Conditions: Fuchs' Endothelial Dystrophy Bullous Keratopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
Cornea transplant recipients who are using topical corticosteroids long-term to prevent transplant rejection will be randomized to use netarsudil or placebo.

Detailed description:

Arms:
arm 1: Netarsudil ophthalmic solution 0.02%, dosed topically once a day for 9 months arm 2: Placebo eye drop, dosed topically once a day for 9 months

Interventions: intervention 1: Netarsudil intervention 2: Placebo
Intervention descriptions: intervention 1: netarsudil opthalmic solution 0.02% intervention 2: Placebo eye drops

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Randomized, double-masked, placebo-controlled evaluation of netarsudil for 
prevention of corticosteroid-induced intraocular pressure elevation 
 
 
 
Name of investigational compound: 
Netarsudil ophthalmic solution 0.02% 
Investigational phase: 
 
 
Physician-sponsored IND 
Principal Investigator:   
 
Francis W. Price, Jr. MD 
Telephone number:  
 
 
317-844-5530 (24 hours) 
Email address:  
 
 
fprice@pricevisiongroup.net 
 
Study number:   
 
 
2017-003 
NCT number 
 
 
 
03248037 
Date: 
 
 
 
 
8/23/2017 
Version: 
 
 
 
2 
 
 
 
 
Sponsor: 
Francis W. Price, Jr. MD 
Cornea Research Foundation of America 
9002 N. Meridian St., Suite 212 
Indianapolis, IN  46260 
Phone: 317-814-2990, FAX: 317-814-2806 
 


2 
 
 
1. Purpose of the Study and Background 
 
1.1  Purpose of the Study:  
The study objective is to determine whether use of netarsudil significantly reduces the rate of steroid-
associated intraocular pressure (IOP) elevation when used by cornea transplant recipients long-term as an 
adjunct to prednisolone acetate (PA) 1% ophthalmic solution (used to prevent transplant rejection).  
 
1.2  Background 
Topical corticosteroids are commonly used to control postoperative ocular inflammation. They are also 
the mainstay for preventing and treating corneal transplant rejection and for treating ocular conditions 
involving immune hyper-reactivity.1 The principal drawbacks include steroid-induced ocular hypertension 
and steroid-induced glaucoma. The incidence varies with the type of glucocorticoid and its formulation, 
the dosing frequency, and the treatment duration.  
 
Prednisolone acetate 1% ophthalmic solution is the most commonly used topical corticosteroid in the 
U.S.2 Treatment duration ranges from a few weeks, for controlling postoperative inflammation, to years, 
for preventing cornea transplant rejection.2 Up to 35% of patients without a prior glaucoma diagnosis and 
up to 80% with pre-existing glaucoma experience clinically significant post-keratoplasty IOP elevation 
with long-term topical corticosteroid use.3 Intraocular pressure elevation is associated with reduced visual 
acuity and increased risk of transplant failure. 
 
Corneal transplantation offers a unique opportunity to evaluate potential methods for preventing IOP 
elevation associated with long-term use of topical corticosteroids, without the confounding factors present 
with immune hyper-reactivity disorders.  
 
1.3 Study Design 
 Prospective, randomized, double-masked, placebo-controlled clinical trial  
 Main Outcome Measure 
o Rate of intraocular pressure elevation 
 
2.0 Characteristics of the Research Population 
 
2.1 
 Number of Subjects: up to 186 cornea transplant (endothelial keratoplasty) patients will 
be enrolled. 
 
2.2 
 Gender of Subjects: both men and women will be enrolled 


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2.3 
 Age of Subjects: 18-90 years of age. The rationale for not including minors is that 
endothelial keratoplasty is performed to treat endothelial dysfunction, a condition usually seen in 
adults over 40 years of age. 
 
2.4 
 Racial and Ethnic Origin: Subjects may be of any racial or ethnic origin. 
 
2.5 
 Inclusion criteria: the following are requirements for study inclusion: 
o At least 18 years of age 
o Male or female patient undergoing Descemet membrane endothelial keratoplasty 
o Patient is able and willing to administer eye drops. 
o Patient is able to comprehend and has signed the Informed Consent form. 
o Patient is likely to complete the nine-month course of the study. 
 
2.6: Exclusion criteria:  
o A patient exhibiting pre-operative intraocular inflammation.  
o A patient with a known sensitivity to any of the ingredients in the study 
medications  
o A patient who has a condition (i.e., UNCONTROLLED systemic disease) or is in a 
situation which in the investigator’s opinion may put the patient at significant 
risk, may confound the study results, or may interfere significantly with the 
patient’s participation in the study 
o A patient with abnormal eyelid function. 
o A patient that is exhibiting active corneal ulceration, keratitis, or conjunctivitis, or 
who has a history of herpetic keratitis.  
o A patient who has been diagnosed with uncontrolled glaucoma, prior aqueous 
shunt or trabeculectomy, or with preoperative IOP > 22 mm Hg in the potential 
study eye. 
o Presence of any ocular disease that would interfere with the evaluation of the 
study treatment.  However, patients with a history of cystoid macular edema, age-
related macular degeneration, corneal neovascularization, and other non-
interfering comorbidities may be enrolled. 
o A patient with a history of non-compliance with using prescribed medication. 
o A patient who is concurrently involved in or participated in another randomized 
clinical trial within 30 days prior to enrollment in this study. 
o Patients who are pregnant or planning to become pregnant within the duration of 
the study 
 
2.7 Vulnerable Subjects: No potentially vulnerable subjects will be enrolled because there may 
be no direct benefit to the patient; rather, important knowledge which may benefit future subjects 
is being sought. As such, the direct benefit would not outweigh risks for vulnerable populations.  
 
Minors will not be enrolled into this study because the conditions being studied under this 
protocol are not typical problems for minors. Endothelial keratoplasty is performed to treat 
endothelial dysfunction, a condition usually seen only in older (>40 years of age) adults.) 
 


4 
 
Pregnant women will not be enrolled into this study as potential risks and harm to the fetus is 
unknown.  
 
This study plans to exclude any person who does not speak English as non- English speaking 
patients are not normally seen at the study site so a translator would not be available to translate 
the consent form into the patient’s native language. 
 
3.0  Methods & Procedures 
 
3.1 Study procedures and assessments. 
 
Screening and Enrollment:  Prospective subjects will be considered for entry into the study. 
Subjects meeting the inclusion and exclusion criteria will be informed of the opportunity to participate in 
the study. Subjects will be entered into the study after providing written informed consent.  Each subject 
will be instructed that if they decide not to participate, they may withdraw at any time.  
 
Randomization:  Netarsudil ophthalmic solution 0.02% and placebo eye drops will be dispensed 
to study subjects in 2.5 ml bottles, identical in appearance.  A designated, unmasked, dosing coordinator 
will apply a coded sticker to each bottle. A computer generated randomization table will be generated. 
During the routine follow up exam 1 or 2 days after transplantation, the study subject will be randomly 
assigned to receive netarsudil or AR-13324 placebo (netarsudil vehicle). Both the subject and the 
investigator will remain masked as to the assigned treatment.  If a study participant elects to have both 
eyes enrolled in the study, the dosing coordinator will automatically assign the second eye to the opposite 
treatment group from that of the first eye. 
 
Study Treatment Regimen: Subjects will be instructed to instill the assigned eye drop into the 
study eye once nightly for the 9-month study duration. As standard of care to prevent cornea transplant 
rejection, subjects will use prednisolone acetate 1% eye drops 4 times daily for the first 3 months, then 3 
times daily during month 4, twice daily during month 5, and once daily during months 6 to 9.  
 
Study Drug Accountability:  Subjects will be asked to bring back to the clinic all study bottles, 
both used and un-used. All study drug bottles will be reconciled and recorded. 
 
Rescue Medication:  if a study subject develops IOP elevation (a measurement ≥ 24 mm Hg or an 
increase over the screening pre-operative reading of ≥ 10 mm Hg), the dosing coordinator will be notified.  
If the affected eye was assigned to the placebo group, the subject will be offered the opportunity to 
crossover to the netarsudil group to determine whether that adequately reduces IOP. Depending upon the 
severity of the IOP increase, the investigator may decide whether it is in the patient’s best interest to 
reduce corticosteroid strength and/or dosing frequency and/or initiate use of approved glaucoma 
medications.     
 
Examinations:  


5 
 
o Schedule: Each subject will be examined at screening, 1, 3, 6 and 9 months after 
endothelial keratoplasty as detailed in Table 1. The examination schedule and 
procedures are standard of care for endothelial keratoplasty patients. 
o Procedures: At 5 day, 1, 3, 6, and 9 month exams, medical and ophthalmic 
histories will be updated, adverse events will be recorded, and measurements of  
visual acuity will be made. At 1, 3, 6 and 9 month exams, measurements of 
manifest refraction, corneal thickness (pachymetry) and intraocular pressure will 
be made. Corneal endothelial cell density will be measured by specular or 
confocal microscopy if possible.. A slit lamp examination will be performed to 
assess the health of the transplant and document any conjunctival or lid 
hyperemia, stromal inflammation, superficial punctate keratitis, other surface 
toxicity of the cornea, neovascularization of the cornea, cells or flare in the 
anterior chamber, or evidence of transplant rejection. 
o Records release: Subjects may be asked to sign a records release form in case the 
subject sees another eye specialist while enrolled in the study. This will allow the 
investigator to determine if there is a rejection episode or elevated intraocular 
pressure at examinations made with other physicians. The primary outcome 
(intraocular pressure) is a routine ophthalmic exam procedure, so the subject may 
have some exams performed by a local eye doctor if returning to the study site for 
all exams is too burdensome. 
o Unscheduled examinations: Subjects will be instructed to return for extra 
examinations if they note any problems with the eye or any early signs of a 
possible rejection episode, such as a change in vision, redness to the eye, 
increased light sensitivity, burning sensation, or foreign body sensation. 
o Study completion: Subjects will be considered to have completed the study after 
they complete the 9-month examination. 
o Subject withdrawal or discontinuation:  Each subject may voluntarily discontinue 
the study at any time they choose. Subjects who cannot complete the study for 
administrative reasons (e.g., non-compliance, failure to meet visit schedule, etc.) 
will be discontinued from the study. Discontinued subjects may be replaced. For 


6 
 
subjects withdrawn from the study, the same measurements and assessments 
should be performed as done at the 9-month exit exam. Adverse events should be 
followed up until resolution or stabilization of the adverse event.  


7 
 
Table 1 
 
Screening 
Randomization 
(1 or 2 days after 
DMEK) 
5 day 
after 
DMEK 
4 (± 2) 
weeks 
after 
DMEK 
3 (± 1) 
months 
after 
DMEK 
6 (± 1) 
months 
after 
DMEK 
9 (± 1) 
months 
after 
DMEK 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Medical and ophthalmic 
history 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Uncorrected visual acuity 
(Snellen) 
X 
X 
X 
X 
X 
X 
X 
Assignment to netarsudil 
or placebo 
 
X 
 
 
 
 
 
Corrected distance visual 
acuity (Snellen) 
X 
 
 
X 
X 
X 
X 
Manifest refraction 
X 
 
 
X 
X 
X 
X 
Endothelial cell density 
(if possible) 
X 
 
 
X 
X 
X 
X 
Intraocular pressure  
X 
 
 
X 
X 
X 
X 
Ultrasonic pachymetry 
X 
 
 
X 
X 
X 
X 
 
3.2 Data Analysis and Data Monitoring: The primary outcome measure is the incidence of clinically 
significant IOP elevation (defined as IOP ≥ 24 mm Hg or a relative increase over the baseline reading of 
≥ 10 mm Hg). Previous study results conservatively suggest that the rate of IOP elevation will be 20% or 
greater in the placebo-control arm.4,5 Based on the mechanism of action and clinical trial results, we 
estimate that the relative odds ratio will be 0.25 in the netarsudil study arm. A sample size of 84 per study 
arm (total = 168) would provide 80% power to detect a statistically significant difference between groups 
at a 5% significance level (two-sided test). Assuming up to 10% drop out, the required recruitment is 186 
study eyes. 


8 
 
Statistical analysis will be conducted on an intent-to-treat basis (i.e. all randomized subjects will be 
included in the analysis). Data will be analyzed with Statistical Analysis Software (SAS Version 9.4, SAS 
Institute, Cary, NC) using Kaplan Meier survival analysis and proportional hazards analysis.   
3.3 Data Storage and Confidentiality: Research data will be stored in a locked cabinet or locked room 
and on a password protected server to prevent unauthorized access to data. The investigators and research 
staff will have access to the data. Subject identifiers will be removed and data will be aggregated for 
publication or presentation of study results.   
4.0  Risk/Benefit Assessment 
 
4.1 Risks and Anticipated Adverse Events: 
Risks: This study is considered moderate risk. Netarsudil is an investigational drug - a New Drug 
Application (NDA) was recently submitted to the U. S. Food and Drug Administration. 
  
A number of complaints and complications are anticipated in patients who have received a 
cornea transplant, regardless of whether they participate in this study.  Therefore, the presence or 
absence of the following anticipated complaints and complications in the study eye will be 
recorded on the electronic case report form (eCRF) for each exam rather than on separate 
adverse event forms.  
 
Complaints of ocular discomfort: (examples include: eye pain, irritation, burning, itching, 
scratchy feeling, foreign body sensation, tired/fatigued feeling, achy/tender/sore feeling, pressure 
sensation, tightness, twinge/twitchy feeling, dry eyes, tearing/watering, eye redness) 
 
Complaints of visual symptoms or disturbances: (examples include: glare or fluctuating vision, 
haloes around lights, diplopia, blurry, hazy, cloudy, filmy or out of focus vision, ghosting or 
shadowing, difficulty reading, difficulty with night driving, floaters, spots in vision, light 
sensitivity, decreased vision, light reflections from intraocular lens or peripheral iridotomy).   
 
Increased ptosis (within the first 6 months of surgery) 
 
Puffy eyelids (within the first 3 months of surgery) 
 
Delayed resolution of corneal haze or edema (within the first 6 months of surgery) 
 
Subconjuntival hemorrhage (within the first 3 months of surgery) 
 
Epithelial defect (within the first month of surgery) 
 
Folds in the transplant 


9 
 
 
Partial graft detachment without further intervention 
 
Development of capsular haze 
 
Superficial punctate keratitis 
 
Pupillary block (within the first 3 months of surgery) 
Adverse events: The type, severity, duration and frequency of the following anticipated adverse 
experiences and any other unanticipated ocular adverse events will be tabulated. If a patient 
experiences an adverse reaction, appropriate medical treatment will be provided.  Examples may 
include:  
 
Graft detachment which requires intervention 
 
Immunologic graft rejection episode 
 
Graft failure and/or regraft 
 
Intraocular pressure elevation which requires intervention 
 
Development of capsular haze which requires intervention 
 
Iris synechia 
 
Cystoid macular edema 
 
Iritis 
Anticipated rare adverse events include retinal detachment, iris synechiae/atrophy, epiretinal membrane, 
infectious keratitis or conjunctivitis, branch retinal vein occlusion, or endophthalmitis.  
Serious Adverse Event: A serious adverse event is one that results in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/ incapacity, or a congenital 
anomaly/birth defect. In the event of a serious adverse event, the investigator will maintain 
complete documentation and promptly inform the governing Institutional Review Board (IRB) of 
the serious adverse event within their required reporting period. 
 
Fellow eye: Patients in this population tend to be affected with the eye condition bilaterally, so 
many of the study subjects may undergo surgery on the fellow eye during study participation.  


10 
 
Routine fellow-eye post-surgical complications will not be transcribed to the eCRF unless the 
fellow eye is enrolled in the study at the time of the event. 
 
4.2 
Protection Against Risks: Every effort will be made to minimize any risks or 
discomforts to study subjects. The investigator will ensure appropriate training of study 
personnel and monitoring of subjects and will provide appropriate treatment for eye-related 
adverse events or referral for treatment of non-eye-related adverse events. The subject and or 
their health insurance plan will be responsible for payment for treatment, counseling or follow 
up. 
 
A Data Safety Monitoring Committee (DSMC) will be chaired by Dr. Gerald Clarke, an 
independent ophthalmologist practicing in Menasha, Wisconsin. The DSMC will review any 
serious adverse events as they occur. The DSMC will also review the interim data (including 
adverse events and subject compliance) every 6 months, to determine if any modifications to the 
original study plan may be warranted. The DSMC meeting minutes and recommendations will be 
documented and shared with IRBCo, Inc. and with the provider of the investigational product, 
Aerie Pharmaceuticals. 
 
4.3 
Potential Benefits to the Subjects: Study subjects may not realize any direct benefit 
from participation in the research; rather, important knowledge which may benefit future 
subjects is being sought.  
 
4.4 
Study termination: The study may be prematurely terminated if, in the opinion of the 
investigator or the Sponsor, there is sufficient reasonable cause. Written notification, 
documenting the reason for study termination, will be provided to the investigator or Sponsor by 
the terminating party. Circumstances that may warrant termination include, but are not limited 
to: 
 Determination of unexpected, significant, or unacceptable risk to subjects. 
 Insufficient adherence to protocol requirements. 
 Data that is not sufficiently complete or evaluable. 


11 
 
 Plans to modify, suspend or discontinue marketing of the Study Product. 
 
5.0 Method of Subject Identification and Recruitment 
5.1 Process of Consent The process of obtaining the consent consists of explaining the eye condition and 
explaining the risks and benefits of the proposed   treatment and alternatives. In addition, the patient will 
be allowed to read the consent and ask questions prior to signing the informed consent form. The patient 
may take home an unsigned copy of this consent form to think about or discuss with family or friends 
before making a decision.  
Study coordinators, who have been trained in obtaining consent by the investigator and who have 
experience in consenting subjects for clinical trials, will obtain informed consent. Consent will be 
obtained in a private exam room with the door closed to protect the privacy of participants. The study will 
be explained to participants and if subjects have specific questions which the study coordinator cannot 
address, the principal investigator will be available to answer the questions. 
5.2 Subject Capacity: All subjects will be evaluated for capacity to consent through the use of the 
Cornea Research Foundation of America Evaluation to Sign a Consent Form. Any subjects who do not 
answer the Evaluation questions satisfactorily will be considered cognitively impaired and will not be 
enrolled into the study as they would not meet the study's inclusion/exclusion criteria. 
5.3 Subject/Representative Comprehension: Subjects will be given time to ask any questions, and 
study information will be explained until it is clear that all information presented is understood.   
5.4 Debriefing Procedures: Not applicable; this is not a psychological study and no information will be 
purposely withheld from the subject. 
6.0 Consent Forms 
6.1 Documentation of Consent Patient's medical records and informed consent documents will be 
maintained and stored with access limited to the authorized personnel. All research records will be kept 
separate and locked with limited access by research personnel only. 
6.2 Costs to the Subject: The subject and or their health insurance plan will be responsible for payment 
for treatment, counseling or follow up. 


12 
 
6.3 Payment for Participation: Subjects will be provided with the assigned study drug (netarsudil or 
placebo eye drops) and with the prednisolone acetate 1% eye drops used to prevent transplant rejection 
for the duration study participation. Subjects will not receive any payment for study participation. 
7.0 References 
1. Fini ME, Schwartz SG, Gao X, Jeong S, Patel N, Itakura T, Price MO, Price FW Jr, Varma R, 
Stamer WD. Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and 
implications for precision medicine. Prog Retin Eye Res 2016 [Epub ahead of print]. 
2. Price FW, Price DA, Ngakeng V, Price MO. Survey of steroid usage patterns during and after 
low-risk penetrating keratoplasty. Cornea 2009;28:865-70. 
3. Vajaranant TS, Price MO, Price FW, Gao W, Wilensky JT, Edward DP. Vision and intraocular 
pressure after Descemet-stripping endothelial keratoplasty in patients with and without pre-
existing glaucoma. Ophthalmology 2009;116:1644-50. 
4. Price MO, Feng MT, Scanameo A, Price FW Jr. Loteprednol etabonate 0.5% gel vs. prednisolone 
acetate 1% solution after Descemet membrane endothelial keratoplasty: prospective randomized 
trial. Cornea 2015;34:853-8. 
5. Price MO, Price FW Jr, Kruse FE, Bachmann BO, Tourtas T. Randomized comparison of topical 
prednisolone acetate 1% versus fluorometholone 0.1% in the first year after Descemet membrane 
endothelial keratoplasty. Cornea 2014;33:880-6.