning 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice daily 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTN 
Clinical Trial Notification 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LASIK 
Laser-Assisted In Situ Keratomileusis 
LDPE 
Low Density Polyethylene 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
MAA 
Marketing Authorisation Application 
mmHg 
Millimeters of Mercury 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labor and Welfare 
MOPs 
Manual of Procedures 
NDA 
New Drug Application 
OHT 
Ocular Hypertension 
OTC 
Over-the-Counter 
OU 
Both Eyes 
PM 
Evening 
PGA 
Prostaglandin 


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PLD 
Phospholipidosis 
PMDA 
Pharmaceuticals and Medical Devices Agency 
POAG 
Primary Open-Angle Glaucoma 
PP 
Per Protocol 
PRK 
Photorefractive Keratectomy 
PT 
Preferred Term 
QD 
Once Daily 
ROCK 
Rho Kinase 
Rx 
Medical Prescription 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SAS 
Statistical Analysis Software 
SITA 
Swedish Interactive Thresholding Algorithm 
SLT 
Selective Laser Trabeculoplasty 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 


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1. INTRODUCTION 
1.1 
Investigational Product 
Glaucoma is a progressive optic neuropathy that causes characteristic loss of visual fields and 
can eventually lead to blindness. A major risk factor for glaucomatous visual field loss is 
elevated intraocular pressure (IOP) (AGIS 2000).  
The need for improved efficacy of glaucoma medications is supported by several clinical 
studies.  Studies such as the Early Manifest Glaucoma Trial (Heijl 2002), the Ocular 
Hypertension Treatment Study (Kass 2002; Kass 2010), and the Collaborative Normal 
Tension Glaucoma Study Group (Collaborative Normal-Tension Glaucoma Study Group 
1998) support the general conclusion that every millimeter of reduction in IOP is significant 
for delaying disease progression. This conclusion holds true not only for high risk ocular 
hypertensive and glaucoma subjects with elevated IOPs but also for glaucoma subjects with 
IOPs in the normal range. Thus, the goal for treating subjects should be to lower IOP to the 
point that it prevents further damage to the optic nerve and achieve this without sacrificing 
safety or convenience. 
Inhibitors of Rho kinase (ROCK) have emerged as a new class of IOP-lowering agents 
(Chen 2011; Kopczynski 2014). Netarsudil mesylate (AR-13324) is a novel Rho kinase and 
norepinephrine transporter inhibitor developed at Aerie Pharmaceuticals, Inc. (Aerie) for 
topical ophthalmic use for lowering IOP. In both rabbit and monkey studies, netarsudil 
produces large reductions in IOP with a longer duration of action than reported for previously 
characterized Rho kinase inhibitors. Netarsudil ophthalmic solution has been shown to 
provide significant IOP lowering when dosed once-daily (QD) in the evening (Clinical Study 
Reports AR-13324-CS202, AR-13324-CS301, AR-13324-CS302, AR-13324-CS304, 
AR-13324-CS205 and AR-13324-CS208), and reduces IOP potentially through several 
mechanisms: increasing trabecular outflow (Clinical Study Report AR-13324-CS102; 
Clinical Study Report AR-13324-CS206; Wang 2015), decreasing aqueous humor production 
(Clinical Study Report AR-13324-CS102; Wang 2015), and reducing episcleral venous 
pressure (Clinical Study Report AR-13324-CS102; Clinical Study Report AR-13324-CS206; 
Kiel 2015). Aerie filed a New Drug Application for once-daily netarsudil 0.02% on 
February 28, 2017 (NDA 208254 for Rhopressa®) which was approved by US FDA on 
December 18, 2017. A Marketing Authorization Application (MAA) was submitted on 
September 10, 2018 in the EU under the trade name of Rhokiinsa®, which was approved by 
the European Commission on November 19, 2019. 
Cornea verticillata, a whorl-like pattern of deposits typically localized to the basal corneal 
epithelium (Mantyjarvi 1998; Hollander 2004) have been reported in Aerie’s completed 
Phase 3 studies (AR-13324-CS301, AR-13324-CS302, AR-13324-CS303, and 
AR-13324-CS304). A variety of cationic, amphiphilic drugs are known to induce cornea 
verticillata, which arise due to the accumulation of phospholipids within corneal epithelial 
cells through a process called phospholipidosis (PLD).  Amiodarone, an antiarrhythmic 
agent, is the most common cause of cornea verticillata, followed by chloroquine, 
hydroxychloroquine, indomethacin, and phenothiazines (Raizman 2017). It is unusual for 


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these deposits to result in reduction of visual acuity or ocular symptoms, and the deposits 
typically resolve with discontinuation of the drug (Mantyjarvi 1998). Corneal changes due to 
amiodarone have been studied over a long period of time and are well characterized; it is of 
note that no routine monitoring, or specific treatment, or precautions are recommended for 
amiodarone-induced cornea verticillata (Ingram 1982, Siddoway 2003). 
The corneal verticillata associated with the use of netarsudil were first detected between 
2-13 weeks, dose dependent, observed in 16.7% (76/454) of netarsudil QD subjects and 
25.3% (64/253) of netarsudil BID subjects. Aerie carried out an observational cohort study 
(AR-13324-OBS01) to follow up the cases of cornea verticillata and demonstrated that 
cornea verticillata did not have any clinically meaningful impact on visual function and 
appeared to resolve after dosing was discontinued.  
For the development in Japan, two Phase 1 studies (AR-13324-CS103; study CS103 and 
AR-13324-CS104; study CS104) that enrolled Japanese-American subjects within the second 
generation were conducted and completed in the United States to evaluate the tolerability and 
safety of netarsudil 0.02%. In study CS103, pharmacokinetics of netarsudil was also 
evaluated. The results of those two Phase 1 studies demonstrated that the netarsudil 0.02% 
formulations were safe and generally well tolerated by the healthy volunteer subjects of 
Japanese ethnicity within the 2nd generation who participated in this study.  
Recently, a Phase 2 study to assess the efficacy and safety of netarsudil ophthalmic solution 
(0.01%, 0.02% and 0.04%) compared to placebo over a 28-day period in Japanese subjects 
with POAG or OHT was completed (AR-13324-CS208). Netarsudil ophthalmic solution 
0.01%, 0.02% and 0.04% demonstrated clinically relevant efficacy and met primary endpoint 
of superiority to placebo in mean diurnal IOP at Week 4 in Japanese subjects. Baseline-
adjusted least squares (LS) mean diurnal IOP at Week 4 (mean value of IOP at 9:00, 11:00, 
and 16:00) was 18.94 mmHg in the placebo group, while it was 16.53, 15.82 and 16.06 
mmHg in the netarsudil 0.01%, 0.02% and 0.04% groups, respectively. The mean difference 
(netarsudil – placebo) (adjusted LS mean [95% confidence interval]) was -2.41 (-3.15, -1.67), 
-3.12 (-3.87, -2.38) and -2.88 (-3.66, -2.10) mmHg in the netarsudil 0.01%, 0.02% and 
0.04% groups, respectively, in which a difference between the placebo group and any of the 
netarsudil 0.01%, 0.02% and 0.04% groups met the pre-defined statistically significant level 
(p-value is <0.05 and the point estimate of the LS mean difference < 0). The ocular 
hypotensive efficacy of netarsudil 0.01% was slightly less than netarsudil 0.02% and 0.04% 
at Week 4. 
In terms of safety, netarsudil ophthalmic solution 0.01%, 0.02% and 0.04% administered QD 
were safe and generally well tolerated in Japanese subjects with POAG or OHT based upon a 
review of adverse events (AEs) and an assessment of ocular parameters, vital signs, and 
clinical laboratory findings. Number of subjects with at least one treatment emergent adverse 
event (TEAE) was 21 (38.2%), 27 (50.0%), and 36 (70.6%) in the netarsudil 0.01%, 0.02%, 
and 0.04% groups, respectively, representing increased incidence with higher dose of 
netarsudil. The most frequent ocular TEAEs were conjunctival hyperemia which was scored 
as mild in the majority of the subjects. 


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In conclusion, netarsudil 0.02% was deemed to provide optimum efficacy and safety based 
on the results of the study, and 0.02% was determined to be the clinically optimum 
concentration of netarsudil for Japanese population. 
The present study is a Phase 3 study to evaluate the ocular hypotensive efficacy and safety 
of netarsudil ophthalmic solution 0.02% QD compared to the active comparator, ripasudil 
hydrochloride hydrate ophthalmic solution 0.4% BID, over a 4-week period (superiority 
study). 
1.2 
Findings from Non-Clinical and Clinical Studies 
Non-Clinical 
Proof of concept for netarsudil in lowering IOP was established in primary pharmacology 
studies in 2 species, rabbits and monkeys.  Safety pharmacology (central nervous system, 
respiratory, and cardiovascular) of netarsudil was investigated in rats and dogs. 
Pharmacokinetics/biodistribution of netarsudil was assessed after systemic and ocular 
administration of netarsudil. Ocular toxicity was investigated in studies up to 6 months in 
rabbits and up to 9 months in monkeys. Repeated dose toxicity of systemically administered 
netarsudil was investigated in studies up to 28 days in rats and dogs. Reproductive toxicity 
was investigated in rats and rabbits. The non-clinical program for netarsudil also included a 
standard range of genotoxicity tests and phototoxicity studies. 
Clinical 
The clinical development of netarsudil ophthalmic solution for Japan includes 
pharmacokinetics, tolerability, and dose-response investigations. The assessment 
of the ocular and systemic safety of netarsudil ophthalmic solution 0.02% for Japanese 
ethnicity in two Phase 1 clinical studies (Clinical Study Reports AR-13324-CS103 
and AR-13324-CS104) have been completed. Results from a previous Phase 2 study 
(Clinical Study Report AR-13324-CS208) investigating a range of netarsudil concentrations 
(0.01%, 0.02%, and 0.04%) in Japanese patients with POAG or OHT were used to select 
the appropriate concentration of netarsudil ophthalmic solution to be tested in the present 
study (0.02%).  
Four overseas Phase 3 clinical studies (Clinical Study Reports AR-13324-CS301, 
AR-13324-CS302, AR-13324-CS303, and AR-13324-CS304) evaluating the safety 
and efficacy of netarsudil ophthalmic solution 0.02% have been completed.  
Detailed information on nonclinical and clinical studies completed with netarsudil 
ophthalmic solution is provided in the Investigator’s Brochure. 
1.3 
Risks and Benefits to Human Subjects 
Netarsudil ophthalmic solution 0.02% was approved in the US on December 18, 2017 and 
in the EU and the UK on November 19, 2019 under the trade name of Rhopressa® and 


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Rhokiinsa®, respectively. In the US Phase 3 studies, AR-13324-CS301, AR-13324-CS302, 
and AR-13324-CS304, netarsudil ophthalmic solution 0.02% QD demonstrated non-
inferiority to timolol 0.5% BID in subjects with POAG or OHT, and it was safe and generally 
well tolerated. The most common ocular adverse reaction observed in controlled clinical 
studies with netarsudil ophthalmic solution 0.02% QD was conjunctival hyperemia which 
was reported in 53% of patients. Other common (approximately 20%) ocular adverse 
reactions reported were: cornea verticillata, instillation site pain, and conjunctival 
hemorrhage. Instillation site erythema, corneal staining, blurred vision, increased lacrimation, 
erythema of eyelid, and reduced visual acuity were reported in 5-10% of patients 
(Rhopressa® PI). 
AR-13324-CS208, a Phase 2 study in Japan, netarsudil ophthalmic solution 0.01%, 0.02% 
and 0.04% demonstrated clinically relevant efficacy and met primary endpoint of superiority 
to placebo in mean diurnal IOP at Week 4 in the primary efficacy population. Netarsudil 
ophthalmic solution 0.01%, 0.02% and 0.04% administered QD were safe and generally well 
tolerated in Japanese subjects with POAG or OHT based upon a review of AEs and an 
assessment of ocular parameters, vital signs, and clinical laboratory findings. 
• Number of subjects with ≥1 TEAE was 21 (38.2%), 27 (50.0%), and 36 (70.6%) 
in the netarsudil 0.01%, 0.02%, and 0.04% groups, respectively, representing 
increased incidence with higher dose of netarsudil. 
• Most (95.2%) TEAEs (ocular and non-ocular) in the netarsudil groups were reported 
as being of mild severity. 
• The most frequent ocular TEAE was conjunctival hyperemia which was scored as 
mild in the majority of the subjects. 
The reader should refer to the Investigator’s Brochure for more detailed information on 
potential risks due to use of netarsudil ophthalmic solution.   
The major potential benefit from exposure to netarsudil ophthalmic solution is reduction in 
IOP in subjects with POAG or OHT. A long-term benefit of reduced IOP could be slowing of 
disease progression and preservation of vision in subjects when measured over periods of 
months to years. 
 
 
 


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2. STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
The objective of this study is: 
• To evaluate the ocular hypotensive efficacy and safety of netarsudil ophthalmic solution 
0.02% QD compared to the active comparator, ripasudil hydrochloride hydrate 
ophthalmic solution 0.4% BID, over a 4-week period (superiority study). 
 
3. INVESTIGATIONAL PLAN 
Figure 1 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Visit 
(Visit 1) 
Subjects with POAG or 
OHT in Japan 
Netarsudil vehicle 
1 drop, QD (OU)  
each morning 
(9:00) 
 
Netarsudil 0.02% 
1 drop, QD (OU)  
each evening 
(21:00) 
Randomize 1:1 
 
N = 240 
 
Stratification by site 
Primary Analysis 
The ocular hypotensive efficacy of netarsudil 
ophthalmic solution relative to ripasudil 
hydrochloride hydrate ophthalmic solution for mean 
diurnal IOP over a 4-week period and the ocular and 
systemic safety of netarsudil ophthalmic solution 
relative to ripasudil hydrochloride hydrate 
ophthalmic solution over a 4-week period. 
Post Randomization Visits  
Visits 4-6 (Weeks 1, 2, 4, respectively)  
(Treatment Period - 28 Days) 
Washout Period          
of Prior Ocular 
Hypotensive Medication 
(if needed) 
Qualification #2 (Visit 3) 
(09:00) – Visit 3.0 
(11:00) – Visit 3.1 
(16:00) – Visit 3.2 
Qualification #1 (Visit 2) 
(09:00) 
Ripasudil 
1 drop, BID (OU)  
each morning and 
evening 
(9:00/21:00) 


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3.1 
Overall Study Design and Plan 
This study will be a prospective, single-masked, randomized, multi-center, parallel-group, 
4-week study evaluating the efficacy and safety of once daily (QD) netarsudil ophthalmic 
solution 0.02% compared to twice daily (BID) ripasudil hydrochloride hydrate ophthalmic 
solution 0.4% in Japanese subjects with POAG or OHT in Japan over a 4-week period.  
Netarsudil ophthalmic solution 0.02% will be dosed QD (21:00) while ripasudil 
hydrochloride hydrate ophthalmic solution 0.4% will be dosed BID (9:00/21:00). In order to 
be adequately masked, subjects dosing with netarsudil ophthalmic solution 0.02% (21:00) 
also will dose with vehicle QD (9:00). 
Subjects eligible to be enrolled in this study will be subjects with diagnosis of either POAG 
or OHT. Approximately 240 subjects will be enrolled in this study. Subjects who agree to 
participate in this study and are enrolled will attend a total of up to 6 study visits: Screening 
Visit, Qualification Visit #1, Qualification Visit #2/Day 1 (baseline), Week 1 (Day 8), 
Week 2 (Day 15), and Week 4 (Day 29). 
Subjects will be required to washout of their pre-study ocular hypotensive medication for a 
prescribed period (i.e., 5 days to 6 weeks, depending on the medication) prior to attending 
Qualification Visit #1. Subjects eligible to be enrolled in this study must meet all inclusion 
criteria and none of the exclusion criteria at each of the Screening Visit and Qualification 
Visits #1 and #2. Subjects will receive a baseline eye examination including IOP 
measurements at the Screening Visit and Qualification Visits #1 and #2 and undergo 
additional testing at Qualification Visit #2. If deemed eligible, subjects will be enrolled at 
Qualification Visit #2 and assigned to either the netarsudil group or ripasudil group in a 1:1 
ratio according to a computer-generated randomization list. Randomization will take place 
using Interactive Web Response System (IWRS) methodology and will stratify subjects by 
site.  
Randomized subjects will dose the assigned study drug in both eyes BID in the morning 
(9:00 ± 1 hour) and in the evening (21:00 ± 1 hour) beginning on Day 1 and up to and 
including the evening prior to the final visit at Visit 6 (Week 4). Procedures conducted at 
each of study Visits 4-6 will include safety measures and efficacy measurements, including 
IOP assessments. At Visits 4-6 (Weeks 1, 2, and 4, respectively), IOP will be assessed at 
pre-dose, 2 hours and 7 hours post-dose of the dose in the morning. Following completion of 
the Visit 6 (Week 4) study visit procedures, subjects will exit the study. For subjects who 
discontinue early, every possible effort will be made to assure there is a final visit that 
includes all examinations listed for Visit 6.0 (Week 4) and dilated ophthalmoscopy. 
3.2 
Rationale for Study Design and Control Group 
This is a randomized, single-masked, comparative study to confirm the superiority of 
netarsudil 0.02% QD to ripasudil hydrochloride hydrate ophthalmic solution 0.4% BID in 
patients with POAG or OHT. The primary efficacy endpoint of the study is mean diurnal IOP 
at Week 4.  


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The clinically optimal concentration of netarsudil was confirmed to be 0.02% in the Japanese 
Phase 2 study (AR-13324-CS208). Since QD dosing in the same study demonstrated a 
statistically significant difference from placebo, netarsudil will be administered once a day in 
the evening. The treatment period was set to be 4 weeks because both netarsudil and ripasudil 
exerted adequate reduction of IOP during 4 weeks of treatment (netarsudil Japanese Phase 2 
study AR-13324-CS208 and non-Japanese Phase 3 studies AR-13324-CS301, 
AR-13324-CS302 and AR-13324-CS304, and ripasudil Japanese Phase 2 study K-115-03 
and Japanese Phase 3 study K-115-05). 
This study will use ripasudil hydrochloride hydrate ophthalmic solution 0.4% as a 
comparator. Ripasudil is positioned in the second-line treatment options after prostaglandin 
analogues (PGAs), a recommended first-line option in the treatment of glaucoma/OHT, 
according to the Japan Glaucoma Society Guidelines for Glaucoma (4th Edition). Also, 
ripasudil belongs to the same ROCK inhibitor class as netarsudil. Therefore, it was selected 
as a comparator in this study. A superiority study is planned as a confirmatory study, based 
on the results of study CS208 and Japanese Phase 2 dose-response study (K-115-03) and 
Japanese Phase 3 placebo-controlled study (K-115-05) of ripasudil for the patients with 
POAG or OHT. 
While this study will be conducted under masked conditions to avoid biases in the efficacy 
and safety evaluations, a single-masked (evaluator-masked) design using different container 
closure systems between netarsudil and ripasudil was selected. 
3.3 
Expected Duration of Subject Participation 
Each subject is planned to undergo a minimum washout period of their current ocular 
hypotensive medications (if needed), followed by approximately 28 days of treatment.  
Treatment duration with the study drug for this study will start on the evening of Visit 3 
(Qualification Visit #2; Day 1) and end on the morning of Visit 6 (Week 4/Day 29). 
If a subject develops an AE during the 28-day treatment period, the duration of the study will 
continue until resolution or stabilization of the AE.  
 
 


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4. STUDY POPULATION SELECTION 
4.1 
Study Population 
A total of approximately 240 Japanese subjects will be enrolled in this study at 
approximately 28 investigational sites in Japan comprising a total of 120 subjects per 
treatment arm for each of the 2 treatment arms. Subjects will be at least 20 years of age with 
diagnosed POAG or OHT, each of whom meets all inclusion criteria and none of the 
exclusion criteria. 
Planned enrollment numbers are higher (240 total, 120 subjects per arm) than statistically 
required for demonstrating efficacy (approximately 93 intent-to-treat [ITT] subjects per arm 
for 90% power) to account for the potential for subjects who do not complete the entire 
dosing period, or who have disqualifications. Over-enrollment (beyond 240 subjects) is to be 
undertaken only after communication between the investigational site and the Sponsor 
representative. 
4.2 
Inclusion Criteria 
Subjects have to meet all of the following criteria at screening and qualification visits to enter 
into the study: 
1. 20 years of age or older  
2. Diagnosis of POAG or OHT in both eyes (POAG in one eye and OHT in the fellow eye 
is acceptable)  
3. Medicated intraocular pressure (IOP) ≥ 14 mmHg in at least one eye and < 30 mmHg in 
both eyes at screening visit (this also applies to treatment naive subjects) 
4. For POAG eyes, unmedicated (post washout) IOP ≥ 15 mmHg and < 35 mmHg in the 
study eye at 2 qualification visits (09:00 hours), 2-7 days apart. At second qualification 
visit IOP ≥ 15 mmHg and < 35 mmHg at 11:00 and 16:00 hour (in the same eye).  
Note: For purposes of determining eligibility of subjects to be enrolled, any 
non-integral mean IOP number should not be rounded 
5. For OHT eyes, unmedicated (post washout) IOP ≥ 22 mmHg and < 35 mmHg in the 
study eye at 2 qualification visits (09:00 hours), 2-7 days apart. At second qualification 
visit IOP ≥ 22 mmHg and < 35 mmHg at 11:00 and 16:00 hours (in the same eye) 
Note: For purposes of determining eligibility of subjects to be enrolled, any 
non-integral mean IOP number should not be rounded 
6. BCVA +0.7 log MAR or better (20/100 Snellen or better or 0.20 or better in decimal 
unit) in each eye 
7. Willingness and ability to give signed informed consent and follow study instructions 


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4.3 
Exclusion Criteria 
Subjects meeting any of the following criteria during screening or qualification evaluations 
(e.g., at the time of randomization) will be excluded from entry into the study: 
Ophthalmic: 
1. Clinically significant ocular disease (e.g., corneal edema, uveitis, or 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 for up to a maximum of 8 weeks 
is not judged safe as it would put the subject at risk for further vision loss  
2. Retinal diseases that may progress during the study period (e.g., Macular edema, retinal 
detachment, diabetic retinopathy, retinal vein occlusion, age-related macular 
degeneration, pathological myopia) 
3. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure 
glaucoma, or narrow angles (i.e., Shaffer Grade 2 or less). Note: Previous laser peripheral 
iridotomy is NOT acceptable 
4. Ocular hyperemia score of moderate (+ 2) or severe (+3) at Qualification Visit #2 
5. Previous glaucoma intraocular surgery, including selective laser trabeculoplasty (SLT) or 
argon laser trabeculoplasty (ALT) in either eye  
6. Refractive surgery in either eye (e.g., radial keratotomy, photorefractive keratectomy 
[PRK], laser-assisted in situ keratomileusis [LASIK], corneal cross-linking) 
7. Ocular trauma within the 6 months prior to screening, or ocular surgery or non-refractive 
laser treatment within the 3 months prior to screening 
8. Recent or current evidence of ocular infection or inflammation in either eye. Current 
evidence of clinically significant blepharitis, conjunctivitis, keratitis, or a history of 
herpes simplex or zoster keratitis in either eye at screening 
9. Any corneal disease or condition in either eye that in the investigator’s opinion, may 
confound assessment of the cornea 
10. Current evidence of corneal deposits or cornea verticillata in either eye 
11. Planned use of any prohibited concomitant medications in either eye during the study  
12. Mean central corneal thickness greater than 620 μm in either eye at screening 
13. Any abnormality preventing reliable Goldmann applanation tonometry of either eye 
(e.g., keratoconus) 


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14. Known hypersensitivity to any component of netarsudil ophthalmic solution 0.02%, 
ripasudil hydrochloride hydrate ophthalmic solution 0.4%, or to topical anesthetic 
15. Cannot demonstrate proper delivery of the eye drop, or, in the principal investigator or 
co-investigator’s opinion, unable to deliver the eye drop consistently 
Systemic: 
16. Clinically significant systemic disease which might interfere with the study or place the 
subject at risk 
17. Participation in any investigational study within 30 days prior to screening 
18. 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 
19. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control. Acceptable birth control includes: 
condoms plus intrauterine devices or condoms plus oral hormonal contraceptives, double 
barrier methods (e.g., condoms with spermicidal gel plus diaphragms). Birth control must 
be continued for at least 30 days after the last dose of the study drug. An adult woman is 
considered to be of childbearing potential unless she is 1 year post-menopausal or 
3 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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5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Study Drug 
Netarsudil mesylate ophthalmic solution is a sterile, isotonic, buffered aqueous solution 
containing netarsudil (0.02%), boric acid, mannitol, water for injection, and preserved with 
benzalkonium chloride (0.015%). The product formulations are adjusted to approximately 
pH 5.   
5.1.2 
Vehicle or Control Drug 
Netarsudil ophthalmic solution vehicle is a sterile, isotonic, buffered aqueous solution 
containing boric acid, mannitol, water for injection, and preserved with benzalkonium 
chloride (0.015%). The product formulations are adjusted to approximately pH 5. 
As for control drug, ripasudil hydrochloride hydrate ophthalmic solution 0.4% is a 
commercially available product (GLANATEC® ophthalmic solution 0.4%) and contains 
benzalkonium chloride as preservative. The product formulations are adjusted from pH 5 to 
pH 7. 
5.2 
Treatments Administered 
Subjects will be randomized to receive investigational product (IP) netarsudil ophthalmic 
solution (0.02%) or ripasudil hydrochloride hydrate ophthalmic solution 0.4% administered 
1 drop into each eye.  Netarsudil ophthalmic solution 0.02% will be dosed QD (21:00) while 
ripasudil hydrochloride hydrate ophthalmic solution 0.4% will be dosed BID (9:00/21:00). 
In order to be adequately masked, subjects dosing with netarsudil ophthalmic solution 0.02% 
(21:00) also will dose with vehicle QD (9:00). 
IP doses will be administered by the study subjects. For subjects deemed unable to self-
administer the doses, a guardian or alternative caregiver will be asked to administer the 
medication. All subjects will administer study treatment for approximately 28 days. 
5.3 
Selection and Timing of Dose for Each Patient 
Netarsudil ophthalmic solution 0.02% doses and treatment period selected for this study are 
based on two Phase 1 studies (AR-13324-CS103 and AR-13324-CS104) and the results of 
the completed Phase 2 study in Japan (AR-13324-CS208) and 4 Phase 3 studies 
(AR-13324-CS301, AR-13324-CS302, AR-13324-CS303 and AR-13324-CS304) completed 
outside Japan. Each dose is being administered QD OU in the evening (21:00 ± 1 hour) 
in this study, since this dosing regimen was found to provide good efficacy and tolerability in 
the previous clinical studies. 


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The control drug, ripasudil hydrochloride hydrate ophthalmic solution 0.4% will be dosed 
BID (9:00/21:00) according to the package insert (GLANATEC® PI). 
5.4 
Method of Assigning Patients 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 IWRS in a 1:1 ratio to receive netarsudil ophthalmic solution 0.02% or 
ripasudil hydrochloride hydrate ophthalmic solution 0.4% and will stratify subjects by site. 
5.5 
Masking 
Treatment assignments will be masked to the Investigator, the clinical study team 
(Sponsor personnel involved in day to day study management, Monitors, Data Managers, 
and Statisticians), and the subjects for the duration of the study.  
This study adopts a single-masked study design. Therefore, to ensure masked state to the 
investigators and the clinical study team, the study medication bottles are placed in a sealed 
kit so that the study medication cannot be identified from the outside of the kit. Study staff 
responsible for dispensing study medications must always prescribe a study medication to the 
subject in a sealed state and should instruct subjects that the study drug must be in the kit 
when it is returned. Unmasked staff responsible for collecting study medication ensures 
masked state to the investigators and the clinical study team by immediately sealing the 
collected study drug. 
Only in case of medical emergency or occurrence of AEs that warrant unmasking in the 
opinion of the Investigator, will the treatment assignment(s) be unmasked and made available 
to the Investigator and the Sponsor Medical Monitor or designee. 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. 
In the absence of medical need, the randomization code will not be available to the above 
personnel until after the study is completed and the database is unlocked.  
If the Investigator judges it is necessary to unmask a subject’s treatment assignment after an 
emergency situation, the Investigator should contact the Sponsor Medical Monitor or 
designee. After consultation with the Sponsor Medical Monitor or designee, a decision will 
be made as to whether or not the treatment should be unmasked. The treatment assignment 
will be revealed on a subject-by-subject basis, thus leaving the masking on the remaining 
subjects. 
If there is an emergency situation in which treatment of an AE requires immediate 
unmasking, and the Investigator is unable to contact the Sponsor Medical Monitor or 
designee, the Investigator may unmask the treatment. The Investigator will perform the 
unmasking through the IWRS or other randomization system. In the case of such unmasking 
in an emergency situation, the Investigator should contact the Sponsor immediately and 


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document unmasking in writing, recording the date, time, and reason for unmasking the study 
drug treatment in the source documentation. 
5.6 
Concomitant Therapy 
As noted in Section 5.7.1, subjects using ocular hypotensive medications at screening are 
required to undergo a washout of their current ocular hypotensive medications. Intermittent 
use of over-the-counter (OTC) artificial tear lubricant products is acceptable, with a 
minimum of 10 minutes between OTC products and study medication. 
Prohibited medications include concurrent therapy of: 
• Any form of ocular hypotensive medications (prescription or OTC)  
• Miotics 
• Epinephrine-related compounds 
• Carbonic anhydrase inhibitors  
• α-adrenoceptor agonists 
• β-adrenoceptor antagonists 
• Muscarinic agonists (e.g., pilocarpine) 
• Ocular prostaglandin analogues 
• Rho kinase inhibitors 
• Any corticosteroid containing ocular or systemic drug regardless of route of 
administration 
Systemic therapy with agents other than corticosteroids 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 is allowed. 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 any drugs such as cannabis or marijuana during the study visit days. 
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. Subjects will be informed that benzalkonium 
chloride contained in this study drug as preservative agent has a risk to distain contact lenses. 


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Use of all medications should be documented on the appropriate case report form (CRF). 
Investigators are encouraged to contact the Sponsor/Sponsor representative 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 (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 in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy/Washout Period 
Subjects currently using ocular hypotensive medications must undergo a minimum washout 
period as specified in Table 1. 
If washout is to be extended beyond 8 weeks (56 days) for logistical or other reasons, 
the Sponsor should be contacted. 
Table 1 
Ocular Hypotensive Medication Washout Period 
Medication Class 
Minimum Washout 
Period 
Rho kinase inhibitor 
6 weeks 
Prostaglandins 
4 weeks 
β-adrenoceptor antagonists 
4 weeks 
Adrenergic agonists (including α-agonists such as brimonidine and apraclonidine) 
2 weeks 
Muscarinic agonists (e.g., pilocarpine), carbonic anhydrase inhibitors (topical or 
oral) 
5 days 
Hughes 2005 
5.7.2 
Fluid and Food Intake 
On days that diurnal IOP measurements are made, subjects may not consume alcohol. 
Otherwise, there are no general restrictions on fluid or food intake for subjects participating 
in this study.  
5.7.3 
Subject Activity Restrictions 
On days that diurnal IOP measurements are made, subjects may not engage in strenuous 
activity. In addition, eye dilation may cause blurred vision and temporary sensitivity to light. 


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While pupils are dilated, subjects should protect eyes while in bright light by wearing 
sunglasses. Subjects should not drive or engage in any hazardous activity until vision returns 
to normal. Otherwise, there are no restrictions on subject activities during their participation 
in this study. 
5.8 
Treatment Compliance 
All subjects will be instructed on the importance of following the twice-daily dosing 
regimen. Dosing should occur in the morning (9:00 ± 1 hour) and in the evening 
(21:00 ± 1 hour). As no commercially available method is readily available for direct, single-
container monitoring of treatment adherence with multi-dose ophthalmic products, no formal 
measure of treatment compliance is planned. Subjects should be reminded at all visits to dose 
every morning and evening.  
5.9 
Packaging and Labeling 
The container-closure systems for all products are multi-dose ophthalmic dropper dose 
bottles. The commercial label from ripasudil will be removed and replaced with an 
investigational label which will be similar in appearance for both treatment groups. 
The labeled bottles will be packaged in identical appearing subject kits to ensure adequate 
masking. 
The container-closure system for the netarsudil ophthalmic solution 0.02% and vehicle in this 
clinical study is a clear, multi-dose low density polyethylene (LDPE) dropper dose 
ophthalmic bottle with a polypropylene white cap. The container for ripasudil hydrochloride 
hydrate ophthalmic solution 0.4% in this study is a clear multi-dose LDPE dropper dose 
ophthalmic bottle with deep green polypropylene cap. Each packaged unit will be labeled 
with an investigational label with the minimal information required per Japan regulatory 
requirements. 
The products for each individual treatment assignment will be packaged into identical subject 
kits; each subject kit will contain 2 bottles of the assigned treatment: netarsudil ophthalmic 
solution 0.02% and vehicle, or ripasudil hydrochloride hydrate ophthalmic solution 0.4%. 
The two bottles contained in one kit will be identified as one for AM and one for PM.  
5.10 
Storage and Accountability 
The study treatments must be dispensed or administered according to the procedures 
prescribed in this protocol. Only subjects enrolled in the study may receive study treatment, 
in accordance with all the applicable regulatory requirements. Any study staff can dispense 
these medications. Only unmasked staff who is not involved in clinical evaluation of the 
subjects is allowed to collect the used/returned medications. 
Under normal conditions of handling and administration, the study treatments are not 
expected to pose significant safety risk to site staff. Adequate precautions must be taken to 
avoid direct contact with the study treatment.  


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The study treatments will be stored in a secure area under the appropriate physical conditions 
for the product. Access to the study treatment will be limited to authorized site staff only. 
The study treatments will be stored as directed on the drug label. The study treatments should 
be stored refrigerated (2°C to 8°C/36°F to 46°F). Temperature of the study treatment storage 
location at the site is to be monitored using a calibrated monitoring device and documented. 
At time of dispensing, the subject will be instructed to store the bottle(s) as directed on the 
drug label. Once the bottle is opened, the product must always be protected from light and is 
recommended to be stored in the carton provided. Subjects should be instructed not to freeze 
the product.  
5.11 
Study drug Retention at Study Site 
5.11.1 
Receipt and Disposition of Study Medication 
Study medication will be shipped to the Investigator’s site from a central depot. The study 
medication storage manager at the Investigator’s site 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 (e.g., study coordinator) at the Investigator’s institution has to 
account for all used, partially used, and unused study medication. The responsible person will 
also maintain the drug accountability records. 
5.11.2 
Return of Study Medication 
When the site is closed, the study is completed, or is terminated by the Sponsor; all study 
material including used and unused study medication will be returned to the Sponsor 
(or its 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 to account for all used, partially used, and unused study medication. The study 
medication storage manager or designee 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 to the Sponsor’s designee. 
 
 


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6. STUDY PROCEDURES 
6.1 
Informed Consent 
Prior to any study procedures, the study will be discussed with each subject. Subjects wishing 
to participate must give written informed consent.  The verbal explanation of the study will 
cover all the elements specified in the written information provided for the subject. 
The Investigator will inform the subject of the aims, methods, anticipated benefits and 
potential hazards of the study, including any discomfort it may entail. The subject must be 
given every opportunity to clarify any points he/she does not understand and, if necessary, 
may ask for more information. At the end of the interview, the subject should be given time 
to reflect. Subjects and/or legally authorized representative then will be required to sign and 
date the informed consent form. 
The informed consent form (ICF) must have received approval/favorable review by a 
properly constituted Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) prior to use. A copy of the signed and dated consent document will be given to each 
subject.  The original signed and dated ICF must be maintained in the study files at the 
Investigator’s site. 
The Investigator and staff are responsible for ensuring that no subject is exposed to any study 
related examination or activity before the subject has given written informed consent. 
It should be emphasized that the subject is at liberty to withdraw consent to participate at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued 
in this study, and should be notified that discontinuation from the study will not impact on 
their subsequent care. 
6.2 
Demographics and Medical History 
Demographic data and any ongoing medication use will be collected and recorded. 
Any medications the subject took but discontinued within the 30 days prior to screening will 
also be recorded. Significant medical history will be collected and any current underlying 
medical conditions, including those that began within the last 30 days and which may have 
resolved before screening, additionally must be recorded. 
6.3 
Concomitant Medication Assessments 
Use of all medications should be documented on the appropriate CRF. The site staff 
responsible for recording all concomitant medications will be identified on the Delegation of 
Responsibilities Log. Investigators are encouraged to contact the Sponsor/Sponsor 
representative 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. 


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6.4 
Ophthalmic Assessment 
The Investigator will review each subject’s medical and ophthalmic history including 
systemic and ocular medication use to determine eligibility for this study. If enrolled, 
the Investigator will determine if there are any changes in health or concomitant medication 
use at each follow-up visit.  
The Investigator or designee will also perform the following ophthalmic assessments as 
described in the Manual of Procedures (MOPs): visual acuity, visual field, IOP, 
biomicroscopy, central corneal thickness, gonioscopy, symptomatology, and dilated 
ophthalmoscopy.  
The Investigator or designee will perform additional assessments for subjects with cornea 
verticillata as described in the MOPs: slit lamp examination and verticillata grading. 
6.5 
Vital Signs 
The Investigator or designee will measure heart rate, pulse, and blood pressure as described 
in the MOPs. 
6.6 
Pregnancy testing (for women of childbearing potential) 
A urine human chorionic gonadotropin (hCG) pregnancy test (only for females who are not 
diagnosed as postmenopausal or surgically sterile) will be used in this study and performed at 
the screening visit to immediately confirm non-pregnancy eligibility for females of 
child-bearing potential. 
The Sponsor will provide urine pregnancy tests to the sites. Expiration dates on the 
pregnancy tests will be reviewed and confirmed by the site prior to use. 
If a female becomes pregnant during the study, the Investigator should notify the Sponsor 
immediately after the pregnancy is confirmed and the subject will be exited from the study. 
The Investigator should follow the progress of the pregnancy until the fetus is carried to term. 
If the female partner of a subject become pregnant, the Investigator should collect 
information on the outcome of the pregnancy and the health of the baby (if applicable). 
The information will be reported to the sponsor to be used to understand the safety of the 
drug used during pregnancy. 
6.7 
Study Eye Selection Process 
Subjects must qualify in the study eye based upon IOP, ocular history and exam. If the 
subject qualifies in only one eye, then this eye is designated the study eye. If the subject 
qualifies in both eyes, then the study eye will be the eye with the higher IOP at 09:00 hours 
on Visit 3. If both eyes have the same IOP at 09:00 hours on Visit 3, then the right eye will 
be the study eye. For each subject, BOTH eyes will be treated. 


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6.8 
Dispensing Study Drug 
Study staff responsible for dispensing study medication 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 group according to the 
IWRS. Any study staff can dispense these medications. Only unmasked staff who is not 
involved in clinical evaluation of the subjects is allowed to collect the used/returned product 
by maintaining a study medication accountability log. 
6.9 
Efficacy Assessments 
6.9.1 
Specification of the Efficacy Parameters 
The primary efficacy outcome will be the comparison of netarsudil ophthalmic 
solution 0.02% relative to ripasudil hydrochloride hydrate ophthalmic solution 0.4% for 
mean diurnal IOP within a treatment at Week 4 (Day 29) by Goldmann Applanation 
Tonometry.  
Secondary efficacy outcomes will be comparison of netarsudil ophthalmic solution 0.02% 
relative to ripasudil hydrochloride hydrate ophthalmic solution 0.4% for: 
• Mean diurnal IOP at Weeks 1 and 2 (Days 8 and 15, respectively) 
• Mean change from baseline in mean diurnal IOP at each post-treatment visit 
• Mean percent change from baseline in mean diurnal IOP at each post-treatment visit 
• Mean IOP at each post-treatment time point  
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment time 
point 
• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in mean diurnal IOP levels 
Other secondary efficacy analyses may be carried out as described in the study Statistical 
Analysis Plan. 
6.9.2 
Method and Timing for Assessing, Recording, and Analyzing of Efficacy 
Parameters 
As detailed in subsequent sections describing each visit and Appendix 1, IOP will be 
measured at a screening visit, at 2 qualification visits after washout of ocular hypotensive 
medications as required, and at each post-Day 1 treatment study visit.  


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6.9.3 
Intraocular Pressure 
Local anesthetic will be applied in order to facilitate IOP measurements with the Goldmann 
Applanation Tonometer. Tonometer calibration on at least a monthly basis must be 
documented. 
Two consecutive IOP measurements of each eye must be obtained. If the 2 measurements 
differ by more than 2 mmHg, a third measurement must be obtained. Intraocular 
pressure will be analyzed as the mean of 2 measurements or as the median of 
3 measurements (Sherwood 2006). 
Each Goldmann tonometry value is read as an integer. When calculating the mean or median, 
it is possible to have a fractional value; any non-integral mean or median IOP number will be 
reported to one decimal place. Note:  For purposes of determining eligibility of subjects to be 
enrolled, any non-integral mean IOP number should not be rounded. 
IOP should be measured by qualified individuals using a calibrated Goldmann applanation 
tonometer. See MOPs for further information. 
6.10 
Safety Assessments 
The primary safety measures in both eyes of enrolled subjects will include: 
• Ocular symptoms/AEs 
• BCVA 
• Objective findings of biomicroscopic examinations (i.e., anterior segment examinations 
including evaluation of cornea, conjunctiva, lids, and lens) 
• Dilated ophthalmoscopy, including vertical cup-disc ratio measurements 
Other safety assessments will be: 
• Systemic safety assessments as measured by heart rate, blood pressure/AEs 
• Pregnancy testing (for women of childbearing potential)  
6.10.1 
Best-Corrected Visual Acuity (BCVA) 
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 
Landolt-C chart or its equivalents. See MOPs for details of the procedures to be followed 
when determining BCVA. 


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6.10.2 
Biomicroscopy 
Biomicroscopic examination of the eyelids, conjunctiva, cornea, anterior chamber, lens, iris, 
and pupil will be carried out at every study visit for both eyes. Normal or abnormal status of 
these ocular tissues will be graded as described in the MOPs. 
6.10.2.1 
Corneal Deposit Grading under Biomicroscopy  
Subjects who are diagnosed with cornea verticillata by slit lamp examination will undergo 
the evaluation for its location and grading using a published grading scale for amiodarone-
induced cornea verticillata (Orlando 1984). See the MOPs for the details of this grading 
scale. 
6.10.3 
Gonioscopy/Pachymetry 
Gonioscopy will be used to confirm the iridocorneal angle is open and to what extent. 
Eligible subjects must have an angle of 3 or 4 (Shaffer grading scale; Stamper 2009) 
for participation in the study. Gonioscopy may be performed up to 3 months prior to 
randomization. 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 the MOPs. 
6.10.4 
Visual Field Testing 
Visual field testing must be performed in both eyes. Visual field testing may be performed up 
to 3 months prior to randomization. Visual fields must be determined as automated threshold 
perimetry (e.g., 30-2 or 24-2 Humphrey, Kowa etc.). SITA Standard is preferred, SITA fast 
or equivalent is also allowed.  Visual fields must be reliable, defined as those with a) fixation 
losses less than or equal to 33%, b) false positives less than or equal to 33%, and c) false 
negatives less than or equal to 33%. Visual fields fixation losses should not be rounded up to 
the next whole number value. The blind spot should be turned on for all visual fields 
assessments in order to calculate the fixation losses. The gaze track should be turned on 
if gaze track is essential to assess fixation losses. See MOPs for further information.  
6.10.5 
Dilated Ophthalmoscopy 
A dilated funduscopic examination including evaluation of the retina, vitreous, macula, 
choroid, optic nerve, and vertical cup/disc ratio will be performed. See MOPs for further 
information on scoring. Evaluation of vertical cup-disc ratio will be performed when 
ophthalmoscopy is performed. 


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6.11 
Adverse Events Assessments 
6.11.1 
Performing Adverse Event (AE) Assessments 
Qualified study staff responsible for assessing AEs will be listed on the Delegation of 
Responsibilities Log. This includes assessment of AE severity and relationship to study 
medication.  Adverse event information may be volunteered by the subject or solicited by 
study personnel through non-leading questions. 
All AEs 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 study medication until Week 4 [Day 29] or study 
discontinuation. 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 AE. As noted in Section 7.3.1, any change in their Visit 1 (Screening) health 
status prior to enrollment should be recorded on the Medical History page of the CRF. 
If a subject has an ongoing AE at the time of study exit, the ongoing AE must be followed-up 
and provided appropriate medical care until the event has resolved or stabilized, the subject is 
lost to follow-up, or there is other resolution to the event. 
Documentation of AEs/adverse reactions includes start date and stop date, severity, action(s) 
taken, seriousness and outcome. 
6.11.2 
Adverse Event Definition 
The following definitions of terms apply to this section: 
• Adverse event (AE): Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. 
• Suspected adverse reaction (SAR): Any AE for which there is a reasonable possibility 
that the drug caused the AE.  For the purposes of clinical trial notification (CTN) safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by 
a drug. 
• Life-threatening AE or life-threatening SAR: An AE or SAR is considered 
“life-threatening” if, in the view of either the Investigator or Sponsor, its occurrence 
places the subject at immediate risk of death. It does not include an AE or SAR that, 
had it occurred in a more severe form, might have caused death. 
• Serious adverse event (SAE) or suspected serious adverse reaction (SSAR). An AE or 
SAR 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 adverse event, subject 


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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. 
• Unexpected AE or unexpected SAR.  An AE or SAR is considered “unexpected” if it is 
not listed in the Investigator’s Brochure or the package insert of GLANATEC® 
ophthalmic solution 0.4% or is not listed at the specificity or severity that has been 
observed. 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 AEs or SARs 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 AE at subsequent visits. 
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 and clinically 
meaningful. Investigators are also asked to note all observations of conjunctival hyperemia 
on the biomicroscopy CRF. 
6.11.3 
Timing for Reporting of Adverse Events 
The AEs occurring during the study must be documented, regardless of the assumption of a 
causal relationship. Adverse events should be documented from the time the subject receives 
the first dose of study medication until Week 4 [Day 29] or study discontinuation. If a subject 
has 1 or more ongoing AEs at the time of study exit, the subject must be followed and 
provided appropriate medical care until the event is resolved or stabilized, the subject is lost 
to follow-up, or there is other resolution to the event. These follow-up visits will be 
documented. 
When recording an AE, the following information should be provided on the study AE CRF: 
 


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1. Action Taken with Study Drug: 
• None 
• Study Drug Discontinued 
• Study Drug 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 coded as: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/Lost to follow-up 
6.11.4 
Severity 
Severity of an AE is defined as a qualitative assessment of the level of discomfort or the 
degree of intensity of an AE 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 


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• 3 = Severe: incapacitating, with inability to work or perform normal daily activity 
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.   
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 6.11.7 for further 
information on serious events). 
6.11.5 
Relationship 
The study medication relationship for each AE/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. 
6.11.6 
Expectedness 
The most frequently reported AE for netarsudil ophthalmic solution in two Phase 2 and four 
Phase 3 studies (Clinical Study Reports AR-13324-CS205, AR-13324-CS208, 
AR-13324-CS301, AR-13324-CS302, AR-13324-CS303 and AR-13324-CS304) has been 
conjunctival hyperemia. Other AEs seen in greater frequency with netarsudil than in active 


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control treatment arms in these studies include conjunctival hemorrhage, and cornea 
verticillata (corneal deposits) which did not affect visual function. 
An AE or SAR is considered “unexpected” if it is not listed in the Investigator’s Brochure or 
the package insert of GLANATEC® ophthalmic solution 0.4% or is not listed at the 
specificity or severity that has been observed.  “Unexpected,” as used in this definition, also 
refers to AEs or SARs that are mentioned in the Investigator’s Brochure as occurring with 
this class of drugs or as anticipated from the pharmacological properties of netarsudil and are 
not specifically mentioned as occurring with the IP. The AEs and adverse reactions that are 
both unexpected and serious should be reported in an expedited fashion to the Sponsor 
(see Section 6.11.7.2 for further details). 
6.11.7 
Serious Adverse Events (SAEs), Suspected Serious Adverse Reactions 
(SSARs), Suspected Unexpected Serious Adverse Reactions (SUSARs) 
6.11.7.1 
Reporting SAEs or SSARs 
An Investigator must immediately (i.e., within 24 hours) report any SAE or SSAR (see 
Section 6.11.2 for definitions) to the representative of contract research organization (CRO) 
of the Sponsor  (see Section 6.11.7.3 for contact information), whether or not the SAE or 
SSAR is considered drug-related, including those listed in the Investigator’s Brochure or the 
package insert of GLANATEC® ophthalmic solution 0.4%.  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 or is observed during the 
study or at a subject’s last study visit.  
SAEs and SSARs must be reported to the IRB according to the IRB requirements. 
6.11.7.2 
Reporting SUSARs 
The Investigator must immediately (i.e., within 24 hours) report SUSARs that occur or are 
observed during the course of the study or at the subject’s last study visit. In the event of a 
SUSAR, the site must notify the representative of CRO of the Sponsor by telephone within 
24 hours of knowledge of the event, whether or not complete information is available. In the case 
of incomplete information, the Investigator must provide follow-up information as soon as 
possible using the SAE report form.  
6.11.7.3 
Safety Reporting Contact Information 
The Investigator must report an SAE, SSAR, or SUSAR occurring at his/her site to the 
representative of CRO of the Sponsor regardless of causality. 
 
 


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6.12 
Pregnancy Reporting 
Pregnancies occurring in subjects enrolled in the study or in their partners must be reported 
and followed to outcome. While pregnancy itself is not considered to be an AE or SAE, 
pregnancy reports are tracked by the representative of CRO of the Sponsor. Premature 
terminations including miscarriage, spontaneous abortion, or elective termination of a 
pregnancy for medical reasons will be reported as an SAE. Other pregnancy complications 
should be reported as SAEs, if they meet serious criteria. Should the pregnancy result in a 
congenital anomaly or birth defect, a separate SAE report must be submitted. Furthermore, 
all neonatal deaths that occur within 30 days of the birth should be reported as SAEs, without 
regard to causality. 
The Investigator must complete the pregnancy report form and fax or email the form to the 
Sponsor or Sponsor representative within 1 business day of knowledge of the pregnancy 
(see Section 6.11.7.3 for contact information). Following delivery or termination of 
pregnancy, the pregnancy report form is to be completed and submitted by fax or email to the 
representative of CRO of the Sponsor. 
Pregnancies occurring up to 30 days after the last administration of study drug are to be 
reported. 
6.13 
Removal of Subjects from the Study or Study Treatment 
6.13.1 
Completed Subject 
A completed subject is defined as one who completes all planned study treatments and visits 
and completion of the post-treatment follow-up visit procedures. 
6.13.2 
Non-completing Subject 
A non-completing subject is defined as one who exits the study by their own volition or at 
the discretion of the Investigator, the Medical Monitor, and/or the Sponsor Safety Officer. 
Any subject may decide to voluntarily withdraw from the study at any time without 
prejudice. During the treatment period, in the event that discontinuation of treatment is 
necessary, the Investigator will make every attempt to complete all subsequent safety 
assessments listed for Visit 6.0 (Day 29) as well as dilated ophthalmoscopy.   
The subject may also be discontinued from the study for the following reasons: 
• 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). 
• Adverse Events (AEs 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 in the CRF). 


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• Withdrawal of Consent 
• Non-compliance (e.g., non-adherence to scheduled follow-up visits or non-compliance 
with dosing)  
• Lost to Follow-up 
• Disallowed Concurrent Medication  
• Investigator Decision  
• Protocol Deviation  
• Death 
• Other 
6.13.3 
Actions after Discontinuation 
All subjects who discontinue study medication due to a report of an AE must be followed and 
provided appropriate medical care until their signs and symptoms have remitted or stabilized. 
For subjects who choose to withdraw consent or who are discontinued for non-compliance 
prior to completing the treatment period, every possible effort should be made by the 
Investigator to assure there is a final visit that includes all examinations listed for Visit 6.0 
(Exit) and dilated ophthalmoscopy. 
6.13.4 
Discontinuation of the Entire Study  
The entire study may be discontinued at a given site (by the Investigator or the Sponsor/ 
Sponsor representative or at 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 and to regulatory authorities is also required. 
6.13.5 
Completed Study 
The study is completed when the planned enrollment has been completed, and all the 
enrolled subjects have completed the study. The Sponsor representative will be in 
communication with the Investigational sites regarding enrollment. 
6.14 
Appropriateness of Measurements 
The ophthalmic and systemic measures used in this study are consistent with standard of 
care. In particular, 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. 
 
 


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7. STUDY ACTIVITIES 
The schedule of study visits and procedures is shown in Appendix 1. 
7.1 
Visit 1 (Screening) 
This visit may occur at any time of the day. The Investigator or a member of his/her 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. A signed written informed consent must be obtained from the subject prior to 
any study specific procedures or assessments. The ICF process will be clearly documented in 
the subject’s source. 
Significant medical and ophthalmic history including concomitant medication use will be 
taken, and demographic measures recorded (see Section 6.2).  
The following procedures will be performed:   
• Heart rate and blood pressure 
• Pregnancy test:  All females of childbearing potential must have a negative urine 
pregnancy test result  
• BCVA 
• Central corneal thickness will be measured by pachymetry (taken at screening or within 
1 week prior to the Screening Visit) 
• IOP (before pupil dilation):  Medicated IOP must be ≥ 14 mmHg in at least one eye and 
< 30 mmHg in both eyes at the Screening Visit (this also applies to treatment naïve 
subjects) 
• Biomicroscopy 
• Dilated ophthalmoscopy (including vertical cup-disc ratio) 
• Visual fields and gonioscopy may be taken up to 3 months prior to randomization in both 
eyes 
• Symptomatology: Individuals will be asked “How are you feeling?” 
The Investigator will evaluate the results of these examinations for possible enrollment of the 
individual into the study. 


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7.1.1 
Evaluation of Eye-Drop Instillation Performance 
Subjects (or legally authorized representative for subjects deemed unable to administer) 
will be provided a bottle of commercially available, multi-dose, 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, guardian, or alternative person to assure that they instill 
1 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 subject (guardian or alternative person) 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. 
7.1.2 
Washout 
As noted in Section 5.7.1, a washout period is required for individuals currently using ocular 
hypotensive medications and who meet the other qualifications for enrollment.   
7.2 
Visit 2 (Qualification Visit #1, for IOP and safety measurements at 09:00 hours) 
After the washout (if needed), individuals will return to the Investigator’s office in the early 
morning. 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 should be recorded on 
the Medical History page of the CRF (e.g., the subject has been diagnosed with cancer). 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. 
The following procedures will be performed: 
• Heart rate and blood pressure 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• BCVA 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured between 09:00 and 09:30 hours. 
For further evaluation of POAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in the study eye. For further evaluation of OHT 
eyes in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg and 
< 35 mmHg in the study eye. This is the first of the four qualifying IOPs for 
randomization. 


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Individuals who do NOT meet the IOP requirements above due to a low IOP may return for 
up to 2 additional qualification visits within 1 week of failing this qualification visit. 
Individuals returning for an unscheduled visit within 1 week to re-attempt IOP qualification 
are required to only re-measure IOP in both eyes. 
Individuals who screen fail due to IOP being ≥ 35 mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits. 
Qualified individuals will be scheduled to return 2-7 days later for the second qualification 
visit. 
7.3 
Treatment Period 
7.3.1 
Visit 3.0 (Qualification Visit #2, Day 1, for IOP and safety measurements at 
09:00 hours)  
Within 2 to 7 days after Visit 2, individuals will return to the Investigator’s office for the next 
09:00 hour IOP measurement. 
The subject will be questioned regarding any changes in their health or concomitant 
medication use.  Any change in the individual’s health status should be recorded on the 
Medical History page of the CRF (e.g., the subject has been diagnosed with cancer). 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. 
The following procedures will be performed: 
• Heart rate and blood pressure 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• BCVA 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured between 09:00 and 09:30 hours. 
For further evaluation of POAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in the study eye. For further evaluation of OHT 
eyes in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg and 
< 35 mmHg in the study eye. This is the second of the four qualifying IOPs for 
randomization. 
Qualified individuals will continue with the measurements of IOP at 11:00 hours and 
16:00 hours. 
Individuals who do NOT meet the IOP requirements above due to a low IOP may return for 
up to 2 additional qualification visits within 1 week of failing this qualification visit. 


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Individuals returning at an unscheduled visit within 1 week are required to only re-measure 
IOP in both eyes. Upon return for an unscheduled qualification visit, such individuals’ IOP 
measurements would need to qualify at 09:00, 11:00, and 16:00 hours.  
Individuals who fail due to IOP being ≥ 35 mmHg in either eye (exclusion criterion) MAY 
NOT return for additional qualification visits. 
Individuals are allowed to leave the Investigator’s office between assessments and eat and 
drink with no restrictions. However, individuals are not to consume alcohol or engage in 
strenuous exercise. 
7.3.2 
Visit 3.1 (Day 1, for IOP and safety measurements at 11:00 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 measurements and 
biomicroscopy.  IOP must be measured between 11:00 to 11:30 hours. 
For further evaluation of POAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in the same eye. For further evaluation of 
OHT eyes in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg 
and < 35 mmHg in the same eye. This is the third of the four qualifying IOPs for 
randomization.   
Qualified individuals will continue with the qualification visit. Individuals who do NOT 
meet this requirement due to low IOP may return for up to 2 additional 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 qualification visit, such individuals would need to qualify at 09:00, 11:00 and 
16:00 hours.  
Individuals who fail due to IOP being ≥ 35 mmHg in either eye (exclusion criterion) MAY 
NOT return for additional qualification visits. 
Individuals are allowed to leave the Investigator’s office between assessments and eat and 
drink with no restrictions.  However, individuals are not to consume alcohol or engage in 
strenuous exercise. 
7.3.3 
Visit 3.2 (Day 1, for IOP and safety measurements 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 measurements and 
biomicroscopy.  IOP must be measured between 15:30 and 16:30 hours. 
For further evaluation of POAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in the same eye. For further evaluation of 
OHT eyes in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg 
and < 35 mmHg in the same eye. This is the fourth of the four qualifying IOPs for 
randomization.  
Individuals who do NOT meet this requirement due to low IOP may return for up to 
2 additional 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 for an unscheduled qualification visit, such individuals would 
need to qualify at 09:00, 11:00 and 16:00 hours.  
Individuals who fail due to IOP being ≥ 35 mmHg in either eye (exclusion criterion) MAY 
NOT return for additional qualification visits. 
As noted in Section 4.2, subjects must qualify in at least one eye based upon IOP and ocular 
history and exam; for a subject who qualifies in only one eye, this eye is designated the study 
eye.  If the subject qualifies in both eyes, then the study eye will be the eye with the higher 
IOP at 09:00 hours on Visit 3. If both eyes have the same IOP at 09:00 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 randomized. The study medication kit containing 
2 bottles will be dispensed to the subject, along with dosing and storage instructions by the 
site staff. 
Subjects will be: 
• Instructed to administer their masked medication OU at home in the morning 
(9:00 ± 1 hour) and in the evening (21:00 ± 1 hour) 
• Instructed to return to the office with their study medication in the kit on Visit 4 
(Week 1 [Day 8]) 
• Instructed not to administer their masked medication OU at home on the morning 
of the next visit (Visit 4) 
A window of ± 2 days for Visit 4 is permitted. 
 


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7.3.4 
Visit 4.0 (Week 1 [Day 8], for IOP and safety measurements at 09:00 hours) 
Subjects will return to the Investigator’s office. 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 
• BCVA 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured between 09:00 and 09:30 hours. 
Subjects are allowed to administer their masked medication after IOP measurements. 
Any new or worsening of symptoms from the time the subject receives the first dose of study 
medication are to be entered as AEs. 
Subjects are allowed to leave the Investigator’s office between assessments and eat and drink 
without restrictions. However, subjects are not to consume alcohol or engage in strenuous 
exercise. 
7.3.5 
Visit 4.1 (Week 1 [Day 8], for IOP and safety measurements at 11:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 2 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 4.0). 
Subjects are allowed to leave the Investigator’s office between assessments and eat and drink 
without restrictions. However, subjects are not to consume alcohol or engage in strenuous 
exercise. 
7.3.6 
Visit 4.2 (Week 1 [Day 8], for IOP and safety measurements at 16:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 


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• Recording of any AEs. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 7 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 4.0). 
Subjects will be: 
• Instructed to continue to administer their study medication at home in the morning 
(9:00 ± 1 hour) and in the evening (21:00 ± 1 hour) 
• Instructed to return to the office with their used study medication in the kit on Visit 5 
(Week 2 [Day 15)) 
• Instructed not to administer their masked medication OU at home on the morning 
of the next visit (Visit 5) 
A window of ± 3 days for Visit 5 is permitted. 
7.3.7 
Visit 5.0 (Week 2 [Day 15], for IOP and safety measurements at 09:00 hours) 
Subjects will return to the Investigator’s office. The subject will be questioned regarding 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 
• BCVA 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured between 09:00 and 09:30 hours. 
Subjects are allowed to administer their masked medication after IOP measurements. 
Any new or worsening of symptoms from the time the subject receives the first dose of study 
medication are to be entered as AEs. 
Subjects are allowed to leave the Investigator’s office between assessments and eat and drink 
without restrictions. However, subjects are not to consume alcohol or engage in strenuous 
exercise. 


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7.3.8 
Visit 5.1 (Week 2 [Day 15], for IOP and safety measurements at 11:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 2 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 5.0). 
Subjects are allowed to leave the Investigator’s office between assessments and eat and drink 
without restrictions. However, subjects are not to consume alcohol or engage in strenuous 
exercise. 
7.3.9 
Visit 5.2 (Week 2 [Day 15], for IOP and safety measurements at 16:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 7 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 5.0). 
Subjects will be: 
• Instructed to continue to administer their masked medication at home in the morning 
(9:00 ± 1 hour) and in the evening (21:00 ± 1 hour) 
• Instructed to return to the office with their study medication in the kit on Visit 6.0 
(Week 4 [Day 29]) 
• Instructed not to administer their masked medication OU at home on the morning 
of the next visit (Visit 6) 
A window of ± 3 days for Visit 6 is permitted. 
7.3.10 
Visit 6.0 (Week 4 [Day 29], for IOP and safety measurements at 09:00 hours) 
Subjects will return to the Investigator’s office. 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: 


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• Heart rate and blood pressure 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• Urine pregnancy test (tests for applicable female subjects of childbearing potential may 
be performed at any time point throughout Visit 6) 
• BCVA 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy.  
IOP must be measured 9:00 and 9:30 hours. 
All used/returned study medication kits will be collected by the unmasked site staff and 
returned to the Sponsor’s designee for destruction.  
Any new or worsening of symptoms from the time the subject receives the first dose of study 
medication are to be entered as AEs. 
Subjects are allowed to leave the Investigator’s office and eat and drink without restrictions. 
However, subjects are not to consume alcohol or engage in strenuous exercise. 
7.3.11 
Visit 6.1 (Week 4 [Day 29], for IOP and safety measurements at 11:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 2 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 6.0).  
Subjects are allowed to leave the Investigator’s office and eat and drink without restrictions. 
However, subjects are not to consume alcohol or engage in strenuous exercise. 
7.3.12 
Visit 6.2 (Week 4 [Day 29], for IOP and safety measurements at 16:00 hours) 
Subjects will be examined, and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs 


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• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured 7 hours (± 30 mins) post-dose of the dose in 
the morning (Visit 6.0). 
• Dilated ophthalmoscopy examination (including vertical cup-disc ratio) 
Subjects will be thanked for their participation, exited from the study, and released to the 
normal care of their Physician. 
7.4 
Unscheduled Visits 
An unscheduled visit may be any visit to the Investigator other than the specific visits 
requested in the protocol as possibly required for the subject’s ophthalmic condition. 
The Investigator will perform all procedures necessary to evaluate the study participant at 
these visits and record any AEs in the CRF.  
 
8. QUALITY CONTROL AND ASSURANCE 
The progress of the study will be monitored by on-site, written, remote review, and telephone 
communications between personnel at the Investigator’s site and the Study Monitor. 
The Investigator will allow the Sponsor or its designee to inspect all CRFs; patient record 
(source documents); signed consent forms; records of study medication receipt, storage, 
preparation, and disposition; and regulatory files related to this study. 
 
9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Summaries will be presented by treatment, visit, and time point (as applicable). Continuous 
and ordinal study assessments will be summarized using descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum). Discrete study assessments will be 
summarized 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 netarsudil 0.02% QD and ripasudil 0.4% BID will be calculated as netarsudil – 
ripasudil.   
All study data will be listed by treatment, subject, visit, and time point (as applicable).   


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For diurnally-adjusted IOP, baseline will refer to the time-relevant measure at Visit 3.0 and 
3.1 (e.g., IOP at 09:00 hours at Visit 3.0 will be the baseline for 09:00 hours at Visit 4.0, 
Visit 5.0, and Visit 6.0; IOP at 11:00 hours at Visit 3.1 will be the baseline for 11:00 hours at 
Visit 4.1, Visit 5.1, and Visit 6.1; etc.). For all other variables, baseline is defined as the last 
non-missing measurement prior to the first dose of study medication. An additional definition 
of baseline for conjunctival hyperemia will also be used: baseline (pre-washout) will be 
defined as the conjunctival hyperemia measure at Visit 1.  
Change from baseline will be calculated as: follow-up minus baseline. 
Mean diurnal IOP values will be constructed by averaging the 3 diurnal IOP measurements 
on each of Week 1, Week 2, and Week 4 visits.  Mean diurnal baseline IOP will be 
constructed as the average of the three Day 1 IOP measurements. Mean change from mean 
diurnal baseline IOP will be created by taking the average of the 3 time points on each of 
Week 1, Week 2, and Week 4 visits and subtracting the single mean baseline diurnal IOP 
measurement. 
The unit of analysis for efficacy will be the study eye. If the subject qualifies in only one eye, 
then this eye is designated the study eye. If the subject qualifies in both eyes, then the study 
eye will be the eye with the higher IOP at 09:00 hours on Visit 3. If both eyes have the same 
IOP at 09:00 hours on Visit 3.0, then the right eye will be the study eye. For each subject, 
BOTH eyes will be treated. Safety will be summarized at the eye level (study eyes and fellow 
eyes separately) for measures captured at the eye level and at the subject level for measures 
not captured at the eye level. Adverse events (AEs) will be summarized at the subject level, 
counting a subject as having had an ocular AE if the subject has the ocular AE in either eye.  
Statistical methods will be more fully described in separate document(s) (i.e., the Statistical 
Analysis Plan). 
9.2 
Hypotheses 
H0: The difference in mean diurnal IOP in study eyes treated with netarsudil QD versus study 
eyes treated with ripasudil BID (netarsudil QD – ripasudil BID) at Week 4 = 0. 
H1: The difference in mean diurnal IOP in study eyes treated with netarsudil QD versus study 
eyes treated with ripasudil BID (netarsudil QD – ripasudil BID) at Week 4 ≠ 0. 
9.3 
Adjustments for Multiplicity 
No adjustment for multiplicity is required for this study with a single primary endpoint and 
no secondary endpoints identified for labeling claims. 
9.4 
Determination of Sample Size 
Ninety three (93) subjects (study eyes) per treatment group are required to have 90% power 
(1-β) to reject H0 in favor of H1 at a two-sided significance level of 5%, assuming that a 


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difference of the change from baseline in mean diurnal IOP (netarsudil QD – ripasudil BID) 
in the proposed study is -1.1 mmHg with a common standard deviation of 2.3. The target 
sample size is set to 120 per treatment group to allow for withdrawals and dropouts. 
Note that change from baseline values from historic studies are being used as estimates from 
which to calculate sample size for a non-change from baseline primary endpoint due to the 
change from baseline estimates for standard deviation better reflecting the standard deviation 
obtained from the primary analysis strategy within this study. 
9.5 
Analysis Populations 
9.5.1 
Intent-to-Treat (ITT) Population 
The ITT population will include all randomized subjects who have received at least 1 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. 
9.5.2 
Per Protocol (PP) Population 
The per protocol (PP) population is a subset of the ITT population, which will include those 
subjects 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. 
9.5.3 
Safety Population 
The safety population will include all randomized subjects who have received at least 1 dose 
of study medication. This population will be used to summarize safety variables and will 
summarize subjects as treated. 
9.6 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, or disease status will be 
summarized and listed. Medical history, history of ocular surgery and procedures, glaucoma 
history and washout period (if needed) will also be summarized and listed. 
9.7 
Primary Efficacy 
9.7.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint will be the comparison of netarsudil ophthalmic 
solution 0.02% relative to ripasudil hydrochloride hydrate ophthalmic solution 0.4% for 
mean diurnal IOP within a treatment group at Week 4 (Day 29) by Goldmann Applanation 
Tonometry. 


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9.7.2 
Primary Efficacy Analyses 
The primary analysis of the primary endpoint will employ a linear model with mean diurnal 
IOP at Week 4 as the response, baseline mean diurnal IOP as a covariate, and treatment as a 
main effect factor, using the ITT population with Monte Carlo Markov Chain and regression 
based multiple imputation techniques used to impute missing data. The least squares mean 
difference (netarsudil QD – ripasudil BID) will be presented as well as the 2-sided p-value 
and 95% confidence interval (CI). Inference will be made on the 2-sided p value. Superiority 
of netarsudil QD over ripasudil BID will be concluded if the 2-sided p-value, for testing the 
difference (netarsudil QD – ripasudil BID) to 0, ≤ 0.05 and the point estimate of the 
difference < 0. 
Analyses will be performed primarily on the ITT population using the following strategy to 
handle intercurrent events: 
Intercurrent event strategy: 
• Discontinuation of study drug and non-optimal compliance will be ignored; IOP will 
continue to be measured and used [treatment policy strategy]. 
• Withdrawal due to lack of efficacy or adverse event: missing data will be imputed 
employing Multiple Imputation (MI) assuming missing not at random using:  Control-
based regression methodology [hypothetical strategy]. 
• Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy 
or adverse event: missing data will be imputed employing Multiple Imputation (MI) 
assuming missing at random using randomized treatment-based regression methodology 
[hypothetical strategy]. 
Sensitivity analyses will be performed on observed data only and where worst on treatment 
time-relevant observation within a subject is carried forward for withdrawal due to lack of 
efficacy or adverse event and last time consistent observation within a subject is carried 
forward for other missing data. 
9.8 
Secondary Efficacy 
9.8.1 
Secondary Efficacy Endpoints 
• Mean diurnal IOP at Weeks 1 and 2 (Days 8 and 15, respectively) 
• Mean change from baseline in mean diurnal IOP at each post-treatment visit 
• Mean percent change from baseline in mean diurnal IOP at each post-treatment visit 
• Mean IOP at each post-treatment time point  


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• Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment time 
point 
• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in mean diurnal IOP levels 
Other secondary efficacy analyses may be carried out 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. 
9.8.2 
Secondary Efficacy Analyses 
Secondary analyses of the primary efficacy endpoint include repeating the primary analysis 
strategy using: observed data only, last observation carried forward (LOCF) where LOCF 
will be performed using time-relevant measures, and using worst on treatment time-relevant 
observation within a subject carried forward for withdrawal due to lack of efficacy or adverse 
event and last time-relevant observation within a subject carried forward for other missing 
data. These analyses will also be repeated on the PP population to determine robustness of 
results. Additional imputation techniques may be designated in the formal statistical analysis 
plan. 
Additionally, secondary analyses of the primary endpoint will be completed using individual 
2-sample t-tests and 95% t-distribution CIs for each comparison netarsudil 0.02% QD versus 
ripasudil 0.4% BID using the ITT population. 
The primary and secondary analyses will also be completed on the secondary endpoints: 
mean diurnal IOP at Weeks 1 and 2, mean IOP measure at each post-treatment time point and 
visit (09:00, 11:00, and 16:00 at the Week 1, Week 2, and Week 4 Visits), mean change from 
baseline in mean diurnal IOP at each post-treatment visit, and mean change from diurnally 
adjusted baseline IOP at each post-treatment time point and visit. 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 a 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 co-variances 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 


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different treatment arms among visits and time points. This model will be run including the 
Week 1, Week 2, and Week 4 visits. 
Mean percent change from baseline in mean diurnal IOP and mean percent change from 
diurnally adjusted baseline IOP at each time point will be analyzed using two-sample t-tests, 
between netarsudil 0.02% QD and ripasudil 0.4% BID at each time point and visit, including 
two-sample t-tests and 95% t-distribution confidence intervals on the difference 
(netarsudil - ripasudil). 
Sub-group analyses based upon pre-study characteristics such as site, demographics, baseline 
IOP categories, or pre-study ocular hypotensive medications may be completed to further 
investigate the efficacy measures. 
Analyses of IOP will also include summarizing the number and percentage of study eyes 
achieving mean diurnal IOP reduction from baseline of ≥ 0 to ≥ 10 mmHg in 2 mmHg 
increments and percent reduction from baseline of ≥ 5% to ≥ 40% in 5% increments at 
Week 1, Week 2, and Week 4. Additionally, the number and percentage of study eyes 
attaining a mean diurnal IOP of ≤ 24 to ≤ 14 mmHg in 1 mmHg increments will be 
summarized at Week 1, Week 2, and Week 4.  Fisher’s exact test (2-sided p-values) will be 
used to test differences between netarsudil 0.02% QD versus ripasudil 0.4% BID for each 
category at each visit. These analyses will be presented for both the ITT and PP populations 
with observed data only. 
9.9 
Safety  
9.9.1 
Safety Endpoints 
The primary safety measures in both eyes of enrolled subjects will include: 
• Ocular symptoms/AEs 
• BCVA 
• Objective findings of biomicroscopic examinations (i.e., anterior segment examinations 
including evaluation of cornea, conjunctiva, lids, and lens) 
• Dilated ophthalmoscopy, including vertical cup-disc ratio measurements 
Other safety assessments will be: 
• Systemic safety assessments as measured by heart rate, blood pressure/AEs  
• Pregnancy testing (for women of childbearing potential) 


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9.9.2 
Safety Analyses 
Verbatim descriptions of AEs will be mapped to MedDRA/J thesaurus terms and be 
presented in a data listing. Treatment emergent AEs (TEAEs), those that occur or worsen 
after the first dose of study medication, will be summarized by treatment group using 
frequency and percent for each system organ class (SOC) and preferred term (PT) within 
each SOC. Summaries will be presented separately for ocular and non-ocular TEAEs.  These 
summaries will also be presented for TEAEs related 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 netarsudil 0.02% vs ripasudil hydrochloride hydrate 
ophthalmic solution 0.4%.   
Best-corrected visual acuity data for both the study eye and the fellow eye will be 
summarized for each visit and for change from baseline to each post-treatment visit using the 
continuous summary statistics. 
Slit lamp biomicroscopy and dilated ophthalmoscopy measures will be summarized at each 
measured visit and time point using discrete summary statistics. Conjunctival hyperemia will 
also be summarized using continuous summary statistics including change from baseline and 
change from baseline (pre-washout). Additionally for slit lamp biomicroscopy, discrete 
summaries will be provided by region, finding, visit, time point, and eye (study eye and 
fellow eye) for the number of subjects with at least one severity grade increase from baseline 
and for the number of subjects judged to be clinically significant by the Investigator. Fisher’s 
exact tests will be used to compare incidence between treatment groups in both tables. 
Cup-to-disc ratio will be summarized at each measured visit and for change from baseline to 
each measured visit using continuous summary statistics by treatment group and visit. 
Vital signs will be summarized at each measured visit and for change from baseline to each 
measured visit using continuous summary statistics by treatment group and visit. 
9.10 
Other Assessments or Analyses 
Other assessments or analyses will be described in the statistical analysis plan as appropriate. 
9.11 
Interim Analysis 
No interim analysis is planned for this study. 
 
 


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10. ADMINISTRATIVE CONSIDERATIONS 
10.1 
Investigators and Study Administrative Structure 
The Principal Investigator is responsible for all site medical-related decisions. The qualified 
sponsor Medical Monitor is responsible for the safety conduct of this study: 
 
 
 
10.2 
Institutional Review Board or Independent Ethics Committee Approval 
This study is to be conducted in accordance with IRB or IEC regulations and ICH-GCP and 
J-GCP. The protocol, protocol amendments, informed consent form, and all documents that 
will be provided to subjects (e.g., subject diary, subject dosing instructions, etc.) will be 
submitted to the central and/or local IRB(s) or IEC(s) for review and approval. This protocol, 
materials used to recruit subjects, and materials used to document consent must be approved 
by the IRB or IEC prior to initiation of the study. Original letter from the IRB or IEC 
indicating approval of an Investigator must be received by the Sponsor prior to conducting 
any study-specific procedures. In addition to approving the protocol and an Investigator 
participating in the study, the IRB or IEC must also approve the Subject Informed Consent 
Form, as well as any advertising tools that will be used for the study. Written approval also 
must indicate whether approval was granted based on full committee review or expedited 
review.   
When the study is completed, the Investigator will provide the governing IRB or IEC with a 
brief final review report. 
10.3 
Ethical Conduct of the Study 
The study will be conducted according to ethical principles based on the Declaration of 
Helsinki and the guidance stipulated in Article 14, Paragraph 3, and Article 80 2 of the 
Pharmaceuticals, Medical devices and Other Therapeutic Products Act of Japan, Ministry of 
Health, Labor and Welfare (MHLW) Ordinance on Good Clinical Practice (MHLW 
Ordinance No 28 (27 March 1997).  
10.4 
Subject Information and Consent 
Informed consent must take place before any study specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject and/or from the 
subject’s legal guardian prior to enrollment into the study in accordance with local regulatory 
requirements. 
All ICFs must be approved for use by the Sponsor or Sponsor representative and receive 
approval/favorable opinion from an IRB or IEC prior to their use. If the consent form 


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requires revision (e.g., due to a protocol amendment or significant new safety information), 
it is the Investigator’s responsibility to ensure that the amended informed consent is reviewed 
and approved by the Sponsor or Sponsor representative prior to submission to the governing 
IRB or IEC and that it is read, signed and dated by all subjects subsequently enrolled in the 
study as well as those currently enrolled in the study if directed by the IRB or IEC. 
10.5 
Subject Confidentiality 
The Investigator and his/her staff will maintain all personal subject data collected and 
processed for the purposes of this study using adequate precautions to ensure confidentiality, 
in accordance with local regulations.  
Monitors, auditors and other authorized representatives of Aerie, the IRB(s) or IEC(s) 
approving this study, and government regulatory authorities (e.g., PMDA and other foreign 
regulatory 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. 
10.6 
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 unmasking of IP 
• source data verification 
• AE and SAE reporting 
• essential documents contained within the regulatory binder 
For source data verification (i.e., comparison of CRF entries with subject records), data will 
be 100% source verified. 


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10.7 
Case Report Forms and Study Records 
Study data will be recorded via electronic CRFs. Each authorized study staff member will 
receive a unique access account in order to use the Electronic Data Capture (EDC) system. 
Access accounts will not be shared among study staff. Authorized users will make entries 
and/or changes to the CRF via a secure internet access. Each completed set of CRFs will be 
reviewed by the Investigator who will then electronically sign and date the CRF confirming 
that data for the subjects are complete and accurate. 
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. 
The study records including but not limited to each CRF; subject charts/source documents; 
Investigator's Brochure; protocol and protocol amendments; correspondence with the 
Sponsor and the IRB; IP storage, receipts, returns and dispensing records; Delegation of 
Responsibilities Log; site training records; records of site monitoring; unmasking 
documentation; AE and SAE reporting; IRB/IEC approvals; advertisements; written 
information provided to subjects; and subject completed ICFs should be stored in a secure 
environment. If the Investigator moves, withdraws from an investigation, or retires, 
the responsibility for maintaining the records may be transferred to another person 
(e.g., 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. 
10.8 
Protocol Deviations 
A protocol deviation occurs when there is non-adherence to study procedures or schedules. 
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. No waivers to inclusion or exclusion criteria are allowed. 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 within 10 days, or sooner, 
if required by the IRB, of becoming aware of any significant protocol deviation. Typically, 
significant protocol deviations 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. 


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The Sponsor will review, designate, and/or approve all protocol deviations prior to database 
lock. 
10.9 
Access to Source Documentation 
Monitors, auditors, and other authorized representatives of the Sponsor, the governing 
IRB(s), and local 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. 
10.10 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 CRFs are monitored in the EDC system, the data management CRO and the 
Sponsor will further check the CRFs 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 (e.g., 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 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. 
10.11 Retention of Data 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of distribution and use of all study drugs, and copies of eCRFs 
should be maintained on file. 
In Japan, the records should be retained until the day on which marketing approval of the test 
drug is obtained or 3 years after the date of premature termination or completion of the 
clinical trial, whichever comes later.  
For countries falling within the scope of the ICH guidelines, study related documents should 
be retained until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing application in an ICH region 


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or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational drug. These documents should be retained for a longer period, if required 
by the applicable regulatory requirements or if needed by Aerie Pharmaceuticals. 
For countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
10.12 Financial Disclosure 
The Principal Investigator and sub-Investigators 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. 
10.13 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 and will be administrated by a steering committee. 
As this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Aerie 
Pharmaceuticals. 
 
 


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11. REFERENCES 
11.1 
External References 
1. 
The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The 
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J Ophthalmol 2000; 130:429-40. 
2. 
Chen J, Runyan SA, Robinson MR.  Novel ocular antihypertensive compounds in 
clinical trials. Clin Ophthalmol 2011; 5:667-77. 
3. 
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. 
4. 
GLANATEC® (ripasudil hydrochloride hydrate ophthalmic solution) 0.4% [package 
insert] Kowa Company, Ltd.; 04/2020 
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. 
Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin 
Ophthalmol. 2004 Dec;15(6):541-8. 
7. 
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. 
8. 
Ingram DV, Jaggarao NS, Chamberlain DA. Ocular changes resulting from therapy 
with amiodarone. Br J Ophthalmol. 1982 Oct;66(10):676-9. 
9. 
Kass MA, Heuer DK, Higginbotham EJ, et al.  The Ocular Hypertension Treatment 
Study. A randomized trial determines that topical ocular hypotensive medication delays 
or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 
120:701-13. 
10. 
Kass MA, Gordon MO, Gao F, et al.  Delaying Treatment of Ocular Hypertension: 
The Ocular Hypertension Treatment Study. Arch Ophthalmol 2010; 128:276-87. 
11. 
Kiel JW, Kopczynski CC.  Effect of AR-13324 on episcleral venous pressure in Dutch 
Belted rabbits.  J Ocul Pharmacol Ther 2015; 31(3):146-51. 
12. 
Kopczynski CC and Epstein DL.  Emerging Trabecular Outflow Drugs.  J Ocul 
Pharmacol Ther 2014; 30:85-7. 
13. 
Mäntyjärvi M, Tuppurainen K, Ikäheimo K. Ocular side effects of amiodarone. Surv 
Ophthalmol. 1998 Jan-Feb;42(4):360-6. 
14. 
Orlando RG, Dangel ME, Schaal SF. Clinical experience and grading of amiodarone 
keratopathy. Ophthalmology. 1984 Oct;91(10):1184-7. 


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15. 
Raizman MB, Hamrah P, Holland EJ. Drug-induced corneal epithelial changes. Surv 
Ophthalmol. 2017 May - Jun;62(3):286-301. 
16. 
Rhopressa® (netarsudil ophthalmic solution) 0.02% [package insert]. Irvine CA: Aerie 
Pharmaceuticals, Inc.; 3/2019. 
17. 
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. 
18. 
Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. 
2003 Dec 1;68(11):2189-96. 
19. 
Stamper RL, Lieberman MF, Drake MV. Clinical Interpretation of gonioscopic 
findings in: Becker Shaffer’s Diagnosis and Therapy of the Glaucomas, pp. 78-90. 8th 
ed. 2009. 
20. 
Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop instillation 
in glaucoma patients. Arch Ophthalmol 2009; 127:732-6. 
21. 
Wang RF, Williamson JE, Kopczynski C, Serle JB.  Effect of 0.04% AR-13324, a 
ROCK, and Norepinephrine Transporter Inhibitor, on Aqueous Humor Dynamics in 
Normotensive Monkey Eyes. J Glaucoma 2015; 24(1):51-4. 
11.2 
Internal References 
1. 
 
2. 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
 


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7. 
 
 
8. 
 
 
9. 
 
 
 
10. 
 
 
 
 
11. 
 
 
 
12. 
 
 
 
 
 
13. 
 
 


  
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Appendix 1 
Schedule of Visits and Procedures  
 
 
 
 
Post Day 1 Treatment1 
Day (D)/Week (W) 
Screening Qual. #1 
Qual. #2 (Day 1) 
W1 (Day 8±2) 
W2 (Day 15±3) 
W42 (Day 29±3) 
Visit 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
4.2 
5.0 
5.1 
5.2 
6.0 
6.1 
6.2 
Hour (XY = XY:00) 
-- 
09 
09 
11 
16 
09 
11 
16 
09 
11 
16 
09 
11 
16 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Washout3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signs (heart rate, blood pressure) 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Symptoms/AEs5 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X  
X 
X 
X 
BCVA6 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
IOP 
X 
X7 
X7 
X7 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy8 / Pachymetry9 
G/P 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual Field10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Eye-Drop Instillation Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medications Dispensed 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Medications Collected 
 
 
 
 
 
 
 
 
 
 
 
X11 
 
 
Study Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


  
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Appendix 1 
Schedule of Visits and Procedures (cont’d) 
Abbreviations:   AE = adverse event; BCVA = best corrected visual acuity; IOP = Intraocular pressure. 
Early Discontinuation: Visit 6.0 procedures are to be completed plus a dilated ophthalmoscopy examination. 
Visit Requirements:  There is no visit time requirement for Visit 1 (Screening). For Visit 2, IOP measurements will be 09:00 (+30 mins). For Visit 3, IOP 
will be measured at 09:00 (+30 mins), 11:00 (+30 mins) and 16:00 (±30 mins) hours. During Post Day 1 (Visit 4, 5, and 6) Treatment visits, study 
medication at 9:00 on the day of the visit will be administered after IOP measurements at 9:00 (+30 mins).   
Two subsequent IOP measurements will be taken 2 hours (±30 mins) and 7 hours (±30mins) after the study medication in the morning, respectively. 
1. 
If subjects develop cornea verticillata at Post Day 1 Treatment (visit 4 to visit 6), additional evaluation of grading and location (e.g. epithelium, stroma, 
or endothelium) of Cornea verticillata will be conducted in parallel. 
2. 
If a subject has an ongoing AE at the time of study completion, the ongoing AE must be followed-up and provided appropriate medical care until the 
event has resolved or stabilized. 
3. 
Subjects currently using ocular hypotensive medications must undergo a minimum washout period. 
Medication Class 
Minimum Washout Period 
Rho kinase inhibitor 
6 weeks 
Prostaglandins 
4 weeks 
-adrenoceptor antagonists 
4 weeks 
Adrenergic agonists (including -agonists such as brimonidine and apraclonidine) 
2 weeks 
Muscarinic agonists (e.g., pilocarpine), carbonic anhydrase inhibitors (topical or oral) 
5 days 
4. 
Urine pregnancy test for women of childbearing potential is required.  
5. 
Ocular symptoms: Subjects will be queried at each visit “How are you feeling?” and treatment emergent AEs beginning at Visit 4 will be documented 
on the AE form. Additional symptoms reported after screening and before randomization will be documented on the medical history form. Adverse 
events will be recorded for every study visit (i.e., at 09:00, 11:00, and 16:00 hours) as needed. 
6. 
BCVA testing should precede IOP measurement, the administration of topical anesthetic agents, or any examination requiring contact with the anterior 
segment. 
7. 
Individuals returning at an Unscheduled Visit within 1 week to re-attempt IOP qualification are required to only re-measure IOP in both eyes. 
8. 
Gonioscopy evaluation up to 3 months prior to randomization is acceptable. 
9. 
Pachymetry within 1 week prior to screening is acceptable. 
10. 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 (e.g., 30-2 or 24-2 Humphrey) and reliability. 
11. Collect kit(s) dispensed during the Day 1 visit, after dosing their masked medication in the morning. 
 


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Appendix 2 
Sponsor’s Obligations 
Aerie Pharmaceuticals is committed to: 
A. Complying with the local health authority regulations for the conduct of clinical research 
studies. 
B. Informing the Investigator of any new information about the study drug that may affect 
the subject's welfare or may influence the subject's decision to continue participation in 
the study. 
C. 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 6.11, Adverse Events 
Assessments). 
D. 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). 
E. 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. 
F. Providing study medications suitably masked/blinded, coded, and packaged for use with 
subjects entered into the study. 
G. Providing statistical and report writing resources to complete appropriate reporting of 
study results. 
H. Ensuring equity considerations among all Investigators in multicenter studies, including 
all matters of publications and meeting presentations, etc. (where applicable). 
I. Prepare documents that state the financial interests and arrangements of clinical 
investigators 


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Appendix 3 
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 6.11, Adverse Events 
Assessments). The Investigator must also notify the Sponsor Representative and the IRB 
to which he/she is responsible. 
2. Prior to initiating the study, sign and return to the Sponsor Representative all the relevant 
forms required by local regulatory agency (e.g. 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 should be included upon local regulation requirements 
3. Cooperate with the Sponsor on the preparation of documents in which financial interests 
and arrangements of clinical investigators are disclosed 
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 1 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 CRF. 
8. 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. 
9. Assure that IP 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. 


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10. Allow a representative of the Sponsor and/or representatives of health regulatory 
agencies to inspect all CRFs and corresponding portions of each study subject's 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 onsite 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 CRFs, resolve any 
apparent discrepancies or inconsistencies in the study records, and account for all 
investigational supplies. 
11. Provide the governing IRB with a brief (i.e., 1 to 3 pages) Investigator's summary within 
90 working days of the study completion. 
12. Complete the study within the time limits agreed upon with the Sponsor prior to the 
initiation of the study. 
13. 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. 
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. In Japan, the records should be retained until the day on which 
marketing approval of the test drug is obtained or 3 years after the date of premature 
termination or completion of the clinical trial, whichever comes later. 
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 4 
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 
abstain from participation in the study and that he or she is free to withdraw his or her 


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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) 
1. 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. 
2. The potential benefits, hazards and discomforts of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
3. 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. 
4. The refusal of the patient to participate in a study must never interfere with the doctor- 
patient relationship. 
5. 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. 
6. 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 patient. 


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III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECT 
(NONCLINICAL BIOMEDICAL RESEARCH) 
1. 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. 
2. The subjects should be volunteers - either healthy person or subjects for whom the 
experimental design is not related to the patient’s illness. 
3. 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. 
4. 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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Appendix 5 
Study Monitoring 
1. Member(s) of the Sponsor or designee will meet with the Investigator prior to the 
initiation of the study in order to assess the adequacy of the Investigator’s patient 
population, facilities, and equipment, and to familiarize the Investigator with the 
protocol. 
2. A member of the Sponsor or designee will 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 Instigator’s regulatory documents, source document, Informed Consent 
Forms, and Case Report Forms of study subjects. 
3. A member of the Sponsor or designee 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.  
4. Interim monitoring visits and telephone consultations will be done by the Study Monitor, 
as necessary, to ensure the proper progression and document of the study.  
 
 


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Appendix 7 
Protocol Amendment 
AMENDMENT 1: 11 January 2021  
 Modified or added text: 
o Cover page: 
 ADDED: ClinicalTrials.gov Identifier: NCT04620135 
o Synopsis Study Design and Section 3.1 Overall Study Design and Plan: 
 WAS: Approximately 208 subjects will be enrolled in this study.   
 IS: Approximately 240 subjects will be enrolled in this study.   
o Synopsis Study Population: 
 WAS: A total of approximately 208 subjects will be enrolled in this study at 
approximately 25 clinical sites, comprising a total of 104 subjects per treatment 
arm for each of two treatment arms. 
 IS: A total of approximately 240 subjects will be enrolled in this study at 
approximately 28 clinical sites, comprising a total of 120 subjects per treatment 
arm for each of two treatment arms. 
o Synopsis Exclusion Criteria and Section 4.3 Exclusion Criteria: 
 ADDED: 2. Retinal diseases that may progress during the study period 
(e.g., Macular edema, retinal detachment, diabetic retinopathy, retinal vein 
occlusion, age-related macular degeneration, pathological myopia) 
o Synopsis Statistical Methods and Section 9.4 Determination of Sample Size: 
 WAS: The target sample size is set to 104 per treatment group to allow for 
withdrawals and dropouts. 
 IS: The target sample size is set to 120 per treatment group to allow for 
withdrawals and dropouts. 
o Section 3. INVESTIGATIONAL PLAN Figure 1: 
 WAS: N = 208 
 IS: N = 240 
o Section 4.1. Study Population: 


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 WAS: A total of approximately 208 Japanese subjects will be enrolled in this 
study at approximately 25 investigational sites in Japan comprising a total of 
104 subjects per treatment arm for each of the 2 treatment arms. 
Planned enrollment numbers are higher (208 total, 104 subjects per arm) than 
statistically required for demonstrating efficacy (approximately 93 intent-to-treat 
[ITT] subjects per arm for 90% power) to account for the potential for subjects 
who do not complete the entire dosing period, or who have disqualifications. 
Over-enrollment (beyond 208 subjects) is to be undertaken only after 
communication between the investigational site and the Sponsor representative. 
 IS: A total of approximately 240 Japanese subjects will be enrolled in this study at 
approximately 28 investigational sites in Japan comprising a total of 120 subjects 
per treatment arm for each of the 2 treatment arms. 
Planned enrollment numbers are higher (240 total, 120 subjects per arm) than 
statistically required for demonstrating efficacy (approximately 93 intent-to-treat 
[ITT] subjects per arm for 90% power) to account for the potential for subjects 
who do not complete the entire dosing period, or who have disqualifications. 
Over-enrollment (beyond 240 subjects) is to be undertaken only after 
communication between the investigational site and the Sponsor representative. 
o Section 6.10. Safety Assessments and Section 9.9.1 Safety Endpoints: 
 WAS: Systemic safety assessments as measured by heart rate, blood pressure 
 IS: Systemic safety assessments as measured by heart rate, blood pressure/AEs 
o Section 6.11.7.3 Safety Reporting Contact Information: 
 
 
             
 
 
 
 
   
 
O Section 7.3.3 Visit 3.2:  
 BOLD FORMATTING APPLIED: Instructed not to administer their masked 
medication OU at home on the morning of the next visit (Visit 4) 
O Section 7.3.4 Visit 4.0 and Section 7.3.7 Visit 5.0:  
 BOLD FORMATTING APPLIED: Subjects are allowed to administer their 
masked medication after IOP measurements. 


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O Section 7.3.6 Visit 4.2:  
 BOLD FORMATTING APPLIED: Instructed not to administer their masked 
medication OU at home on the morning of the next visit (Visit 5) 
O Section 7.3.9 Visit 5.2:  
 BOLD FORMATTING APPLIED: Instructed not to administer their masked 
medication OU at home on the morning of the next visit (Visit 6) 
o Appendix 2 Sponsor’s Obligations C and Appendix 3 Investigator’s Obligations 1: 
 WAS: (see Section 6.10.1, Adverse Events Assessments). 
 IS: (see Section 6.11, Adverse Events Assessments). 
 

SAP_003.pdf: 
 
Title: ClinicalTrials.gov Results Submission - 
Cover Page (Redacted Documents) 
 
Form No.: FM-CL-0024  
Ver.: 1.0 
 
Associated Document No.: SOP-CL-000021 
 
Page 1 of 1 
 
Efficacy and Safety Study of Netarsudil 0.02% Ophthalmic 
Solution Compared to Ripasudil Hydrochloride Hydrate 0.4% 
Ophthalmic Solution in Japanese Subjects With Primary Open 
Angle Glaucoma or Ocular Hypertension 
NCT04620135 
Version 1 dated 26 August 2021 
 
 


 
STATISTICAL ANALYSIS PLAN  
 
A single-masked, randomized, multi-center, parallel-group, 4-week study 
evaluating the efficacy and safety of once daily netarsudil ophthalmic solution 
0.02% compared to twice daily ripasudil hydrochloride hydrate ophthalmic solution 
0.4% in Japanese subjects with primary open angle glaucoma (POAG) or ocular 
hypertension (OHT) 
 
 
 
Sponsor:   
 
Aerie Pharmaceuticals Ireland Limited 
 
 
 
 
 
 
Protocol Number: 
AR-13324-CS305 
 
 
Author:   
 
 
 
 
 
 
 
 
Date:    
 
26AUG2021 
Version:  
 
1.0 
 
 
 
 


 
 
 
Page 2 of 40 
A single-masked, randomized, multi-center, parallel-group, 4-week study evaluating the efficacy 
and safety of once daily netarsudil ophthalmic solution 0.02% compared to twice daily ripasudil 
hydrochloride hydrate ophthalmic solution 0.4% in Japanese subjects with primary open angle 
glaucoma (POAG) or ocular hypertension (OHT) 
 
Protocol Number: 
AR-13324-CS305 
SAP Version:   
1.0 
SAP Date:   
 
26AUG2021 
 
Statistical Analysis Plan Approval 
 
 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
Reviewed by:  
 
 
 
 
          
_____________ 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
             Date 
 
 
 
 
 


 
 
 
Page 3 of 40 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
             Date 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
  
 
 
Date 
 
 
 


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Table of Contents 
1. 
Introduction............................................................................................................................... 7 
2. 
Study Objectives ...................................................................................................................... 7 
2.1 Primary Objective ..................................................................................................................... 7 
3. 
Efficacy Assessments .............................................................................................................. 7 
3.1 Primary Endpoint ...................................................................................................................... 7 
3.2 Secondary Endpoints ............................................................................................................... 7 
3.3 Safety Assessments ................................................................................................................. 8 
3.4 Statistical Hypotheses .............................................................................................................. 8 
3.5 Estimands ................................................................................................................................. 8 
3.5.1 
Primary Estimand ............................................................................................................. 8 
4. 
Study Design and Procedures ................................................................................................. 9 
4.1 General Study Design and Plan ............................................................................................... 9 
4.2 Schedule of Visits and Assessments ..................................................................................... 11 
5. 
Study Treatments ................................................................................................................... 13 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 13 
5.2 Masking and Unmasking ........................................................................................................ 13 
6. 
Sample Size and Power Considerations ................................................................................ 14 
7. 
Data Preparation .................................................................................................................... 14 
7.1 Input Data ............................................................................................................................... 14 
7.2 Output Data ............................................................................................................................ 14 
8. 
Analysis Populations .............................................................................................................. 15 
8.1 Intent-to-Treat......................................................................................................................... 15 
8.2 Per Protocol............................................................................................................................ 15 
8.3 Safety ..................................................................................................................................... 15 
9. 
General Statistical Considerations ......................................................................................... 15 
9.1 Unit of Analysis....................................................................................................................... 15 
9.2 Missing or Inconclusive Data Handling .................................................................................. 15 
9.3 Definition of Baseline ............................................................................................................. 17 
9.4 Data Analysis Conventions .................................................................................................... 17 
9.5 Adjustments for Multiplicity ..................................................................................................... 17 
9.6 Assessment Time Windows ................................................................................................... 17 
10. 
Disposition of Subjects ........................................................................................................... 18 
11. 
Demographic and Baseline Characteristics ........................................................................... 19 
11.1 Demographics ........................................................................................................................ 19 
11.2 Baseline Characteristics ......................................................................................................... 19 
12. 
Medical History and Concomitant Medications ...................................................................... 19 


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12.1 Medical History ....................................................................................................................... 19 
12.2 Prior and Concomitant Medications ....................................................................................... 20 
13. 
Treatment Exposure ............................................................................................................... 20 
13.1 Treatment Exposure ............................................................................................................... 20 
14. 
Efficacy Analyses ................................................................................................................... 21 
14.1 Primary Analysis .................................................................................................................... 21 
14.2 Secondary Analyses .............................................................................................................. 24 
14.3 Subgroup Analyses ................................................................................................................ 28 
15. 
Exploratory Analyses ............................................................................................................. 29 
16. 
Safety Analyses ..................................................................................................................... 29 
16.1 Adverse Events ...................................................................................................................... 29 
16.2 Best-Corrected Visual Acuity ................................................................................................. 31 
16.3 Biomicroscopy Examination ................................................................................................... 31 
16.4 Dilated Ophthalmoscopy ........................................................................................................ 32 
16.5 Vital Signs .............................................................................................................................. 32 
16.6 Pregnancy Test ...................................................................................................................... 32 
17. 
Interim Analyses ..................................................................................................................... 32 
18. 
Changes from Protocol-Stated Analyses ............................................................................... 32 
19. 
References ............................................................................................................................. 33 
20. 
Tables ..................................................................................................................................... 33 
21. 
Listings ................................................................................................................................... 38 
22. 
Figures ................................................................................................................................... 40 
 
 
 


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List of Abbreviations 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BID 
Bis in die (Twice Daily) 
CI 
Confidence Interval 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MNAR 
Missing Not at Random 
NCS 
Not Clinically Significant 
ODO 
Observed Data Only 
OHT 
Ocular Hypertension 
PDF 
Portable Document Format 
POAG 
Primary Open Angle Glaucoma 
PP 
Per Protocol 
PT 
Preferred Term 
QD 
Quaque die (Once Daily) 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHODrug 
World Health Organization Drug Dictionary 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol AR-13324-CS305, version Rev 1 dated 11JAN2021. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: 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. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives 
2.1 
Primary Objective 
The objective of this study is to evaluate the ocular hypotensive efficacy and safety of netarsudil ophthalmic 
solution 0.02% once daily (QD) compared to the active comparator, ripasudil hydrochloride hydrate 
ophthalmic solution 0.4% twice daily (BID), over a 4-week period (superiority study). 
3. Efficacy Assessments 
3.1 
Primary Endpoint 
 
Comparison of netarsudil ophthalmic solution 0.02% relative to ripasudil hydrochloride hydrate 
ophthalmic solution 0.4% for mean of mean diurnal intraocular pressure (IOP) within a treatment at 
Week 4 (Day 29) by Goldmann Applanation Tonometry. 
3.2 
Secondary Endpoints 
Secondary efficacy outcomes will be comparison of netarsudil ophthalmic solution 0.02% relative to 
ripasudil hydrochloride hydrate ophthalmic solution 0.4% for: 
 
Mean of mean diurnal IOP at Weeks 1 and 2 (Days 8 and 15, respectively) 
 
Mean change from baseline in mean diurnal IOP at each post-treatment visit 
 
Mean percent change from baseline in mean diurnal IOP at each post-treatment visit 
 
Mean IOP at each post-treatment time point 
 
Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
 
Mean percent change from diurnally adjusted IOP at each post-treatment time point 
 
Percentages of subjects achieving pre-specified mean, mean change, and percent mean change 
in mean diurnal IOP levels   


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3.3 
Safety Assessments  
The safety of netarsudil ophthalmic solution 0.02% and ripasudil hydrochloride hydrate ophthalmic solution 
0.04% will be evaluated in both eyes and will include the following: 
 
Ophthalmic and systemic adverse events (AEs) 
 
Best corrected visual acuity (BCVA) 
 
Objective findings of biomicroscopic examinations (i.e., anterior segment examinations including 
evaluation of cornea, conjunctiva, lids, and lens) 
 
Dilated ophthalmoscopy, including vertical cup-disc ratio measurements 
 
Systemic safety assessments as measured by heart rate and blood pressure 
 
Pregnancy testing (for women of childbearing potential) 
3.4 
Statistical Hypotheses 
The null and alternative hypotheses, based on the primary variables, are as follows: 
H0: The difference in mean of mean diurnal IOP in study eyes treated with netarsudil QD versus study eyes 
treated with ripasudil BID (netarsudil QD  ripasudil BID) at Week 4 = 0. 
H1: The difference in mean of mean diurnal IOP in study eyes treated with netarsudil QD versus study eyes 
treated with ripasudil BID (netarsudil QD  
 
3.5 
Estimands 
3.5.1 
Primary Estimand 
The primary comparison in this trial will be between netarsudil ophthalmic solution 0.02% and ripasudil 
hydrochloride hydrate ophthalmic solution 0.04% at Week 4 in the intent-to-treat (ITT) population with 
intercurrent events handled as described in the following estimand: 
 
Population: subjects with primary open angle glaucoma (POAG) or ocular hypertension (OHT) as 
defined through enrollment criteria 
 
Endpoint:  
o 
Mean of mean diurnal IOP  (average over 09:00, 11:00, and 16:00 hour time points) (mmHg) 
at Week 4 Visit in the study eye 
 
Intercurrent event:  
o 
Discontinuation of study drug and non-optimal compliance will be ignored; IOP will continue to 
be measured and used [treatment policy strategy]. 
o 
Withdrawal due to lack of efficacy or AE: missing data will be imputed employing Multiple 
Imputation (MI) assuming missing not at random (MNAR) using control-based regression 
methodology [hypothetical strategy]. 
o 
Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy or AE: 
missing data will be imputed employing MI assuming missing at random (MAR) using 
randomized treatment-based regression methodology [hypothetical strategy]. 
 
Population-level summary:  


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o 
The difference (netarsudil QD  ripasudil BID) in mean of mean diurnal IOP at Week 4 between 
study eyes treated with netarsudil QD and ripasudil BID. 
Sensitivity analyses will be performed on observed data only (ODO) and where the worst on-treatment 
time-consistent observation within a subject is carried forward for withdrawal due to lack of efficacy or AE 
and the last time-consistent observation within a subject is carried forward for other missing data.  
4. Study Design and Procedures 
4.1 
General Study Design and Plan 
This study will be a prospective, single-masked, randomized, multi-center, parallel-group, 4-week study 
evaluating the efficacy and safety of QD netarsudil ophthalmic solution 0.02% compared to BID ripasudil 
hydrochloride hydrate ophthalmic solution 0.4% in Japanese subjects with POAG or OHT in Japan over a 
4-week period.  
Netarsudil ophthalmic solution 0.02% will be dosed QD (21:00) while ripasudil hydrochloride hydrate 
ophthalmic solution 0.4% will be dosed BID (9:00/21:00). In order to be adequately masked, subjects dosing 
with netarsudil ophthalmic solution 0.02% (21:00) also will dose with vehicle QD (9:00).  
Subjects eligible to be enrolled in this study will be subjects with a diagnosis of either POAG or OHT. 
Approximately 240 subjects will be enrolled in this study. Subjects who agree to participate in this study 
and are enrolled will attend a total of up to 6 study visits: Screening Visit, Qualification #1, Qualification  #2 
(Day 1), Week 1 (Day 8), Week 2 (Day 15), and Week 4 (Day 29).  
Subjects will be required to washout of their pre-study ocular hypotensive medication for a prescribed period 
(i.e., 5 days to 6 weeks, depending on the medication) prior to attending Qualification Visit #1. Subjects 
eligible to be enrolled in this study must meet all inclusion criteria and none of the exclusion criteria at each 
of the Screening Visit and Qualification Visits #1 and #2. Subjects will receive a baseline eye examination 
including IOP measurements at the Screening Visit and Qualification Visits #1 and #2 and undergo 
additional testing at Qualification Visit #2. If deemed eligible, subjects will be enrolled at Qualification Visit 
#2 and assigned to either the netarsudil group or ripasudil group in a 1:1 ratio according to a computer-
generated randomization list. Randomization will take place using Interactive Web Response System 
(IWRS) methodology and will stratify subjects by site.  
Randomized subjects will dose the assigned study drug in both eyes BID in the morning (9:00 ± 1 hour) 
and in the evening (21:00 ± 1 hour) beginning on Day 1 and up to and including the evening prior to the 
final Week 4 (Day 29) visit. Procedures conducted at each of study Visits 4-6 will include safety measures 
and efficacy measurements, including IOP assessments. At Week 1 (Day 8), Week 2 (Day 15), and Week 
4 (Day 29) visit, IOP will be assessed at pre-dose, and 2 hours and 7 hours post-dose of the dose in the 
morning. Following completion of the Week 4 (Day 29) study visit procedures, subjects will exit the study. 
For subjects who discontinue early, every possible effort will be made to assure there is a final visit that 
includes all examinations listed for Week 4 (Day 29) visit and dilated ophthalmoscopy. 


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Study visits will be referred to in all tables and listings as the expected study day corresponding to the visit 
to enable reviewers to understand the assessment timing without referring to the protocol visit schedule. 
 
 
 


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4.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is shown below. 
 
 
 
 
Post Day 1 Treatment1 
Day (D)/Week (W) 
Screening 
Qual. #1 
Qual. #2 (Day 1) 
W1 (Day 8±2) 
W2 (Day 15±3) 
W42 (Day 29±3) 
Visit 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
4.2 
5.0 
5.1 
5.2 
6.0 
6.1 
6.2 
Hour (XY = XY:00) 
-- 
09 
09 
11 
16 
09 
11 
16 
09 
11 
16 
09 
11 
16 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Washout3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Vital Signs (heart rate, blood 
pressure) 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Symptoms/AEs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA6 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
IOP 
X 
X7 
X7 
X7 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy8/Pachymetry9 
G/P 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual Field10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Eye-Drop Instillation Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medications Dispensed 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Medications Collected 
 
 
 
 
 
 
 
 
 
 
 
X11 
 
 
Study Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; BCVA = best corrected visual acuity; IOP = Intraocular pressure. 
Early Discontinuation: Visit 6.0 procedures are to be completed plus a dilated ophthalmoscopy examination.  
Visit Requirements: There is no visit time requirement for Visit 1 (Screening). For Visit 2, IOP measurements will be 09:00 (+30 mins). For Visit 3, 
IOP will be measured at 09:00 (+30 mins), 11:00 (+30 mins) and 16:00 (±30 mins) hours. During Post Day 1 (Visit 4, 5, and 6) Treatment visits, 
study medication at 9:00 on the day of the visit will be administered after IOP measurements at 9:00 (+30 mins).  
Two subsequent IOP measurements will be taken 2 hours (±30 mins) and 7 hours (±30mins) after the study medication in the morning, 
respectively. 
1. If subjects develop cornea verticillata at Post Day 1 Treatment (visit 4 to visit 6), additional evaluation of grading and location (e.g. epithelium, 
stroma, or endothelium) of Cornea verticillata will be conducted in parallel. 


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2. If a subject has an ongoing AE at the time of study completion, the ongoing AE must be followed-up and provided appropriate medical care until 
the event has resolved or stabilized. 
3. Subjects currently using ocular hypotensive medications must undergo a minimum washout period. 
Medication Class 
Minimum Washout Period 
Rho kinase inhibitor 
6 weeks 
Prostaglandins 
4 weeks 
-adrenoceptor antagonists 
4 weeks 
-agonists such as brimonidine and 
apraclonidine 
2 weeks 
Muscarinic agonists (e.g., pilocarpine), carbonic anhydrase 
inhibitors (topical or oral) 
5 days 
4. Urine pregnancy test for women of childbearing potential is required.  
5. 
4 will be 
documented on the AE form. Additional symptoms reported after screening and before randomization will be documented on the medical history 
form. Adverse events will be recorded for every study visit (i.e., at 09:00, 11:00, and 16:00 hours) as needed.  
6. BCVA testing should precede IOP measurement, the administration of topical anesthetic agents, or any examination requiring contact with the 
anterior segment.  
7. Individuals returning at an Unscheduled Visit within 1 week to re-attempt IOP qualification are required to only re-measure IOP in both eyes.  
8. Gonioscopy evaluation up to 3 months prior to randomization is acceptable.  
9. Pachymetry within 1 week prior to screening is acceptable.  
10. 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 (e.g., 30-2 or 24-2 Humphrey) and reliability.  
11. Collect kit(s) dispensed during the Day1 visit, after dosing their masked medication in the morning. 
 


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5. Study Treatments 
Subjects meeting all eligibility criteria will be randomized 1:1 to one of the following two treatment groups: 
Netarsudil ophthalmic solution 0.02% 
 
Vehicle dose in each eye QD (9:00) and netarsudil ophthalmia solution 0.02% dose in each eye 
QD (21:00) for approximately 28 days. 
Ripasudil hydrochloride hydrate ophthalmic solution 0.4% 
 
Dosed BID (9:00/21:00) for approximately 28 days. 
5.1 
Method of Assigning Subjects to Treatment Groups 
Approximately 240 subjects will be randomized in this study using IWRS methodology and will stratify 
subjects by site using a dynamic blocking design to maintain balance across treatment groups. Study 
medications will be allocated via the IWRS.     
5.2 
Masking and Unmasking 
This study will be conducted in a single-masked where treatment assignments will be masked to the 
Investigator, the clinical study team (Sponsor personnel involved in day to day study management, 
Monitors, Data Managers, and Statisticians), and the subjects for the duration of the study.  
To ensure masked state to the investigators and the clinical study team, the study medication bottles are 
placed in a sealed kit so that the study medication cannot be identified from the outside of the kit. Study 
staff responsible for dispensing study medications must always prescribe a study medication to the 
subject in a sealed state and should instruct subjects that the study drug must be in the kit when it is 
returned. Unmasked staff responsible for collecting study medication ensures masked state to the 
investigators and the clinical study team by immediately sealing the collected study drug.  
Only in case of medical emergency or occurrence of AEs that warrant unmasking in the opinion of the 
Investigator, will the treatment assignment(s) be unmasked and made available to the Investigator and 
the Sponsor Medical Monitor or designee. 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. In the absence of medical need, the randomization code will not be 
available to the above personnel until after the study is completed and the database is locked.  
If the Investigator judges that 
emergency situation, the Investigator should contact the Sponsor Medical Monitor or designee. After 
consultation with the Sponsor Medical Monitor or designee, a decision will be made as to whether or not 
the treatment should be unmasked. The treatment assignment will be revealed on a subject-by-subject 
basis, thus maintaining the masking on the remaining subjects.  
If there is an emergency situation in which treatment of an AE requires immediate unmasking and the 
Investigator is unable to contact the Sponsor Medical Monitor or designee, the Investigator may unmask 


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the treatment. The Investigator will perform the unmasking through the IWRS. In the case of such 
unmasking in an emergency situation, the Investigator should contact the Sponsor immediately and 
document unmasking in writing, recording the date, time, and reason for unmasking the study drug 
treatment in the source documentation. 
6. Sample Size and Power Considerations 
Ninety three (93) subjects (study eyes) per treatment group are required to have 90% power (1-
H0 in favor of H1 at a 2-sided significance level of 5%, assuming that a difference of the mean change from 
baseline in mean diurnal IOP (netarsudil QD  ripasudil BID) in the proposed study is -1.1 mmHg with a 
common standard deviation (SD) of 2.3. The target sample size is set to 120 subjects per treatment group 
to allow for withdrawals and dropouts. Note that change from baseline values from historic studies are being 
used as estimates from which to calculate sample size for a non-change from baseline primary endpoint 
due to the change from baseline estimates for SD better reflecting the SD obtained from the primary 
analysis strategy within this study. 
7. Data Preparation 
7.1 
Input Data 
Study data will be recorded on the electronic case report forms (eCRF) supplied by Statistics & Data 
Corporation (SDC) using Rave 2020.3.1. The treatment assignment data is not captured directly within the 
Rave system but is obtained from Suvoda, an external vendor; no other data will be obtained from external 
vendors.    
When all prerequisites for database lock have been met, including availability of all masked data, the 
database will be locked. Following database lock, approval will be obtained from the Sponsor to unmask 
the study. Any changes to the database after data have been locked can only be made with the approval 
of the Sponsor in consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
 
Database lock has occurred, including receipt of written authorization provided by appropriate SDC 
and Sponsor personnel. 
 
Protocol deviations have been identified and status defined (major/minor deviations). 
 
Analysis populations have been determined. 
 
Randomized treatment codes have been unmasked. 
7.2 
Output Data 
Data from the Rave system and external treatment assignment data will be transferred to Biostatistics and 
incorporated into standard formats following the Study Data Tabulation Model (SDTM). Data will then be 
mapped to analysis datasets using the Analysis Data Model (ADaM). Both SDTM- and ADaM-formatted 
data will be used to create the subject listings, while all tables and figures will be based on the ADaM-
formatted data. 


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Output data will use the latest applicable SDTM and ADaM models and guidelines and will be validated 
with the latest Pinnacle 21 version. Any discrepancies in the va
accompanying the final data transfers. 
Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model. 
8. Analysis Populations 
8.1 
Intent-to-Treat 
The ITT population will include all randomized subjects who have received at least 1 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. 
8.2 
Per Protocol 
The per protocol (PP) population is a subset of the ITT population and will include those subjects 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. 
8.3 
Safety 
The Safety population will include all randomized subjects who have received at least 1 dose of study 
medication. This population will be used to summarize safety variables and will summarize subjects as 
treated. 
9. General Statistical Considerations 
9.1 
Unit of Analysis 
The unit of analysis for efficacy will be the study eye. If the subject qualifies in only one eye, then this eye 
is designated the study eye. If the subject qualifies in both eyes, then the study eye will be the eye with the 
higher IOP at 09:00 hours on Visit 3. If both eyes have the same IOP at 09:00 hours on Visit 3.0, then the 
right eye will be the study eye. For each subject, both eyes will be treated. Safety will be summarized at the 
eye level (study eyes and fellow eyes separately) for measures captured at the eye level and at the subject 
level for measures not captured at the eye level. Adverse events will be summarized at the subject level, 
counting a subject as having an ocular AE if the subject has the ocular AE in either eye. 
9.2 
Missing or Inconclusive Data Handling 
Analyses of all efficacy endpoints will be performed primarily using the ITT population with MI techniques 
to impute missing data (where missing data for withdrawal due to lack of efficacy or AE will be imputed 
using control-based monotone regression, and missing data for all other reasons will be imputed using 
randomized treatment-based monotone regression). Sensitivity analysis of the primary endpoint will also 
be completed using ODO and where the worst on treatment time-consistent observation within a subject is 


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carried forward for withdrawal due to lack of efficacy or AE and the last time-consistent observation within 
a subject is carried forward for other missing data. Imputation will only be performed on missing data for 
the study eye at post-baseline scheduled visits; no imputation will be performed for fellow eye data or 
unscheduled post-baseline visits. 
Analyses of safety endpoints will be performed using the Safety population, and there will be no imputation 
of missing data other than for partial or missing dates where complete dates are required to flag data as 
treatment-emergent or concomitant with treatment. Partial/missing start and end dates for AEs and 
concomitant medications will be imputed as follows:  
Partial/missing start date:  
 
Dates with missing day only will be imputed as the 1st of the month unless the month and year 
are same as the month and year of first dose of study medication, in which case missing day will 
be imputed as the first dose day of study medication.  
 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as 
the first dose day and month of study medication.  
Partial/missing end date: 
 
Dates with missing day only will be imputed as the last day of the month unless the month and 
year are the same as the month and year of the last dose of study medication, in which case 
missing day will be imputed as the last dose day of study medication.  
 
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the 
year of the last dose of study medication, in which case missing day and month will be imputed 
as the last dose day and month of study medication.  
 
available, in which case the missing date will be imputed as the death date. 
then the missing end date will be imputed as the last dose date.  
 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death. 
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc). 
Completely missing dates will be imputed as the first dose date of study medication unless the end date is 
on or before the first dose date of study medication, in which case missing date will be imputed as 1 Jan of 
the same year as the end date. 


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9.3 
Definition of Baseline 
For diurnally adjusted IOP and biomicroscopy, baseline will refer to the time-consistent measure at Visit 3 
(e.g., IOP at 09:00 at Qualification Visit #2 will be the baseline for 09:00 at Week 2 and Week 4 visits; IOP 
at 11:00 at Qualification Visit #2 will be the baseline for 11:00 at Week 2 and Week 4 visits). For all other 
variables, baseline is defined as the last measurement prior to the first dose of study medication. An 
additional definition of baseline for conjunctival hyperemia will also be used: baseline (pre-washout) will be 
defined as the conjunctival hyperemia measure at Visit 1. Change from baseline will be calculated as follow-
up visit  baseline visit. 
9.4 
Data Analysis Conventions 
All final data analysis will be performed by SDC after the study is completed and the database has been 
locked and released for unmasking. Statistical programming and analyses will be performed using SAS® 
version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable document 
format (PDF) for tables, listings, and figures using landscape orientation. Unless otherwise specified, all 
study data for treated subjects will be listed by treatment group, subject number, visit, and parameter as 
applicable.  
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, median, minimum, and maximum. Minima and maxima will be reported with the same precision 
as the raw values; means and medians will be presented to one additional decimal place than reported in 
the raw values. Standard deviations will be presented to two additional decimal places than reported in the 
raw values. Summaries for discrete variables will include counts and percentages. All percentages will be 
rounded to one decimal place (i.e., XX.X%).  
All statistical tests will be 2-
 unless otherwise specified. 
Where applicable, 2-sided 95% confidence intervals (CIs) will be reported. All p-values will be rounded to 
4 decimal places; p-values less than 0.0001 wi
-values greater than 0.9999 
wi
.  
9.5 
Adjustments for Multiplicity 
No adjustment for multiplicity is required for this study with a single primary endpoint and no secondary 
endpoints identified for labeling claims. 
9.6 
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 and efficacy data, unscheduled visits are not included in the analyses unless they are 
considered as baseline. 


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The assessment visit date or start date (e.g., AEs) will be used to calculate study day, defined as the 
number of days from the day of first dose. The day of first dose is considered study day 1, so study day will 
be computed as: (Date of Assessment Data  Date of First Dose) + 1.  
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 Week 1 (Day 8) visit has a ± 2-day window, and Week 2 (Day 15), Week 
4 (Day 29) visits have a ± 3-day window.   
10. Disposition of Subjects 
Disposition will be summarized by overall and by treatment group in terms of numbers and percentage of 
subjects who were randomized, completed the study, and discontinued from the study. The number of 
subjects in each of the analysis populations (ITT, PP, and Safety) will be displayed by treatment group and 
percentages will be calculated using randomized subjects as the denominator unless otherwise specified. 
The reasons for study discontinuation will also be summarized and will include: lack of efficacy, AE, 
withdrawal of consent, non-compliance, lost to follow-up, disallowed concurrent medication, Investigator 
decision, protocol deviation, death, and other. Subjects who complete the study through Visit 6.2 will be 
considered study completers.  
The total number of screened subjects with the number of screen failure subjects will also be tabulated.  
Subject listings of disposition will be produced for all randomized subjects, subjects who prematurely 
discontinued, and screen failed subjects separately. The disposition listings for all randomized subjects and 
for randomized subjects who discontinued prematurely will include sex/age, protocol version, and end of 
study information. The disposition listing of screen failed subjects will include sex/age, visit and date of 
screen failure, and reason for screen failure; if the primary reason for screen failure 
ligibility Criteria 
Not Met,  then the criteria not met will also be listed. The subject randomization information, 
analysis population and inclusion criteria not met/ exclusion criteria met for screen failures will be presented 
in separate listings.  
The number and percentage of subjects with protocol deviations will be summarized according to type of 
deviation: any deviation, minor deviation, major deviation, and deviations related to COVID-19 
(major/minor), overall and by treatment group. Major or minor deviations will be assigned by the Sponsor. 
A subject listing will be provided that includes the date of each deviation and the discovery date of each 
deviation, if the deviation was related to COVID-19, the category and description of the deviation, whether 
the deviation is reportable to the Institutional Review Board, and the classification of whether the deviation 
was judged to be major or minor.   


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11. Demographic and Baseline Characteristics 
11.1 
Demographics 
The demographic variables will include age and sex. Age (years) will be summarized, overall and by 
treatment group, using continuous descriptive statistics. Age will be reported in years and calculated using 
the following formula: 
Age = (Informed Consent Date  Date of Birth) / 365.25, truncated as an integer 
Age will also be categorized as follows: 
The number and percentage of subjects 
will be presented for age group and sex. Race will not be collected in this study; all subjects will be enrolled 
as Asian (Japanese). A subject listing that includes all demographic variables will be provided. The 
childbearing potential responses for female subjects will be presented in a separate listing.  
11.2 
Baseline Characteristics 
Baseline characteristics will include study eye diagnosis of OHT or POAG, length of time since study eye 
diagnosis of OHT or POAG (weeks), prior hypotensive therapy, time on prior hypotensive therapy (weeks), 
study eye IOP at Screening Visit, study eye mean diurnal IOP on Qualification #2 (Day 1) Visit. Additionally, 
visual field mean deviation, central corneal thickness and cup to disc ratio will be summarized separately 
for the study eye and fellow eye.  
All pretreatment variables will be included along with their respective post-treatment variables in the 
relevant summaries and listings. Separate listings of visual field examinations and pachymetry will be 
produced. 
12. Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities in Japanese (MedDRA/J) 
Version 23.1. Medical history will be collected at Screening Visit; medical history will also be collected at 
Qualification Visits #1 and #2.  
Non-ocular and ocular medical histories will be summarized separately using discrete summary statistics 
and presented by treatment group and overall at the subject level by System Organ Class (SOC) and 
Preferred Term (PT) using the Safety population. If a subject reports the same PT multiple times within the 
same SOC, that PT will only be reported once within that SOC. As with the PT, if a subject reports multiple 
conditions within the same SOC, that SOC will only be reported once. The SOCs will be listed in alphabetical 
order; PTs within a SOC will be listed in the order of descending frequency across all subjects. 
A separate summary table of glaucoma history by treatment group will also be presented.  
Listings of medical history will be generated separately for ocular and non-ocular data. A listing of ocular 
surgery/laser procedures will also be produced. 


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12.2 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global (B3, September 2020) and summarized to the therapeutic drug class 
(Anatomical Therapeutic Chemical [ATC] 4 classification) and preferred name. If the ATC 4 classification is 
not provided, then the next highest classification that is provided in the coding dictionary will be used. The 
preferred name will be defined as the active ingredient; if the active ingredient is not provided or includes 
more than two ingredients (e.g., multivitamins), then the drug name will be summarized as the preferred 
name. 
Prior medications are defined as those medications listed as having been taken within 30 days prior to 
the start of Screening with a stop date prior to study drug administration. Concomitant medications are 
defined as those medications listed as having been taken (1) prior to study drug administration and 
continuing for any period of time following the first administration of study drug through the Week 4 (Day 
29) Visit or (2) at any time following the first administration of study drug through the Week 4 (Day 29) Visit. 
Prior and concomitant medications will be summarized separately for non-ocular (as distinguished in 
-
 by study eye and fellow eye using the safety population. 
Medications will be tabulated for each treatment group and for all subjects using frequencies and 
percentages. Subjects may have more than one medication per ATC class. At each level of subject 
summarization, a subject will be counted once if he/she reports one or more medications. Percentages will 
be based on the number of subjects in each treatment group. The ATC classes and preferred names within 
an ATC class will be listed in alphabetical order. 
A listing of combined ocular and non-ocular prior and concomitant medications will be generated and will 
include the dose, route, frequency, and indication, as well as the start and stop dates of 
the medication, whether the medication was administered for an AE (and if yes, the AE term), and whether 
a medication was a prior and/or concomitant medication. A separate listing of washout medications will also 
be presented, and will include the medicated eye, the medication stop date, the specific medication class 
(Rho kinase inhibitor, prostaglandin ana
-adrenoceptor antagonist, adrenergic agonist, muscarinic 
agonist, carbonic anhydrase inhibitor, or other), and the length of washout (weeks)/washout period 
appropriate . 
13. Treatment Exposure 
13.1 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 
Extent of Exposure (days) = (Date of Last Dose  Date of First Dose) + 1 


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Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population.   
Several subject listings will be produced, including study drug administration, eye drop instillation 
evaluation, study medication dispensation, study medication collected, study drug eye drop, and study drug 
interruption. 
14. Efficacy Analyses 
14.1 
Primary Analysis  
The primary efficacy endpoint will be the mean of mean diurnal IOP at Week 4 (Day 29). The primary 
analysis of the primary endpoint will employ an analysis of covariance (ANCOVA) model with mean diurnal 
IOP at Week 4 as the response, baseline mean diurnal IOP as a covariate, and treatment as a main effect, 
using the ITT population with Markov Chain Monte Carlo (MCMC) and regression-based MI techniques 
used to impute missing data. The least squares (LS) mean difference (netarsudil QD  ripasudil BID) will 
be presented with a 2-sided p-value and 95% CI; if the p-value is  0.05 and the point estimate of the LS 
mean difference is < 0, then the netarsudil group will be considered superior to the ripasudil group. 
The SAS® pseudo-code for the imputation and primary analysis is as follows, the actual code might be 
slightly different than the pseudo-code: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.2 
Secondary Analyses  
Secondary analyses of the primary efficacy endpoint include repeating the primary analysis strategy using: 
1. Observed data (ODO): For calculating the diurnal mean IOP, subjects who are missing all three 
IOP values at a given visit are removed from the analysis, and any observed IOP at the visit will be 
used to calculate the diurnal mean IOP. For example, a subject with only one IOP measurement at 
Week 4 will be included and the single IOP measurement will serve as the diurnal mean IOP. 
2. Last observation carried forward (LOCF): Subjects who are missing any of the three IOP results at 
a given visit will have their worst on treatment time-consistent observation within a subject carried 
forward for withdrawal due to lack of efficacy or adverse event and last time-consistent observation 
within a subject carried forward for other missing data. For example, last observed IOP value at 
any 09:00 time point will be carried forward to replace a missing IOP value at 09:00 Week 4 visit if 
missing value is not due to AE or lack of efficacy; worst IOP value at 09:00 time point at any post-
baseline visit will be carried forward to replace a missing IOP value at 09:00 time point at Week 4 
visit if missing value is due to AE or lack of efficacy. Once a subject has all three IOP values at a 
given visit, their diurnal mean IOP at that visit will be calculated; if three values are not available for 
a subject, then their diurnal mean IOP will be left as missing. 
In addition: 
 
ANCOVA with MI, LOCF, and ODO will be repeated using PP population.  
 
Analysis of the primary endpoint will be completed using individual 2-sample t-tests and 95% t-
distribution CIs for each comparison netarsudil 0.02% QD versus ripasudil 0.4% BID using the ITT 
and PP populations with MI, LOCF, and ODO. 
Qualifying fellow eyes will be evaluated separately using ANCOVA and 2-sample t-tests with ITT population 
with MI.The primary and secondary analyses described above will also be completed on the following 
secondary endpoints: 
 
Mean of Mean diurnal IOP at Weeks 1 and 2 (Days 8 and 15, respectively) 
 
Mean change from baseline in mean diurnal IOP at each post-treatment visit 
 
Mean IOP at each post-treatment time point 
 
Mean change from diurnally-adjusted baseline IOP at each post-treatment time point 
Models adjusting for baseline will only be performed on the mean IOP response variable as that inference 
is identical between this response and the change from baseline IOP response variable in such a model.  
Additionally, for IOP at each post-treatment time point and visit, mixed model repeated measures (MMRM) 
will be run using ITT ODO population . The model will include baseline time-matched IOP as a covariate; 
treatment, visit, time point, treatment by visit, treatment by time point, visit by time point, and treatment by 
visit by time point as fixed effects; and subject as a random effect. 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 


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in IOP in the different treatment arms among visits and time points. An unstructured covariance matrix will 
be used to model between visit and time point variances within each subject. This allows for different 
variances and co-variances within and between time points and visits. Other covariance structures, in the 
order of autoregressive, Toeplitz, and compound symmetry, will be used if an unstructured covariance does 
not converge. The following SAS® pseudo-code using PROC MIXED will be used: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean percent change from baseline in mean diurnal IOP and mean percent change from diurnally adjusted 
baseline IOP at each time point will be analyzed using 2-sample t-tests, between netarsudil 0.02% QD and 
ripasudil 0.4% BID at each time point and visit, including 2-sided p-values and 95% t-distribution CIs on the 
difference (netarsudil - ripasudil). These analyses will be presented for ITT population with ODO. 
4 
4 mmHg in 1 mmHg 
increments will be summarized at Week 1, Week 2, and Week 4. Analyses of IOP will also be summarized 
0 to 
0 mmHg in 2 mmHg increments and percent 
2-sided p-values) will be used to test differences 
between netarsudil versus ripasudil for each category at each visit. These analyses will be presented for 
both the ITT and PP populations with ODO. 
All primary and secondary efficacy variables, along with the corresponding planned analysis methods, are 
presented in Table 1 below. 
Table 1. Summary of Efficacy Variables and Analysis Methods (see the next page) 
 
 


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Endpoints
Analysis method
population
Imputation
Tables
Mean of mean diurnal IOP at Week 4 
(study eye) 
ANCOVA1 
ITT 
MI 
14.2.1.1.1, 
14.2.1.1.3 
ODO 
14.2.1.1.4 
LOCF 
14.2.1.1.5 
PP 
MI 
14.2.1.2.1 
ODO 
14.2.1.2.2 
LOCF 
14.2.1.2.3 
two-sample t-tests2 
ITT 
MI 
14.2.2.1.1 
ODO 
14.2.2.1.2.1 
LOCF 
14.2.2.1.3 
PP 
MI 
14.2.2.2.1 
ODO 
14.2.2.2.2 
LOCF 
14.2.2.2.3 
Mean of mean diurnal IOP at Week 4 
(fellow eye) 
ANCOVA 
ITT 
MI 
14.2.1.4 
Mean of mean diurnal IOP at Weeks 
1 and 2 
ANCOVA 
ITT 
MI 
14.2.1.1.2, 
14.2.1.1.3 
ODO 
14.2.1.1.4 
LOCF 
14.2.1.1.5 
PP 
MI 
14.2.1.2.1 
ODO 
14.2.1.2.2 
LOCF 
14.2.1.2.3 
two-sample t-tests 
ITT 
MI 
14.2.2.1.1 
ODO 
14.2.2.1.2.1 
LOCF 
14.2.2.1.3 
PP 
MI 
14.2.2.2.1 
ODO 
14.2.2.2.2 
LOCF 
14.2.2.2.3 
Mean of mean diurnal IOP at Weeks 
1 and 2 (fellow eye) 
ANCOVA 
ITT 
MI 
14.2.1.4 
Mean IOP at each time point; Mean 
of mean diurnal IOP at each visit 
ANCOVA 
(post-treatment) 
ITT 
MI 
14.2.1.1.3 
ODO 
14.2.1.1.4 
LOCF 
14.2.1.1.5 
PP 
MI 
14.2.1.2.1 
ODO 
14.2.1.2.2 
LOCF 
14.2.1.2.3 
two-sample t-tests 
 
ITT 
MI 
14.2.2.1.1 
ODO 
14.2.2.1.2.1 
LOCF 
14.2.2.1.3 
PP 
MI 
14.2.2.2.1 
ODO 
14.2.2.2.2 


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LOCF 
14.2.2.2.3 
Mean IOP at each time point; Mean 
of  mean diurnal IOP at each visit 
(fellow eye) 
ANCOVA 
(post-treatment) 
 
ITT 
MI 
14.2.1.4 
two-sample t-tests 
ITT 
MI 
14.2.2.3 
Mean change from diurnally adjusted 
baseline IOP at each post-treatment 
time point 
two-sample t-tests 
ITT 
MI 
14.2.2.1.1 
ODO 
14.2.2.1.2.1 
LOCF 
14.2.2.1.3 
PP 
MI 
14.2.2.2.1 
ODO 
14.2.2.2.2 
LOCF 
14.2.2.2.3 
Mean change from diurnally adjusted 
baseline IOP at each post-treatment 
time point (fellow eye) 
two-sample t-tests 
ITT 
MI 
14.2.2.3 
Mean change from baseline in mean 
diurnal IOP at each post-treatment 
visit 
two-sample t-tests 
ITT 
MI 
14.2.2.1.1 
ODO 
14.2.2.1.2.1 
LOCF 
14.2.2.1.3 
PP 
MI 
14.2.2.2.1 
ODO 
14.2.2.2.2 
LOCF 
14.2.2.2.3 
Mean change from baseline in mean 
diurnal IOP at each post-treatment 
visit (fellow eye) 
two-sample t-tests 
ITT 
MI 
14.2.2.3 
Mean percent change from baseline 
in mean diurnal IOP at each post-
treatment visit 
two-sample t-tests 
ITT 
ODO 
14.2.4.1 
Mean percent change from diurnally 
adjusted baseline IOP at each post-
treatment time point 
two-sample t-tests 
ITT 
ODO 
14.2.4.1 
Mean percent change from baseline 
in mean diurnal IOP at each post-
treatment visit (fellow eye) 
two-sample t-tests 
ITT 
ODO 
14.2.4.2 
Mean percent change from diurnally 
adjusted baseline IOP at each post-
treatment time point (fellow eye) 
two-sample t-tests 
ITT 
ODO 
14.2.4.2 
Percentages of subjects achieving 
pre-specified mean, mean change, 
and percent mean change in mean 
diurnal IOP levels 
3 
ITT 
ODO 
14.2.5.1 
PP 
ODO 
14.2.5.2 
Mean IOP at each post-treatment 
visit and time point 
MMRM4 
ITT 
ODO 
14.2.3 
 


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1 ANCOVA model including treatment as the main effect and baseline as the covariate. Individual models 
will be fit for each visit and time point. 
2 Two sample t-test comparing actual mean diurnal IOP or mean IOP value at each time point between 
netarsudil and ripasudil. 
3 
ripasudil. 
4 Mixed model repeated measures analysis has treatment, visit, time point, treatment*visit, treatment*time 
point, visit*time point, and treatment*visit*time point as fixed effects, time-matched baseline IOP as 
covariate, visit*time point within a subject as repeated measures, using an unstructured (or other specified) 
covariance matrix. 
Additionally, plots of IOP measurements over time point in the ITT population (ODO) will be provided to 
visually assess the IOP dynamics in each treatment group: 
 
Line plot of mean and SE of study eye intraocular pressure (mmHg) by treatment group, visit, and 
time point  
 
Bar graph of mean (SD) of study eye mean diurnal intraocular pressure (mmHg) by treatment group 
and visit 
 
Bar graph of mean (SD) change from baseline of study eye mean diurnal intraocular pressure 
(mmHg) by treatment group and visit 
 
Bar graph of mean (SD) percent change from baseline of study eye mean diurnal intraocular 
pressure (mmHg) by treatment group and visit 
A subject listing of IOP will also be produced. 
14.3 
Subgroup Analyses 
Subgroup analyses of primary efficacy endpoint include the following pre-study characteristic variables. 
The subgroup analyses will be based on the ITT population and use ODO. 
 
Site 
 
 
 
Sex 
 
Prior ocular hypotensive medication class:  
o 
No prior hypotensive medication 
o 
Prostaglandin analogues (monotherapy) only 
o 
Beta-adrenoceptor antagonists (monotherapy) only 
o 
Other monotherapy 
o 
Prostaglandin analogues + Beta-adrenoceptor antagonists (two drugs) 
o 
Other combination therapy 
 


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Mean diurnal baseline IOP : 
o 
< 20 mmHg versus  20 mmHg 
 
Subjects with diagnosis of the study eye (POAG versus OHT) 
For all subgroup analyses, mean diurnal IOP at Week 4 will be compared between treatment groups using 
an ANCOVA model with treatment and subgroup as the main effects, mean diurnal baseline IOP as a 
covariate, and the interaction of treatment and subgroup. The p-values for the subgroup and the interaction 
of treatment by subgroup, overall LS means, LS means by subgroup, and LS mean differences (netarsudil 
 ripasudil) within each subgroup category with associated p-values and 95% CIs will be presented.  
Sites with fewer than five subjects will be pooled together for the analysis. 
The primary efficacy ANCOVA analysis of study eye IOP at each time point and for diurnal mean will be 
completed for each of the mean diurnal baseline IOP categories and study eye diagnosis categories. 
The secondary efficacy analysis of two-sample t-test for mean and mean change from baseline in IOP at 
each time point and for diurnal mean will be completed for the following: mean diurnal baseline IOP of < 20 
mmHg and  20 mmHg and study eye diagnosis of POAG and OHT 
15. Exploratory Analyses 
There are no exploratory analyses planned for this study. 
16. Safety Analyses  
All safety analyses will be conducted using the Safety population. 
16.1 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
the event is considered drug related. The AE reporting period starts from the time the subject receives the 
first dose of study medication until Week 4 (Day 29). All AEs collected will be treated as TEAEs as the 
definition of TEAE is AE that occurs or worsens after the first dose of study medication. Documentation of 
AEs includes AE term, event type, eye(s), start date and time, severity, frequency, action taken with study 
drug, if the subject was withdrawn from the study due to the AE, other action taken, causality (relationship 
to study drug), outcome, stop date and time, and seriousness. All AEs will be coded using MedDRA/J 
(Version 23.1) SOC and PT and listed. 
Severity of an AE is defined as a qualitative assessment of the level of discomfort or the degree of intensity 
of an AE 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 will 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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The causal relationship of the AE to study drug will be assessed by the Investigator. The following definitions 
will be used in assessment: 
 
Not Related: The e
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 
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 
utic 
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 
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. 
 
An overall summary will be presented that includes the number of TEAEs and the number and percentage 
of subjects who experienced at least one TEAE. This summary will also include breakdowns of TEAEs 
further categorized as ocular or non-ocular, TE-SAEs (treatment-emergent serious adverse events),  
treatment-related TEAEs (reported as possibly related or related to the study drug), treatment-related TE-
SAEs, TEAEs by maximum severity, TEAEs by maximum relationship, TEAEs leading to treatment 
discontinuation (derived from AE CRF: Action Taken with Study Drug
= Investigational Product 
Discontinued ), TEAEs leading to study discontinuation (derived from AE 
, and TEAEs resulting in death.  
Additional summaries of ocular TEAEs will be summarized using discrete summary statistics at the subject 
level by SOC and PT. Non-ocular TEAEs will be similarly summarized. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, if 
a subject reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summaries, SOCs and PTs within SOCs will be listed in alphabetical order. 
The occurrence of ocular and non-ocular TEAEs will also be tabulated together by SOC and PT for the 
following:  
 
TE-SAEs   


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Related TEAEs 
 
Maximum severity 
. 
Separate listings will be provided for all AEs, all SAEs, AEs leading to study drug discontinuation and AEs 
resulting in death. 
16.2 
Best-Corrected Visual Acuity 
Best corrected visual acuity will be measured using Landolt-C chart or its equivalents at screening visit, 
Qualification #1 visit, Qualification  #2 (Day 1) visit, Week 1 (Day 8) visit, Week 2 (Day 15) visit, and Week 
4 (Day 29) visit.  
Best corrected visual acuity observed and change from baseline results for both the study eye and the 
fellow eye will be summarized for each visit using the continuous summary statistics.  
Separate listings of the all visual acuity results and subjects who lost three or more lines from baseline will 
be produced. 
16.3 
Biomicroscopy Examination 
Biomicroscopy examination of the conjunctiva, cornea, anterior chamber, lids, iris/pupil, and lens will be 
performed for both eyes of subjects at every study visit and time point.   
The results will be summarized using counts and percentages for each treatment group at each visit and 
time point for study eye and fellow eye separately. Percentages will be based on the number of subjects in 
each treatment group with non-missing values.  
Conjunctival hyperemia will also be summarized separately by study eye and fellow eye using continuous 
summary statistics including mean, mean change from screening and change from baseline. Two-sample 
t-tests as well as Wilcoxon rank sum tests will be used to test the difference between treatment groups. 
The number and percentage of subjects with a clinically significant increase from baseline in conjunctival 
hyperemia will also be summarized in a table, the clinically significant increase is defined as +1 unit score 
change from baseline in either eye, with baseline defined as the maximum score prior to first dose of study 
medication (any time point). 
A summary table of the number and percentage of subjects with at least one severity grade increase from 
baseline will be presented by region, parameter, visit and time point, and eye (study eye and fellow eye). 
Another summary table will be presented for the number and percentage of subjects with biomicroscopy 
finding judged to be clinically significant by the Investigator by region, parameter, visit and time point, and 
groups in both tables. The iris/pupil region will not be analyzed in the table. 
If subjects develop cornea verticillata at Week 1 (Day 8), Week 2 (Day 15), or Week 4 (Day 29), additional 
evaluation of grading and location (e.g. epithelium, stroma, or endothelium) of cornea verticillata will be 


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conducted in parallel. A separate table will be presented by parameter, visit and time point, and eye (study 
eye and fellow eye). 
A subject listing of the biomicroscopy parameter results will be produced. A separate listing will be 
generated for subjects with a criterion change, defined as a +1 unit increase from baseline. 
16.4 
Dilated Ophthalmoscopy 
A dilated funduscopic examination including evaluation of the retina, vitreous body, macula, choroid, optic 
nerve, and vertical cup-disc ratio will be performed at Screening and Week 4 (Day 29). 
The results, including retina, macula, choroid, optic nerve, and vitreous body, will be summarized using 
counts and percentages for each treatment group at each visit for study eye and fellow eye. Percentages 
will be based on the number of subjects in each treatment group with non-missing values. A shift table of 
ophthalmoscopy results from baseline will also be presented by treatment group for study eye and fellow 
eye separately. 
The vertical cup-disc ratio and change from baseline will be summarized for study eye and fellow eye 
separately at each visit using continuous summary statistics. 
Subject listings of the dilated ophthalmoscopy results, including retina, vitreous body, macula, choroid, optic 
nerve and vertical cup-disc ratio, will be produced. A separate listing will be created for those subjects with 
 Not 
 
 a listing of subjects with increases 
-disc ratio will be created. 
16.5 
Vital Signs 
Vital signs, including heart rate and blood pressure, will be measured at Screening Visit, Qualification #1, 
Qualification  #2/Day 1, Week 1 (Day 8), Week 2 (Day 15), and Week 4 (Day 29).  
Vital signs will be summarized for each visit and for change from baseline to each post-treatment visit using 
the continuous summary statistics. 
A subject listing of the vital signs results will also be produced. 
16.6 
Pregnancy Test 
Urine pregnancy will be measured at Screening and Week 4 (Day 29) visit. A subject listing of the urine 
pregnancy test results will be produced. 
17. Interim Analyses 
No interim analysis is planned for this study. 
18. Changes from Protocol-Stated Analyses 
as 
 to differentiate mean, mean change, percent mean change in mean diurnal IOP. 


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19. References 
None.  
20. Tables 
The topline tables are defined in bold.  
Table Number 
Title 
Population 
Table  14.1.1 
Subject Disposition 
 
Table  14.1.2 
Demographics and Baseline Characteristics by 
Treatment Group 
ITT Population 
Table  14.1.3.1 
Number and Percentage of Non-Ocular Medical History 
Safety Population 
Table  14.1.3.2 
Number and Percentage of Ocular Medical History 
Safety Population 
Table  14.1.3.3 
Summary of Glaucoma History by Treatment Group 
Safety Population 
Table  14.1.4.1 
Number and Percentage of Subjects with Non-Ocular 
Prior and Concomitant Medications 
Safety Population  
Table  14.1.4.2 
Number and Percentage of Subjects with Ocular Prior 
and Concomitant Medications 
Safety Population 
Table  14.1.5 
Exposure to Study Medication by Treatment Group 
Safety Population 
Table  14.2.1.1.1 
ANCOVA for Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 
ITT Population (Multiple 
Imputations)  
Table  14.2.1.1.2 
ANCOVA for Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 1 and 2 
ITT Population (Multiple 
Imputations)  
Table  14.2.1.1.3 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (Multiple 
Imputations)  
Table  14.2.1.1.4 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (ODO) 
Table  14.2.1.1.5 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (LOCF) 
Table  14.2.1.2.1 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
Per-Protocol Population 
(Multiple Imputations) 
Table  14.2.1.2.2 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) Study Eye at Each Post-Treatment Visit and 
Time Point 
Per-Protocol Population 
(ODO) 


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Table  14.2.1.2.3 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
Per-Protocol Population 
(LOCF) 
Table  14.2.1.3.1 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (ODO: 
Subjects with Mean 
Diurnal Baseline (Visit 3) 
IOP < 20 mmHg) 
Table  14.2.1.3.2 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (ODO: 
Subjects with Mean 
Diurnal Baseline (Visit 3) 
IOP >= 20 mmHg) 
Table  14.2.1.3.3 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (ODO: 
Subjects with Diagnosis of 
the Study Eye POAG) 
Table  14.2.1.3.4 
ANCOVA for Study Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (ODO: 
Subjects with Diagnosis of 
the Study Eye OHT) 
Table  14.2.1.4 
ANCOVA for Fellow Eye Intraocular Pressure (IOP; 
mmHg) at Each Post-Treatment Visit and Time Point 
ITT Population (Multiple 
Imputations)  
Table  14.2.2.1.1 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (Multiple 
Imputations)  
Table  14.2.2.1.2.1 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (ODO) 
Table  14.2.2.1.2.2 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (ODO: 
Subjects with Mean 
Diurnal Baseline (Visit 3) 
IOP < 20 mmHg) 
Table  14.2.2.1.2.3 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (ODO: 
Subjects with Mean 
Diurnal Baseline (Visit 3) 
IOP >= 20 mmHg) 
Table  14.2.2.1.2.4 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (ODO: 
Subjects with POAG) 
Table  14.2.2.1.2.5 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (ODO: 
Subjects with OHT) 
Table  14.2.2.1.3 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (LOCF) 


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Table  14.2.2.2.1 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
Per-Protocol Population 
(Multiple Imputations) 
Table  14.2.2.2.2 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
Per-Protocol Population 
(ODO) 
Table  14.2.2.2.3 
Mean and Mean Change from Baseline in Study Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
Per-Protocol Population 
(LOCF) 
Table  14.2.2.3 
Mean and Mean Change from Baseline in Fellow Eye 
Intraocular Pressure (mmHg) by Visit and Time Point 
ITT Population (Multiple 
Imputations)  
Table  14.2.3 
MMRM for Study Eye Intraocular Pressure (mmHg) by 
Visit and Time Point 
ITT Population (ODO) 
Table  14.2.4.1 
Mean Percent Change from Baseline in Study Eye 
Intraocular Pressure (IOP; mmHg) by Visit and Time 
Point 
ITT Population (ODO) 
Table  14.2.4.2 
Mean Percent Change from Baseline Fellow Eye 
Intraocular Pressure (IOP; mmHg) by Visit and Time 
ITT Population (ODO) 
Table  14.2.5.1 
Categorical Summary in Study Eye Diurnal Mean 
Intraocular Pressure (IOP; mmHg) by Visit  
ITT Population (ODO) 
Table  14.2.5.2 
Categorical Summary in Study Eye Diurnal Mean 
Intraocular Pressure (IOP; mmHg) by Visit  
Per-Protocol Population 
(ODO) 
Table  14.2.6.1 
ANCOVA for Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 by Site  
ITT Population (ODO) 
Table  14.2.6.2 
Summary of Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 by Age Category (<65, 
>=65) 
ITT Population (ODO) 
Table  14.2.6.3 
Summary of Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 by Sex  
ITT Population (ODO) 
Table  14.2.6.4 
Summary of Mean Diurnal Intraocular Pressure (IOP; 
mmHg) in the Study Eye at Week 4 by Prior Ocular 
Hypotensive Class  
ITT Population (ODO) 
Table  14.2.6.5 
Summary of Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 by Mean Diurnal 
Baseline IOP 
ITT Population (ODO) 
Table  14.2.6.6 
Summary of Study Eye Mean Diurnal Intraocular 
Pressure (IOP; mmHg) at Week 4 by Study Eye Diagnosis 
ITT Population (ODO) 
Table  14.3.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events by Treatment Group  
Safety Population 
Table 14.3.1.2 
Number and Percentage of Subjects with Ocular 
Treatment-Emergent Adverse Events by Treatment 
Group, System Organ Class, and Preferred Term 
Safety Population 


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Table  14.3.1.3 
Number and Percentage of Subjects with Non-Ocular 
Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Treatment Group  
Safety Population 
Table  14.3.1.4 
Number and Percentage of Subjects with Treatment-
Emergent Serious Adverse Events by System Organ 
Class, Preferred Term, and Treatment Group 
Safety Population 
Table  14.3.1.5 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Related or Possibly Related to 
Study Medication by System Organ Class, Preferred 
Term, and Treatment Group 
Safety Population 
Table  14.3.1.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events by Maximum Severity, 
Treatment Group, System Organ Class, and Preferred 
Term  
Safety Population 
Table  14.3.2.1 
Mean and Mean Change from Baseline in Study Eye 
Best Corrected Visual Acuity Scores by Treatment Group 
and Visit  
Safety Population 
Table  14.3.2.2 
Mean and Mean Change from Baseline in Fellow Eye 
Best Corrected Visual Acuity Scores by Treatment Group 
and Visit 
Safety Population 
Table  14.3.3.1 
Summary of Study Eye Biomicroscopy Results by 
Treatment Group and Visit 
Safety Population 
Table  14.3.3.2 
Summary of Fellow Eye Biomicroscopy Results by 
Treatment Group and Visit 
Safety Population 
Table 14.3.3.3 
Mean, Mean Change from Screening, and Mean 
Change from Baseline in Study Eye Conjunctival 
Hyperemia by Treatment Group and Visit 
Safety Population 
Table  14.3.3.4 
Mean, Mean Change from Screening, and Mean Change 
from Baseline in Fellow Eye Conjunctival Hyperemia by 
Treatment Group and Visit 
Safety Population 
Table  14.3.3.5 
Number and Percentage of Subjects with a Clinically 
Significant Increase from Baseline in Conjunctival 
Hyperemia 
Safety Population 
Table  14.3.3.6 
Number and Percentage of Subjects with at Least One 
Severity Grade Increase from Baseline in Biomicroscopy 
Findings 
Safety Population 
Table  14.3.3.7 
Number and Percentage of Subjects with Biomicroscopy 
Finding Judged to be Clinically Significant by the 
Investigator 
Safety Population 
Table  14.3.3.8 
Summary of Cornea Verticillata Grading 
Safety Population 
Table 14.3.4.1 
Summary of Study Eye Dilated Ophthalmoscopy Results 
by Treatment Group and Visit 
Safety Population 


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Table  14.3.4.2 
Summary of Fellow Eye Dilated Ophthalmoscopy Results 
by Treatment Group and Visit 
Safety Population 
Table  14.3.4.3 
Shift Table of Study Eye Dilated Ophthalmoscopy 
Results by Treatment Group 
Safety Population 
Table  14.3.4.4 
Shift Table of Fellow Eye Dilated Ophthalmoscopy 
Results by Treatment Group 
Safety Population 
Table  14.3.5.1 
Mean and Mean Change from Baseline in Study Eye 
Vertical Cup-to-Disc Ratio by Treatment Group and Visit 
Safety Population 
Table  14.3.5.2 
Mean and Mean Change from Baseline in Fellow Eye 
Vertical Cup-to-Disc Ratio by Treatment Group and Visit 
Safety Population 
Table  14.3.6 
Mean and Mean Change from Baseline in Vital Signs by 
Treatment Group and Visit 
Safety Population 
 
 


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21. Listings 
Listing Number 
Title 
Population 
Listing  16.1.7 
Randomization 
Randomized Population 
Listing  16.2.1.1 
Subject Disposition 
Randomized Population 
Listing  16.2.1.2 
Subject Who Prematurely Discontinued 
Randomized Population 
Listing  16.2.1.3 
Subject Disposition for Screen Failure 
Subjects 
All Screened Subjects 
Listing  16.2.2 
Protocol Deviations 
Randomized Population 
Listing  16.2.3.1 
Analysis Populations 
Randomized Population 
Listing  16.2.3.2 
Inclusion Criteria Not Met/Exclusion 
Criteria Met for Screen Failures 
All Screened Subjects 
Listing  16.2.4.1 
Demographics and Baseline 
Characteristics 
Randomized Population 
Listing  16.2.4.2 
Childbearing Potential Responses for 
Female Subjects 
Randomized Population 
Listing  16.2.4.3 
Medical History (Non-Ocular) 
Randomized Population 
Listing  16.2.4.4 
Medical History (Ocular) 
Randomized Population 
Listing  16.2.4.5 
Ocular Surgery/Laser Procedures  
Randomized Population 
Listing  16.2.4.6 
Pachymetry: Central Corneal Thickness 
Randomized Population 
Listing  16.2.4.7 
Visual Field Exams 
Randomized Population 
Listing  16.2.4.8 
Prior and Concomitant Medications 
Randomized Population 
Listing  16.2.4.9 
Washout Medications 
Randomized Population 
Listing  16.2.5.1 
Study Drug Administration 
Randomized Population 
Listing  16.2.5.2 
Eye-Drop Instillation Evaluation 
Randomized Population 
Listing  16.2.5.3 
Study Medication Dispensation 
Randomized Population 
Listing  16.2.5.4 
Study Medication Collected 
Randomized Population 
Listing  16.2.5.5 
Study Drug Eye Drop 
Randomized Population 
Listing  16.2.5.6 
Study Drug Interruption 
Randomized Population 
Listing  16.2.6 
Intraocular Pressure 
Randomized Population 
Listing  16.2.7.1 
Adverse Events 
Randomized Population 
Listing  16.2.7.2 
Serious Adverse Events 
Randomized Population 
Listing  16.2.7.3 
Adverse Events Leading to Study Drug 
Discontinuation 
Randomized Population 
Listing  16.2.7.4 
All Adverse Events Resulting in Death 
Randomized Population 
Listing  16.2.8.1 
Visual Acuity 
Randomized Population 
Listing  16.2.8.2 
Visual Acuity - Subjects Who Lost Three or 
More Lines from Baseline 
Randomized Population 
Listing  16.2.9.1 
Biomicroscopy 
Randomized Population 
Listing  16.2.9.2 
Biomicroscopy - Subjects with a Criterion 
Change   
Randomized Population 
Listing  16.2.10.1 
Dilated Ophthalmoscopy 
Randomized Population 
Listing  16.2.10.2 
Dilated Ophthalmoscopy - Subjects with a 
Criterion Change 
Randomized Population 


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Listing  16.2.10.3 
Cup-to-Disc Ratio
Randomized Population
Listing  16.2.10.4 
Cup-to-Disc Ratio - Subjects with a
Clinically Significant Increase 
Randomized Population 
Listing  16.2.11 
Vital Signs 
Randomized Population 
Listing  16.2.12 
Urine Pregnancy Test 
Randomized Population 
Listing  16.2.13 
Ocular Symptoms 
Randomized Population 
 
 
 


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22. Figures 
 
Figure 
Number 
Title 
Population 
Figure 14.2.1 
Mean +/- SE Study Eye Intraocular Pressure (mmHg) by 
Treatment Group, Visit, and Time Point 
ITT Population (ODO) 
Figure 14.2.2 
Mean (SD) of Study Eye Mean Diurnal Intraocular 
Pressure (mmHg) by Treatment Group and Visit 
ITT Population (ODO) 
Figure 14.2.3 
Mean (SD) Change from Baseline of Study Eye Mean 
Diurnal Intraocular Pressure (mmHg) by Treatment Group 
and Visit 
ITT Population (ODO) 
Figure 14.2.4 
Mean (SD) Percent Change from Baseline of Study Eye 
Mean Diurnal Intraocular Pressure (mmHg) by Treatment 
Group and Visit  
ITT Population (ODO)