Clinical trial NCT03233308
Conditions: Primary Open Angle Glaucoma or Ocular Hypertension
Keywords: Aqueous Humor Dynamics Trabecular Outflow Netarsudil
Sponsor: Aerie Pharmaceuticals
Start date: 2017-10-20; Completion date: 2018-04-19
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the effect on trabecular outflow facility of Netarsudil ophthalmic solution 0.02% compared to placebo

Detailed description:
Trabecular outflow facility is a measure of aqueous humor dynamics; effect of netarsudil on this parameter as well as on intraocular pressure and episcleral venous pressure was evaluated in this study. Netarsudil treatment was given in one eye and placebo given in contralateral eye for 7 consecutive days.

Arms: arm 1: Netarsudil Ophthalmic Solution 0.02% was administered in one eye and Placebo comparator in contralateral eye arm 2: Placebo comparator administered in one eye and Netarsudil Ophthalmic Solution 0.02% in contralateral eye
Interventions: intervention 1: Netarsudil Ophthalmic Solution 0.02% intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: 1 drop daily (QD), in the morning (AM) Netarsudil Ophthalmic Solution 0.02% administered to one eye and Placebo comparator to the contralateral eye intervention 2: 1 drop daily (QD), in the morning (AM) of Placebo comparator administered to one eye and Netarsudil Ophthalmic Solution 0.02% to the contralateral eye

Protocol documents:
Prot_000.pdf: 
 
 
 
 A Double-Masked, Randomized, Placebo- 
Controlled Study of Trabecular Outflow 
Facility Following Treatment with Netarsudil 
Ophthalmic Solution 0.02% (AR-13324) in 
Subjects with Elevated Intraocular Pressure 
 
 
 
NCT03233308 
 
16August2017 
 


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Clinical Study Protocol:  
Study Title: 
AR-13324-CS206: A Double-Masked, Randomized, Placebo-
Controlled Study of Trabecular Outflow Facility Following Treatment 
with Netarsudil Ophthalmic Solution 0.02% (AR-13324) in Subjects 
with Elevated Intraocular Pressure 
Study Number: 
AR-13324-CS206 
Study Phase: 
2 
Product Name: 
Netarsudil (AR-13324) 0.02% ophthalmic solution  
Indication: 
Elevated intraocular pressure 
Investigators: 
Multi-center 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Sponsor Contact: 
135 US Highway 206, Suite 15 
Bedminster, NJ 07921 
(908) 470-4320
Medical Monitor: 
 
Date 
Original Protocol (Rev 0): 
10 May 2017 
Amendment 1 (Rev 1): 
16 August 2017 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals®, Inc.’s (Aerie) information that is 
confidential, a trade secret and/or proprietary in nature.  It is loaned to you for your 
confidential use on behalf of Aerie and is not to be photocopied, disclosed or transmitted to 
any other person or party who is not covered by a Confidential Disclosure Agreement with 
Aerie.  As the Principal Investigator you are responsible for the safekeeping and return of this 
document to Aerie upon request.  You will be sent updated information and/or amendments 
as they become available. 












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SYNOPSIS 
Sponsor: 
Aerie Pharmaceuticals, Inc. 
Name of Finished Product: 
Netarsudil Ophthalmic Solution 0.02% 
Name of Active Ingredients: 
Netarsudil mesylate (AR-13324) 
Study Title: 
A Double-Masked, Randomized, Placebo-Controlled Study of Trabecular Outflow Facility Following 
Treatment with Netarsudil Ophthalmic Solution 0.02% (AR-13324) in Subjects with Elevated Intraocular 
Pressure 
Study Number: 
AR-13324-CS206 
Study Phase: 
2 
Primary Objective: 
To evaluate the effect on trabecular outflow facility of netarsudil ophthalmic solution 0.02% compared to 
placebo 
Secondary Objective(s): 
To evaluate the effect on intraocular pressure (IOP) and episcleral venous pressure (EVP) of netarsudil 
ophthalmic solution 0.02% compared to placebo 
To evaluate the ocular and systemic safety of netarsudil ophthalmic solution 0.02% 
Study Design: 
This will be a double-masked, placebo-controlled, paired-comparison study conducted at approximately 2 
centers in the US to evaluate the effect of treatment with netarsudil ophthalmic solution 0.02% (netarsudil) on 
trabecular outflow facility.  Netarsudil will be administered to one eye and Placebo to the contralateral eye once 
daily, 1 drop in the morning (QD, AM), in adult subjects at least 18 years of age with primary open angle 
glaucoma (POAG) or ocular hypertension (OHT).  Study medication will be administered for 7 consecutive 
days, although the total time of subject participation in the study (including washout from prior treatment, if 
necessary) may be up to 7 weeks.  
Subjects will be eligible to enroll in the study if they have a current diagnosis of POAG or OHT in both eyes 
(POAG in one eye and OHT in the contralateral eye is also acceptable), and may be treatment-naïve or taking 
topical ocular hypotensive medication. If necessary, subjects who agree to participate in the study will be 
required to washout from their current IOP-lowering treatment for a minimum specified period of time (5 days 
to at least 4 weeks), according to the type of treatment. Subjects will attend a total of 3 study visits: a screening 
visit (Visit 1), to be conducted up to 6 weeks prior to a qualification visit (Visit 2, Day 1, baseline), and a final 
visit after 6 days on-treatment (Visit 3, Day 8, exit) where a member of the site staff will administer their 7th 
dose after completing their 08:00 hour assessments.  
Both eyes must qualify for the study with an unmedicated (post-washout or treatment-naïve) IOP of >20 mmHg 
but <30 mmHg at 08:00 hours and >17 mmHg but <30 mmHg at 13:00 and 16:00 hours at the qualification 
visit. In order to be randomized into the study, eligible subjects must meet all of the inclusion, and none of the 
exclusion criteria at both the screening and at the qualification visit, following washout from their current ocular 
hypotensive treatment, if required. 
If the subject continues to be eligible, they will be randomized at the end of their qualification visit (Visit 2, 
Day 1, baseline) to receive netarsudil ophthalmic solution 0.02% in one eye and placebo in the contralateral eye 
for 7 days, QD (AM). Subjects will be randomized as to which eye will receive netarsudil ophthalmic solution 


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0.02% and which eye will receive netarsudil ophthalmic solution placebo.  Subjects will be asked to begin self-
administration of their assigned medications in the morning on Day 2 following their baseline (Day 1) visit.  
Subjects will be instructed to administer 1 drop from each bottle of their study medication into the assigned eye 
for that bottle, every morning at approximately the same time (between 08:00 and 10:00 hours) for 6 
consecutive days. On the day of the final (exit) visit (Visit 3, Day 8), subjects will return to the site at 08:00 
hours for their final dose of study medication and to complete their on-treatment measurements before exiting. 
Safety measures (including visual acuity, biomicroscopy, and adverse events) will be evaluated at all visits.  
Efficacy assessments will include IOP at 08:00, 13:00 and 16:00 hours, and trabecular (tonographic) outflow 
facility and EVP, which will be measured at 13:00 and 16:00 hours. Tonographic outflow facility (primary 
endpoint) and IOP (secondary endpoint) will be collected in all subjects. The other secondary endpoint, EVP, 
will be measured in a subset of subjects. 
Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria  
Subjects have to meet all of the following criteria at screening and qualification visits to enter into the study: 
1. Must be 18 years of age or older 
2. Diagnosis of POAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is acceptable) 
3. Unmedicated (post-washout, or treatment-naive) IOP >20 mmHg and <30 mmHg in both eyes at 08:00 
hours, and >17 mmHg but <30 mmHg at 13:00 and 16:00 hours at the qualification (Day 1, baseline) visit 
4. Corrected visual acuity in each eye +1.0 on the logarithm of minimum angle of resolution (logMAR) scale 
or better by early treatment diabetic retinopathy study (ETDRS) chart or its equivalent in each eye 
(equivalent to 20/200 or better Snellen visual acuity in each eye) 
5. Be able and willing to provide signed informed consent and follow study instructions 
Key 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 (eg, corneal edema, uveitis, severe keratoconjunctivitis sicca) which 
might interfere with interpretation of the study efficacy endpoints or with safety assessments, including 
subjects with glaucomatous damage so severe that washout of ocular hypotensive medications for one 
month is not judged to be safe by the Investigator  
2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure glaucoma, or 
narrow angles (as assessed by the Investigator, e.g. Grade 2 or less, Shaffer Scale). Note: Previous laser 
peripheral iridotomy is NOT acceptable 
3. Intraocular pressure ≥30 mmHg (unmedicated) in either eye (individuals who are excluded for this criterion 
are not allowed to attempt requalification) 
4. A difference in IOP between eyes >4 mmHg (unmedicated) at any baseline time point 
5. Use of more than two ocular hypotensive medications within 30 days of screening.  Note: fixed dose 
combination medications, for the purpose of this exclusion criterion, count as two medications 
6. Known hypersensitivity to any component of the formulation (e.g., benzalkonium chloride, etc.), or to 
topical anesthetic. 
7. Previous glaucoma intraocular surgery or glaucoma laser procedures in either eye  
8. Keratorefractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, corneal cross-linking, etc.)  
9. Report of ocular trauma in either eye within the six months prior to screening, or ocular surgery or non-
refractive laser treatment within the three months prior to screening 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current evidence of clinically 
significant blepharitis, conjunctivitis, or a history of herpes simplex or zoster keratitis in either eye at 


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screening.  
11. Use of ocular medication in either eye of any kind within 30 days of screening, 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), or c) lubricating drops for dry eye (which may 
be used throughout the study) 
12. Mean central corneal thickness greater than 620 μm in either eye at screening 
13. Any abnormality preventing reliable applanation tonometry of either eye (e.g., keratoconus, etc.) 
14. Lack of suitable episcleral vein prior to performing EVP measurement at Visit 2/Day 1 (applicable to 1 site 
only [
 
Systemic: 
15. Clinically significant abnormalities (as determined by the Investigator) in any recent (within 6 weeks prior 
to screening) laboratory tests which may affect the study results. Laboratory assessments, other than 
pregnancy tests in females of child-bearing potential and vital signs, will not be conducted for this study 
16. Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, hepatic, renal, 
endocrine or cardiovascular disorders) which might interfere with the study 
17. Participation in any investigational (interventional) study within 60 days prior to screening  
18. Changes of systemic medication that could have an effect on IOP within 30 days prior to screening, or 
anticipated during the study, including use of any steroid-containing drug regardless of route of systemic 
administration (e.g., steroid inhalers) 
19. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a 
medically acceptable form of birth control.  An adult woman is considered to be of childbearing potential 
unless she is one year post-menopausal or three months post-surgical sterilization.  All females of 
childbearing potential must have a negative pregnancy test result at the screening examination and must not 
intend to become pregnant during the study 
Study Population: 
Approximately 20 subjects will be randomized 
Investigational Product, Dose, and Mode of Administration: 
Netarsudil ophthalmic solution 0.02%, 1 drop daily, in the morning (QD AM), topical ocular 
Duration of Treatment: 
7 days 
Efficacy Assessments: 
The principal efficacy assessments of this study pertain to aqueous humor dynamics: 
• 
Trabecular (tonographic) outflow facility 
• 
IOP 
• 
EVP 
Safety Assessments: 
The assessment of safety and tolerability is a secondary objective of this study.  The assessment of safety will 
be evaluated by: 
• 
Ocular signs and symptoms / adverse events (AEs) 
• 
Visual Acuity   
• 
Biomicroscopy of anterior segment including evaluation of cornea, conjunctiva and anterior chamber.  
• 
Ophthalmoscopy 
• 
Pachymetry and Gonioscopy (screening only) 
• 
Heart rate and blood pressure 


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Statistical Methods: 
Sample Size Determination  
Among the aqueous humor dynamics (AHD) parameters, trabecular outflow facility is of key interest and 
therefore used for the overall sample size calculation. Assuming a one-sided alpha = 0.05, a standard deviation 
for the difference between treatments in the diurnal mean change from baseline of 0.07 mmHg (calculated with 
a common standard deviation of 0.06 μL/min/mmHg within each treatment and a correlation of 40% between 
eyes within the same subject), and a difference in mean change from baseline between treatments (active -
placebo) in diurnal means of 0.08 μL/min/mmHg, a sample size of 16 yields >95% power.  
Assuming approximately 20% of the randomized subjects may be non-evaluable i.e. either non-responders 
(see modified intent-to-treat population below for the definition of responder) or discontinue prior to Day 8, the 
required number of subjects to be randomized will be 20 subjects. 
Analysis Populations 
Modified Intent-to-Treat  
The modified intent-to-treat (mITT) population will include all randomized subjects who meet the following 
criteria: 1) have received at least one dose of study medication, 2) have all baseline measurements and all post-
baseline measurements for trabecular outflow facility, and 3) have mean diurnal IOP that is at least 2 mmHg 
lower than baseline mean diurnal IOP in the same eye treated with Netarsudil (responders).  
These subjects will be analyzed in accordance with the treatment they actually received, even if that treatment is 
different from the planned treatment (i.e., in the event of a randomization or dispensing error, subjects in the 
mITT population will be analyzed as treated). The mITT population will serve as the primary analysis 
population for efficacy variables. 
Per Protocol 
The per protocol (PP) population is a subset of the mITT, which will include those subjects (and their visits) 
who do not have major protocol violations likely to seriously affect the primary outcome of the study as judged 
by a masked evaluation prior to the unmasking of the study treatment. These subjects will be analyzed in 
accordance with the treatment they actually received, even if that treatment is different from the planned 
treatment (i.e., in the event of a randomization or dispensing error, subjects in the PP population will be 
analyzed as treated). The analysis with PP population is secondary. 
Safety 
All subjects who receive at least one dose of study drug will be included in the safety population. These subjects 
will be analyzed in accordance with the treatment they actually received, even if that treatment is different from 
the planned treatment (i.e., in the event of a randomization or dispensing error, subjects in the safety population 
will be analyzed as treated). Safety will be analyzed using the safety population. 
Analysis of Primary Endpoint 
The primary endpoint is the mean change from baseline in the mean diurnal trabecular outflow facility on 
Day 8. The null and alternative hypotheses, based on the primary variable are as follows: 
H01: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% and study eyes 
treated with Placebo, in the mean change from baseline of mean diurnal trabecular outflow facility = 0 on 
Day 8. 
H11: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% and study eyes 
treated with Placebo, in the mean change from baseline of mean diurnal trabecular outflow facility > 0 on 
Day 8. 
The null hypothesis will be tested using a paired t-test with alpha=0.05. One-sided p-values, two-sided 90% CIs, 
and two-sided 95% CIs will be presented.  
Analysis of Secondary Efficacy Endpoints 
Secondary AHD measures: IOP and EVP will be analyzed similarly to the primary endpoint. 
Similar to the primary efficacy analysis, mean differences in diurnal means of AHD measures and mean 


 
 
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differences at the individual time points will be tested with paired t-tests. One-sided p-values, two-sided 90% 
CIs, and two-sided 95% CIs will be presented. Means within each treatment comparing diurnal mean on Day 8 
with baseline diurnal mean and comparing individual time points on Day 8 with the corresponding time points 
at baseline visit will also be tested using paired t-tests. The same inferential statistics will be presented for these.   
Mean percent change from baseline in diurnal means of AHD measures and mean percent change from baseline 
in AHD measures at individual timepoints will be tested using paired t-tests. The same inferential statistics as 
for the primary endpoint will be presented for these. 
All AHD measures will be summarized by treatment and visit/time point using descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum). 
Safety: 
The observed and change from baseline in visual acuity (VA; logMAR) will be summarized using continuous 
descriptive statistics by visit/time point for each treatment. The proportion of subjects with a worsening of ≥3 
lines (≥0.3 logMAR) from baseline will also be summarized. 
Shift tables for the slit-lamp biomicroscopy parameters will be provided, comparing follow-up visit with the 
baseline by treatment. 
All treatment-emergent AEs (TEAEs, defined as an AE that occurs or worsens on or after the first treatment) 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) to identify system organ class 
(SOC) and preferred term (PT). 
An overall summary of TEAEs will be presented including the number of events and the number and 
percentage of subjects who experienced any TEAE, ocular TEAE, TEAE by maximum severity and relationship 
to study drug, death, treatment-emergent serious adverse event (SAE), and TEAEs resulting in withdrawal from 
study. 
In addition, TEAEs will be summarized by SOC and PT for the following: 
• 
TEAEs 
• 
Ocular TEAEs 
• 
Non-Ocular TEAEs 
• 
Study Drug Related Ocular TEAEs 
• 
Study Drug Related Non-Ocular TEAEs 
• 
SAEs 
• 
TEAEs by Severity 
The above summaries will include the number and percentage of subjects experiencing at least one TEAE in 
each SOC and PT. The number and percentage of subjects experiencing any TEAE will also be provided. All 
percentages will use the number of safety subjects as the denominator. If a subject has more than one AE within 
SOC, the subject will be counted only once in that SOC. If a subject has more than one AE that codes to the 
same PT, the subject will be counted only once for that PT. The tabular summary will be sorted by descending 
order of frequency in SOC and PT in all subjects. Non-ocular AEs will be summarized at the subject level 
without assignment to a specific treatment.  Ocular AEs will be summarized at the eye level by treatment group. 
Relationship to study drug will be rated by the Investigator as Not Related, Unlikely Related, Possibly Related, 
and Related. Related AEs will be classified as those rated as Possibly Related and Related. Severity will be 
rated by the Investigator as Mild, Moderate, and Severe. In the event that relationship or severity data are 
missing, the study analysis will follow the assumption of maximum relationship or severity in the summary 
tables.  
All AEs will be presented in a by-subject data listing. In addition, SAEs, TEAEs leading to study withdrawal, 
and TEAEs leading to death will be listed separately. 
Date of Original Approved Protocol (Rev 0): 
10 May 2017 
Date of Protocol Amendment 1 (Rev 1):16 August 2017 
Prepared in: 
Microsoft Word 2010 


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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................7 
TABLE OF CONTENTS ................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................15 
1.
INTRODUCTION ....................................................................................................17 
1.1 
Background – Elevated IOP and Aqueous Humor Dynamics .........................17 
1.2 
Investigational Product and Prior Experience ..................................................18 
1.3 
Potential Risks to Human Subjects ....................................................................18 
2.
STUDY OBJECTIVES ............................................................................................20 
2.1 
Primary Objective(s) ...........................................................................................20 
2.2 
Secondary Objective(s) ........................................................................................20 
3.
INVESTIGATIONAL PLAN ..................................................................................21 
3.1 
Overall Study Design and Plan ...........................................................................21 
3.2 
Rationale for Study Design and Control Group ...............................................22 
3.3 
Study Duration and Dates ...................................................................................22 
4.
STUDY POPULATION SELECTION ...................................................................23 
4.1 
Study Population ..................................................................................................23 
4.2 
Inclusion Criteria .................................................................................................23 
4.3 
Exclusion Criteria ................................................................................................23 
5.
STUDY TREATMENTS ..........................................................................................26 
5.1 
Description of Treatments ...................................................................................26 
5.1.1 
Investigational Product .................................................................................26 
5.1.2 
Placebo ............................................................................................................26 
5.1.3 
Treatments of Subjects ..................................................................................26 
5.2 
Selection and Timing of Dose for Each Patient .................................................26 
5.3 
Method of Assigning Patients to Treatment Groups ........................................26 
5.4 
Masking .................................................................................................................27 
5.5 
Concomitant Therapy ..........................................................................................27 
5.6 
Restrictions ...........................................................................................................28 
5.6.1 
Prior Therapy .................................................................................................28 
5.6.2 
Fluid and Food Intake ...................................................................................28 
5.6.3 
Subject Activity Restrictions .........................................................................28 
5.7 
Treatment Compliance ........................................................................................28 
5.8 
Packaging and Labeling ......................................................................................28 
5.9 
Storage and Accountability .................................................................................29 
5.10 
Investigational Product Retention at Study Site ...............................................29 
5.10.1 
Receipt and disposition of study medication ...............................................29 
5.10.2 
Return of study medication ...........................................................................29 
6.
STUDY PROCEDURES ..........................................................................................30 
6.1 
Informed Consent ................................................................................................30 
6.2 
Medical History ....................................................................................................30 
6.3 
Vital Signs .............................................................................................................30 
6.3.1 
Heart Rate.......................................................................................................30 
6.3.2 
Blood Pressure ................................................................................................31 
6.4 
Clinical Laboratory Tests....................................................................................31 


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6.4.1 
Laboratory Parameters .................................................................................31 
6.4.2 
Sample Collection, Storage and Shipping ....................................................31 
6.5 
Dispensing Investigational Product ....................................................................31 
6.6 
Efficacy Assessments ...........................................................................................31 
6.7 
Safety Assessments ...............................................................................................32 
6.8 
Adverse Events Assessments ...............................................................................32 
6.8.1 
Performing Adverse Event Assessments ......................................................32 
6.8.2 
Timing .............................................................................................................33 
6.8.3 
Severity............................................................................................................33 
6.8.4 
Relationship ....................................................................................................33 
6.8.5 
Action Taken with Study Drug .....................................................................34 
6.8.6 
Expectedness ...................................................................................................35 
6.8.7 
Clinical Significance.......................................................................................35 
6.8.8 
Clinical Laboratory Adverse Events ............................................................35 
6.8.9 
Serious Adverse Events or Serious Suspected Adverse Events .................35 
6.8.9.1 
Definition ..................................................................................................36 
6.8.9.2 
Reporting Serious Adverse Events or Serious Suspected Adverse 
Reactions ...................................................................................................36 
6.9 
Concomitant Medication Assessments ...............................................................37 
6.10 
Removal of Subjects from the Study or Investigational Product ....................37 
6.10.1 
Completed Subject .........................................................................................38 
6.10.2 
Non-completing Subject ................................................................................38 
6.10.3 
Subject Discontinuation ................................................................................38 
6.10.4 
Entire Study Terminated ..............................................................................38 
6.10.5 
Completed Study ............................................................................................38 
6.11 
Appropriateness of Measurements .....................................................................39 
7. 
STUDY ACTIVITIES ..............................................................................................40 
7.1 
Screening Visit (Visit 1) .......................................................................................40 
7.2 
Treatment Period .................................................................................................41 
7.2.1 
Visit 2 (Day 1, Qualification/Baseline) Procedures .....................................41 
7.2.1.1 
Visit 2 08:00 hours (± 30 min) .................................................................41 
7.2.1.2 
Visit 2 13:00 hours (± 30 min) .................................................................41 
7.2.1.3 
Visit 2 16:00 hours (± 30 min) .................................................................42 
7.2.2 
Visit 3 (Day 8, Exit) ........................................................................................42 
7.2.2.1 
Visit 3 08:00 hour (± 30 min) ..................................................................42 
7.2.2.2 
Visit 3 13:00 hours (± 30 min) .................................................................43 
7.2.2.3 
Visit 3 16:00 hours (± 30 min) .................................................................43 
7.3 
Unscheduled Visit.................................................................................................43 
8. 
QUALITY CONTROL AND ASSURANCE .........................................................44 
9. 
PLANNED STATISTICAL METHODS ................................................................45 
9.1 
General Considerations .......................................................................................45 
9.2 
Determination of Sample Size .............................................................................45 
9.3 
Analysis Populations ............................................................................................45 
9.3.1 
Modified Intent-to-Treat (mITT) Population .............................................45 
9.3.2 
Per Protocol (PP) Population ........................................................................46 


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9.3.3 
Safety Population ...........................................................................................46 
9.4 
Statistical Methods ...............................................................................................46 
9.4.1 
Demographics and Baseline Characteristics ...............................................46 
9.4.2 
Subject Disposition.........................................................................................46 
9.4.3 
Efficacy Analysis ............................................................................................46 
9.4.4 
Safety Analysis ...............................................................................................47 
9.5 
Missing or Inconclusive Data Handling .............................................................48 
9.6 
Adjustments for Multiplicity ..............................................................................48 
9.7 
Interim Analysis ...................................................................................................48 
10. ADMINISTRATIVE CONSIDERATIONS ...........................................................49 
10.1 
Investigators and Study Administrative Structure ...........................................49 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval.....................................................................................................49 
10.3 
Ethical Conduct of the Study ..............................................................................49 
10.4 
Subject Information and Consent ......................................................................49 
10.5 
Subject Confidentiality ........................................................................................50 
10.6 
Study Monitoring .................................................................................................50 
10.7 
Case Report Forms and Study Records .............................................................51 
10.8 
Protocol Deviations ..............................................................................................51 
10.9 
Access to Source Documentation ........................................................................52 
10.10 Data Generation and Analysis ............................................................................52 
10.11 Retention of Data .................................................................................................52 
10.12 Financial Disclosure .............................................................................................52 
10.13 Publication and Disclosure Policy ......................................................................53 
11. REFERENCES .........................................................................................................54 
11.1 
External References .............................................................................................54 
11.2 
Internal References ..............................................................................................55 
 
TABLE OF TABLES 
Table 1 
Ocular Hypotensive Medication Washout Period ................................28 
Table 2 
Comparison of Snellen ratio and logMAR units ...................................59 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................56 
 
 
Appendix 3 
Sponsor’s Obligations ..............................................................................64 
Appendix 4 
Investigator’s Obligations .......................................................................65 
Appendix 5 
Declaration of Helsinki ............................................................................68 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
AHD 
AM 
Aqueous humor dynamics 
Morning 
BP 
CI 
Blood Pressure 
Confidence Interval 
CRF 
Case Report Form 
EDC 
ETDRS 
EVP 
Electronic Data Capture 
Early Treatment Diabetic Retinopathy Study 
Episcleral Venous Pressure 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IOP 
IP 
Intraocular Pressure 
Investigational Product 
IRB 
ITT 
Institutional Review Board 
Intent To Treat 
logMAR 
MedDRA 
Logarithm of Minimum Angle of Resolution 
Medical Dictionary for Regulatory Activities 
Min 
mITT 
Minute 
Modified Intent-to-Treat 
mmHg 
OD 
Millimeters Mercury 
Right Eye 


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OHT 
OS 
OTC 
Ocular Hypertension 
Left Eye 
Over-the-Counter 
POAG 
PP 
PT 
Primary Open-Angle Glaucoma 
Per Protocol 
Preferred Term 
QD 
Once Daily 
SAE 
SAR 
SOC 
TEAE 
TM 
US 
Serious Adverse Event 
Suspected Adverse Reaction 
System Organ Class 
Treatment-Emergent Adverse Event 
Trabecular Meshwork 
United States 
VA 
Visual Acuity 
 
 
 


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1. INTRODUCTION 
1.1 
Background – Elevated IOP and Aqueous Humor Dynamics 
Glaucoma is a progressive, neuropathology affecting approximately 60 million people 
globally, and uncontrolled, glaucoma can result in atrophy of the optic nerve, loss of visual 
fields and ultimately, irreversible blindness (Alward 1998, Casson 2012). Although any form 
of glaucoma can lead to vision loss, the most common form of the disease is primary 
open-angle glaucoma (POAG), which is defined by an open anterior chamber angle upon 
gonioscopic observation, some evidence of optic nerve damage or dysfunction (eg, visual 
field loss), and frequently, elevated intraocular pressure (IOP).  A second disease condition, 
ocular hypertension (OHT), has been identified as one in which patients have an elevated 
IOP compared to population-based cut-off values, but with an apparent absence of optic 
nerve damage (Kass 2002). Elevated IOP is a major risk factor for development of 
glaucomatous visual field loss (The AGIS Investigators 2000), and a surrogate marker for 
disease progression, although other risk factors can also contribute to the development of 
glaucoma, including age, family history, and African race or Hispanic ethnicity 
(Varma 2004; Sommer 1991).  
Pharmacological therapies aim to control and/or delay disease progression by reducing 
elevated IOP. However, given that every millimeter of IOP reduction is significant in 
delaying disease progression (Heijl 2011, Kass 2010 and Anderson 2003), and yet there is no 
single treatment that is universally effective, there is still a need for improved efficacy of 
glaucoma medications. The IOP itself is the result of the fluid dynamics of aqueous humor 
and its interaction with various tissues of the outflow system. IOP has a circadian variation as 
well as more rapid changes in response to multiple factors, including Valsalva maneuvers, 
changes in body position, water ingestion, and lid blinking.  
IOP can be modeled as a function of 4 independent variables:   
 
IOP = Pe + (Q - U) / c 
 
 
 
 
 
 
(1) 
where Pe is episcleral venous pressure (EVP), Q is the aqueous humor production rate, c is 
the trabecular outflow facility (inverse of outflow resistance), and U is the pressure-
independent uveoscleral outflow rate. The interaction of the parameters that determine IOP is 
termed Aqueous Humor Dynamics (AHD). 
In a glaucomatous eye, elevated IOP is due primarily to an abnormally high resistance to 
outflow through the trabecular meshwork (TM, [Stamer 2012]), the primary drainage 
pathway for aqueous humor produced by the ciliary body. Current treatments target reducing 
aqueous humor production, and/or shunting aqueous outflow to the uveoscleral pathway. In 
both cases, it is possible that the TM degradation continues unchecked, even if target IOP is 
reached and maintained. Thus a cause of elevated IOP – the diseased TM itself – is not 
addressed.  




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indicate that there is minimal risk involved in a short (7 day) course of netarsudil, and 
treatment with placebo in one eye is of sufficiently short duration to not be considered a risk 
for disease progression. Please refer to the Investigators’ Brochure for more detailed 
information on potential risks. 
Previous animal (AR-13324-APH07) and human (AR-13324-CS102, and AR-13324-CS201) 
studies indicate a minimal contralateral effect, thus suggesting that the paired-comparison 
design is appropriate. 
 
 


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2. STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
The primary objective of this study is to evaluate the effect on trabecular outflow facility of 
netarsudil ophthalmic solution 0.02%, compared to placebo, in subjects with POAG or OHT. 
2.2 
Secondary Objective(s) 
To evaluate the effect on IOP and EVP of netarsudil ophthalmic solution 0.02% compared to 
placebo in subjects with POAG or OHT. 
To evaluate the ocular and systemic safety of netarsudil ophthalmic solution 0.02%. 
 
 


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3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This will be a double-masked, placebo-controlled, paired-comparison study conducted at 
approximately 2 centers in the US to evaluate the effect of treatment with netarsudil 
ophthalmic solution 0.02% (netarsudil) on trabecular outflow facility.  Netarsudil will be 
administered to one eye and Placebo to the contralateral eye once daily, 1 drop in the 
morning (QD, AM), in adult subjects at least 18 years of age with primary open angle 
glaucoma (POAG) or ocular hypertension (OHT).  Study medication will be administered for 
7 consecutive days, although the total time of subject participation in the study 
(including washout from prior treatment, if necessary) may be up to 7 weeks.  
Subjects will be eligible to enroll in the study if they have a current diagnosis of POAG or 
OHT in both eyes (POAG in one eye and OHT in the contralateral eye is also acceptable), 
and may be treatment-naïve or taking topical ocular hypotensive medication. If necessary, 
subjects who agree to participate in the study will be required to washout from their current 
intraocular pressure (IOP)-lowering treatment for a minimum specified period of time 
(5 days to at least 4 weeks), according to the type of treatment. Subjects will attend a total of 
3 study visits: a screening visit (Visit 1), to be conducted up to 6 weeks prior to a 
qualification visit (Visit 2, Day 1, baseline), and a final visit after 6 days on-treatment 
(Visit 3, Day 8, exit) where a member of the site staff will administer their 7th dose after 
completing their 08:00 hour assessments.  
Both eyes must qualify for the study with an unmedicated (post-washout or treatment-naïve) 
IOP of >20 mmHg but <30 mmHg at 08:00 hours and >17 mmHg but <30 mmHg at 13:00 
and 16:00 hours at the qualification visit. In order to be randomized into the study, eligible 
subjects must meet all of the inclusion, and none of the exclusion criteria at both the 
screening and at the qualification visit, following washout from their current ocular 
hypotensive treatment, if required.  
If the subject continues to be eligible, they will be randomized at the end of their 
qualification visit (Visit 2, Day 1, baseline) to receive netarsudil ophthalmic solution 0.02% 
in one eye and Placebo in the contralateral eye for 7 days, QD (AM).  Subjects will be asked 
to begin self-administration of their assigned medications in the morning on Day 2 following 
their baseline (Day 1) visit.  Subjects will be instructed to administer 1 drop from each bottle 
of their study medication into the assigned eye for that bottle, every morning at 
approximately the same time (between 08:00 and 10:00 hours) for 6 consecutive days. On the 
day of the final (exit) visit (Visit 3, Day 8), subjects will return to the site at 08:00 hours for 
their final dose of study medication and to complete their on-treatment measurements before 
exiting. 
Safety measures (including visual acuity, biomicroscopy, and AEs) will be evaluated at all 
visits. Efficacy assessments will include IOP at 08:00, 13:00 and 16:00 hours, and trabecular 
(tonographic) outflow facility and EVP, which will be measured at 13:00 and 16:00 hours. 
Tonographic outflow facility (primary endpoint) and IOP (secondary endpoint) will be 


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collected in all subjects. The other secondary endpoint, EVP, will be measured in a subset of 
subjects. 
3.2 
Rationale for Study Design and Control Group 
The primary treatment effect of netarsudil 0.02% is lowering IOP in subjects with glaucoma 
or OHT. From the results of mechanism of action studies conducted in both rabbits and 
monkeys, netarsudil is believed to lower IOP by several mechanisms including increasing 
aqueous humor outflow via the trabecular meshwork, reducing EVP and reducing aqueous 
humor production. Based on results from the Phase 1 study in healthy volunteers 
(AR-13324-CS102), the current study is designed to evaluate trabecular outflow facility, 
EVP and IOP in response to treatment with netarsudil ophthalmic solution 0.02% compared 
to placebo in subjects with elevated IOP.  
The current design is powered on the most clinically-relevant component of AHD, trabecular 
outflow facility, thought to be the primary mechanism of action of netarsudil in lowering 
IOP.  
Since the study treatment period is short (7 days), there is not believed to be a significant risk 
to subjects of the paired comparison design (i.e. active treatment in one eye and placebo in 
the fellow eye). Additionally, washing-out from their prior ocular hypotensive therapy, if 
necessary, should not pose a significant risk of clinically-relevant disease progression, since 
subjects will only be on investigational treatment or placebo for 7 days then can revert to 
their prior IOP-lowering treatment.  
3.3 
Study Duration and Dates 
The duration of treatment in this study is 7 consecutive days following randomization. 
Subjects will begin dosing on Day 2, in the morning following their Day 1 
(qualification/baseline) visit, and dose for the next 6 days, returning to the site on Day 8 
where their 7th and final dose will be administered. Subjects that are taking ocular 
hypotensive treatments at Screening will be required to wash-out of their current treatments 
as specified in Table 1. 


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4. STUDY POPULATION SELECTION
4.1 
Study Population 
Adult subjects aged 18 years and older are eligible to be enrolled into this study. Subjects 
should have a current diagnosis of POAG or OHT. POAG in one eye and OHT in the other is 
acceptable. Subjects may be treatment-naïve or taking prescribed ocular hypotensive therapy 
at the time of screening. However if currently on ocular hypotensive treatment, they must 
discontinue from it for the duration of the study, and follow a prescribed washout period 
depending on the class of medication they are taking (see Table 1). Further details regarding 
subject eligibility are provided below (Sections 4.2 and 4.3). 
Approximately 2 sites in the USA will participate in the study. 
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 18 years of age or older
2. Diagnosis of POAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is
acceptable)
3. Unmedicated (post-washout, or treatment-naive) IOP >20 mmHg and <30 mmHg in both
eyes at 08:00 hours, and >17 mmHg but <30 mmHg at 13:00 and 16:00 hours at the
qualification (Day 1, baseline) visit
4. Corrected visual acuity in each eye +1.0 on the logMAR scale or better by ETDRS chart
or its equivalent in each eye (equivalent to 20/200 or better Snellen visual acuity in each
eye)
5. Be able and willing to provide signed informed consent and follow study instructions
4.3 
Exclusion Criteria 
Subjects meeting any of the following criteria during screening or qualification evaluations 
(eg, at the time of randomization) will be excluded from entry into the study: 
Ophthalmic: 
1. Clinically significant ocular disease (eg, corneal edema, uveitis, severe
keratoconjunctivitis sicca) which might interfere with interpretation of the study efficacy
endpoints or with safety assessments, including subjects with glaucomatous damage so
severe that washout of ocular hypotensive medications for one month is not judged to be
safe by the Investigator


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2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure 
glaucoma, or narrow angles (as assessed by the Investigator, e.g. Grade 2 or less, Shaffer 
Scale). Note: Previous laser peripheral iridotomy is NOT acceptable 
3. Intraocular pressure ≥30 mmHg (unmedicated) in either eye (individuals who are 
excluded for this criterion are not allowed to attempt requalification) 
4. A difference in IOP between eyes >4 mmHg (unmedicated) at any baseline time point 
5. Use of more than two ocular hypotensive medications within 30 days of screening.  Note: 
fixed dose combination medications, for the purpose of this exclusion criterion, count as 
two medications 
6. Known hypersensitivity to any component of the formulation (eg, benzalkonium chloride, 
etc.), or to topical anesthetic. 
7. Previous glaucoma intraocular surgery or glaucoma laser procedures in either eye  
8. Keratorefractive surgery in either eye (eg, radial keratotomy, PRK, LASIK, corneal 
cross-linking, etc.)  
9. Report of ocular trauma in either eye within the six months prior to screening, or ocular 
surgery or non-refractive laser treatment within the three months prior to screening 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current 
evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex 
or zoster keratitis in either eye at screening.  
11. Use of ocular medication in either eye of any kind within 30 days of screening, 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), or c) lubricating drops for dry eye (which may be used throughout the study) 
12. Mean central corneal thickness greater than 620 μm in either eye at screening 
13. Any abnormality preventing reliable applanation tonometry of either eye 
(eg, keratoconus, etc.)  
14. Lack of suitable episcleral vein prior to performing EVP measurements at Visit 2/Day 1 
(applicable to 1 site only [Mayo Clinic]) 
Systemic: 
15. Clinically significant abnormalities (as determined by the Investigator) in any recent 
(within 6 weeks prior to screening) laboratory tests at screening which may affect the 
study results. Laboratory assessments, other than pregnancy tests in females of 
child-bearing potential and vital signs, will not be conducted for this study 


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16. Clinically significant systemic disease (eg, uncontrolled diabetes, myasthenia gravis, 
hepatic, renal, endocrine or cardiovascular disorders) which might interfere with the 
study 
17. Participation in any investigational (interventional) study within 60 days prior to 
screening  
18. Changes of systemic medication that could have an effect on IOP within 30 days prior to 
screening, or anticipated during the study, including use of any steroid-containing drug 
regardless of route of systemic administration (eg, steroid inhalers) 
19. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control.  An adult woman is considered to be 
of childbearing potential unless she is one year post-menopausal or three months 
post-surgical sterilization.  All females of childbearing potential must have a negative 
pregnancy test result at the screening examination and must not intend to become 
pregnant during the study 
 
 


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5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Investigational Product 
Netarsudil ophthalmic solution 0.02% is a sterile, isotonic, buffered aqueous solution 
containing netarsudil mesylate (0.02%), boric acid, mannitol, water for injection, and 
preserved with benzalkonium chloride (0.015%).  The product formulation is adjusted to 
approximately pH 5. 
5.1.2 
Placebo 
Netarsudil ophthalmic solution 0.02% placebo is a sterile, isotonic, buffered aqueous solution 
containing boric acid, mannitol, water for injection, and preserved with benzalkonium 
chloride (0.015%).  The product formulation is adjusted to approximately pH 5. 
5.1.3 
Treatments of Subjects 
Enrolled subjects will receive both investigational products (IPs), Netarsudil Ophthalmic 
Solution 0.02% (QD AM) and Netarsudil Ophthalmic Solution Placebo (QD AM).  
Individual eyes will be randomized to receive active treatment or placebo; one treatment will 
be dosed in the right eye (OD), and the other treatment will be dosed in the left eye (OS).  
Each IP dose will be self-administered by the study subjects.  For subjects deemed unable to 
self-administer the doses at the qualification visit (Visit 2, Day1), a guardian or caregiver will 
be asked to administer the medication. 
5.2 
Selection and Timing of Dose for Each Patient 
Masked kits containing identical bottles of IP labelled “right eye” or “left eye” will be 
provided to all subjects at the end of Visit 2 (Day 1, qualification, baseline). They will be 
instructed to begin self-administration in the morning of Day 2 at approximately the same 
time each day (between 08:00 and 10:00 hours) for the following 6 days, returning to the site 
on Day 8 where study personnel will administer the final dose.   
5.3 
Method of Assigning Patients to Treatment Groups 
A randomization schedule will be prepared by an independent individual (unmasked 
personnel) who is not involved in the day-to-day conduct of the study. Randomization will be 
stratified by site using permuted blocks, such that there will be an approximately equal 
number of subjects assigned to each of the two sequences ([Active Left Eye and Placebo 
Right Eye] and [Active Right Eye and Placebo Left Eye]) at each site.  
The randomization schedule will be provided to the investigational site. The eligible subjects 
will be assigned a randomization number at the end of Visit 2, Day 1. Randomization 
numbers will be assigned sequentially to subjects in the order in which they become eligible 


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for randomization.  The site staff will dispense to the subject the study kit labeled with the 
corresponding randomization number.  Each subject kit will contain one bottle of each 
product labeled “RIGHT EYE” (OD) and “LEFT EYE” (OS). The randomization number 
will be recorded on the subject’s source document and electronic case report form (eCRF).   
5.4 
Masking 
The study is designed as double-masked for the duration of the study. Assignment to 
treatment with netarsudil ophthalmic solution 0.02% or placebo will be randomized. The 
container-closure systems for both treatments are identical to preserve masking.  
Given the nature of this study design, each subject will receive 2 bottles of masked 
medication, one labelled “right eye” and one labelled “left eye”. The final (7th) dose will be 
administered at the clinical site by study personnel, after all of the 08:00 hour procedures and 
measurements have been performed. 
5.5 
Concomitant Therapy 
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. However, 
concurrent therapy with any form of ocular hypotensive medications (prescription or OTC) is 
not allowed during the study.  Disallowed ocular medications include: 
• Miotics,  
• Epinephrine-related compounds,  
• Carbonic anhydrase inhibitors (ocular or systemic),  
• β-adrenoceptor agonists,  
• α- adrenoceptor antagonists, and  
• Prostaglandin analogues   
Systemic therapy with agents that could have a substantial effect on IOP within the 30 days 
prior to screening and throughout the study is an exclusion criterion; see Table 1. Subjects 
who are stable on a β-adrenoreceptor antagonist (“β-blocker”) for cardiac arrhythmia, 
hypertension, etc. may enter the study provided their dose or dosing regimen has not been 
changed within the 3 months prior to Screening. 
Contact lens wear must be stopped at least one week prior to the study, and during the study.  




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Each packaged unit will be labeled with an investigational label with the following minimal 
information: the study number, kit number, right/left eye designation, and storage statement, 
including a statement “Caution - New Drug - Limited by Federal (US) Law to Investigational 
Use” or equivalent.  
5.9 
Storage and Accountability 
The products should be stored in refrigerated conditions (2°C to 8°C/ 36°F to 46°F).  The 
subject should be instructed to continue storing the product in the refrigerator (2°C to 8°C/ 
36°F to 46°F) even after the bottle has been opened.  Do not freeze the product.  
Prior to dispensing to the subject, all investigational material must be stored in a secure 
location at the recommended long-term storage condition (2°C to 8°C) with strictly limited 
access documented by signature of authorized persons who may dispense investigational 
materials.   
5.10 
Investigational Product Retention at Study Site 
5.10.1 
Receipt and disposition of study medication 
Study medication (i.e., investigational product) will be shipped to the Investigator’s site from 
a central depot.  The study personnel 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 bottles of investigational products.  
The investigational product(s) must not be used outside this protocol.  A Drug Accountability 
Log will be kept.  
5.10.2 
Return of study medication  
When the study is completed or is terminated by the Sponsor, all study material including 
used and unused study medication kits will be returned to the Sponsor’s 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 bottles of investigational products.  The CRA assigned to the 
Investigator’s institution will complete a study drug returns form or equivalent that will be 
signed by the Investigator or designee prior to returning the used and unused study 
medication kits to the Sponsor’s designee. 
 


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6. STUDY PROCEDURES 
All study procedures should be completed as described in the protocol within the timings 
specified, unless otherwise noted. 
6.1 
Informed Consent 
Prior to any study procedures, the study will be discussed with each subject and 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 (ICF). 
The ICF must have received approval/favorable review by a properly constituted Institutional 
Review Board (IRB) prior to use.  A copy of the signed and dated consent document will be 
given to each subject.  The original signed and dated informed consent document must be 
maintained in the study files at the Investigator’s site.   
The Investigator or staff is responsible for ensuring that no subject undergoes 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 
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 also 
will 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 
Vital Signs 
6.3.1 
Heart Rate 
Subject heart rate will be measured at screening, and at 08:00 hours (±30 minutes) during 
each subsequent study visit attended by the subject.  Heart rate will be determined only once 
during each study visit by the method described in Appendix 2. 


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6.3.2 
Blood Pressure 
Blood pressure will be measured once for each subject after the subject heart rate has been 
determined, with the subject in a sitting position.  A mechanical or digital 
sphygmomanometer may be used, but effort should be made to use the same instrument and 
the same arm of the subject for each reading.  Blood pressure will be determined only once 
during each study visit by the method described in Appendix 2. 
6.4 
Clinical Laboratory Tests 
6.4.1 
Laboratory Parameters 
Pregnancy testing will be conducted at any time prior to randomization for females of child-
bearing potential. A female of child-bearing potential is defined as an adult woman unless 
she is one year post-menopausal or three months post-surgical sterilization. Any female who 
is pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth 
control will be excluded from the study.  All females of childbearing potential must have a 
negative pregnancy test result at the screening examination or at any time after screening and 
prior to Visit 2 (qualification, Day 1, baseline) and must not intend to become pregnant 
during the study. 
No other laboratory testing is planned for this study. 
6.4.2 
Sample Collection, Storage and Shipping 
Not applicable. 
6.5 
Dispensing Investigational Product 
Study staff responsible for dispensing IP will be listed on the Delegation of Responsibilities 
log.  When a subject meets all criteria for selection and has completed all screening and 
qualification assessments, the subject will be randomly assigned masked treatment to one eye 
(left eye or right eye) and masked placebo assigned to the contralateral eye, according to the 
randomization schedule (Section 5.3).IP will be then dispensed to randomized subjects at the 
end of Visit 2 (Day 1), and subjects will be instructed to begin dosing the following morning 
(Day 2).  The responsible study staff will account for all used and unused IP kits and their 
contents by maintaining an IP accountability log. 
6.6 
Efficacy Assessments 
The primary and key secondary efficacy assessments for this study are AHD per treatment. 
Mean change from baseline diurnal trabecular outflow facility (average of 13:00 and 16:00 
hour measurements) per treatment on Day 8 is the primary efficacy endpoint. Baseline mean 
diurnal outflow facility is defined as the average of 13:00 and 16:00 hour measurements on 
Day 1, Visit 2. Secondary efficacy endpoints include: 


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• Mean change from baseline in mean diurnal IOP (average of 13:00 and 16:00 hour 
measurements) and mean diurnal EVP per treatment on Day 8 
• Mean diurnal values for all AHD (trabecular outflow facility, IOP, EVP) per treatment on 
Day 8 
• Mean values for all AHD at the individual 13:00 and 16:00 hour time points per 
treatment on Day 8 
• Mean change from baseline for all AHD at the individual 13:00 and 16:00 hour time 
points per treatment on Day 8. Baseline individual time points are defined as the 
corresponding measurements on Day 1, Visit 2. 
• Percent (%) change from baseline for all AHD per treatment on Day 8 
6.7 
Safety Assessments 
The assessment of safety and tolerability is a secondary objective of this study.  
The assessment of safety will be evaluated by: 
• Ocular signs and symptoms / AEs 
• Best Corrected Visual Acuity   
• Biomicroscopy of anterior segment including evaluation of cornea, conjunctiva and 
anterior chamber 
• Ophthalmoscopy 
• Pachymetry and Gonioscopy (screening only) 
• Heart rate and blood pressure 
6.8 
Adverse Events Assessments 
If an AE/adverse reaction occurs, the Investigator will institute support and/or treatment as 
deemed appropriate.  If a 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. 
6.8.1 
Performing Adverse Event Assessments 
The Principal Investigator at each site is responsible for defining and reporting any AE, its 
severity, seriousness, relatedness and outcome, and for ensuring proper and timely reporting 
of any events as described below. All AEs occurring during the study, regardless of the 
assumption of causal relationship, must be documented on the respective CRF.  


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6.8.2 
Timing 
Adverse events that occur at any time after the subject has signed informed consent, 
including during the washout period for prior ocular hypotensive medication for a particular 
subject, if necessary, (i.e. between Visit 1 and Visit 2) will be collected at the next visit 
(Visit 2) or earlier (i.e. during an unscheduled visit), and should be documented as part of the 
medical history. 
Adverse events will be considered treatment-emergent (TEAEs) if they occur at any time 
from the time the subject receives the first dose of IP (Day 2, morning following Visit 2, 
baseline/qualification) until the subject’s participation in the study has been completed.  If a 
subject has an ongoing TEAE at the time of study completion, the ongoing TEAE must be 
followed-up and provided appropriate medical care until the event has resolved or stabilized.    
6.8.3 
Severity 
Severity (intensity) of a TEAE is defined as a qualitative assessment of the level of 
discomfort of a TEAE, as determined by the Investigator or reported to him/her by the 
subject.  The assessment of intensity is made irrespective of study medication relationship or 
seriousness of the event and should be evaluated according to the following scale: 
1 = Mild:  present, but not distressing, and no disruption of normal daily activity 
2 = Moderate:  discomfort sufficient to 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 
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 6.8.9 for 
reporting requirements of serious AEs (SAEs). 
6.8.4 
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 factor 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.  


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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. 
6.8.5 
Action Taken with Study Drug 
The following actions may be taken with the study drug in response to an AE based on the 
clinical judgement of the Investigator, and should be recorded in the appropriate CRF:   
• None  
• Investigational Product Discontinued  
• Investigational Product Interrupted 
• Other Action Taken:  
o None  
o Non - Drug Therapy  
o New OTC or Rx Drug Added 
o Hospitalized less than 24 hours 
o Hospitalized greater than or equal to 24 hours  
o Unknown 
 


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Outcome of an AE is coded as follows, and may require completion of additional CRFs: 
• Fatal    
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/lost to follow-up 
6.8.6 
Expectedness 
In previous clinical studies of netarsudil, the most frequently reported AE was conjunctival 
hyperemia.  In the present study, investigators are asked to use the appropriate verbatim term 
on the AE form to describe this observation if it is increased from baseline:   
• Redness related to instillation  = “conjunctival hyperemia upon instillation” 
• Redness that persists and is deemed not related to instillation = “conjunctival hyperemia” 
In this regard, investigators are asked to appropriately note all observations of conjunctival 
hyperemia also on the biomicroscopy case report form.  Please refer to the Investigator’s 
Brochure for further details on AEs observed in previous studies with netarsudil.  
6.8.7 
Clinical Significance 
Determination of the significance of any AE for a particular subject, and in the context of the 
entire study, is the responsibility of the Investigator. The Sponsor additionally has overall 
responsibility for the safety of all subjects, and timely documentation and reporting of any 
safety concerns. 
6.8.8 
Clinical Laboratory Adverse Events 
Other than pregnancy testing for females of child-bearing potential and vital signs, clinical 
laboratory testing is not planned for this study. 
6.8.9 
Serious Adverse Events or Serious Suspected Adverse Events 
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 patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 


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6.8.9.1 
Definition 
A "suspected adverse reaction" (SAR) means any AE for which there is a reasonable 
possibility that the drug caused the AE. For purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
AE. “Suspected adverse reaction” implies a lesser degree of certainty about causality than 
“adverse reaction”, which means any AE caused by a drug. 
A serious adverse event (SAE) or serious suspected adverse reaction (SSAR) is considered 
“serious” if, in the view of either the investigator or sponsor, it results in any of the following 
outcomes:  
• Death 
• Life-threatening AE 
• Hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 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 or 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 inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
6.8.9.2 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions 
An investigator must immediately report to the Sponsor or Sponsor representative any SAE 
or SSAR (see Section 6.8.9.1 for definitions), whether or not considered drug-related, 
including those listed in the protocol or Investigator’s Brochure and 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 course of the study 
and within four (4) weeks of last administration of the study medication. Study endpoints that 
are serious adverse events (eg, all-cause mortality) must be reported in accordance with the 
protocol unless there is evidence suggesting a causal relationship between the drug and the 
event (eg, death from anaphylaxis).  In that case, the Investigator must immediately report 
the event to the Sponsor.  The investigator must record non-serious adverse events and report 
them to the Sponsor according to the timetable for reporting specified in the protocol.  
In case of incomplete information, the Investigator must provide follow-up information as 
soon as possible, again using the SAE report form. 




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6.10.1 
Completed Subject 
A completed subject is defined as one who completes all days of planned participation 
through completion of the Day 8 procedures.   
6.10.2 
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 and/or the Sponsor Safety Officer.  Any subject may decide 
to voluntarily withdraw from the study at any time without prejudice.  In the event that 
discontinuation of treatment is necessary, the Investigator will make every attempt to 
complete all subsequent safety assessments.   
6.10.3 
Subject Discontinuation 
The subject may discontinue from the study for the following reasons (to be recorded on the 
CRF): 
• Adverse Events (AEs including, in the opinion of the investigator, clinically relevant 
abnormalities and intercurrent diseases reported by the subject or observed by the 
investigator with documentation on the CRF).   
• Administrative: This category is for reasons unrelated to the investigational product 
including: 
o Non-compliance (e.g., use of prohibited concomitant medication and/or failure to 
attend scheduled follow-up visits) 
o Other 
All subjects who discontinue Investigational Product due to a report of an AE must be 
followed-up and provided appropriate medical care until their signs and symptoms have 
remitted or stabilized or until abnormal laboratory findings have returned to acceptable or 
pre-study limits.   
6.10.4 
Entire Study Terminated 
The entire study may be discontinued by the Investigator or the Sponsor.  Prompt, written 
notice of reasonable cause to the other party (Sponsor or Investigator, respectively) is 
required.  Prompt notice to the IRB and to regulatory authorities is also required. 
6.10.5 
Completed Study 
The study is completed when the planned enrollment has been completed, and all the 
enrolled subjects have completed the study.   


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6.11 
Appropriateness of Measurements 
The ophthalmic and systemic measures used in this study are consistent with standard of 
care.   


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7. STUDY ACTIVITIES
A detailed Schedule of Visits and Procedures is provided in Appendix 1. Details of 
procedures to be performed are provided in Appendix 2. 
7.1 
Screening Visit (Visit 1) 
This visit may take place at any time of the day.  
Subjects with a diagnosis of POAG or OHT in both eyes (POAG in one eye and OHT in the 
fellow eye is acceptable) are eligible to be screened for this study. Individuals who are 
potential subjects will arrive at the Investigator’s office.  A member of the Investigator’s staff 
will interview the individual as to their qualifications for participation in the study.  
Individuals will be asked to review the informed consent, discuss issues as needed, and to 
sign the form.  A medical and ophthalmic history including systemic and ocular medication 
use will be taken, and demographic measures recorded.  An examination will be conducted, 
including measurement of heart rate and blood pressure, and an ophthalmic examination 
(to include ocular symptoms, visual acuity (VA), central corneal thickness by ultrasound 
pachymetry, IOP, biomicroscopy, gonioscopy, and identification of episcleral vein (utilizing 
a slit lamp) that will be used for EVP measurement [
]). If no exclusion 
criteria are identified, dilated ophthalmoscopy will be performed. Subject symptoms will be 
queried. The investigator will evaluate the results of these examinations for possible 
enrollment of the individual into the study. 
Subjects may be treatment-naïve or taking a prescribed IOP-lowering medication at the time 
of Screening. If the subject is currently taking an ocular hypotensive medication, once they 
have agreed to participate in the study and have signed informed consent, they will agree to 
washout from their current medication and refrain from taking it until they have exited the 
study. Washout from current ocular hypotensive medication will be conducted according to 
the times noted in Table 1, and depends on the type of IOP-lowering treatment.  
Evaluation of eyedrop instillation performance:  Subjects will be provided a bottle of 
commercially available, multi-dose, non-medicated artificial tears in a room with access to 
water and soap.  They 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 to 
assure that the subject instills one drop (and one drop only) 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 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. 
All females of childbearing potential must have a negative pregnancy test result at the 
screening examination and must not intend to become pregnant during the study. 


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7.2 
Treatment Period 
7.2.1 
Visit 2 (Day 1, Qualification/Baseline) Procedures 
This visit should occur no more than 2 to 7 days following the Screening visit, if the subject 
is treatment-naïve, or following the appropriate washout time prescribed for the IOP-
lowering medication(s) they were taking at screening (Table 1).  
Individuals who do NOT meet the IOP requirements at any of the timepoints in this visit may 
return for up to 2 additional visits within 1 week of failing this 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.   
Upon return of the requalification visit, such individuals’ IOP measurements would need to 
qualify at all timepoints (08:00, 13:00, and 16:00)  
Individuals who screen fail due to IOP being ≥ 30 mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits. 
7.2.1.1 
Visit 2 08:00 hours (± 30 min) 
Vital signs will be collected (heart rate and blood pressure), and the subject’s general 
well-being and ocular symptoms will be collected (including medical history, concomitant 
medications and any adverse events). An ocular examination will then take place, including 
VA, IOP, and biomicroscopy.   
Please note that the episcleral vein may be assessed during this visit timepoint if it was not 
able to assessed during the Screening visit. 
IOP should be >20 mmHg and <30 mmHg in both eyes in order for the subject to continue to 
be eligible for qualification and enrollment into the study. Furthermore, the IOP should not 
differ by more than 4 mmHg between the eyes. Subjects will be re-examined at 13:00 hours. 
Note; subjects are free to leave the site between visits, provided they agree to not participate 
in strenuous activities or consume alcohol, and return promptly for the next visit. 
7.2.1.2 
Visit 2 13:00 hours (± 30 min) 
The following procedures will be conducted: 
•
IOP, which must be >17 mmHg but <30 mmHg in order for the subject to be considered 
eligible to proceed with the Qualification visit.
•
EVP (see Appendix 2 for procedures).
•
Trabecular (tonographic) outflow facility (see Appendix 2 for procedures). 


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The subject will then return for their final Qualification examination at 16:00 hours. Note; 
subjects are free to leave the site between visits, provided they agree to not participate in 
strenuous activities or consume alcohol, and return promptly for the next visit 
7.2.1.3 
Visit 2 16:00 hours (± 30 min) 
The following procedures will be conducted: 
•
IOP, which must be >17 mmHg but <30 mmHg in order for the subject to be considered 
eligible to proceed in the study.
•
EVP (see Appendix 2 for procedures)
•
Trabecular (tonographic) outflow facility (see Appendix 2 for procedures) 
Provided the Investigator is satisfied that the subject meets all of the Inclusion criteria and 
none of the Exclusion criteria, and the subject continues to be willing to participate in the 
study, then the subject will be enrolled and randomized to a treatment schedule. After 
obtaining randomization information, the appropriate subject kit will be provided to the 
subject.  
The subject will be instructed to begin dosing the following day (Day 2) between 08:00 and 
10:00 hours, and to dose every day for 6 days at the same time (between 08:00 and 10:00 
hours). One drop from the bottle labelled “Right Eye” should be dispensed into the right eye 
every day, and one drop from the bottle labelled “Left Eye” into the fellow eye once every 
day. Subjects will return to the site 7 days later (Day 8) BEFORE taking their study 
medication for their exit visit procedures. 
7.2.2 
Visit 3 (Day 8, Exit) 
This visit should occur 7 days after Visit 2 (qualification/baseline visit), and the subject 
should be instructed to bring all medications with them to the site. The subject should not 
take their study medication before arriving at the site, but should be instructed that they will 
administer their medication at the site following their 08:00 hour assessments have been 
performed.  
7.2.2.1 
Visit 3 08:00 hour (± 30 min) 
Subjects will be asked how they have been feeling since their last visit, and to describe any 
TEAEs they may have experienced. 
The following procedures will be performed: 
•
Heart rate and blood pressure
•
Ocular symptoms
•
Visual Acuity


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•
Biomicroscopy
•
IOP
Site personnel will then instill their final doses of study medication and all medication, used 
and unused, will be collected from the subject. The subject will then be asked to return for 
their next assessments at 13:00 hours. Note; subjects are free to leave the site between visits, 
provided they agree to not participate in strenuous activities or consume alcohol, and return 
promptly for the next visit. 
7.2.2.2 
Visit 3 13:00 hours (± 30 min) 
The following procedures will be conducted: 
•
IOP
•
EVP (see Appendix 2 for procedures).
•
Trabecular (tonographic) outflow facility (see Appendix 2 for procedures). 
The subject will then return for their final examination at 16:00 hours. Note; subjects are free 
to leave the site between visits, provided they agree to not participate in strenuous activities 
or consume alcohol, and return promptly for the next visit 
7.2.2.3 
Visit 3 16:00 hours (± 30 min) 
The following procedures will be conducted: 
•
IOP
•
EVP (see Appendix 2 for procedures).
•
Trabecular (tonographic) outflow facility (see Appendix 2 for procedures). 
The subject will then be thanked for their participation in the study, and will be dismissed. 
7.3 
Unscheduled Visit 
An unscheduled visit is any visit to the Investigator other than the specific visits requested in 
the protocol, as may be 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 TEAEs in the eCRF. If the unscheduled visit occurs prior to Day 8, and 
the subject is to discontinue from the study for any reason, every effort should be made by 
the site to conduct the assessments and procedures outlined above (Section 7.2.1.3) for the 
Exit visit. 


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8. QUALITY CONTROL AND ASSURANCE
The progress of the study will be monitored by on-site, written, and telephone 
communications between personnel at the Investigator’s site and the Study Monitor.  
The Investigator will allow the Sponsor or designee to inspect all documents pertinent to the 
study, including (but not limited to): 
•
CRFs
•
Subject records (source documents)
•
Signed consent forms
•
Records of study medication receipt, storage, preparation, and disposition
•
Regulatory files related to this study


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9. PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All statistical analyses will be performed by the Sponsor designee using SAS® software. 
A separate Statistical Analysis Plan will be produced that will provide complete details 
regarding the data handling and analysis methods.  
Continuous summary statistics (sample size, mean, SD, median, minimum, and maximum) 
will be presented by treatment for each time point (and for the diurnal mean) at each visit and 
for the change from baseline and percent change from baseline. All study data will be listed 
by treatment, subject, and time point (as applicable). 
For measurements of AHD, baseline will refer to the time-relevant measure at Visit 2, Day 1 
(e.g., IOP at 13:00 hours at Visit 2 will be the baseline for IOP at 13:00 hours at Visit 3).  
For all other variables, baseline is defined as the last measurement prior to the first dose of 
study medication. 
All statistical tests will use one-sided significance level of 5%. Where applicable, 2-sided 
90% (equivalent to one-sided 90% confidence intervals [CIs]) and 95% CIs will be reported 
9.2 
Determination of Sample Size 
Among the AHD parameters, trabecular outflow facility is of key interest and therefore used 
for the overall sample size calculation. Assuming a one-sided alpha = 0.05, a standard 
deviation for the difference between treatments in the mean change from baseline in diurnal 
means of 0.07 mmHg (calculated with a common standard deviation of 0.06 μL/min/mmHg 
within each treatment and a correlation of 40% between eyes within the same subject), and a 
difference in mean change from baseline between treatments (active - placebo) in diurnal 
means of 0.08 μL/min/mmHg, a sample size of 16 subjects (32 eyes) yields greater than 95% 
power.  
Assuming approximately 20% of the randomized subjects will be non-evaluable i.e. either 
non-responders (see modified intent-to-treat population below for the definition of responder) 
or discontinue prior to Day 8, the required number of subjects to be randomized will be 
20 subjects. 
9.3 
Analysis Populations 
9.3.1 
Modified Intent-to-Treat (mITT) Population 
The modified intent-to-treat (mITT) population will include all randomized subjects who 
meet the following criteria: 1) have received at least one dose of study medication, 2) have 
all baseline measurements and all post-baseline measurements for trabecular outflow facility, 
and 3) have mean diurnal IOP that is at least 2 mmHg lower than baseline mean diurnal IOP 
in the same eye treated with Netarsudil (responders).  


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These subjects will be analyzed in accordance with the treatment they actually received, even 
if that treatment is different from the planned treatment (i.e., in the event of a randomization 
or dispensing error, subjects in the mITT population will be analyzed as treated). The mITT 
population will serve as the primary analysis population for efficacy variables. 
9.3.2 
Per Protocol (PP) Population 
The per protocol (PP) population is a subset of the mITT, 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. 
These subjects will be analyzed in accordance with the treatment they actually received, even 
if that treatment is different from the planned treatment. The analysis with PP population is 
secondary. 
9.3.3 
Safety Population 
All subjects who receive at least one dose of study drug will be included in the safety 
population. These subjects will be analyzed in accordance with the treatment they actually 
received, even if that treatment is different from the planned treatment (i.e., in the event of a 
randomization or dispensing error, subjects in the safety population will be analyzed as 
treated). Safety will be analyzed using the safety population. 
9.4 
Statistical Methods 
9.4.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics and 
presented in individual listings. 
9.4.2 
Subject Disposition 
Subject enrollment, inclusion into each analysis population, and withdrawal from the study 
will be summarized and listed. 
9.4.3 
Efficacy Analysis 
The primary endpoint is the mean change from baseline in the mean diurnal trabecular 
outflow facility on Day 8. The null and alternative hypotheses, based on the primary variable 
are as follows: 
H01: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% 
and study eyes treated with Placebo, in the mean change from baseline of mean diurnal 
trabecular outflow facility = 0 on Day 8. 
H11: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% 
and study eyes treated with Placebo, in the mean change from baseline of mean diurnal 
trabecular outflow facility > 0 on Day 8. 


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The null hypothesis will be tested using a paired t-test with alpha=0.05. One-sided p-values, 
two-sided 90% CIs, and two-sided 95% CIs will be presented. 
Secondary AHD measures: IOP and EVP will be analyzed similarly to the primary endpoint. 
Similar to the primary efficacy analysis, mean differences in diurnal means of AHD 
measures and mean differences at the individual time points will be tested with paired t-tests. 
One-sided p-values, two-sided 90% CIs, and two-sided 95% CIs will be presented. Means 
within each treatment comparing diurnal mean on Day 8 with baseline diurnal mean and 
comparing individual time points on Day 8 with the corresponding time points at baseline 
visit will also be tested using paired t-tests. The same inferential statistics will be presented 
for these.   
Mean percent change from baseline in diurnal means of AHD measures and mean percent 
change from baseline in AHD measures at individual timepoints will be tested using paired 
t-tests. The same inferential statistics as for the primary endpoint will be presented for these. 
All AHD measures will be summarized by treatment and visit/time point using descriptive 
statistics (n, mean, median, standard deviation, minimum, and maximum). 
9.4.4 
Safety Analysis 
The observed and change from baseline in BCVA (logMAR) will be summarized using 
continuous descriptive statistics by visit/time point for each treatment. The proportion of 
subjects with a worsening of ≥3 lines (≥0.3 logMAR) from baseline will also be summarized. 
Shift tables for the slit-lamp biomicroscopy parameters will be provided, comparing 
follow-up visit with the baseline by treatment. 
All TEAEs (TEAEs, defined as an AE that occurs or worsens on, or after the first treatment) 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) to identify 
system organ class (SOC) and preferred term (PT). 
An overall summary of TEAEs will be presented including the number of events and the 
number and percentage of subjects who experienced any TEAE, ocular TEAE, TEAE by 
maximum severity and relationship to study drug, death, treatment-emergent SAE, and 
TEAEs resulting in withdrawal from study. 
In addition, TEAEs will be summarized by SOC and PT for the following: 
• TEAEs 
• Ocular TEAEs 
• Non-Ocular TEAEs 
• Study Drug Related Ocular TEAEs 


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• Study Drug Related Non-Ocular TEAEs 
• SAEs 
• TEAEs by Severity 
The above summaries will include the number and percentage of subjects experiencing at 
least one TEAE in each SOC and PT. The number and percentage of subjects experiencing 
any TEAE will also be provided. All percentages will use the number of safety subjects as 
the denominator. If a subject has more than one AE within SOC, the subject will be counted 
only once in that SOC. If a subject has more than one AE that codes to the same PT, the 
subject will be counted only once for that PT. The tabular summary will be sorted by 
descending order of frequency in SOC and PT in all subjects. Non-ocular AEs will be 
summarized at the subject level without assignment to a specific treatment.  Ocular AEs will 
be summarized at the eye level by treatment group. 
Relationship to study drug will be rated by the Investigator as Not Related, Unlikely Related, 
Possibly Related, and Related. Related AEs will be classified as those rated as Possibly 
Related and Related. Severity will be rated by the Investigator as Mild, Moderate, and 
Severe. In the event that relationship or severity data are missing, the study analysis will 
follow the assumption of maximum relationship or severity in the summary tables.  
All AEs will be presented in a by-subject data listing. In addition, SAEs, TEAEs leading to 
study withdrawal, and TEAEs leading to death will be listed separately. 
9.5 
Missing or Inconclusive Data Handling 
Missing data will not be imputed. For measurements of AHD, if the result is missing in one 
eye, then the result for the contralateral eye will be assumed to be missing at the same time 
point. 
9.6 
Adjustments for Multiplicity 
No adjustments for multiplicity are planned. 
9.7 
Interim Analysis 
Not applicable. 
 
 




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All ICFs must be approved for use by the Sponsor and receive approval/favorable opinion 
from an IRB/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 prior to submission to the governing IRB 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. 
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, state and federal laws and regulations.  
Monitors, auditors and other authorized representatives of Aerie, the IRB approving this 
study, and government regulatory authorities (eg, FDA 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 eCRFs 
• 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 eCRF entries with subject records), data will 
be 100% source verified and will include, but not be limited to: subject identification, 
informed consent and assent, if applicable (procedure, signature, and date), selection criteria, 
and primary efficacy and safety parameters (i.e., AEs). 


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10.7 
Case Report Forms and Study Records 
Study data will be recorded via eCRFs. 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 eCRF via a secure internet access. Each completed set of eCRFs will be 
reviewed by the Investigator who will then electronically sign and date the eCRF confirming 
that data for the subjects are complete and accurate. 
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 must include a copy of each Investigator's CV and medical license, 
completed, FDA Form 1572 or statement of Investigator, each eCRF, subject charts/source 
documents, Investigator's Brochure, protocol, protocol amendments, correspondence with the 
Sponsor and the IRB, 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 approvals, advertisements, written information 
provided to subjects, and subject completed ICFs. If the Investigator moves, withdraws from 
an investigation, or retires, the responsibility for maintaining the records may be transferred 
to another person (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 
which does not involve inclusion/exclusion criteria or the primary efficacy endpoint and 
which does not place the subject at any added risk or affect the data quality or study outcome. 
Examples of deviations include common out of window visits or timed procedures, a missed 
procedure, etc. Sites will record protocol deviations in the study records. To the extent 
possible, sites will make their best efforts to quickly remedy deviations. 
The site will contact the Sponsor for clarification of inclusion/exclusion criteria as needed 
prior to enrollment of a study subject. The Sponsor will document clarification requests and 
responses. 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 3 days of becoming 
aware of any significant protocol deviation. Typically, significant protocol deviation include 
significant deviations from the inclusion and exclusion criteria that may impact interpretation 
or the quality of efficacy information or the safety of a subject, concomitant medication 


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restrictions, or any other protocol requirement that results in a significant added risk to the 
subject or has an impact on the quality of the data collected or the outcome of the study. 
The Sponsor will review, designate, and/or approve all protocol deviations prior to database 
lock. 
10.9 
Access to Source Documentation 
Monitors, auditors, and other authorized representatives of the Sponsor, the governing 
IRB(s), the FDA, the DHHS, other domestic government agencies, and other foreign 
regulatory agencies will be granted direct access to the study subject’s original medical and 
study records for verification of the data and/or clinical study procedures. Access to this 
information will be permitted to representatives of the aforementioned organizations to the 
extent permitted by law. 
10.10 Data Generation and Analysis 
For data captured on a paper CRF (eg, subject diary, subject questionnaire), the completed 
CRF will be sent to the data management CRO after monitoring is complete or will be faxed 
to the data management CRO upon completion by the subject. Once the CRFs are monitored 
in the EDC system and double data entry of the paper CRFs into the clinical database has 
been completed, 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 (eg, range checks, cross checks and other edit checks). 
Where required, the Investigator will be asked for supplementary information through a 
query. 
Data will be checked per CRO’s SOPs. The database 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 
The Investigator shall retain study records for a period of 2 years following the date a 
marketing application is approved for the drug for the indication for which it is being 
investigated, or for a period of 2 years after all investigations with the drug are discontinued 
and FDA has been duly notified in the circumstance that no application is to be filed or the 
application is not approved for such indication. The Sponsor will inform the Investigator 
when the study records can be destroyed. 
10.12 Financial Disclosure 
The Principal Investigator and Sub-investigators (as listed on Form FDA 1572) will provide 
financial disclosure information prior to participation in the study. The Principal Investigator 
and any Sub-investigators will notify the Sponsor promptly of any required revision to their 
financial disclosure status during the term of this study, annually, or at the end of the study 


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(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 
Sponsor policy encourages the presentation and publication of clinical study data. Prior to 
any presentation of results, draft versions of manuscripts will be made available to co-authors 
and to the Sponsor for review and comment. At least 30 days (for abstracts) or 60 days 
(for full papers) should be allowed for comments prior to submission of manuscripts or 
abstracts for consideration of acceptance of presentation or publication. 
 
 


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11. REFERENCES  
11.1 
External References 
1. 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. Alward WL. Medical management of glaucoma. N Engl J Med 1998; 339:1298-307. 
3. Anderson DR, Drance SM, Schulzer M. The Collaborative Normal-Tension Glaucoma 
Study Group. Factors that predict the benefit of lowering intraocular pressure in normal 
tension glaucoma. Am J Ophthalmol 2003; 136:820–9. 
4. Casson RJ, Chidlow G, Wood JP, et al. Definition of glaucoma: clinical and experimental 
concepts. Clin Exp Ophthalmol 2012; 40:341-9. 
5. Grant WM. Tonographic method for measuring the facility and rate of aqueous flow in 
human eyes. Arch Ophthal 1950; 44(2):204-14. 
6. Heijl A, Leske MC, Hyman L, et al. Intraocular Pressure Reduction With a Fixed 
Treatment Protocol in the Early Manifest Glaucoma Trial. Acta Ophthalmol. 
2011;89:749-54.  
7. Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-masked 
study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution 
compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed 
concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma 
2005;14:392-9. 
8. Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of Uveitis Nomenclature 
(SUN) Working Group. Am J Ophthalmol 2005; 140:509-16. 
9. Kass MA, Heuer DK, Higginbotham EJ, et al.  The Ocular Hypertension Treatment 
Study.  Arch Ophthalmol 2002; 120:701-13. 
10. Kass MA, Gordon MO, Gao F, et al. The Ocular Hypertension Treatment Study. Arch 
Ophthalmol 2010; 128:276-87. 
11. Kiel JW, Kopczynski CC.  Effect of AR-13324 on episcleral venous pressure in Dutch 
Belted rabbits.  J Ocul Pharmacol Ther 2015; 31(3):146-51. 
12. 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 


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13. Sit AJ, Ekdawi NS, Malihi M, McLaren JW. A novel method for computerized 
measurement of episcleral venous pressure in humans. Exp Eye Res 2011-1; 92(6):537-
44. 
14. Sit AJ, McLaren JW. Measurement of episcleral venous pressure. Exp Eye Res 2011-2; 
93:291-8. 
15. Sommer A, Tielsch JM, Katz J, et al.  Relationship between intraocular pressure and 
primary open angle glaucoma among white and black Americans.  The Baltimore Eye 
Survey.  Arch Ophthalmol 1991; 109:1090-1095. 
16. Stamer WD, Acott TS.  Current understanding of conventional outflow dysfunction in 
glaucoma.  Curr Opin Ophthalmol 2012; 23:135-43. 
17. Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop instillation 
in glaucoma patients. Arch Ophthalmol 2009; 127:732-6 
18. Varma R, Ying-Lai M, Francis BA, et al.  Los Angeles Latino Eye Study Group.  
Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles 
Latino Eye Study.  Ophthalmology 2004; 111:1439-1448. 
19. 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 
20. Zeimer, RC, Gieser, DK, Wilensky, JT, et al. Practical Venomanometer: Measurement of 
Episcleral Venous Pressure and Assessment of the Normal Range. Arch Ophthalmol; 
1983; 101:1447-9 
11.2 
Internal References 
1. Aerie Pharmaceuticals, Inc. Investigators’ Brochure 
2. Aerie Pharmaceuticals, Inc. AR-13324-CS102 Clinical Study Report 
3. Aerie Pharmaceuticals, Inc. AR-13324-CS201 Clinical Study Report 
4. Aerie Pharmaceuticals, Inc. AR-13324-APH07 Non-Clinical Study Report 
 
 


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Appendix 1 
Schedule of Events 
Day (D)/Week(W)/Month(M) 
Screening 
Qualification/Day 1 
Exit/Day 8 
Visit 
1 
2/Baseline7 
3/On-drug7 
Hour 
-- 
08:00 
13:00 
16:00 
08:00 
13:00 
16:00 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
X 
X 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
 
 
 
 
 
 
HR/BP 
X 
X 
 
 
X 
 
 
Pregnancy test1  
X 
 
 
 
 
 
 
Ocular symptoms/AEs2  
X 
X 
 
 
X 
 
 
Visual Acuity (ETDRS) 
X 
X 
 
 
X 
 
 
IOP 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
 
 
X 
 
 
Gonioscopy3 
X 
 
 
 
 
 
 
Pachymetry3  
X 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
Eye-Drop Instillation Evaluation 
X 
 
 
 
 
 
 
EVP4 
X6 
 
X 
X 
 
X 
X 
Tonography  
 
 
X 
X 
 
X 
X 
Study meds dispensed 
 
 
 
X 
 
 
 
Study meds instilled5 
 
 
 
 
X 
 
 
Study meds collected 
 
 
 
 
X 
 
 
Study completed 
 
 
 
 
 
 
X 
1. Pregnancy test for females of child-bearing potential only. 
2. Ocular Symptoms: Patients will be queried at each visit “how are your eyes feeling” and 
TEAEs will be documented on the AE form. Additional symptoms reported after screening 
and before randomization will be documented on the medical history form. 
3. Gonioscopy within 3 months prior to screening, and Pachymetry within 1 week of 
screening are acceptable. 
4. Measurement of EVP will only be conducted at 1 site (
). 
5. Study medications to be instilled after 08:00 hour measurements are completed on Day 8. 
6. Only an assessment of a suitable episcleral vein prior to performing EVP measurements at 
Visit 2/Day 1.  If unable to assess at screening, it may be assessed at Visit 2 during the 
08:00 timepoint  
7. A visit variation of ± 30 minutes is allowed. 
 
 














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Appendix 3 
Sponsor’s Obligations 
Aerie Pharmaceuticals, Inc. is committed to: 
1. Complying with the local health authority regulations for the conduct of clinical research 
studies. 
2. Informing the Investigator of any new information about the investigational product that 
may affect the subject's welfare or may influence the subject's decision to continue 
participation in the study. 
3. In the event of a serious adverse experience, whether related to the use of the study 
medication or not, or the death of a subject, the Sponsor is responsible for notifying the 
regulatory authority(ies) immediately (see Section 6.8.9, Adverse Event Assessments).  
4. When the study is terminated the Sponsor should promptly inform the regulatory 
authority(ies) of the termination and the reason(s) for it. The IRB should also be informed 
promptly and provide the reason(s) for the termination by the Sponsor as specified by the 
applicable regulatory requirement(s).  
5. Providing to the Investigator the most up-to-date editions of the Clinical Investigator’s 
Brochure (for the investigational product), the protocol, Serious Adverse Experience 
forms, and a full set of Case Report Forms for each subject entered into the study to 
document the study evaluation parameters. 
6. Providing study medications suitably masked/blinded, coded and packaged for use with 
subjects entered into the study. 
7. Providing statistical and report writing resources to complete appropriate reporting of 
study results. 
8. Ensuring equity considerations among all Investigators in multicenter studies, including 
all matters of publications and meeting presentations, etc. (where applicable). 
9. Prepare an FDA Form No. 3454 (Certification: Financial Interests and Arrangements of 
Clinical Investigators) or 3455 (Disclosure: Financial Interests and Arrangements of 
Clinical Investigators) or Sponsor’s equivalent 
 
 


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Appendix 4 
Investigator’s Obligations 
The Investigator is obligated to: 
1. In the event of a serious adverse experience, whether related to the use of the study 
medication or device or not, or the death of a subject, the Investigator is responsible for 
notifying the Sponsor Safety Officer immediately (see Section 6.8, Adverse events). The 
Investigator must also notify the Sponsor Representative and the Institutional Review 
Board (IRB) to which he/she is responsible. 
2. Prior to initiating the study, sign and return to the Sponsor Representative, the relevant 
form (Statement of Investigator form provided by the Sponsor for studies involving non 
significant risk devices, or OTC drugs; or an FDA No. 1572 is required for IND Phase I, 
II, III and IV studies). Each sub-Investigator who will assist in the study is to be 
identified in the required form. The current curriculum vitae (signed and dated) of the 
principal Investigator and of each sub-Investigator named in the Statement of Investigator 
form or 1572 form is to accompany the form.  
3. Cooperate with the Sponsor on the preparation of an FDA Form No. 3454 (Certification: 
Financial Interests and Arrangements of Clinical Investigators) or 3455 (Disclosure: 
Financial Interests and Arrangements of Clinical Investigators).  
4. Obtain and submit to the Sponsor a copy of his/her IRB approval of the protocol prior to 
initiating the study. 
5. Obtain signed informed consent from each subject or his/her legal guardian prior to 
acceptance of the subject into the study. 
6. Read, and agree to adhere to the study protocol prior to the initiation of the study. 
Deviations from the study protocol are not to be implemented without the prior written 
approval of the Sponsor and IRB, unless protection of the safety and welfare of study 
subjects requires prompt action. During the study, if the Investigator feels that in his/her 
clinical judgment, it is necessary to promptly terminate one or more subjects from the 
study, or to promptly implement reasonable alternatives to, or deviations from the 
protocol in consideration of the safety of study subjects, the Sponsor is to be notified of 
these terminations, alternatives, and deviations, and the reasons for such changes are to 
be documented in the study records. The Investigator is to also notify his/her IRB of any 
such changes. 
7. Accurately record, at the Investigator’s site, all required data on each subject's electronic 
Case Report Form.  
8. 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. 


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Before returning the study medications or devices to the Sponsor, a detailed inventory 
should be recorded and placed in the Investigator’s file. 
9. Assure that Investigational Products will be dispensed or administered only to subjects 
under his/her personal supervision, or under the supervision of authorized sub-
Investigators responsible to him/her. 
10. Allow a representative of the Sponsor and/or representatives of health regulatory 
agencies to inspect all Case Report Forms and corresponding portions of each study 
subject's source documentation (ie, original office, hospital, and laboratory records) at 
mutually convenient times at regular intervals during the study, and upon request after the 
study has been completed. The purpose of these on site monitoring visits is to provide the 
Sponsor the opportunity to evaluate the progress of the study, document compliance with 
the protocol and with regulatory requirements, verify the accuracy and completeness of 
subject electronic Case Report Forms, resolve any apparent discrepancies or 
inconsistencies in the study records, and account for all investigational supplies. 
11. Provide the governing IRB with a brief (ie, one to three pages) Investigator's summary 
within 90 working days of the study completion.  
12. Complete the study within the time limits agreed upon with the Sponsor prior to the 
initiation of the study. 
13. Maintenance of records 
a. Disposition of drug. An investigator is required to maintain adequate records of the 
disposition of the drug, including dates, quantity, and use by subjects. If the 
investigation is terminated, suspended, discontinued, or completed, the investigator 
shall return the unused supplies of the drug to the Sponsor, or otherwise provide for 
disposition of the unused supplies of the drug under 21 CFR 312.59. 
 
b. Case histories. An investigator is required to prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each individual administered the investigational drug or employed as 
a control in the investigation. Case histories include the case report forms and 
supporting data including, for example, signed and dated consent forms and medical 
records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.  
c. Record retention. An investigator shall retain records required to be maintained under 
this part for a period of 2 years following the date a marketing application is approved 
for the drug for the indication for which it is being investigated; or, if no application 
is to be filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and FDA is notified.  


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


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


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

SAP_001.pdf: 
 
 
 
 A Double-Masked, Randomized, Placebo- 
Controlled Study of Trabecular Outflow 
Facility Following Treatment with Netarsudil 
Ophthalmic Solution 0.02% (AR-13324) in 
Subjects with Elevated Intraocular Pressure 
 
 
 
NCT03233308 
 
05February2018 
 










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13.2 Secondary Analyses .......................................................................................................... 1516 
14. 
Exploratory Analyses ............................................................................................................. 16 
15. 
Safety Analyses ..................................................................................................................... 16 
15.1 Adverse Events .................................................................................................................. 1617 
15.2 Visual Acuity (ETDRS) ........................................................................................................... 18 
15.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 18 
15.4 Vital Signs .......................................................................................................................... 1819 
15.5 Clinical Laboratory Data ......................................................................................................... 19 
16. 
Interim Analyses .................................................................................................................... 19 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 19 
18. 
References ............................................................................................................................. 19 
19. 
Revision History ..................................................................................................................... 19 
20. 
Tables .................................................................................................................................... 19 
21. 
Listings ................................................................................................................................... 21 
22. 
Figures ................................................................................................................................... 21 
 
 
 






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 
Ophthalmoscopy 
 
Pachymetry and Gonioscopy (screening only) 
 
Heart rate (HR) and blood pressure 
2.4 
Statistical Hypotheses 
The primary endpoint is the mean change from baseline in the mean diurnal trabecular outflow facility 
on Day 8. The null and alternative hypotheses, based on the primary variable are as follows: 
H01: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% and study 
eyes treated with Placebo, in the mean change from baseline of mean diurnal trabecular outflow facility 
= 0 on Day 8. 
H11: The difference between study eyes treated with Netarsudil Ophthalmic Solution 0.02% and study 
eyes treated with Placebo, in the mean change from baseline of mean diurnal trabecular outflow facility 
> 0 on Day 8. 
3. Study Design and Procedures 
3.1 
General Study Design 
This will be a double-masked, Placebo-controlled, paired-comparison study conducted at approximately 
2 centers in the US to evaluate the effect of treatment with Netarsudil Ophthalmic Solution 0.02% 
(Netarsudil) on trabecular outflow facility. Netarsudil will be administered to one eye and Placebo to the 
contralateral eye once daily, 1 drop in the morning (QD, AM), in adult subjects at least 18 years of age 
with POAG or OHT. Study medication will be administered for 7 consecutive days, although the total 
time of subject participation in the study (including washout from prior treatment, if necessary) may be 
up to 7 weeks.  
Subjects will be eligible to enroll in the study if they have a current diagnosis of POAG or OHT in both 
eyes (POAG in one eye and OHT in the contralateral eye is also acceptable), and may be treatment-
naïve or taking topical ocular hypotensive medication. If necessary, subjects who agree to participate in 
the study will be required to washout from their current IOP-lowering treatment for a minimum specified 
period of time (5 days to at least 4 weeks), according to the type of treatment. Subjects will attend a total 
of 3 study visits: a screening visit (Visit 1), to be conducted up to 6 weeks prior to a qualification visit 
(Visit 2, Day 1, baseline), and a final visit after 7 days on-treatment (Visit 3, Day 8, exit) where a member 
of the site staff will administer their 7th dose after completing their 08:00 hour assessments.  
Both eyes must qualify for the study with an unmedicated (post-washout or treatment-naïve) IOP of >20 
mmHg but <30 mmHg at 08:00 hours and >17 mmHg but <30 mmHg at 13:00 and 16:00 hours at the 
qualification visit. In order to be randomized into the study, eligible subjects must meet all of the 


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inclusion, and none of the exclusion criteria at both the screening and at the qualification visit, following 
washout from their current ocular hypotensive treatment, if required.  
If the subject continues to be eligible, they will be randomized at the end of their qualification visit (Visit 
2, Day 1, baseline) to receive Netarsudil Ophthalmic Solution 0.02% in one eye and Placebo in the 
contralateral eye for 7 days, QD (AM). Subjects will be asked to begin self-administration of their 
assigned medications in the morning on Day 2 following their baseline (Day 1) visit. Subjects will be 
instructed to administer 1 drop from each bottle of their study medication into the assigned eye for that 
bottle, every morning at approximately the same time (between 08:00 and 10:00 hours) for 6 consecutive 
days. On the day of the final (exit) visit (Visit 3, Day 8), subjects will return to the site at 08:00 hours for 
their final dose of study medication and to complete their on-treatment measurements before exiting. 
Safety measures (including VA, biomicroscopy, and AEs) will be evaluated at all visits. Efficacy 
assessments will include IOP at 08:00, 13:00 and 16:00 hours, and trabecular outflow facility and EVP, 
which will be measured at 13:00 and 16:00 hours. Trabecular outflow facility (primary endpoint) and IOP 
(secondary endpoint) will be collected in all subjects. The other secondary endpoint, EVP, will be 
measured in a subset of subjects. 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below. 
Day (D)/Week(W)/Month(M) 
Screening 
Qualification/Day 1 
Exit/Day 8 
Visit 
1 
2/Baseline7 
3/On-drug7 
Hour 
-- 
08:00 
13:00 
16:00 
08:00 
13:00 
16:00 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
X 
X 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
 
 
 
 
 
 
HR/BP 
X 
X 
 
 
X 
 
 
Pregnancy test1  
X 
 
 
 
 
 
 
Ocular symptoms/AEs2  
X 
X 
 
 
X 
 
 
VA (ETDRS) 
X 
X 
 
 
X 
 
 
IOP 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
 
 
X 
 
 
Gonioscopy3 
X 
 
 
 
 
 
 
Pachymetry3  
X 
 
 
 
 
 
 
Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 


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Eye-Drop Instillation Evaluation 
X 
 
 
 
 
 
 
EVP4 
X6 
 
X 
X 
 
X 
X 
Tonography  
 
 
X 
X 
 
X 
X 
Study meds dispensed 
 
 
 
X 
 
 
 
Study meds instilled5 
 
 
 
 
X 
 
 
Study meds collected 
 
 
 
 
X 
 
 
Study completed 
 
 
 
 
 
 
X 
1. Pregnancy test for females of child-bearing potential only. 
2. Ocular Symptoms: Patients will be queried at each visit “how are your eyes feeling” and 
TEAEs will be documented on the AE form. Additional symptoms reported after screening 
and before randomization will be documented on the medical history form. 
3. Gonioscopy within 3 months prior to screening, and Pachymetry within 1 week of 
screening are acceptable. 
4. Measurement of EVP will only be conducted at 1 site 
 
5. Study medications to be instilled after 08:00 hour measurements are completed on Day 8. 
6. Only an assessment of a suitable episcleral vein prior to performing EVP measurements at 
Visit 2/Day 1. If unable to assess at screening, it may be assessed at Visit 2 during the 
08:00 timepoint  
7. A visit variation of ±  30 minutes is allowed.
4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
Enrolled subjects will receive both investigational products (IPs), Netarsudil Ophthalmic Solution 0.02% 
(QD AM) and Placebo (QD AM). Individual eyes will be randomized to receive active treatment or 
Placebo; one treatment will be dosed in the right eye (OD), and the other treatment will be dosed in the 
left eye (OS). Each IP dose will be self-administered by the study subjects. For subjects deemed unable 
to self-administer the doses at the qualification visit (Visit 2, Day 1), a guardian or caregiver will be asked 
to administer the medication. 
Masked kits containing identical bottles of IP labelled “right eye” or “left eye” will be provided to all 
subjects at the end of Visit 2 (Day 1, qualification, baseline). They will be instructed to begin self-
administration in the morning of Day 2 at approximately the same time each day (between 08:00 and 
10:00 hours) for the following 6 days, returning to the site on Day 8 where study personnel will administer 
the final dose.  
A randomization schedule will be prepared by an independent individual (unmasked personnel) who is 
not involved in the day-to-day conduct of the study. Randomization will be stratified by site using 
permuted blocks, such that there will be an approximately equal number of subjects assigned to each 
of the two sequences ([Active Left Eye and Placebo Right Eye] and [Active Right Eye and Placebo Left 
Eye]) at each site.  


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The randomization schedule will be provided to the investigational site. The eligible subjects will be 
assigned a randomization number at the end of Visit 2, Day 1. Randomization numbers will be assigned 
sequentially to subjects in the order in which they become eligible for randomization. The site staff will 
dispense to the subject the study kit labeled with the corresponding randomization number. Each kit will 
contain one bottle of each product labeled “right eye” (OD) and “left eye” (OS). The randomization 
number will be recorded on the subject’s source document and electronic case report form (eCRF).  
5. Sample Size and Power Considerations 
Among the AHD parameters, trabecular outflow facility is of key interest and therefore used for the 
overall sample size calculation. Assuming a one-sided alpha = 0.05, a standard deviation for the 
difference between treatments in the mean change from baseline in diurnal means of 0.07 mmHg 
(calculated with a common standard deviation of 0.06 μL/min/mmHg within each treatment and a 
correlation of 40% between eyes within the same subject), and a difference in mean change from 
baseline between treatments (Active - Placebo) in diurnal means of 0.08 μL/min/mmHg, a sample size 
of 16 subjects (32 eyes) yields greater than 95% power.  
Assuming approximately 20% of the randomized subjects will be non-evaluable, i.e. either non-
responders (see modified intent-to-treat [mITT] population below for the definition of responder) or 
discontinue prior to Day 8, the required number of subjects to be randomized will be 20 subjects. 
6. Data Preparation 
Study data will be recorded via eCRFs. 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 eCRF via a secure internet 
access. Each completed set of eCRFs will be reviewed by the Investigator who will then electronically 
sign and date the eCRF confirming that data for the subjects are complete and accurate. 
All final analyses outlined in this document will be carried out after the following have occurred: 
 
All data management requirements are met according to 
 
standard operating procedures, including data entry, performance of edit and validation 
checks, documentation and resolution of data queries, and database lock with written 
authorization provided by appropriate 
 and Sponsor personnel; 
 
Protocol deviations have been identified and status defined (major/minor deviations);  
 
Analysis populations have been determined; and 
 
Randomized treatment codes have been unmasked. 




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Baseline mean diurnal values for all AHD is defined as the average of 13:00 and 16:00 hour 
measurements on Day 1, Visit 2. 
8.4 
Data Analysis Conventions 
All data analysis will be performed by 
. Statistical programming and analyses will be performed 
using SAS® Version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable 
document format (PDF) for tables, listings, and figures using landscape orientation. All study data will 
be listed by subject, treatment, visit, and time point (as applicable) based on all randomized subjects 
unless otherwise specified. 
All continuous study assessments will be summarized by treatment and visit (as applicable) using 
descriptive statistics (number of observations [n], mean, median, standard deviation, minimum, and 
maximum). All categorical study assessments will be summarized by treatment, visit, and time point(as 
applicable) using frequency counts and percentages. 
All study data entered in the database will be listed by subject, visit, and time point (as applicable). 
All statistical tests will be performed with a significance level of 5% (one-tailed). Where applicable, two-
sided 90% and 95% CIs will be reported.  
8.5 
Adjustments for Multiplicity 
No adjustments for multiplicity are planned. 
9. Disposition of Subjects 
The following disposition items will be summarized:  
 
The number and percentage of subjects in each analysis population 
 
The number and percentage of subjects who completed the study  
 
The number and percentage of subjects who withdrew from the study and the reasons for      
premature discontinuation  
 
The number and percentage of subjects with any major deviations  
All percentages will use the number of subjects treated as the denominator, unless indicated otherwise.  
In addition, subject disposition and protocol deviation listings will be provided. 
10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include age, gender, race, and ethnicity. Subjects who 
record more than one race will be grouped into a single category denoted as multi-racial. Demographic 
variables will be summarized for all randomized subjects.