Clinical trial NCT03808688
Conditions: Glaucoma, Open-Angle Ocular Hypertension
Sponsor: Aerie Pharmaceuticals
Start date: 2018-12-27; Completion date: 2019-07-26
Enrollment: 261 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the IOP lowering efficacy of netarsudil ophthalmic solution 0.02% when used as monotherapy or when used concomitantly with other IOP-lowering agents in subjects with elevated IOP due to open angle glaucoma or ocular hypertension in a real-world clinical setting. The study is an open-label design. The patients will receive treatment for 12 weeks.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Netarsudil Ophthalmic Solution 0.02%
Intervention descriptions: intervention 1: 1 drop in each eye once daily in the evening

Protocol documents:
Prot_000.pdf: 
MA-RHO-18-002 
 
 
 A MULTICENTER, OPEN-LABEL 
STUDY OF RHOPRESSA® 
(NETARSUDIL OPHTHALMIC 
SOLUTION) 0.02% FOR THE 
REDUCTION OF ELEVATED 
INTRAOCULAR PRESSURE IN 
PATIENTS WITH GLAUCOMA OR 
OCULAR HYPERTENSION IN A 
REAL-WORLD SETTING  
 
 
 
 
NCT03808688 
 
 
18 December 2018 




 
CONFIDENTIAL 
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A MULTICENTER, OPEN-LABEL STUDY OF RHOPRESSA® (NETARSUDIL OPHTHALMIC 
SOLUTION) 0.02% FOR THE REDUCTION OF ELEVATED INTRAOCULAR PRESSURE IN 
PATIENTS WITH GLAUCOMA OR OCULAR HYPERTENSION IN A REAL-WORLD SETTING 
 
MOST: Multi-center, Open-label STudy 
 
 
 
PROTOCOL NUMBER 
 
MA-RHO-18-002 
ORIGINAL PROTOCOL DATE  
 
18 Dec 2018 
REVISED PROTOCOL DATE  
 
N/A 
 
 
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 
 
Fax or email signed/dated Investigator’s Signature Page to 
 
. 


 
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A MULTICENTER, OPEN-LABEL STUDY OF RHOPRESSA® (NETARSUDIL OPHTHALMIC 
SOLUTION) 0.02% FOR THE REDUCTION OF ELEVATED INTRAOCULAR PRESSURE IN 
PATIENTS WITH GLAUCOMA OR OCULAR HYPERTENSION IN A REAL-WORLD SETTING 
 
MOST: Multi-center, Open-label STudy 
 
 
 
PROTOCOL NUMBER 
 
MA-RHO-18-002 
ORIGINAL PROTOCOL DATE  
 
18 Dec 2018 
REVISED PROTOCOL DATE  
 
N/A 
 
 
 
 
 
 
PERSONNEL AND FACILITIES 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE .................................................................................................. 6 
2.0 
STUDY OBJECTIVE ......................................................................................................................... 6 
3.0  
STUDY DESIGN ............................................................................................................................... 6 
4.0  
STUDY POPULATION ..................................................................................................................... 6 
4.1     Number of Subjects ................................................................................................................ 6 
4.2     Number of Study Centers ....................................................................................................... 7 
4.3     Subject Eligibility ..................................................................................................................... 7 
4.3.1 Inclusion Criteria ........................................................................................................... 7 
4.3.2 Exclusion Criteria ......................................................................................................... 7 
4.3.3 Subject Withdrawal Criteria .......................................................................................... 7 
5.0 
STUDY MEDICATION AND OTHER STUDY SUPPLY INFORMATION .......................................... 8 
5.1     Study Medications .................................................................................................................. 8 
5.1.1 Study Medication Information ....................................................................................... 8 
5.1.2 Formulations ................................................................................................................. 8 
5.1.3 Storage, Handling, Dispensing and Reconciliation of Study Medications ..................... 8 
5.1.4 Site Personnel Study Medication Instructions .............................................................. 9 
5.1.5 Subject Dosing and Storage Instructions (Visits 1 & 2) ................................................ 9 
5.2     Additional Study Supplies ....................................................................................................... 9 
6.0 
PRIOR AND CONCOMITANT THERAPIES ................................................................................... 10 
6.1     Allowed Medications or Treatments ...................................................................................... 10 
7.0 
STUDY PROCEDURES ................................................................................................................. 10 
7.1     Subject Entry Procedures ..................................................................................................... 10 
7.1.1 Overview of Entry Procedures .................................................................................... 10 
7.1.2 Informed Consent and HIPAA Authorization .............................................................. 10 
7.1.3 Method for Assignment of Subject ID Number ........................................................... 10 
7.2     Study Procedures ................................................................................................................. 10 
7.3     Overall Instructions ............................................................................................................... 10 
7.4     Visit 1 (Day 0): Baseline ....................................................................................................... 10 
7.5     Visit 2 (Week 6): Follow-Up .................................................................................................. 11 
7.6     Visit 3 (Week 12): Final Visit ................................................................................................. 11 
7.7     Unscheduled Visits ............................................................................................................... 12 
8.0  
CLINICAL ASSESSMENTS ............................................................................................................ 12 
8.1     Efficacy Assessment ............................................................................................................. 12 
8.1.1 Intraocular Pressure ................................................................................................... 12 
8.2     Safety Assessments ............................................................................................................. 12 
8.2.1 Adverse Events .......................................................................................................... 12 
8.2.2 Best Corrected Visual Acuity ...................................................................................... 12 
8.2.3 Pregnancy Testing ..................................................................................................... 13 
8.2.4 Blood Pressure Measurement .................................................................................... 13 
8.3     Other Assessments .............................................................................................................. 13 
8.3.1 
 Questionnaire ........................................................... 13 
8.3.2 
 Questionnaire .................................................................................. 13 
9.0 
END OF STUDY ............................................................................................................................. 13 
9.1     Completion of the Study ....................................................................................................... 13 
9.2     Subject Discontinuation ........................................................................................................ 13 
9.3     Study Termination ................................................................................................................. 14 
10.0 ADVERSE EVENT DEFINITIONS AND REPORTING ................................................................... 14 
10.1   Adverse Events ..................................................................................................................... 14 


 
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10.1.1 
Severity of Adverse Events .................................................................................... 14 
10.1.2 
Relationship of Adverse Events ............................................................................. 15 
10.2   Serious Adverse Events ....................................................................................................... 15 
10.3   Pregnancy............................................................................................................................. 16 
11.0 STATISTICAL CONSIDERATIONS ................................................................................................ 16 
11.1   Sample Size.......................................................................................................................... 16 
11.2   Analysis Populations ............................................................................................................. 16 
11.3   Statistical Methods ................................................................................................................ 17 
11.3.1 
Baseline Analyses .................................................................................................. 17 
11.3.2 
Efficacy Analysis .................................................................................................... 17 
11.3.3 
Safety Analyses ..................................................................................................... 17 
11.3.4 
Other Assessments ................................................................................................ 18 
11.4   Interim Analysis .................................................................................................................... 18 
12.0 ADMINISTRATIVE CONSIDERATIONS......................................................................................... 18 
12.1   Protection of Human Subjects .............................................................................................. 18 
12.1.1 
Informed Consent Regulations ............................................................................... 18 
12.1.2 
Ethics Committee and Independent Review Board Regulations ............................ 18 
12.1.3 
Good Clinical Practice Regulations ........................................................................ 18 
12.2   Changes to Protocol ............................................................................................................. 18 
12.3   Quality Control and Assurance ............................................................................................. 19 
12.4   Subject Confidentiality .......................................................................................................... 19 
12.5   Required Study Documents .................................................................................................. 19 
12.6   Record Retention .................................................................................................................. 19 
13.0 REFERENCES ............................................................................................................................... 20 
APPENDIX 1:  
 QUESTIONNAIRE ....................................... 21 
APPENDIX 2:  
 QUESTIONNAIRE ......................................................................... 22 
APPENDIX 3:  STUDY MEDICATION PACKAGE INSERT ...................................................................... 23 
APPENDIX 4:  SCHEDULE OF VISITS/PROCEDURES .......................................................................... 24 
APPENDIX 5:  EXAMINATION PROCEDURES ....................................................................................... 25 
 
 


 
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1.0 
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). The need for improved efficacy of glaucoma medications is 
supported by several clinical studies. Studies such as the Early Manifest Glaucoma Trial (Heijl 2002), the 
Ocular Hypertension Treatment Study (Kass 2002; Kass 2010), and the Collaborative Normal Tension 
Glaucoma Study Group (Collaborative Normal-Tension Glaucoma Study Group 1998) support the general 
conclusion that 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. Thus, the foundational goal for treating 
patients should be to lower the IOP, to the point that it prevents further damage to the optic nerve and 
achieve this without sacrificing safety or convenience. 
Inhibitors of Rho kinase (ROCK) have emerged as a new class of IOP-lowering agents and recently, 
Rhopressa® (netarsudil ophthalmic solution) 0.02% was approved by the United States Food and Drug 
Administration for reducing elevated IOP. Three randomized and controlled clinical trials demonstrated up 
to 5 mmHg reductions in IOP for subjects treated with netarsudil 0.02% once daily (QD) in the evening. 
For subjects with baseline IOP <25 mmHg, the IOP reductions with netarsudil 0.02% dosed QD were 
similar to those with timolol 0.5% dosed twice daily (Rhopressa® Prescribing Information 2017). 
Netarsudil 0.02% is a novel Rho kinase and norepinephrine transporter inhibitor developed at Aerie 
Pharmaceuticals, Inc. Netarsudil 0.02% 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 0.02% 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 0.02% 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). 
2.0 
STUDY OBJECTIVE 
The objective of this study is to to evaluate the IOP lowering efficacy of netarsudil 0.02% when used as 
monotherapy or when used concomitantly with other IOP-lowering agents in subjects with elevated IOP 
due to open-angle glaucoma or ocular hypertension in a real-world clinical setting.    
3.0  
STUDY DESIGN 
This is a multicenter, prospective, open-label 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 enrolled subjects will be dispensed netarsudil 0.02% and 
instructed to begin dosing in each eye QD in the evening. During the 12-week follow-up period, subjects 
will complete 2 visits (Visit 2: 6 weeks [±7 days], Visit 3: 12 weeks [±7 days]), during which IOP will be 
evaluated. 
4.0  
STUDY POPULATION 
4.1     Number of Subjects 
Approximately two hundred and fifty (250) male or female subjects will participate in this 
study. 


 
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4.2     Number of Study Centers 
Approximately 32 study centers will be utilized in this study. 
4.3     Subject Eligibility 
To be eligible for enrollment into the study, subjects must meet all inclusion and 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.  Criteria required at the Baseline 
Visit (Visit 1, Day 0) ONLY are so indicated. 
1. Male or female subjects (aged 18 or older) 
2. Subjects diagnosed with open-angle glaucoma or ocular hypertension, and 
determined by the treating physician to require additional IOP-lowering 
treatment with netarsudil 0.02% either as first-line monotherapy, as a 
replacement of prior IOP-lowering medication, or used concomitantly with 
other IOP-lowering medication  
3. Willingness to follow protocol requirements, including signed informed 
consent, routine follow-up schedule, completing questionnaires and 
completing laboratory tests 
4.3.2 
Exclusion Criteria  
The following are criteria for exclusion from the study: 
1. Have any active ocular disease other than glaucoma or ocular hypertension 
that would interfere with study interpretation 
2. Women of childbearing potential who are pregnant, nursing, or planning a 
pregnancy and not using a medically acceptable form of birth control. An 
adult woman is considered to be of childbearing potential unless she is 1 
year post-menopausal or has a documented plasma follicle-stimulating 
hormone (FSH) level > 35 mIIU/mL in conjunction with hormone replacement 
therapy or post-surgical sterilization (see Section 7.4). Male subjects with a 
female partner of childbearing potential must have had a prior vasectomy or 
agree to use an effective method of birth control during the treatment period 
and for 3 months after the subject has completed the study. All women of 
childbearing potential must have a negative pregnancy test result at the 
Baseline Visit and must not intend to become pregnant during the study 
3. Known sensitivity or allergy to the study medication or components  
4. 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 
5. Concurrent participation or prior participation in any investigational drug or 
device study within the last 30 days prior to the Baseline Visit 
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. 


 
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5.0 
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 netarsudil 0.02% in each 
eye QD in the evening, beginning the evening of the Baseline Visit (Visit 1). 
Netarsudil ophthalmic solution 0.02% 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 Rhopressa Package Insert (Appendix 3). 
5.1.2 
Formulations 
Netarsudil 0.02% 
Name: 
Rhopressa® (netarsudil ophthalmic solution) 0.02%  
 
Active ingredient:  
netarsudil mesylate 0.285 mg  
Other ingredients:  
mannitol, boric acid, sodium hydroxide to adjust pH and water 
for injection, benzalkonium chloride 0.15 mg (preservative) 
5.1.3 
Storage, Handling, Dispensing and Reconciliation of Study Medications  
The study medication must be stored refrigerated at 2º to 8ºC (36º to 46ºF) at the 
study site in a secure area and administered only to subjects entered into the clinical 
study, at no cost to the subject, in accordance with the conditions specified in the 
protocol. 
Store netarsudil 0.02% 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.  
Subjects are to save all used/unused bottles for presentation to designated study 
staff during office visits. 
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 (eg, 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 
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5.1.4 
Site Personnel Study Medication Instructions 
Subjects will be instructed to start self-administering study medication in each eye in 
the evening of the Baseline Visit (Visit 1) (see Section 5.1.5 below). There is no 
washout period required for subjects replacing prior IOP-lowering therapy with 
netarsudil ophthalmic solution 0.02%.   
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. 
If netarsudi 0.02% is to be used concomitantly with other topical ophthalmic drug 
products to lower IOP, each drug product should be administered at least 5 minutes 
apart to prevent washout. 
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 netarsudil 0.02% at the Baseline Visit (Visit 
1) and will be instructed to refrigerate both the unopened bottles (2º to 8ºC [36º to 
46ºF]).  
 
 
 
 
 
 
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  
Subjects will receive 2 bottles of netarsudil 0.02% at Visit 2 (Week 6) and will be 
instructed to refrigerate both the unopened bottles (2º to 8ºC [36º to 46ºF]). 
 
 
 
 
 
 
 
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 
• 
Electronic case report form (eCRF) completion guidelines 
• 
Study medication reconciliation logs  


 
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• 
Package insert for Rhopressa (netarsudil ophthalmic solution) 0.02% 
6.0 
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). 
7.0 
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. 
 
 
 
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. 
7.1.3 
Method for Assignment of Subject ID Number 
 
 
 
   
7.2     Study Procedures 
The Schedule of Visits/Procedures for this study is included in Appendix 4. 
Clinical assessments will be performed throughout the study as detailed in Section 8.0. All 
clinical assessments will be performed by the investigator (or designee). 
7.3     Overall Instructions 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible. If this is not possible, 2 evaluators should assess the same subject simultaneously 
and reach agreement on results. 
7.4     Visit 1 (Day 0): Baseline 
The investigator (or designee) will perform/administer the following assessments: 
• 
Written informed consent and HIPAA authorization 
• 
Demographics 


 
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• 
Subject eligibility (inclusion/exclusion criteria) 
• 
Urine pregnancy test (if applicable) 
• 
Medical and IOP history  
• 
Prior and concomitant medications and/or procedures review 
• 
Best-corrected visual acuity (BCVA) 
• 
Biomicroscopy 
• 
IOP assessment (measured in each eye using Goldmann applanation tonometer) 
• 
Blood pressure measurement (sitting position) 
• 
Corneal pachymetry to measure central corneal thickness 
• 
Assign subject ID number 
• 
Dispense netarsudil 0.02% and have a staff member instruct the subject on use 
• 
Schedule Visit 2 (Week 6)  
Women of childbearing potential* must be willing to practice medically effective contraception 
for the duration of the study (ie, abstinence, condoms or diaphragm with spermicide, 
intrauterine device (IUD), or birth control pills) and must not be lactating. 
 
*A woman of childbearing potential is one who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation or bilateral oophorectomy), or is not postmenopausal. Postmenopausal is 
defined as amenorrhea for at least 12 consecutive months or a documented plasma 
FSH level >35 mlU/mL in conjunction with hormone replacement therapy. Women who 
are using oral, implanted, skin patches, or injectable contraceptive hormones, an IUD, 
or barrier methods (diaphragm, condoms, spermicide) to prevent pregnancy, practicing 
abstinence, or where partner is sterile (eg, vasectomy), are considered to be of 
childbearing potential.  
7.5     Visit 2 (Week 6): Follow-Up  
The investigator (or designee) will perform/administer the following assessments: 
• 
Concomitant medications and/or procedures review 
• 
BCVA 
• 
Biomicroscopy 
• 
IOP assessment (measured in each eye using Goldmann applanation tonometer) 
• 
Blood pressure measurement (sitting position) 
• 
Adverse event (AE) assessment 
• 
Collect used/unused study medication containers 
• 
Dispense netarsudil 0.02% and have a staff member instruct the subject on use 
• 
Schedule subject’s next visit (Visit 3, Week 12) 
7.6     Visit 3 (Week 12): Final Visit  
The investigator (or designee) will perform/administer the following assessments: 
• 
Concomitant medications and/or procedures review 


 
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• 
BCVA 
• 
Biomicroscopy 
• 
IOP assessment (measured in each eye using Goldmann applanation tonometer) 
• 
Blood pressure measurement (sitting position)   
• 
 Questionnaire 
• 
 Questionnaire 
• 
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). 
8.0  
CLINICAL ASSESSMENTS  
The following clinical assessments will be performed according to the schedule as indicated in the 
Schedule of Visits/Procedures (Appendix 4). 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 using a Goldmann applanation tonometer affixed 
to a slit lamp at the Baseline Visit, Visit 2, and Visit 3. 
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 10.0 for further details). 
Please see “Rhopressa Package Insert” (Appendix 3) 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 5 for detailed information on this 
examination). 
8.2.3 
Biomicroscopy 
Biomicroscopy will be performed by the investigator (or designee) for both eyes at the 
Baseline Visit and at each follow-up visit by slit lamp examination without pupil 
dilation.  Eye structures/surfaces to be assessed include, but are not limited to, 


 
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lids/lashes, conjunctiva (palpebral and bulbar), cornea, anterior chamber and lens.  
All observations will be recorded. (see Appendix 5 for detailed information on this 
examination). 
8.2.3 
Pregnancy Testing 
A urine human chorionic gonadotropin (hCG) pregnancy test (only for females who 
are not diagnosed as postmenopausal or surgically sterile) will be used in this study 
and performed at the Baseline Visit to immediately confirm non-pregnancy eligibility 
for women of child-bearing potential. 
The investigator must immediately notify the Ethics Committee/IRB and Aerie, of any 
pregnancy associated with the study medication exposure and keep careful source 
documentation of the event. In addition, the investigator must complete the 
pregnancy surveillance form(s) to ensure all required information is reported. 
8.2.4 
Blood Pressure Measurement 
Systemic safety assessment measured by the investigator (or designee) at the 
Baseline Visit (Visit 1) and at Visit 2 (Week 6) and Visit 3 (Week 12).  
8.3     Other Assessments 
8.3.1 
 Questionnaire 
An 
 Questionnaire (see Appendix 1 for detailed 
information on this questionnaire) will be administered by the investigator (or 
designee) at Visit 3 (Week 12). 
8.3.2 
 Questionnaire 
At Visit 3 (Week 12), the investigator will complete a 
 Questionnaire 
(see Appendix 2 for detailed information on this questionnaire). 
9.0 
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. 
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 
• 
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 4).   
Subjects who are prematurely withdrawn or discontinued from the study will not be replaced. 


 
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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. 
10.0 
ADVERSE EVENT DEFINITIONS AND REPORTING 
10.1   Adverse Events 
An AE is defined as any untoward medical occurrence in a subject during the course of a 
study. An AE can, therefore, be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational or marketed medicinal product, whether or not considered related to 
the investigational or marketed medicinal product. 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 must be completely recorded on the appropriate AE form. The severity of each AE 
will be graded by the investigator, using the definitions in Section 10.1.1. If known, the 
investigator should report the diagnosis of the underlying illness or disorder, rather than its 
individual symptoms. 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). 
10.1.1 Severity of Adverse Events  
The severity of AEs will be graded by the investigator using the following definitions: 
Mild: The AE is noticeable by the subject but does not interfere in a significant 
manner with the subject’s normal functioning and is not sufficiently intense to result in 
medication dose reduction or discontinuation of treatment; remedial therapy may be 
given. 
Moderate: The AE is sufficiently intense to produce some impairment of functioning 
and may require a reduction in medication dose or discontinuation of treatment; 
remedial therapy may be given. 
Severe: The AE produced a significant impairment of functioning or incapacitation 
and may require a reduction in medication dose or discontinuation of treatment; 
therapy is needed. 


 
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MA-RHO-18-002 Study 
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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: 
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, at any dose, meets one or 
more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe) 
• 
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. 
NOTE: Aerie considers all cancer AEs as SAEs.   
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 
 
 using one of the following mechanisms within 24 hours of learning of the 
event: 


 
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MA-RHO-18-002 Study 
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• 
Email: 
 
• 
Phone Hotline: 
 
• 
Fax: 
 
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 – eg, Serious Adverse Event Form or 
equivalent form (eg, 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 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 
Sexually active women of child bearing potential (See Section 7.4 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 (eg, 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 (eg, x-ray studies).   
The investigator must immediately notify the Ethics Committee/IRB and Aerie, of any 
pregnancy associated with the study medication exposure and keep careful source 
documentation of the event. In addition, the investigator must complete the pregnancy 
surveillance form(s) to ensure all required information is reported. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1   Sample Size 
The planned enrollment is approximately 250 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. 


 
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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. 
11.3   Statistical Methods 
Summary tables (descriptive statistics and/or frequency distributions) will be provided for all 
baseline variables, efficacy variables, and safety variables. 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. Additional analyses may be conducted as described in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to database 
lock. 
11.3.1 Baseline Analyses  
Demographic variables (age, sex, race, etc.) will be summarized by treatment group 
for analysis population. 
Baseline characteristics (as recorded on the eCRF) will be summarized by treatment 
group for analysis population. 
11.3.2 Efficacy Analysis 
Efficacy data will be analyzed using ITT (with and without imputation of missing Week 
12 assessments), mITT (without imputation of missing values), and PP populations 
(without imputation of missing values). No imputation will be performed for missing 
Week 6 values. Imputation for missing Week 12 values will be performed using the 
method of last observation carried forward from Week 6.   
Efficacy data will be evaluated for overall, monotherapy. and concomitant participant 
groups. 
11.3.2.1   IOP 
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. 
The primary efficacy variable is percent reduction from baseline IOP. 
11.3.3 Safety Analyses 
Safety data will be summarized for the Safety population.   
11.3.3.1   Adverse Events 
All treatment-emergent AEs/SAEs will be summarized with frequency 
distributions by treatment group, system organ class, and preferred term 
using version 21.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA) as well as by ocular versus non-ocular. Specific AEs/SAEs 
occurring with a frequency of 5% or more will be summarized in a separate 
listing. 


 
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Descriptive statistics will also be provided as data summaries. 
11.3.3.2   Other Safety Assessments 
 
Other safety variables (as recorded on the eCRF) will be either 
summarized or listed based on the frequency. 
11.3.4 Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.4   Interim Analysis 
No interim analyses are planned. 
12.0 
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 (eg, change of telephone numbers, etc.). 


 
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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. 
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 (eg, 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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Final 18Dec2018 
 
13.0 
REFERENCES 
 
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. 
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. 
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. 
Kass MA, Gordon MO, Gao F, el al. Delaying Treatment of Ocular Hypertension: The Ocular 
Hypertension Treatment Study. Arch Ophthalmol. 2010;125:276-287. 
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. 
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. 
Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. 
J Ocul Pharmacol Ther. 2015;31:146–151. 
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. 
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. 
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. 
Rhopressa (netarsudil ophthalmic solution) 0.02% for topical ophthalmic use. Prescribing 
Information. Revised: December 2017. 
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 2:  
 QUESTIONNAIRE 
 
Subject I.D. 
  ______________________ 
Study Site: 
  ______________________ 
Date Completed:   _____/_____/_____ 
 
 
 
  Month/Day/Year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX 3:  STUDY MEDICATION PACKAGE INSERT 
 
Package Insert for Rhopressa (netarsudil ophthalmic solution) 0.02% will be supplied separately to each 
study site.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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APPENDIX 5:  EXAMINATION PROCEDURES 
 
1. Best Corrected Visual Acuity 
At all study visits, BCVA will be assessed in both eyes of each subject using a logarithmic visual acuity 
chart (Snellen or equivalent) at a distance of 12 feet. 
Ensure subject is seated in a position whereby his/her eyes are 12 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 (eg, 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 equivalent units, eg, 20/80) 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 without fluorescein and without dilation of the pupil will be performed during the study 
(fluorescein may be used if corneal erosion is suspected).  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 


 
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MA-RHO-18-002 Study 
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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 
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 
 
 


 
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MA-RHO-18-002 Study 
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Staining/Erosion 
 
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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MA-RHO-18-002 Study 
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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 study coordinator (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 (eg, 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. Blood Pressure 
Resting state blood pressure will be measured after the subject has been seated quietly for at least 5 
minutes. Blood pressure will be measured with a sphygmomanometer with appropriate size cuff and a 
stethoscope or with a measurement device. 
 
5. Pregnancy Testing 
A urine human chorionic gonadotropin (hCG) pregnancy test (only for females who are not diagnosed as 
postmenopausal or surgically sterile) will be used in this study and performed at the Baseline Visit to 
immediately confirm non-pregnancy eligibility for women of childbearing potential. 
 
6. 
 Questionnaire 
The investigator (or designee) will administer the 
 Questionnaire and 
record the subject’s responses on the appropriate CRF at Visit 3 (Week 12). 
 
 
 


 
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MA-RHO-18-002 Study 
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Final 18Dec2018 
 
7. 
 Questionnaire 
The investigator will complete the 
 Questionnaire at Visit 3 (Week 12) for all subjects who 
complete the study. 
 
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. 

SAP_001.pdf: 
MA-RHO-18-002 
 
 
 A MULTICENTER, OPEN-LABEL 
STUDY OF RHOPRESSA® 
(NETARSUDIL OPHTHALMIC 
SOLUTION) 0.02% FOR THE 
REDUCTION OF ELEVATED 
INTRAOCULAR PRESSURE IN 
PATIENTS WITH GLAUCOMA OR 
OCULAR HYPERTENSION IN A 
REAL-WORLD SETTING  
 
 
 
NCT03808688 
 
 
15 August 2019