Pilot Phase I/II Study of the Evaluation of Interferon Gamma-1b Administered Topically for Macular Edema/Intraretinal Schisis Cysts in Rod-Cone Dystrophy (RCD) and Enhanced S-Cone Syndrome (ESCS)
Phase: PHASE1
Conditions: Inherited Ophthalmic Diseases, Inherited Retinal Degeneration
Sponsor: National Eye Institute (NEI)

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Protocol Title: Pilot Phase I/II Study of the Evaluation of Interferon Gamma-1b Administered 
Topically for Macular Edema/Intraretinal Schisis Cysts in Rod-Cone Dystrophy 
(RCD) and Enhanced S-Cone Syndrome (ESCS) 
Protocol Number: 15-EI-0052 
Date of This Submission/Version: May 27, 2016/ v5.0 
Principal Investigator (PI) 
Wadih Zein, MD 
NEI/NIH 
Bldg. 10, 
Rm. 10D45 
301-496-8118 
zeinw@nei.nih.gov 
Accountable Investigator 
Wadih Zein, MD 
NEI/NIH 
Bldg. 10, 
Rm. 10D45 
301-496-8118 
zeinw@nei.nih.gov 
Associate Investigators (AI) 
Catherine Cukras, MD, PhD 
NEI/NIH 
Bldg. 10, 
Rm. 10C438 
301-435-5061 
cukrasc@nei.nih.gov 
Brett Jeffrey, PhD 
NEI/NIH 
Bldg. 10, 
Rm. 10C442 
301-402-2391 
jeffreybg@nei.nih.gov 
Emily Chew, MD 
NEI/NIH 
Bldg. 10, 
Rm. 3-2531 
301-496-6583 
echew@nei.nih.gov 
Amy Turriff, ScM 
NEI/NIH 
Bldg. 10, 
Rm. 11C432B 
301-402-4175 
turriffa@nei.nih.gov 
Henry Wiley, MD 
NEI/NIH 
Bldg. 10, 
Rm. 10D45 
301-451-4260 
henry.wiley@nih.gov 
Wai T. Wong, MD, PhD 
NEINIH 
Bldg. 6, 
Rm. 217 
301-496-7566 
wongw@nei.nih.gov 
Brian Brooks, MD, PhD 
NEI/NIH 
Bldg. 10, 
Room 10B16 
301-451-2238 
brooksb@nei.nih.gov 
Kapil Bharti, PhD 
NEI/NIH 
Bldg. 35, 
Rm. 2A-102 
301-496-9661 
kapilbharti@nei.nih.gov 
Anand Swaroop, PhD 
NEI/NIH 
Bldg. 6,  
Rm. 338 
301-435-5754 
swaroopa@nei.nih.gov 
Arvydas Maminishkis, PhD 
NEI/NIH 
Bldg. 10, 
Rm. 10B04 
301-435-4902 
arvydas.maminishkis@nih.gov 
Sheldon Miller, PhD 
NEI/NIH 
Bldg. 31, 
Rm. 6A22 
301-496-3180 
sheldon.miller@nih.gov 
H. Nida Sen, MD, MHSc 
NEI/NIH 
Bldg. 10, 
Rm. 10N112 
301-402-3254 
senh@nei.nih.gov 
Laryssa Huryn, MD 
NEI/NIH 
Bldg. 10, 
Rm. 10D45 
301-443-8556 
laryssa.huryn@nih.gov 
Robert Hufnagel, MD, PhD 
NEI/NIH 
Bldg. 10, 
Rm, 10D45 
301-496-3577 
robert.hufnagel@nih.gov 
Allison Bamji, RN 
NEI/NIH 
Bldg. 10 
Rm. 10D45 
301-451-3437 
bamjia@nei.nih.gov 
Angel Garced, BSN, MPH 
NEI/NIH 
Bldg. 10 
Rm. 10C408 
301-594-3141 
garceda@nei.nih.gov 

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Referral Contact 
Angel Garced, BSN, MPH 
NEI/NIH 
Bldg. 10 
Rm. 10C408 
301-594-3141 
garceda@nei.nih.gov 
 
Human Research Protections Program Investigator and Staff Training: 
For this protocol, the following “Just in time” human subjects protection training courses are 
required for investigators and staff: 
Biomedical-Vulnerable Subjects-Research with Children 
Coordinating Center : 
The Emmes Corporation (Emmes) 
401 North Washington St. 
Suite 700 
Rockville, MD 20850 USA 
Phone: (301) 251-1161 
Facsimile: (202) 478-0243 
Total Requested Accrual: 
12 Participants: 
• Up to 5 Participants with Rod-cone dystrophy and macular 
edema 
• Up to 5 Participants with Enhanced S-cone syndrome and 
macular edema 
• Up to an additional two participants may be enrolled to 
account for participants who withdraw from the study prior 
to receiving five days of treatment 
 
0 Healthy Volunteers 
Project Uses Ionizing Radiation:   
 
 No   
 Yes 
IND/IDE: 
 
 
 
 
 
 No  
 Yes 
Drug #:  
105,631 
Sponsor:  
Wadih Zein, MD, National Eye Institute 
Durable Power of Attorney:  
  
 
 No   
 Yes 
Multi-institutional Project:   
 
 
No   
 Yes 
Data and Safety Monitoring Board:  
 
 No   
 Yes 

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Technology Transfer Agreement:  
 
 No  
 Yes 
Agreement type and number: CTA 00935-13 with Horizon Pharma [Vidara Therapeutics 
Research Limited (Vidara)] 
Expiration Date: September 30, 2016 
Samples Being Stored for Future Research: 
 No   
 Yes 
Flesch-Kincaid Reading Level of Consent Form: 8.6 
Flesch-Kincaid Reading Level of Assent Form: 5.7 
 
 

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TABLE OF CONTENTS 
PROTOCOL ABBREVIATION LIST .................................................................................................. VI 
PRÉCIS ............................................................................................................................................ 1 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE ........................................................................... 3 
2.0 
STUDY OBJECTIVES ............................................................................................................. 5 
3.0 
PARTICIPANTS ..................................................................................................................... 5 
3.1 
Participant Eligibility Criteria .......................................................................................... 6 
3.1.1 
Inclusion Criteria ...................................................................................................... 6 
3.1.2 
Exclusion Criteria ..................................................................................................... 6 
3.2 
Study Eye Eligibility Criteria ........................................................................................... 7 
3.2.1 
Study Eye Inclusion Criteria ..................................................................................... 7 
3.2.2 
Study Eye Exclusion Criteria .................................................................................... 7 
3.2.3 
Study Eye Selection Criteria in Cases of Bilateral Disease ...................................... 7 
4.0 
STUDY DESIGN AND METHODS ........................................................................................... 8 
4.1 
Study Overview ................................................................................................................ 8 
4.2 
Recruitment ...................................................................................................................... 8 
4.3 
Screening .......................................................................................................................... 9 
4.4 
Study Visits ...................................................................................................................... 9 
4.4.1 
Study Evaluations ................................................................................................... 11 
4.5 
Study and Concomitant Therapies ................................................................................. 12 
4.5.1 
Product Overview ................................................................................................... 12 
4.5.2 
Investigational New Drug (IND) Requirement....................................................... 12 
4.5.3 
Preparation and Administration .............................................................................. 12 
4.5.4 
Drug Accountability................................................................................................ 13 
4.5.5 
Concomitant Medications and Treatments ............................................................. 13 
4.6 
Follow-up/Termination Procedures................................................................................ 14 
4.7 
Storage of Samples and Data ......................................................................................... 14 
5.0 
RISKS AND DISCOMFORTS ................................................................................................. 15 
5.1 
Risks and Discomforts Associated with the Clinical Assessments ................................ 15 
5.2 
Risks and Discomforts Associated with the Investigational Product ............................. 16 
6.0 
PARTICIPANT MONITORING .............................................................................................. 17 
6.1 
Participant Withdrawal Criteria ..................................................................................... 17 
6.2 
Reporting of Pregnancy .................................................................................................. 18 
7.0 
OUTCOME MEASURES ....................................................................................................... 18 
7.1 
Primary Outcome Measures ........................................................................................... 18 
7.2 
Secondary Outcome Measures ....................................................................................... 18 
8.0 
STATISTICAL ANALYSIS .................................................................................................... 19 
8.1 
Analysis .......................................................................................................................... 19 

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8.2 
Sample Size .................................................................................................................... 19 
9.0 
HUMAN SUBJECTS PROTECTION ....................................................................................... 19 
9.1 
Equitability ..................................................................................................................... 19 
9.1.1 
Justification for Exclusion of Children Below 12 Years of Age ............................ 20 
9.1.2 
Justification for Inclusion of Children Ages 12 and Above ................................... 20 
9.1.3 
Safeguards for Vulnerable Populations .................................................................. 20 
9.1.4 
Consideration of Persons Who Cannot Consent ..................................................... 20 
9.1.5 
Justification for Exclusion of Pregnant or Lactating Women ................................. 21 
9.2 
Qualifications of Investigators ....................................................................................... 21 
10.0 ANTICIPATED BENEFIT...................................................................................................... 23 
11.0 CLASSIFICATION OF RISK ................................................................................................. 23 
12.0 CONSENT DOCUMENTS AND PROCESS .............................................................................. 24 
12.1 Non-English Speaking Participants ................................................................................ 24 
13.0 DATA AND SAFETY MONITORING ..................................................................................... 25 
13.1 Coordinating Center ....................................................................................................... 25 
13.2 NEI Serious Adverse Event Review Committee............................................................ 26 
13.3 Criteria for Stopping the Study ...................................................................................... 26 
14.0 QUALITY ASSURANCE ....................................................................................................... 27 
15.0 REPORTING OF UNANTICIPATED PROBLEMS, PROTOCOL DEVIATIONS AND ADVERSE 
EVENTS ......................................................................................................................................... 27 
16.0 ALTERNATIVES TO PARTICIPATION .................................................................................. 28 
17.0 PRIVACY ............................................................................................................................ 28 
18.0 CONFIDENTIALITY ............................................................................................................. 28 
19.0 CONFLICT OF INTEREST .................................................................................................... 29 
20.0 TECHNOLOGY TRANSFER.................................................................................................. 29 
21.0 RESEARCH AND TRAVEL COMPENSATION........................................................................ 29 
22.0 REFERENCES ...................................................................................................................... 30 
APPENDIX 1: STUDY FLOWSHEET ................................................................................................ 33 
APPENDIX 2: STUDY AND CONCOMITANT MEDICATION INSTRUCTION SHEET ......................... 35 
APPENDIX 3: NATIONAL EYE INSTITUTE VISUAL FUNCTIONING QUESTIONNAIRE-25 .............. 37 
APPENDIX 4: ELECTRONIC VISUAL ACUITY (EVA) AND MANIFEST REFRACTION ................... 45 
APPENDIX 5: DETERMINING CHILDBEARING POTENTIAL .......................................................... 63 
 
 

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Protocol Abbreviation List 
Abbreviation 
Term 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
µg 
Microgram 
µL 
Microliter 
AE 
Adverse Event 
BCVA 
Best-corrected visual acuity 
BP 
Blood pressure 
CAI 
Carbonic Anhydrase Inhibitor 
CBC 
Complete Blood Count 
CC 
Clinical Center 
CD 
Clinical Director 
CFP 
Color Fundus Photography 
CFR 
Code of Federal Regulations 
CNS IRB 
Combined Neuroscience Institutional Review Board 
CNV 
Choroidal Neovascularization 
CRIS 
Clinical Research Information System 
CTA 
Clinical Trial Agreement 
DSMC 
Data and Safety Monitoring Committee 
Emmes 
The Emmes Corporation 
EMR 
Electronic Medical Record 
EOG 
Electrooculography 
ERG 
Electroretinogram/Electroretinography 
ESCS 
Enhanced S-Cone Syndrome 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EVA 
Electronic Visual Acuity 
FA 
Fluorescein Angiography 
FAF 
Fundus Autoflourescence Imaging 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
HRPP 
Human Research Protection Program 
HSPU 
Human Subjects Protection Unit 
IFN 
Interferon 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
iPSC 
Induced pluripotent stem cell 

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Abbreviation 
Term 
IRB 
Institutional Review Board 
IU 
International Unit 
kg 
Kilogram 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MD 
Doctor of Medicine 
mg 
Milligram 
mIU 
Milli International Unit 
mL 
Milliliter 
mm 
Millimeter 
mmol 
Millimole 
MS 
Multiple Sclerosis 
MSHSc 
Master of Science in Health Sciences 
NEI 
National Eye Institute 
NEI QA 
National Eye Institute Quality Assurance 
NEIS 
National Eye Institute Support 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NR2E3 
Nuclear Receptor Subfamily 2, Group E, Member 3 
OCT 
Optical Coherence Tomography 
OHSRP 
Office of Human Subjects Research Protections 
OMIM 
Online Mendelian Inheritance in Man 
PhD 
Doctor of Philosophy 
PI 
Principal Investigator 
RCD 
Rod-cone dystrophy 
RN 
Registered Nurse 
RP 
Retinitis Pigmentosa 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
ScM 
Master of Science 
SOP 
Standard Operating Procedures 
VA 
Visual Acuity 
VFQ 
Visual Field Questionnaire 
 

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PRÉCIS 
Objective: Rod-cone dystrophy (RCD) is a term applied to a number of genetically 
heterogenous diseases presenting with night vision abnormalities, visual field defects and 
reduced rod electroretinography responses. Enhanced S-Cone syndrome (ESCS) is a rare 
autosomal recessive retinal disease with a developmental and a degenerative aspect. Macular 
cystic changes, often florid and usually resulting in a reduction of central acuity, are frequently 
associated with both diseases. The reason for this association is not well understood. 
Acetazolamide (Diamox) and Dorzolamide (Trusopt) have been reported to have variable 
success in reducing these cystic changes but the effect is frequently inadequate. The objective of 
this study is to evaluate the safety and potential efficacy of Interferon (IFN) gamma-1b 
administered topically for macular edema/retinal schisis cysts in RCD and ESCS. Possible 
disease-related pathophysiologic mechanisms will be explored using induced pluripotent stem 
cell (iPSC) protocols leading to iPSC-derived retinal pigment epithelium (RPE) and 
photoreceptor generation. 
Study Population: Up to five participants with RCD with significant macular cystic changes 
and up to five participants with ESCS with significant macular cystic changes will be enrolled to 
receive IFN gamma-1b administered topically in one eye. However, up to an additional two 
participants may be enrolled in order to obtain the five participants in each disease group to be 
included in the primary analysis if any participants withdraw from the study prior to receiving 
five days of treatment. 
Design: This is a single-center, prospective, uncontrolled, unmasked pilot Phase I/II study of the 
safety, tolerability and possible efficacy of IFN gamma-1b in participants with RCD and ESCS 
and macular cystic changes. One eye of up to five participants with RCD with significant 
macular cystic changes and up to five participants with ESCS with significant macular cystic 
changes [evidenced by optical coherence tomography (OCT) >275 microns central macular 
thickness and/or disruption of foveal contour] will receive topical IFN gamma-1b instilled as 
drops on the cornea. The initial stage of the study will include two participants from each disease 
category. Once all four participants have completed the 8-week visit, enrollment will be halted. 
Safety Adverse Event Review Committee members unaffiliated with the study will review the 

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data as a preliminary assessment of safety and efficacy and to determine whether enrollment 
should continue. If the committee determines enrollment will continue, three additional 
participants with RCD and three participants with ESCS will be enrolled. The study will be 
completed once the final participant has received one year of follow-up. 
Outcome Measures: The primary outcome measure related to the safety and tolerability of IFN 
gamma-1b administered topically at the prescribed dosage for macular cystic changes in 
participants with RCD and ESCS will be assessed by the number and severity of adverse events 
related to the IP and the number of withdrawals at 52 weeks (one year) post-administration. 
Additional safety of IFN gamma-1b administered topically in participants with RCD and ESCS 
will be determined from the assessment of retinal function, ocular structure and occurrence of 
adverse events at all time points. Secondary outcomes include changes in visual function 
including visual acuity and microperimetry, and retinal imaging with OCT and fluorescein 
angiography. 
 
 

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1.0 
INTRODUCTION/SCIENTIFIC RATIONALE 
RCD is a broad category of genetically heterogeneous diseases that includes many different 
forms of primary photoreceptor abnormalities − typically affecting rods first and cones later. 
Retinitis pigmentosa (RP) is the most common form of RCD. The prevalence is in the range of 
1:3000–1:5000.1 The natural history of the disease involves progressive visual field loss and 
difficulties with night vision. Reduction in central vision can develop secondary to macular 
atrophy in advanced stages of the disease or due to cystic macular changes at any stage. Early 
studies on macular changes in RP gave macular edema a prevalence of around 13% based on 
clinical examination and fluorescein angiography.2, 3 Cystic macular changes were noted in up to 
one third of patients on OCT with visual loss that is correlated with the degree of macular 
thickening.4,5 The cystic changes are frequently bilateral and may respond to treatment with 
carbonic anhydrase inhibitors (CAIs).6-8 Some patients do not respond well to CAI therapy and a 
rebound effect has been noted with extended use.9 
ESCS (OMIM 268100; http://www.ncbi.nlm.nih.gov/omim/ Online Mendelian Inheritance in 
Man; NCBI, Bethesda, MD) is a rare autosomal recessive disease primarily associated with 
mutations in the gene NR2E3 (OMIM 604485). The disorder was first recognized as a separate 
entity by Jacobson and Marmor in 199010,11 and association with the NR2E3 gene was described 
by Haidar et al. in 2000.12 The phenotype is variable but early hemeralopia, visual field 
constriction, nummular pigmentary clumping in the retinal midperiphery and pathognomonic 
electroretinographic changes aid in suspecting the diagnosis.10,11,13-15 The disease is commonly 
associated with significant central retinal cystic changes showing variable response to treatment 
with topical or systemic CAIs.13,14,16-19 No leakage has been noted on fluorescein angiography, 
leading Audo et al. to ascribe these changes to schisis rather than edema.13 The exact mechanism 
behind these often dramatic cystoid changes, with associated reduction in acuity, is still elusive. 
Milam et al. reported on the histopathology in a 77-year-old patient with ESCS (confirmed 
molecularly) indicating that the retina was disorganized with densely packed cones in the center 
(most of which were labeled with S-cone opsins). They note that the peripheral retina was 
degenerative with no rods identified. The RPE was variably depigmented.20 
 
 

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Multiple investigators have studied electroretinographic responses in ESCS. The main findings 
include almost absent rod responses, delayed scotopic maximal response and photopic flash 
responses (thus the two waveforms look similar in shape) and a more robust S-cone response 
compared to the reduced L- and M-cone responses.10,11,13,14,21-24 Pattern electroretinography 
showed variable reduction in amplitude and delay of the P50 component.13,23 Variable degrees of 
dyschromatopsia have been reported on color vision testing with many patients demonstrating 
relative tritan axis sparing and moderately elevated protan and deutan thresholds.13 
The NR2E3 gene was identified in 1999 as a photoreceptor cell-specific nuclear receptor.25  
The association of mutations in this nuclear receptor gene with ESCS was made by  
Haider et al.12 The molecular biology of this gene is also of interest because of the role it plays in 
photoreceptor development, differentiation, and maintenance.20,26-34 It has also been noted that 
mutations in other genes that interact with NR2E3 can, less commonly, cause a similar 
phenotype.35 Recently, Mustafi et al. reported on defective photoreceptor phagocytosis in a 
mouse model of ESCS as a possible contributor to the progressive degeneration.36 They do not 
indicate defective RPE but rather an abnormal interaction between the photoreceptors and the 
RPE. Personal communication with Kapil Bharti, PhD indicates that NR2E3 is part of the adult 
RPE transcriptome (based on work by Strunnikova et al.).37 All previous reports had indicated 
that the gene is photoreceptor specific. Given the above body of work, it would be very helpful if 
iPSC-derived photoreceptor and RPE cells were available to further study the disease 
mechanisms. 
The fluid transport role of the RPE is important in the control of subretinal fluid.38 The active 
“pump” role of the RPE is believed to be important in the maintenance of retinal attachment and 
fluid absorption. This role can be modified with the use of medications.39 In vivo rodent studies 
have shown that IFN gamma-1b applied to the anterior surface of the eye results in significant, 
rapid decrease in retinal detachment volume.40 A number of National Eye Institute (NEI) 
protocols address the question of the safety (and possible efficacy) of topical IFN gamma-1b for 
the treatment of macular edema in different disease models (Central Serous Chorioretinopathy 
(CSC) in NIH protocol 12-EI-0013; Uveitis in NIH protocol 09-EI-0191 and NIH protocol  
11-EI-0167). Topical IFN gamma-1b was first evaluated in uveitic macular edema at the NEI 
(NIH protocol 09-EI-0191). This pilot, phase I, dose-escalation study found topical IFN  

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gamma-1b to be safe and well tolerated with no systemic adverse events or abnormal laboratory 
values (unpublished data). Two participants received 10 micrograms (µg) of topical IFN  
gamma-1b (one instillation), two participants received 20 µg (two instillations) and one 
participant received 30 µg (three instillations). Variable changes in retinal thickness were noted 
using OCT testing; for that study, topical IFN gamma-1b was administered as a one-time 
instillation or series of instillations and OCT testing was performed over a three-hour time 
period. We propose to study the safety and potential efficacy of topical IFN gamma-1b for 
macular cystic changes in the setting of RCD and ESCS. In the proposed protocol, ESCS would 
serve as a model of hereditary retinal diseases associated with significant macular cystic/schisis 
changes and RCD would serve as a model for the more common presentation of macular changes 
in a hereditary retinal degeneration. 
2.0 
STUDY OBJECTIVES 
The primary objective of this study is to explore the safety, tolerability, and possible efficacy of 
the topical application of IFN gamma-1b used as a therapeutic option in patients with macular 
cystic changes associated with RCD and ESCS. Participants will be assessed for systemic and 
ocular side effects. The study is a safety trial but will also provide information about the possible 
therapeutic effect of IFN gamma-1b in a model of florid cystic macular edema and in hereditary 
retinal degenerations. Insight into the pathophysiology of the diseases will be possible by 
obtaining skin biopsy and blood samples for stem cell derived studies. 
3.0 
PARTICIPANTS 
Up to five participants with RCD with significant macular cystic changes and up to five 
participants with ESCS with significant macular cystic changes will be enrolled to receive 
topical IFN gamma-1b in one eye. However, up to an additional two participants may be enrolled 
in order to obtain the five participants in each disease group to be included in the primary 
analysis if any participants withdraw from the study prior to receiving five days of treatment. 
The inclusion and exclusion criteria are outlined in the following sections. 
 
 

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3.1 
Participant Eligibility Criteria 
3.1.1 Inclusion Criteria 
To be eligible, the following inclusion criteria must be met, where applicable. 
1. Participant must be 12 years of age or older. 
2. Participant (or legal guardian or legal representative) must understand and sign the 
protocol informed consent.  
3. Participant is willing to comply with the study procedures and is expected to be able to 
return for all study visits. 
4. Participant must carry a clinical diagnosis of RCD or ESCS. 
5. ESCS participant must have molecular confirmation with two alleles for NR2E3 gene 
mutations 
6. Female participant of childbearing potential (see Appendix 5 for definition) must not be 
pregnant or breast-feeding, must have a negative pregnancy test at screening and must be 
willing to undergo pregnancy tests at scheduled study visits. 
7. Female participant of childbearing potential (see Appendix 5), and any male participant 
able to father children must have (or have a partner who has) had a hysterectomy or 
vasectomy, be completely abstinent from intercourse or must agree to practice two 
reliable methods of contraception while taking the IP and six weeks after completion. 
Acceptable methods of contraception include: 
• 
Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch 
or vaginal ring); 
• 
Intrauterine device; 
• 
Barrier methods (diaphragm, condom) with spermicide; or 
• 
Surgical sterilization (tubal ligation). 
3.1.2 Exclusion Criteria 
A participant is not eligible if any of the following exclusion criteria are present. 
1. Participant has a history of other ocular disease likely to contribute significantly to visual 
disruption (e.g., optic neuropathy, glaucoma, uveitis, or other retinal disease). 
2. Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma 
skin cancer) within the previous five years. 

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3. Participant has received investigational treatment in another clinical study related to an 
ocular condition in the last six months. 
4. Participant is pregnant, lactating, planning to become pregnant (or father a child) during 
the study follow-up period. 
5. Participant is allergic to fluorescein dye. 
6. Participant has a systemic condition that, in the opinion of the investigator, would 
preclude participation in the study (e.g., multiple sclerosis (MS), as IFN gamma may 
cause MS exacerbations). 
3.2 
Study Eye Eligibility Criteria 
A participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.2.1 Study Eye Inclusion Criteria 
1. The study eye must retain adequate fixation to allow for completion of protocol 
assessments. 
2. The study eye must have macular cystic changes (>275 microns and/or disruption of 
foveal contour on OCT). 
3.2.2 Study Eye Exclusion Criteria 
1. The study eye has lens, cornea, or other media opacities that preclude adequate 
visualization and testing of the retina. 
2. The study eye has undergone intraocular surgery within 6 months prior to enrollment. 
3. The study eye has a disease that may confound the outcome of the study [e.g., choroidal 
neovascularization (CNV) in the fovea or parafoveal area]. 
4. Participant is unwilling to discontinue wearing a contact lens in the study eye during IP 
administration. 
3.2.3 Study Eye Selection Criteria in Cases of Bilateral Disease 
RCD and ESCS usually affect both eyes to a similar degree. In case both eyes of a participant 
meet the study eye eligibility criteria, the following criteria will be used to select the study eye: 
• The eye with more intraretinal fluid will be selected as the study eye; 

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• If both eyes have similar levels of intraretinal fluid, the eye with worse visual acuity will 
be selected as the study eye; 
• If both eyes have the similar levels of intraretinal fluid and visual acuities, the right eye 
will be selected as the study eye. 
4.0 
STUDY DESIGN AND METHODS 
4.1 
Study Overview 
This is a single-center, prospective, uncontrolled, unmasked pilot Phase I/II study of the safety, 
tolerability and possible efficacy of IFN gamma-1b in participants with RCD and ESCS and 
macular cystic changes. Initially, one eye of two RCD participants with macular cystic changes 
and one eye of two ESCS participants with macular cystic changes will receive topical IFN 
gamma-1b. Enrollment will be halted and the Serious Adverse Event Review Committee will 
conduct a preliminary assessment of safety and efficacy after two participants in each disease 
category have completed the 8-week visit. If the committee approves study continuation, three 
additional participants with RCD and three participants with ESCS will be enrolled. All 
participants receiving IP will be followed for 52 weeks (one year). During the first study visit, 
participants receiving IP will be provided with on-campus lodging to evaluate and monitor the 
participants (baseline, Days 1 and 2). The visits at Weeks 2, 5, 8 and 52 will be outpatient visits. 
The study will be completed once the final participant has received 52 weeks of follow-up. 
4.2 
Recruitment 
Participants may enroll in this study after referral by a medical practitioner in the private sector, 
or by another clinic, hospital or medical institution. Participants may enroll in this study 
concurrently with another NEI or NIH protocol that does not offer ocular treatment with an 
investigational product, or following completion of another study. Self-referral is permitted. 
Participants enrolled or previously enrolled in other active NEI protocols may be contacted.  
If any recruitment materials are used, IRB-approval will be obtained prior to distribution. It is 
expected that recruitment will be complete within a 12-month period. 
 
 

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4.3 
Screening 
Screening may be performed using the NEI Screening Study for the Evaluation and Diagnosis of 
Potential Research Participants (08-EI-0102) or the NEI Evaluation and Treatment Protocol for 
Potential Research Participants with Ocular Diseases (08-EI-0169). Participants may also enter 
this protocol while enrolled in another study or after exiting another. Participants will undergo a 
standardized medical ophthalmic history, family history and a comprehensive standard-of-care 
ophthalmologic examination for their disease. Female participants of childbearing potential  
(see Appendix 5) will undergo a pregnancy test. Positive pregnancy test results from female 
minors will be shared with both the legal guardian(s) and the minor. Participants who are 
sexually active will be referred to the NIH gynecologist consult service to discuss appropriate 
contraception methods prior to completing any study procedures or dispensing investigational 
product. Consent will be obtained before any study procedures are performed. Screening 
procedures may include assessment of visual acuity, visual field, color vision, biomicroscopy 
and 
fundus 
examination, 
electroretinography 
(ERG), 
fundus 
imaging, 
and 
OCT  
(see Appendix 1). A blood sample for genetic testing of the NR2E3 gene or of RCD-associated 
genes may be obtained under other NEI protocols. 
4.4 
Study Visits 
Participants receiving IP will be provided with on-campus lodging for the first three days to 
complete the baseline assessments and for frequent monitoring to ensure good compliance and 
correct eye drop instillation technique (Days 1, 2 and 3). Scheduled clinic visits will occur at 
baseline, Days 1, 2 and 3, and Weeks 2, 5 and 8. A 52-week (one year) safety visit may be 
conducted at the NIH (on site) or with a local ophthalmologist (if the participant is 
unable/unwilling to come to NIH). Although there may be differences in testing among the 
various private physicians, at a minimum, all participants receiving IP must provide 
documentation of the assessments noted in Week 52 on the study flowsheet. After the participant 
signs a release of information with his/her ophthalmologist, the examination results will be sent 
to NEI. NEI will pay for the costs associated with obtaining medical records. 

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In addition, one of the investigators will conduct a phone interview with participants receiving IP 
at Weeks 1 and 6 to inquire about ocular complications. One or more unscheduled visits for 
safety assessment can be added based on the discretion of the investigators. 
The regimen of IFN gamma-1b administration will consist of two weeks of therapy, dosing the 
study eye four times daily, with each dose consisting of a four-drop series, each drop spaced by  
5 minutes, for a total of 16 drops delivered per day. The daily dose of IFN gamma-1b will be  
112 µg topically (7 µg per drop, applied in 16 drops). Punctal occlusion will be employed to 
reduce systemic absorption. Investigators will train participants receiving IP on proper drop 
administration and monitor participants during the initial visits. 
If at any time during the study participants experience ocular redness or other ocular concerns, 
they will be evaluated as soon as possible and the investigator may choose to terminate or reduce 
the dosage of the IFN gamma-1b eye drops. The dosage may be reduced to a three-drop series 
four times daily if symptomatic ocular surface disease and/or red eye develops. 
Participants receiving IP may be restarted on the drops if the ocular condition resolves, at the 
investigator’s and participant’s discretion. Follow-up visits to manage ocular complications will 
be arranged, independent of and in addition to the prescribed visit schedule of the protocol. 
If the participants agree, a skin biopsy and/or blood samples will be obtained, to develop 
fibroblast and lymphoblast cell lines that will be used to develop stem cells. Participants will be 
required to submit a blood sample but they will have the option to provide a skin biopsy. 
Participants who do not agree to a skin biopsy will not be excluded from the protocol. 
It is anticipated that participants in this study will occasionally miss or fail to complete an 
assessment, procedure or study visit. These omissions will be considered expected events and not 
protocol deviations provided they are infrequent and do not include data needed to assess safety 
or the primary study outcome. Cumulative proportions of these missed events in the study 
population will be presented to the IRB annually. In addition, the rate of omissions will be 
monitored by the Investigators and biannually by the NEI SAE Review Committee. If an 
individual misses more than 15% of the required investigational product doses, 
assessments/procedures or study visits (or completes them outside the visit window), or if more 

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than 15% of the participants miss completion of the same assessment or procedure, it will be 
considered a deviation and a deviation report will be sent to the IRB within two weeks. 
4.4.1 Study Evaluations 
The following examinations will be performed at the study visits as indicated in the study 
flowsheet (Appendix 1). Examinations will be performed both as clinical care and for research 
purposes. 
1. Medical/Ophthalmic History 
2. Brief Physical Examination 
3. Concomitant Medication Assessment 
4. Adverse Event Assessment 
5. Vital Signs (weight, blood pressure (BP), respiration, temperature) 
6. Best-corrected Visual Acuity (BCVA) using EVA (Appendix 4) 
7. Manifest Refraction 
8. Slit Lamp Examination 
9. Dilated Fundus Examination 
10. Intraocular Pressure (IOP) 
11. Color Vision Assessment (Cambridge Color Test) 
12. Color Fundus Photography (CFP) / Fundus Autofluorescence Imaging (FAF) 
13. Lens photography 
14.  Optical Coherence Tomography (OCT) 
15. Fluorescein Angiography (FA) 
16. Microperimetry 
17. Electroretinography (ERG) 
18. Electrooculography (EOG) 
19. National Eye Institute Visual Functioning Questionnaire - 25 (VFQ – 25) (Appendix 3) 
20. Serum Chemistry Panels (Acute Care and Hepatic) 
21. Serum Chemistry to obtain IFN gamma levels and antibody titers 
22.  Complete Blood Count (CBC) with differential 

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23.  Pregnancy Testing 
24. Skin Biopsy and blood sample to derive iPSCs* 
a. A 3 mm skin biopsy may be collected. The same procedure will be used for adults 
and children. *Participants who do not agree to a skin biopsy will not be 
excluded. 
b. Thirty (30) mL of blood may be collected by phlebotomy to derive iPSCs. For 
children, no more than the lesser of 5 mL/kg or 30 mL of blood will be collected. 
4.5 
Study and Concomitant Therapies 
4.5.1 Product Overview 
IFN gamma-1b, (Actimmune®, Horizon Pharma), a biologic response modifier, is a single chain 
polypeptide containing 140 amino acids. Actimmune® is a highly purified sterile solution 
consisting of non-covalent dimmers of two identical 16,465 dalton monomers. 
Actimmune® is a sterile, clear, colorless solution. Each 50 microliters (µL) of solution contains 
10 µg (200,000 IU) of IFN gamma-1b with 2 mg mannitol, 14 µg succinic acid, 37 µg of 
disodium succinate hexahydrate and 5 µg of polysorbate 20 in sterile water for injection. This 
solution has a pH of approximately 5.2 and an osmolality of 221 mmol/kg. 
4.5.2 Investigational New Drug (IND) Requirement 
The study will be conducted under IND 105,631. 
4.5.3 Preparation and Administration 
Commercially-available Actimmune®, manufactured by Horizon Pharma, will be used in this 
study and provided to the NIH CC Pharmacy. Vials of Actimmune® will be placed in a 2-8° C 
(36-46° F) refrigerator immediately upon receipt to ensure optimal retention of physical and 
biochemical integrity. The vials will not be frozen. Excessive or vigorous agitation will be 
avoided and the vials will not be shaken. The vials will be shipped from the NIH CC Pharmacy 
under controlled conditions to Pine Pharmaceuticals (100 Colvin Woods Parkway, Tonawanda, 
New York) to be re-packaged into single daily use 1 mL dropper bottles. IFN gamma-1b will be 
supplied to participants in the re-packaged single daily-use dropperettes to be stored in a 2-8° C 
(36-46° F) refrigerator. A single dropperette contains 1 mL of IFN gamma-1b (Actimmune®) at a 

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concentration of 200 µg/mL, which is equivalent to 28 drops. Each drop provides a dose of 7 µg 
of investigational product. Between daily uses, participants will store the open dropperette in the 
refrigerator or in a cooler with a cold pack at 2-8° C. Participants will be given cooler bags for 
transporting dropperettes. Once opened, each dropperette should be discarded within 24 hours. 
Participants will be given containers for disposal of the used dropperettes. 
Participants will use a new dropperette each day as instructed from the Day 1 visit through the 
day prior to the Week 2 visit (see Appendix 2). Administration of topical IFN gamma-1b drops 
should be spaced throughout the day (approximately at breakfast, lunch, dinner and bedtime 
depending upon the dosage received) as instructed. Participants will be instructed to immediately 
discard dropperettes after each day’s use in the provided disposal container which will be 
returned to the clinic at their next visit. Participants will be instructed on the proper 
administration techniques during their initial visit. 
4.5.4 Drug Accountability 
The NIH CC Pharmacy is responsible for the accountability of all unused investigational 
product. Adequate drug accountability records include documentation of all investigational 
products and supplies shipped, received, prepared and dispensed by the NIH CC Pharmacy. 
Participants will be asked to complete an eye drop diary documenting the number of drops as 
well as the days and times the investigational product was administered. At each applicable visit, 
participants will return the eye drop diary, unused investigational product and used 
investigational product dropperettes in the disposal container. The investigator/study staff will 
review the eye drop diary with the participant for completeness and accuracy and document the 
number of returned dropperettes (both used and unused). Missed doses of investigational product 
and incorrect doses below the prescribed amount will be documented in the eye drop diary but 
will not be reported to the IRB as protocol deviations. The study staff will dispose of returned 
investigational product dropperettes in the hazardous waste disposal bins. 
4.5.5 Concomitant Medications and Treatments 
Attempts at treating the macular cystic changes in retinal degenerations with CAIs  
[e.g., Acetazolamide (Diamox) or topical Dorzolamide (Trusopt)] have had variable success.  
The half-life of the systemic Acetazolamide is 3-9 hours and a rebound effect has been 

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described. If the potential participant receiving IP is using a CAI at the time of screening, s/he 
will be asked to continue using the medication at the same dosage during the study. The 
investigator should only initiate changes to the participant’s CAI regimen for safety reasons. The 
effect of the addition of IFN gamma-1b on recalcitrant macular cystic changes will be assessed. 
4.6 
Follow-up/Termination Procedures 
At the conclusion of the study, the participants will no longer be able to be seen under this 
protocol. Follow-up care will be arranged with an outside ophthalmologist or the participant will 
continue to be seen at the NIH under another protocol, if available and the participant is eligible. 
The participants and their physicians, with written consent, will be informed of the participant’s 
disease status during this study. Clinical data obtained during participation will be shared with 
the participants and their private physicians (with written permission from the participant). 
Results from the overall study will be shared once the study team has analyzed the data from all 
participants. 
4.7 
Storage of Samples and Data 
Skin biopsy and blood samples to develop fibroblast and lymphoblast cell lines that will be used 
to develop stem cells may be stored. Personal identifiers will be removed from samples prior to 
processing and all samples will be coded. After processing, specimens will be stored in freezers 
in secured buildings on the NIH campus. The manipulation of somatic cells may include the 
propagation, creation, and study of iPSCs, as well as the establishment of in vitro cultures. Cells 
may be genetically altered in the laboratory for experimental purposes and may be used for  
in vivo research. No cells, tissue or other sample components will be used for reproduction, 
cloning, or growth of new organisms. 
Research samples may be stored for future use at the NEI as specified in the informed consent 
document. The participant has a choice to limit sample usage by selecting one of the following 
consent options: 
Your data and samples may be used for other research projects, including those not related to 
retinal diseases, if you agree. Please initial on the line below that reflects your choice: 
______ YES. You may use my data and samples for other research projects, including those 
not related to retinal diseases.  

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______ NO. I do not want my data and samples used for other research projects. Please 
destroy my samples once this project is complete. 
The clinical data will be stored in the NEI’s research database, the Clinical Research Information 
System (CRIS) and The Emmes Corporation’s database. All individual data will remain 
confidential. 
5.0 
RISKS AND DISCOMFORTS 
5.1 
Risks and Discomforts Associated with the Clinical Assessments 
The clinical visits will involve assessments that are commonly performed in the regular care of 
patients with RCD and ESCS. 
1. Dilating drops may sting, cause an allergic reaction, precipitate an attack of angle closure 
glaucoma, worsen the participant’s light sensitivity and distort near vision making tasks 
such as reading and computer work difficult. Vision typically returns to normal after two 
to four hours but, may be blurry up to 24 hours. Serious side effects (e.g., high blood 
pressure, confusion, hallucinations and seizures) are very rare and pupillary dilation is 
accepted as part of the standard of care for individuals with RCD and ESCS. 
2. In rare instances, the cornea may be abraded during measurement of intra-ocular pressure 
or use of a contact lens (used for examination purpose only and not a contact lens used to 
correct one's refractive error). A corneal abrasion of this sort may be painful, but it heals 
quickly with no lasting effects. 
3. The 3 mm punch skin biopsy can cause some post procedural pain and lead to limited 
scarring at the site of the biopsy. 
4. Blood draws can cause discomfort and bleeding/bruising at the site of venous puncture. 
There is a remote risk of fainting or local infection. If any of these conditions arise, they 
will be treated. 
5. The fluorescein dye used in fluorescein angiography can make a participant’s skin turn 
yellow for several hours; also, the participant’s urine will turn orange for up to 24 hours 
after the exam. Some participants may be slightly nauseated during the exam, but their 
nausea usually lasts only a few seconds. If the dye extravasates during the injection, the 
skin around the injection site may feel mildly uncomfortable or become yellow. In rare 

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cases, participants may have an allergic reaction to the dye. Participants with known 
allergies to the procedure are excluded from this study. Treatment typically consists of an 
oral antihistamine medication but may require intravenous antihistamine administration if 
the symptoms are severe. Very rarely will a participant experience anaphylaxis. This 
would be treated immediately by trained personnel with drugs or, if necessary, intubation. 
6. The medical/ophthalmic history, microperimetry and physical examination entail no 
medical risk. No additional risks or discomforts are expected for the other clinical 
procedures. 
5.2 
Risks and Discomforts Associated with the Investigational Product 
Systemic use of IFN gamma-1b is approved by the Food and Drug Administration (FDA) for use 
in chronic granulomatous disease and malignant osteoporosis. Limited information is available 
regarding the risks of the topical administration of IFN gamma-1b; however, it has previously 
been found to be safe and well-tolerated in humans. No significant side effects were noted at the 
30 µg dose previously tested at NEI (NIH protocol 09-EI-0191). NIH Protocol 12-EI-0013 
(completed in December 2013) explored the use of IFN gamma-1b in patients with CSC. Two of 
four participants on that protocol experienced painless ocular redness during the second week of 
a two-week dosing regimen at the same dosing concentration and frequency proposed in this 
study. The ocular redness resolved within one day upon cessation of IFN gamma-1b therapy. 
One participant developed cataract in the study eye almost six months after stopping the 
investigational product. The participant denied trauma to the eye as a possible etiology (diabetes 
and steroid intake were also ruled out). The participant’s age (58 years old) was consistent with 
the possibility of early senile cataract. In fact, this participant was noted to have an early nuclear 
cataract bilaterally prior to enrollment. Although cataract formation was observed six months 
after the last study point, its causal relationship to the investigational product cannot be 
absolutely ruled out. However, previous studies have shown that elevation of IFN gamma is 
completely dissipated after a period of four weeks. It is also noteworthy that the participant who 
developed the cataract had received a higher total cumulative dose of the investigational product 
than the one proposed for the present study. Also notable is the absence of lenticular opacities in 
all of the other 14 study participants who had received the investigational product (some at much 
higher doses) and who were examined specifically for a similar adverse event. Potential 

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theoretical discomforts of the investigational product include transient conjunctival edema or 
erythema. Other theoretical side effects may include intraocular inflammation, corneal toxicity 
and cataract. Possible discomforts associated with punctal pressure application include eye 
irritation and redness. Possible risks associated with eye drop administration include eye 
inflammation and infection if the dropperette tip becomes contaminated. This risk is reduced by 
using daily dropperettes for each set of instillations. 
6.0 
PARTICIPANT MONITORING 
Participants will be monitored for adverse events over the course of the study by the study 
investigators. The principal investigator (PI) will be responsible for individual safety monitoring. 
Monitoring will be performed through interim systemic and ocular history, ophthalmic 
examination and assessment of the results of study examinations. In particular, the following 
adverse events will be closely monitored for safety: 
1. Anterior surface injection/ocular erythema 
2. Ocular inflammation 
3. Increase or decrease in intraocular pressure 
4. Formation of cataract or lenticular opacities 
5. Development of CNV in the study eye, in which case it may be considered a safety event 
and treatment termination considered 
6. Changes in visual function, different from those expected in the natural history of RCD 
or ESCS - (Adverse changes in visual function such as a decrease in visual acuity of >  
0.3 logMAR from baseline). 
7. Serious adverse reactions where there is a reasonable possibility that the IP caused the 
event 
6.1 
Participant Withdrawal Criteria 
Participants may choose to withdraw from this study for any reason at any time without penalty 
or prohibition from enrolling in other clinical protocols. Investigators may withdraw a participant 
from study participation if a new health condition becomes evident that requires care proscribed 
by the protocol. Investigators may also withdraw a participant if s/he experiences a serious 
adverse reaction. 

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6.2 
Reporting of Pregnancy 
If the staff becomes aware that a female study participant has become pregnant during the study, 
investigational product will be discontinued. The investigator and participant will determine 
whether to continue any remaining study visits or to exit the study. 
If the staff becomes aware that a male study participant impregnates his partner during the study, 
the investigator will remind the participant of the potential risks to the unborn fetus. 
In either case of reported pregnancy, participant (or partner) will be referred to the NIH 
OB/GYN consultation service for evaluation and counseling. The investigator must follow the 
participant (or partner) until the pregnancy outcome. 
7.0 
OUTCOME MEASURES 
7.1 
Primary Outcome Measures 
The primary outcome measure related to the safety and tolerability of IFN gamma-1b 
administered topically at the prescribed dosage for macular cystic changes in participants with 
RCD and ESCS will be assessed by the number and severity of adverse events related to the IP 
and the number of withdrawals. 
7.2 
Secondary Outcome Measures 
Evidence of efficacy will be assessed from any improvement in visual function and reduction in 
macular cystic changes with respect to baseline measurements and with respect to the fellow 
untreated eye, herein referred to as the control eye. 
The following secondary outcomes of visual function will be assessed on both the study  
(and control eyes where applicable): 
• Change in BCVA from baseline at all time points; 
• Change in the maximum subretinal fluid volume as measured on OCT at all 
applicable time points compared to baseline; 
• Change in the central retinal thickness as measured on OCT at all applicable time 
points compared to baseline; 

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• Change in central visual field sensitivity as measured by microperimetry testing at 
Day 2 and Week 5 compared to baseline. 
For those participants who enroll on CAIs, the effect of the addition of IFN gamma-1b on 
recalcitrant macular cystic changes will also be assessed. 
8.0 
STATISTICAL ANALYSIS 
This study is not designed to detect or estimate accurately the true pre-post changes in secondary 
outcomes related to visual function and macular cysts. Therefore, no formal statistical hypothesis 
tests will be performed. Analyses will be primarily descriptive and by per participant. 
8.1 
Analysis 
All reported adverse events will be tabulated and presented by system organ class, severity and 
relationship to study therapy. 
Secondary outcomes will be presented for each participant and tabulated over time, as described 
in Section 7.2. Additionally, these outcomes will compare the changes within the study eye from 
baseline and the changes between the study eye and control eye over time. 
8.2 
Sample Size 
No formal sample size calculation has been performed as this is a Phase I/II pilot study to 
evaluate safety. Up to five eyes in each disease group will be evaluated for safety and toxicity 
following IFN gamma-1b administered topically. 
9.0 
HUMAN SUBJECTS PROTECTION 
9.1 
Equitability 
Accrual for this study will be equitable among participants meeting the enrollment criteria. 
Participants of any ethnic background, gender, sexual orientation, or health status will be 
included according to the inclusion and exclusion criteria previously listed. 
 
 

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9.1.1 Justification for Exclusion of Children Below 12 Years of Age 
Children below 12 years of age will be excluded from the study due to limited experience with 
the treatment in that group of pediatric age patients. 
9.1.2 Justification for Inclusion of Children Ages 12 and Above 
Children ages 12 and above are eligible for this study as the age of symptom onset for RCD and 
ESCS is frequently late childhood to early teenage years and there are many affected teenagers. 
Individuals who are affected earlier tend to have the most severe disease presentation and are the 
most likely to enroll in future clinical trials. It is anticipated that many children ages 12 and 
above will be able to comply with the extensive examinations required for this study; however, 
those who are unable to do so will be excluded. 
9.1.3 Safeguards for Vulnerable Populations 
The standard in the community is for retinal specialists and general ophthalmologists to provide 
care and perform procedures for children with RCD and ESCS. Dr. Brooks and Dr. Zein are 
fellowship-trained pediatric ophthalmologists and the clinic is designed to accommodate 
children. All of the investigators on this protocol have experience working with children.  
A pediatrician will be available for consultation if necessary. 
9.1.4 Consideration of Persons Who Cannot Consent 
Adults unable to understand and sign an informed consent are not excluded from this study 
unless they are unable to cooperate with evaluation and testing that will be done under this 
protocol. Experience at the NEI clinic suggests that few, if any, such participants who cannot 
consent will be able to comply with the extensive examinations required for this study, given that 
sedation will not be used. In the event that such persons are considered for enrollment, 
consultation to assess whether an individual has the capacity to provide consent or is able to 
assign a surrogate, as well as the appropriateness of a surrogate, will be obtained by contacting 
the NIH Ability to Consent Assessment Team (ACAT) (301-496-9675 or 301-496-2429), which 
is a group trained to conduct these assessments and includes members from Psychiatry, Bioethics 
and other disciplines. 
 
 

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9.1.5 Justification for Exclusion of Pregnant or Lactating Women 
Pregnant women are excluded because the teratogenicity of IFN gamma-1b on a fetus is 
unknown. Lactating women will also be excluded as it is not known whether or not IFN  
gamma-1b is excreted in breast milk. 
9.2 
Qualifications of Investigators 
The investigators who will be performing study procedures are experienced in caring for patients 
with RCD and ESCS. In addition, they are experienced in conducting studies similar to this 
protocol. Credentialed NEI staff physicians/fellows may also conduct procedures under the 
direction of the Investigator physicians. 
The Principal Investigator has verified that all individuals working on this protocol required to 
take HRPP training under OHSRP SOP 25 (Training requirements for the NIH Human Research 
Protections Program) have completed all required training. The investigators and roles are as 
follows: 
Wadih Zein, MD is the Principal Investigator and is responsible for the conduct and oversight of 
the study. He is responsible for obtaining informed consent, obtaining participant history, 
performing ophthalmic and physical examinations, performing skin biopsies, dispensing 
medication, completing regulatory documentation and IRB submissions, generating clinical 
source documents and overseeing data entry and data query resolution. Dr. Zein is a  
fellowship-trained pediatric ophthalmologist, has clinical experience and has conducted research 
studies as a Principal and Associate Investigator on related ocular diseases. 
Catherine Cukras, MD, PhD, Emily Chew MD, Laryssa Huryn, MD, Henry Wiley, MD, Wai T. 
Wong, MD, PhD, Brian Brooks, MD, PhD, Robert Hufnagel, MD, PhD and H. Nida Sen, MD, 
MHSc are Associate Investigators with the ability to obtain informed consent. They are 
responsible for obtaining participant history, performing ophthalmic and physical examinations, 
performing skin biopsies, dispensing medication and generating clinical source documents. They 
have clinical experience and conducted research studies as Principal and Associate Investigators 
on related ocular diseases. Dr. Brooks is a fellowship-trained pediatric ophthalmologist. Dr. Sen 

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was the Principal Investigator on NIH protocol 09-EI-0191 and NIH protocol 11-EI-0167. Dr. 
Chew is the Principal Investigator on NIH protocol 12-EI-0013. 
Amy Turriff, ScM is an Associate Investigator participating as an integral part in the consenting 
process but without the ability to obtain informed consent. She is a certified genetic counselor 
with NEI and is responsible for generating clinical source documents. Ms. Turiff currently serves 
as an Associate Investigator on related ocular research studies. 
Arvydas Maminshkis, PhD is an Associate Investigator without the ability to obtain informed 
consent. He is responsible for providing input on the scientific question and study design, as well 
as study analysis. He works on the basic research used to develop the scientific question.  
Dr. Maminshkis was an Associate Investigator on the NIH protocol 09-EI-0191. 
Sheldon Miller, PhD is an Associate Investigator without the ability to obtain informed consent. 
He is responsible for providing input on the scientific question and study design as well as study 
analysis. He is currently the Scientific Director of the NEI and oversees the basic research used 
to develop the scientific question. Dr. Miller was the Lead Associate Investigator on the NIH 
protocol 09-EI-0191. 
Brett Jeffrey, PhD is an Associate Investigator without the ability to obtain informed consent. He 
is an ocular electrophysiologist by training with experience in clinical electrophysiology, 
psychophysics and implementation of clinical studies and will assist in the interpretation of eye 
examinations. 
Kapil Bharti, PhD is an Associate Investigator without the ability to obtain informed consent.  
He will be responsible for the processing and storage of samples collected from participants.  
Dr. Bharti has expertise in experimental models of eye disease and has published widely on the 
biophysical, molecular, and developmental characteristics of the RPE. He also has expertise in 
creating iPSCs from somatic cells. 
Anand Swaroop, PhD is an Associate Investigator without the ability to obtain informed consent. 
He will be involved in the processing and storage of certain samples collected from the 
participants. Dr. Swaroop has expertise in experimental models of eye disease and has published 
widely on the biophysical and molecular biological characteristics of the retina. 

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Angel Garced, BSN, MPH is an Associate Investigator and the primary research contact 
participating as an integral part in the consenting process but without the ability to obtain 
informed consent. Mr. Garced has previous experience in clinical trials as a study coordinator. 
He is responsible for obtaining participant history, ensuring that the study visits are scheduled 
per protocol, generating clinical source documents, entering data and resolving data queries.  
Allison Bamji, RN is an Associate Investigator and will be the back-up study coordinator.  
Ms. Bamji has led several NEI protocols as the clinical trials coordinator on related ocular diseases. 
As a back-up study coordinator, she will be involved in the consenting process but without the 
ability to obtain informed consent. She is responsible for obtaining participant history, ensuring 
that the study visits are scheduled per protocol, generating clinical source documents, entering data 
and resolving data queries if Mr. Garced is unavailable.  
10.0 
ANTICIPATED BENEFIT 
Participants receiving IP may benefit directly from this study if topical IFN gamma-1b improves 
visual function. This may include an improvement in visual acuity, visual field, or color vision. 
Any improvements are expected to persist through the study duration. It is unknown whether 
participants will maintain any improvements beyond the duration of the trial. The study will also 
lead to generalizable knowledge that will enhance the investigators’ understanding of the use of 
IFN gamma-1b in macular cystic disease in RCD or ESCS. 
11.0 
CLASSIFICATION OF RISK 
Risk is classified as more than minimal risk for participants receiving IP. For minor children 
receiving IP, risk is classified as research involving greater than minimal risk, but presenting the 
prospect of direct benefit to the individual subjects (45CFR 46.405). The risks of this study are 
reasonable given that the participants suffer significant visual disruption due to macular cystic 
changes associated with RCD or ESCS. For adults unable to consent, risk is classified as 
research involving greater than minimal risk but presenting the prospect of direct benefit to the 
individual subjects. 
 

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12.0 
CONSENT DOCUMENTS AND PROCESS 
Study investigators with consenting privileges will obtain informed consent. All study 
investigators obtaining informed consent have completed the NIMH HSPU “Elements of 
Successful Informed Consent” training. Assent will be obtained from minor participants.  
All participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures and potential risks of the study. Participants must have the ability to 
understand and sign an informed consent form, which must be signed prior to enrollment. 
Participants will have the opportunity to carefully review the consent and ask questions 
regarding this study prior to signing and they will be informed that they may withdraw from the 
study at any time without prejudice to themselves. 
If a participant requires the consent to be in larger font in order to read it well, this will be 
provided. If a participant is visually impaired to the point of being unable to read the consent, 
s/he can take the consent back with them to read it over with a family member or with the use of 
magnifying devices. If a participant chooses, the investigator can also read the consent verbatim 
to the participant and answer any questions that may arise. 
The investigator obtaining consent will document the consent process in the participant’s 
medical record. A signed copy of the informed consent form will be provided to the participant 
to take home. 
12.1 
Non-English Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the participant will 
be provided with the CC Short Written Consent Form for Non-English Speaking Research 
Subjects in the participant’s native language and a verbal explanation of the purpose, procedures 
and risks of the study. The IRB-approved English consent form will serve as basis for the verbal 
explanation of the study. The investigator will obtain an interpreter unless the investigator is 
fluent in the prospective participant’s language. Preferably, the interpreter will be someone who 
is independent of the participant (i.e., not a family member). Attempts to locate independent 
interpreters will be made through the Clinical Center. The interpreters will translate the  
IRB-approved English consent form verbatim and facilitate discussion between the participant 
and investigator. 

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The IRB-approved English consent form will be signed by the investigator obtaining consent and 
a witness to the oral presentation. The CC Short Written Consent Form will be signed by the 
participant and a witness who observed the presentation of information. The interpreter may sign 
the consent document as the witness and, in this case, will note “Interpreter” under the signature 
line. A copy of both signed forms will be provided to the participant to take home. 
The investigator obtaining consent will document the consent process in the participant’s 
medical record, including the name of the interpreter. Further, all instances of use of the CC 
Short Written Consent Form will be reported to the IRB at the time of annual review. If the CC 
Short Written Consent Form is used three times or more for the same language within an IRB 
approval period, this will be reported to the IRB immediately. 
Interpreters will also be present for other protocol procedures as necessary. 
13.0 
DATA AND SAFETY MONITORING 
The NEI Serious Adverse Event (SAE) Review Committee is responsible for monitoring data 
and safety and will exercise oversight of the clinical investigation independently from the study 
investigators. 
13.1 
Coordinating Center 
The Emmes Corporation (Emmes) has been assigned as the Coordinating Center for this trial to 
conduct data collection, protocol monitoring, data analysis and reporting. The Coordinating 
Center provides routine monitoring of study participants’ data. Monitoring visits will occur on a 
schedule depending on the status of the study. More frequent monitoring visits will be performed 
at the beginning of the study when enrollment is open. Monitoring will decrease as enrollment 
closes and as participant follow-up continues. 
Although Emmes advises the NEI Clinical Director (CD) and Principal Investigator on data and 
statistical activities, the Coordinating Center staff does not have direct access to or interaction 
with participants. 
 
 

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13.2 
NEI Serious Adverse Event Review Committee 
The NEI Serious Adverse Event Review Committee, which consists of the NEI Clinical Director 
and three other NEI physicians, will be responsible for reviewing any reported serious safety 
events, if they occur under this protocol. The Committee will review accumulating data on a 
semiannual basis to determine whether the study should continue. If changes to the protocol are 
indicated, recommendations will be made to the NEI Director and IRB who will consider and act 
on such recommendations in a timely manner. Should any serious suspected adverse reactions 
occur, the NEI Clinical Director may, at his discretion, assemble the Review Committee before 
the scheduled date to consider whether the study should move forward. The Review Committee 
or Principal Investigator can stop the study at any time if it appears there are any unexpected 
serious suspected adverse reactions that would outweigh any potential benefits of treatment. In 
addition, if three or more participants experience non-serious suspected adverse reactions that 
require temporary or permanent cessation of the investigational product, the Principal 
Investigator shall report this to the NEI Clinical Director. The NEI Clinical Director may 
convene the Review Committee before the scheduled time to consider the cessation of the study 
as a whole. The NEI Serious Adverse Event Review Committee or IRB may recommend 
temporarily suspending or closing enrollment, or stopping the study at any time due to safety 
concerns, demonstration of efficacy or lack of efficacy or slow recruitment. 
13.3 
Criteria for Stopping the Study 
The NEI SAE Review Committee may recommend temporarily suspending or closing 
enrollment, or stopping the study at any time due to safety concerns. Enrollment will be 
temporarily suspended if a participant experiences a suspected serious adverse reaction. The NEI 
SAE Review Committee will review the event and determine whether enrollment may be 
restarted. Enrollment will be permanently suspended if two or more participants experience 
serious adverse reactions assessed as related to the investigational product itself. Irrespective of 
study status, participants who are already enrolled will be followed up for the previously 
delineated time period. 
 
 

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14.0 
QUALITY ASSURANCE 
The NEI and Emmes maintain quality control by adhering to standard operating procedures (NEI 
QA program and NEIS standard operating procedures). These procedures cover the full protocol 
cycle beginning with staff credentialing and training, and protocol development and approval, 
through database development, data collection, monitoring and analysis, and finally manuscript 
preparation at the conclusion of the study. Data quality assurance is of the utmost importance to 
the NEI and Emmes. The two groups use a quality assurance system that relies on real-time data 
checks and reports throughout the course of a study to ensure the accuracy of information. This 
system is a secure and confidential data management system that stores data and provides quality 
assurance and reporting. Emmes has developed a number of routine reports specifically designed 
for monitors (e.g., listings of serious adverse events, etc.). 
Additionally, Emmes has developed summary reports of discrepancies, as well as reports of the 
exceptions databases, which include requests and reasons for exceptions. The results of the 
reports are communicated back to site staff and along with protocol compliance issues, to the 
DSMC (if applicable). 
Following the monitoring plan for this study, Emmes will perform monitoring activities, 
including on-site audits, review of database entries and the resolution of study issues. In addition 
to monitoring, Emmes performs various detailed automated and manual data quality checks. The 
results from these checks and any protocol compliance issues are communicated back to site staff 
and to the NEI Project Officer, NEI Clinical Director and applicable regulatory bodies. 
15.0 
REPORTING OF UNANTICIPATED PROBLEMS, PROTOCOL DEVIATIONS AND ADVERSE 
EVENTS 
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in 
accordance with NIH policy, IRB requirements, and federal regulations. Relatedness to the 
research of all serious adverse events will be determined by the PI in consultation with the 
Clinical Director (CD). 

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Serious unanticipated problems, serious adverse events (including deaths) that are not 
unanticipated problems and serious protocol deviations will be reported to the IRB and CD as 
soon as possible and in writing not more than 7 days after the PI first learns of the event, unless 
immediate reporting is waived for specific serious adverse events as noted below. Not serious 
unanticipated problems and not serious deviations will be reported to the IRB and CD as soon as 
possible and in writing not more than 14 days after the PI first learns of the event. Written 
reports will be submitted in PTMS. 
All adverse events, deviations, and unanticipated problems will be summarized and reported at 
the time of Continuing Review. 
The PI will immediately report SAEs to the Sponsor according to the requirements of 21 CFR 
312.64(b). The PI will record non-serious AEs and report them to the Sponsor as soon as 
possible. 
16.0 
ALTERNATIVES TO PARTICIPATION 
Current therapy for patients with RCD or ESCS and macular cystic changes is treatment with a 
topical or systemic CAI. This study calls for recruitment of patients that have not been exposed 
to CAI, have been unable to use CAI due to side effects, or have not had an adequate response to 
CAI. 
17.0 
PRIVACY 
All research activities will be conducted in as private a setting as possible. 
18.0 
CONFIDENTIALITY 
All medical records will be kept confidential and will only be reviewed by the participating 
investigators. Data will be kept in password-protected computers held at the NEI and The 
Emmes Corporation. Only study investigators and Emmes staff will have access to the study 
data. The participants’ names will not appear on any of the data forms reported to the 
coordinating center. A unique identifier, a study registration number, will identify the participant 
to the coordinating center. Participants’ personal information will be kept as private as possible. 
However, records can be inspected by organizations for quality assurance and data analysis. 

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These include the members of the IRB and the NEI SAE Review Committee. Clinical and 
demographic information will be kept in the Eye Clinic Electronic Medical Record (EMR). 
Access will be password-protected and restricted to authorized users. In most cases, the NIH will 
not release any information about research involvement without written permission. However, if 
the participant signs a release of information form, the NIH will give the requestor information 
from the participant’s medical record. We will try to keep personal information as private as 
possible. However, medical records may be inspected by various governmental and regulatory 
entities for auditing and other purposes. De-identified results from this clinical trial will be 
posted on http://www.clinicaltrials.gov. 
19.0 
CONFLICT OF INTEREST 
The NIH guidelines on conflict of interest were distributed to all the investigators and none of 
the NIH investigators had any conflicts of interest. 
20.0 
TECHNOLOGY TRANSFER 
Horizon 
Pharma 
(formerly 
Vidara) 
will 
provide 
the 
investigational 
product  
(IFN gamma-1b injection solution, ACTIMMUNE®) as outlined in a signed clinical trial 
agreement with NEI (CTA #00935-13). NEI may provide summary information and  
de-identified coded data to Horizon Pharma, if requested. NEI will ship collected, coded samples 
to Horizon Pharma or their designee for IFN gamma level testing. 
21.0 
RESEARCH AND TRAVEL COMPENSATION 
For this study, there is no compensation for participation. This protocol will include 
reimbursement for travel and subsistence. 
 
 

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22.0 
REFERENCES 
1. 
Boughman, J.A., P.M. Conneally, and W.E. Nance, Population genetic studies of retinitis 
pigmentosa. Am J Hum Genet, 1980. 32(2): p. 223-35. 
2. 
Fetkenhour, C.L., et al., Cystoid macular edema in retinitis pigmentosa. Trans Sect 
Ophthalmol Am Acad Ophthalmol Otolaryngol, 1977. 83(3 Pt 1): p. OP515-21. 
3. 
Fishman, G.A., J.M. Maggiano, and M. Fishman, Foveal lesions seen in retinitis 
pigmentosa. Arch Ophthalmol, 1977. 95(11): p. 1993-6. 
4. 
Hajali, M. and G.A. Fishman, The prevalence of cystoid macular oedema on optical 
coherence tomography in retinitis pigmentosa patients without cystic changes on fundus 
examination. Eye (Lond), 2009. 23(4): p. 915-9. 
5. 
Sandberg, M.A., et al., Visual acuity is related to parafoveal retinal thickness in patients 
with retinitis pigmentosa and macular cysts. Invest Ophthalmol Vis Sci, 2008. 49(10): p. 
4568-72. 
6. 
Grover, S., et al., Efficacy of dorzolamide hydrochloride in the management of chronic 
cystoid macular edema in patients with retinitis pigmentosa. Retina, 1997. 17(3):  
p. 222-31. 
7. 
Moldow, B., et al., The effect of acetazolamide on passive and active transport of 
fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by 
macular oedema. Graefes Arch Clin Exp Ophthalmol, 1998. 236(12): p. 881-9. 
8. 
Chen, J.C., F.W. Fitzke, and A.C. Bird, Long-term effect of acetazolamide in a patient 
with retinitis pigmentosa. Invest Ophthalmol Vis Sci, 1990. 31(9): p. 1914-8. 
9. 
Apushkin, M.A., et al., Rebound of cystoid macular edema with continued use of 
acetazolamide in patients with retinitis pigmentosa. Retina, 2007. 27(8): p. 1112-8. 
10. 
Jacobson, S.G., et al., SWS (blue) cone hypersensitivity in a newly identified retinal 
degeneration. Invest Ophthalmol Vis Sci, 1990. 31(5): p. 827-38. 
11. 
Marmor, M.F., et al., Diagnostic clinical findings of a new syndrome with night 
blindness, maculopathy, and enhanced S cone sensitivity. American journal of 
ophthalmology, 1990. 110(2): p. 124-34. 
12. 
Haider, N.B., et al., Mutation of a nuclear receptor gene, NR2E3, causes enhanced S 
cone syndrome, a disorder of retinal cell fate. Nature genetics, 2000. 24(2): p. 127-31. 
13. 
Audo, I., et al., Phenotypic variation in enhanced S-cone syndrome. Investigative 
ophthalmology & visual science, 2008. 49(5): p. 2082-93. 
14. 
Pachydaki, S.I., et al., Phenotypic features of patients with NR2E3 mutations. Archives of 
ophthalmology, 2009. 127(1): p. 71-5. 
15. 
Bandah, D., et al., The spectrum of retinal diseases caused by NR2E3 mutations in Israeli 
and Palestinian patients. Archives of ophthalmology, 2009. 127(3): p. 297-302. 
16. 
Genead, M.A., G.A. Fishman, and J.J. McAnany, Efficacy of topical dorzolamide for 
treatment of cystic macular lesions in a patient with enhanced S-cone syndrome. 
Documenta ophthalmologica. Advances in ophthalmology, 2010. 121(3): p. 231-40. 
17. 
Hayashi, T. and K. Kitahara, Optical coherence tomography in enhanced S-cone 
syndrome: large macular retinoschisis with disorganized retinal lamination. Eur J 
Ophthalmol, 2005. 15(5): p. 643-6. 
18. 
Iannaccone, A., et al., Treatment of adult-onset acute macular retinoschisis in enhanced 
s-cone syndrome with oral acetazolamide. American journal of ophthalmology, 2009. 
147(2): p. 307-312.e2. 

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19. 
Marmor, M.F., A teenager with nightblindness and cystic maculopathy: enhanced S cone 
syndrome (Goldmann-Favre syndrome). Documenta ophthalmologica. Advances in 
ophthalmology, 2006. 113(3): p. 213-5. 
20. 
Milam, A.H., et al., The nuclear receptor NR2E3 plays a role in human retinal 
photoreceptor differentiation and degeneration. Proc Natl Acad Sci U S A, 2002. 99(1): 
p. 473-8. 
21. 
Greenstein, V.C., et al., The enhanced S cone syndrome: an analysis of receptoral and 
post-receptoral changes. Vision Res, 1996. 36(22): p. 3711-22. 
22. 
Jacobson, S.G., et al., Relatively enhanced S cone function in the Goldmann-Favre 
syndrome. Am J Ophthalmol, 1991. 111(4): p. 446-53. 
23. 
Marmor, M.F., et al., Topography of cone electrophysiology in the enhanced S cone 
syndrome. Invest Ophthalmol Vis Sci, 1999. 40(8): p. 1866-73. 
24. 
Sustar, M., M. Hawlina, and J. Brecelj, Electroretinographic evaluation of the retinal S-
cone system. Documenta ophthalmologica. Advances in ophthalmology, 2011. 123(3):  
p. 199-210. 
25. 
Kobayashi, M., et al., Identification of a photoreceptor cell-specific nuclear receptor. 
Proceedings of the National Academy of Sciences of the United States of America, 1999. 
96(9): p. 4814-9. 
26. 
Chen, J., A. Rattner, and J. Nathans, The rod photoreceptor-specific nuclear receptor 
Nr2e3 represses transcription of multiple cone-specific genes. J Neurosci, 2005. 25(1):  
p. 118-29. 
27. 
Cheng, H., et al., In vivo function of the orphan nuclear receptor NR2E3 in establishing 
photoreceptor identity during mammalian retinal development. Hum Mol Genet, 2006. 
15(17): p. 2588-602. 
28. 
Cheng, H., et al., Photoreceptor-specific nuclear receptor NR2E3 functions as a 
transcriptional activator in rod photoreceptors. Hum Mol Genet, 2004. 13(15): p. 1563-
75. 
29. 
Haider, N.B., et al., The transcription factor Nr2e3 functions in retinal progenitors to 
suppress cone cell generation. Visual neuroscience, 2006. 23(6): p. 917-29. 
30. 
Haider, N.B., et al., Nr2e3-directed transcriptional regulation of genes involved in 
photoreceptor development and cell-type specific phototransduction. Exp Eye Res, 2009. 
89(3): p. 365-72. 
31. 
Hennig, A.K., G.H. Peng, and S. Chen, Regulation of photoreceptor gene expression by 
Crx-associated transcription factor network. Brain Res, 2008. 1192: p. 114-33. 
32. 
Oh, E.C., et al., Rod differentiation factor NRL activates the expression of nuclear 
receptor NR2E3 to suppress the development of cone photoreceptors. Brain Res, 2008. 
1236: p. 16-29. 
33. 
Peng, G.H., et al., The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx 
and exerts opposing effects on the transcription of rod versus cone genes. Hum Mol 
Genet, 2005. 14(6): p. 747-64. 
34. 
Webber, A.L., et al., Dual role of Nr2e3 in photoreceptor development and maintenance. 
Exp Eye Res, 2008. 87(1): p. 35-48. 
35. 
Wright, A.F., et al., Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone 
Syndrome. Human mutation, 2004. 24(5): p. 439. 
 
 

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36. 
Mustafi, D., et al., Defective photoreceptor phagocytosis in a mouse model of enhanced 
S-cone syndrome causes progressive retinal degeneration. FASEB journal : official 
publication of the Federation of American Societies for Experimental Biology, 2011. 
25(9): p. 3157-76. 
37. 
Strunnikova, N.V., et al., Transcriptome analysis and molecular signature of human 
retinal pigment epithelium. Hum Mol Genet, 2010. 19(12): p. 2468-86. 
38. 
Marmor, M.F., Control of subretinal fluid: experimental and clinical studies. Eye (Lond), 
1990. 4 ( Pt 2): p. 340-4. 
39. 
Marmor, M.F. and T. Maack, Enhancement of retinal adhesion and subretinal fluid 
resorption by acetazolamide. Invest Ophthalmol Vis Sci, 1982. 23(1): p. 121-4. 
40. 
Li, R., et al., IFN{gamma} regulates retinal pigment epithelial fluid transport. Am J 
Physiol Cell Physiol, 2009. 297(6): p. C1452-65. 
 

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APPENDIX 1: STUDY FLOWSHEET 
Visit Schedule 
Baseline
Day 
1 
Day 
2 
Day 
3 
Week 
1 
Week 
2 
Week 
5 
Week 
6 
Week 
8 
Week 
52 
Visit Number 
000 
000A 
000B 
000C 
001 
002 
005 
006 
008 
SFTY8 
Target Day from Baseline 
0 
1 
2 
3 
7 
14 
35 
42 
56 
365 
Visit Window 
 
 
 
 
±1 day 
±5 
days 
±7 
days 
±7 
days 
±7 
days 
±30 
days 
Investigational Product 
 
 
 
 
 
 
 
 
 
 
Interferon Gamma-1b 
Droperrettes Dispensed 
 
X1 
X1 
X1 
 
 
 
 
 
 
Drug Accountability Review 
 
 
 
 
 
X 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
 
 
 
 
 
 
 
 
 
Brief Physical Examination 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
Assessment 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Vital Signs 
X 
X 
X 
 
 
X 
 
 
X 
 
Telephone Assessment 
 
 
 
 
X 
 
 
X 
 
 
Ophthalmic Assessments 
 
 
 
 
 
 
 
 
 
 
BCVA (EVA) 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Manifest Refraction2 
X 
 
 
 
 
 
 
 
X 
 
Slit Lamp Examination  
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Dilated Fundus Examination 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Intraocular Pressure (IOP) 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Color Vision Assessment 
(Cambridge Color Test) 
X3 
 
 
 
 
 
X 
 
 
 
Color Fundus Photography (CFP) 
X3 
 
 
 
 
X 
 
 
X 
 
Fundus Autofluorescence (FAF) 
X3 
 
 
 
 
X 
 
 
X 
 
Lens Photography 
X3 
 
 
 
 
X 
 
 
X 
 
Optical Coherence Tomography 
(OCT) 
X4 
X4 
X4 
X4 
 
X 
X 
 
X 
 
Fluorescein Angiogram (FA) 
X3 
 
 
 
 
X 
 
 
 
 
Microperimetry 
X3 
 
X 
 
 
 
X 
 
X 
 
Electroretinography (ERG) 
X 
 
 
 
 
 
X 
 
 
 
Electrooculography (EOG) 
X 
 
X 
 
 
X 
X 
 
X 
 
NEI VFQ-25 
X3 
 
 
 
 
X 
 
 
X 
 
Research Sample Collection 
 
 
 
 
 
 
 
 
 
 
Skin Biopsy for iPSCs5 
 
X 
 
 
 
 
 
 
 
 
Blood Sample for iPSCs5 
 
X 
 
 
 
 
 
 
 
 
 

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Visit Schedule 
Baseline Day 
1 
Day 
2 
Day 
3 
Week 
1 
Week 
2 
Week 
5 
Week 
6 
Week 
8 
Week 
52 
Visit Number 
000 
000A 000B 
000C 
001 
002 
005 
006 
008 
SFTY8 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
CBC with differential  
X3  
 
 
 
 
X 
 
 
X 
 
Chemistry Panels (Acute Care and 
Hepatic) 
X3 
 
 
 
 
X 
 
 
X 
 
Serum IFN gamma levels and 
antibody titers6 
X 
 
X 
 
 
X 
 
 
 
 
Pregnancy Testing7 
X 
 
 
 
 
 
X 
 
X 
 
 
1    Investigational product may be instilled by clinic staff during the first three days of IP administration and will be 
prescribed as necessary to maintain the dosing regimen. 
2 
BCVA with manifest refraction must be performed when scheduled and when there is a change in EVA of >10  
E-ETDRS letters (> 0.20 logMAR) as compared with relevant baseline. 
3 
These procedures can be completed under NEI protocols 08-EI-0102 or 08-EI-0169 if performed within 9 days 
prior to Visit 000. 
4 
This test will be performed at least once but can be performed up to three times daily to assess for acute/subacute 
changes in macular cysts. 
5 
These procedures (skin biopsy for iPSCs and blood sample for iPSCs) may be performed at any study visit. The 
skin biopsy is only for participants who consent to providing skin biopsy samples for iPSC generation as this 
procedure is optional.  
6 
Collected samples will be shipped to Horizon Pharma (or their designee) for analysis. 
7 
This test is for women of childbearing potential only and they must have a negative test prior to the investigational 
product administration on enrollment day. 
8 
Visit records from a local ophthalmologist can substitute for the Week 52 safety visit if participant is unwilling or 
unable to come to NIH. 
 

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APPENDIX 2: STUDY AND CONCOMITANT MEDICATION INSTRUCTION SHEET 
Participant Reminders 
1. At your Day 1 visit, we will give you your first dose of your interferon gamma-1b eye 
drops in your study eye in the clinic. For the first three days of treatment, we will 
show you how to use the drops.  
2. Before you leave NIH, you will be given a supply of study eye drops and instructed to 
take the rest of your daily doses in your study eye. You will be called after you have 
been home one week to see how you are doing. You will continue taking your daily 
dose of interferon gamma-1b eye drops in your study eye until the day before your 
Week 2 visit. 
3. The study eye drops will be in daily-use dropperettes. The dropperettes should be 
stored in your refrigerator or in a cooler with a cold pack when you are not using 
them. You will be given a small cooler to transport the dropperettes. Do not shake the 
dropperettes. 
4. To take your study eye drops after opening your dropperette, you will use your 
fingers to press on the area between your study eye and your nose. This is known as 
“punctal pressure.” Punctal pressure helps the study eye drops stay on your eye and 
should be used for each eye drop. After applying punctal pressure to your study eye, 
you will take the opened dropperette and apply one drop of interferon gamma-1b 
directly into your study eye without touching the surface of your eye, wait 5 minutes 
and then apply the next drop until the dose is complete (for a total of 4 drops). You 
will repeat this procedure four times a day as prescribed (around breakfast, lunch, 
dinner and bedtime). 
5. To avoid an eye infection, it is very important that the dropperette tip not touch 
anything, including the surface of your eye. However, it is not necessary to dispose of 
the dropper if this happens. 
6. Each dropperette must be thrown out within 24 hours after it is opened. We will give 
you a container to dispose of your empty dropperettes. 
7. You must use a new dropperette each day. Take the study eye drops at approximately 
the same time every day to help you to remember to take them. Remember to place 
each study drop in your study eye 5 minutes apart. 
8. Do not forget to make notes on your eye drop diary about when you took the study 
eye drops and ANYTHING that you feel is a side effect. 
9. Please inform any physician who is prescribing new medication that you are using 
interferon gamma-1b eye drops. If a new medication is prescribed to you, please 
inform a study team member at your next visit. 
10. You may use other eye drops during the study. If you need to use other eye drops, 
you should wait at least 5 minutes before using the interferon gamma-1b eye drops. 
11. If you forget to take your study eye drops, you should take them when you remember 
and take the next dose at your regularly scheduled time. If you forget to take your 
study eye drops and it is more than 6 hours after the missed dose, you should skip 
that dose and take the next dose at your regularly scheduled time. 

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12. Be sure to always bring your eye drop diary, your disposal container with your used, 
empty dropperettes and any unused dropperettes with you to your next appointment.  
13. If for any reason you miss a study visit, contact a member of the study team so that 
your appointment can be rescheduled.  
14. Do not wear a contact lens in your study eye during the two weeks of using interferon 
gamma-1b eye drops. 
Contact your study team with any questions: 
NEI Study Coordinator:  
Angel Garced, BSN, MPH 
301-594-3141- Eye Clinic - OP10 
Principal Investigator: 
Wadih Zein, MD 
301-496-8118 
Please note: If any questions or issues arise after normal business hours or on the 
weekend, you may call the page operator at 301-496-1211 and ask to speak to the 
Ophthalmology Fellow on call. Be sure to identify the study you are on. 
YOUR STUDY IS: 15-EI-0052 
“Pilot Phase I/II Study of the Evaluation of Interferon Gamma-1b Administered Topically 
for Macular Edema/Intraretinal Schisis Cysts in Rod-Cone Dystrophy (RCD) and 
Enhanced S-Cone Syndrome (ESCS)” 
 
 

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APPENDIX 3: NATIONAL EYE INSTITUTE VISUAL FUNCTIONING QUESTIONNAIRE-25 
 
©1996, Rand 
 
Instructions: 
 
I’m going to read you some statements about problems which involve your vision or feelings that 
you have about your vision condition. After each question I will read you a list of possible 
answers. Please choose the response that best describes your situation. 
 
Please answer all the questions as if you were wearing your glasses or contact lenses (if any). 
 
Please take as much time as you need to answer each question. All your answers are confidential. 
In order for this survey to improve our knowledge about vision problems and how they affect 
your quality of life, your answers must be as accurate as possible. Remember, if you wear 
glasses or contact lenses for a particular activity, please answer all of the following questions as 
though you were wearing them. 
 
PART 1 - GENERAL HEALTH AND VISION 
 
1. In general, would you say your overall health is*: 
 
 
READ CATEGORIES:  
(Circle One) 
 
 
Excellent ................................................................. 1 
 
 
Very Good ............................................................... 2 
 
 
Good ........................................................................ 3 
 
 
Fair .......................................................................... 4 
 
 
Poor ......................................................................... 5 
 
2. At the present time, would you say your eyesight using both eyes (with glasses or contact 
lenses, if you wear them) is excellent, good, fair, poor, or very poor or are you completely 
blind? 
 
 
READ CATEGORIES:  
(Circle One) 
 
 
Excellent ................................................................. 1 
 
 
Good ........................................................................ 2 
 
 
Fair .......................................................................... 3 
 
 
Poor ......................................................................... 4 
 
 
Very Poor ................................................................ 5 
 
 
Completely Blind .................................................... 6 
 
 
 

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3. How much of the time do you worry about your eyesight? 
 
 
READ CATEGORIES:  
(Circle One) 
 
 
None of the time...................................................... 1 
 
 
A little of the time ................................................... 2 
 
 
Some of the time ..................................................... 3 
 
 
Most of the time ...................................................... 4 
 
 
All of the time ......................................................... 5 
 
4. How much pain or discomfort have you had in and around your eyes (for example, burning, 
itching, or aching)? Would you say it is: 
 
 
READ CATEGORIES:  
(Circle One) 
 
 
None ........................................................................ 1 
 
 
Mild ......................................................................... 2 
 
 
Moderate ................................................................. 3 
 
 
Severe ...................................................................... 4 
 
 
Very severe ............................................................. 5 
 
PART 2 - DIFFICULTY WITH ACTIVITIES 
 
The next questions are about how much difficulty, if any, you have doing certain activities 
wearing your glasses or contact lenses if you use them for that activity. 
 
5. How much difficulty do you have reading ordinary print in newspapers? Would you say you 
have: 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 

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6. How much difficulty do you have doing work or hobbies that require you to see well up 
close, such as cooking, sewing, fixing things around the house, or using hand tools? Would 
you say: 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
7. Because of your eyesight, how much difficulty do you have finding something on a crowded 
shelf? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
8. How much difficulty do you have reading street signs or the names of stores? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficult ................................................... 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 

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9. Because of your eyesight, how much difficulty do you have going down steps, stairs, or curbs 
in dim light or at night? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
10. Because of your eyesight, how much difficulty do you have noticing objects off to the side 
while you are walking along? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
11. Because of your eyesight, how much difficulty do you have seeing how people react to things 
you say? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 

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12. Because of your eyesight, how much difficulty do you have picking out and matching your 
own clothes? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
13. Because of your eyesight, how much difficulty do you have visiting with people in their 
homes, at parties, or in restaurants ? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
14. Because of your eyesight, how much difficulty do you have going out to see movies, plays, 
or sports events? 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 

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15. Now, I’d like to ask about driving a car. Are you currently driving, at least once in a while? 
 
 
 
(Circle One) 
 
 
Yes .................................................. 1 
Skip To Q 15c 
 
 
No .................................................... 2 
 
15a. IF NO, ASK: Have you never driven a car or have you given up driving? 
 
 
(Circle One) 
 
 
Never drove ..................................... 1 
Skip To Part 3, Q 17 
 
 
Gave up ........................................... 2 
 
15b. IF GAVE UP DRIVING: Was that mainly because of your eyesight, mainly for some 
other reason, or because of both your eyesight and other reasons? 
 
 
 
(Circle One) 
 
 
Mainly eyesight ....................................................... 1  
Skip To Part 3, Q 17 
 
 
Mainly other reasons ............................................... 2  
Skip To Part 3, Q 17 
 
 
Both eyesight and other reasons ............................. 3  
Skip To Part 3, Q 17 
 
15c. IF CURRENTLY DRIVING: How much difficulty do you have driving during the 
daytime in familiar places? Would you say you have: 
 
 
 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
16. How much difficulty do you have driving at night? Would you say you have: 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 

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16a. How much difficulty do you have driving in difficult conditions, such as in bad 
weather, during rush hour, on the freeway, or in city traffic? Would you say you have: 
 
 
(READ CATEGORIES AS NEEDED) 
(Circle One) 
 
 
No difficulty at all ................................................... 1 
 
 
A little difficulty ..................................................... 2 
 
 
Moderate difficulty ................................................. 3 
 
 
Extreme difficulty ................................................... 4 
 
 
Stopped doing this because of your eyesight .......... 5 
 
 
Stopped doing this for other reasons or not 
 
 
interested in doing this ............................................ 6 
 
PART 3: RESPONSES TO VISION PROBLEMS 
 
The next questions are about how things you do may be affected by your vision. For each one, 
I’d like you to tell me if this is true for you all, most, some, a little, or none of the time. 
 
 
(Circle One On Each Line) 
 
READ CATEGORIES: 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
17. Do you accomplish less than you would 
like because of your vision? 
1 
2 
3 
4 
5 
18. Are you limited in how long you can 
work or do other activities because of 
your vision? 
1 
2 
3 
4 
5 
19. How much does pain or discomfort in or 
around your eyes, for example, burning, 
itching or aching, keep you from doing 
what you’d like to be doing? Would you 
say: 
1 
2 
3 
4 
5 
 

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For each of the following statements, please tell me if it is definitely true, mostly true, mostly 
false or definitely false for you or you are not sure. 
 
 
(Circle One On Each Line) 
 
READ CATEGORIES: 
Definitely 
true 
Mostly 
true 
Not 
sure 
Mostly 
false 
Definitely 
false 
20. I stay home most of the time because of my 
eyesight. 
1 
2 
3 
4 
5 
21. I feel frustrated a lot of the time because of 
my eyesight. 
1 
2 
3 
4 
5 
22. I have much less control over what I do, 
because of my eyesight. 
1 
2 
3 
4 
5 
23. Because of my eyesight, I rely too much on 
what other people tell me. 
1 
2 
3 
4 
5 
24. I need a lot of help from others because of 
my eyesight. 
1 
2 
3 
4 
5 
25. I worry about doing things that will 
embarrass myself or others, because of my 
eyesight. 
1 
2 
3 
4 
5 
 
That’s the end of the interview. Thank you very much for your time and your help. 
 
 
 

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APPENDIX 4: ELECTRONIC VISUAL ACUITY (EVA) AND MANIFEST REFRACTION 
 

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APPENDIX 5: DETERMINING CHILDBEARING POTENTIAL 
A female participant who is considered non-childbearing due to a medical condition  
(i.e., participant has previously undergone a hysterectomy) does not need a pregnancy test, 
Follicle-stimulating Hormone (FSH) test or contraception. 
If a female participant is considered non-childbearing due to menopause, it must be in 
accordance with the CNS IRB/NIH Ob-Gyn guidance on the definition of menopause. This 
guidance defines menopause as: 
• Women over age 55 who have not had a period for one year will be considered 
menopausal and do not need a pregnancy test, FSH test or contraception. 
• Women between 50 and 55, who have not had a period for one year, should have an FSH 
test. If their FSH level is ≥ 20 mIU/mL, they will be considered menopausal and do not 
need pregnancy testing or contraception. If their FSH level is < 20 mIU/mL, they will 
need pregnancy testing and contraception as required by the protocol. 
• Women between 45 and 50 who have not had a period for one year will need both an 
FSH test and a pregnancy test. If they are not pregnant and their FSH level is  
≥ 20 mIU/mL, they will be considered menopausal and will not require contraception or 
additional pregnancy testing. If their FSH test is < 20 mIU/mL, they will need pregnancy 
testing and contraception as required by the protocol.