A Prospective, Double-masked, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Assessing the Safety, Ocular Hypotensive Efficacy and Optimum Dose Concentration to be Used Clinically of Netarsudil Ophthalmic Solution in Subjects With Open-angle Glaucoma or Ocular Hypertension in Japan
Phase: PHASE2
Conditions: Open Angle Glaucoma, Ocular Hypertension
Sponsor: Aerie Pharmaceuticals

AR-13324-CS208 
 
A Prospective, Double-Masked, 
Randomized, Multicenter, Placebo-
Controlled, Parallel-Group Study Assessing 
The Safety, Ocular Hypotensive Efficacy And 
Optimum Dose Concentration To Be Used 
Clinically Of Netarsudil Ophthalmic Solution 
In Subjects With Open-Angle Glaucoma Or 
Ocular Hypertension In Japan 
 
 
NCT 03844945 
 
06 December 2018 

Netarsudil Ophthalmic Solution 0.01%, 0.02% and 0.04% 
Clinical Study Protocol: AR-13324-CS208, Amendment 1 
Aerie Pharmaceuticals Ireland Ltd.
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Clinical Study Protocol 
Study Title: 
A prospective, double-masked, randomized, multicenter, 
placebo-controlled, parallel-group study assessing the safety, ocular 
hypotensive efficacy and optimum dose concentration to be used 
clinically of netarsudil ophthalmic solution in subjects with open-
angle glaucoma or ocular hypertension in Japan 
Study Number: 
AR-13324-CS208 
Study Phase: 
2 
Product Name: 
Netarsudil 0.01%, 0.02% and 0.04% Ophthalmic Solution   
Indication: 
Reduction of elevated intraocular pressure (IOP) in subjects with 
open-angle glaucoma (OAG) or ocular hypertension (OHT) 
Investigators: 
Multicenter 
Sponsor: 
Aerie Pharmaceuticals Ireland Limited 
Sponsor 
Contact: 
135 US Highway 206, Suite 15 
Bedminster, NJ 07921 
+1 908 470-4320
Medical 
Monitor: 
 
 
 
 
 
Date 
Original Protocol (Rev 0): 
26 September 2018 
Amendment 1 (Rev 1) 
06 December 2018 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals Ireland Limited (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. 

Netarsudil Ophthalmic Solution 0.01%, 0.02% and 0.04% 
Clinical Study Protocol: AR-13324-CS208, Amendment 1 
Aerie Pharmaceuticals Ireland Ltd. 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: A prospective, double-masked, randomized, multicenter, placebo-controlled, 
parallel-group study assessing the safety, ocular hypotensive efficacy and optimum dose 
concentration to be used clinically of netarsudil ophthalmic solution in subjects with open-angle 
glaucoma or ocula'r hypertension in Japan 
Study No: AR-13324-CS208 
Original Protocol Date: 26 September 2018 
Protocol Version No: Rev I 
Protocol Version Date: 06 December 2018 
Role 
Clinical Operations 
Aerie Management and Sponsor 
Safety Officer 
Confidential 
Contact information 
 
 
 
 
 
 
 
 
 
 
 
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Biostatistics and Data Management 
 
 
 
 
 
 
 
 
 
  
 
 

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AMENDMENT 1: 06 DECEMBER 2018 
•
Modified or added text:
o
Synopsis and Section 4.3 exclusion criteria number 14:

ADDED: Cannot demonstrate proper delivery of the eye drop, or in the 
investigator or co-investigator’s opinion, unable to deliver the eye drop 
consistently.
o
Synopsis and Section 4.3 exclusion criteria number 20:

ADDED: 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.
o
Section 5.6

WAS: Ocular or systemic medication known to cause cornel deposits or cornea 
verticillata, including but not limited to, indomethacin, ibuprofen, naproxen, 
amiodarone, chloroquine, hydroxychloroquine, mepacrine, tafenoquine, 
tamoxifen, and phenothiazine.

IS: Systemic medications known to cause corneal deposits or cornea verticillata 
including nonsteroidal anti-inflammatory drugs (NSAIDs), amiodarone, 
chlorpromiazine, hydroxychloroquine, tamoxifen and phenothiazines.

ADDED: Subjects will be informed that benzalkonium chloride contained in this 
study drug as preservative agent has a risk to distain contact lenses.
o
Section 5.7.3

ADDED: In addition, eye dilation may cause blurred vision and temporary 
sensitivity to light.  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.
o
Section 6.10.3

ADDED: 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. 

 
 
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SYNOPSIS 
Sponsor: 
Aerie Pharmaceuticals Ireland Limited 
Name of Finished Product: 
Netarsudil 0.01%, 0.02% and 0.04% Ophthalmic Solution   
Name of Active Ingredients: 
Netarsudil 
Study Title: 
A prospective, double-masked, randomized, multicenter, placebo-controlled, parallel-group study assessing 
the safety, ocular hypotensive efficacy and optimum dose concentration to be used clinically of netarsudil 
ophthalmic solution in subjects with open-angle glaucoma or ocular hypertension in Japan 
Study Number: 
AR-13324-CS208 
Study Phase: 
2 
Primary Objective(s): 
In this Phase 2 study, the primary objectives are to evaluate: 
• The ocular hypotensive efficacy of netarsudil ophthalmic solutions relative to placebo over a 
28-day period 
• The ocular and systemic safety of netarsudil ophthalmic solutions relative to placebo over a 
28-day period 
Secondary Objective(s): 
None. 
Study Design: 
This will be a prospective, double-masked, randomized, multicenter, placebo-controlled, parallel group 
efficacy and safety trial evaluating the intraocular pressure (IOP) lowering effect of 3 concentrations of 
netarsudil ophthalmic solution over a 28-day treatment period. The purpose of this study is to assess the 
efficacy and safety of netarsudil ophthalmic solution (0.01%, 0.02% and 0.04%) compared to placebo in 
subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT) in Japan.  
All investigational products will be dosed in both eyes (OU) once daily (QD) in the evening (PM). Subjects 
eligible to be enrolled in this study will be subjects with diagnosis of either OAG or OHT. Approximately 
208 subjects will be enrolled in this study. Subjects who agree to participate in this study and are enrolled 
will attend a total of 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 at least 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 including National Eye Institute Visual Function 
Questionnaire (VFQ-25), Best Corrected Visual Acuity (BCVA), and Contrast Sensitivity (CS) testing. If 
deemed eligible, subjects will be enrolled at Qualification Visit #2 and assigned to placebo or 1 of 3 
investigational products in a 1:1:1:1 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.  

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Randomized subjects will dose the assigned investigational product in both eyes QD in the evening (between 
20:00 and 22:00 hours) 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 09:00, 11:00 and 16:00 hours. 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. 
For subjects who show any evidence of cornea verticillata by slit lamp examination using the grading system 
for amiodarone keratopathy (Orlando, 1984) during the 28-day treatment period, the assigned investigational 
product will be discontinued, all examinations for exit visit (Visit 6) will be completed and subject will enter 
into an observational period to follow up and collect visual function data.  Subjects will be evaluated at the 
time of discontinuation of study medication as OBS Visit 1 (Day 1), followed by monthly visits for 3 
consecutive months (OBS Visit 2, 3 and 4). If cornea verticillata persists at OBS Visit 4, subjects will return 
every 2 months until resolution or stabilization. Resolution is defined as grading of zero of the cornea 
verticillata grading and stabilization is defined as no worsening of the cornea verticillata grading for a 
minimum of one year from the commencement of dosing. Procedures conducted at OBS visit 1 will include 
VFQ-25, BCVA, CS testing and cornea verticillata grading. If cornea verticillata persists, BCVA testing and 
cornea verticillata grading will be evaluated at each visit thereafter until resolution or stabilization of the 
cornea verticillata grading. Once resolution is recorded with cornea verticillata grading of zero or 
stabilization is confirmed in both eyes, the subject will undergo VFQ-25, BCVA testing, CS testing, and exit 
the study. 
Inclusion Criteria: 
Subjects have to meet all of the following criteria at screening and qualification visits to enter into the study: 
1. Must be 20 years of age or older  
2. Diagnosis of OAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is acceptable) 
3. Medicated 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 OAG 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).  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 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).  Note: For purposes of determining eligibility 
of subjects to be enrolled, any non-integral mean IOP number should not be rounded 
6. BCVA 0.1 or better in decimal unit using Landolt-C chart or its equivalent (+ 1.0 logMAR or better by 
Early Treatment of Diabetic Retinopathy Study [ETDRS] or 20/200 or better by Snellen chart) 
7. Be able and willing 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 8 weeks is not judged safe as it would put the subject at risk for further vision loss  

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2. 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 
3. Ocular hyperemia score of moderate (+ 2) or severe (+3) at Qualification Visit #2 
4. Previous glaucoma intraocular surgery, including selective laser trabeculoplasty (SLT) or argon laser 
trabeculoplasty (ALT) in the study eye  
5. Refractive surgery in either eye (e.g., radial keratotomy, photorefractive keratectomy [PRK], laser-
assisted in situ keratomileusis [LASIK], corneal cross-linking) 
6. Ocular trauma within the 6 months prior to screening, or ocular surgery or non-refractive laser treatment 
within the 3 months prior to screening 
7. 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 
8. Any corneal disease or condition in either eye that in the investigator opinion, may confound assessment 
of the cornea 
9. Current evidence of corneal deposits or cornea verticillata in either eye 
10. Use of ocular medication in either eye of any kind within 30 days of screening and throughout the study, 
with the exception of a) ocular hypotensive medications (which must be washed out according to the 
provided schedule), b) lid scrubs (which may be used prior to, but not after, screening), c) lubricating 
drops for dry eye (which may be used throughout the study), or d) non-steroid allergy drops (note: must 
not contain a vasoconstrictor) as prescribed by the Investigator 
11. Mean central corneal thickness greater than 620 μm in either eye at screening 
12. Any abnormality preventing reliable applanation tonometry of either eye (e.g., keratoconus) 
13. Known hypersensitivity to benzalkonium chloride or excipients of netarsudil ophthalmic solution 
14. Cannot demonstrate proper delivery of the eye drop, or in the investigator or co-investigator’s opinion, 
unable to deliver the eye drop consistently 
Systemic: 
15. Current use of systemic medications known to cause corneal deposits or cornea verticillata including 
nonsteroidal anti-inflammatory drugs (NSAIDs), amiodarone, chlorpromazine, hydroxychloroquine, 
tamoxifen and phenothiazines 
16. Clinically significant abnormalities in laboratory tests at screening 
17. Clinically significant systemic disease which might interfere with the study 
18. Participation in any investigational study within 30 days prior to screening 
19. 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 
20. 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 Population: 
A total of approximately 208 subjects will be enrolled in this study at approximately 30 investigational sites 
across Japan comprising a total of 52 subjects per treatment arm for each of the 4 treatment arms. Subjects 

 
 
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will be at least 20 years of age with diagnosed OAG or OHT, each of whom meets all inclusion criteria and 
none of the exclusion criteria. 
Investigational Product, Dose, and Mode of Administration: 
• Netarsudil Ophthalmic Solution 0.01%, 1 drop QD (PM), OU 
• Netarsudil Ophthalmic Solution 0.02%, 1 drop QD (PM), OU 
• Netarsudil Ophthalmic Solution 0.04%, 1 drop QD (PM), OU 
• Netarsudil Ophthalmic Solution Placebo, 1 drop QD (PM), OU 
Duration of Treatment: 
Dosing will continue daily for 28 days continuously. 
Efficacy Assessments: 
The primary efficacy outcome will be the comparison of netarsudil ophthalmic solutions (0.01%, 0.02% and 
0.04%) relative to placebo 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 solutions relative to placebo 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: 
Treatment Period: 
Primary safety assessments: 
• Ocular symptoms/adverse events 
• VFQ-25 at baseline 
• BCVA will be determined and completed prior to any IOP measurements   
• CS testing at baseline 
• 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, blood pressure, and clinical laboratory 
evaluations (including hematology, clinical chemistry, and urinalysis)  
• Pregnancy testing (for women of child bearing potential) 
Observational Period (For subjects who develop cornea verticillata): 
• VFQ-25  
• BCVA 
• CS testing 
• Cornea verticillata grading 

 
 
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• Time to cornea verticillata resolution or stabilization of cornea verticillata grading score 
Statistical Methods: 
The primary efficacy endpoint is the mean diurnal IOP (average of 09:00, 11:00, and 16:00 hours) at Week 4.  
Assuming a two-sided test with alpha = 0.05, a common standard deviation (SD) of 3.5 mmHg at each time 
point yielding a common SD of 3.0 for the mean diurnal IOP, and a correlation among time points of 0.60, 
49 ITT subjects per arm yields 90% power to demonstrate superiority for each concentration of netarsudil 
(0.01%, 0.02% or 0.04%) to placebo in study eye mean diurnal IOP at the Week 4 Visit assuming a 
difference of at least 2.0 mmHg in the mean diurnal IOP. The study will be considered a success and 
superiority of netarsudil to placebo will be concluded if the two-sided p-value is ≤ 0.05 at Week 4 for at least 
one concentration of netarsudil. Accounting for approximately a 5% discontinuation rate, 52 subjects per arm 
(208 total) will be enrolled.  
The primary analysis of the primary outcome 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 
intent to treat population with Monte Carlo Markov Chain multiple imputation techniques used to impute 
missing data.  The least squares mean differences (netarsudil – placebo) will be presented separately for 
netarsudil 0.01%, 0.02% and 0.04% as well as 2-sided p-values and 95% confidence intervals (CIs). 
Inference will be made on the 2-sided p-values. Superiority for a concentration (0.01%, 0.02% and 0.04%) 
will be concluded if the 2-sided p-value, for testing the difference (netarsudil – placebo) to 0, is ≤ 0.05 and 
the point estimate of the difference is < 0 at Week 4 for that concentration. 
There will be no adjustment for the multiplicity of the 3 active concentrations (0.01%, 0.02% and 0.04%) 
tested against placebo in this Phase 2 study. 
In subjects who have cornea verticillata, CS and BCVA will be summarized at the eye level for the initial 
assessments and for follow-up visits as well as change from the initial assessment by treatment group and by 
whether or not the cornea verticillata event was ongoing at a given visit. The VFQ-25 scores will be 
summarized similarly at the subject level. 
The grading of the cornea verticillata will be summarized at eye level for initial and follow-up visits in a 
similar manner to that described above for the visual function parameters. 
Follow-up information, including the duration of the cornea verticillata event and time to resolution will be 
also summarized by treatment group and observational study group. 
Date of Original Approved Protocol (Rev 0): 26 September 2018 
Date of Amendment 1 Approved Protocol (Rev 1): 06 December 2018 
 

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TABLE OF CONTENTS 
AMENDMENT 1: 06 DECEMBER 2018 ........................................................................4 
SYNOPSIS ..........................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................14 
1. 
INTRODUCTION ....................................................................................................16 
1.1 
Investigational Product .......................................................................................16 
1.2 
Findings from Non-Clinical and Clinical Studies .............................................17 
1.3 
Risks and Benefits to Human Subjects ..............................................................18 
2. 
STUDY OBJECTIVES ............................................................................................19 
2.1 
Primary Objective(s) ...........................................................................................19 
2.2 
Secondary Objective(s) ........................................................................................19 
3. 
INVESTIGATIONAL PLAN ..................................................................................20 
3.1 
Overall Study Design and Plan ...........................................................................21 
3.2 
Rationale for Study Design and Control Group ...............................................22 
3.3 
Expected Duration of Subject Participation......................................................22 
4. 
STUDY POPULATION SELECTION ...................................................................23 
4.1 
Study Population ..................................................................................................23 
4.2 
Inclusion Criteria .................................................................................................23 
4.3 
Exclusion Criteria ................................................................................................24 
5. 
STUDY TREATMENTS ..........................................................................................26 
5.1 
Description of Treatments ...................................................................................26 
5.1.1 
Study Drug ......................................................................................................26 
5.1.2 
Placebo or Control Drug ...............................................................................26 
5.2 
Treatments Administered ...................................................................................26 
5.3 
Selection and Timing of Dose for Each Patient .................................................26 
5.4 
Method of Assigning Patients to Treatment Groups ........................................26 
5.5 
Masking .................................................................................................................27 
5.6 
Concomitant Therapy ..........................................................................................27 
5.7 
Restrictions ...........................................................................................................29 
5.7.1 
Prior Therapy/Washout Period ....................................................................29 
5.7.2 
Fluid and Food Intake ...................................................................................29 
5.7.3 
Subject Activity Restrictions .........................................................................29 
5.8 
Treatment Compliance ........................................................................................29 
5.9 
Packaging and Labeling ......................................................................................30 
5.10 
Storage and Accountability .................................................................................30 
5.11 
Investigational Product Retention at Study Site ...............................................30 
5.11.1 
Receipt and Disposition of Study Medication .............................................30 
5.11.2 
Return of Study Medication ..........................................................................31 
6. 
STUDY PROCEDURES ..........................................................................................32 
6.1 
Informed Consent ................................................................................................32 
6.2 
Demographics and Medical History ...................................................................32 
6.3 
Concomitant Medication Assessments ...............................................................32 
6.4 
Ophthalmic/Physical Assessment .......................................................................33 
6.5 
Dispensing Investigational Product ....................................................................33 

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6.6 
Efficacy Assessments ...........................................................................................33 
6.6.1 
Specification of the Efficacy Parameters .....................................................33 
6.6.2 
Method and Timing for Assessing, Recording, and Analyzing of 
Efficacy Parameters .......................................................................................34 
6.7 
Safety Assessments ...............................................................................................34 
6.8 
Adverse Events Assessments ...............................................................................35 
6.8.1 
Performing Adverse Event (AE) Assessments ............................................35 
6.8.2 
Adverse Event Definition ..............................................................................35 
6.8.3 
Timing for Reporting of Adverse Events .....................................................36 
6.8.4 
Severity............................................................................................................37 
6.8.5 
Relationship ....................................................................................................38 
6.8.6 
Expectedness ...................................................................................................38 
6.8.7 
Clinical Laboratory Adverse Events ............................................................39 
6.8.8 
Serious Adverse Events or Serious Suspected Adverse Events .................39 
6.8.9 
Serious Unexpected Suspected Adverse Reactions (SUSARs) ...................40 
6.9 
Vital Signs .............................................................................................................40 
6.10 
Clinical Laboratory Tests....................................................................................40 
6.10.1 
Laboratory Parameters .................................................................................40 
6.10.2 
Sample Collection, Storage and Shipping ....................................................41 
6.10.3 
Pregnancy testing (for women of child bearing potential) .........................41 
6.11 
Best Corrected Visual Acuity (BCVA) ...............................................................41 
6.12 
National Eye Institute Visual Function Questionnaire (VFQ-25) ...................41 
6.13 
Contrast Sensitivity Testing ................................................................................42 
6.14 
Biomicroscopy ......................................................................................................42 
6.14.1 
Corneal Deposit Grading under Biomicroscopy .........................................42 
6.15 
Gonioscopy/Pachymetry ......................................................................................42 
6.16 
Visual Field Testing .............................................................................................42 
6.17 
Dilated Ophthalmoscopy .....................................................................................42 
6.18 
Intraocular Pressure ............................................................................................43 
6.19 
Study Eye Selection Process ................................................................................43 
6.20 
Removal of Subjects from the Study or Study Treatment ...............................43 
6.20.1 
Completed Subject .........................................................................................43 
6.20.2 
Non-completing Subject ................................................................................43 
6.20.3 
Actions after Discontinuation .......................................................................44 
6.20.4 
Discontinuation of the Entire Study .............................................................45 
6.20.5 
Completed Study ............................................................................................45 
6.21 
Appropriateness of Measurements .....................................................................45 
7. 
STUDY ACTIVITIES ..............................................................................................46 
7.1 
Visit 1 (Screening) ................................................................................................46 
7.1.1 
Evaluation of Eye-Drop Instillation Performance ......................................47 
7.1.2 
Washout ..........................................................................................................47 
7.2 
Visit 2 (Qualification Visit #1, for IOP and safety measurements at 09:00 
hours) ....................................................................................................................47 
7.3 
Treatment Period .................................................................................................48 

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7.3.1 
Visit 3.0 (Qualification Visit #2, Day 1, for IOP and safety 
measurements at 09:00 hours) ......................................................................48 
7.3.2 
Visit 3.1 (Day 1, for IOP and safety measurements at 11:00 hours) .........49 
7.3.3 
Visit 3.2 (Day 1, for IOP and safety measurements at 16:00 hours) .........50 
7.3.4 
Visit 4.0 (Week 1 [Day 8], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................51 
7.3.5 
Visit 4.1 (Week 1 [Day 8], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................51 
7.3.6 
Visit 4.2 (Week 1 [Day 8], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................52 
7.3.7 
Visit 5.0 (Week 2 [Day 15], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................52 
7.3.8 
Visit 5.1 (Week 2 [Day 15], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................52 
7.3.9 
Visit 5.2 (Week 2 [Day 15], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................53 
7.3.10 
Visit 6.0 (Week 4 [Day 29], for IOP and safety measurements at 09:00 
hours) ..............................................................................................................53 
7.3.11 
Visit 6.1 (Week 4 [Day 29], for IOP and safety measurements at 11:00 
hours) ..............................................................................................................54 
7.3.12 
Visit 6.2 (Week 4 [Day 29], for IOP and safety measurements at 16:00 
hours) ..............................................................................................................54 
7.4 
Observational Period ...........................................................................................54 
7.4.1 
OBS Visit 1 (any visit between Visits 4 to 6 when cornea verticillata is 
detected) ..........................................................................................................55 
7.4.2 
OBS Visits 2, 3 and 4 (3 monthly visits 1 month (30 ± 5 days) from 
prior OBS Visit) .............................................................................................55 
7.4.3 
Subsequent bimonthly visits (60 days +/- 5 days from prior OBS Visit) ..55 
7.4.4 
Final Study Visit Procedures ........................................................................56 
7.5 
Unscheduled Visits ...............................................................................................56 
8. 
QUALITY CONTROL AND ASSURANCE .........................................................56 
9. 
PLANNED STATISTICAL METHODS ................................................................56 
9.1 
General Considerations .......................................................................................56 
9.2 
Determination of Sample Size .............................................................................57 
9.3 
Analysis Populations ............................................................................................57 
9.3.1 
Intent-to-Treat (ITT) Population .................................................................57 
9.3.2 
Per Protocol (PP) Population ........................................................................57 
9.3.3 
Safety Population ...........................................................................................58 
9.3.4 
Cornea Verticillata Safety Population .........................................................58 
9.4 
Demographics and Baseline Characteristics .....................................................58 
9.5 
Primary Efficacy ..................................................................................................58 
9.5.1 
Primary Efficacy Endpoint(s) .......................................................................58 
9.5.2 
Primary Efficacy Analyses ............................................................................58 
9.6 
Secondary Efficacy...............................................................................................59 
9.6.1 
Secondary Efficacy Endpoints ......................................................................59 

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9.6.2 
Secondary Efficacy Analyses ........................................................................59 
9.7 
Safety .....................................................................................................................60 
9.7.1 
Safety Endpoints ............................................................................................60 
9.7.2 
Safety Analyses ...............................................................................................61 
9.8 
Other Assessments or Analyses ..........................................................................62 
9.9 
Interim Analysis ...................................................................................................63 
10. ADMINISTRATIVE CONSIDERATIONS ...........................................................64 
10.1 
Investigators and Study Administrative Structure ...........................................64 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .....64 
10.3 
Ethical Conduct of the Study ..............................................................................64 
10.4 
Subject Information and Consent ......................................................................64 
10.5 
Subject Confidentiality ........................................................................................65 
10.6 
Study Monitoring .................................................................................................65 
10.7 
Case Report Forms and Study Records .............................................................66 
10.8 
Protocol Deviations ..............................................................................................66 
10.9 
Access to Source Documentation ........................................................................67 
10.10 Data Generation and Analysis ............................................................................67 
10.11 Retention of Data .................................................................................................67 
10.12 Financial Disclosure .............................................................................................68 
10.13 Publication and Disclosure Policy ......................................................................68 
11. REFERENCES .........................................................................................................69 
11.1 
External References .............................................................................................69 
11.2 
Internal References ..............................................................................................70 
 
TABLE OF TABLES 
Table 1 
Ocular Hypotensive Medication Washout Period ................................29 
 
TABLE OF FIGURES 
Figure 1 
Study Design .............................................................................................20 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Visits and Procedures .............................................................72 
Appendix 2 Sponsor’s Obligations .................................................................................75 
Appendix 3 Investigator’s Obligations...........................................................................76 
Appendix 4 Declaration of Helsinki ...............................................................................79 
Appendix 5 Study Monitoring ........................................................................................82 
Appendix 6 Sample SAS Code ........................................................................................83 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
A/G 
Albumin/globulin 
ALT 
Argon Laser Trabeculoplasty 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BCVA 
Best Corrected Visual Acuity 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
CS 
Curriculum Vitae 
Contrast Sensitivity 
DHHS 
Department of Health and Human Services 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
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 

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mmHg 
Millimeters of Mercury 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOPs 
Manual of Procedures 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
OTC 
Over-the-Counter 
OU 
Both Eyes 
PM 
Evening 
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 
SD 
Standard Deviation 
SITA 
Swedish Interactive Thresholding Algorithm 
SLT 
Selective Laser Trabeculoplasty 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSAR 
Serious Suspected Adverse Reaction 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
UA 
Urinalysis 
US 
VFQ-25 
United States 
National Eye Institute Visual Function Questionnaire-25 

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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. 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, and AR-13324-CS304), 
and reduces IOP potentially through several mechanisms: increasing trabecular outflow 
(Clinical Study Report AR-13324-CS102; 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; 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. 
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 
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 

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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.  
As part of the development plan in Japan, a Phase 1 ocular and systemic safety study 
comparing netarsudil ophthalmic solution 0.02% and 0.04% to placebo after a single dose 
and daily QD dosing over a 7-day period (AR-13324-CS104) in patients of Japanese 
ethnicity was recently completed in the United States. The study results demonstrated that the 
netarsudil 0.02% and 0.04 % formulations were safe and generally well tolerated by the 
healthy volunteer subjects of Japanese ethnicity within the 2nd generation who participated 
in this study. 
The present study is 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 subjects 
with open-angle glaucoma (OAG) or ocular hypertension (OHT) in Japan.  
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 a phototoxicity study. 
Clinical 
The clinical development of netarsudil ophthalmic solution includes pharmacokinetics, 
tolerability, and dose-response investigations. The assessment of the ocular and systemic 
safety of netarsudil ophthalmic solution 0.02% in three Phase 1 clinical studies (Clinical 
Study Reports AR-13324-CS101, AR-13324-CS102 and AR-13324-CS104 have been 
completed. Results from a previous Phase 2 study (Clinical Study Report AR-13324-CS201) 
investigating a range of netarsudil concentrations (0.01%, 0.02%, and 0.04%) were used to 
select the appropriate concentrations of netarsudil ophthalmic solution to be tested in the 
present study (0.01%, 0.02% and 0.04%). Four Phase 3 clinical studies (Clinical Study 

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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 
Rhopressa® (netarsudil ophthalmic solution) 0.02% was approved in the US on 
December 18, 2017.  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 OAG or OHT, and it was safe and generally well 
tolerated. The most common ocular adverse reaction observed in controlled clinical studies 
with Rhopressa® dosed once daily 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).  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 OAG 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) 
In this Phase 2 study, the primary objectives are: 
• The ocular hypotensive efficacy of netarsudil ophthalmic solutions relative to placebo 
over a 28-day period 
• The ocular and systemic safety of netarsudil ophthalmic solutions relative to placebo over 
a 28-day period 
2.2 Secondary Objective(s) 
None.

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3. INVESTIGATIONAL PLAN 
Figure 1 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Visit 
(Visit 1) 
Subjects with OAG or OHT 
in Japan 
Netarsudil 0.02% 
1 drop, QD (OU)  
each evening 
Randomize 1:1:1:1 
 
N = 208 
 
Stratification by site 
Primary Analysis 
The ocular hypotensive efficacy of Netarsudil 
Ophthalmic Solutions relative to placebo for mean 
diurnal IOP over a 28-day period and the ocular and 
systemic safety of Netarsudil Ophthalmic Solutions 
relative to placebo over a 28-day 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) 
Netarsudil 0.04% 
1 drop, QD (OU)  
each evening 
Netarsudil placebo 
1 drop, QD (OU)  
each evening 
OBSERVATIONAL PERIOD 
 
Netarsudil 0.01% 
1 drop, QD (OU)  
each evening 
Visits until Resolution/Stabilization of Cornea 
Verticillata 
OBS Visit 1 (Day 1), OBS Visits 2-4 (Monthly x3). If cornea 
verticillata persists at OBS Visit 4, subjects will return every 2 
months until resolution or stabilization of cornea verticillata 
grading  
 
If cornea verticillata is reported,  
Study medication will be discontinued and exit visit 
(visit 6) procedures will be completed 
Safety Analysis 
Time to resolution of corneal verticillata,  
VFQ-25, BCVA, CS testing and corneal 
verticillata grade at initial assessment and change 
from initial level 

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3.1 
Overall Study Design and Plan 
This will be a double-masked, randomized, multicenter, placebo-controlled, parallel-group 
efficacy and safety trial evaluating reduction of elevated IOP with netarsudil ophthalmic 
solution over a 28-day treatment period. The purpose of this study is to assess the efficacy 
and safety of netarsudil ophthalmic solution (0.01%, 0.02% and 0.04%) compared to placebo 
in subjects that are 20 years of age or older with OAG or OHT in Japan. 
All investigational products will be dosed in both eyes (OU) QD in the evening (PM). 
Subjects eligible to be enrolled in this study will be those with a diagnosis of either OAG or 
OHT. Approximately 208 subjects will be enrolled. Subjects who agree to participate in this 
study and are enrolled in the study will attend a total of 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 at least 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 including VFQ-25, BCVA, and CS testing. If 
deemed eligible, the subject will be enrolled at Qualification Visit #2 and assigned to placebo 
or 1 of 3 investigational products in a 1:1:1:1 ratio according to a computer-generated 
randomization list. Randomization will take place using IWRS methodology and will stratify 
subjects by site.  
Randomized subjects will dose the assigned investigational product in both eyes QD in the 
evening (between 20:00 and 22:00 hours) 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 
09:00, 11:00 and 16:00 hours.  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.  
For subjects who show any evidence of cornea verticillata by slit lamp examination using the 
grading system for amiodarone keratopathy (Orlando 1984) during the 28-day treatment 
period, the assigned study medication will be discontinued, all exit visit procedures (Visit 6) 
will be completed and subject will be followed in an observational period starting as OBS 
Visit 1 (Day 1) in which subjects will undergo VFQ-25, BCVA testing, CS testing and 
cornea verticillata grading. All subjects with cornea verticillata will return for monthly 
surveillance visits (OBS Visit 2, 3 and 4) where they will undergo BCVA testing and cornea 
verticillata grading for 3 months.  If cornea verticillata persists at the 3-month time point 

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(OBS Visit 4), subjects will return every 2 months for BCVA testing and cornea verticillata 
grading until resolution or stabilization. Resolution is defined as grading of zero of the 
cornea verticillata grading and stabilization is defined as no worsening of the cornea 
verticillata grading for a minimum of one year from the commencement of dosing. Once 
resolution or stabilization is confirmed in both eyes, the subject will undergo VFQ-25, 
BCVA testing, CS testing and exit the study. 
3.2 
Rationale for Study Design and Control Group 
In order to further evaluate the hypotensive efficacy of netarsudil ophthalmic solution 
relative to its placebo in subjects with OAG or OHT and to generate additional safety data for 
netarsudil in Japanese population, a double-masked, parallel group, 4-arm active- and 
placebo-controlled study design was selected.  
As the intended route of administration for netarsudil ophthalmic solution is topical ocular, 
this is the route to be used in this study. The dosage regimen selected for this study is based 
on a previously completed Phase 2 study (AR-13324-CS201) and 4 completed Phase 3 
studies (AR-13324-CS301, AR-13324-CS302, AR-13324-CS303, and AR-13324-CS304).  
A Phase 1 study (AR-13324-CS104) evaluating the ocular and systemic safety of 2 
concentrations of netarsudil (0.02% and 0.04%) ophthalmic solution compared to placebo 
over a 7-day period was conducted in healthy volunteers of Japanese ethnicity within the 
second generation in the United States. However, efficacy results with netarsudil ophthalmic 
solution to date have been generated in a mostly non-Japanese population.  In order to ensure 
that similar results are observed in Japanese subjects, this study is being conducted in 
subjects in Japan. 
The design of the observational period for subjects who develop cornea verticillata during the 
study is based on an observational study conducted in the United States in a non-Japanese 
population (AR-13324-OBS01). Per discussion at PMDA meeting, long term follow-up is 
necessary in order to understand the impact on visual function and resolution of cornea 
verticillata in Japanese population.  
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 investigational product (IP) for this study will start on the 
evening of Visit 3 (Qualification Visit #2; Day 1) and end on the evening before Visit 6 
(Week 4/Day 28).  
If a subject develops cornea verticillata during the 28-day treatment period, the duration of 
the study will continue until resolution or stabilization of the cornea verticillata. This 
observational period has no set duration since resolution of cornea verticillata varies from 
subject to subject. The Sponsor’s expectation is that subjects will participate until resolution 
of the cornea verticillata. 

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4. STUDY POPULATION SELECTION 
4.1 
Study Population 
A total of approximately 208 Japanese subjects will be enrolled in this study at 
approximately 30 investigational sites in Japan comprising a total of 52 subjects per 
treatment arm for each of the 4 treatment arms. Subjects will be at least 20 years of age with 
diagnosed OAG or OHT, each of whom meets all inclusion criteria and none of the exclusion 
criteria. 
Planned enrollment numbers are higher (208 total, 52 subjects per arm) than statistically 
required for demonstrating efficacy (approximately 49 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. 
4.2 
Inclusion Criteria 
Subjects have to meet all of the following criteria at screening and qualification visits to enter 
into the study: 
1. Must be of 20 years of age or older  
2. Diagnosis of open-angle glaucoma (OAG) or ocular hypertension (OHT) in both eyes 
(OAG in one eye and OHT in the fellow eye is acceptable)  
3. 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 OAG 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 0.1 or better in decimal unit using Landolt-C chart or its equivalent (+ 1.0 
logMAR or better by Early Treatment of Diabetic Retinopathy Study [ETDRS] or 20/200 
or better by Snellen chart) 

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7. Be able and willing to give signed informed consent and follow study instructions 
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 8 weeks is not judged 
safe as it would put the subject at risk for further vision loss  
2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure 
glaucoma, or narrow angles (i.e., Shaffer Grade 2 or less). Note: Previous laser peripheral 
iridotomy is NOT acceptable 
3. Ocular hyperemia score of moderate (+ 2) or severe (+3) at Qualification Visit #2 
4. Previous glaucoma intraocular surgery, including selective laser trabeculoplasty (SLT) or 
argon laser trabeculoplasty (ALT) in the study eye  
5. Refractive surgery in either eye (e.g., radial keratotomy, photorefractive keratectomy 
[PRK], laser-assisted in situ keratomileusis [LASIK], corneal cross-linking) 
6. Ocular trauma within the 6 months prior to screening, or ocular surgery or non-refractive 
laser treatment within the 3 months prior to screening 
7. 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 
8. Any corneal disease or condition in the either eye that in the investigator opinion, may 
confound assessment of the cornea 
9. Current evidence of corneal deposits or cornea verticillata in either eye 
10. Use of ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications 
(which must be washed out according to the provided schedule), b) lid scrubs (which may 
be used prior to, but not after, screening), c) lubricating drops for dry eye (which may be 
used throughout the study), or d) non-steroid allergy drops (note: must not contain a 
vasoconstrictor) as prescribed by the Investigator 
11. Mean central corneal thickness greater than 620 μm in either eye at screening 

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12. Any abnormality preventing reliable applanation tonometry of either eye 
(e.g., keratoconus) 
13. Known hypersensitivity to benzalkonium chloride or excipients of netarsudil ophthalmic 
solution 
14. 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: 
15. Current use of systemic medications known to cause corneal deposits or cornea 
verticillata including nonsteroidal anti-inflammatory drugs (NSAIDs), amiodarone, 
chlorpromazine, hydroxychloroquine, tamoxifen and phenothiazines 
16. Clinically significant abnormalities in laboratory tests at screening 
17. Clinically significant systemic disease which might interfere with the study 
18. Participation in any investigational study within 30 days prior to screening 
19. 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 
20. 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 
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5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Study Drug 
Netarsudil mesylate (AR-13324) Ophthalmic Solution is a sterile, isotonic, buffered aqueous 
solution containing netarsudil (0.01%, 0.02% or 0.04%), 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 
Placebo or Control Drug 
Netarsudil ophthalmic solution placebo 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. 
5.2 
Treatments Administered 
Subjects will be randomized to receive IP netarsudil ophthalmic solution (0.01%, 0.02% or 
0.04%) or its placebo administered OU.  Subjects will instill 1 drop into each eye QD in the 
evening between 20:00 and 22:00 hours. 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 
The study drug doses and treatment period selected for this study are based on one Phase 1 
study (AR-13324-CS101) and the positive outcomes seen for netarsudil in 2 previously 
completed Phase 2 studies (AR-13324-CS201 and AR-13324-CS202) and 4 completed Phase 
3 studies (AR-13324-CS301, AR-13324-CS302, AR-13324-CS303 and AR-13324-CS304). 
Each dose is being administered QD OU in the evening (between 20:00 and 22:00 hours) in 
this study, since this dosing regimen was found to provide good efficacy and tolerability in 
the previous clinical studies.   
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 1:1:1:1 ratio to receive netarsudil ophthalmic solution 
(0.01%, 0.02% or 0.04%) or its placebo and will stratify subjects by site. 

 
 
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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. 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 feels 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 
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 

 
 
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• 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 medications known to cause corneal deposits or cornea verticillata including 
nonsteroidal anti-inflammatory drugs (NSAIDs), amiodarone, chlorpromazine, 
hydroxychloroquine, tamoxifen and phenothiazines 
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. 
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. 

 
 
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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.  
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 once-daily dosing regimen. 
Dosing should occur in the evening between 20:00 and 22:00 hours. 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 evening. In addition, 
subjects will be provided with dosing reminders. 

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5.9 
Packaging and Labeling 
The container-closure system for the netarsudil ophthalmic solution (0.01%, 0.02% or 
0.04%) and netarsudil ophthalmic solution placebo in this clinical study is a white, 
multi-dose low density polyethylene (LDPE) dropper dose ophthalmic bottle with a 
polypropylene white 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 one of 4 treatments: netarsudil ophthalmic solution 0.01%, 
0.02% or 0.04% or netarsudil ophthalmic solution placebo. 
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. Only authorized staff is 
allowed to dispense these 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.  
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. Subjects should be instructed not to freeze the product.  
5.11 
Investigational Product 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. 

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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 or staff is 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/Physical 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): VFQ-25, visual acuity, CS testing, 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: VFQ-25, CS testing and cornea verticillata grading 
6.5 Dispensing Investigational Product 
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. The responsible study staff will account for used and unused investigation product by 
maintaining a study medication accountability log. 
6.6 Efficacy Assessments 
6.6.1 
Specification of the Efficacy Parameters 
The primary efficacy outcome will be the comparison of netarsudil ophthalmic 
solution (0.01%, 0.02% and 0.04%) relative to placebo 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 relative to 
placebo 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 

 
 
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• 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. 
6.6.2 
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.  
6.7 Safety Assessments 
The primary safety measures in both eyes of enrolled subjects will include: 
• Ocular symptoms/adverse events 
• VFQ-25 at baseline  
• BCVA will be determined and completed prior to any IOP measurements.   
• CS testing at baseline 
• 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, and clinical 
laboratory evaluations (including hematology, clinical chemistry, and urinalysis)  
For subjects who develop cornea verticillata, safety measures include: 
• VFQ-25 
• BCVA 
• CS testing 
• Cornea verticillata grading 
• Time to cornea verticillata resolution 

 
 
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6.8 Adverse Events Assessments 
6.8.1 
Performing Adverse Event (AE) Assessments 
Qualified study staff responsible for assessing adverse events (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 30 days after the last dose of 
study drug.  
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.  
Documentation of AEs/adverse reactions includes start date and stop date, severity, action(s) 
taken, seriousness and outcome. 
6.8.2 
Adverse Event Definition 
The following definitions of terms apply to this section: 
• Adverse event. Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
• Life-threatening AE or life-threatening suspected adverse reaction (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 serious suspected 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 
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. 

 
 
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• Suspected adverse reaction (SAR) means any AE for which there is a reasonable 
possibility that the drug caused the AE.  For the purposes of 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 adverse event caused by a drug. 
• Unexpected AE or unexpected SAR.  An AE or SAR is considered ‘‘unexpected’’ if it is 
not listed in the Investigator’s Brochure or is not listed at the specificity or severity that 
has been observed.  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: 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. 
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 as well as on the study AE form. 
6.8.3 
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 subject participation in the study has been completed.  
If a subject has 1 or more ongoing AEs at the time of study completion, the subject must be 
followed and provided appropriate medical care until the sign(s) and/or symptoms(s) of the 
AE have remitted or stabilized in the opinion of the Investigator. 
When recording an AE, the following information should be provided on the study AE CRF: 
1. Action Taken with Study Drug: 
• None 

 
 
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• Investigational Product Discontinued 
• Investigational Product Interrupted 
2. Other Action Taken: 
• None 
• Non-Drug Therapy 
• New OTC or Rx Drug Added 
• Hospitalized less than 24 hours 
• Hospitalized greater than or equal to 24 hours 
3. Outcome of an adverse event is coded as: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/Lost to follow-up 
6.8.4 
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 
• 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 

 
 
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mild to severe or from severe to moderate.  In either case, the start and stop dates should be 
recorded.   
Please note: a severe AE is not the same as a serious AE.  Seriousness of an AE (NOT 
severity) serves as a guide for defining regulatory reporting obligations (see Section 6.8.8 for 
further information on serious AEs [SAEs]). 
6.8.5 
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. 
6.8.6 
Expectedness 
The most frequently reported AE for netarsudil ophthalmic solution in two Phase 2 and four 
Phase 3 studies (Clinical Study Reports AR-13324-CS201, AR-13324-CS202, 
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 
control treatment arms in these studies include cornea verticillata, instillation site pain, 
conjunctival hemorrhage, instillation site erythema, corneal staining, blurred vision, 
increased lacrimation, erythema of eyelid, and reduced visual acuity. 

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An AE or SAR is considered “unexpected” if it is not listed in the Investigator’s Brochure or 
is not listed at the specificity or severity that has been observed.  “Unexpected,” as used in 
this definition, also refers to 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 that are both 
unexpected and serious should be reported in an expedited fashion to the Sponsor 
(see Section 6.8.9 for further details). 
6.8.7 
Clinical Laboratory Adverse Events 
Clinical laboratory values (other than pregnancy test results) that are noted as abnormal and 
clinically significant at study exit and that are changes from Visit 1 (Screening) values will 
be documented as AEs. 
6.8.8 
Serious Adverse Events or Serious Suspected Adverse Events 
An Investigator must immediately report any SAE or SSAR (see Section 6.8.2 for 
definitions) to the Sponsor contract research organization (CRO) representative (contact 
information below), whether or not the SAE or SSAR is considered drug-related, including 
those listed in the protocol or Investigator’s Brochure.  The Investigator report must include 
an assessment of whether there is a reasonable possibility that the drug caused the event.  The 
Investigator must report any SAE or SSAR that occurs during the study for a subject or any 
SAE or SSAR that occurs within 4 weeks (i.e., 30 days) after the last administration of study 
medication. Study endpoints that are SAEs (e.g., all-cause mortality) must be reported in 
accordance with Section 6.9.2 of the protocol unless there is evidence suggesting a causal 
relationship between the drug and the event (e.g., death from anaphylaxis).  In that case, the 
Investigator must immediately report the event to the Sponsor CRO representative.  In case 
of incomplete information, the Investigator must provide follow-up information as soon as 
possible, again using the SAE report form.   
In addition, in the case of immediately life-threatening AEs or AEs with fatal outcome, or 
AEs that are serious, unexpected (i.e., not in the Investigator’s Brochure) and judged related 
to the study medication, the Investigator must inform the Sponsor CRO representative by 
phone within 24 hours of notification or occurrence of the SAE. 
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 Sponsor CRO representative.  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.   

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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. 
Following delivery or termination of pregnancy, the pregnancy report form is to be 
completed and submitted by fax or email to the Sponsor CRO representative. 
Pregnancies occurring up to 30 days after the last administration of study drug are to be 
reported.   
Serious adverse events must be reported to the IRB according to the IRB requirements. 
6.8.9 
Serious Unexpected Suspected Adverse Reactions (SUSARs) 
The Investigator must immediately report serious unexpected suspected adverse reactions 
(SUSARs) that occur or are observed during the course of the study or within 4 weeks 
(ie, 30 days) of the last administration of investigational product to a subject. In the event of a 
SUSAR, the site must notify the Sponsor CRO representative by telephone within 24 hours of 
knowledge of the event.  
In addition, an SAE report form must be completed and sent by FAX to CRO Drug Safety within 
24 hours of notification, observation, or occurrence of the SUSAR, whether or not complete 
information is available. In case of incomplete information, the Investigator must provide follow-
up information as soon as possible, using the SAE report form. 
Important: The Investigator must report an SAE, SSAR, or SUSAR occurring at his/her site 
to the Sponsor and IRB, regardless of causality.   
Follow-up of Subjects after Adverse Events 
If an AE/adverse reaction occurs, the Investigator will institute support and/or treatment as 
deemed appropriate. If a serious or non-serious AE/adverse reaction is unresolved at the time 
of the last visit, efforts will be made to follow up until the AE/adverse reaction is resolved or 
stabilized, the subject is lost to follow-up, or there is other resolution to the event. 
6.9 
Vital Signs 
The Investigator or designee will measure heart rate, pulse, and blood pressure as described 
in the MOPs. 
6.10 
Clinical Laboratory Tests 
6.10.1 
Laboratory Parameters 
A chemistry panel, complete blood count (hematology and differential), and urinalysis will 
be performed as shown. 
Note that fasting will NOT be required and specific values may be out of the typical fasting 
range. 

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The clinical laboratory results must be reviewed by the Investigator prior to subject 
enrollment, and the tests CANNOT be indicative of any clinically significant disease in the 
opinion of the Investigator.  
6.10.2 
Sample Collection, Storage and Shipping  
The site staff responsible for collecting the laboratory samples will be identified on the 
Delegation of Responsibilities Log. Details for the preparation and shipment of samples and 
reference ranges will be provided in the laboratory manual 
6.10.3 
Pregnancy testing (for women of child bearing 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. 
6.11 
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. 
6.12 
National Eye Institute Visual Function Questionnaire (VFQ-25) 
The VFQ-25 is a reliable and valid 25-item version of the 51-item National Eye Institute 
Visual Function Questionnaire that measures subjective assessment of patient-reported 
vision-targeted health status elements that are most important to people with eye disease.  All 
subjects will undergo VFQ-25 at Visit 3. Subjects noted to have cornea verticillata will 
undergo additional VFQ-25 throughout the study.  A Japanese version of the VFQ-25 will be 
used, the responses will be documented, and a score assigned. See MOPs for additional 
details. 

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6.13 
Contrast Sensitivity Testing  
Contrast sensitivity charts will be used to assess visual function. All subjects will have a CS 
testing at Visit 3. Subjects noted to have cornea verticillata will undergo CS testing during 
the study. See MOPs for additional details. 
6.14 
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. 
6.14.1 
Corneal Deposit Grading under Biomicroscopy  
Subjects who are diagnosed with cornea verticillata by slit lamp examination will undergo 
grading of the corneal deposits using a published grading scale for amiodarone-induced 
cornea verticillata (Orlando 1984). See the MOPs for the details of this grading scale. 
6.15 
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. 
6.16 
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). SITA Standard is preferred, SITA fast 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 gaze track and blind spot should be turned on for all visual fields 
assessments in order to calculate the fixation losses. See MOPs for further information.  
6.17 
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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6.18 
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. 
6.19 
Study Eye Selection Process 
Subjects must qualify in both eyes based upon IOP, ocular history and exam; 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. 
6.20 
Removal of Subjects from the Study or Study Treatment 
6.20.1 
Completed Subject 
A completed subject is defined as one who completes all 28 days of planned dosing and 
completion of the post-treatment follow-up visit procedures. For the subgroup of subjects 
who develop cornea verticillata, a completed subject is defined as one who completes all 
observational visits until resolution or stabilization of the cornea verticillata. 
6.20.2 
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: 

 
 
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• 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). 
• 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 
6.20.3 
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 
or until clinically meaningful abnormal laboratory findings have returned to acceptable or 
pre-study limits.  
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. 
For subjects who discontinue study medication due to cornea verticillata, subjects will 
complete Exit Visit (Visit 6) procedures and will be followed in an observational period until 
resolution/stabilization of the cornea verticillata. Subjects will not be treated with any 
investigational product during this observational period. They may, however, continue 
treatment with IOP-lowering agents or other topical ocular medications (Rx or OTC) as 
recommended by their eye care provider/practitioner. 

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6.20.4 
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. 
6.20.5 
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. 
6.21 
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 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?” 
Blood samples will be taken for clinical chemistry and hematology, and a urine sample will 
be taken for urinalysis. The results of blood work and urinalysis should be reviewed after this 
study visit in order to determine eligibility of the subject prior to undertaking the examination 
at Visit 2 (Qualification Visit #1).  

 
 
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For subjects who are unable or unwilling to have blood drawn and urine collected for clinical 
labs at Visit 1 (Screening), the blood and urine sample may be drawn at Visit 2 (Qualification 
Visit #1) so long as the results of the clinical labs are available and reviewed for eligibility 
for that subject prior to Visit 3 (Qualification Visit #2). 
The Investigator will evaluate the results of these examinations for possible enrollment of the 
individual into the study. 
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. Results of the 
clinical laboratory tests from Visit 1 need to be available and reviewed by the Investigator. 
For subjects who were unable or unwilling to have blood drawn and urine collected for the 
clinical labs at Visit 1, the blood and urine sample may be drawn at Visit 2 (Qualification 
Visit #1) so long as the results of the clinical labs are available for that subject prior to Visit 3 
(Qualification Visit #2). 
The following procedures will be performed: 
• Heart rate and blood pressure 

 
 
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• 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 OAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in both eyes. For further evaluation of OHT eyes 
in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg and 
< 35 mmHg in both eyes. This is the first of the four qualifying IOPs for randomization.   
Individuals who do NOT meet the IOP requirements above 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 results of the clinical laboratory tests from Visit 1 or Visit 2 (if not performed at Visit 1) 
need to be available and reviewed by the Investigator. In order for the individual to be 
enrolled, the tests CANNOT be indicative of any clinically significant disease in the opinion 
of the Investigator.  
The subject will be questioned regarding any changes in their health or concomitant 
medication use.  Any change in the individual’s health 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?” 

 
 
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• VFQ-25 
• BCVA 
• CS testing  
• 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 OAG eyes in the study, at this time, unmedicated (post washout) 
IOP must be ≥ 15 mmHg and < 35 mmHg in both eyes. For further evaluation of OHT eyes 
in the study, at this time, unmedicated (post washout) IOP must be ≥ 22 mmHg and 
< 35 mmHg in both eyes. 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 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’ 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 OAG 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.   

 
 
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Qualified individuals will continue with the qualification visit.  Individuals who do NOT 
meet this requirement 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: 
• 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 OAG 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 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 both eyes based upon IOP and ocular 
history for a subject who qualifies; the study eye will be the eye with the higher IOP at 
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. 

 
 
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Subjects will be: 
• Instructed to administer their masked medication OU at home between 
20:00 - 22:00 hours beginning with the first dose on the evening of this study visit 
• Instructed to return to the office with their study medication on Week 1 (Day 8) 
For post randomization assessments, a window of ± 2 days for Visit 4 is permitted, and a 
window of ± 3 days for Visits 5 and 6 is permitted. 
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. 
After randomization, any new or worsening of symptoms 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 between 11:00 to 11:30 hours. 
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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7.3.6 
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?” 
• Recording of any AEs. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured between 15:30 and 16:30 hours. 
Subjects will be: 
• Instructed to continue to administer their study medication at home between 
20:00 - 22:00 hours (taking the daily evening dose on that day) 
• Instructed to return to the office with their used study medication on Week 2 (Day 15) 
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. 
Any new or worsening of symptoms beyond those collected at baseline 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. 
7.3.8 
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?” 

 
 
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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 between 11:00 to 11:30 hours. 
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 between 15:30 and 16:30 hours. 
Subjects will be: 
• Instructed to continue to administer their masked medication at home between 
20:00 - 22:00 hours (taking the daily evening dose on that day) 
• Instructed to return to the office with their study medication on Week 4 (Day 29) 
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: 
• 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 child bearing potential may 
be performed at any time point throughout Visit 6) 
• Blood samples will be taken for clinical chemistry and hematology, and a urine sample 
will be taken for urinalysis (samples may be taken at any time point throughout Visit 6) 
• BCVA 

 
 
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• 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 site staff and returned to the 
Sponsor’s designee for destruction.  
Any new or worsening of symptoms beyond those collected at baseline 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 between 11:00 and 11:30 hours.  
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 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured between 15:30 and 16:30 hours. 
• 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 Observational Period 
Subjects will undergo the following visits until resolution/stabilization of the cornea 
verticillata. Resolution of the cornea verticillata will occur when a subject has a cornea 
verticillata grading of zero in both eyes. Stabilization is defined as no worsening of the 

 
 
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cornea verticillata grading for a minimum of one year from the commencement of dosing. 
The duration of the observational period will vary from subject to subject.  
7.4.1 
OBS Visit 1 (any visit between Visits 4 to 6 when cornea verticillata is 
detected) 
Subjects will discontinue study medication and undergo the following assessments: 
• Completion of Visit 6 procedures (Exit Visit) 
• Concomitant medication use 
• VFQ-25 
• BCVA 
• CS testing 
• Cornea verticillata grading 
7.4.2 
OBS Visits 2, 3 and 4 (3 monthly visits 1 month (30 ± 5 days) from prior OBS 
Visit) 
At each monthly visit, the subject should be questioned regarding any changes in their health 
or concomitant medication use.  The following procedures will be performed:  
• BCVA   
• Cornea verticillata grading  
If cornea verticillata grading is higher than zero at this Month 1 Visit, the subject will return 
for a Second and/or Third Monthly Visit at which the procedures and assessments done at the 
first Monthly Visit will be repeated.   
7.4.3 
Subsequent bimonthly visits (60 days +/- 5 days from prior OBS Visit) 
 
If at the Third Monthly Visit (OBS Visit 4) the subject has a cornea verticillata grading 
higher than zero, the subject will return for bimonthly (60 days +/- 5 days) visits until 
resolution or stabilization.  
 
At each visit, subject will be questioned regarding any changes in their health or concomitant 
medication use.  The following procedures will be performed:  
• BCVA   
• Cornea verticillata grading   

 
 
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7.4.4 
Final Study Visit Procedures  
Upon resolution or stabilization of cornea verticillata at any OBS Visit, subjects will be 
questioned regarding any changes in their health or concomitant medication use. The 
following procedures will be performed and the subject will exit the study:  
• VFQ-25  
• BCVA 
• CS testing 
• Cornea verticillata grading 
7.5 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 
All continuous study assessments will be summarized by treatment and time point 
(as applicable) using descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum).  All categorical study assessments will be summarized by treatment and time 
point (as applicable) using frequency counts and percentages.   
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 
0.05 significance level.  When applicable, two-sided 95% confidence intervals will be 
reported.  All p-values will be displayed to four decimal places, with p-values less than 
0.0001 presented as 
'<0.0001
' and p-values greater than 0.9999 presented as ‘>0.9999’.  
Differences between netarsudil (0.01%, 0.02% or 0.04%) and placebo will be calculated as 
netarsudil – placebo.   
All study data will be listed by treatment, subject, 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 
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. 
The unit of analysis for efficacy will be the study eye.  For a subject who qualifies, the study 
eye will be the eye with the higher IOP at 09:00 hours on Visit 3.0. If both eyes have the 
same IOP at 09:00 hours on Visit 3.0, then the right eye will be the study eye. 
Statistical methods will be more fully described in separate document(s) (i.e., the Statistical 
Analysis Plan). 
9.2 
Determination of Sample Size 
Assuming a 2-sided test with alpha = 0.05, a common standard deviation (SD) of 3.5 mmHg 
at each time point yielding a common SD of 3.0 for the diurnal mean, and a correlation 
among time points of 0.60, 49 ITT subjects per arm yields at least 90% power to demonstrate 
superiority of netarsudil (0.01%, 0.02% or 0.04%) to placebo in mean diurnal study eye IOP 
(average of 09:00, 11:00, and 16:00 hours) at the Week 4 visit assuming a difference of at 
least 2.0 mmHg in the mean diurnal IOP. The study will be considered a success and 
superiority of netarsudil to placebo will be concluded if the two-sided p-value ≤ 0.05 at 
Week 4.  Accounting for approximately a 5% discontinuation rate, 52 subjects per arm (208 
total) will be enrolled. 
9.3 
Analysis Populations 
9.3.1 
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. 
9.3.2 
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. 

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9.3.3 
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. 
9.3.4 
Cornea Verticillata Safety Population 
The cornea verticillata safety population will include all subjects in the safety population 
who develop cornea verticillata during the study.  This population will be used to summarize 
safety variables within the observational period and will summarize subjects as treated. 
9.4 
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. 
9.5 
Primary Efficacy 
9.5.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint will be the comparison of netarsudil ophthalmic 
solution (0.01%, 0.02% or 0.04%) relative to its placebo for mean diurnal IOP within a 
treatment group at Week 4 (Day 29) by Goldmann Applanation Tonometry. 
9.5.2 
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 multiple 
imputation techniques used to impute missing data.  The least squares mean differences 
(netarsudil – placebo) will be presented separately for netarsudil 0.01%, 0.02% and 0.04% as 
well as 2-sided p-values and 95% confidence intervals (CIs). Inference will be made on the 
2-sided p values. Superiority for a concentration (0.01%, 0.02% and 0.04%) will be 
concluded if the 2-sided p-value, for testing the difference (netarsudil – placebo) to 0, ≤ 0.05 
and the point estimate of the difference < 0 at Week 4 for that concentration. 
There will be no adjustment for the multiplicity of the 3 active concentrations (0.01%, 
0.02% and 0.04%) tested against placebo in this Phase 2 study. 
Analyses will be performed primarily on the ITT population using multiple imputation 
techniques to impute missing data.  Sample SAS code to demonstrate the methodology that 
will be used for data imputation can be found in Appendix 6. 

 
 
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9.6 Secondary Efficacy 
9.6.1 
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  
• 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. 
9.6.2 
Secondary Efficacy Analyses 
Secondary analyses of the primary efficacy endpoint include repeating the primary analysis 
strategy using: observed data only, and last observation carried forward (LOCF) where 
LOCF will be performed using time-relevant measures. 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 (0.01%, 0.02% or 
0.04%) versus placebo 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.  

 
 
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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 
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 (0.01%, 0.02% or 0.04%) and placebo, at each time point and visit, 
including two-sample t-tests and 95% t-distribution confidence intervals on the difference 
(netarsudil - placebo).   
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 
baseline diurnal 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. 
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 ≥ 4 to_≥ 12 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 ≤ 22 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 (0.01, 0.02% or 0.04%) versus placebo for each 
category at each visit.  These analyses will be presented for both the ITT and PP populations 
with observed data only. 
9.7 Safety  
9.7.1 
Safety Endpoints 
Treatment Period: 
• Ocular symptoms/adverse events 

 
 
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• VFQ-25 at baseline 
• BCVA 
• CS testing at baseline 
• 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, and clinical 
laboratory evaluations (including hematology, clinical chemistry, and urinalysis)  
• Pregnancy testing (for women of child bearing potential) 
Observational Period:  
In all subjects who are noted to have cornea verticillata at the initial visit of this observational 
period:  
• VFQ-25 
• BCVA 
• CS testing 
• Cornea verticillata grading 
• Time to cornea verticillata resolution/stabilization  
9.7.2 
Safety Analyses 
Treatment Period 
Verbatim descriptions of AEs will be mapped to MedDRA thesaurus terms and be presented 
in a data listing.  Treatment emergent AEs, those that occur after the first dose of study 
medication, will be summarized by treatment group using 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 AEs.  These summaries will also be presented 
for relation to Investigational Product and by severity.  Fisher’s exact test will be used to test 
the difference in proportions of subjects with each AE between treatment groups netarsudil 
(0.01%, 0.02% or 0.04%) vs placebo.   

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Visual acuity data will be summarized at each time point using both continuous summaries 
including change from baseline, and discrete summaries, including change from baseline on 
an ETDRS chart (or equivalent) in the number of letters and the proportion of subjects with a 
worsening of ≥ 15 letters from baseline.   
Slit lamp biomicroscopy and dilated ophthalmoscopy measures will be summarized at each 
measured 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). 
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. 
Clinical laboratory results will be summarized using both continuous summaries, including 
change from baseline, and discrete summaries, including frequency and percent of subjects 
with an abnormal value and shift tables from baseline.  Additionally, laboratory data will be 
presented in data listings.  A copy of the certification and a table of the normal ranges for the 
reference laboratory conducting any clinical laboratory tests required by this protocol must 
be provided. 
Observational Period 
In subjects who develop cornea verticillata, CS and BCVA will be summarized at the eye 
level (that is, if a subject has a cornea verticillata in both eyes, then both eyes will be 
included) for the initial assessments and for follow-up visits as well as change from the initial 
assessment (for visual acuity, change from baseline, as defined for the Treatment Period will 
also be completed), by treatment group and by whether or not the cornea verticillata deposit 
event is ongoing at given visit. The VFQ-25 scores will be summarized similarly at the 
subject level. 
Resolution of cornea verticillata is defined as a cornea verticillata deposit grade of zero. 
Stabilization is defined as no worsening of the cornea verticillata grading for a minimum of 
one year from the commencement of dosing. The time to cornea verticillata 
resolution/stabilization will be evaluated in days related to start date of cornea verticillata at 
the eye level.  Kaplan-Meier methods will be used to estimate median time to cornea 
verticillata resolution/stabilization, as well as the 25th and 75th percentiles by treatment 
group and overall netarsudil treated subjects. Associated 95% confidence interval will also be 
estimated.  Kaplan-Meier curves will also be presented by treatment group and overall 
netarsudil treated subjects. 
9.8 
Other Assessments or Analyses 
Other assessments or analyses will be described in the statistical analysis plan as appropriate. 

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9.9 
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 

 
 
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subject’s parent or 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 
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 investigational products, 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 
relationship between control of intraocular pressure and visual field deterioration. Am 
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. 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. 
5. Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin 
Ophthalmol. 2004 Dec;15(6):541-8. 
6. Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-masked 
study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution 
compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed 
concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma 
2005; 14:392-9. 
7. Ingram DV, Jaggarao NS, Chamberlain DA. Ocular changes resulting from therapy 
with amiodarone. Br J Ophthalmol. 1982 Oct;66(10):676-9. 
8. 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. 
9. Kass MA, Gordon MO, Gao F, et al.  Delaying Treatment of Ocular Hypertension: The 
Ocular Hypertension Treatment Study. Arch Ophthalmol 2010; 128:276-87. 
10. 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. 
11. Kopczynski CC and Epstein DL.  Emerging Trabecular Outflow Drugs.  J Ocul 
Pharmacol Ther 2014; 30:85-7. 
12. Mäntyjärvi M, Tuppurainen K, Ikäheimo K. Ocular side effects of amiodarone. Surv 
Ophthalmol. 1998 Jan-Feb;42(4):360-6. 

 
 
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13. Orlando RG, Dangel ME, Schaal SF. Clinical experience and grading of amiodarone 
keratopathy. Ophthalmology. 1984 Oct;91(10):1184-7. 
14. Raizman MB, Hamrah P, Holland EJ. Drug-induced corneal epithelial changes. Surv 
Ophthalmol. 2017 May - Jun;62(3):286-301. 
15. Rhopressa® (netarsudil ophthalmic solution) 0.02% [package insert]. Irvine CA: Aerie 
Pharmaceuticals, Inc.; 12/2017 
16. 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. 
17. Siddoway LA. Amiodarone: guidelines for use and monitoring. Am Fam Physician. 2003 
Dec 1;68(11):2189-96. 
18. 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. 
19. Stewart WC, Holmes KT, Johnson MA. Washout periods for brimonidine 0.2% and 
latanoprost 0.05%. Am J Ophthalmol. 2001;798-9. 
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. Aerie Pharmaceuticals, Inc., AR-13324 and PG324 Investigator’s Brochure. 
2. AR-13324-CS101 Clinical Study Report: An Open-Label Study Assessing the Ocular and 
Systemic Safety and Systemic Absorption of AR-13324 Ophthalmic Solution 0.02% in 
Healthy Volunteers (2014). 
3. AR-13324-CS102 Clinical Study Report: A double-masked, randomized, paired-
comparison, controlled study of the aqueous humor dynamics of AR-13324 Ophthalmic 
Solution 0.02% in healthy volunteers (2015). 
4. AR-13324-CS104: A prospective, double-masked, randomized, multicenter, placebo 
controlled, parallel-group study assessing the safety of two concentrations of netarsudil 
ophthalmic solution in healthy Japanese/Japanese American volunteers in the United 
States (2018). 

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5. AR-13324-CS201 Clinical Study Report: A Phase 2, double-masked, randomized, 
placebo-controlled, dose-response study assessing the safety and ocular hypotensive 
efficacy of three doses of AR-13324 Ophthalmic Solution in patients with elevated 
intraocular pressure (2012). 
6. AR-13324-CS202 Clinical Study Report: A phase 2, double-masked, randomized, 
multi-center, active-controlled, dose-response parallel-group study comparing the safety 
and ocular hypotensive efficacy of AR-13324 to latanoprost in patients with elevated 
intraocular pressure (2013). 
7. AR-13324-CS301 Clinical Study Report: A double-masked, randomized, multi-center, 
active-controlled, parallel, 3-month study assessing the safety and ocular hypotensive 
efficacy of AR-13324 Ophthalmic Solution, 0.02% compared to timolol maleate 
ophthalmic solution, 0.5% in patients with elevated intraocular pressure (2016). 
8. AR-13324-CS302 Clinical Study Report: A double-masked, randomized, multi-center, 
active-controlled, parallel, 12-month study assessing the safety and ocular hypotensive 
efficacy of AR 13324 Ophthalmic Solution, 0.02% compared to timolol maleate 
ophthalmic solution, 0.5% in patients with elevated intraocular pressure (2016). 
9. AR-13324-CS303 Clinical Study Report: A double-masked, randomized, multi-center, 
active-controlled, parallel group, 12-month study assessing the safety of AR-13324 
Ophthalmic Solution, 0.02% QD and BID compared to Timolol Maleate Ophthalmic 
Solution, 0.5% BID in patients with elevated intraocular pressure. Rho Kinase Elevated 
Intraocular Pressure Treatment Trial (ROCKET 3) (2018). 
10. AR-13324-CS304 Clinical Study Report: A double-masked, randomized, multi-center, 
active-controlled, parallel group, 6-month study with a 3-month interim analysis 
assessing the ocular hypotensive efficacy and safety of AR-13324 Ophthalmic Solution, 
0.02% QD compared to Timolol Maleate Ophthalmic Solution, 0.5% BID in patients 
with elevated intraocular pressure. Rho Kinase Elevated Intraocular Pressure Treatment 
Trial (ROCKET 4) (2017). 
11. AR-13324-OBS01 Clinical Study Report: A prospective, targeted, non-interventional 
(observational) study of subjects who developed corneal deposits in clinical trials AR-
13324-CS301 and AR-13324-CS302 (2017) 
 

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Appendix 1 Schedule of Visits and Procedures  
Treatment Period 
 
 
 
Post Day 1 Treatment 
Day (D)/Week (W) 
Screening Qual. #1 
Qual. #2 (Day 1) 
W1 (Day 8±2) 
W2 (Day 15±3) 
W41 (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 
 
 
 
 
 
 
 
 
 
Washout2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HR/BP 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Urine Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Clinical Labs (Chem/Hem/UA) 
X4 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Symptoms/AEs5 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X  
X 
X 
X 
NEI VFQ-25 Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BCVA  
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Contrast Sensitivity 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IOP 
X 
X6 
X6 
X6  
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy7 / Pachymetry8 
G/P 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual Field9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Eye-Drop Instillation Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medications Dispensed 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Medications Collected 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
Study Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Abbreviations:   HR/BP = heart rate/blood pressure; Chem/Hem/UA = Chemistry/Hematology/Urinalysis; AE = adverse event; IOP = Intraocular pressure. 
Early Discontinuation: Visit 6.0 procedures are to be completed plus a dilated ophthalmoscopy examination. 
Visit Requirements:+  IOP measurements will be 09:00 (+30 mins), 11:00 (+30 mins) and 16:00 (±30 mins) hours with the exception of the Visit 1 
(Screening). 
1. If subjects develop cornea verticillata at visit 4 or visit 5, study procedures for visit 6 (Exit Visit) will be completed before entering into the 
observational period 
2. Subjects currently using ocular hypotensive medications must undergo a minimum washout period (see Section 5.7.1). 
3. Urine pregnancy test for women of childbearing potential is required.  
4. For subjects who are unable or unwilling to have blood drawn and urine collected for clinical labs at Visit 1 (Screening), the blood and urine sample 
may be drawn at Visit 2 (Qualification Visit #1) so long as the results of the clinical labs are available for that subject prior to Visit 3 (Qualification 
Visit #2). 
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. Individuals returning at an Unscheduled Visit within 1 week to re-attempt IOP qualification are required to only re-measure IOP in both eyes. 
7. Gonioscopy evaluation up to 3 months prior to randomization is acceptable. 
8. Pachymetry within 1 week prior to screening is acceptable. 
9. Entry visual field evaluation up to 3 months prior to randomization is acceptable. Visual field collection must meet the requirement for automated 
threshold visual field assessment (e.g., 30-2 or 24-2 Humphrey) and reliability. 
10. Collect kit(s) dispensed during the Day 1 visit. 

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Observational Period 
Study Procedures 
OBS Visit 1 
(Day 1) 
Visit when cornea 
verticillata is diagnosed 
OBS Visits 2-4 Monthly 
Visit x3 
(30 ± 5 days if Cornea 
Verticillata Persist) 
OBS Visit 5 and up 
Bi-monthly Visits after 
3rd Monthly visit (60 ± 5 
days if Cornea 
Verticillata Persist) 
Final Visit if 
Resolution/ 
Stabilization 
of Cornea 
Verticillata 1,2 is 
confirmed 
Discontinuation of IP 
X 
 
 
 
Conmed Review 
X 
X 
X 
X 
Symptoms/ 
Assessment of Ocular 
and General Health 
X 
X 
X 
X 
VFQ-25  
X 
 
 
X 
Best Corrected Visual 
Acuity  
X 
X 
X 
X 
Contrast Sensitivity 
X 
 
 
X 
Cornea Verticillata 
Grading 
X 
X 
X 
X 
1.  Should have a grading score of zero OU or stabilization confirmed to exit the study. 
2.   If cornea verticillata grading is zero at any visit, or stabilization of cornea verticillata is confirmed, the subject 
completes outlined procedures listed in Final Visit and exits the study. 
 

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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 investigational product 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 6.8, 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: 
A. 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 6.8, Adverse Events 
Assessments). The Investigator must also notify the Sponsor Representative and the IRB 
to which he/she is responsible. 
B. 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 
C. Cooperate with the Sponsor on the preparation of documents in which financial interests 
and arrangements of clinical investigators are disclosed 
D. Obtain and submit to the Sponsor a copy of his/her IRB approval of the protocol prior to 
initiating the study. 
E. Obtain signed informed consent from each subject or his/her legal guardian prior to 
acceptance of the subject into the study. 
F. 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. 
G. Accurately record, at the Investigator’s site, all required data on each subject's CRF. 
H. 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. 

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I. 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. 
J. 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. 
K. Provide the governing IRB with a brief (i.e., 1 to 3 pages) Investigator's summary within 
90 working days of the study completion. 
L. Complete the study within the time limits agreed upon with the Sponsor prior to the 
initiation of the study. 
M. 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 

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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. 
 
 

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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 
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 6 Sample SAS Code 
The following SAS code will be used for multiple imputations using the Monte-Carlo 
Markov Chain method, where a separate model will be fit for each time point at each visit. 
proc mi data = indata seed = 6876 out = outdata1; 
mcmc initial = em; 
var trt01pn baseline IOP; 
run; 
where 
- 
indata is the name of the input dataset 
- 
outdata1 is the name of the output dataset 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
baseline captures the baseline IOP for the given time point 
- 
IOP is the name of the IOP measure. 
Thirty complete data sets will be generated from the above code. Each complete data set will 
be used to analyze this primary efficacy endpoint separately using analysis of variance. Then, 
the SAS procedure MIANALYZE will be used to analyze the results from the 30 complete 
data sets to generate a combined inference. The following SAS code will be used: 
ods output diffs = outdata2; 
proc mixed data= outdata1; 
 
by _IMPUTATION_; 
 
class trt01pn; 
 
model IOP = trt01pn baseline; 
 
lsmeans trt01pn / cl pdiff; 
run; 
proc sort data= outdata2; 
 
by trt01pn _trt01pn; 

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run; 
ods output ParameterEstimates = outdata3; 
proc mianalyze data= outdata2 alpha = 0.05; 
 
by trt01pn _trt01pn; 
 
class trt01pn _trt01pn; 
 
modeleffects estimate; 
 
stderr;  
run; 
where 
- 
outdata1 is the name of the input dataset from Proc MI 
- 
_IMPUTATION_ is the imputation number 
- 
trt01pn is the name of the treatment group variable in numeric format 
- 
IOP is the name of the IOP measure 
- 
baseline captures the baseline IOP for the given time point 
- 
outdata2 is the name of the output dataset that contains the statistical results of the 
difference between treatment groups  
- 
outdata3 is the name of the output dataset that contains summary and inferential 
statistics.