Universal Rare Gene Study: A Registry and Natural History Study of Retinal Dystrophies Associated With Rare Disease-Causing Genetic Variants
Conditions: Inherited Retinal Degeneration, Retinitis Pigmentosa
Sponsor: Jaeb Center for Health Research

 
Foundation Fighting Blindness (FFB) 
Consortium  
 
Universal Rare Gene Study: A Registry and Natural History 
Study of Retinal Dystrophies Associated with Rare Disease-
Causing Genetic Variants 
 
Protocol Identifying Number: Uni-Rare 
Funded by: Foundation Fighting Blindness  
Version Number: 1.2 
12DEC2022 
 

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Key Roles and Signature Page 
Universal Rare Gene Study 
  
Protocol Identifying Number: Uni-Rare 
 
Version Number: v1.2 
12DEC2022 
 
Protocol Chair 
Name, degree 
José-Alain Sahel, M.D. 
Signature/Date 
 
 
JCHR Protocol Director (Sponsor) 
Name, degree 
Allison Ayala, MS 
Signature/Date 
 
 
FFB Representative (Funder) 
Name, degree 
Todd Durham, PhD. 
Signature/Date 
 
 
Statistician 
Name, degree 
Maureen Maguire, PhD, FARVO 
Signature/Date 
 
 
 

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 TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 23 
1.1 Introduction ....................................................................................................................................... 23 
1.1.1 Identifying Optimal IRD Patient Populations for Target Therapies ............................................ 23 
1.1.2 Develop and Validate Outcome Measures for Progression of IRDs ........................................... 23 
1.1.3 Other Gaps Addressed by Natural History Studies ..................................................................... 24 
1.1.4 Unique Challenges in Ultra-Rare Genes ..................................................................................... 24 
1.2 Rationale for a Universal Rare Gene Study ....................................................................................... 24 
1.3 Study Objectives ................................................................................................................................ 25 
1.4 Potential Risks and Benefits .............................................................................................................. 26 
1.4.1 Known Potential Risks ................................................................................................................ 26 
1.4.2 Known Potential Benefits ............................................................................................................ 26 
1.4.3 Risk Assessment .......................................................................................................................... 27 
1.5 General Considerations...................................................................................................................... 27 
CHAPTER 2: REGISTRY ENROLLMENT AND REGISTRY/SCREENING VISIT ........................................... 28 
2.1 Registry Recruitment and Enrollment ............................................................................................... 28 
2.2 Cohort Definitions ............................................................................................................................. 28 
2.3 Registry Informed Consent and Authorization Procedures ............................................................... 29 
2.4 Registry/Screening Visit .................................................................................................................... 31 
2.4.1 Registry Eligibility Criteria ......................................................................................................... 31 
2.4.1.1 Participant Inclusion Criteria .............................................................................................. 31 
2.4.1.2 Ocular Inclusion Criteria ..................................................................................................... 32 
2.4.1.3 Participant Exclusion Criteria ............................................................................................. 32 
2.4.1.4 Ocular Exclusion Criteria.................................................................................................... 32 
2.4.2 Registry/Screening Visit Data Collection and Testing ................................................................ 33 
2.4.3 Initial Screen Failures .................................................................................................................. 35 
2.5 Genetic Screening Phase ................................................................................................................... 35 
2.5.1 Genetic Screen Failures ............................................................................................................... 35 
2.5.2 Genetics Committee Review ....................................................................................................... 36 
2.6 Final Registry Cohort Criteria ........................................................................................................... 36 
CHAPTER 3: REGISTRY PHASE ................................................................................................................. 37 
3.1 Evaluation of Natural History Study (NHS) Target Gene Status ...................................................... 37 
3.2 Annual Phone Calls ........................................................................................................................... 37 
3.3 Completion of Registry Phase ........................................................................................................... 37 
CHAPTER 4: NATURAL HISTORY STUDY ENROLLMENT AND BASELINE VISIT ..................................... 38 

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4.1 Natural History Study (NHS) Target Gene Selection ........................................................................ 38 
4.2 NHS Enrollment ................................................................................................................................ 38 
4.2.1 NHS Informed Consent and Authorization Procedures .............................................................. 38 
4.2.2 NHS Eligibility Criteria ............................................................................................................... 39 
4.3 Baseline Visit Testing Procedures ..................................................................................................... 39 
4.3.1 Younger Age Cohort ................................................................................................................... 40 
4.3.2 Vision Cohorts 1 & 2 ................................................................................................................... 41 
4.3.3 Vision Cohort 3 ........................................................................................................................... 43 
CHAPTER 5: NATURAL HISTORY STUDY FOLLOW-UP VISITS ................................................................ 45 
5.1 Follow-up Schedule ........................................................................................................................... 45 
5.2 Target Timelines ................................................................................................................................ 45 
5.3 Follow-up Visit Testing Procedures .................................................................................................. 46 
5.3.1 Younger Age Cohort ................................................................................................................... 46 
5.3.1.1 Age-Up Procedures ............................................................................................................. 47 
5.3.2 Vision Cohorts 1 & 2 ................................................................................................................... 47 
5.3.3 Vision Cohort 3 ........................................................................................................................... 48 
5.3.4 Unscheduled Visits ...................................................................................................................... 49 
CHAPTER 6: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 50 
6.1 Study Procedure Requirements ......................................................................................................... 50 
6.2 Questionnaires ................................................................................................................................... 52 
CHAPTER 7: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING ....................................... 54 
7.1 Unanticipated Problems ..................................................................................................................... 54 
7.2 Adverse Events .................................................................................................................................. 54 
7.2.1 Definitions ................................................................................................................................... 54 
7.2.2 Reportable Adverse Events ......................................................................................................... 55 
7.2.3 Relationship of Adverse Event to Study Procedure .................................................................... 55 
7.2.4 Severity (Intensity) of Adverse Event ......................................................................................... 56 
7.2.5 Expectedness ............................................................................................................................... 56 
7.2.6 Coding of Adverse Events ........................................................................................................... 56 
7.2.7 Outcome of Adverse Event ......................................................................................................... 56 
7.3 Timing of Event Reporting ................................................................................................................ 57 
CHAPTER 8: MISCELLANEOUS CONSIDERATIONS ................................................................................... 58 
8.1 New or Ongoing Medical Conditions and Medications .................................................................... 58 
8.1.1 Pre-Existing Conditions............................................................................................................... 58 
8.1.2 Medications ................................................................................................................................. 58 

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8.1.3 Medical Conditions During the Natural History Study ............................................................... 58 
8.2 Prohibited Medications, Treatments, and Procedures During the Natural History Study ................. 58 
8.2.1 Prohibited Medications and Treatment for Retinal Degeneration ............................................... 58 
8.2.2 Intraocular Surgical Procedures .................................................................................................. 58 
8.2.3 Treatment for Cystoid Macular Edema (CME) ........................................................................... 59 
8.3 Pregnancy Reporting ......................................................................................................................... 59 
8.4 Participant Compensation .................................................................................................................. 59 
8.5 Participant Withdrawal ...................................................................................................................... 59 
8.6 Confidentiality ................................................................................................................................... 59 
CHAPTER 9: STATISTICAL CONSIDERATIONS .......................................................................................... 60 
9.1 Sample Size Approach....................................................................................................................... 60 
9.1.1 General Considerations ............................................................................................................... 60 
9.1.2 Registry Sample Size Considerations .......................................................................................... 60 
9.1.3 Natural History Study Sample Size Considerations .................................................................... 62 
9.2 Data Analysis ..................................................................................................................................... 67 
9.2.1 Registry Data Analysis ................................................................................................................ 67 
9.2.2 Natural History Data Analysis ..................................................................................................... 68 
9.2.3 Interim Data Analysis .................................................................................................................. 70 
CHAPTER 10: DATA COLLECTION AND MONITORING ............................................................................ 71 
10.1 Case Report Forms and Other Data Collection ............................................................................... 71 
10.1.1 Central Genetics Auditor (CGA) ............................................................................................... 71 
10.1.2 Genetics Committee (GC) ......................................................................................................... 71 
10.1.3 Reading Center (RC) ................................................................................................................. 71 
10.2 Study Records Retention ................................................................................................................. 71 
10.3 Quality Assurance and Monitoring .................................................................................................. 72 
10.4 Protocol Deviations ......................................................................................................................... 72 
CHAPTER 11: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 74 
11.1 Ethical Standard ............................................................................................................................... 74 
11.2 Institutional Review Boards ............................................................................................................ 74 
11.3 Informed Consent Process ............................................................................................................... 74 
11.3.1 Consent Procedures and Documentation ................................................................................... 74 
11.3.2 Participant and Data Confidentiality ......................................................................................... 74 
11.3.3 Future Use of Data and Ocular Images ..................................................................................... 75 
CHAPTER 12: REFERENCES ....................................................................................................................... 76 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADRP 
Autosomal Dominant Retinitis Pigmentosa 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
BRVT 
Berkeley Rudimentary Vision Test 
CC 
Coordinating Center 
CFR 
Code of Federal Regulations 
CGA 
Central Genetics Auditor 
CI 
Confidence Interval 
CME 
Cystoid Macular Edema 
CRF 
Case Report Form 
DHA 
Docosahexaenoic Acid 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ERG 
Electroretinogram 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EVA 
Electronic Visual Acuity 
EZ 
Ellipsoid Zone 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FFB 
Foundation Fighting Blindness 
ffERG 
Full-field Electroretinogram 
FST 
Full-field Stimulus Threshold 
GC 
Genetics Committee 
GCP 
Good Clinical Practice 
HOV 
Hill of Vision 
HRPP 
Human Research Protection Program 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRD 
Inherited Retinal Degeneration 
KP 
Kinetic Perimetry 
LAR 
Legally Authorized Representative 
LLVA 
Low Luminance Visual Acuity 
LVP-FVQ II 
L.V. Prasad-Functional Vision Questionnaire  

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ABBREVIATION 
DEFINITION 
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Microperimetry 
MRDQ 
Michigan Retinal Degeneration Questionnaire 
N 
Number or Sample Size 
OCT 
Optical Coherence Tomography 
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PRO 
Patient Reported Outcome 
PROMIS®-29 
Patient-Reported Outcomes Measurement Information System 
QA 
Quality Assurance  
QC 
Quality Control  
r 
Pearson Correlation Coefficient 
RC 
Reading Center 
RD 
Retinal Dystrophy 
RBM 
Risk-Based Monitoring  
RP 
Retinitis Pigmentosa 
RUSH2A 
Rate of Progression in USH2A Related Retinal Degeneration Study 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SP 
Static Perimetry 
ULV-VFQ-50 
Ultra Low Vision-Visual Functioning Questionnaire 
VA 
Visual Acuity 
VF 
Visual Field 
ViSIO-PRO 
Visual Symptom and Impact Outcomes-Patient Reported Outcome 
ViSIO-ObsRO 
Visual Symptom and Impact Outcomes-Observer Reported Outcome 
Vtot 
Total Volume 
VUS 
Variant(s) of Unknown Significance 
YAC 
Younger Age Cohort 
α 
Type I Error 
 
 
 

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PROTOCOL OUTLINE 
CATEGORY 
DESCRIPTION 
Title 
Universal Rare Gene Study: A Registry and Natural History Study of Retinal Dystrophies 
Associated with Rare Disease-Causing Genetic Variants  
Abbreviated 
Name 
Uni-Rare 
Number of 
Sites 
Approximately 40 
Study Design 
 
There are two components of this international, multicenter study:  
Registry  
• 
A standardized genetic screening and a prospective, standardized, cross-sectional clinical data 
collection  
• 
Enrollment is open to all genes on the RD Rare Gene List   
 
Natural History Study   
• 
A prospective, standardized, longitudinal Natural History Study 
• 
Enrollment opens gene-by-gene, based on funding and within-gene Registry enrollment 
Objectives 
 
 
The study objectives are as follows. See section 1.3 for details. 
Registry Objectives 
1. Genotype Characterization 
2. Cross-Sectional Phenotype Characterization (within gene) 
3. Establish a Link to My Retina Tracker Registry (MRTR) 
4. Ancillary Exploratory Studies – Pooling of Genes 
 
Natural History Study Objectives 
1. Natural History (within gene) 
2. Structure-Function Relationship (within gene) 
3. Risk Factors for Progression (within gene) 
4. Ancillary Exploratory Studies – Pooling of Genes 
Précis 
The Registry will establish genetically and clinically well-characterized cohorts of patients across 
hundreds of genetic variants associated with retinal dystrophy (RD). Characterization of these 
patients will accelerate eligibility screening for the Natural History Study, provide cross-sectional 
data on phenotype-genotype associations, and contribute to our knowledge of pathogenicity of 
these rare disease-causing variants.  
 
The Natural History Study will accelerate the identification and development of sensitive, 
reliable outcome measures for clinical trials, which will facilitate development of treatments for 
retinal dystrophies due to disease-causing genetic variants. The expected impact of the Natural 
History Study is as follows: 
1. Describe the natural history of retinal degeneration in patients with rare disease-causing 
genetic variants  
2. Identify sensitive structural and functional outcome measures to use for future multicenter 
clinical trials of rare inherited retinal degeneration  

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CATEGORY 
DESCRIPTION 
3. Identify well-defined subpopulations for future clinical trials of investigative treatments 
for rare inherited retinal degeneration 
Participant 
Duration 
Registry 
• 
Registry/Screening Visit: Approximately 1-90 days 
• 
Genetic screening: Approximately 30 days  
• 
Annual phone calls: Up to approximately 48 months (or until gene is moved to the 
Natural History Study) 
 
Natural History Study 
• 
Baseline Visit to 48-Month Follow-up Visit: Approximately 48 Months 
Younger Age 
Cohort 
• 
Participants ages ≥ 4 years and < 8 years old will be designated as the Younger Age 
Cohort. 
• 
Participants in this cohort will not be assigned a Vision Cohort. 
• 
Registry/Screening Visit and Natural History Study Visits will have an abbreviated testing 
schedule, detailed in the Schedule of Study Visits and Procedures table. 
Vision Cohorts   
Participants who are aged ≥ 8 years old will be designated into one of the following Vision 
Cohorts based on data in the better eye, at the Registry/Screening Visit. See section 2.2 for the 
detailed definitions.  
 
VF diameter ≥10° in 
every meridian 
VF diameter <10° in 
any meridian 
20/80 or better 
Vision Cohort 1 
Vision Cohort 2 
20/100-20/400 
Vision Cohort 2 
Vision Cohort 2 
20/500 or worse 
Vision Cohort 3 
Vision Cohort 3 
Protocol 
Overview 
 
 
The protocol overview is as follows. Also see flow charts in next section. 
1. Screening Phase  
o Review patient’s current genetic report* as having at least one gene on the RD 
Rare Gene List meeting one of the eligible Genetic Screening Criteria and 
review other eligibility criteria that can be evaluated based on medical history. 
o Complete Registry informed consent procedures according to overseeing 
Institutional Review Board (IRB)/Ethics Committee (EC) requirements. 
o Obtain ID on study website to be enrolled into initial screening. 
o Complete the Registry/Screening Visit  
i. Confirm Registry eligibility criteria 
ii. Determine Vision Cohort**  
iii. Confirm Genetic Screening Criteria  
iv. Complete Registry data collection as part of the Registry/Screening Visit 
v. Participants meeting eligibility criteria to continue will be enrolled into 
the genetic screening phase 
*Genetic testing will not be performed in this study. A prior conclusive genetic test will be 
assessed for screening analysis. 
** Participants in the Younger Age Cohort will not be assigned a Vision Cohort. 

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CATEGORY 
DESCRIPTION 
2. Genetic Screening Phase 
o Genetic reports* for participants enrolled into the genetic screening phase will 
be uploaded to study website for review and confirmation by Central Genetics 
Auditor (CGA) as meeting Genetic Screening Criteria.   
o Participants confirmed as meeting those criteria will be considered enrolled into 
the Registry. 
*Genetic testing will not be performed in this study. A prior conclusive genetic test will be 
assessed for screening analysis.  
 
3. Registry Phase 
o The flow of participants who are enrolled into the Registry depends on whether 
their causal gene is designated as a Natural History Study (NHS) Target Gene: 
 
Not designated as NHS Target Gene: Annual phone calls up to 48 
months from the Registry/Screening Visit or until gene is designated as 
NHS Target Gene. 
 
Designated as NHS Target Gene: Participants will be considered 
pending enrollment into the NHS. 
 
4. Natural History Study (NHS) Phase 
o Participants pending enrollment into the NHS will do the following: 
i. Return to the clinic for the NHS Enrollment/Baseline Visit  
1. Complete NHS informed consent procedures according to 
overseeing Institutional Review Board (IRB)/Ethics Committee 
(EC) requirements 
2. Confirm NHS eligibility criteria  
3. Complete Baseline testing 
4. Participants completing these steps will be considered enrolled 
into the NHS 
ii. Return to the clinic for follow-up visits according to Cohort 
specifications.   
1. Participants in the Younger Age Cohort and Vision Cohorts 1 and 
2 will return to the clinic at 12, 24, 36 and 48 months from the 
Baseline Visit date for follow-up visits.  
2. Participants in Vision Cohort 3 will have phone calls at 12, 24 
and 36 months from the Baseline Visit date, and a study visit at 
48 months. 
iii. After the 48-month follow-up visit, participation in the study will be 
completed for participants in all cohorts. 

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Outcomes 
Functional Outcomes: 
Key Assessments 
Test 
Equipment 
Reading 
Center 
Registry (R) 
or Natural 
History Study 
(NHS) 
Visual field sensitivity 
measured with quantitative 
topographic analysis (hill of 
vision [HOV]) 
Static Perimetry 
(SP) 
Octopus 900 Pro 
Yes 
R, NHS 
Early Treatment of Diabetic 
Retinopathy Study 
(ETDRS) / HOTV Best 
Corrected Visual Acuity 
(BCVA) letter score 
Visual Acuity (VA) 
Electronic Visual 
Acuity (EVA) 
system or 
ETDRS/HOTV 
charts 
N/A 
R, NHS 
Low visual acuity test – for 
participants unable to see 
ETDRS letters 
Low Visual Acuity 
Berkeley 
Rudimentary 
Vision Test 
(BRVT) 
N/A 
R, NHS 
ETDRS/HOTV best 
corrected low luminance 
visual acuity letter score  
Low Luminance 
Visual Acuity 
(LLVA) 
Electronic Visual 
Acuity (EVA) 
system or 
ETDRS/HOTV 
charts 
N/A 
R, NHS 
Mean retinal sensitivity 
Fundus guided 
Microperimetry 
(MP) 
MAIA 
Yes 
NHS 
Contrast sensitivity function 
Contrast sensitivity 
CSV-1000E chart 
N/A 
NHS 
Retinal function using 
amplitudes and timing in 
response to rod- and cone-
specific stimuli 
Full-field 
Electroretinogram 
(ffERG) 
Diagnosys Espion 
No 
NHS 
Full-field retinal sensitivity 
Full-field stimulus 
threshold (FST) 
testing to blue, 
white, and red 
stimuli 
Diagnosys Espion 
No 
NHS 
Color vision function 
Color vision 
Lanthony D15 
N/A 
NHS 
 
Structural Outcomes: 
Key Assessments 
Test 
Equipment 
Reading 
Center 
Registry (R) 
or Natural 
History Study 
(NHS) 
Ellipsoid zone (EZ) area; 
outer nuclear layer and 
ganglion cell layer 
thicknesses 
Spectral Domain 
Optical Coherence 
Tomography (SD-
OCT) 
Heidelberg 
Spectralis 
Yes 
R, NHS 

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Qualitative and quantitative 
assessments of 
autofluorescence pattern 
Fundus 
Autofluorescence 
(FAF) 
Optos 
Yes 
NHS 
 
Patient Reported Outcomes (PROs) (NHS only): 
• 
Adults 18 years or older at Baseline: 
o Michigan Retinal Degeneration Questionnaire (MRDQ) 
o Patient-Reported Outcomes Measurement Information System (PROMIS®-29) 
o Visual Symptom and Impact Outcomes-Patient Reported Outcome (ViSIO-PRO) 
o Ultra Low Vision-Visual Functioning Questionnaire (ULV-VFQ-50) – Vision Cohort 3 
only 
• 
Adolescents 12-17 years at Baseline: 
o Visual Symptom and Impact Outcomes-Patient Reported Outcome (ViSIO-PRO) 
o L. V. Prasad-Functional Vision Questionnaire (LVP-FVQ II) 
 
• 
Children 8-11 years at Baseline: 
o Visual Symptom and Impact Outcomes-Observer Reported Outcome (ViSIO-ObsRO) 
o L. V. Prasad-Functional Vision Questionnaire (LVP-FVQ II) 
 
• 
Children 4-7 years at Baseline: 
o Visual Symptom and Impact Outcomes-Observer Reported Outcome (ViSIO-ObsRO) 
 
RD Rare Gene 
List 
The RD Rare Gene List for the Uni-Rare study (see Uni-Rare Clinical Site Manual of 
Procedures) represents all known genes for which variants may be associated with retinal 
dystrophy (RD) and have not already been studied in a trial at the time this protocol was finalized.  
Population 
Key Eligibility Criteria – Determined at the Registry/Screening Visit 
The entire list of eligibility criteria in protocol section 2.4.1 must be reviewed at the 
Registry/Screening Visit. Participants meeting eligibility criteria will continue to enroll into the 
genetic screening phase.  
 
A key subset of the eligibility criteria includes the following: 
• 
Age ≥ 4 years of age 
• 
Clinical diagnosis of retinal dystrophy (RD) 
• 
Must have a gene on the RD Rare Gene List which meets one of the following Genetic 
Screening Criteria*   
o Inheritance Pattern is Recessive and has at least 2 disease-causing variants which 
are homozygous or heterozygous in trans 
OR  
o Inheritance Pattern is Recessive and has 2 disease-causing variants with unknown 
phase and meets all the following additional informatic criteria that are consistent 
with likely segregation in trans: 
1. Investigator confirms genotype and phenotype are consistent with 
autosomal recessive inheritance  
2. The 2 disease-causing variants have not been reported in cis in variant 
databases 

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3. No additional potentially pathogenic variants were found on the gene 
(and the sequencing data for the gene were sufficiently robust to detect 
any additional potentially pathogenic variants) 
4. No potentially pathogenic variants were found in other common, likely 
candidate genes for the proposed condition 
OR  
o Inheritance Pattern is Dominant, X-linked, or Mitochondrial and has at least 1 
disease-causing variant 
*Based on prior conclusive genetic report from a clinically certified lab (or from a 
research lab that has been approved by the study Genetics Committee). 
 
Genetic Screening Phase 
The Genetic Screening Phase will confirm genetic cause of disease via final Central Genetics 
Auditor (CGA) review for all participants.  
 
Registry Cohort Criteria 
At the end of the Genetic Screening Phase the following must be documented to be eligible to 
enroll into the Registry: 
 Participant’s genetic cause of disease has been confirmed by Central Genetics Auditor (CGA) 
as meeting one of the Genetic Screening Criteria for a gene on the RD Rare Gene List. 
 
Natural History Study Cohort Criteria 
Participants who meet the final Registry Cohort Criteria will be eligible to enroll into the NHS if 
and when their causal gene is designated as an NHS Target Gene. This gene-by-gene 
designation will be made by the Executive Committee on an ongoing basis and may depend on 
funding resources as well as Registry enrollment numbers within gene. NHS consent will be 
required, and additional NHS eligibility criteria will be confirmed prior to enrollment into the 
NHS.  
Sample Size 
Registry  
• 
Recruitment will continue until 1,500 participants meet the final Registry Cohort Criteria, 
unless the Executive Committee terminates recruitment due to feasibility. 
• 
A maximum of 150 participants in Vision Cohort 3.     
• 
A maximum of 100 participants where Inheritance Pattern is Recessive and phase is unknown. 
• 
A maximum of 100 participants within gene.  
The Executive Committee will monitor enrollment distributions across genes, inheritance patterns, 
vision cohorts, and age cohorts with the planned caps as noted. Enrollment in some genes, 
inheritance patterns, vision cohorts, or age cohorts may be encouraged to ensure appropriate 
representation, and some caps may be adjusted if needed. 
 
Natural History Study   
• 
The Natural History Study sample size for each gene will depend on the Registry enrollment; 
a maximum of 100 participants within gene.  

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FLOW CHART – SCREENING PHASE   
 
 

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FLOW CHART – GENETIC SCREENING PHASE   
 
 
 

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FLOW CHART – REGISTRY PHASE   
 

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FLOW CHART – NATURAL HISTORY STUDY  
 
 
 
 

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 SUMMARY OF PROCEDURES FOR THE REGISTRY/SCREENING VISIT, 
GENETIC SCREENING PHASE, AND REGISTRY PHASE 
Visit/Phase 
Registry/ 
Screening 
Visit 
Genetic 
Screening 
Phase 
12M 
24M 
36M 
48M 
Phone Call Target Windows a 
Wk 
52 ± 8 
Wk 
104 ± 8 
Wk 
156 ± 8 
Wk 
208 ± 8 
Participant-Level Procedures 
Registry Informed Consent 
X 
 
 
 
 
 
Collect MyRetinaTrackerID (if participating and consented to provide) 
X 
 
 
 
 
 
Eligibility Criteria Assessment  
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Medical History (incl. pre-existing conditions, symptomology history, 
medications) 
X 
 
 
 
 
 
Genetic Report Assessment (incl. Genetic Screening Criteria) 
X 
 
 
 
 
 
Determination of Vision Cohort c 
X 
 
 
 
 
 
CGA Confirmation of Genetic Cause of Disease and Final Genetic Eligibility 
 
X 
 
 
 
 
Phone Call (patient contact only; no data collection) 
 
 
X 
X 
X 
X 
Ocular Procedures b – all testing performed in each eye 
Complete Ophthalmic Exam d 
X 
 
 
 
 
 
Visual Acuity (EVA preferred or ETDRS charts); with refraction and 
LLVA/BRVT c 
X 
 
 
 
 
 
Intraocular Pressure e 
X 
 
 
 
 
 
SD-OCT Volume Scans c (Heidelberg Spectralis) 
X 
 
 
 
 
 
SD-OCT Vertical and Horizontal Scans c (Heidelberg Spectralis) 
X 
 
 
 
 
 
Static Perimetry c (Octopus 900 Pro) 
X 
 
 
 
 
 
Kinetic VF III4e c, f (Kinetic Perimetry) 
X 
 
 
 
 
 
a. 
Timed from Registry/Screening Visit; annually up to four (4) years or until participant’s gene is designated as 
an NHS Target Gene.  
b. The Registry/Screening Visit date is defined as the start date of all Registry/Screening testing. All 
Registry/Screening testing must be completed within ninety (90) days of the Registry/Screening Visit date 
(except for ophthalmic exam and kinetic VF, as noted in d and f below). All procedures are considered 
standard care. 
c. 
Testing not performed in Younger Age Cohort. 
d. Ophthalmic exam can be performed at Registry/Screening Visit, or a historical measurement performed within 
the last six (6) months prior to the Registry/Screening Visit. The ophthalmic exam includes slit-lamp 
biomicroscopy and indirect ophthalmoscopy. 
e. 
Intraocular pressure (IOP) measurements are to be taken prior to pupil dilation. 
f. 
Vision Cohort 1 and 2: Historical measurement performed within the last eighteen (18) months prior to the 
Registry/Screening Visit. If a historical measurement is not available, then perform the Kinetic VF III4e at the 
Registry/Screening Visit. Vision Cohort 3: Collect the most recent historical measurement prior to the 
Registry/Screening Visit, if available. Kinetic VF III4e does not need to be performed at screening if a 
historical measurement is not available. 
 
 
 

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SCHEDULE OF STUDY VISITS AND PROCEDURES FOR THE NATURAL 
HISTORY STUDY: YOUNGER AGE COHORT            
Visit 
 Baseline a 
12M b 
24M b 
36M b 
48M b 
Target Windows 
(Day 0) 
Wk 
52 ± 4 
Wk 
104 ± 4 
Wk 
156 ± 4 
Wk 
208 ± 4 
Participant-Level Procedures 
NHS Informed Consent 
X 
 
 
 
 
Eligibility Criteria Assessment 
X 
 
 
 
 
Concomitant Medications / Adverse Events / Medical History Update 
X 
X 
X 
X 
X 
Patient Reported Outcomes (PROs) 
X 
 
X 
 
X 
Ocular Procedures – all testing performed in each eye 
Complete Ophthalmic Exam c 
X 
X 
X 
X 
X 
Visual Acuity (HOTV); with refraction and LLVA/BRVT 
X 
X 
X 
X 
X 
Intraocular Pressure d 
X 
X 
X 
X 
X 
Color Vision (Lanthony D15) 
X 
X 
X 
X 
X 
SD-OCT Volume Scans (Heidelberg Spectralis e) 
X 
X 
X 
X 
X 
SD-OCT Vertical and Horizontal Scans (Heidelberg Spectralis e) 
X 
X 
X 
X 
X 
Axial Length and Corneal Curvature Measurements 
X 
X 
X 
X 
X 
Optos Color Photos h 
X 
 
 
 
 
Optos Fundus Autofluorescence h 
X 
X 
X 
X 
X 
Full-field ERG (Diagnosys Espion) f, h 
X 
 
 
 
X 
Full-field Stimulus Threshold (Diagnosys Espion) h 
X 
X 
X 
X 
X 
Age-Up Procedures g – for participants who turn 8 y/o during study period 
Static Perimetry (Octopus 900 Pro) 
 
X 
X 
X 
X 
Fundus Guided Microperimetry (MAIA) h 
 
X 
X 
X 
X 
Contrast Sensitivity (CSV-1000E) 
 
X 
X 
X 
X 
a. 
Baseline testing must be started within seven (7) days of NHS eligibility confirmation. The Baseline Visit date 
is defined as the start date of all Baseline testing. All Baseline testing must be completed within thirty (30) days 
of the Baseline Visit date, with the following exceptions:  
• 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit testing date for the 
ophthalmic exam or IOP exam, the testing performed as part of the Registry/Screening Visit for 
these modalities may be used for the Baseline Visit. 
• 
PROs may be completed in person or remotely any time within 6 months after Baseline Visit date. 
b. 
All NHS Follow-up Visit testing must be completed on the same day, with the following exception: 
• 
PROs may be completed in person or remotely any time within the Allowable Window of the 
associated visit. 
c. 
Ophthalmic exam includes slit-lamp biomicroscopy and indirect ophthalmoscopy. It is recommended that the 
ocular exam is completed at approximately the same time of day at each visit using the same equipment.   
d. 
Intraocular pressure (IOP) measurements are to be taken prior to pupil dilation. 
e. 
If a Younger Age Cohort participant is unable to perform OCT testing on the Heidelberg Spectralis, the 
handheld Bioptogen/Envisu may be used to perform OCT testing for qualitative purposes with approval from 
the Coordinating Center. 
f. 
If ERG has been undetectable in the past, there is no need to perform at Baseline Visit; if ERG is undetectable 
at Baseline Visit, there is no need to perform at 48M - at the investigator’s discretion. 
g. 
Participants in the Younger Age Cohort who turn 8 years old (age-up) during the NHS study period should 
attempt to have static perimetry, microperimetry, and contrast sensitivity testing performed at the next study 
visit after they turn 8 years old and at every subsequent visit, until the end of the study period.  
h. 
If a site does not have the required equipment, participation in this test may be waived with approval from the 
Coordinating Center. 

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SCHEDULE OF STUDY VISITS AND PROCEDURES FOR THE NATURAL 
HISTORY STUDY: VISION COHORTS 1 AND 2            
Visit 
Baseline a 
12M b 
24M b 
36M b 
48M b 
Visit Target Windows 
(Day 0) 
Wk 
52 ± 4 
Wk 
104± 4 
Wk 
156± 4 
Wk 
208± 4 
Participant-Level Procedures 
NHS Informed Consent 
X 
 
 
 
 
Eligibility Criteria Assessment 
X 
 
 
 
 
Concomitant Medications / Adverse Events / Medical History Update 
X 
X 
X 
X 
X 
Patient Reported Outcomes (PROs) 
X 
 
X 
 
X 
Ocular Procedures – all testing performed in each eye 
Complete Ophthalmic Exam c 
X 
X 
X 
X 
X 
Visual Acuity (EVA preferred or ETDRS charts); with refraction and LLVA/BRVT 
X 
X 
X 
X 
X 
Intraocular Pressure d 
X 
X 
X 
X 
X 
Color Vision (Lanthony D15) 
X 
X 
X 
X 
X 
Contrast Sensitivity (CSV-1000E) 
X 
X 
X 
X 
X 
SD-OCT Volume Scans (Heidelberg Spectralis) 
X 
X 
X 
X 
X 
SD-OCT Vertical and Horizontal Scans (Heidelberg Spectralis) 
X 
X 
X 
X 
X 
Axial Length and Corneal Curvature Measurements e 
X 
X 
X 
X 
X 
Optos Color Photo h 
X 
 
 
 
 
Optos Fundus Autofluorescence h 
X 
X 
X 
X 
X 
Full-field ERG (Diagnosys Espion) f, h 
X 
 
 
 
X 
Full-field Stimulus Threshold (Diagnosys Espion) h 
X 
X 
X 
X 
X 
Static Perimetry (Octopus 900 Pro) g 
X 
X 
X 
X 
X 
Fundus Guided Microperimetry (MAIA) g, h 
X 
X 
X 
X 
X 
a. 
Baseline testing must be started within seven (7) days of eligibility confirmation. Baseline Visit date is defined 
as the start date of all Baseline testing. All Baseline testing must be completed within thirty (30) days of the 
Baseline Visit date, with the following exceptions:  
• 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit testing date for the 
visual acuity (VA), static perimetry, SD-OCT (volume and V/H), ophthalmic exam or IOP exams, 
the testing performed as part of the Registry/Screening Visit may be used for the Baseline Visit. A 
second static perimetry test would still need to be performed at the Baseline Visit, as noted in h 
below. 
• 
PROs may be completed in person or remotely any time within 6 months after Baseline Visit date. 
b. All NHS Follow-up Visit testing must be completed on the same day, with the following exception: 
• 
PROs may be completed in person or remotely any time within the Allowable Window of the 
associated visit. 
c. 
Ophthalmic exam includes slit-lamp biomicroscopy and indirect ophthalmoscopy. It is recommended that the 
ocular exam be completed at approximately the same time of day at each visit using the same equipment. 
d. Intraocular pressure (IOP) measurements are to be taken prior to pupil dilation. 
e. 
Axial length and corneal curvature measurements will be completed at the Baseline Visit for all participants. 
Only individuals who are under 18 years old at the Baseline Visit will continue to have measurements taken at 
every annual visit until study completion. 
f. 
If ERG has been undetectable in the past, there is no need to perform at Baseline Visit; if ERG is undetectable 
at Baseline Visit, there is no need to perform at 48M - at the investigator’s discretion. 

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g. For static perimetry and microperimetry, all participants will complete two tests for the Baseline Visit. The 
results will be compared according to the visual field criteria in section 4.3.2 to determine if a third test is 
needed. 
h. If a site does not have the required equipment, participation in this test may be waived with approval from the 
Coordinating Center. 

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SCHEDULE OF STUDY VISITS AND PROCEDURES FOR THE NATURAL 
HISTORY STUDY: VISION COHORT 3 
Visit 
Baseline a 
12M 
24M 
36M 
48M b 
Target Windows 
(Day 0) 
Wk 
52 ± 4 
(Phone call 
only) 
Wk 
104± 4 
(Phone call 
only) 
Wk 
156± 4 
(Phone call 
only) 
Wk 
208± 4 
Participant-Level Procedures 
NHS Informed Consent 
X 
 
 
 
 
Eligibility Criteria Assessment 
X 
 
 
 
 
Concomitant Medications / Adverse Events / Medical History Update 
X 
X 
X 
X 
X 
Patient Reported Outcomes (PROs) 
X 
 
 
 
X 
Ocular Procedures – all testing performed in each eye 
Complete Ophthalmic Exam c 
X 
 
 
 
X 
Visual Acuity (EVA preferred or ETDRS charts); with refraction and 
LLVA/BRVT 
X 
 
 
 
X 
Intraocular Pressure d 
X 
 
 
 
X 
SD-OCT Volume Scans (Heidelberg Spectralis) 
X 
 
 
 
X 
SD-OCT Vertical and Horizontal Scans (Heidelberg Spectralis) 
X 
 
 
 
X 
Axial Length and Corneal Curvature Measurements e 
X 
 
 
 
X 
Optos Color Photos f 
X 
 
 
 
 
Optos Fundus Autofluorescence f 
X 
 
 
 
X 
Full-field Stimulus Threshold (Diagnosys Espion) f 
X 
 
 
 
X 
a. 
Baseline testing must be started within seven (7) days of eligibility confirmation. Baseline Visit date is defined 
as the start date of all Baseline testing. All Baseline testing must be completed within thirty (30) days of the 
Baseline Visit date, with the following exceptions:  
• 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit testing date for the 
visual acuity (VA), SD-OCT (volume and V/H), ophthalmic exam or IOP exams, the testing 
performed as part of the Registry/Screening Visit may be used for the Baseline Visit. 
• 
PROs may be completed in person or remotely any time within 6 months after Baseline Visit date. 
b. 
All NHS Follow-up Visit testing must be completed on the same day, with the following exception: 
• 
PROs may be completed in person or remotely any time within the Allowable Window of the 
associated visit. 
c. 
Ophthalmic exam includes slit-lamp biomicroscopy and indirect ophthalmoscopy. It is recommended that the 
ocular exam is completed at approximately the same time of day at each visit using the same equipment.   
d. 
Intraocular pressure (IOP) measurements are to be taken prior to pupil dilation. 
e. 
Axial length and corneal curvature measurements will be completed at the Baseline Visit for all participants. 
Only individuals who were under 18 years old at the Baseline Visit will also have measurements taken at the 
48M visit. 
f. 
If a site does not have the required equipment, participation in this test may be waived with approval from the 
Coordinating Center 

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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
Inherited retinal degenerations (IRDs) affect approximately 2 to 3 million people worldwide.1 
3 
The rise of promising treatment approaches has increased rapidly in recent years, include gene 
4 
editing and augmentation (early-stage disease), neuroprotection (mid-stage disease), prosthetics, 
5 
optogenetics, and cell therapy to restore some light sensation (late-stage disease).1,2 Despite 
6 
advancements in therapy development, and a growing number of interventional trials 
7 
(https://www.clinicaltrials.gov/) for IRDs, there remain significant hurdles to designing trials and 
8 
moving therapy through the development process. Several papers have reviewed unmet needs 
9 
and identified top priorities to move the promise of treatment forward amongst a complex 
10 
landscape of IRD research.3-7 The common theme among the recommendations is the vital need 
11 
for natural history studies, the foundational basis for trial design and drug development. The 
12 
following sections summarize the key gaps in IRD research that natural history studies can 
13 
address.   
14 
1.1.1 Identifying Optimal IRD Patient Populations for Target Therapies 
15 
IRDs are genetically diverse (280 causative genes have been identified to date) 
16 
(https://sph.uth.edu/retnet/) and have vastly different clinical manifestations, including age of 
17 
onset, severity of disease, rate of progression, and structural and functional abnormalities. 
18 
Understanding this phenotypic heterogeneity is a major challenge for potential therapy 
19 
developers. It is critical to identify genetic factors impacting disease severity and progression, 
20 
including the impact of mutation-specific variations within genes. Natural history data, both 
21 
longitudinal and cross-sectional, within each gene population is needed to understand these 
22 
differences, and ideally these studies would include enough cases to evaluate a variety of 
23 
subgroups across genetic, phenotypic, and environmental factors.3-7   
24 
1.1.2 Develop and Validate Outcome Measures for Progression of IRDs 
25 
The cornerstone of good trial design is a good endpoint. Identifying the best candidate endpoint 
26 
for evaluating progression of disease, and ultimately treatment effects in a trial, requires 
27 
consideration of many properties. These include sensitivity, reproducibility, correlation with 
28 
other measures of disease progression, how much within-person change is beyond measurement 
29 
variability, and whether within-person change is clinically meaningful. For a given treatment, the 
30 
best measure also depends on the expected benefit; restoration of vision versus slowing of 
31 
progression. Since IRDs are genetically diverse, understanding these properties within each gene 
32 
is important.3-7    
33 
 
34 
The list of candidate endpoints to measure and understand IRD progression is vast. Visual 
35 
function outcomes, such as visual acuity (VA), contrast sensitivity, color vision, microperimetry 
36 
(MP), full-field stimulus threshold (FST) and full-field electroretinogram (ffERG), measure 
37 
performance of the components of the visual system in the clinical environment and represent the 
38 
measures of what is clinically meaningful. Structural or anatomical measures, such as fundus 
39 
autofluorescence (FAF) and optical coherence tomography (OCT), represent candidate 
40 
biomarkers or surrogate endpoints that hold the potential to predict clinical benefit. Structural 
41 
measures are an expanding area of IRD research due to new technologies and better imaging 
42 

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acquisition and interpretation techniques and is an area of priority identified by gap analyses. 
43 
Functional vision measures, which are designed to reflect real-life challenges in daily activities, 
44 
include patient-reported outcomes. Although a variety of tools exist, little is known about their 
45 
applicability within each genotype.3-7 
46 
 
47 
A relatively small number of endpoints defined by these measures have been accepted by the 
48 
Food and Drug Administration (FDA) and other regulatory bodies to study therapeutic efficacy 
49 
in IRD trials. The extreme genetic heterogeneity of IRDs and diversity of resulting disease 
50 
progression further complicates the decision of which endpoint to use for a given gene therapy 
51 
trial. Gene-specific natural history studies can provide longitudinal data to understand the 
52 
properties of these measures and facilitate development of appropriate endpoints for trial design.     
53 
1.1.3 Other Gaps Addressed by Natural History Studies 
54 
Natural history studies address numerous other challenges faced in clinical trial design and 
55 
implementation, including understanding the time course of disease progression (which informs 
56 
trial duration and testing schedule), evaluating demographic and epidemiological estimates of 
57 
prevalence and disease characteristics (which may be addressed by cross-sectional studies), and 
58 
identifying expert clinical centers with staff trained to follow standardized protocols. They also 
59 
shed light on intangibles and unknowns, which ultimately saves resources, increases efficiencies, 
60 
and improves quality of future interventional trials built upon these lessons learned.  
61 
1.1.4 Unique Challenges in Ultra-Rare Genes 
62 
Ultra-rare genes present a special challenge in addressing these knowledge gaps and represent a 
63 
significant portion of IRD genes. Two hundred and forty-eight (248) genes out of three hundred 
64 
and seventy-four (374) potential IRD genes listed in the FFB Consortium 2021 Gene Poll had 
65 
less than twenty (20) patients counted as having retinal dystrophy (RD) linked to that causal 
66 
gene, across all thirty-two (32) sites reporting in the Poll (data not published). Small sample sizes 
67 
create less precision around estimates and difficulty or inability to evaluate factors related to 
68 
disease severity and progression or correlation among outcomes. Further study is needed to 
69 
identify similar disease mechanisms and whether there are methods by which researchers could 
70 
pool data across genes for these objectives.   
71 
1.2 Rationale for a Universal Rare Gene Study 
72 
Individual natural history studies for each rare RD gene are not feasible. Many centers have as 
73 
few as one (1) – two (2) patients for a particular RD gene and may not be able to devote 
74 
resources needed to implement each study. Individual studies also require considerable startup 
75 
time (e.g., contracts, IRB/Ethics Committee approvals) and study management expenses 
76 
regardless of the number of patients. A single, universal protocol under which all rare RD genes 
77 
may be enrolled would address these inefficiencies.     
78 
Because of the vast phenotypic diversity, simultaneous open enrollment of all rare RD genes 
79 
directly into a longitudinal natural history study is problematic. Unfocused enrollment efforts 
80 
spread across hundreds of genes will dilute timelines for data collection and analysis objectives 
81 
within targeted genes. A solution is to create a universal registry open to all rare RD genes, to 
82 
cross-sectionally characterize patients within all rare RD genes (mild, moderate, and severe 
83 
vision loss) so they are ready to be enrolled into a subsequent universal longitudinal natural 
84 

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history study as their gene is selected. This two-phase platform will (1) eliminate repetitive 
85 
processes like certification, training, regulatory approval, contract agreements, (2) reduce costs 
86 
and accelerate timelines for longitudinal studies and (3) leverage a large sample size and 
87 
standardized data collection in the cross-sectional study to explore the extent to which genes with 
88 
common mechanisms of disease have similar clinical manifestations (e.g., determine if and how 
89 
some genes may be pooled in some analyses).  
90 
1.3 Study Objectives 
91 
Registry Objectives 
92 
1. Genotype Characterization 
93 
a. Establish a database of patients completing a standardized genetic screening 
94 
process confirming retinal dystrophy is associated with disease-causing genetic 
95 
variants (and thereby confirmed genetically eligible for a potential natural 
96 
history study) 
97 
b. Evaluate characteristics of genetic variants  
98 
2. Cross-Sectional Phenotype Characterization* 
99 
a. Characterize cross-sectional retinal dystrophy associated with disease-causing 
100 
genetic variants using functional and structural measures, within gene 
101 
i. Ideally where within-gene sample size is 20 or more 
102 
b. Structure-function relationships will also be explored within-gene  
103 
i. Ideally where within-gene sample size is 20 or more 
104 
c. Risk factors for disease severity will also be explored within-gene  
105 
i. Ideally where within-gene sample size is 40 or more 
106 
3. Establish a Link to My Retina Tracker Registry (MRTR) 
107 
a. Register MRTR participants for exploratory analysis of data between registry 
108 
databases, as permissible within the scope of signed informed consent(s) 
109 
4. Ancillary Exploratory Studies - Pooling of Genes 
110 
a. Explore whether phenotype-genotype associations within biological mechanisms 
111 
or other factors (such as age or disease duration) will allow pooling of genes for 
112 
cross-sectional analysis objectives 
113 
b. If pooling is determined appropriate, evaluate objective 2 above within 
114 
appropriate pooling groups 
115 
 
116 
Natural History Study Objectives 
117 
Within-Gene Objectives* 
118 
The following objectives will be evaluated within gene.   
119 
1. Natural History  
120 
a. Characterize the natural history of retinal degeneration associated with disease-
121 
causing genetic variants over 4 years, using functional, structural, and patient-
122 
reported outcome measures 
123 
b. Ideally where within-gene sample size is 20 or more 
124 
2. Structure-Function Relationship 
125 
a. Explore whether structural outcome measures can be validated as surrogates for 
126 
functional outcomes in individuals with disease-causing genetic variants   
127 
b. Ideally where within-gene sample size is 20 or more 
128 
 
 
129 

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3. Risk Factors for Progression 
130 
a. Explore possible risk factors (genotype, phenotype, environmental, and 
131 
comorbidities) for progression of the outcome measures at 4 years in individuals 
132 
with disease-causing genetic variants 
133 
b. Ideally where within-gene sample size is 40 or more 
134 
 
135 
*Applicability of within-gene objectives will depend on within-gene sample size as noted above. 
136 
If less than 20, the primary objective will be limited to describing the cohort in the form of case 
137 
histories. Objectives may still be explored depending on the needs of a specific gene. 
138 
 
139 
Across-Genes Objective 
140 
The following objective will be evaluated across genes. 
141 
4. Ancillary Exploratory Studies - Pooling of Genes 
142 
a. Explore whether phenotype-genotype associations within biological mechanisms 
143 
or other factors (such as age or disease duration) will allow pooling of genes for 
144 
longitudinal analysis objectives 
145 
1.4 Potential Risks and Benefits 
146 
1.4.1 Known Potential Risks 
147 
Most examination procedures are considered part of standard care for retinal degenerations. This 
148 
study will be capturing some information about participants that include identifiable, personal 
149 
information, like date of birth (will be collected if permitted by site’s regulatory bodies). The 
150 
study has procedures in place to protect that information. However, there is a chance that a loss 
151 
of that protection could occur. This would be a loss of confidentiality. There are special efforts 
152 
being made to ensure that this does not happen.  
153 
The sections below summarize the risks and discomforts that may be occur during the period of 
154 
prospective data collection. 
155 
• Risks associated with testing VA, KP, SP, MP, FST, ERG, OCT, and PROs may include 
156 
boredom and frustration, but no lasting adverse effects are associated with these 
157 
noninvasive tests 
158 
• Dilating eye drops will be used as part of the ophthalmic examination and before some 
159 
tests. Dilating eye drops may sting, cause light-sensitivity, or an allergic reaction. There 
160 
is a small risk of inducing a narrow-angle glaucoma attack from the pupil dilation. 
161 
However, all participants will have had prior pupil dilation usually on multiple occasions 
162 
and therefore the risk is extremely small. If glaucoma occurs, treatment is available. 
163 
• In rare instances, the cornea may be scratched during measurement of IOP or use of a 
164 
contact lens electrode. An abrasion like this may be painful, but it heals quickly with no 
165 
lasting effects. If a participant experiences a corneal abrasion, a tear ointment may be 
166 
administered, and an eye patch or gauze may be placed over the eye. 
167 
1.4.2 Known Potential Benefits 
168 
Study participants are not expected to benefit directly from participation in this study. Study 
169 
participants participating in this study may benefit from close attention from the study personnel 
170 

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and Investigator(s). The risks of participating in the study are outweighed by the benefits. 
171 
Benefits include increased attention from the study personnel and the ability to contribute to 
172 
increased understanding of the cross-sectional description and natural history of retinal 
173 
degenerations due variants in rare genes, which may contribute to future development of 
174 
treatments. 
175 
1.4.3 Risk Assessment 
176 
The risk level for this protocol is considered no greater than minimal risk. A risk-based 
177 
monitoring approach will be followed, consistent with the FDA “Guidance for Industry 
178 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). 
179 
1.5 General Considerations 
180 
The study is being conducted in compliance with the policies described in the study policies 
181 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
182 
the protocol described herein, and with the standards of Good Clinical Practice (GCP).  
183 
Employing a cross-sectional registry component combined with the Natural History Study 
184 
prospective longitudinal study design is advantageous because it reflects a systematic method of 
185 
data collection. By doing so, this study addresses the need to evaluate disease progression while 
186 
also accounting for prevalence and disease characteristics. This study design incorporates several 
187 
strategies to minimize bias, detailed below, using considerations from “Rare Diseases: Natural 
188 
History Studies for Drug Development: Guidance for Industry, Draft Guidance.8 These are 
189 
considered standard for treatment trials and will enhance the translation of the data from this 
190 
study to a treatment trial. 
191 
Establishing standardized testing procedures and specific required equipment for all 
192 
investigators, leading to greater consistency and precision in the information collected. 
193 
Training and certification of study staff who will perform primary outcome procedures by a 
194 
Reading Center. The Reading Center will grade test results in a uniform manner independently 
195 
from study sites. 
196 
Use of standard, consistent definitions of pre-existing medical conditions, medications and 
197 
treatments, and adverse events (AEs) across all clinical sites. 
198 
A consistent schedule of follow-up visits for all participants with established visit time frames. 
199 
A coordinating center (CC) is responsible for monitoring the conduct of the study to ensure 
200 
adherence to protocol. 
201 
When feasible, data will be directly collected in electronic case report forms, which will be 
202 
considered the source data. 
203 

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Chapter 2: Registry Enrollment and Registry/Screening Visit 
204 
2.1 Registry Recruitment and Enrollment 
205 
Registry participants will be recruited from approximately forty (40) clinical sites worldwide. All 
206 
eligible participants will be included without regard to gender, race, or ethnicity. The primary 
207 
recruitment strategy will be patient referral from the site Investigator(s). However, recruitment 
208 
materials may be made used upon IRB or Ethics Committee approval.  
209 
The Executive Committee will review recruitment progress and feasibility at regular intervals.  
210 
Registry recruitment will continue until approximately 1,500 participants meet the final 
211 
Registry Cohort Criteria (see section 2.6), unless the Executive Committee terminates 
212 
recruitment due to feasibility. The Executive Committee will monitor enrollment distributions 
213 
across genes, inheritance patterns, vision cohorts, and age cohorts with the planned caps as noted 
214 
below. Enrollment in some genes, inheritance patterns, vision cohorts, or age cohorts may be 
215 
encouraged to ensure appropriate representation, and some caps may be adjusted if needed. 
216 
  
217 
• A maximum of 100 participants will be enrolled within gene.  
218 
• Recruitment will be tracked within the three (3) vision cohorts as defined below:   
219 
o A maximum of 150 participants will be enrolled in Vision Cohort 3 (across 
220 
genes).  
221 
o Approximate target distribution of Vision Cohort 1 and 2 is 2:1 overall and within 
222 
gene. This will be monitored and encouraged, but not required. 
223 
• A maximum of 100 participants will be enrolled where Inheritance Pattern is Recessive 
224 
and phase is unknown. 
225 
• Participants will not be counted as enrolled into the Registry until Genetic Screening 
226 
Criteria have been confirmed (see section 2.5). This means that potentially more 
227 
participants will complete the Registry/Screening Visit than are enrolled into the 
228 
Registry. The number and reasons for screen failures will be tracked. It is possible that 
229 
some participants will have completed the Registry/Screening Visit and will be awaiting 
230 
genetic confirmation at the time the enrolled numbers reach the limits above. Therefore, 
231 
the actual enrolled numbers may be larger. To limit over-enrollment, clinical sites will be 
232 
notified as the recruitment limits are reached and efforts will be made to accurately 
233 
predict numbers in the genetic screening queue. 
234 
2.2 Cohort Definitions 
235 
Vision Cohort Definitions 
236 
Vision Cohort 1 
Approximately 
900 participants 
Criteria that must be met in the better eye* at the Registry/Screening Visit:  
o visual acuity ETDRS letter score of 54 or more (approximate Snellen 
equivalent 20/80 or better) and visual field** diameter 10 degrees or more in 
every meridian of the central field 
Vision Cohort 2 
Approximately 
450 participants 
Criteria that must be met in the better eye* at the Registry/Screening Visit: 
o visual acuity ETDRS letter score of 19-53 (approximate Snellen equivalent 
20/100 to 20/400)  
OR  

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o visual acuity ETDRS letter score of 54 or more (approximate Snellen 
equivalent 20/80 or better) and visual field** diameter less than 10 degrees in 
any meridian of the central field 
Vision Cohort 3 
Approximately 
150 participants 
Criteria that must be met in the better eye* at the Registry/Screening Visit: 
o visual acuity ETDRS letter score of 18 or less (approximate Snellen equivalent 
20/500 or worse) 
 
 
*Better Eye 
The better eye is defined as the eye with the better Registry/Screening Visit 
ETDRS visual acuity. However, if both eyes have the same visual acuity, which 
is defined as the same Snellen equivalent, then the determination will be made at 
the Investigator’s discretion. In this scenario, the Investigator will consider the 
eye with better fixation or clearer ocular media to permit highest quality retinal 
imaging. 
**Visual Field 
The visual field (VF) is defined as the clinically determined kinetic VF III4e 
performed within the last 18 months prior to the Registry/Screening Visit or 
performed on the day of the Registry/Screening Visit. 
  
237 
Vision Cohort Grid 
238 
VF diameter ≥10° in 
every meridian 
VF diameter <10° in 
any meridian 
20/80 or better 
Vision Cohort 1 
Vision Cohort 2 
20/100-20/400 
Vision Cohort 2 
Vision Cohort 2 
20/500 or worse 
Vision Cohort 3 
Vision Cohort 3 
 
239 
Younger Age Cohort Definition 
240 
Younger Age 
Cohort 
• 
Participants who are between the ages of ≥ 4 years and < 8 years old will be 
designated as the Younger Age Cohort.  
• 
Participants in this cohort will not be assigned a Vision Cohort. 
• 
Registry/Screening Visit and Natural History Study Visits will have an 
abbreviated testing schedule. 
2.3 Registry Informed Consent and Authorization Procedures 
241 
There will be two separate consent processes for the two phases of the Uni-Rare study. There 
242 
will be one (1) consent process for the Registry phase and one (1) for the NHS phase. The 
243 
Registry consent process is as follows. Some sites outside the US may have alternative or 
244 
additional Ethics Committee requirements, which will be followed as applicable, once reviewed 
245 
and approved by the FFB Consortium. 
246 
 Registry Consent Process for Age of Majority: For study participants who are the age of 
247 
majority, e.g., at least eighteen (18) years of age in the US, the study will be discussed 
248 
with the potential study participant by trained and delegated study staff. The potential 
249 

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study participant will be given the current, approved Registry Informed Consent Form 
250 
(ICF) to read and will be given the opportunity to ask questions about the Registry. 
251 
Potential study participants will be encouraged to discuss the study with family members 
252 
and their personal physicians(s) before deciding whether to participate in the study. If the 
253 
person wishes to be a participant, then the Registry ICF will be signed/dated and a 
254 
signed/dated copy of the Registry ICF will be provided to the participant and another 
255 
copy will be added to the participant’s study record.  
256 
 Registry Consent Process for Minors: For potential participants who are minors, e.g., 
257 
under eighteen (18) years of age in the US, a parent/legal guardian (referred to 
258 
subsequently as “parent”) will be provided with the Registry Informed Consent Form 
259 
(ICF) to read and will be given the opportunity to ask questions about the Registry. If the 
260 
parent agrees to participate, the Registry ICF will be signed/dated by the parent. The 
261 
signed/dated Registry ICF will be provided to the parent and another copy will be added 
262 
to the participant’s study record. Participants who become age of majority, e.g., eighteen 
263 
(18) years of age in the US, while in the Registry will need to re-consent with a Registry 
264 
ICF (and authorization as described below), as applicable to the IRB or Ethics Committee 
265 
requirements and as instructed by the FFB Consortium. 
266 
Note: Some Ethics Committees might require a separate Registry Assent for minors who 
267 
are participating in the Registry, in addition to the Registry ICF signed by the parent/legal 
268 
guardian. Such applicable requirements will be followed as instructed by the FFB 
269 
Consortium. 
270 
 Authorization for Use/Release of Personal Information: As part of the informed consent 
271 
process, each participant and/or parent will be asked to sign/date an authorization for 
272 
release of personal information (or other such document, e.g., HIPAA Authorization, 
273 
GDPR Consent, LGPD Consent, etc.), as applicable to the IRB or Ethics Committee 
274 
requirements. The trained and delegated study staff will review the study-specific 
275 
information that will be collected and to whom that information will be disclosed. While 
276 
speaking with the participant, questions will be answered about the details regarding 
277 
authorization. If they wish to proceed, then they will receive a copy of the signed/dated 
278 
authorization and another copy will be filed in the participant’s study record.     
279 
 Other Consent Options:   
280 
o Short Form: If a participant or parent prefers that the study information be 
281 
presented verbally/orally (e.g., they have significant visual impairments), a short 
282 
form version of the Informed Consent Form, with the corresponding short form 
283 
summary, may be used as approved by the IRB or Ethics Committee requirements 
284 
and as instructed by the FFB Consortium.  
285 
 Note: This process does require a witness. This process is not to be used 
286 
as a substitute for presenting study information to the participant either 
287 
due to written material not being translated in the native language of the 
288 
participant/LAR or because a participant lacks the capacity to consent. 
289 
o Remote Consent: At the discretion of the site, as applicable to the IRB or Ethics 
290 
Committee requirements, and with the approval of the FFB Consortium, some 
291 
participants may complete the consent process remotely.  
292 

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 Note: This process typically requires additional documentation regarding 
293 
the remote consent process (e.g., remote consent checklist). 
294 
 Completion of Consent Process and Enrollment: A participant is considered enrolled into 
295 
initial screening when the Registry informed consent process has been completed and a 
296 
participant ID has been obtained on the study website. 
297 
2.4 Registry/Screening Visit  
298 
After the informed consent documents have been signed, the participant will be evaluated for 
299 
study eligibility through the elicitation of a medical history and performance of ophthalmic tests 
300 
as described below. The Registry/Screening Visit date will be documented as the date 
301 
Registry/Screening procedures begin. All Registry/Screening Visit testing procedures must be 
302 
completed within ninety (90) days of the Registry/Screening Visit date, unless specified below. 
303 
2.4.1 Registry Eligibility Criteria 
304 
To be eligible to enroll into the genetic screening phase, a study participant must meet all the 
305 
inclusion criteria and none of the exclusion criteria at the Registry/Screening Visit. 
306 
2.4.1.1 Participant Inclusion Criteria 
307 
Participants must meet all the following inclusion criteria at the Registry/Screening Visit to be 
308 
eligible to enroll into the genetic screening phase: 
309 
1. Willing to participate in the study and able to communicate consent during the consent 
310 
process 
311 
2. Willing and able to complete all applicable Registry/Screening Visit assessments   
312 
3. Age ≥ 4 years  
313 
4. Must have a single gene on the RD Rare Gene List which meets one of the Genetic 
314 
Screening Criteria below based on a genetic report* from a clinically certified lab (or 
315 
from a research lab which has been approved by the study Genetics Committee): 
316 
o Inheritance Pattern is Recessive and has at least 2 disease-causing variants which 
317 
are homozygous or heterozygous in trans  
318 
OR  
319 
o Inheritance Pattern is Recessive and has 2 disease-causing variants with unknown 
320 
phase and meets all the following additional informatic criteria that is consistent 
321 
with likely segregation in trans: 
322 
1. Investigator confirms genotype and phenotype are consistent with 
323 
autosomal recessive inheritance  
324 
2. The 2 disease-causing variants have not been reported in cis in variant 
325 
databases 
326 
3. No additional potentially pathogenic variants were found on the gene (and 
327 
the sequencing data for the gene were sufficiently robust to detect any 
328 
additional potentially pathogenic variants) 
329 
4. No potentially pathogenic variants were found in other common, likely 
330 
candidate genes for the proposed condition 
331 
OR 
332 

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o Inheritance Pattern is Dominant, X-linked, or Mitochondrial and has at least 1 
333 
disease-causing variant 
334 
 
335 
Important Note: 
 Genes Listed as Variable Mode of Inheritance on RD Rare Gene List 
o If the site is able to determine the inheritance pattern from the participant’s genetic 
report*, the Genetic Screening Criteria above may be followed to determine eligibility 
based on the site determined inheritance pattern. 
o If the site is unable to determine the inheritance pattern from the participant’s genetic 
report*, the site should use the most common inheritance pattern to follow the Genetic 
Screening Criteria above. The most common inheritance pattern will be provided to 
sites for each gene that is listed as having a variable mode of inheritance.    
 If there are questions about interpretations of the genetic reports* prior to the genetic 
screening phase, the Genetics Committee (GC) and/or the Central Genetics Auditor (CGA) 
may be consulted. The Coordinating Center (CC) must be contacted first to determine the 
appropriate mechanism of consultation, consistent with regulatory and consent requirements. 
*Genetic testing will not be performed in this study. A prior conclusive genetic test is 
336 
what will be assessed for screening analysis.  
337 
2.4.1.2 Ocular Inclusion Criteria 
338 
Both eyes must meet the following criteria at the Registry/Screening Visit to enroll into the 
339 
genetic screening phase. 
340 
1. Both eyes must have a clinical diagnosis of retinal dystrophy 
341 
2. Both eyes must permit good quality photographic imaging (e.g., but not limited to, clear 
342 
ocular media, adequate pupil dilation, stable fixation) 
343 
2.4.1.3 Participant Exclusion Criteria 
344 
Participants must not meet any of the following exclusion criteria at the Registry/Screening Visit 
345 
to be eligible to enroll into the genetic screening phase. 
346 
1. History of more than 1 year of cumulative treatment, at any time, with an agent 
347 
associated with pigmentary retinopathy including amiodarone, chloroquine, 
348 
deferoxamine, hydroxychloroquine, pentosan polysulfate, tamoxifen, and deferoxamine 
349 
Note: Since this is an observational study, pregnant women will not be specifically excluded 
350 
from participation. However, minors that are pregnant shall be precluded from 
351 
participation until they become the age of majority.  
352 
2.4.1.4 Ocular Exclusion Criteria 
353 
If either eye has any of the following ocular exclusion criteria at the Registry/Screening Visit, 
354 
then the participant is not eligible to enroll into the genetic screening phase. 
355 
1. Current vitreous hemorrhage 
356 
2. Current complications of pathological myopia (for example, but not limited to, myopic 
357 
maculopathy including atrophy, scar, choroidal neovascularization, schisis) that could 
358 
inhibit ability to obtain good quality photographic imaging  
359 

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3. History of intraocular surgery (for example, but not limited to, cataract surgery, 
360 
vitrectomy, penetrating keratoplasty, or LASIK) within 3 months of Registry/Screening 
361 
Visit 
362 
4. Current or any history of confirmed diagnosis of glaucoma (for example, but not limited 
363 
to, glaucomatous VF changes or nerve changes, or history of glaucoma filtering surgery) 
364 
5. Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy 
365 
6. History or current evidence of ocular disease that, in the opinion of the Investigator, may 
366 
confound assessment of visual function (for example, but not limited to, tractional or 
367 
rhegmatogenous retinal detachment, any vitreoretinal surgery, retinal vascular occlusion, 
368 
proliferative diabetic retinopathy) 
369 
7. The following medications and treatments are prohibited as they can affect progression of 
370 
retinitis pigmentosa (RP). The participant must not have received the following 
371 
treatments: 
372 
 
Any use of ocular stem cell or gene therapy 
373 
 
Any treatment with ocriplasmin 
374 
 
Treatment with Ozurdex (dexamethasone), Iluvien, or Yutiq (fluocinolone acetonide) 
375 
intravitreal implant 
376 
8. The following medications and treatments are excluded within the specified timeframe: 
377 
 
Treatment with an ophthalmic oligonucleotide within the last 9 months (last 
378 
treatment date is less than 9 months prior to Registry/Screening Visit date) 
379 
 
Treatment with any other product within five times the expected half-life of the 
380 
product (time from last treatment date to Registry/Screening Visit date is at least 5 
381 
times the half-life of the given product) 
382 
2.4.2 Registry/Screening Visit Data Collection and Testing 
383 
The following procedures will be performed at the Registry/Screening Visit. An overview of the 
384 
equipment and certification requirements for all testing is in section 6.1. All Registry/Screening 
385 
Visit testing procedures must be completed within ninety (90) days of the Registry/Screening 
386 
Visit date, unless specified below. All ocular testing will be performed in each eye, right eye 
387 
(OD) first and then left eye (OS). Screening procedures will last approximately two (2) hours. 
388 
The testing procedures are detailed in the Uni-Rare Clinical Site Manual of Procedures.  
389 
All Registry/Screening Visit testing procedures are considered standard care.   
390 
 
391 
The following procedures will be performed and documented (including data collection and 
392 
eligibility criteria checks) at the Registry/Screening Visit: 
393 
1. Inclusion and exclusion criteria assessed 
394 
2. Demographics (date of birth, sex, race, and ethnicity) 
395 
3. Contact information (retained at the site and not entered on the study database) 
396 
4. Collection of MyRetinaTracker Registry ID (if participating and consented to provide) 
397 
5. Medical history – will be elicited from the study participant and extracted from available 
398 
medical records, including patient-reported daily activities, pre-existing medical 
399 
conditions, medications, and audiology history 
400 

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6. Concomitant medications 
401 
7. Ophthalmic examination 
402 
 
Can be performed within ninety (90) days of the Registry/Screening Visit or a 
403 
historical measurement performed within the last six (6) months prior to the 
404 
Registry/Screening Visit. 
405 
 
Complete ophthalmic examination to include: 
406 
 
Slit lamp biomicroscopy 
407 
 
Indirect ophthalmoscopy 
408 
8. Visual acuity (including refraction, ETDRS, BRVT if needed, and LLVA if needed)* 
409 
 
The VA letter score will determine whether LLVA or BRVT will be performed.  
410 
The criteria are defined in the Uni-Rare Clinical Site Manual of Procedures. 
411 
9. Intraocular Pressure (IOP) 
412 
 
IOP measurements are to be taken prior to pupil dilation. 
413 
10. Spectral Domain Optical Coherence Tomography (SD-OCT)* 
414 
 
Volume Scan  
415 
 
Vertical and Horizontal Scan  
416 
11. Static Perimetry (SP)*  
417 
12. Kinetic Visual Field III4e (Kinetic Perimetry [KP])* 
418 
 
Vision Cohort 1 and 2: Historical measurement performed within the last 
419 
eighteen (18) months prior to the Registry/Screening Visit. If a historical 
420 
measurement is not available, then perform the Kinetic VF III4e during the 
421 
Registry/Screening Visit.  
422 
 
Vision Cohort 3: Collect the most recent historical measurement prior to the 
423 
Registry/Screening Visit, if available. Kinetic VF III4e does not need to be 
424 
performed at screening if a historical measurement is not available. 
425 
13. Determination of Vision Cohort (see section 2.2) 
426 
 
If the participant’s determined Vision Cohort is closed for enrollment, the 
427 
remainder of procedures and testing are not required. Participant will be 
428 
discontinued as an initial screen failure. 
429 
 
Participants in the Younger Age Cohort will not be assigned to a Vision Cohort. 
430 
14. Genetic screening assessment, including number and phase of mutations in the causal 
431 
gene, history of consanguinity, and collection of the source genetic report(s) available at 
432 
the clinical site. 
433 
 
This includes an assessment that the participant meets one of the Genetic 
434 
Screening Criteria. If the participant does not meet one of these criteria, then the 
435 
remainder of procedures and testing are not required. The participant will be 
436 
discontinued as an initial screen failure. 
437 
*This testing procedure will not be completed for participants in the Younger Age Cohort. 
438 

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2.4.3 Initial Screen Failures 
439 
Participants who do not meet criteria to continue as noted above will be discontinued as an initial 
440 
screen failure. The Screening Visit Form will still be completed, entering “Not Done” for testing 
441 
not finished. A Final Status Form will be completed, and the reason for screen failure will be 
442 
noted. 
443 
2.5 Genetic Screening Phase 
444 
Participants passing the initial screening and enrolled into the genetic screening phase will have 
445 
their genetic lab reports submitted for Central Genetics Auditor (CGA) review. The schematic of 
446 
study design at the beginning of the protocol summarizes the flow of the Genetic Screening 
447 
Phase. Reference the Uni-Rare Clinical Site Manual of Procedures for detailed procedures. 
448 
All genetic reports will be uploaded to the FFB study website by the clinical site. These reports 
449 
may be reviewed by the CC, associated clinical site, CGA, Genetics Committee, and 
450 
Investigator(s) involved in the oversight of the study (which includes the study chair, Operations 
451 
Committee, and Executive Committee). All genetic reports will be de-identified and redacted of 
452 
all personal data prior to uploading on the FFB study website. 
453 
The CGA will review the genetic documentation provided by the clinical site to verify the 
454 
genetic screening data entry and appropriate documentation of the Genetic Screening Criteria. 
455 
Additional documentation, including relevant family history information, may be requested as 
456 
needed to complete this verification process.  
457 
 
If Genetic Screening Criteria are verified, then the participant will be considered 
458 
enrolled into the Registry. 
459 
 
If the final study cohort is not verified, then the participant will be a genetic screen 
460 
failure. 
461 
 
NOTE: Genetic screen failures may include cases where CGA determines the 
462 
following: 
463 
 
More than one gene meets Genetic Screening Criteria 
464 
 
The actual inheritance pattern, according to CGA review, for the participant 
465 
differs from the common designation on the RD Rare Gene List or identified 
466 
by the site, and the associated Genetic Screening Criteria are no longer met  
467 
 
Informatic criteria for Recessive with unknown phase is not confirmed to be 
468 
consistent with segregation in trans 
469 
 
Any of the inclusion/exclusion criteria under section 2.4.1 related to genetics 
470 
are not met 
471 
2.5.1 Genetic Screen Failures 
472 
Participants who do not meet criteria to continue in the study will be discontinued as a genetic 
473 
screen failure. A Final Status Form will be completed, and the reason for screen failure will be 
474 
indicated. 
475 

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2.5.2 Genetics Committee Review 
476 
A Genetics Committee (GC) will review the genetic documentation of participants enrolled into 
477 
the Registry for interpretation and evaluation of whether the mutations in the affected gene are 
478 
causative of the disease (for example, pathogenic, likely pathogenic). Cases that are not 
479 
confirmed as disease causing will remain in the study and will not be considered ineligible. 
480 
However, their data may be analyzed separately from those with pathogenic mutations. 
481 
2.6 Final Registry Cohort Criteria 
482 
Participants who meet the Genetic Screening Criteria (section 2.4.1.1) and have those criteria 
483 
confirmed by a CGA will be considered enrolled into the Registry.  
 
484 

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Chapter 3: Registry Phase 
485 
3.1 Evaluation of Natural History Study (NHS) Target Gene Status 
486 
Participants meeting criteria to enroll into the Registry (section 2.6) will be evaluated for NHS 
487 
status.  
488 
 If the participant’s causal gene is designated as an NHS Target Gene at the time the 
489 
CGA confirmation of Genetic Screening Criteria occurs, the participant will be 
490 
considered pending NHS and will be asked to return to the clinical site for NHS 
491 
Enrollment and Baseline Visit (procedures detailed in chapter 4).  
492 
 If the participant’s causal gene is not designated as an NHS Target Gene at the time the 
493 
CGA confirmation of Genetic Screening Criteria occurs, the participant will remain 
494 
active in the Registry Phase as follows: 
495 
o Participants who are active in the Registry Phase will follow section 3.2 until the 
496 
end of the Registry Phase of the study or until the participant’s causal gene is 
497 
designated as an NHS Target Gene.  
498 
o When the causal gene is designated as an NHS Target Gene, the participant will 
499 
be considered pending NHS and will be asked to return to the clinical site for 
500 
NHS Enrollment and Baseline Visit (procedures detailed in chapter 4). 
501 
3.2 Annual Phone Calls 
502 
The clinical site will call participants who are active in the Registry Phase annually according to 
503 
the schedule below and will log the phone call on the study website. The purpose of the call is to 
504 
maintain contact with the participant and update the participant on the status of the study, 
505 
including any potential for their causal gene to become an NHS Target Gene or potential for 
506 
interest in other studies.  
507 
Schedule for Phone Calls 
508 
PHONE CALL 
SCHEDULE  
TARGET DATE* 
TARGET 
WINDOW*  
ALLOWABLE 
WINDOW* 
12-Month  
52 Weeks  
± 8 Weeks 
± 26 Weeks 
24-Month  
104 Weeks 
± 8 Weeks 
± 26 Weeks 
36-Month  
156 Weeks  
± 8 Weeks 
± 26 Weeks 
48-Month  
208 Weeks 
± 8 Weeks 
± 26 Weeks 
*Timed from Registry/Screening Visit Date 
509 
3.3 Completion of Registry Phase  
510 
If a participant’s causal gene has not been designated as an NHS Target Gene by the time of the 
511 
48-Month phone call, they will complete the Registry Phase and Uni-Rare study. The participant 
512 
will be told on the 48-Month phone call that the annual study phone calls will discontinue and 
513 
their study status will be complete. A Final Status Form will be completed. 
514 

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Chapter 4: Natural History Study Enrollment and Baseline Visit 
515 
4.1 Natural History Study (NHS) Target Gene Selection  
516 
The designation of NHS Target Genes will be made by the Executive Committee on an ongoing 
517 
basis and may depend on funding resources as well as Registry enrollment numbers within gene.  
518 
The Natural History Study sample size for each gene will depend on Registry enrollment. Since 
519 
the within-gene Registry limit is 100 participants, this will be the maximum sample size for NHS 
520 
Target Genes. As noted in section 2.1, the actual enrolled numbers may be larger due to lag in 
521 
genetic screening phase confirmation of participant meeting the final Registry Cohort Criteria.  
522 
Within-gene sample size justification can be derived from the sample size estimates and 
523 
statistical considerations in chapter 9.  
524 
4.2 NHS Enrollment  
525 
When a participant’s causal gene is designated as an NHS Target Gene, the participant will be 
526 
considered pending NHS and will be asked to return to the clinical site for NHS Enrollment and 
527 
the Baseline Visit. 
528 
4.2.1 NHS Informed Consent and Authorization Procedures 
529 
There will be two separate consent process for the two phases of the Uni-Rare study. There will 
530 
be one (1) consent process for the Registry phase and one (1) for the NHS phase. The NHS 
531 
consent process is as follows. Some sites outside the US may have alternative or additional 
532 
Ethics Committee requirements which will be followed as applicable, once reviewed and 
533 
approved by the FFB Consortium. 
534 
 NHS Consent Process for Age of Majority: For study participants who are the age of 
535 
majority, e.g., at least eighteen (18) years of age in the US, the study will be discussed 
536 
with the potential study participant by trained and delegated study staff. The potential 
537 
study participant will be given the current, approved NHS Informed Consent Form (ICF) 
538 
to read and will be given the opportunity to ask questions about the NHS. Potential study 
539 
participants will be encouraged to discuss the study with family members and their 
540 
personal physicians(s) before deciding whether to participate in the study. If the person 
541 
wishes to be a participant, then the NHS ICF will be signed/dated and a signed/dated 
542 
copy of the NHS ICF will be provided to the participant and another copy will be added 
543 
to the participant’s study record.  
544 
 NHS Consent Process for Minors: For potential participants who are minors, e.g., under 
545 
eighteen (18) years of age in the US, a parent/legal guardian (referred to subsequently as 
546 
“parent”) will be provided with the NHS Informed Consent Form (ICF) to read and will 
547 
be given the opportunity to ask questions about the NHS. If the parent agrees 
548 
to participate, the NHS ICF will be signed/dated by the parent. The signed/dated NHS 
549 
ICF will be provided to the parent and another copy will be added to the participant’s 
550 
study record. Participants who become age of majority, e.g., eighteen (18) years of age in 
551 
the US, while in the NHS will need to re-consent with an NHS ICF (and authorization as 
552 
described below), as applicable to the IRB or Ethics Committee requirements and as 
553 
instructed by the FFB Consortium.  
554 

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Note: Some Ethics Committees might require a separate NHS Assent for minors who are 
555 
participating in the Natural History Study, in addition to the NHS ICF signed by the 
556 
parent/legal guardian. Such applicable requirements will be followed as instructed by the 
557 
FFB Consortium. 
558 
Please reference section 2.3 for details regarding the Authorization for Use/Release of Personal 
559 
Information, Short Form Option, and Remote Consent Option. 
560 
4.2.2 NHS Eligibility Criteria 
561 
To be eligible to enroll into the NHS, a study participant must meet the following criteria:  
562 
1. Enrolled into the Registry  
563 
a. Registry eligibility criteria (section 2.4.1) must be reviewed to confirm nothing 
564 
has changed and criteria are still met 
565 
b. Genetic Screening Criteria do not require a second review 
566 
2. Willing to participate in the Natural History Study and able to communicate consent 
567 
during the consent process 
568 
3. Willing and able to complete all Natural History Study visit assessments at each visit 
569 
over the forty-eight (48) month study period 
570 
4. Is not planning or expected to enter experimental treatment trial at any time during the 
571 
Natural History Study 
572 
5. Is not planning to receive any treatments or medications in either eye or systemically that 
573 
could affect progression of retinitis pigmentosa (RP), including the following: 
574 
 
Any use of ocular stem cell or gene therapy 
575 
 
Any treatment with ocriplasmin 
576 
 
Treatment with Ozurdex (dexamethasone), Iluvien or Yutiq (fluocinolone acetonide) 
577 
intravitreal implant 
578 
A participant is considered enrolled into the NHS when the required NHS informed consent 
579 
document(s) have been signed, NHS eligibility criteria are confirmed, and an NHS Enrollment 
580 
Form is completed on the study website. This date is considered the NHS Enrollment Date.  
581 
Participants who do not meet criteria to continue as noted above will be discontinued as an NHS 
582 
screen failure. A Final Status Form will be completed, and the reason for screen failure will be 
583 
noted. 
584 
4.3 Baseline Visit Testing Procedures 
585 
The Baseline Visit must begin on or within seven (7) days of NHS Enrollment Date. The 
586 
Baseline Visit date will be documented as the date Baseline testing procedures begin. All 
587 
Baseline Visit testing procedures must be completed within thirty (30) days of the Baseline Visit 
588 
date, unless specified below.  
589 
The following procedures will be performed at the Baseline Visit. An overview of the equipment 
590 
and technician requirements for all testing is in section 6.1. All ocular testing will be performed 
591 
in each eye, right eye (OD) first and then left eye (OS). Baseline procedures will last 
592 

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approximately four (4) hours. The testing procedures are detailed in the Uni-Rare Clinical Site 
593 
Manual of Procedures. 
594 
4.3.1 Younger Age Cohort 
595 
1. Medical updates to include: 
596 
 
New or changed adverse events (AEs) 
597 
 
New ocular procedures 
598 
 
New or changed medications 
599 
2. Patient Reported Outcomes (PROs) 
600 
 
ViSIO-ObsRO 
601 
 
The PROs may be completed in person or remotely (phone or other remote 
602 
methods) any time within six (6) months of the Baseline Visit (not required to be 
603 
the same day as the rest of the Baseline Visit). 
604 
3. Complete ophthalmic examination to include: 
605 
 
Slit lamp biomicroscopy  
606 
 
Indirect ophthalmoscopy  
607 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
608 
testing date and the ophthalmic examination was performed during the 
609 
Registry/Screening Visit (i.e., not historical)– the ophthalmic examination 
610 
testing procedure may be skipped. 
611 
4. Visual Acuity (including refraction, HOTV, BRVT if needed, LLVA if needed) 
612 
 
The visual acuity (VA) Snellen score will determine whether LLVA or BRVT 
613 
will be performed. The criteria are defined in the Uni-Rare Clinical Site Manual 
614 
of Procedures. 
615 
5. Intraocular Pressure (IOP) 
616 
 
IOP measurements are to be taken prior to pupil dilation. 
617 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
618 
testing date – the IOP testing procedure may be skipped. 
619 
6. Color Vision 
620 
 
Desaturated (Lanthony D15) 
621 
7. Spectral Domain Optical Coherence Tomography (SD-OCT) 
622 
 
Volume Scan  
623 
 
Vertical and Horizontal Scan  
624 
 
If unable to perform OCT testing on the Heidelberg Spectralis, a site may use the 
625 
handheld Bioptogen/Envisu to perform OCT testing for qualitative purposes with 
626 
approval from the Coordinating Center. 
627 
8. Axial Length and Corneal Curvature Measurements 
628 

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9. Optos Color Photos* 
629 
10. Optos Fundus Autofluorescence (FAF)* 
630 
11. Full-field Electroretinogram (ffERG)* 
631 
12. Full-field Stimulus Threshold (FST)* 
632 
Note: All testing procedures are to be attempted for participants in the Younger Age Cohort. 
633 
If a child is unwilling to or unable to complete an examination, the procedure is to be 
634 
skipped. 
635 
*If a site does not have the required equipment, participation in this test may be waived with 
636 
approval from the Coordinating Center. 
637 
4.3.2 Vision Cohorts 1 & 2 
638 
1. Medical updates to include: 
639 
 
New or changed adverse events (AEs) 
640 
 
New ocular procedures 
641 
 
New or changed medications 
642 
2. Patient Reported Outcomes (PROs) 
643 
 
Adults (18+ years at Baseline): PROMIS®-29, MRDQ, ViSIO-PRO 
644 
 
Adolescents (12-17 years at Baseline): LVP-FVQ II, ViSIO-PRO 
645 
 
Children (8-11 years at Baseline): LVP-FVQ II, ViSIO-ObsRO 
646 
 
The PROs may be completed in person or remotely (phone or other remote 
647 
methods) any time within six (6) months of the Baseline Visit (not required to be 
648 
the same day as the rest of the Baseline Visit). 
649 
3. Complete ophthalmic examination to include: 
650 
 
Slit lamp biomicroscopy  
651 
 
Indirect ophthalmoscopy  
652 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
653 
testing date and the ophthalmic examination was performed during the 
654 
Registry/Screening Visit (i.e., not historical) – the ophthalmic examination 
655 
testing procedure may be skipped. 
656 
4. Visual Acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed) 
657 
 
The visual acuity (VA) letter score will determine whether LLVA or BRVT will 
658 
be performed. The criteria are defined in the Uni-Rare Clinical Site Manual of 
659 
Procedures. 
660 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
661 
testing date – the VA testing procedure may be skipped.   
662 
5. Intraocular Pressure (IOP) 
663 
 
IOP measurements are to be taken prior to pupil dilation. 
664 

JAEB CENTER FOR HEALTH RESEARCH 
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 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
665 
testing date – the IOP testing procedure may be skipped. 
666 
6. Color Vision 
667 
 
Desaturated (Lanthony D15) 
668 
7. Contrast Sensitivity 
669 
8. Spectral Domain Optical Coherence Tomography (SD-OCT) 
670 
 
Volume Scan  
671 
 
Vertical and Horizontal Scan  
672 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
673 
testing date – the SD-OCT testing procedure may be skipped. 
674 
9. Axial Length and Corneal Curvature Measurements 
675 
10. Optos Color Photos* 
676 
11. Optos Fundus Autofluorescence (FAF)* 
677 
12. Full-field Electroretinogram (ffERG)* 
678 
13. Full-field Stimulus Threshold (FST)* 
679 
14. Static Perimetry (SP) 
680 
 
Two (2) tests will be performed. The clinical site will compare the certified 
681 
technician determined mean sensitivity from test one (1) versus test two (2).  
682 
(a) If the absolute value of the difference between the two tests is ≤ 2.4 dB, 
683 
then the participant passes static perimetry reliability criteria. A third test 
684 
is not needed. 
685 
(b) If the absolute value of the difference between the two tests is > 2.4 dB, 
686 
then the participant does not pass static perimetry reliability criteria. A 
687 
third test will be required. 
688 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
689 
testing date – the SP performed during the Registry/Screening Visit may be 
690 
considered the first test and does not need to be repeated. Only the second test 
691 
will need to be performed at the Baseline Visit; the need for a third test will be 
692 
assessed using Test 1 from the Registry/Screening Visit and Test 2 from the 
693 
Baseline Visit.    
694 
15. Fundus Guided Microperimetry (MP)* 
695 
 
Two (2) tests will be performed. The clinical site will compare the certified 
696 
technician determined mean sensitivity from test one (1) versus test two (2).  
697 
(a) If the absolute value of the difference between the two tests divided by 
698 
the average between them is ≤ 50% OR the absolute value of the 
699 
difference between the two tests is ≤ 0.5 dB, then the participant passes 
700 
the microperimetry reliability criteria. A third test is not needed. 
701 

JAEB CENTER FOR HEALTH RESEARCH 
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702 
(b) If the absolute value of the difference between the two tests divided by 
703 
the average between them is > 50% AND the absolute value of the 
704 
difference between the two tests is > 0.5 dB, then the participant does not 
705 
pass microperimetry reliability criteria. A third test will be required. 
706 
*If a site does not have the required equipment, participation in this test may be waived with 
707 
approval from the Coordinating Center. 
708 
4.3.3 Vision Cohort 3 
709 
1. Medical updates to include 
710 
 
New or changed adverse events (AEs) 
711 
 
New ocular procedures 
712 
 
New or changed medications 
713 
2. Patient Reported Outcomes (PROs) 
714 
 
Adults (18+ years at Baseline): PROMIS®-29, MRDQ, ViSIO-PRO, ULV-
715 
VFQ-50 
716 
 
Adolescents (12-17 years at Baseline): LVP-FVQ II, ViSIO-PRO 
717 
 
Children (8-11 years at Baseline): LVP-FVQ II, ViSIO-ObsRO 
718 
 
The PROs may be completed in person or remotely (phone or other remote 
719 
methods) any time within six (6) months of the Baseline Visit (not required to be 
720 
the same day as the rest of the Baseline Visit). 
721 
3. Complete ophthalmic examination to include: 
722 
 
Slit lamp biomicroscopy  
723 
 
Indirect ophthalmoscopy  
724 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
725 
testing date and the ophthalmic examination was performed during the 
726 
Registry/Screening Visit – the ophthalmic examination testing procedure may 
727 
be skipped. 
728 
4. Visual Acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed) 
729 
 
The visual acuity (VA) letter score will determine whether LLVA or BRVT will 
730 
be performed. The criteria are defined in the Uni-Rare Clinical Site Manual of 
731 
Procedures. 
732 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
733 
testing date – the VA testing procedure may be skipped.   
734 
5. Intraocular Pressure (IOP) 
735 
 
IOP measurements are to be taken prior to pupil dilation. 
736 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
737 
testing date – the IOP testing procedure may be skipped. 
738 

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6. Spectral Domain Optical Coherence Tomography (SD-OCT) 
739 
 
Volume Scan  
740 
 
Vertical and Horizontal Scan  
741 
 
If the Baseline Visit date is within 3 months of the Registry/Screening Visit 
742 
testing date – the SD-OCT testing procedure may be skipped 
743 
7. Axial Length and Corneal Curvature Measurements 
744 
8. Optos Color Photos* 
745 
9. Optos Fundus Autofluorescence (FAF)* 
746 
10. Full-field Stimulus Threshold (FST)* 
747 
*If a site does not have the required equipment, participation in this test may be waived with 
748 
approval from the Coordinating Center. 
749 
 
750 
 
751 
 
 
752 

JAEB CENTER FOR HEALTH RESEARCH 
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PAGE 45 OF 76 
Chapter 5: Natural History Study Follow-up Visits 
753 
5.1 Follow-up Schedule  
754 
Follow-up Visits or phone calls will occur annually. Participants in the Younger Age Cohort 
755 
(YAC) and Vision Cohorts 1 and 2 will have annual in-person follow-up visits for four years 
756 
after the Baseline Visit. Participants in Vision Cohort 3 will receive annual follow-up phone calls 
757 
for three years after the Baseline Visit and will only return to the site for the last study visit (48-
758 
Month Visit). 
759 
The Baseline Visit date is considered study day zero (0) from which follow-up windows are 
760 
timed. The Follow-up Visit date will be the date the Follow-up Visit testing procedures started. 
761 
All Follow-up Visit testing procedures will be completed on the same date, other than the PROs 
762 
as noted in Section 5.3 Follow-up Procedures.  
763 
5.2 Target Timelines 
764 
Target dates and windows for each study Follow-up Visit for all cohorts are shown below.  Dates 
765 
and windows are timed from Baseline Visit date.  
766 
Schedule for Follow-up Visits or Phone Calls 
767 
VISIT 
SCHEDULE 
VISIT TYPE 
TARGET 
DATE* 
TARGET 
WINDOW* 
ALLOWABLE 
WINDOW* 
12-Month 
YAC + Vision Cohort 1 & 2: 
In-person Visit 
52 Weeks 
± 4 Weeks 
± 6 Weeks 
Vision Cohort 3: 
Phone Call 
24-Month 
YAC + Vision Cohort 1 & 2: 
In-person Visit 
104 Weeks 
± 4 Weeks 
± 6 Weeks 
Vision Cohort 3: 
Phone Call 
36-Month 
YAC + Vision Cohort 1 & 2: 
In-person Visit 
156 Weeks 
± 4 Weeks 
± 6 Weeks 
Vision Cohort 3: 
Phone Call 
48-Month 
All Cohorts 
In-person Visit 
208 Weeks 
± 4 Weeks 
± 6 Weeks 
*Timed from Baseline Visit Date 
768 
The goal is for all participants to complete all scheduled study visits. However, participants who 
769 
(because of unforeseen circumstances) are unable or unwilling to return for all follow-up visits 
770 
will be permitted to return for key visits only as an alternative to withdrawal from the study. 
771 
Additional office visits may occur as needed. 
772 

JAEB CENTER FOR HEALTH RESEARCH 
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5.3 Follow-up Visit Testing Procedures 
773 
The following procedures will be performed at the Follow-Up Visits, unless otherwise specified. 
774 
An overview of the equipment and certification requirements for all testing is in section 6.1. All 
775 
ocular testing will be performed in each eye, OD first and then OS. Follow-up Visit procedures 
776 
will last approximately three (3) hours. The testing procedures are detailed in the Uni-Rare 
777 
Clinical Site Manual of Procedures.  
778 
5.3.1 Younger Age Cohort 
779 
1. Medical updates to include: 
780 
 
New or changed adverse events (AEs) 
781 
 
New ocular procedures 
782 
 
New or changed medications 
783 
2. Patient Reported Outcomes (PROs) 
784 
 
ViSIO-ObsRO 
785 
 
The PROs may be completed in person or remotely (phone or other remote 
786 
methods) any time within the Allowable Window of the associated visit (not 
787 
required to be the same day as the rest of the Follow-up Visit). 
788 
3. Complete ophthalmic examination to include: 
789 
 
Slit lamp biomicroscopy  
790 
 
Indirect ophthalmoscopy  
791 
4. Visual Acuity (including refraction, HOTV, BRVT if needed, LLVA if needed) 
792 
 
The visual acuity (VA) Snellen score will determine whether LLVA or BRVT 
793 
will be performed. The criteria are defined in the Uni-Rare Clinical Site Manual 
794 
of Procedures. 
795 
5. Intraocular Pressure (IOP) 
796 
 
IOP measurements are to be taken prior to pupil dilation. 
797 
6. Color Vision 
798 
 
Desaturated (Lanthony D15) 
799 
7. Spectral Domain Optical Coherence Tomography (SD-OCT) 
800 
 
Volume Scan  
801 
 
Vertical and Horizontal Scan  
802 
 
If unable to perform OCT testing on the Heidelberg Spectralis, a site may use the 
803 
handheld Bioptogen/Envisu to perform OCT testing for qualitative purposes with 
804 
approval from the Coordinating Center. 
805 
8. Axial Length and Corneal Curvature Measurements 
806 
9. Optos Fundus Autofluorescence (FAF)* 
807 

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10. Full-field Electroretinogram (ffERG)* 
808 
 
Complete at 48-Month Follow-up Visit Only 
809 
11. Full-field Stimulus Threshold (FST)* 
810 
5.3.1.1 Age-Up Procedures 
811 
Participants in the Younger Age Cohort who turn 8 years old (age-up) during the NHS study 
812 
period should attempt to have static perimetry, microperimetry, and contrast sensitivity 
813 
testing performed at the next study visit after they turn 8 years old and at every subsequent 
814 
visit, until the end of the study period. 
815 
12. Static Perimetry (SP) 
816 
13. Fundus Guided Microperimetry (MP)*  
817 
14. Contrast Sensitivity 
818 
Note: All testing procedures are to be attempted for participants in the Younger Age Cohort. 
819 
If a child is unwilling to or unable to complete an examination, the procedure is to be 
820 
skipped. 
821 
*If a site does not have the required equipment, participation in this test may be waived with 
822 
approval from the Coordinating Center. 
823 
5.3.2 Vision Cohorts 1 & 2 
824 
1. Medical updates to include: 
825 
 
New or changed adverse events (AEs) 
826 
 
New ocular procedures 
827 
 
New or changed medications 
828 
2. Patient Reported Outcomes (PROs) 
829 
 
Complete at 24-Month and 48-Month Follow-up Visits Only  
830 
 
Adults (18+ years at Baseline): PROMIS®-29, MRDQ, ViSIO-PRO 
831 
 
Adolescents (12-17 years at Baseline): LVP-FVQ II, ViSIO-PRO 
832 
 
Children (8-11 years at Baseline): LVP-FVQ II, ViSIO-ObsRO 
833 
 
The PROs may be completed in person or remotely (phone or other remote 
834 
methods) any time within the Allowable Window of the associated visit (not 
835 
required to be the same day as the rest of the Follow-up Visit). 
836 
3. Complete ophthalmic examination to include: 
837 
 
Slit lamp biomicroscopy  
838 
 
Indirect ophthalmoscopy  
839 
4. Visual Acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed) 
840 

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 
The visual acuity (VA) letter score will determine whether LLVA or BRVT will 
841 
be performed. The criteria are defined in the Uni-Rare Clinical Site Manual of 
842 
Procedures. 
843 
5. Intraocular Pressure (IOP) 
844 
 
IOP measurements are to be taken prior to pupil dilation. 
845 
6. Color Vision 
846 
 
Desaturated (Lanthony D15) 
847 
7. Contrast Sensitivity 
848 
8. Spectral Domain Optical Coherence Tomography (SD-OCT) 
849 
 
Volume Scan  
850 
 
Vertical and Horizontal Scan  
851 
9. Axial Length and Corneal Curvature Measurements 
852 
 
Only individuals who are under 18 years old at the Baseline Visit will continue to 
853 
have measurements taken at every annual visit until study completion. 
854 
10. Optos Fundus Autofluorescence (FAF)* 
855 
11. Full-field Electroretinogram (ffERG)* 
856 
 
Complete at 48-Month Follow-up Visit Only 
857 
12. Full-field Stimulus Threshold (FST)* 
858 
13. Static Perimetry (SP) 
859 
14. Fundus Guided Microperimetry (MP)* 
860 
*If a site does not have the required equipment, participation in this test may be waived with 
861 
approval from the Coordinating Center. 
862 
5.3.3 Vision Cohort 3 
863 
Phone contact will be scheduled at 12-, 24-, and 36-Month intervals. The purpose of the 
864 
phone contact will be to keep the participants engaged in the study during the interim 
865 
between the Baseline and 48-Month Follow-up Visits and to keep contact information 
866 
updated. Changes in medications and AEs will also be collected. 
867 
The following will only be performed at 48-Month Visit: 
868 
1. Medical updates to include 
869 
 
New or changed adverse events (AEs) 
870 
 
New ocular procedures 
871 
 
New or changed medications 
872 
2. Patient Reported Outcomes (PROs) 
873 
 
Adults (18+ years at Baseline): PROMIS®-29, MRDQ, ViSIO-PRO, ULV-
874 
VFQ-50 
875 

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 
Adolescents (12-17 years at Baseline): LVP-FVQ II, ViSIO-PRO 
876 
 
Children (8-11 years at Baseline): LVP-FVQ II, ViSIO-ObsRO 
877 
 
The PROs may be completed in person or remotely (phone or other remote 
878 
methods) any time within the Allowable Window of the associated visit (not 
879 
required to be the same day as the rest of the Follow-up Visit). 
880 
3. Complete ophthalmic examination to include: 
881 
 
Slit lamp biomicroscopy  
882 
 
Indirect ophthalmoscopy  
883 
4. Visual Acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed) 
884 
 
The visual acuity (VA) letter score will determine whether LLVA or BRVT will 
885 
be performed. The criteria are defined in the Uni-Rare Clinical Site Manual of 
886 
Procedures. 
887 
5. Intraocular Pressure (IOP) 
888 
 
IOP measurements are to be taken prior to pupil dilation. 
889 
6. Spectral Domain Optical Coherence Tomography (SD-OCT)  
890 
 
Volume Scan  
891 
 
Vertical and Horizontal Scan   
892 
7. Axial Length and Corneal Curvature Measurements 
893 
 
Only individuals who were under 18 years old at the Baseline Visit will have 
894 
measurements taken at 48M visit. 
895 
8. Optos Fundus Autofluorescence (FAF)* 
896 
9. Full-field Stimulus Threshold (FST)* 
897 
*If a site does not have the required equipment, participation in this test may be waived with 
898 
approval from the Coordinating Center. 
899 
5.3.4 Unscheduled Visits 
900 
Testing procedures at unscheduled visits are at the Investigator’s discretion. However, it is 
901 
recommended that procedures performed during these visits follow the standard protocol for 
902 
each procedure and be performed by certified personnel. Unscheduled visits will be recorded on 
903 
the FFB Consortium study website. Study images taken during unscheduled visits do not require 
904 
submission to the study website. 
905 
 
 
906 

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Chapter 6: Testing Procedures and Questionnaires 
907 
6.1 Study Procedure Requirements 
908 
The study procedure instructions are detailed in the Uni-Rare Clinical Site Manual of 
909 
Procedures. An overview of the equipment and certification requirements for all testing are 
910 
provided in the table below. 
911 
Study Procedures 
Description 
Equipment 
Required 
(If applicable) 
Site Personnel 
Delegation 
Investigator taking 
overall responsibility for a 
visit 
Oversees that consent process was 
performed in accordance with 
IRB/EC requirements; signs off on 
all eCRFs for a participant, eCRF 
edits, and protocol deviations. 
N/A 
Certified investigator 
Coordinator taking 
responsibility for the visit  
Oversees the data entry aspect of the 
visit; addresses protocol queries and 
signs off on deviations. 
N/A 
Certified coordinator 
Informed Consent Form 
(ICF) Process 
Explanation/review of study with 
the potential participant, including 
signature on the ICF. 
N/A 
Certified investigator or 
coordinator as permitted 
by the IRB/EC 
Signature of Informed 
Consent Form 
The participant and/or LAR sign the 
ICF. The person obtaining the ICF 
will also sign. 
N/A 
Certified investigator or 
coordinator as permitted 
by the IRB/EC 
Data entry on study 
website 
Data collected from the study 
participant will be directly entered 
on the FFB Study Website (strongly 
encouraged) or written on the paper 
CRF and transcribed on the FFB 
Study Website within seven (7) 
days. 
Computer and 
internet 
connection 
Certified coordinator or 
certified investigator with 
additional study website 
certification  
Collect information 
regarding medical history, 
demographics, adverse 
events, medications 
Sites will collect medical history, 
demographic information, Aes, and 
medications from the participant 
during each visit. This information 
can be confirmed by requesting 
medical records if needed. 
N/A 
Certified investigator or 
coordinator 
Patient Reported 
Outcome (PRO) 
There are six (6) questionnaires 
depending on age and Vision Cohort 
(details in section 6.2).   
Study will 
provide 
Certified investigator or 
coordinator 
Ocular Exam  
Including slit lamp biomicroscopy 
and indirect ophthalmoscopy 
Any equipment 
is acceptable 
Certified investigator 
Intraocular Pressure 
(IOP) 
Measurement of the fluid pressure 
inside the eye 
Any equipment 
is acceptable 
Clinical site personnel 
performing this test does 
not require a study 
specific certification. 
However, they must be 
trained and delegated by 
the PI per the SSDL. 

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Study Procedures 
Description 
Equipment 
Required 
(If applicable) 
Site Personnel 
Delegation 
Visual Acuity – 
Refraction  
Refraction is done as a routine part 
of an eye exam to achieve best 
corrected visual acuity measures. 
N/A 
Clinical site personnel 
certified for refraction 
Visual Acuity – ETDRS  
Traditional measure of central 
visual function that represents 
foveal cone function. 
EVA system or 
ETDRS charts 
Clinical site personnel 
certified for VA 
(including ETDRS) 
Visual Acuity – LLVA  
Measures vision function in low 
luminance conditions 
EVA system or 
ETDRS charts 
2.0 neutral 
density filter to 
be provided by 
study 
Clinical site personnel 
certified for VA 
(including LLVA) 
Visual Acuity – BRVT  
A three-level hierarchy for visual 
acuity testing better suited for low 
vision participants 
BRVT charts 
provided by 
study 
Clinical site personnel 
certified for BRVT 
Visual Acuity – HOTV 
Pediatric measure of central visual 
function that represents foveal cone 
function. 
HOTV chart and 
lap card 
provided by 
study 
Clinical site personnel 
certified for VA 
(including HOTV) 
Color Vision 
Measures the type and severity of 
color blindness  
Lanthony D15 
provided by 
study 
Clinical site personnel 
performing this test does 
not require a study 
specific certification. 
However, they must be 
trained and delegated by 
the PI per the SSDL. 
Contrast Sensitivity 
Measure ability to distinguish 
between increments of light versus 
dark 
CSV-1000E 
provided by 
study 
Clinical site personnel 
performing this test does 
not require a study 
specific certification. 
However, they must be 
trained and delegated by 
the PI per the SSDL. 
Spectral Domain Optical 
Coherence Tomography 
(SD-OCT) – Volume Scan  
Scans provide objective, non-
invasive measures of retinal 
structure 
Heidelberg 
Spectralis** 
Clinical site personnel 
certified for SD-OCT 
Spectral Domain Optical 
Coherence Tomography 
(SD-OCT) – Vertical and 
Horizontal Scan  
Scans provide objective, non-
invasive measures of retinal 
structure 
Heidelberg 
Spectralis** 
Clinical site personnel 
certified for SD-OCT and 
vertical and horizontal 
scan 
Axial Length and Corneal 
Curvature 
Axial length measures the distance 
between the anterior and posterior 
poles of the eye. Corneal curvature 
determines the power of the cornea. 
Any equipment 
is acceptable 
Clinical site personnel 
performing this test does 
not require a study 
specific certification. 
However, they must be 
trained and delegated by 
the PI per the SSDL. 

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Study Procedures 
Description 
Equipment 
Required 
(If applicable) 
Site Personnel 
Delegation 
Optos Color Photos 
Images provide objective, non-
invasive visualization of the 
photoreceptor layer and RPE 
Optos* 
Clinical site personnel 
certified for Optos Color 
photos 
Optos Fundus 
Autofluorescence (FAF) 
Images provide objective, non-
invasive map of lipofuscin in RPE 
Optos* 
Clinical site personnel 
certified for Optos FAF 
Full-field 
Electroretinogram 
(ffERG) 
Measures rod- and cone-mediated 
parts of the visual field 
Diagnosys 
Espion*  
Clinical site personnel 
certified for ffERG 
Full-field Stimulus 
Threshold (FST) 
Measures rod- and cone-mediated 
parts of the visual field 
Diagnosys 
Espion* 
Clinical site personnel 
performing this test does 
not require a study 
specific certification. 
However, they must be 
trained and delegated by 
the PI per the SSDL. 
Static Perimetry (SP) 
Measures sensitivity thresholds at 
specified test locations 
Octopus 900 Pro 
(GATE 
Protocol) 
Clinical site personnel 
certified for SP 
Fundus guided 
microperimetry (MP) 
Measures sensitivity thresholds at 
specified test locations 
MAIA* 
Clinical site personnel 
certified for MP 
Kinetic Perimetry (KP) 
Measures sensitivity thresholds at 
specified test locations 
Any equipment 
is acceptable 
(Historical) Does not need 
to be performed by study 
certified personnel or 
recorded in the SSDL 
*If site does not have required equipment, participation in this test may be waived with 
912 
approval from the Coordinating Center 
913 
**If Younger Age Cohort participant is unable to perform OCT testing on the Heidelberg 
914 
Spectralis, a site may use the handheld Bioptogen/Envisu to perform OCT testing for qualitative 
915 
purposes with approval from the Coordinating Center. 
916 
6.2 Questionnaires 
917 
The following questionnaires will be administered in the study by a certified investigator or 
918 
coordinator. Each questionnaire takes about 15 minutes to administer. 
919 
Questionnaire 
Type 
Description 
Vision 
Cohort 
Age at 
Baseline 
Michigan Retinal 
Degeneration 
Questionnaire 
(MRDQ) 
Vision 
Function 
The MRDQ is a psychometrically validated patient-
reported outcome measure for inherited retinal 
degenerations questionnaire which consists of fifty-
nine (59) questions measuring seven (7) 
unidimensional domains: central vision, color vision, 
contrast sensitivity, scotopic function, photopic 
peripheral vision, mesopic peripheral vision, and 
photosensitivity. 
All 
Adults  
≥18 years 

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PROMIS-29® 
(Patient-Reported 
Outcomes 
Measurement 
Information 
System®) 
Global 
Physical, 
Mental, 
and Social 
Health 
The PROMIS®-29 contains items from seven 
PROMIS domains: depression; anxiety; physical 
function; pain interference; fatigue; sleep 
disturbance; and ability to participate in social roles 
and activities. The seven domains cover the most 
relevant areas of self-reported health for most people 
with chronic illness. There is also one 11-point rating 
scale for pain intensity. 
All 
Adults  
≥18 years 
Visual Symptom 
and Impact 
Outcomes Patient 
Reported Outcome 
(ViSIO-PRO) 
Vision 
Function 
and 
HRQoL 
The ViSIO-PRO instrument is designed to assess 
visual function symptoms, impacts on functional 
vision, and impacts on wider health-related quality of 
life (HRQoL). It has been designed for completion 
by adolescents (12-17) and adults (18 +) with retinitis 
pigmentosa (RP). 
All 
Adolescents 
(12-17 years)  
& Adults 
(≥18 years) 
Visual Symptom 
and Impact 
Outcomes Observer 
Reported Outcome 
(ViSIO-ObsRO) 
Vision 
Function 
and 
HRQoL 
The ViSIO-ObsRO instrument is designed to assess 
visual function symptoms, impacts on functional 
vision, and impacts on wider health-related quality of 
life (HRQoL). It has been designed for completion 
by parents/caregivers of children with retinitis 
pigmentosa (RP) aged 3-11 years. 
All 
Children  
4-11 years 
L. V. Prasad-
Functional Vision 
Questionnaire 
(LVP-FVQ II) 
Vision 
Function 
The LVP-FVQ-II questionnaire consists of 23 
questions. The questionnaire is used to assess self-
reported difficulties in performing daily tasks in 
children with visual impairment. 
All  
Adolescents 
(12-17 years)  
& Children 
(8-11 years) 
Ultra-Low Vision 
Visual Functioning 
Questionnaire  
(ULV-VFQ-50) 
Vision 
Function 
The ULV-VFQ-50 psychometrically evaluates a 
visual functioning questionnaire (VFQ) in an ultra-
low vision (ULV) population 
Vision 
Cohort 
3 
Adults  
≥18 years 
 
 
920 

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Chapter 7: Unanticipated Problem and 
921 
Adverse Event Reporting 
922 
7.1 Unanticipated Problems 
923 
Site investigators will promptly report all unanticipated problems meeting the criteria below on 
924 
an electronic case report form (eCRF). Sites overseen by the JCHR IRB must report 
925 
Unanticipated Problems to the IRB within seven (7) calendar days of recognition. For this 
926 
protocol, an unanticipated problem is an incident, experience, or outcome that meets all the 
927 
following criteria: 
928 
 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
929 
procedures that are described in the protocol related documents, such as the IRB-
930 
approved research protocol and informed consent document; and (b) the 
931 
characteristics of the subject population being studied. 
932 
 
Related or possibly related to participation in the research (possibly related means 
933 
there is a reasonable possibility that the incident, experience, or outcome may have 
934 
been caused by the procedures involved in the research). 
935 
 
Suggests that the research places participants or others at a greater risk of harm than 
936 
was previously known or recognized (including physical, psychological, economic, or 
937 
social harm). 
938 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
939 
involving a specific site such as unanticipated problems that occur at the Coordinating Center or 
940 
at another participating entity such as a laboratory.  
941 
These instances must be reported to the JCHR IRB within seven (7) calendar days of recognition. 
942 
The Director of the Human Research Protection Program (HRPP) will report to the appropriate 
943 
regulatory authorities if the IRB determines that the event indeed meets the criteria of an 
944 
Unanticipated Problem that requires further reporting to fulfill the reporting obligations of the 
945 
HRPP. 
946 
7.2 Adverse Events 
947 
The following section on adverse events applies to the Natural History Study phase of the 
948 
study.   
949 
7.2.1 Definitions 
950 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) 
951 
associated with study procedures whether the event is considered related. 
952 
Serious Adverse Event (SAE): Any untoward medical occurrence that results in any of the 
953 
following outcomes: 
954 
 
Death. 
955 
 
A life-threatening adverse event: (a non-life-threatening event which, had it been 
956 
more severe, might have become life-threatening, is not necessarily considered a 
957 
serious adverse event). 
958 

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 
Inpatient hospitalization or prolongation of existing hospitalization. 
959 
 
A persistent or significant disability/incapacity or substantial disruption of the ability 
960 
to conduct normal life functions. 
961 
 
A congenital anomaly or birth defect. 
962 
An important medical event that may not result in death, be life-threatening, or require 
963 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
964 
may jeopardize the patient or subject and may require medical and surgical intervention to 
965 
prevent one of the outcomes listed in this definition.  
966 
Note: As this is a Natural History Study, the Investigator(s) will make the categorical 
967 
determinations of Adverse Events, as described above, and will report each determination to the 
968 
Coordinating Center, as per data collection. 
969 
7.2.2 Reportable Adverse Events 
970 
For this protocol, a reportable adverse event includes all events meeting the definition of an 
971 
adverse event. 
972 
All reportable Adverse Events whether volunteered by the participant, discovered by study 
973 
personnel during questioning, or detected through ophthalmological examination, laboratory test, 
974 
or other means will be reported on an adverse event form online. 
975 
The purpose of AE collection for the Uni-Rare study will be to provide historical controls for 
976 
future clinical trials. As a no greater than minimal risk study, AEs do not require any specific 
977 
reporting to regulatory or oversight bodies. However, each Principal Investigator (PI) is 
978 
responsible for abiding by any other reporting requirements specific to their IRB or equivalent 
979 
ethics oversight committee. 
980 
7.2.3 Relationship of Adverse Event to Study Procedure 
981 
The study Investigator(s) will assess the relationship of any adverse event to be related or 
982 
unrelated to a study procedure by determining if there is a reasonable possibility that the adverse 
983 
event may have been caused by the study procedure.  
984 
To ensure consistency of adverse event causality assessments, the Investigator(s) should apply 
985 
the following general guideline when determining whether an adverse event is related: 
986 
Yes 
987 
There is a plausible temporal relationship between the onset of the adverse event and the study 
988 
procedure, and the adverse event cannot be readily explained by the participant’s clinical state, 
989 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
990 
of response to the study procedure; and/or the adverse event abates or resolves upon 
991 
discontinuation of the study procedure. 
992 
No 
993 
Evidence exists that the adverse event has an etiology other than the study procedure (for 
994 
example, preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
995 
medication); and/or the adverse event has no plausible temporal relationship to study procedure. 
996 

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7.2.4 Severity (Intensity) of Adverse Event 
997 
A severity assessment is a clinical determination of the intensity of an event. Thus, a severe 
998 
adverse event is not necessarily serious. For example, itching for several days may be rated as 
999 
severe, but may not be clinically serious.  
1000 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) 
1001 
moderate, or (3) severe. 
1002 
1. MILD: Usually transient, requires no special treatment, and does not interfere with 
1003 
the participant’s daily activities. 
1004 
2. MODERATE: Usually causes a low level of inconvenience, discomfort or concern 
1005 
to the participant and may interfere with daily activities but is usually ameliorated by 
1006 
simple therapeutic measures and participant is able to continue in study. 
1007 
3. SEVERE: Interrupts a participant’s usual daily activities and causes severe 
1008 
discomfort. 
1009 
7.2.5 Expectedness 
1010 
As this is a Natural History Study, the expectedness for a serious adverse event will not be 
1011 
assessed. 
1012 
7.2.6 Coding of Adverse Events 
1013 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
1014 
(MedDRA). To facilitate coding, the site will enter a preliminary MedDRA code 
1015 
7.2.7 Outcome of Adverse Event 
1016 
The outcome of each reportable adverse event will be classified by the Investigator(s) as follows: 
1017 
1. RECOVERED/RESOLVED (COMPLETE RECOVERY) – The participant 
1018 
recovered from the AE/SAE without sequelae. Record the AE/SAE stop date. 
1019 
2. RECOVERED/RESOLVED WITH SEQUELAE – AE/SAE where the subject 
1020 
recuperated but retained pathological conditions resulting from the prior disease or 
1021 
injury. Record the AE/SAE stop date. 
1022 
3. FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the 
1023 
event that was the cause of death should be reported as fatal. AEs/SAEs that were 
1024 
ongoing at the time of death; however, were not the cause of death, will be recorded 
1025 
as “resolved” at the time of death. 
1026 
4. ONGOING NOT RECOVERED/NOT RESOLVED – An ongoing AE/SAE is 
1027 
defined as an ongoing event with an undetermined outcome. 
1028 
 
An ongoing outcome will require follow-up by the site in order to determine the 
1029 
final outcome of the AE/SAE. 
1030 
 
The outcome of an ongoing event at the time of death that was not the cause of 
1031 
death, will be updated and recorded as “resolved” with the date of death recorded 
1032 
as the stop date. 
1033 

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5. ONGOING (MEDICALLY STABLE) – AE/SAE is ongoing, but medically stable. 
1034 
For example, a chronic condition where no further change is expected. 
1035 
If any reported adverse events are ongoing when a participant completes the study (or 
1036 
withdraws), they will be followed until they are either resolved, or have no prospect of 
1037 
improvement or change, even after the participant has completed all applicable study 
1038 
visits/contacts. For all other adverse events, data collection will end at the time the participant 
1039 
completes the study.  
1040 
Note: Participants should continue to receive appropriate medical care for an adverse event after 
1041 
their participation in the study ends. 
1042 
If a participant is lost to follow up and participant outcome cannot be determined, outcome 
1043 
classification will be the last known outcome. 
1044 
7.3 Timing of Event Reporting 
1045 
Investigator(s) are responsible for reporting Adverse Events on the electronic case report form 
1046 
(eCRF) through the study website in a timely manner. 
1047 
Each Principal Investigator (PI) is responsible for reporting serious study-related adverse events 
1048 
and abiding by any other reporting requirements specific to his/her Institutional Review Board 
1049 
(IRB) or Ethics Committee (EC). Where the JCHR IRB is the overseeing IRB, sites must report 
1050 
all serious, related adverse events regardless of whether they are expected/anticipated and 
1051 
regardless of whether they are fatal or life-threatening within seven (7) calendar days. 
1052 
 
 
1053 

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Chapter 8: Miscellaneous Considerations 
1054 
8.1 New or Ongoing Medical Conditions and Medications 
1055 
8.1.1 Pre-Existing Conditions  
1056 
Any medical condition that is either present at screening, a chronic disease, or a prior condition 
1057 
that could impact the participant’s health during the study (for example, prior myocardial 
1058 
infarction or stroke). 
1059 
8.1.2 Medications 
1060 
All medication for the treatment of chronic pre-existing conditions, medical conditions, and/or 
1061 
adverse events that the participant is currently taking at screening and during the study should be 
1062 
recorded. Certain nutraceuticals and preventative treatments that are of interest to the study 
1063 
should also should be recorded. 
1064 
8.1.3 Medical Conditions During the Natural History Study  
1065 
In addition to conditions meeting the reporting requirements for an adverse event or as described 
1066 
above, the following medical conditions should also be reported: (1) new diagnosis of a chronic 
1067 
disease (for example, not present at the time of enrollment), and (2) any medical condition that 
1068 
could affect the participant’s ability to carry out any aspect of the protocol or could affect an 
1069 
outcome assessment. These will be reported as adverse events. See chapter 7 for more detail. 
1070 
8.2 Prohibited Medications, Treatments, and Procedures During the Natural History Study 
1071 
8.2.1 Prohibited Medications and Treatment for Retinal Degeneration 
1072 
Participants who are enrolled into the NHS should not administer IRD treatments during the 
1073 
study. This includes enrolling into an experimental treatment trial of underlying conditions 
1074 
related to the causal gene during the 4-year study duration. However, if the participants enroll in 
1075 
a treatment trial the Executive Committee will be consulted and will determine if the participant 
1076 
will continue in the study. 
1077 
Examples of prohibited medications and treatments include, but are not limited to the following: 
1078 
 
use of ocular stem cell or gene therapy 
1079 
 
ocriplasmin 
1080 
 
ophthalmic oligonucleotide 
1081 
 
Ozurdex (dexamethasone) 
1082 
 
Iluvien 
1083 
 
Yutiq (fluocinolone acetonide) intravitreal implant 
1084 
8.2.2 Intraocular Surgical Procedures  
1085 
Participants enrolled into the NHS, who have intraocular surgery during the study, will have 
1086 
follow-up visits timed either before the surgery date or at least three (3) months after the surgery 
1087 
date, to minimize the impact on the natural history outcome measures. Clinical sites will make 
1088 
reasonable efforts to schedule the participant’s follow-up visit as close to the visit target window 
1089 
as possible. 
1090 

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8.2.3 Treatment for Cystoid Macular Edema (CME) 
1091 
Participants enrolled into the NHS, who need to receive treatment for CME during the study, 
1092 
may do so without affecting their participation in the study. 
1093 
8.3 Pregnancy Reporting  
1094 
If a pregnancy occurs, the participant will remain in the study. The occurrence of pregnancy will 
1095 
be reported to the Coordinating Center within seven (7) days of the site’s discovery of the 
1096 
pregnancy (including at screening) and the Confirmed Pregnancy Notification Worksheet will be 
1097 
completed within seven (7) calendar days. Sites will collect concomitant medications throughout 
1098 
the pregnancy. If an Adverse Event occurs because of the pregnancy, then the site will record the 
1099 
Adverse Event on the Adverse Event form.  
1100 
8.4 Participant Compensation 
1101 
Participant compensation will be specified in the informed consent form. 
1102 
8.5 Participant Withdrawal 
1103 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1104 
participants who withdraw, their data will be used up until the time of withdrawal. 
1105 
8.6 Confidentiality 
1106 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1107 
used instead of their name. Protected health information (PHI) gathered for this study will be 
1108 
shared with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-
1109 
identified participant information may also be provided to research sites involved in the study. 
1110 

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Chapter 9: Statistical Considerations 
1111 
The approach to sample size (N) and statistical analyses are summarized below. 
1112 
9.1 Sample Size Approach 
1113 
The following is a framework for evaluating and justifying within-gene sample size for any gene 
1114 
in the Uni-Rare Study.   
1115 
9.1.1 General Considerations 
1116 
Both eyes of a participant will be assessed for the main ocular measures of interest. Thus, if there 
1117 
are N participants, 2N eyes will be available for analysis. However, outcome measures from two 
1118 
(2) eyes of a person are typically strongly correlated (r ≥0.5). The contribution of information 
1119 
from the two (2) eyes in this case is (2/(1+r)) instead of two (2). Values for the multiplier to the 
1120 
number of participants to obtain an effective sample size are given below in Table 9-1. The 
1121 
correlation between eyes (inter-eye correlation) for each outcome measure is not known. We 
1122 
assume an inter-eye correlation of 0.8 throughout all sample size calculations throughout section 
1123 
1.1. This assumption is conservative in that it requires a higher number of participants than lower 
1124 
plausible values of r.  
1125 
Table 9-1. Multiplier to Obtain Effective N Based on Inter-Eye Correlation   
1126 
r 
0.0 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
1.0 
Multiplier for 
Effective N 
2.00 
1.82 
1.67 
1.54 
1.43 
1.33 
1.25 
1.18 
1.11 
1.05 
1.00 
9.1.2 Registry Sample Size Considerations 
1127 
As noted in section 2.1, the Registry recruitment will remain open until a total of 1,500 
1128 
participants meeting Registry Cohort Criteria are enrolled, with a maximum of 100 
1129 
participants enrolled within any gene. The following Registry sample size considerations 
1130 
focus on Registry Objective 2 (see section 1.3). 
1131 
Registry Objective 2 (Cross-Sectional Phenotype Characterization) 
1132 
 Registry Objective 2 is to characterize cross-sectional retinal dystrophy associated with 
1133 
disease-causing genetic variants using functional and structural measures, within gene.    
1134 
 For a given gene, the potential sample size for the gene will impact the precision around 
1135 
the point estimates for the key measures of interest.  
1136 
 Table 9-2, 9-3, and 9-4 provide the half-width of the 95% confidence interval (CI) 
1137 
around the estimated cross-sectional mean value, for three key measures of interest 
1138 
(visual acuity, OCT EZ area, and SP Vtot, respectively) under different possible sample 
1139 
sizes and standard deviations (SD) of the distribution of the cross-sectional measure. The 
1140 
larger the SD and/or the smaller the sample size, the wider the CI, meaning the range of 
1141 
possible true values grows.   
1142 

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Table 9-2.  Half-Width of 95% Confidence Intervals Around the Estimated Mean Cross-
1143 
Sectional Visual Acuity   
1144 
 
Sample Size 
 (effective sample size after adjusting for inter-eye correlation r=0.8) 
 
N=10 
N=20 
N=30 
N=40 
N=50 
N=60 
N=70 
N=80 
N=90 
N=100 
 
 (11) 
 (22) 
 (33) 
 (44) 
 (56) 
 (67) 
 (78) 
 (89) 
 (100) 
 (111) 
SD=5 
3.4 
2.2 
1.8 
1.5 
1.3 
1.2 
1.1 
1.1 
1.0 
0.9 
SD=10 
6.7 
4.4 
3.5 
3.0 
2.7 
2.4 
2.3 
2.1 
2.0 
1.9 
SD=15 
10.1 
6.7 
5.3 
4.6 
4.0 
3.7 
3.4 
3.2 
3.0 
2.8 
SD=20 
13.4 
8.9 
7.1 
6.1 
5.4 
4.9 
4.5 
4.2 
4.0 
3.8 
Units = letter score  
1145 
Table 9-3.  Half-Width of 95% Confidence Intervals Around the Estimated Mean Cross-
1146 
Sectional OCT Ellipsoid Zone Area  
1147 
 
Sample Size 
 (effective sample size after adjusting for inter-eye correlation r=0.8) 
 
N=10 
N=20 
N=30 
N=40 
N=50 
N=60 
N=70 
N=80 
N=90 
N=100 
 
 (11) 
 (22) 
 (33) 
 (44) 
 (56) 
 (67) 
 (78) 
 (89) 
 (100) 
 (111) 
SD=2 
1.3 
0.9 
0.7 
0.6 
0.5 
0.5 
0.5 
0.4 
0.4 
0.4 
SD=5 
3.4 
2.2 
1.8 
1.5 
1.3 
1.2 
1.1 
1.1 
1.0 
0.9 
SD=8 
5.4 
3.5 
2.8 
2.4 
2.1 
2.0 
1.8 
1.7 
1.6 
1.5 
SD=10 
6.7 
4.4 
3.5 
3.0 
2.7 
2.4 
2.3 
2.1 
2.0 
1.9 
Units = mm2 
1148 
Table 9-4.  Half-Width of 95% Confidence Intervals Around the Estimated Mean Cross-
1149 
Sectional Static Perimetry Vtot (Hill of Vision)  
1150 
 
Sample Size 
 (effective sample size after adjusting for inter-eye correlation r=0.8) 
 
N=10 
N=20 
N=30 
N=40 
N=50 
N=60 
N=70 
N=80 
N=90 
N=100 
 
 (11) 
 (22) 
 (33) 
 (44) 
 (56) 
 (67) 
 (78) 
 (89) 
 (100) 
 (111) 
SD=10 
6.7 
4.4 
3.5 
3.0 
2.7 
2.4 
2.3 
2.1 
2.0 
1.9 
SD=15 
10.1 
6.7 
5.3 
4.6 
4.0 
3.7 
3.4 
3.2 
3.0 
2.8 
SD=20 
13.4 
8.9 
7.1 
6.1 
5.4 
4.9 
4.5 
4.2 
4.0 
3.8 
SD=25 
16.8 
11.1 
8.9 
7.6 
6.7 
6.1 
5.6 
5.3 
5.0 
4.7 
Units = dB-sr 
1151 
 
1152 
 
1153 
 
1154 
 
1155 
 
1156 
Registry Sample Size Example  
1157 

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The following is an example of using the tables above and a set of assumptions for a given gene 
1158 
of interest to determine the precision of cross-sectional estimates of key measures.  
1159 
Gene  
BBS1 
Anticipated Sample Size 
50 
Key Measure 
Assumed Standard 
Deviation (SD) 
Precision around estimated mean 
value (half-width of 95% CI) 
Visual Acuity  
10 
2.7 
OCT EZ Area  
5 
1.3 
SP Vtot            
20 
5.4 
Assumptions based on Mean (standard deviation) of RUSH2A baseline Vtot, VA, and OCT EZ 
1160 
RUSH2A shown below 
1161 
 
Overall 
USH2 
ARRP 
VA 
77.9 (11.7) 
76.5 (12.4) 
80.3 (10.2) 
OCT EZ area 
3.6 (5.6) 
3.1 (5.7) 
4.3 (5.6) 
SP Vtot 
27.8 (23.7) 
22.5 (21.5) 
37.1 (24.7) 
9.1.3 Natural History Study Sample Size Considerations  
1162 
As noted in section 4.1, the designation of NHS Target Genes will be made by the Executive 
1163 
Committee on an ongoing basis and may depend on funding resources as well as Registry 
1164 
enrollment numbers within gene. The Natural History Study sample size for each gene will 
1165 
depend on the Registry enrollment.  Since the within-gene Registry limit is 100 participants, this 
1166 
will be the maximum sample size for NHS Target Genes.  
1167 
The following NHS sample size considerations focus on NHS Objectives 1-3 (see section 1.3).  
1168 
For all of these objectives, the following principles will apply in the sections below: 
1169 
 For simplicity across all measures, percent change will be considered for sample size 
1170 
justification purposes.  
1171 
 Also for simplicity, although statistical analyses will include the data from each annual 
1172 
visit, change from baseline to four (4) years will be considered for sample size 
1173 
justification purposes.  
1174 
 This simplistic approach will produce conservative estimates, in terms of precision.  
1175 
Future work will include exploring impact of sample sizes on these estimates when using 
1176 
all available longitudinal data, for example, how much will this improve precision. This 
1177 
will be documented separately.  
1178 

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NHS Objective 1 (Natural History) 
1179 
 NHS Objective 1 is to characterize the natural history of retinal degeneration associated 
1180 
with disease-causing genetic variants over 4 years, using functional, structural, and 
1181 
patient-reported outcome measure, within gene.    
1182 
 For a given gene, the potential sample size for the gene will impact the precision around 
1183 
the point estimates for changes in the outcome measures of interest.   
1184 
 Table 9-5 provides the half-width of the 95% confidence interval (CI) around the 
1185 
estimated percent change in outcome measures under different possible sample sizes and 
1186 
standard deviations (SD) of the distribution of the percent change for any given outcome 
1187 
measure. The larger the SD and/or the smaller the sample size, the wider the CI, meaning 
1188 
the range of possible true values grows.   
1189 
Table 9-5. Half-Width of 95% Confidence Intervals Around the Estimated Percent Change 
1190 
 
Sample Size 
 (effective sample size after adjusting for inter-eye correlation r=0.8) 
 
N=10 
N=20 
N=30 
N=40 
N=50 
N=60 
N=70 
N=80 
N=90 
N=100 
 
 (11) 
 (22) 
 (33) 
 (44) 
 (56) 
 (67) 
 (78) 
 (89) 
 (100) 
 (111) 
SD=5% 
3% 
2% 
2% 
2% 
1% 
1% 
1% 
1% 
1% 
1% 
SD=10% 
7% 
4% 
4% 
3% 
3% 
2% 
2% 
2% 
2% 
2% 
SD=20% 
13% 
9% 
7% 
6% 
5% 
5% 
5% 
4% 
4% 
4% 
SD=30% 
20% 
13% 
11% 
9% 
8% 
7% 
7% 
6% 
6% 
6% 
SD=40% 
27% 
18% 
14% 
12% 
11% 
10% 
9% 
8% 
8% 
8% 
SD=50% 
34% 
22% 
18% 
15% 
13% 
12% 
11% 
11% 
10% 
9% 
SD=60% 
40% 
27% 
21% 
18% 
16% 
15% 
14% 
13% 
12% 
11% 
 
1191 
NHS Objective 2 (Structure-Function Relationship) 
1192 
 NHS Objective 2 is to explore whether structural outcome measures can be validated as 
1193 
surrogates for functional outcomes in individuals with disease-causing genetic variants, 
1194 
within gene.    
1195 
 For a given gene, the potential sample size for the gene will impact the precision around 
1196 
the point estimates for the correlation between the outcome measures of interest.   
1197 
 Table 9-6 provides the 95% confidence intervals around the estimated correlation 
1198 
between outcome measures under different possible sample sizes and Pearson correlation 
1199 
coefficients.  
1200 
o The Pearson correlation coefficient (r) can be used to assess the correlation 
1201 
between two different outcome measures. The distribution of r is not symmetric; 
1202 
therefore, CIs for the estimated correlation coefficient are not symmetric. A 
1203 
transformation of r (z = 0.5 * ln ((1+r)/1-r)) is used to create a variable that is 
1204 
asymptotically distributed N (0, 1/(sqrt(N-3))) under the null hypothesis that r=0. 
1205 
Table 9-6. 95% Confidence Intervals for an Observed Value of the Correlation between 
1206 
Outcome Measures. 
1207 

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Sample Size 
 (effective sample size after adjusting for inter-eye correlation r=0.8) 
N=10 
N=20 
N=30 
N=40 
N=50 
N=60 
N=70 
N=80 
N=90 
N=100 
 (11) 
 (22) 
 (33) 
 (44) 
 (56) 
 (67) 
 (78) 
 (89) 
 (100) 
 (111) 
r=0.3 
(-0.41,0.78) 
(-0.16,0.66) 
(-0.07,0.60) 
(-0.01,0.56) 
(0.02,0.53) 
(0.05,0.51) 
(0.07,0.50) 
(0.09,0.49) 
(0.10,0.48) 
(0.11,0.47) 
r=0.4 
(-0.31,0.82) 
(-0.05,0.72) 
(0.05,0.66) 
(0.10,0.63) 
(0.14,0.61) 
(0.16,0.59) 
(0.18,0.58) 
(0.20,0.57) 
(0.21,0.56) 
(0.22,0.55) 
r=0.5 
(-0.19,0.86) 
(0.07,0.77) 
(0.17,0.73) 
(0.22,0.70) 
(0.26,0.68) 
(0.28,0.67) 
(0.30,0.66) 
(0.31,0.65) 
(0.33,0.64) 
(0.34,0.63) 
r=0.6 
(-0.05,0.89) 
(0.21,0.82) 
(0.31,0.79) 
(0.35,0.77) 
(0.39,0.75) 
(0.41,0.74) 
(0.42,0.73) 
(0.44,0.72) 
(0.45,0.72) 
(0.46,0.71) 
r=0.7 
(0.13,0.92) 
(0.37,0.87) 
(0.45,0.85) 
(0.50,0.83) 
(0.52,0.82) 
(0.54,0.81) 
(0.56,0.80) 
(0.57,0.80) 
(0.58,0.79) 
(0.58,0.79) 
r=0.8 
(0.34,0.95) 
(0.55,0.92) 
(0.62,0.90) 
(0.65,0.89) 
(0.67,0.88) 
(0.69,0.88) 
(0.70,0.87) 
(0.70,0.87) 
(0.71,0.86) 
(0.72,0.86) 
r=0.9 
(0.62,0.98) 
(0.76,0.96) 
(0.80,0.95) 
(0.82,0.95) 
(0.83,0.94) 
(0.84,0.94) 
(0.84,0.94) 
(0.85,0.93) 
(0.85,0.93) 
(0.85,0.93) 
 
1208 
NHS Objective 3 (Risk Factors for Progression) 
1209 
 NHS Objective 3 is to explore possible risk factors (genotype, phenotype, 
1210 
environmental, and comorbidities) for progression of the outcome measures at 4 years in 
1211 
individuals with disease-causing genetic variants, within gene.    
1212 
 For a given gene, the potential sample size for the gene will impact the power to detect 
1213 
differences in changes from baseline among subgroups of interest.  
1214 
 Figure 9-1 evaluates the power to detect differences in percent change from baseline to 
1215 
four (4) years among two (2) subgroups of equally distributed sizes, under various 
1216 
assumptions of true mean difference (x-axis) and standard deviation (SD) of the 
1217 
distribution of percent change. If subgroups are not equally sized, the smallest detectable 
1218 
difference (with the same power) will be larger. All calculations are based on a Type I (α) 
1219 
error rate of 0.05.  
1220 
o For example, with a total sample size of twenty (20), assuming ten (10) in each of 
1221 
two (2) subgroups, to have power of 80% or more, the true difference needs to be 
1222 
approximately 1.25 SDs (a mean difference of 25% if the SD of the percent 
1223 
change over four (4) years 20%) 
1224 
 Also Note: Within-subgroup point estimates and CIs will also be important. Table 9-3 
1225 
above can be applied to potential subgroup sample sizes as well to consider the precision 
1226 
that would be observed.   
1227 
 
1228 
 
1229 
 
1230 
 
1231 
 
 
1232 

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Figure 9-1 Power to Detect Differences in Subgroups 
1233 
Total Sample Size N= 10 
(N=11 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
Total Sample Size N= 20 
(N=22 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
Total Sample Size N= 30 
(N=33 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
 
 
Total Sample Size N= 40 
(N=44 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
 
 
 
Total Sample Size N= 50 
(N=56 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
 
 
 
 
Total Sample Size N= 60 
(N=67 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
 
 
 
 
 
 
1234 

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Total Sample Size N= 70 
(N=78 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
Total Sample Size N= 80 
(N=89 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
Total Sample Size N= 90 
(N=100 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
Total Sample Size N= 100 
(N=111 effective sample size after adjusting for inter-eye 
correlation r=0.8) 
 
1235 
NHS Sample Size Example  
1236 
The following is an example template of using the tables above and a set of assumptions for a 
1237 
given gene of interest to determine the impact on NHS Objectives.  
1238 
Target Gene  
MYO7A 
Target Sample Size 
50 
Data to consider for 
assumptions 
Data 
• RUSH2A Data – Mean (SD) percent change at 24M 
o Visual Acuity: -2.3 (5.1)% 
o OCT EZ area: -2.2 (21.8)% 
o Static Perimetry HOV: -12.4 (28.2)%  
Assume: 
• Inter-eye correlation = 0.8 
• SD for percent change at 4 years  
o Visual Acuity  5% 
o OCT EZ area  20% 
o Static Perimetry HOV  30% 
 

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NHS Objective 1 (Natural 
History) 
 
The half-width of a 95% CI around the point estimate for mean 
percent change at 4 years would be  
Visual Acuity 
OCT EZ area 
Static Perimetry 
HOV 
1% 
5% 
8% 
 
 
NHS Objective 2 (Structure-
Function Relationship) 
 
The 95% CI around correlation between any two outcome measures 
would be 
if the observed correlation r = 0.3 
(0.02, 0.53)  
if the observed correlation r = 0.5 
(0.26, 0.68) 
if the observed correlation r = 0.8 
(0.67, 0.88) 
NHS Objective 3 (Risk 
Factors for Progression) 
 
A comparison of two equal-sized subgroups (N=25 each group) 
would have about 80% power to conclude there is a difference if the 
true difference is  
Visual Acuity 
OCT EZ area 
Static Perimetry 
HOV 
4% 
15% 
23%* 
[Type I (α) error rate of 0.05] 
* For example, if one subgroup had a percent change of 13%, the 
other subgroup would need a percent change of 36% to statistically 
conclude there is a difference.  
 
1239 
9.2 Data Analysis 
1240 
The analysis plans below are written with respect to the majority of outcomes of interest.  
1241 
Analyses will include data on both eyes for each participant, and confidence intervals will adjust 
1242 
for correlation between two (2) eyes of the same participant.     
1243 
9.2.1 Registry Data Analysis 
1244 
The following Registry data analysis considerations focus on Registry Objective 2 (see section 
1245 
1.3). Applicability of within-gene objectives will depend on within-gene sample size as noted 
1246 
below. If less than 20, limit primary objective to describing the cohort in the form of case 
1247 
histories. Objectives may still be explored depending on the needs for a specific gene. 
1248 
 
1249 
Registry Objective 2 (Cross-Sectional Phenotype Characterization) 
1250 
 Registry Objective 2 is to characterize cross-sectional retinal dystrophy associated with 
1251 
disease-causing genetic variants using functional and structural measures (visual acuity, 
1252 
OCT, static perimetry), within-gene. Structure-function relationships and risk factors for 
1253 
disease severity will also be explored within-gene.  
1254 
o The distribution of each cross-sectional outcome measure will be summarized 
1255 
(including tabulating categorically, as well as means, SDs, medians, quartiles, 
1256 
ranges; where sample size 20 or more).  
1257 

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o Scatterplots and Spearman correlation coefficients between cross-sectional 
1258 
outcome measures will be explored (where sample size is 20 or more) 
1259 
o Possible risk factors (genotype, phenotype, environmental, and comorbidities) 
1260 
for cross-sectional outcome measures will be explored (where sample size is 
1261 
40 or more).    
1262 
o Methods will include univariate and multivariate analysis of 
1263 
covariance (ANCOVA) models. A stepwise selection procedure will 
1264 
be used to build the final model.  A threshold of P<0.10 will be used to 
1265 
add to the model, and a threshold of P<0.05 will be used to remain in 
1266 
the multivariate model.  Linearity of continuous factors will be 
1267 
assessed, and possibly quadratic or cubic terms will be considered if 
1268 
non-linear. 
1269 
o Potential risk factors to evaluate include: 
1270 
 Phenotypic: 
1271 
• Clinical diagnosis (if applicable) 
1272 
• Duration of disease   
1273 
• Age of onset of initial vision symptoms 
1274 
• Gender  
1275 
• Race/ethnicity 
1276 
• Visual acuity  
1277 
• Lens Status (phakic/pseudophakic/aphakic)  
1278 
 Genotypic: 
1279 
• Characterizations of the variants  
1280 
 Environmental factors 
1281 
• Smoking status  
1282 
• Vitamin A use  
1283 
• Docosahexaenoic acid (DHA) use  
1284 
• Lutein use  
1285 
o Variability of symmetry of left and right eye cross-sectional outcome 
1286 
measures will be evaluated by scatterplots. Bland-Altman plots of the inter-
1287 
eye difference versus the mean value will be inspected and a linear regression 
1288 
model for the differences will be used to test whether the intercept (overall 
1289 
mean difference) and slope is 0. The plot will be inspected to evaluate whether 
1290 
variability between eyes changes with greater mean values. The intraclass 
1291 
correlation coefficient of the values and the within-person variance will be 
1292 
estimated.  
1293 
9.2.2 Natural History Data Analysis 
1294 
The following Natural History Study data analysis considerations focus on NHS Objectives 1-3 
1295 
(see section 1.3). Applicability of within-gene objectives will depend on within-gene sample size 
1296 

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as noted below. If less than 20, limit primary objective to describing the cohort in the form of 
1297 
case histories. Objectives may still be explored depending on the needs for a specific gene. 
1298 
 
1299 
NHS Objective 1 (Natural History) 
1300 
 NHS Objective 1 is to characterize the natural history of retinal degeneration associated 
1301 
with disease-causing genetic variants over 4 years, using functional, structural, and 
1302 
patient-reported outcome measure, within-gene (where sample size 20 or more). 
1303 
o Analysis plan for functional and structural measures: The distribution of each 
1304 
outcome at each visit will be summarized (including tabulating categorically, as 
1305 
well as means, SDs, medians, quartiles, ranges; both the absolute change and 
1306 
percent change will be evaluated, tests performed multiple times will be analyzed 
1307 
using average of all available tests). To determine the average annual rate of 
1308 
progression in the population for each outcome, a repeated measure least squares 
1309 
regression model will be fit using all available outcome data at baseline and all 
1310 
annual visits. Multiple imputation will be used to impute the outcome values for 
1311 
all missing time points (including participants who discontinue follow up prior to 
1312 
48 months).  Secondary analyses using binary definitions of outcome measures 
1313 
will also be explored in time to event analyses; Kaplan-Meier estimates with 95% 
1314 
confidence intervals will be calculated.  
1315 
o Analysis plan for PRO measures: The scoring of each questionnaire will be 
1316 
completed according to the procedures for each instrument and is detailed further 
1317 
in a separate statistical analysis plan. Baseline scores will be cross tabulated with 
1318 
categorical (severity of disease) versions of the outcome measures of interest at 
1319 
baseline. Changes in scores will be cross tabulated with binary (progression of 
1320 
disease) versions of the outcome measures of interest at the 24- and 48-month 
1321 
visits. A generalized linear model adjusted for baseline differences will be 
1322 
explored. 
1323 
NHS Objective 2 (Structure-Function Relationship) 
1324 
 NHS Objective 2 is to explore whether structural outcome measures can be validated as 
1325 
surrogates for functional outcomes in individuals with disease-causing genetic variants, 
1326 
within gene (where sample size 20 or more).    
1327 
o Analysis plan:  Scatterplots and Spearman correlation coefficients of changes in 
1328 
functional and structural outcome measures of progression from baseline to each 
1329 
visit will be evaluated.   
1330 
NHS Objective 3 (Risk Factors for Progression) 
1331 
 NHS Objective 3 is to explore possible risk factors (genotype, phenotype, 
1332 
environmental, and comorbidities) for progression of the outcome measures at 4 years in 
1333 
individuals with disease-causing genetic variants, within-gene (where sample size 40 or 
1334 
more).    
1335 
o Analysis plan: The distribution of each outcome in terms of both absolute 
1336 
change and percent change from baseline to 4 years will be summarized 
1337 
(including tabulating categorically, as well as means, standard deviations, 
1338 

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medians, quartiles), stratified by categorical levels of each potential risk factor 
1339 
of interest (listed below). Potential risk factors to evaluate include: 
1340 
o Phenotypic: 
1341 
 Clinical diagnosis (if applicable) 
1342 
 Duration of disease 
1343 
 Age of onset of initial vision symptoms 
1344 
 Gender  
1345 
 Race/ethnicity 
1346 
 Visual Acuity  
1347 
 Lens Status (phakic/pseudophakic/aphakic)  
1348 
o Genotypic: 
1349 
 Characterizations of the variants  
1350 
o Environmental factors 
1351 
 Smoking status at baseline 
1352 
 Vitamin A use at baseline 
1353 
 Docosahexaenoic acid (DHA) use at baseline 
1354 
 Lutein use at baseline 
1355 
Other Planned Analyses  
1356 
 Analysis plan for variability of repeat perimetry testing at baseline:  Scatterplots and 
1357 
Spearman correlation coefficients for pairs (first versus second) of testing values for each 
1358 
repeated perimetry test.  Bland-Altman plots of difference versus the mean value will be 
1359 
inspected. The intraclass correlation coefficient of the values and the within-eye variance will 
1360 
be estimated. 
1361 
 Analysis plan for the symmetry of left eye versus right eye:  At baseline and each subsequent 
1362 
testing time, the symmetry of the test result values from the left and right eyes will be 
1363 
assessed and the symmetry of the change from baseline from the left and right eyes will be 
1364 
assessed for each follow-up visit. Bland-Altman plots of the inter-eye difference versus the 
1365 
mean value will be inspected. The intraclass correlation coefficient of the values will be 
1366 
estimated. 
1367 
9.2.3 Interim Data Analysis 
1368 
No formal interim analysis or “stopping guidelines” are planned for determining early stopping 
1369 
according to statistical rules, as no intervention is being studied and thus early efficacy and 
1370 
safety signals are not applicable.   
1371 
Interim analyses will be planned for other reasons, including to evaluate data at baseline and 
1372 
annual visits for reporting in preliminary manuscripts, as well as monitoring data for recruitment 
1373 
and retention benchmarks, and quality assurance throughout the duration of the study.  The FFB 
1374 
Consortium Executive Committee will review and oversee these data and their use in reporting.    
1375 
 
 
1376 

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Chapter 10: Data Collection and Monitoring 
1377 
10.1 Case Report Forms and Other Data Collection  
1378 
The main study data are collected on electronic case report forms (eCRFs). When data are 
1379 
directly collected in electronic case report forms, this will be considered the source data. For any 
1380 
data points for which the eCRF is not considered source (e.g., lab results that are transcribed 
1381 
from a printed report into the eCRF), the original source documentation must be maintained in 
1382 
the participant’s study chart or medical record. This source must be readily verifiable against 
1383 
the values entered into eCRF. Even where all study data are directly entered into the eCRFs at 
1384 
office visits, evidence of interaction with a live subject must be recorded (e.g., office note, visit 
1385 
record, etc.) and provided to the coordinating center for review. 
1386 
Each participating site will maintain appropriate medical and research records for this trial, in 
1387 
compliance with International Council for Harmonisation of Technical Requirements for 
1388 
Pharmaceuticals for Human Use (ICH) E6 and regulatory and institutional requirements for the 
1389 
protection of confidentiality of participants 
1390 
10.1.1 Central Genetics Auditor (CGA) 
1391 
The CGA will review the genetic lab report(s) submitted by the clinical site during genetic 
1392 
screening and will document their verification of these genetic data on the FFB Consortium 
1393 
study website.  
1394 
10.1.2 Genetics Committee (GC) 
1395 
In addition to providing assistance in the interpretation/evaluation of whether the mutations are 
1396 
causative of the disease on the FFB Consortium study website, the Genetics Committee will 
1397 
review and provide approval for the use of genetic reports from research labs to be used for 
1398 
determining participant eligibility.  
1399 
10.1.3 Reading Center (RC) 
1400 
Reading Centers will conduct grading of the study data collected using the FFB Consortium 
1401 
study website. The Reading Centers will provide the graded data through a data transfer or by 
1402 
entering the graded data on the study website. These data will remain in the study database and 
1403 
will not be provided to the clinical site. 
1404 
10.2 Study Records Retention 
1405 
Each participating site will maintain appropriate medical and research records for this trial, in 
1406 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1407 
confidentiality of participants. 
1408 
Study documents will be retained for a minimum of six (6) years from the date on which the CC 
1409 
receives IRB approval to close the study. These documents should be retained for a longer 
1410 
period, however, if required by local regulations. No records will be destroyed without the 
1411 
written consent of the Sponsor. It is the responsibility of the Sponsor to inform the Principal 
1412 
Investigator (PI) when these documents no longer need to be retained. 
1413 

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10.3 Quality Assurance and Monitoring 
1414 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1415 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1416 
conducted and data are generated, documented and reported in compliance with the protocol, 
1417 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1418 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1419 
accurate, complete, and verifiable. 
1420 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1421 
consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1422 
Based Approach to Monitoring” (August 2013).9 Study conduct and monitoring will conform 
1423 
with 21 Code of Federal Regulations (CFR) 312.10 This plan describes in detail who will conduct 
1424 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
1425 
will be performed, and the distribution of monitoring reports. 
1426 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1427 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1428 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1429 
verity and completeness of the key site data. Elements of the RBM may include: 
1430 
 
Qualification assessment, training, and certification for sites and site personnel 
1431 
 
Oversight of Institutional Review Board (IRB) coverage and informed consent 
1432 
procedures 
1433 
 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, 
1434 
protocol review of entered data and edits, statistical monitoring, study closeout 
1435 
 
On-site monitoring (site visits): source data verification, site visit report 
1436 
 
Communications with site staff 
1437 
 
Patient retention and visit completion 
1438 
 
Quality control reports 
1439 
 
Management of noncompliance 
1440 
 
Documenting monitoring activities 
1441 
 
Adverse event reporting and monitoring 
1442 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1443 
order to maintain current and personal knowledge of the study through review of records, 
1444 
comparison with source documents, observation and discussion of the conduct and progress of 
1445 
the study. The investigational site will provide direct access to all trial-related sites, source 
1446 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
1447 
inspection by local and regulatory authorities. 
1448 
10.4 Protocol Deviations 
1449 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1450 
requirements. The noncompliance may be either on the part of the participant, the Investigator(s), 
1451 
or the study site staff.  
1452 

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A significant (or major) deviation is any deviation that departs from the established materials in 
1453 
such a way that it poses an increase in the risk to the study participants, adversely affects the 
1454 
welfare, rights, or safety of the research study participants, or negatively influences the scientific 
1455 
study integrity. As a result of significant deviations, corrective and preventive actions are to be 
1456 
developed by the site and implemented promptly. 
1457 
The site Principal Investigator (PI) and study staff are responsible for knowing and adhering to 
1458 
their IRB/EC requirements.  
1459 

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Chapter 11: Ethics/Protection of Human Participants 
1460 
11.1 Ethical Standard 
1461 
The Principal Investigator (PI) will ensure that this study is conducted in full conformity with 
1462 
Regulations for the Protection of Human Participants of Research in accordance with ICF 
1463 
E6/GCP, EC requirements, and local laws and regulations, as applicable.  
1464 
11.2 Institutional Review Boards 
1465 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1466 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1467 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1468 
require review and approval by the IRB before the changes are implemented to the study. All 
1469 
changes to the consent form will be IRB approved; a determination will be made regarding 
1470 
whether previously consented participants need to be re-consented. 
1471 
11.3 Informed Consent Process 
1472 
11.3.1 Consent Procedures and Documentation 
1473 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1474 
the study and continues throughout the individual’s study participation. Extensive discussion of 
1475 
risks and possible benefits of participation will be provided to the participants and their families. 
1476 
Consent forms will be IRB/EC-approved, and the participant will be asked to read and review the 
1477 
document. The Investigator(s) will explain the research study to the participant and answer any 
1478 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1479 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1480 
research participants. Participants will have the opportunity to carefully review the written 
1481 
consent form and ask questions prior to signing. 
1482 
The participants will have the opportunity to discuss the study with their surrogates or think 
1483 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1484 
prior to any procedures being done specifically for the study. The participants may withdraw 
1485 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1486 
will be given to the participants for their records. The rights and welfare of the participants will 
1487 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1488 
affected if they decline to participate in this study. 
1489 
11.3.2 Participant and Data Confidentiality 
1490 
Participant confidentiality is strictly held in trust by the participating Investigator(s), their staff, 
1491 
and the Sponsor(s) and their agents. This confidentiality is extended to cover use of genetic tests 
1492 
in addition to the clinical information relating to participants. Therefore, the study protocol, 
1493 
documentation, data, and all other information generated will be held in strict confidence. No 
1494 
information concerning the study, or the data will be released to any unauthorized third party 
1495 
without prior written approval of the Sponsor. 
1496 
The study monitor, other authorized representatives of the Sponsor, representatives of the 
1497 
IRB/EC, regulatory agencies or company supplying study product may inspect all documents 
1498 

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and records required to be maintained by the Principal Investigator, including but not limited to, 
1499 
medical records (office, clinic, or hospital) for the participants in this study. The clinical study 
1500 
site will permit access to such records. 
1501 
The study participant’s contact information will be securely stored at each clinical site for 
1502 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1503 
secure location for as long a period as dictated by the reviewing IRB/EC, institutional policies, or 
1504 
Sponsor requirements. 
1505 
Study participant research data, which is for purposes of statistical analysis and scientific 
1506 
reporting, will be transmitted to and stored at the FFB Consortium Coordinating Center, located 
1507 
at the Jaeb Center for Health Research in Tampa, FL. This will not include the participant’s 
1508 
contact or identifying information, unless otherwise specified in the informed consent form. 
1509 
Rather, individual participants and their research data will be identified by a unique study 
1510 
identification number. The study data entry and study management systems used by clinical sites 
1511 
and by the FFB Consortium Coordinating Center research staff will be secured and password 
1512 
protected. At the end of the study, all study databases will be de-identified and archived at the 
1513 
FFB Consortium Coordinating Center. 
1514 
11.3.3 Future Use of Data and Ocular Images 
1515 
Data and images collected for this study will be analyzed and stored at the FFB Coordinating 
1516 
Center and the Reading Centers. After the study is completed, the de-identified, archived data 
1517 
will be transmitted to and stored at the FFB Consortium Coordinating Center, under the 
1518 
supervision of the Protocol Director, for use by other researchers including those outside of the 
1519 
study. Permission to transmit data to the FFB Consortium Coordinating Center will be included 
1520 
in the informed consent. 
 
1521 

JAEB CENTER FOR HEALTH RESEARCH 
UNI-RARE PROTOCOL V1.2 2022-12-12 
PAGE 76 OF 76 
Chapter 12: References 
1522 
References 
1523 
 
1524 
1. 
Sahel JA, Bennett J, Roska B. Depicting brighter possibilities for treating blindness. Sci 
1525 
Transl Med. 2019;11(494). 
1526 
2. 
Scholl HP, Strauss RW, Singh MS, et al. Emerging therapies for inherited retinal 
1527 
degeneration. Sci Transl Med. 2016;8(368):368rv366. 
1528 
3. 
Duncan JL, Pierce EA, Laster AM, et al. Inherited Retinal Degenerations: Current 
1529 
Landscape and Knowledge Gaps. Transl Vis Sci Technol. 2018;7(4):6. 
1530 
4. 
Thompson DA, Iannaccone A, Ali RR, et al. Advancing Clinical Trials for Inherited 
1531 
Retinal Diseases: Recommendations from the Second Monaciano Symposium. Transl Vis 
1532 
Sci Technol. 2020;9(7):2. 
1533 
5. 
Csaky K, Ferris F, 3rd, Chew EY, Nair P, Cheetham JK, Duncan JL. Report From the 
1534 
NEI/FDA Endpoints Workshop on Age-Related Macular Degeneration and Inherited 
1535 
Retinal Diseases. Invest Ophthalmol Vis Sci. 2017;58(9):3456-3463. 
1536 
6. 
Sahel JA, Grieve K, Pagot C, et al. Assessing Photoreceptor Status in Retinal 
1537 
Dystrophies: From High-Resolution Imaging to Functional Vision. Am J Ophthalmol. 
1538 
2021;230:12-47. 
1539 
7. 
Cideciyan AV, Krishnan AK, Roman AJ, Sumaroka A, Swider M, Jacobson SG. 
1540 
Measures of Function and Structure to Determine Phenotypic Features, Natural History, 
1541 
and Treatment Outcomes in Inherited Retinal Diseases. Annu Rev Vis Sci. 2021;7:747-
1542 
772. 
1543 
8. 
Food and Drug Administration. Rare Diseases: Natural History Studies for Drug 
1544 
Development. In. Draft Guidance for Industry,2019. 
1545 
9. 
Food and Drug Administration. Guidance for Industry Oversight of Clinical 
1546 
Investigations - A Risk-Based Approach to Monitoring. In:2013. 
1547 
10. 
Food and Drug Administration. 21 Code of Federal Regulations (CFR) 312. In:2022. 
1548 
 
1549