Conditions: Glaucoma
Keywords: Glaucoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 136
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the IOP-lowering effect when subjects are switched from various latanoprost-based regimens to Rocklatan. Subjects will stop their IOP-lowering medical therapy regimen and dose with Rocklatan for the duration of the study (12 weeks).

Detailed description:
Enrollment will be stratified according to subject's IOP-lowering medical therapy regimen as follows:

* Latanoprost monotherapy (Latanoprost Mono)
* Latanoprost plus 1 additional IOP-lowering agent (Latanoprost +1)
* Latanoprost plus 2 additional IOP-lowering agents (Latanoprost +2)

Aerie Pharmaceuticals was acquired by Alcon Research LLC on November 22, 2022.

Arms:
arm 1: Netarsudil 0.02%/latanoprost 0.005% fixed dose combination ophthalmic solution, one drop in each eye in the evening for 12 weeks

Interventions: intervention 1: Netarsudil 0.02%/latanoprost 0.005% fixed dose combination ophthalmic solution
Intervention descriptions: intervention 1: Commercially available ophthalmic solution indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
A MULTICENTER, OPEN-LABEL ROCKLATAN® 
(NETARSUDIL/LATANOPROST OPHTHALMIC SOLUTION) 
0.02%/0.005% EVALUATION OF IOP LOWERING EFFICACY 
AND SAFETY AS REPLACEMENT OF CURRENT MEDICAL THERAPY 
REGIMEN FOR THE REDUCTION OF ELEVATED INTRAOCULAR 
PRESSURE IN PATIENTS WITH GLAUCOMA OR OCULAR 
HYPERTENSION 
 
MORE: Multi-center, Open-label Rocklatan® Evaluation 
 
STUDY ID: 
MA‐ROC‐22‐003 
 
PROTOCOL 
30‐Sep‐2022 
 
 
NCT05283395 
 
 




 
CONFIDENTIAL 
MA-ROC-22-003 Study, Amendment 1 
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A MULTICENTER, OPEN-LABEL ROCKLATAN® (NETARSUDIL/LATANOPROST OPHTHALMIC 
SOLUTION) 0.02%/0.005% EVALUATION OF IOP LOWERING EFFICACY AND SAFETY AS 
REPLACEMENT OF CURRENT MEDICAL THERAPY REGIMEN FOR THE REDUCTION OF 
ELEVATED INTRAOCULAR PRESSURE IN PATIENTS WITH GLAUCOMA OR OCULAR 
HYPERTENSION 
 
 
MORE: Multi-center, Open-label Rocklatan® Evaluation 
 
 
PROTOCOL NUMBER 
 
MA-ROC-22-003, Amendment 1 
ORIGINAL PROTOCOL DATE  
 
24 Feb 2022 
REVISED PROTOCOL DATE  
 
30 Sep 2022 
 
INVESTIGATOR’S SIGNATURE PAGE 
 
I agree to: 
 
1. Implement and conduct this study diligently and in strict compliance with the protocol, Good 
Clinical Practice, and all applicable laws and regulations. 
 
2. Maintain all information supplied by Aerie Pharmaceuticals, Inc. in confidence and, when this 
information is submitted to an Institutional Review Board, Independent Ethics Committee, or 
another group, it will be submitted with a designation that the material is confidential. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
Investigator’s Title 
Name of Facility 
Location of Facility (City, State) 
 
Acknowledged By: 
 
 
 
Signature of Sponsor’s Representative 
 
Date 
 
 
 
Printed Name and Title 
 
Date 
 
 
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A MULTICENTER, OPEN-LABEL ROCKLATAN® (NETARSUDIL/LATANOPROST 
OPHTHALMIC SOLUTION) 0.02%/0.005% EVALUATION OF IOP LOWERING EFFICACY 
AND SAFETY AS REPLACEMENT OF CURRENT MEDICAL THERAPY REGIMEN FOR THE 
REDUCTION OF ELEVATED INTRAOCULAR PRESSURE IN PATIENTS WITH GLAUCOMA 
OR OCULAR HYPERTENSION 
 
MORE: Multi-center, Open-label Rocklatan® Evaluation 
 
 
PROTOCOL NUMBER 
 
MA-ROC-22-003, Amendment 1 
ORIGINAL PROTOCOL DATE  
 
24 Feb 2022 
REVISED PROTOCOL DATE  
 
30 Sep 2022 
 
 
 
 
 
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Final 30Sep2022 
 
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Final 30Sep2022 
 
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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ................................................................... 8 
2. 
STUDY OBJECTIVE ............................................................................................ 8 
3. 
STUDY DESIGN .................................................................................................... 9 
4. 
STUDY POPULATION ......................................................................................... 9 
4.1 
Number of Subjects ........................................................................................... 9 
4.2 
Number of Study Centers .................................................................................. 9 
4.3 
Subject Eligibility .............................................................................................. 9 
4.3.1 
Inclusion Criteria  ........................................................................................ 9 
4.3.2 
Exclusion Criteria ...................................................................................... 10 
4.3.3 
Subject Withdrawal Criteria ..................................................................... 11 
5. 
STUDY MEDICATION AND OTHER STUDY SUPPLY INFORMATION ... 11 
5.1 
Study Medications ........................................................................................... 11 
5.1.1 
Study Medication Information .................................................................. 11 
5.1.2 
Formulations .............................................................................................. 11 
5.1.3 
Storage, Handling, Dispensing and Reconciliation of Study Medications 11 
5.1.4 
Site Personnel Study Medication Instructions .......................................... 12 
5.1.5 
Subject Dosing and Storage Instructions (Visits 1 & 2) ........................... 12 
5.2 
Additional Study Supplies ............................................................................... 13 
6. 
PRIOR AND CONCOMITANT THERAPIES ................................................... 13 
6.1 
Allowed Medications or Treatments ............................................................... 13 
7. 
STUDY PROCEDURES ...................................................................................... 13 
7.1 
Subject Entry Procedures ............................................................................... 13 
7.1.1 
Overview of Entry Procedures .................................................................. 13 
7.1.2 
Informed Consent and HIPAA Authorization .......................................... 14 
 
 
7.2 
Study Procedures ............................................................................................. 14 
7.3 
Overall Instructions ......................................................................................... 14 
7.4 
Visit 1 (Day 0): Baseline .................................................................................. 14 
7.4.1 
Women of Childbearing Potential and Acceptable Contraceptive 
Methods ...................................................................................................... 15 
7.5 
Visit 2 (Week 6): Follow-Up ............................................................................ 15 
7.6 
Visit 3 (Week 12): Final Visit .......................................................................... 16 
7.7 
Unscheduled Visits ........................................................................................... 16 
8. 
CLINICAL ASSESSMENTS ............................................................................... 16 
8.1 
Efficacy Assessment ......................................................................................... 16 
8.1.1 
Intraocular Pressure .................................................................................. 16 
8.2 
Safety Assessments .......................................................................................... 16 
8.2.1 
Adverse Events ........................................................................................... 16 
8.2.2 
Best Corrected Visual Acuity .................................................................... 17 
8.2.3 
Biomicroscopy ............................................................................................ 17 
8.2.4 
Pregnancy Testing ..................................................................................... 17 
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9. 
END OF STUDY .................................................................................................. 17 
9.1 
Completion of the Study .................................................................................. 18 
9.2 
Subject Discontinuation................................................................................... 18 
9.3 
Study Termination ........................................................................................... 18 
10. ADVERSE EVENT DEFINITIONS AND REPORTING .................................. 18 
10.1 
Adverse Events ................................................................................................ 18 
10.1.1 
Severity of Adverse Events ........................................................................ 19 
10.1.2 
Relationship of Adverse Events ................................................................. 19 
10.2 
Serious Adverse Events ................................................................................... 20 
10.3 
Pregnancy ........................................................................................................ 21 
11. STATISTICAL CONSIDERATIONS ................................................................. 21 
11.1 
Sample Size ...................................................................................................... 21 
11.2 
Analysis Populations ........................................................................................ 21 
11.3 
Statistical Methods .......................................................................................... 22 
11.3.1 
Baseline Analyses ....................................................................................... 22 
11.3.2 
Efficacy Analysis ........................................................................................ 22 
11.3.3 
Safety Analyses .......................................................................................... 22 
 
 
 
 
12. ADMINISTRATIVE CONSIDERATIONS ........................................................ 23 
12.1 
Protection of Human Subjects ........................................................................ 23 
12.1.1 
Informed Consent Regulations .................................................................. 23 
12.1.2 
Ethics Committee and Independent Review Board Regulations ............. 23 
12.1.3 
Good Clinical Practice Regulations ........................................................... 23 
12.2 
Changes to Protocol ......................................................................................... 23 
12.3 
Quality Control and Assurance....................................................................... 23 
12.4 
Subject Confidentiality .................................................................................... 24 
12.5 
Required Study Documents ............................................................................. 24 
12.6 
Record Retention ............................................................................................. 24 
13. REFERENCES ..................................................................................................... 25 
14. APPENDICES ...................................................................................................... 26 
 
TABLE OF APPENDICES 
Appendix 4 
STUDY MEDICATION PACKAGE INSERT ................................... 30 
Appendix 5 
SCHEDULE OF VISITS/PROCEDURES .......................................... 31 
Appendix 6 
EXAMINATION PROCEDURES ...................................................... 32 
 
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1. BACKGROUND AND RATIONALE 
Glaucoma is a progressive optic neuropathy that causes characteristic loss of visual fields and can 
eventually lead to blindness. A major risk factor for glaucomatous visual field loss is elevated intraocular 
pressure (IOP); (The AGIS Investigators 2000). While numerous products are approved for use in the 
United States to lower IOP, the need for new options with improved efficacy is supported by several 
clinical studies. Studies such as the Early Manifest Glaucoma Trial (Heijl 2002), the Ocular Hypertension 
Treatment Study (Kass 2002; Kass 2010), and the Collaborative Normal Tension Glaucoma Study Group 
(Collaborative Normal-Tension Glaucoma Study Group 1998) support the general conclusion that for 
delaying disease progression, every millimeter of reduction in IOP is significant. This conclusion holds 
true not only for ocular hypertensive and glaucoma patients with elevated IOPs but also for glaucoma 
patients with IOPs in the statistically normal range.  In addition, for many individuals with glaucoma, 
current IOP-lowering medications are not sufficiently effective as monotherapy to achieve target IOP and 
the majority of glaucoma patients often need more than one drug to reach their target IOP 
(Lichter 2001). Increasing complexity of the dosing regimen often leads to decreased compliance with 
dosing.   
 
Thus, the goal for treating patients should be to maximally lower the IOP, to the point that it prevents 
further damage to the optic nerve and achieve this without sacrificing safety or convenience so as to 
maintain compliance. 
 
Inhibitors of Rho kinase (ROCK) have emerged as a new class of IOP-lowering agents.  Netarsudil 0.02% 
is a novel Rho kinase and norepinephrine transporter inhibitor developed at Aerie Pharmaceuticals, Inc. 
Netarsudil lowers IOP through a distinct mechanism of action: increasing trabecular outflow by 
decreasing acto-myosin–driven cellular contraction and reducing production of extracellular matrix 
proteins (Kazemi 2018; Lin 2018). In preclinical studies, netarsudil was shown to not only increase 
trabecular outflow facility (Lin 2018; Wang 2015; Ren 2016; Li 2016), but also to decrease episcleral 
venous pressure (Kiel 2015) and aqueous humor production (Wang 2015). The mechanisms of action of 
netarsudil were further explored in a phase 1 study of healthy human volunteers, in whom netarsudil 
0.02% QD was demonstrated to lower IOP primarily by increasing outflow facility, but also by reducing 
episcleral venous pressure (Kazemi 2018). 
 
Prostaglandin analogues are another class of IOP-lowering agents that are highly effective at lowering 
IOP when dosed once daily in the evening, primarily acting on uveoscleral outflow. 
 
 As netarsudil lowers IOP through different mechanisms of action than prostaglandin analogues, 
netarsudil provides additional IOP-lowering efficacy when used in combination with a prostaglandin 
analogue.  Recently, ROCKLATAN® 0.02%/.005% was approved by the United States Food and Drug 
Administration for reducing elevated IOP. ROCKLATAN® 0.02%/0.005% is a fixed dose combination of a 
Rho kinase inhibitor and a prostaglandin F2α analogue indicated for the reduction of elevated intraocular 
pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. 
 
Two randomized and controlled clinical trials enrolled subjects with IOP > 36 mmHg and compared IOP 
lowering effect of ROCKLATAN® dosed once daily (QD) to individually administered netarsudil 0.02% 
once daily and latanoprost 0.005% once daily.  Studies demonstrated 1 to 3 mmHg reductions in IOP 
greater than monotherapy with either netarsudil 0.02% or latanoprost 0.005% throughout 3 months in one 
study and reductions were maintained throughout 12 months in the other study (Rocklatan™ Prescribing 
Information 2019). 
   
2. STUDY OBJECTIVE 
The objective of this study is to to evaluate the IOP lowering, and number of agents/bottles required to 
achieve similar or additional IOP lowering with Rocklatan® in subjects on a current regimen of latanoprost 
alone or latanoprost plus addition of either one or 2 IOP-lowering agents. 
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3. STUDY DESIGN 
This is a multicenter, prospective, open-label stratified by baseline IOP lowering regimen groups study. 
Subjects diagnosed with open-angle glaucoma or ocular hypertension will be evaluated at a Baseline Visit 
(Visit 1, Day 0). Subjects satisfying Visit 1 inclusion/exclusion criteria will be invited to participate in this 
study.   
At the Baseline Visit (Visit 1, Day 0), all qualified subjects will be enrolled and dispensed Rocklatan®.  
Subjects will be instructed to stop their current IOP lowering medical therapy regimen and to begin dosing 
Rocklatan® in each eye daily in the evening of the Baseline Visit and for the duration of the 12-week 
study. Subjects will complete 2 follow up visits (Visit 2: 6 weeks [±7 days], Visit 3: 12 weeks [±7 days]), 
during which efficacy and safety assessments will take place.  The subjects will be exited from the study 
at the end of Visit 3. 
4. STUDY POPULATION 
4.1 
 Number of Subjects 
Approximately one hundred and sixty (160) male or female subjects will participate in this study.  
Enrollment will be stratified based on subject’s current Baseline IOP lowering therapy regimen: 
• 
60 subjects whose Baseline therapy regimen is latanoprost monotherapy 
• 
60 subjects whose Baseline therapy regimen is latanoprost plus 1 additional individual IOP-
lowering agent* 
• 
40 subjects whose Baseline therapy regimen is latanoprost plus 2 additional IOP-lowering agents   
Two additional IOP-lowering agents include two individual IOP-lowering agents* as well as fixed 
dose combinations**. 
*additional individual agent(s) include the following IOP lowering classes: beta blocker, alpha agonist, 
carbonic anhydrase inhibitor.   
**fixed-dose combinations combining two active ingredients will be considered as two IOP lowering 
agents. 
Note: latanoprost may be brand name or generic drug 
4.2 
Number of Study Centers 
Approximately 22 study centers in the United States will be utilized in this study. 
4.3 
Subject Eligibility 
To be eligible for enrollment into the study, subjects must qualify in at least one eye and meet all inclusion 
and none of the exclusion criteria detailed in Section 4.3.1 and Section 4.3.2. 
4.3.1 
Inclusion Criteria  
The following are criteria for inclusion in the study.  All must be met at the Baseline Visit (Visit 1, Day 0) to 
be eligible for participation. 
1. Male or female subjects age 18 or older 
2. Current diagnosis of open-angle glaucoma or ocular hypertension  
3. Subject currently being treated with latanoprost alone or latanoprost plus 1 or 2 additional 
agents/bottles.  Current IOP lowering regimen is stable for at least 30 days prior to Baseline Visit 
and is one of the regimens listed below: 
• 
Latanoprost monotherapy 
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• 
Latanoprost + 1 additional individual IOP-lowering agent * 
• 
Latanoprost + 2 additional IOP-lowering agents   
Two additional agents include two individual IOP-lowering agents * as well as fixed 
dose combinations** 
*additional individual agent(s) include the following IOP lowering classes: beta blocker, alpha 
agonist, carbonic anhydrase inhibitor.  
**fixed-dose combinations combining two active ingredients will be considered as two IOP 
lowering agents. 
Note: latanoprost may be brand name or generic drug 
4. Treated IOP ≥ 20 mmHg measured in the morning (before noon) at the Baseline Visit by 
Goldmann applanation tonometer 
5. Best corrected Snellen visual acuity of 20/100 or better in both eyes 
6. Willingness to follow protocol requirements, including signed informed consent and health 
information release forms, routine follow-up schedule, completing questionnaires 
 
4.3.2 
Exclusion Criteria  
The following are criteria for exclusion from the study: 
 
Ophthalmic: 
7. Have any active ocular disease other than open-angle glaucoma or ocular hypertension that 
would interfere with study interpretation 
8. Use of fixed dose combination agents as part of the patient’s Baseline IOP lowering therapy 
regimen, if not also on latanoprost 
9. Treatment naïve glaucoma or ocular hypertension patients 
10. Mean central corneal thickness greater than 620 µm in either eye 
11. Have any corneal abnormality preventing reliable applanation tonometry in either eye (e.g., scar, 
edema, keratoconus) 
12. Active ocular infection/inflammation or history of uveitis 
13. Aphakic or pseudophakic patients with a torn posterior lens capsule, or with known risk factors for 
macular edema 
14. Visual field loss, which, in the opinion of the investigator, is evidence of end-stage glaucomatous 
visual field loss 
15. History of corneal refractive laser surgery (e.g., LASIK, LESEK, RK, PRK) in the study eye within 
3 months prior to Baseline Visit 
16. History of intraocular surgery in the study eye within 3 months prior to Baseline, including 
glaucoma laser surgery (e.g., ALT, SLT), cataract surgery and minimally invasive glaucoma 
surgery (MIGS) 
 
Systemic: 
17. Any systemic disease or clinical evidence of any condition which would make the subject, in the 
opinion of the investigator, unsuitable for the study or could potentially confound the study results 
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18. Use of topical, periorbital, intravitreal or systemic steroid within previous 3 months or expected 
use during the course of the study 
19. Use of systemic medications(s) or therapy that may have a substantial effect on IOP unless such 
medication(s) or therapy has/have been used for a minimum of 3 months prior to Baseline Visit, 
is/are expected to remain constant throughout the course of the study and is/are considered 
necessary for a subjects’ welfare 
20. Prior participation in any investigational drug or device study within the last 30 days prior to the 
Baseline Visit. 
21. Known sensitivity or allergy to the study medication or components 
22. Females who are pregnant, nursing, or planning a pregnancy during the study  
23. Positive pregnancy test at Baseline Visit (women of childbearing potential only)  
24. Women of childbearing potential who are not using a medically acceptable form of birth control 
 
4.3.3 
Subject Withdrawal Criteria 
Criteria and procedures for handling subjects who are discontinued from the study are described in 
Section 9.2. Subjects who are discontinued will not be replaced. 
5. STUDY MEDICATION AND OTHER STUDY SUPPLY INFORMATION 
5.1 
Study Medications 
5.1.1 
Study Medication Information 
Enrolled subjects will be instructed to self-instill 1 drop of Rocklatan® (netarsudil/latanoprost ophthalmic 
solution) 0.02%/0.005% in each eye daily in the evening, beginning the evening of the Baseline Visit (Visit 
1). 
Rocklatan® 0.02%/0.005% will be provided by Aerie Pharmaceuticals, Inc. in the marketed containers and 
available for dispensing at the Baseline Visit (Visit 1, Day 0) and Visit 2 (Week 6).   
Detailed information is provided in the Rocklatan® Package Insert (Appendix 4). 
5.1.2 
Formulations 
Netarsudil 0.02%/latanoprost 0.005% 
Name: 
Rocklatan® (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005%  
 
Active ingredient:  
netarsudil dimesylate 0.28 mg and 0.05 mg latanoprost 
Other ingredients:  
boric acid, mannitol, sodium hydroxide to adjust pH and water for injection, 
benzalkonium chloride 0.02% (preservative) 
5.1.3 
Storage, Handling, Dispensing and Reconciliation of Study Medications  
The study medication must be stored protected from light and refrigerated at 2º to 8ºC (36º to 46ºF) at the 
study site in a secure area and administered only to subjects enrolled into the clinical study, at no cost to 
the subject, in accordance with the conditions specified in the protocol. 
Store Rocklatan® 0.02%/0.005% at 2º to 8ºC (36º to 46ºF) until opened. After opening, the product may 
be kept at 2º to 25ºC (36º to 77ºF) for up to 6 weeks.   If after opening the product is kept refrigerated at 
2°C to 8°C (36°F to 46°F), then the product can be used until the expiration date stamped on the bottle. 
Subjects are to save all used/unused bottles for presentation to designated study staff during office visits. 
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Study Medication Supply Records at Study Sites: 
It is the responsibility of the investigator to ensure that a current record of study medication disposition is 
maintained. Records or logs should include: 
• 
Amount received and placed in storage area 
• 
Dates and initials of the person(s) responsible for each product inventory entry/movement 
• 
Amount dispensed to and returned by each subject, including unique subject identifiers 
• 
Amount transferred to another area for dispensing or storage if necessary 
• 
Non-study disposition (e.g., lost, wasted, broken) 
Destruction of Study Medication Supplies:  
After subjects have completed study medication usage, all study medications (used and unused) will be 
collected by a designated staff. Only upon direction of sponsor and after reconciliation, all used/unused or 
undispensed study medication will be destroyed at the study site according to the site’s usual medication 
destruction practices. 
5.1.4 
Site Personnel Study Medication Instructions 
Enrolled subjects will be instructed to stop their current IOP lowering therapy regimen at the Baseline 
Visit (Visit 1) and to begin self-administering study medication, Rocklatan® 0.02%/0.005%, 1 drop in each 
eye daily in the evening of the Baseline Visit (Visit 1) (see Section 5.1.5 below). There is no washout 
period required for subjects.   
Instruct subjects that contact lens wear during the study is acceptable. However, subjects must remove 
their contact lenses before instillation of study medication and not place them in their eye(s) until 15 
minutes after instillation.   
Instruct subjects to avoid allowing the tip of the bottle to touch the eye to avoid bacterial eye infection 
which has been reported with the use of multiple-dose containers of topical ophthalmic products.  
 
5.1.5 
Subject Dosing and Storage Instructions (Visits 1 & 2) 
 
Baseline Visit (Visit 1) and Follow-Up Visit 2  
Visit 1 Study Medication Dosing Instructions  
Enrolled subjects will receive 2 bottles of Rocklatan® 0.02%/0.005% at the Baseline Visit (Visit 1) and will 
be instructed to refrigerate both the unopened bottles (2º to 8ºC [36º to 46ºF]).  
During the evening of the day each subject attends his/her Baseline Visit (Visit 1), subjects will remove 1 
bottle from refrigeration and commence administering Rocklatan® 0.02%/0.005% 1 drop in each eye daily 
in the evening until returning to the clinic for Visit 2. The opened bottle of Rocklatan® 0.02%/0.005% may 
be stored at 2º to 25ºC (36º to 77ºF) for 6 weeks. Subjects will be instructed to completely use up study 
medication in 1 bottle before removing the second bottle from refrigeration to begin dosing. 
Avoid allowing the tip of the bottle to touch the eye to avoid bacterial eye infection which has been 
reported with the use of multiple-dose containers of topical ophthalmic products. 
Contact lenses should be removed prior to using Rocklatan®. Contact lenses can be reinserted 15 
minutes following administration of Rocklatan®. 
Subjects will return to clinic as instructed by clinic site staff for Visit 2 (Week 6) with all used/unused study 
medication bottles. 
Visit 2 Study Medication Dosing Instructions  
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Subjects will receive 2 bottles of Rocklatan® 0.02%/0.005% at Visit 2 (Week 6) and will be instructed to 
refrigerate both the unopened bottles (2º to 8ºC [36º to 46ºF]). 
During the evening on the day each subject attends his/her Visit 2 (Week 6), subjects will remove 1 bottle 
from refrigeration and commence administering Rocklatan® 0.02%/0.005% 1 drop in each eye daily in the 
evening until returning to the clinic for the final study visit, Visit 3 (Week 12). The opened bottle of 
Rocklatan® 0.02%/0.005% may be stored at 2º to 25ºC (36º to 77ºF) for 6 weeks. Subjects will be 
instructed to completely use up study medication in 1 bottle before removing the second bottle from 
refrigeration to begin dosing. 
Avoid allowing the tip of the bottle to touch the eye to avoid bacterial eye infection which has been 
reported with the use of multiple-dose containers of topical ophthalmic products. 
Contact lenses should be removed prior to using Rocklatan®. Contact lenses can be reinserted 15 
minutes following administration of Rocklatan®. 
Subjects will return to clinic as instructed by clinic site staff for Visit 3 (Week 12) with all used/unused 
study medication bottles. 
5.2 
Additional Study Supplies 
The following supplies will be provided to the study site: 
• 
Combined Informed Consent/ Health Insurance Portability and Accountability Act of 1996 
(HIPAA) form, as applicable per Institutional Review Board (IRB) 
• 
Screening and Enrollment logs 
• 
Source documents 
• 
Electronic case report form (eCRF) completion guidelines 
• 
Study medication reconciliation logs  
• 
Package insert for Rocklatan® (netarsudil/latanoprost ophthalmic solution) 0.02%/0.005% 
6. PRIOR AND CONCOMITANT THERAPIES 
6.1 
Allowed Medications or Treatments 
Therapy considered necessary for a subject’s welfare will be given at the discretion of the investigator 
and documented during the course of the study. The use of any concurrent medication (prescription or 
over-the-counter, including herbal medications) is to be recorded in a subject’s source documentation 
(charts), as well as in the case report forms (CRFs), noting the date, dosage, frequency, start date, and 
reason for taking the medication(s). 
7. STUDY PROCEDURES 
7.1 
Subject Entry Procedures 
7.1.1 
Overview of Entry Procedures 
Subjects meeting inclusion and exclusion criteria (Section 4.3.1 and Section 4.3.2, respectively) will be 
considered for enrollment in this study. 
 
 
 
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7.1.2 
Informed Consent and HIPAA Authorization 
Subjects meeting enrollment criteria at the Baseline Visit (Visit 1) will be asked to participate in the study. 
The study design, follow-up, and participation parameters/criteria will be discussed with each subject. 
Subjects wishing to participate must provide written informed consent and sign an “Authorization for Use 
and Disclosure of Health Information for Research” release as a component of the informed consent 
document (HIPAA authorization) prior to any study-related procedures. 
 
 
 
 
   
7.2 
Study Procedures 
The Schedule of Visits/Procedures for this study is included in Appendix 5. 
Clinical assessments will be performed throughout the study as detailed in Section 8. All clinical 
assessments will be performed by the investigator (or designee). 
7.3 
Overall Instructions 
Subject’s Baseline Visit should occur in the morning (before noon). Subjects should be seen at each 
follow up visit at a time similar to that of the Baseline Visit.  Evaluations should be performed by the same 
evaluator throughout the study whenever possible.  
7.4 
Visit 1 (Day 0): Baseline 
Subject’s Baseline Visit should occur in the morning (before noon). 
The investigator (or designee) will perform/administer the following assessments: 
• 
Written informed consent and HIPAA authorization 
• 
Demographics 
• 
Subject eligibility (inclusion/exclusion criteria) 
• 
Urine pregnancy test (women of childbearing potential only) 
• 
Medical and IOP history  
• 
Prior and concomitant medications and/or procedures review 
• 
Best-corrected visual acuity (Snellen visual acuity chart) 
• 
Biomicroscopy 
• 
IOP assessment (morning measurement in each eye using Goldmann applanation 
tonometer) 
• 
Corneal pachymetry to measure central corneal thickness 
• 
Enrollment 
• 
Assign subject ID number 
• 
Dispense 2 bottles of Rocklatan® 0.02%/0.005% and have a staff member instruct 
the subject on use 
• 
Schedule Visit 2 (Week 6) at a similar time in the morning to that of the Baseline Visit 
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7.4.1 
Women of Childbearing Potential and Acceptable Contraceptive Methods 
An adult woman is considered to be of childbearing potential unless she is at least 1-year post-
menopause (no menses for 12 months or more without an alternative medical cause) or at least 3 months 
post-surgical sterilization. Subjects must not intend to become pregnant during the study and must 
properly use an acceptable effective method of contraception.  
If a woman is of childbearing potential, she must have a pregnancy test performed at the visits specified 
in the Schedule of Visits and Procedures (Appendix 5). Additional pregnancy tests may also be required 
per local regulatory guidelines. Subjects with positive pregnancy test result must be excluded from the 
study. Subjects with negative pregnancy test must agree to use an acceptable effective contraception 
method during the study.  
Acceptable contraceptive methods when used consistently and in accordance with both the product label 
and the instructions of the physician (Clinical Trials Facilitation Group 2014), include: 
1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal, or transdermal) 
2. 
Progestogen-only hormonal contraception (oral, injectable, or implantable) 
3. 
Intrauterine device (IUD) 
4. 
Intrauterine hormone-releasing system (IUS) 
5. 
Bilateral tubal occlusion  
6. 
Vasectomized partner [1]  
7. 
Sexual abstinence [2]  
8. 
Male or female condom with or without spermicide 
9. 
Cap, diaphragm, or sponge with spermicide 
 [1] Vasectomized partner is considered to be a highly effective birth control method providing that the partner is the 
sole sexual partner of the women of childbearing potential and that the vasectomized partner has received a medical 
assessment of the surgical success 
[2] Sexual abstinence is considered to be an acceptable method of contraception when defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study interventions. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of 
the subject 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. 
7.5 
Visit 2 (Week 6): Follow-Up  
Subject’s Visit 2 should occur in the morning (before noon) at a time similar to that of the 
Baseline Visit. 
The investigator (or designee) will perform/administer the following assessments: 
• 
Concomitant medications and/or procedures review 
• 
Best corrected visual acuity (Snellen visual acuity chart) 
• 
Biomicroscopy 
• 
IOP assessment (morning measurement in each eye using Goldmann applanation 
tonometer) 
• 
Adverse event (AE) assessment 
• 
Collect used/unused study medication containers 
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• 
Dispense 2 bottles of Rocklatan® 0.02%/0.005% and have a staff member instruct the 
subject on use 
• 
Schedule subject’s next visit (Visit 3, Week 12) at a similar time in the morning to that 
of the Baseline Visit 
7.6 
Visit 3 (Week 12): Final Visit  
Subject’s Visit 3 should occur in the morning (before noon) at a time similar to that of the 
Baseline Visit. 
The investigator (or designee) will perform/administer the following assessments: 
• 
Concomitant medications and/or procedures review 
• 
Best corrected visual acuity (Snellen visual acuity chart) 
• 
Biomicroscopy 
• 
IOP assessment (morning measurement in each eye using Goldmann applanation 
tonometer) 
• 
AE assessment 
• 
Collect used/unused study medication containers 
• 
Complete End of Study (Exit) Form 
7.7 
Unscheduled Visits 
In the event a subject returns for an unscheduled visit, the investigator (or designee) will 
perform/administer necessary assessments. Information collected from an unscheduled visit will be 
reported on Interim/Unscheduled Visit CRF(s). 
8. CLINICAL ASSESSMENTS  
The following clinical assessments will be performed according to the schedule as indicated in the 
Schedule of Visits/Procedures (Appendix 5). The same investigator (or designee) should complete the 
evaluations for a given subject throughout the study. 
8.1 
Efficacy Assessment 
8.1.1 
Intraocular Pressure 
IOP will be measured in both eyes in the morning (before noon) using a Goldmann applanation tonometer 
affixed to a slit lamp at the Baseline Visit, Visit 2, and Visit 3 (see Appendix 6 for detailed information on 
this examination). 
8.2 
Safety Assessments 
8.2.1 
Adverse Events 
At both Visit 2 (Week 6) and Visit 3 (Week 12) the investigator (or designee) will question each subject 
regarding adverse experiences that may have occurred since a previous visit. Subjects will be queried 
“How are you feeling?” and all AEs will be recorded in the CRFs including severity, action taken, and 
relationship to the study medication(s) (see Section 10 for further details). 
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Please see “Rocklatan® Package Insert” (Appendix 4) for further details regarding possible adverse 
experiences associated with the use of study medication. 
8.2.2 
Best Corrected Visual Acuity 
BCVA will be measured for both eyes by the investigator (or designee) at the Baseline Visit (Visit 1) and 
at both Visit 2 (Week 6) and Visit 3 (Week 12) using a Snellen Visual Acuity Chart (see Appendix 6 for 
detailed information on this examination). 
8.2.3 
Biomicroscopy 
Biomicroscopy will be performed according to the site’s usual practice by the investigator (or designee) 
for both eyes at the Baseline Visit and at each follow-up visit by slit lamp examination.  Eye 
structures/surfaces to be assessed include, but are not limited to, lids/lashes, conjunctiva (palpebral and 
bulbar), cornea, anterior chamber and lens.  All observations will be recorded. (see Appendix 6 for 
detailed information on this examination). 
8.2.4 
Pregnancy Testing 
A urine human chorionic gonadotropin (hCG) pregnancy test (only for females of childbearing potential) 
will be used in this study and performed at the Baseline Visit to immediately confirm non-pregnancy 
eligibility for women of child-bearing potential. 
If pregnancy occurs during the study, the investigator must immediately notify the Ethics Committee/IRB 
and Aerie.   In addition, every attempt will be made to collect data on the pregnancy of female subjects. 
Signature of a separate consent form will be requested of the pregnant woman. Information on pregnant 
partners of study subjects will not be collected. 
Every attempt will be made to collect data regarding the newborn child born to a female subject with 
parent/guardian permission. One parent or the legal guardian will be requested to provide permission for 
the minor to participate in this part of the research      
9. END OF STUDY 
At the end of each subject’s participation in the study, the investigator (or designee) will complete an End 
of Study Form (Completion) for all completed and discontinued subjects. 
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9.1 
Completion of the Study 
Each subject who completes the entire Schedule of Visits as specified in this protocol will have completed 
the study. 
9.2 
Subject Discontinuation 
A subject may be withdrawn from the study prior to completion for any reason and categorized as follows: 
• 
AEs 
• 
Lost to follow-up 
• 
Subject decides it is in his/her best interest to withdraw 
• 
Investigator decides it is in the subject’s best interest to be withdrawn 
• 
Noncompliance 
• 
Other (administrative reasons, etc.) 
If a subject discontinues from the study for any reason at any point beyond his/her Baseline Visit (Visit 1), 
he/she should be requested to return for a final visit at which time all Visit 3 (Week 12) procedures should 
be performed according to the protocol Schedule of Visits/Procedures (see Appendix 5).   
Subjects who are prematurely withdrawn or discontinued from the study will not be replaced. 
9.3 
Study Termination 
The study may be terminated by the investigator or the sponsor. If, in the opinion of the investigator, 
clinical observations made during the study suggest that it may be unwise to continue, the investigator 
may stop the study. Study termination by the investigator will be reported to the sponsor. 
In addition, a written statement fully documenting the reasons for this action will be submitted to the 
sponsor and the IRB by the investigator within 5 working days. 
In the event that the sponsor chooses to discontinue or terminate the study, appropriate notification will 
be given to the investigator. 
10. ADVERSE EVENT DEFINITIONS AND REPORTING 
10.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the administration of the study 
intervention in humans, whether or not considered related to the study medication.  AEs include any 
illness, sign, symptom, or clinically significant laboratory test abnormality that has appeared or worsened 
during the course of the clinical trial, regardless of causal relationship to the study medication(s) under 
study. 
Study medication is defined as a pharmaceutical form of an active ingredient or vehicle/placebo being 
tested or used as a reference in the study, whether masked or unmasked. AEs may be either 
spontaneously reported or elicited during questioning and examination of a subject. 
 
All AEs will be collected from visits 2 and 3 as well as upon subject report after visit 1, 
and will continue until the final protocol required visit and/or continue through resolution, 
stabilization, or the Investigator assesses them as chronic or stable or the subject’s 
participation in the trial ends, whichever occurs first.  Documentation of AEs will include AE description, 
start date and stop date, severity, relationship, action(s) taken, seriousness, and outcome.   
If a disease is known at the time an AE is reported, this diagnosis should be recorded rather than listing of 
individual symptoms. However, if a cluster of symptoms cannot be identified as a single diagnosis, each 
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individual event should be reported separately. If a diagnosis is subsequently known, it should be 
reported as follow-up information. 
When recording an AE, the following information should be provided on the study AE CRF: 
1. Action Taken with Study Intervention: 
• None 
• Study Intervention Discontinued 
• Study Intervention Interrupted 
2. AE Outcome: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/Lost to follow-up 
Subjects experiencing AEs that cause interruption or discontinuation of study medication, or those 
experiencing AEs that are present at the end of their participation in the study should receive follow-up, 
as appropriate. If possible, report the outcome of any AE that caused permanent discontinuation or that 
was present at the end of the study, particularly if the AE was considered by the investigator to be related, 
or possibly/unlikely related to investigational product. 
AEs should be followed to resolution or stabilization and reported as serious adverse events (SAEs) if 
they become serious (Section 10.2). 
 
Adverse drug reactions that are both serious and unexpected (suspected unexpected 
serious adverse reactions [SUSARs]) will be subject to expedited reporting by the Sponsor 
to the FDA as required by the relevant regulations. 
10.1.1 
Severity of Adverse Events  
Severity of an AE is defined as a qualitative assessment of the level of discomfort or the degree of 
intensity of an AE as determined by the Investigator or reported to them by the subject. The assessment 
of severity is made irrespective of study medication relationship or seriousness of the event and should 
be evaluated according to the following scale: 
Mild: present and noticeable, but not distressing, and no disruption of normal daily activities 
Moderate: bothersome, discomfort sufficient to possibly reduce or affect normal daily activity 
Severe: incapacitating, with inability to work or perform normal daily activity 
A change in increased 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 
moderate, or from moderate to severe. In either case, the start and stop dates should be recorded. 
Note: A severe AE is not the same as a serious AE. Seriousness of an AE (NOT severity) serves as a 
guide for defining regulatory reporting obligations (see Section 10.2 for further information on SAEs). 
10.1.2 
Relationship of Adverse Events 
The relationship of the AE(s) to the study medication(s) must be specified by the investigator using the 
following definitions: 
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Not Related: The event is clearly related to other factors, such as subject’s clinical condition, therapeutic 
interventions, concomitant disease, or therapy administered to the subject and does not follow a known 
response pattern to the product. 
Unlikely Related: The event is most probably caused by other etiologies. such as participant’s underlying 
condition, therapeutic intervention, or concomitant therapy; or the delay between administration and the 
onset of the AE is incompatible with a causal relationship. Therefore, there is not a reasonable possibility 
that the AE was caused by the study medication. 
Possibly Related: The event follows a reasonable, temporal sequence from the time of study medication 
administration and/or follows a known response pattern to the study medication but could have been 
produced by other factors, such as the subject’s clinical state, therapeutic interventions, or concomitant 
therapy administered to the subject. 
Related: The event follows a reasonable, temporal sequence from the time of study medication 
administration and/or follows a known response pattern to the study medication and cannot be 
reasonably explained by other factors, such as subject’s clinical state, therapeutic interventions, or 
concomitant therapy administered to the subject and either occurs immediately following study 
medication administration, improves on stopping the study medication, reappears on repeat exposure, or 
there is a positive reaction at the application site. 
10.2 
Serious Adverse Events  
SAEs or reactions are any untoward medical occurrence that, results in any of the following outcomes: 
• 
Results in death 
• 
Is life-threatening (defined as an event in the view of either the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require non-surgical or surgical intervention to 
prevent one of the other serious outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
Investigators must record all SAEs using the appropriate CRFs. 
All SAEs, whether related or unrelated to study medication, must also be immediately reported by 
investigators to Drug Safety at ProTrials, Contract Research Organization using one of the 
following mechanisms within 24 hours of learning of the event: 
In addition, the governing Ethics Committee/IRB and Aerie Pharmaceuticals, Inc. (sponsor) must 
also be notified by telephone or confirmed facsimile transmission should an SAE occur. 
If only limited information is initially available, follow-up reports are required. Documentation of all SAEs 
must be maintained in the study files – e.g., Serious Adverse Event Form or equivalent form (e.g., 
MedWatch Form). Should the investigator become aware of an SAE (regardless of its relationship to 
investigational product) that occurs within 30 days after stopping the study medication, the SAE must be 
reported in accordance with procedures specified in this protocol. In the event of death, if an autopsy is 
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performed, a copy of the report should be sent to the Ethics Committee/IRB. Aerie will report any 
SAEs/serious adverse device effects to other investigators, relevant competent authorities, and Ethics 
Committee/IRB, as required by local health care authorities. 
The investigator(s) should always group signs and symptoms into a single term that constitutes a single 
unifying diagnosis. The investigator’s opinion of the relationship of the SAE to study medication, the 
duration, intensity, frequency, serious criteria, countermeasures taken with study medication, and the 
outcome of the SAE should be documented. 
10.3 
Pregnancy 
Women of childbearing potential (See Section 7.4.1 for definition of women of childbearing potential) must 
use an effective method of birth control during the course of the study, in a manner such that risk of 
failure is minimized. Prior to study enrollment, women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.   
During the study, all women of childbearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period). If pregnancy is 
suspected in any female subject while the subject is receiving study treatment, the study medication must 
immediately be withheld until the result of pregnancy testing is known. If pregnancy is confirmed, the 
study therapy will be permanently discontinued and the subject will be withdrawn from the trial. Protocol-
required procedures for those subjects that are discontinued from the study must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies).   
If pregnancy occurs during the study, the investigator must immediately notify the Ethics Committee/IRB 
and Aerie.   In addition, every attempt will be made to collect data on the pregnancy of female subjects. 
Signature of a separate consent form will be requested of the pregnant woman. Information on pregnant 
partners of study subjects will not be collected. 
Every attempt will be made to collect data regarding the newborn child born to a female subject with 
parent/guardian permission. One parent or the legal guardian will be requested to provide permission for 
the minor to participate in this part of the research 
11. STATISTICAL CONSIDERATIONS 
11.1 
Sample Size 
The planned enrollment is approximately 180 subjects. 
11.2 
Analysis Populations 
An intent-to-treat (ITT) population will include all subjects who were enrolled into the study. 
A modified intent-to-treat (mITT) population will include all subjects who were treated and had at least 1 
follow-up visit with a completed IOP measurement. 
A per-protocol (PP) population will include all subjects who completed 3 months of treatment without 
significant protocol violations. Subjects to be excluded from the PP analysis are subjects who have: 1) no 
efficacy evaluation at baseline, and/or have no follow-up visit; 2) used any prohibited medications during 
the study period that would interfere with the study objectives; 3) had any prohibited procedures during 
the study period that would interfere with the study objectives. 
A safety population will include all subjects who have received at least 1 dose of study medication. This 
population will be used to summarize safety variables and will summarize subjects as treated. 
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12. ADMINISTRATIVE CONSIDERATIONS 
12.1 
Protection of Human Subjects  
12.1.1 
Informed Consent Regulations 
Written informed consent is to be obtained from each subject prior to enrollment into the study, and/or 
from the subject's legally authorized representative. 
12.1.2 
Ethics Committee and Independent Review Board Regulations 
This study is to be conducted in accordance with Ethics Committee/IRB regulations. The investigator 
must obtain approval from a properly constituted Ethics Committee/IRB prior to initiating the study and re-
approval or review at least annually. Aerie is to be notified immediately if the responsible Ethics 
Committee/IRB has been disqualified or if proceedings leading to disqualification have begun. Copies of 
all Ethics Committee/IRB correspondence with the investigator should be provided to Aerie. 
12.1.3 
Good Clinical Practice Regulations 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice regulations and 
guidelines. 
12.2 
Changes to Protocol 
The investigator should not implement any deviation from or changes to the protocol without approval by 
Aerie and prior review and documented approval/favorable opinion from the Ethics Committee/IRB of a 
protocol amendment, except where necessary to eliminate immediate hazards to study subjects, or when 
the changes involve only logistical or administrative aspects of the study (e.g., change of telephone 
numbers, etc.). 
12.3 
Quality Control and Assurance 
The progress of this 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 informed consents, records of study medication receipt, storage and 
disposition and regulatory files related to the study. 
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12.4 
Subject Confidentiality 
Written authorization is to be obtained from each subject prior to enrollment into the study, and/or from 
the subject's legally authorized representative in accordance with the applicable privacy requirements 
(e.g., HIPAA). 
12.5 
Required Study Documents 
The investigator will maintain documentation demonstrating Ethics Committee/IRB approval of the study 
protocol and informed consent at his/her study site. 
The investigator is responsible for ensuring that data are properly recorded on each subject's CRFs and 
related documents. The CRFs are to be submitted in a timely manner and according to an Aerie-specified 
schedule. 
12.6 
Record Retention 
The investigator must maintain records related to this study for a minimum of 3 years after study 
completion.  
  
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13. REFERENCES 
 
1. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS):7. The relationship 
between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am 
J Ophthalmol. 2000;130:429-440. 
2. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure 
reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126:498-505. 
3. Heijl A, Leske MC, Bengtsson B, el al. Reduction of intraocular pressure and glaucoma 
progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-
1279. 
4. Kass MA, Gordon MO, Gao F, el al. Delaying Treatment of Ocular Hypertension: The Ocular 
Hypertension Treatment Study. Arch Ophthalmol. 2010;125:276-287. 
5. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study. A 
randomized trial determines that topical ocular hypotensive medication delays or prevents the 
onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713. 
6. Kazemi A, McLaren JW, Kopczynski CC, Heah TG, Novack GD, Sit AJ. The effects of netarsudil 
ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocul 
Pharmacol Ther. 2018;34:380–386. 
7. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted 
rabbits. J Ocul Pharmacol Ther. 2015;31:146–151. 
8. Li G, Mukherjee D, Navarro I, et al. Visualization of conventional outflow tissue responses to 
netarsudil in living mouse eyes. Eur J Pharmacol. 2016;787:20–31. 
9. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial 
Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. 
Ophthalmology 2001; 108:1943–53. 
10. Lin CW, Sherman B, Moore LA, et al. Discovery and preclinical development of netarsudil, a 
novel ocular hypotensive agent for the treatment of glaucoma. J Ocul Pharmacol Ther. 
2018;34:40–51. 
11. Ren R, Li G, Le TD, et al. Netarsudil increases outflow facility in human eyes through multiple 
mechanisms. Invest Ophthalmol Vis Sci. 2016;57:6197–6209. 
12. ROCKLATAN™ (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005%, for topical 
ophthalmic use. Prescribing Information.  Revised: June 2020. 
 
13. 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;24:51–54. 
 
 
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Appendix 4 
STUDY MEDICATION PACKAGE INSERT 
 
Package Insert for Rocklatan™ (netarsudil/latanoprost ophthalmic solution) 0.02%/0.005% will be 
supplied separately to each study site.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 6 
EXAMINATION PROCEDURES 
1. Best Corrected Visual Acuity 
At all study visits, BCVA will be assessed in both eyes of each subject using a Snellen visual acuity chart  
at a distance of 20 feet. 
Ensure subject is seated in a position whereby his/her eyes are 20 feet from the chart, which is hung on 
the wall at eye level. Mark a spot on the floor with a piece of tape to ensure subjects are seated in the 
exact same position every time they take the test. Also ensure subject is fitted with appropriate lenses as 
to provide “best correction” each time he/she takes the test. In order to standardize the conditions of the 
test as much as possible, all visual acuity testing should be performed in the same room under the same 
lighting conditions for every subject. 
Perform the test on the right eye first. Ask the subject to read each letter, line by line, left to right 
beginning with line #1 on the top of the chart. Subjects should be told that the chart contains only letters, 
not numbers. If the subject reads a number, he/she should be instructed that the chart only contains 
letters and for him/her to “try again.” Subjects should be asked to read the letters slowly as to achieve 
best identification of each letter. There is no time limit for this test. Subjects are not to proceed to the next 
letter (or line) until they have given a finite answer. 
If a subject changes a response (e.g., that should be a “C” not an “O”) before he/she has read the next 
letter, the change will be accepted. If the subject attempts to change a response after reading the next 
letter in the series, the change will not be accepted. 
When the letters become difficult to read or if the subject identifies a letter as 1 of 2 letters, he/she should 
be instructed to choose 1 letter and, if necessary, to guess. The examiner should consider the lowest line 
read with no more than 1 mistake as the extent of a subject’s visual acuity. This visual acuity should then 
be recorded (in Snellen units, e.g., 20/70) on the appropriate CRF. 
Repeat for the left eye. 
 
2. Biomicroscopy 
Any findings from the gross examination will be recorded in this section on the CRF.  Slit lamp 
biomicroscopy will be performed by the investigator (or designee) according to the site’s usual practice 
during the study.  Observations for the slit lamp biomicroscopy examination will be graded as follows: 
 
Lids/Lashes (upper and lower) 
 
Erythema 
 
Rating Score 
Description 
None 0 
Normal, without redness 
Trace +0.5 
Minimal flush reddish color, confined to a small region 
Mild +1 
A flush reddish color, confined to a small region 
Moderate +2 
Diffused reddish color encompassing the entire lid margin 
Severe +3 
Deep diffuse reddish color of lid margins and superior or inferior 
eye lid 
 
 
Edema 
 
Rating Score 
Description 
None 0 
Normal. No swelling of the eyelid tissue 
Trace +0.5 
Minimal swelling of the lids, above normal, which is regional 
Mild +1 
Slight swelling of the lids, above normal, which is regional 
Moderate +2 
General swelling 
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Severe +3 
Extensive swelling of the eyelids, with or without eversion of upper 
and/or lower lids 
 
Conjunctiva (Palpebral and Bulbar) 
 
Hyperemia 
 
Rating Score 
Description 
None 0 
Normal.  May appear blanched to reddish-pink without perilimbal 
injection.  Vessels of palpebral or bulbar conjunctiva easily 
observed 
Trace +0.5 
Minimal flush, reddish color predominantly confined to the 
palpebral or bulbar conjunctiva 
Mild +1 
A flush, reddish color predominantly confined to the palpebral or 
bulbar conjunctiva 
Moderate +2 
Bright red color of the palpebral or bulbar conjunctiva 
Severe +3 
Deep, bright diffuse redness of the palpebral or bulbar conjunctiva 
 
Edema 
 
Rating Score 
Description 
None 0 
Normal. No swelling of the conjunctiva 
Trace +0.5 
Minimal swelling of the conjunctiva, above normal, which is 
regional 
Mild +1 
Mild swelling of the conjunctiva, above normal, which is regional 
Moderate +2 
General swelling of the conjunctiva 
Severe +3 
Extensive swelling of the conjunctiva 
 
Follicles 
 
Rating Score 
Description 
None 0 
No follicles 
Trace +0.5 
Minimal number of elevated follicles, with minimal surrounding 
vasculature 
Mild +1 
Few elevated follicles with minimal surrounding vasculature 
Moderate +2 
Multiple elevated follicles with moderate surrounding vasculature 
Severe +3 
Elevated follicles which may involve the entire conjunctiva, with 
engorged vasculature 
 
Cornea 
 
Edema 
 
Rating Score 
Description 
None 0 
No edema  
Trace +0.5 
Localized, minimal (trace) epithelial haze 
Mild +1 
Dull glass appearance of epithelium that may include fine localized 
microcystic changes 
Moderate +2 
Dull glass appearance of epithelium with large number of cystic 
changes with or without stromal edema 
Severe +3 
Epithelial bullae and/or stromal edema, localized or diffuse, with or 
without stromal striae 
 
 
 
Staining/Erosion 
 
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Rating Score 
Description 
None 0 
No erosion  
Trace +0.5 
Minimal fluorescein staining confined to small focus 
Mild +1 
Slight fluorescein staining confined to small focus 
Moderate +2 
Regionally dense fluorescein staining (1 mm or greater in 
diameter) with underlying structure moderately visible 
Severe +3 
Marked fluorescein staining or epithelial loss 
 
 
Anterior Chamber 
 
For the measurements of cells and flare the following settings should be used: 
 
• 1x1 mm slit 
• Highest slit lamp voltage 
• Illumination angle of 45 degrees 
• High magnification 
• Low ambient lighting 
• Same grader and slit lamp whenever possible 
 
Cells 
 
Rating Score 
Description 
None 0 
No cells seen 
Trace +0.5 
1-5 cells seen 
Mild +1 
6-25 cells seen 
Moderate  +2 
26-50 calls seen 
Severe +3 
Too many cells to count 
 
Flare 
 
Rating Score 
Description 
None 0 
No Tyndall effect 
Trace +0.5 
Tyndall effect barely discernible 
Mild +1 
Tyndall beam in the anterior chamber has a mild intensity 
Moderate  +2 
Tyndall beam in the anterior chamber has a moderate-strong 
intensity 
Severe +3 
Tyndall beam is very intense, and the aqueous has a white and 
milky appearance 
 
 
 
Lens Status 
 
Lens status will be described by the observer as phakic, pseudophakic or aphakic. 
 
Lens Appearance (phakic eyes only) 
 
Rating Score 
Description 
None 0 
No cataract 
Trace +0.5 
Trace lens opacity 
Mild +1 
Early lens opacity 
Moderate  +2 
Intermediate lens opacity 
Severe +3 
Advanced lens opacity 
 
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3. Intraocular Pressure 
NOTE: The examination procedure described below are to be completed for both eyes. 
IOP should be measured by the investigator (or designee) in each eye using a Goldmann applanation 
tonometer affixed to a slit lamp. Measurements will be recorded on an appropriate CRF. 
Please ensure tight-fitting neck wear has been loosened prior to initiating the examination. Both eyes will 
be tested, with the right eye preceding the left. 
Instill 1 drop of topical anesthetic (e.g., Ophthetic®) into each eye and wait 4 minutes before continuing 
with the test procedure. 
 
Test Procedure: 
1. With the subject seated, both he/she and the slit lamp should be adjusted so that the 
subject’s head is firmly positioned on the chin rest and against the forehead rest without 
leaning forward or straining. 
2. Look through the binocular viewer of the slit lamp at low power making sure the tension knob 
is pre-set to the low-pressure value (4-6 mmHg). 
3. Follow the image of the fluorescein-stained semicircles while rotating the tension knob until 
the inner borders of the fluorescein rings touch each other at the midpoint of their pulsation in 
response to the cardiac cycle. 
4. When this image is reached, remove your fingers from the tension knob and record the IOP 
reading along with the time of day in the CRF. 
Please note: 
• 
IOP readings should not be adjusted for corneal thickness. 
• 
The tonometer should be calibrated prior to or at the Baseline Visit (Visit 1) and calibration 
should be documented. 
 
4. Pregnancy Testing 
A urine human chorionic gonadotropin (hCG) pregnancy test (only for females of childbearing potential) 
will be used in this study and performed at the Baseline Visit to immediately confirm non-pregnancy 
eligibility for women of childbearing potential. 
 
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8. Adverse Events 
At both Visit 2 (Week 6) and Visit 3 (Week 12), the investigator (or designee) will question each subject 
regarding adverse experiences that may have occurred since a previous visit. Subjects will be queried 
“How are you feeling?” and all AEs will be recorded in the CRFs, including severity, action taken, and 
relationship to study medication. 
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Signature Page for V-CLN-0090845 v2.0

SAP_001.pdf: 
 
 
 
 
 
A MULTICENTER, OPEN-LABEL ROCKLATAN® 
(NETARSUDIL/LATANOPROST OPHTHALMIC SOLUTION) 
0.02%/0.005% EVALUATION OF IOP LOWERING EFFICACY 
AND SAFETY AS REPLACEMENT OF CURRENT MEDICAL THERAPY 
REGIMEN FOR THE REDUCTION OF ELEVATED INTRAOCULAR 
PRESSURE IN PATIENTS WITH GLAUCOMA OR OCULAR 
HYPERTENSION 
 
MORE: Multi-center, Open-label Rocklatan® Evaluation 
 
STUDY ID: 
MA‐ROC‐22‐003 
 
STATISTICAL ANALYSIS PLAN 
24‐FEB‐2022 
 
 
NCT05283395 
 
 


 
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Aerie Pharmaceuticals 
 
Protocol #:  MA-ROC-22-003 
 
Protocol Name: A Multicenter, Open-Label 
Rocklatan® (Netarsudil/Latanoprost Ophthalmic 
Solution) 0.02%/0.005% Evaluation of IOP Lowering 
Efficacy and Safety as Replacement of Current 
Medical Therapy Regimen for the Reduction of 
Elevated Intraocular Pressure in Patients with 
Glaucoma or Ocular Hypertension 
 
  
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 


 
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SAP Approval 
 
By signing the following, I agree to the contents in the Statistical Analysis Plan and its 
associated attachments. Once the SAP has been signed, the analyses and programming of the 
tables, listings, and figures (TLFs) based upon this document can proceed. Any modifications 
to the SAP and TLFs made after signing may result in a change order. 
 
 
Approved by: 
 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation Definition 
AA 
Alpha Agonists  
AE 
Adverse event 
BB 
Beta Blockers  
BCVA 
Best Corrected Visual Acuity 
CAI 
Carbonic Anhydrase Inhibitor (CAI) 
CI 
Confidence interval 
CM 
Concomitant medication  
FDC 
Fixed Dose Combination 
ITT 
Intent to Treat  
IOP 
Intraocular Pressure  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat Population 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TLF 
Tables, listings, and figures 
 


 
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permission of the management of Clinical Trial Data Services. 
 
Table of Contents 
 
SAP APPROVAL ........................................................................................................................................................ 2 
LIST OF ABBREVIATIONS ..................................................................................................................................... 3 
1 
PROTOCOL SUMMARY .................................................................................................................................. 5 
2 
STATISTICAL METHODOLOGY ................................................................................................................ 10 
2.1 
GENERAL CONSIDERATIONS ............................................................................................................... 10 
2.2 
SUBJECT POPULATION ........................................................................................................................... 10 
2.2.1 
Sample Size ......................................................................................................................................... 10 
2.3       STUDY ASSESSMENT TIME POINTS .................................................................................................... 11 
2.3.1 
Schedule of Events............................................................................................................................... 11 
2.4       STUDY POPULATIONS FOR ANALYSIS ............................................................................................... 12 
2.4.1 
Intent to Treat (ITT) Population .......................................................................................................... 12 
2.4.2 
Modified Intent to Treat (ITT) Population ........................................................................................... 12 
2.4.3 
Safety Population ................................................................................................................................. 12 
2.4.4 
Per-Protocol (PP) Population ............................................................................................................... 12 
2.5       SUBJECT DISPOSITION ........................................................................................................................... 12 
2.6       BASELINE CHARACTERISTICS & MEDICAL HISTORY .................................................................... 13 
2.7       METHODS FOR HANDLING MISSING DATA ...................................................................................... 13 
2.7.1 
Imputation Methods ............................................................................................................................. 13 
2.8       EFFICACY ANALYSIS .............................................................................................................................. 14 
2.8.1 
Primary Endpoint ................................................................................................................................. 14 
      
 
 
 
 
 
2.10    SAFETY ANALYSES .................................................................................................................................. 16 
2.10.1 
Adverse Events ................................................................................................................................ 16 
2.10.1.1 
Serious Adverse Events ............................................................................................................... 17 
2.10.1.2 
AEs with a Frequency of 5% or Greater ...................................................................................... 17 
2.10.1.3 
Deaths .......................................................................................................................................... 18 
2.10.2 
Best Corrected Visual Acuity .......................................................................................................... 18 
2.10.3 
Biomicroscopy ................................................................................................................................. 18 
2.10.4 
Pregnancy Testing............................................................................................................................ 19 
2.10.5 
Concomitant Medications & Procedures ......................................................................................... 19 
3 
DOCUMENT VERSION CONTROL ............................................................................................................. 19 
APPENDIX A - PROGRAMMING SPECIFICATIONS FOR TABLES AND LISTINGS ............................... 20 
  
 
 
 
 
 
 
 


 
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1 Protocol Summary    
Title 
MORE: Multi-center, Open-label Rocklatan® Evaluation  
 
A Multicenter, Open-Label Rocklatan® (Netarsudil/Latanoprost 
Ophthalmic Solution) 0.02%/0.005% Evaluation of Intraocular 
Pressure (IOP) Lowering Efficacy and Safety as Replacement of 
Current Medical Therapy Regimen for The Reduction of Elevated 
Intraocular Pressure in Patients with Glaucoma or Ocular 
Hypertension 
Study Objective 
The objective of this study is to evaluate the IOP lowering and 
number of agents/bottles required to achieve similar or additional 
IOP lowering with Rocklatan® in subjects on a current regimen of 
latanoprost alone or latanoprost plus addition of either one or 2 
IOP-lowering agents. 
Efficacy Analysis  
The primary efficacy variable is percent reduction from baseline 
IOP in the study eye at Week 12. 
Safety Analyses 
Safety analysis includes assessment of Adverse Events (AEs) and 
clinical assessments such as Best Corrected Visual Acuity 
(BCVA), Biomicroscopy, and Pregnancy Testing. 


 
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Test Product, Dose, 
Duration, and Mode of 
Administration 
Enrolled subjects will be instructed to self-instill 1 drop of 
Rocklatan® (netarsudil/latanoprost ophthalmic solution) 
0.02%/0.005% in each eye daily in the evening, beginning the 
evening of the Baseline Visit (Visit 1) until the Final (Week 12) 
Visit. 
Study Design: 
This is a multicenter, prospective, open-label stratified by baseline 
IOP lowering regimen groups study.  
Subjects diagnosed with open-angle glaucoma or ocular 
hypertension will be evaluated at a Baseline Visit (Visit 1, Day 0). 
Subjects satisfying Visit 1 inclusion/exclusion criteria will be 
invited to participate in this study.  
At the Baseline Visit (Visit 1, Day 0), all qualified subjects will be 
enrolled and dispensed Rocklatan®. Subjects will be instructed to 
stop their current IOP lowering medical therapy regimen and to 
begin dosing Rocklatan® in each eye daily in the evening of the 
Baseline Visit and for the duration of the 12-week study. Subjects 
will complete 2 follow up visits (Visit 2: 6 weeks [±7 days], Visit 
3: 12 weeks [±7 days]), during which efficacy and safety 
assessments will take place. The subjects will be exited from the 
study at the end of Visit 3. 
 
Inclusion Criteria 
The following are criteria for inclusion in the study. All must be 
met at the Baseline Visit (Visit 1, Day 0) to be eligible for 
participation: 
 
1. Male or female subjects, age 18 or older  
2. Current diagnosis of open-angle glaucoma or ocular 
hypertension  
3. Subject currently being treated with latanoprost alone or 
latanoprost plus 1 or 2 additional agents/bottles. Current 
IOP lowering regimen is stable for at least 30 days prior to 
Baseline Visit and is one of the regimens listed below:  
 


 
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• Latanoprost monotherapy  
• Latanoprost + 1 additional individual IOP-
lowering agent *  
• Latanoprost + 2 additional IOP-lowering agents   
Two additional agents include two individual IOP-lowering 
agents* as well as fixed dose combinations** 
*Additional individual agent(s) include the following IOP 
lowering classes: beta blocker, alpha agonist, carbonic 
anhydrase inhibitor.  
**Fixed-dose combinations combining two active 
ingredients will be considered as two IOP lowering agents. 
Note: latanoprost may be brand name or generic drug  
 
4. Treated IOP ≥ 20 mmHg measured in the morning 
(before noon) at the Baseline Visit by Goldmann 
applanation tonometer  
5. Best corrected Snellen visual acuity of 20/100 or better 
in both eyes  
6. Willingness to follow protocol requirements, including 
signed informed consent and health information release 
forms, routine follow-up schedule, completing 
questionnaires  
Exclusion Criteria 
The following are criteria for exclusion from the study:  
Ophthalmic:  
7. Have any active ocular disease other than open-angle 
glaucoma or ocular hypertension that would interfere with 
study interpretation  
8. Use of fixed dose combination agents as part of the 
patient’s Baseline IOP lowering therapy regimen, if not 
also on latanoprost  
9. Treatment naïve glaucoma or ocular hypertension 
patients  
10. Mean central corneal thickness greater than 620 μm in 
either eye  


 
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11. Have any corneal abnormality preventing reliable 
applanation tonometry in either eye (e.g., scar, edema, 
keratoconus)  
12. Active ocular infection/inflammation or history of 
uveitis  
13. Aphakic or pseudophakic patients with a torn posterior 
lens capsule, or with known risk factors for macular edema  
14. Visual field loss, which, in the opinion of the 
investigator, is evidence of end-stage glaucomatous visual 
field loss  
15. History of corneal refractive laser surgery in the study 
eye within 3 months prior to Baseline Visit  
16. History of intraocular surgery in the study eye within 3 
months prior to Baseline, including glaucoma laser surgery 
cataract surgery and minimally invasive glaucoma surgery   
Systemic:  
17. Any systemic disease or clinical evidence of any 
condition which would make the subject, in the opinion of 
the investigator, unsuitable for the study or could 
potentially confound the study results  
18. Use of topical, periorbital, intravitreal or systemic 
steroid within previous 3 months or expected use during 
the course of the study  
19. Use of systemic medications(s) or therapy that may 
have a substantial effect on IOP unless such medication(s) 
or therapy has/have been used for a minimum of 3 months 
prior to Baseline Visit, is/are expected to remain constant 
throughout the course of the study and is/are considered 
necessary for a subjects’ welfare  
20. Prior participation in any investigational drug or device 
study within the last 30 days prior to the Baseline Visit.  
21. Known sensitivity or allergy to the study medication or 
components  
22. Females who are pregnant, nursing, or planning a 
pregnancy during the study  


 
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23. Positive pregnancy test at Baseline Visit (women of 
childbearing potential only)  
24. Women of childbearing potential who are not using a 
medically acceptable form of birth control  
 
Statistical Methods 
Summary tables (descriptive statistics and/or frequency 
distributions) will be provided for all baseline variables, efficacy 
variables, safety variables, and any other assessments. Continuous 
variables will be described by descriptive statistics (n, mean, 
standard deviation, range, and median). Frequency distributions 
(counts and percentage) of subjects within each category will be 
provided for categorical data. 
Sample Size  
Approximately one hundred and sixty (160) male or female 
subjects will participate in this study.  
Approximately 22 study centers in the United States will be 
utilized. 
Stratification 
Enrollment will be stratified based on subject’s current Baseline 
IOP lowering therapy regimen:  
 60 subjects whose Baseline therapy regimen is latanoprost 
monotherapy  
 60 subjects whose Baseline therapy regimen is latanoprost 
plus 1 additional individual IOP-lowering agent* 
 40 subjects whose Baseline therapy regimen is latanoprost 
plus 2 additional IOP-lowering agents  
Two additional agents include two individual IOP-lowering 
agents* as well as fixed dose combinations** 
 
*Additional individual agent(s) include the following IOP 
lowering classes: beta blocker, alpha agonist, carbonic 
anhydrase inhibitor.  
**Fixed-dose combinations combining two active 
ingredients will be considered as two IOP lowering agents. 
Note: latanoprost may be brand name or generic dru 
 


 
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permission of the management of Clinical Trial Data Services. 
 
2 Statistical Methodology 
 
2.1 
General Considerations 
 
The objective of this study is to evaluate the IOP lowering and number of agents/bottles 
required to achieve similar or additional IOP lowering with Rocklatan® in subjects on a 
current regimen of latanoprost alone or latanoprost plus addition of either one or 2 IOP-
lowering agents. 
 
All statistical analyses will be performed using SAS Version 9.4 or higher. The following 
summary statistics will be reported for continuous data: the number of eyes or subjects, 
as applicable, and the mean, median, standard deviation, minimum, and maximum.  
Confidence intervals (CIs) may be provided where appropriate. For categorical data, the 
number and percentage of eyes or subjects will be reported.  The number of subjects or 
eyes in the population of interest will be used as the denominator for the percentage at 
that time point unless otherwise indicated. Percentages will be rounded to one decimal 
place, and thus may not always add up to exactly 100%. All tests will be performed at 
two-sided 0.05 level, unless otherwise specified. 
For some analyses, results will be separated for the study eye and fellow eye (e.g., non-
study eye). If both eyes qualify for study inclusion, the study eye will be the eye with the 
higher IOP at baseline. If both study eyes are the same at baseline, then the right eye will 
be considered the study eye. 
In general, all summary tables will be supported by a relevant subject data listing 
including all subjects who received study treatment.  The listings will include all data 
collected, and will be sorted by subject identification, and actual visit date, as applicable, 
unless otherwise noted.  
Concomitant medications (CMs) will be coded using the WHO Drug Dictionary and AEs 
and medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The dictionary versions will be documented in the Data Management Plan 
for the study. 
Study Day 0 (Visit 1) is the day of baseline assessment. Study day is the day relative to 
Study Day 0. Change from baseline is the post-treatment value minus baseline value. 
 
2.2 
Subject Population 
 
2.2.1 Sample Size    
Approximately 160 male or female subjects will participate in this study. 
Enrollment will be stratified based on subject’s current Baseline IOP lowering 
therapy regimen: 




 
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2.4 
Study Populations for Analysis 
The following are the analysis populations to be used: 
2.4.1 Intent to Treat (ITT) Population 
The ITT population will include all subjects who were enrolled into the study. 
2.4.2 Modified Intent to Treat (mITT) Population 
The mITT population will include all subjects who were treated and had at least 1 
follow-up visit with a completed IOP measurement. 
2.4.3 Safety Population 
The Safety Population will include all subjects who received any amount of study 
drug. This population will be used to summarize safety variables and will 
summarize subjects as treated. 
 
2.4.4 Per-Protocol (PP) Population 
The PP population will include all subjects who completed 3 months of treatment 
without significant protocol violations. Subjects to be excluded from the PP 
analysis are subjects who have: 1) no efficacy evaluation at baseline, and/or have 
no follow-up visit; 2) used any prohibited medications during the study period that 
would interfere with the study objectives; 3) had any prohibited procedures during 
the study period that would interfere with the study objectives.  
 
           A listing of subjects excluded from the mITT and PP populations will be provided.  
 
2.5 
Subject Disposition 
All subjects enrolled into the study that are issued a subject number will be accounted for 
in Subject Disposition.  Data will be tabulated by overall and baseline IOP lowering therapy 
participant groups. 
 
The numbers and percentages of subjects who are enrolled and treated, who comprise each 
of the analysis populations (e.g., PP, Safety Population, etc.) and who complete the study 
or withdraw prematurely along with the reason for discontinuation will be presented. The 
number of subjects enrolled will also be presented by clinical site. 
 
Reasons for any early withdrawals and the last date of dosing completed prior to 
discontinuation will be provided in a listing. 
 
Protocol deviations (major and minor) will be defined prospectively prior to database lock 
and will be tabulated by overall and baseline IOP lowering therapy participant groups for 
the ITT, mITT, and Safety populations. Deviations will also be presented in listings. 


 
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2.6 
Baseline Characteristics & Medical History 
Demographics and baseline characteristics will be summarized by overall and baseline 
IOP lowering therapy participant groups for all subjects included in the safety population. 
Where applicable, data will be presented separately for the study eye vs. fellow eye (e.g., 
non-study eye), else data will be presented by subject. 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
General medical history will be coded using MedDRA and will be summarized by System 
Organ Class (SOC) and Preferred Term (PT). Prior ocular procedures will also be tabulated 
by procedure category and procedure name. Data will be stratified by overall and baseline 
IOP lowering therapy participant groups for all subjects included in the safety population. 
 
Additionally, current use of any IOP lowering medications will be tabulated by medication 
category and medication name. Data will be stratified by overall and baseline IOP lowering 
therapy participant groups for all subjects included in the safety population.  
 
All demographic, baseline characteristics, medical history, and IOP medication history will 
be presented in listings.  
 
2.7 
Methods for Handling Missing Data 
 
2.7.1 Imputation Methods 


 
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Imputation will only be performed on IOP data for the primary endpoint analysis 
(Week 12) of the ITT population. No imputation will be performed for any missing 
Week 6 values. Imputation for missing Week 12 values will be performed using the 
method of last observation carried forward from Week 6. If there is no Week 6 
value, then subjects missing Week 12 and Week 6 data will be excluded from 
analysis. 
2.8 
Efficacy Analysis 
Efficacy data will be analyzed using 
 
 mITT (without imputation of missing values),
 
. 
If both eyes qualify for study inclusion, analyses will be provided for the worse eye at 
baseline. If both study eyes are the same at baseline, then data for only the right eye will 
be analyzed. 
2.8.1 Primary Endpoint  
The primary efficacy variable is percent reduction from baseline IOP in the study 
eye at Week 12 in the mITT population. Percent reduction will be presented by 
overall and baseline IOP lowering therapy participant groups. Summary statistics 
will include mean and median values, standard deviations, minimum and 
maximum ranges for IOP (mmHg), change from baseline IOP, and % change in 
IOP from baseline at Week 6 and Week 12 Figures will be provided for mean 
change from baseline and % change from baseline.  No imputation of data will be 
performed. 
 
 
 
 
  
 
All collected IOP data will be displayed in listings.  
 


 
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2.10 
Safety Analyses 
 
Safety analyses will be based on the Safety Population and be presented by overall subjects 
and baseline IOP lowering therapy participant groups. Where appropriate, results from the 
study eye and fellow eye (e.g., non-study eye) will be analyzed separately. 
 
2.10.1 Adverse Events 
Adverse events and serious adverse events (SAEs) will be summarized with 
frequency distributions by overall subjects and baseline IOP lowering therapy 
participant groups. Results will be summarized by subject rather than eye. If an 
event occurs in both eyes it will only be counted once in tables. All events will be 
provided in listings.  
Only those adverse events determined to be treatment emergent (TEAE) will be 
presented. Treatment emergent adverse events are those events with the date of AE 
onset being greater than or equal to the first date of dosing.  
 
Verbatim terms on the case report forms will be linked to preferred terms and 
related body systems using the MedDRA Coding Dictionary version 25.0 (Release 
date: 01Mar22).  The number and percentage of subjects who experience treatment-
emergent adverse events will be tabulated by SOC and PT by baseline IOP lowering 
therapy participant group and overall.  
 
Adverse events will be counted only once for a subject within each PT and SOC; 
thus, since a subject may have more than one PT within an SOC, percentages of PT 
may not sum to the percentage in the SOC.  If a subject reports a PT multiple times 
with differing severities, only the most severe is counted.  If a subject reports a PT 
multiple times with differing relationships to study medication, only the one related 
to study drug is counted. Adverse events are defined as having a causality rating of 
being related, possibly related, unlikely related, or not related.  
 
All reported AEs will be tabulated as described above. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Ocular and non-ocular AEs will be tabulated separately. Adverse events judged by 
the Investigator to be SAEs, SAEs resulting in death, AEs leading to 
discontinuation, any AEs that occur at a frequency of 5% or greater, and AEs that 
occurred after date of discontinuation will be summarized in tables or listings. In 
addition, all TEAEs and treatment related (unlikely, possibly, or related to study 
medication) AEs will be tabulated by severity. 
 
 All safety events and related data will be provided in listings.  
 
2.10.1.1 
Serious Adverse Events 
The number and percentage of subjects experiencing any SAE will be 
tabulated by SOC and PT by baseline IOP lowering therapy participant 
group and overall.  Serious AEs will be counted only once for a subject 
within each PT and SOC. Ocular and non-ocular events will be tabulated 
separately. 
 
All recorded SAE data will be presented in listings.  
 
2.10.1.2 
AEs with a Frequency of 5% or Greater  
All events that occur at a frequency of 5% of greater will be tabulated by 
SOC and PT by baseline IOP lowering therapy participant group and 
overall. Data will also be provided in a listing.  
 
2.10.1.3 
AEs Leading to Discontinuation  
All events that lead to discontinuation will be tabulated by SOC and PT by 
baseline IOP lowering therapy participant group and overall. Data will also 
be provided in a listing.  
 
2.10.1.4 
AEs Occurring after Discontinuation  
All events that occurred after the date if subject discontinuation will be 
provided in a listing and tabulated as necessary. These events are still 
considered treatment emergent and will also be included in main TEAE 
listings and tables.  
 


 
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                    Rev: A 
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2.10.1.5 
Deaths 
A listing of subjects who die while on study will be prepared along with the 
adverse event associated with the cause of death. 
 
2.10.2 Best Corrected Visual Acuity  
Monocular Best Corrected Visual Acuity will be measured in each eye by the 
investigator (or designee) at the Baseline Visit (Visit 1) and at both Visit 2 (Week 
6) and Visit 3 (Week 12) using a Snellen Visual Acuity Chart. Parameters (e.g., 
sphere, cylinder, axis, visual acuity) will be summarized descriptively by baseline 
IOP lowering therapy participant group and overall at each visit. Results will be 
presented separately for study eyes versus fellow eyes. Note that in reporting 
cylinder, all positive measurements will be converted to the negative scale. 
 
2.10.3 Biomicroscopy  
Biomicroscopy will be performed according to the site’s usual practice by the 
investigator (or designee) for both eyes at the Baseline Visit and at each follow-up 
visit by slit lamp examination. Eye structures/surfaces to be assessed include, but 
are not limited to, lids/lashes, conjunctiva (palpebral and bulbar), cornea, anterior 
chamber and lens. Parameters will be summarized descriptively by baseline IOP 
lowering therapy participant group and overall at each visit. Results will be 
presented separately for study eyes versus fellow eyes. 
 
Observations for the slit lamp Biomicroscopy examination (except lens status) will 
be graded on a 5-pont scale as follows: 
 0= None 
 0.5 = Trace 
 1.0 = Mild 
 2 = Moderate 
 3 = Severe 
 
Mean grading score of each eye area (e.g., Hyperemia, edema, etc.), as well as a 
change from baseline (n, %) analysis will be provided at Week 6 and Week 12 visit 
summaries. Change from baseline will be categorized as follows: No change, 
Decrease ≥ 0.5, Decrease ≥ 1, Increase ≥ 0.5, and Increase ≥ 1.  
 
The frequency and percentage of subjects with hyperemia that occurred at both 
Weeks 6 and Week 12, or subjects with any pre-existing hyperemia that worsened 
at Week 6 and maintained worsening or worsened at Week 12 (Consecutive), as 
well as subjects with hyperemia that occurred or worsened at only one of the two 
follow-up visits (Sporadic) will also be summarized. 
 


 
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            Statistical Analysis Plan 
 
                    Rev: A 
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All biomicroscopy data will be provided in listings.  
 
2.10.4 Pregnancy Testing 
A urine human chorionic gonadotropin pregnancy test (only for females of 
childbearing potential) will be used in this study and performed at the Baseline Visit 
to immediately confirm non-pregnancy eligibility for women of child-bearing 
potential. Results will be presented in listings only. 
 
2.10.5 Concomitant Medications & Procedures  
Concomitant medications other than IOP lowering drugs will be coded per the 
WHO Drug Dictionary Version 1 Mar 2022 and summarized by Drug Class 
(pharmacological level, ATC3) and Drug Name (chemical substance level, ATC5). 
Results will be stratified by overall and baseline IOP lowering therapy participant 
groups. Results will be summarized by subject rather than eye. If a medication 
occurs in both eyes it will only be counted once in tables. All medications will be 
provided in listings. Any concomitant procedures will be similarly summarized. 
 
These data will also be provided in subject data listings along with the verbatim 
drug term and usage details (e.g., dose, frequency, route).  
 
3 Document Version Control 
Revision History: 
 
REVISION 
RELEASE 
DATE 
AUTHOR 
SUMMARY OF CHANGES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
                    Rev: A 
    MA-ROC-22-003  
                         Page 20 of 21 
 
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This document is the property of Clinical Trial Data Services and may not be reproduced without the written 
permission of the management of Clinical Trial Data Services. 
 


 
FM DM015.1 
            Statistical Analysis Plan 
 
                    Rev: A 
    MA-ROC-22-003  
                         Page 21 of 21 
 
CONFIDENTIAL 
This document is the property of Clinical Trial Data Services and may not be reproduced without the written 
permission of the management of Clinical Trial Data Services.