Rate of Progression of PCDH15-Related Retinal Degeneration in Usher
Conditions: Retinal Degeneration, Retinitis Pigmentosa, Eye Diseases, Hereditary
Sponsor: Jaeb Center for Health Research

JAEB CENTER FOR HEALTH RESEARCH 
RUSH1F PROTOCOL V1.0 _2020_12_21 
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Foundation Fighting Blindness (FFB) 
Consortium  
Rate of Progression of PCDH15-Related Retinal 
Degeneration in Usher Syndrome 1F (RUSH1F) 
Funded by: Foundation Fighting Blindness and Usher 1F Collaborative
 
Version Number: 1.0 
21-Dec-2020

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Key Roles and Signature Page 
Rate of Progression of PCDH15-Related Retinal 
Degeneration in Usher Syndrome 1F (RUSH1F) 
Protocol Identifying Number: RUSH1F 
Version Number: v1.0 
21-Dec-2020 
 
RUSHF Protocol Chair 
 
Name, degree 
Katarina Stingl, M.D. 
Signature/Date 
 
 
JCHR RUSH1F Protocol 
Director 
 
Name, degree 
Allison Ayala, MS 
Signature/Date 
 
 
 
FFB Representative 
 
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  ............................................................................................. 15 
1.1 Introduction ....................................................................................................................................... 15 
1.2 Scientific Rationale for Study Design ............................................................................................... 17 
1.3 Study Objectives ................................................................................................................................ 17 
1.4 General Considerations...................................................................................................................... 17 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING VISIT .................................................................... 19 
2.1 Participant Recruitment and Enrollment ........................................................................................... 19 
2.1.1 Participant Recruitment Goals and Strategy ................................................................................ 19 
2.2 Informed Consent and Authorization Procedures .............................................................................. 20 
2.3 Screening Visit .................................................................................................................................. 20 
2.3.1 Eligibility Criteria ........................................................................................................................ 21 
2.3.1.1 Participant Criteria .............................................................................................................. 21 
2.3.1.2 Ocular Criteria .................................................................................................................... 22 
2.3.2 Screening Data Collection and Testing ....................................................................................... 22 
2.3.3 Initial Screen Failures .................................................................................................................. 23 
2.4 Genetic Screening Phase ................................................................................................................... 23 
2.4.1 Genetic Screen Failures ............................................................................................................... 25 
2.4.2 Genetics Committee Review ....................................................................................................... 25 
2.5 Participants Enrolled into the Natural History Study ........................................................................ 25 
CHAPTER 3: NATURAL HISTORY STUDY PROCEDURES  .......................................................................... 26 
3.1 Baseline Visit ..................................................................................................................................... 26 
3.2 Baseline Testing Procedures .............................................................................................................. 26 
3.3 Follow-up Visits ................................................................................................................................ 27 
3.3.1 Follow-up Visit Testing Procedures ............................................................................................ 28 
3.3.2 Unscheduled Visits ...................................................................................................................... 28 
3.4 Personnel and Equipment Requirements for Study Procedures ........................................................ 29 
CHAPTER 4: UNANTICIPATED PROBLEMS AND ADVERSE EVENT REPORTING  ..................................... 31 
4.1 Unanticipated Problems ..................................................................................................................... 31 
4.2 Adverse Events .................................................................................................................................. 31 
4.2.1 Definition ..................................................................................................................................... 31 
4.2.2 Reportable Adverse Events ......................................................................................................... 32 
4.2.3 Relationship of Adverse Event to Study Procedure .................................................................... 32 
4.2.4 Severity (Intensity) of Adverse Event ......................................................................................... 32 
4.3 Pregnancy Reporting ......................................................................................................................... 33 

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CHAPTER 5: MISCELLANEOUS CONSIDERATIONS ................................
................................
................... 34 
5.1 Treatments During the Study
 ................................
................................
................................
............. 34 
5.1.1 Treatment for PCDH15-Related Retinal Degeneration
 ................................
...............................
 34 
5.1.2 Treatment for Cystoid Macular Edema
 ................................
................................
....................... 34 
5.1.3 Intraocular Surgical Procedures
 ................................
................................
................................
.. 34 
5.2 Risks and Benefits
 ................................
................................
................................
.............................
 34 
5.2.1 Risks and Discomforts
 ................................
................................
................................
................. 34 
5.2.2 Benefits ................................
................................
................................
................................
........ 35 
5.3 Collection of Pre-Existing Conditions and Medications
 ................................
................................
... 35 
5.4 Participant Compensation
 ................................
................................
................................
.................. 35 
5.5 Participant Withdrawal
 ................................
................................
................................
...................... 35 
5.6 Confidentiality ................................
................................
................................
................................
... 35 
CHAPTER 6: STATISTICAL CONSIDERATIONS ................................
................................
.......................... 36 
6.1 Sample Size
 ................................
................................
................................
................................
....... 36 
6.1.1 Sample Size Considerations for Evaluating Percent Change from Baseline 
to 4 Years (All Outcomes)
 ................................
................................
................................
.................... 36 
6.1.2 Sample Size Considerations for Comparing Percent Change from Baseline 
to 4 Years within Subgroups of Interest (All Outcomes)
 ................................
................................
..... 37 
6.1.3 Sample Size Considerations for Precision of the Estimate of the Correlation 
between Eyes ................................
................................
................................
................................
........ 38 
6.1.4 Final Sample Size Justification
 ................................
................................
................................
... 39 
6.2 Data Analysis ................................
................................
................................
................................
..... 40 
6.2.1 Primary Objectives Analyses
 ................................
................................
................................
...... 40 
6.2.2 Interim Data Analysis
 ................................
................................
................................
.................. 42 
CHAPTER 7: DATA COLLECTION AND MONITORING  ................................
................................
.............. 43 
7.1 Case Report Forms and Other Data Collection
 ................................
................................
................. 43 
7.2 Study Records Retention
 ................................
................................
................................
................... 43 
7.3 Quality Assurance and Monitoring
 ................................
................................
................................
.... 43 
7.4 Protocol Deviations
 ................................
................................
................................
........................... 44 
CHAPTER 8: ETHICS/PROTECTION OF HUMAN PARTICIPANTS  ................................
..............................
 45 
8.1 Ethical Standard
 ................................
................................
................................
................................
. 45 
8.2 Institutional Review Boards and Ethics Committees
 ................................
................................
........ 45 
8.3 Informed Consent Process
 ................................
................................
................................
................. 45 
8.3.1 Consent Procedures and Documentation
 ................................
................................
..................... 45 
8.3.2 Participant and Data Confidentiality
 ................................
................................
........................... 45 
8.4 Stored Specimens
 ................................
................................
................................
..............................
 46 

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CHAPTER 9: REFERENCES  ......................................................................................................................... 47 
 
 
 
 

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LIST OF ABBREVIATIONS  
 
ABBREVIATION  
DEFINITION  
ACMG 
American College of Medical Genetics 
ADRP 
Autosomal dominant retinitis pigmentosa 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
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 
CSF 
Contrast Sensitivity Function 
DHA 
Docosahexaenoic acid 
EC 
Ethics Committee 
ERG 
Electroretinogram 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EVA 
Electronic Visual Acuity 
EZ 
Ellipsoid Zone 
FAF 
Fundus Autofluorescence 
FFB 
Foundation Fighting Blindness 
FST 
Full-field stimulus threshold 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Committee of Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IS/OS 
Inner Segment/ Outer Segment 
LLVA 
Low Luminance Visual Acuity 
LPV-FVQ II 
L.V. Prasad-Functional Vision Questionnaire  
MRDQ 
Michigan Retinal Degeneration Questionnaire 
MP 
Microperimetry 
N 
Number or sample size 
OD 
Right Eye 
OS 
Left Eye 

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ABBREVIATION  
DEFINITION  
OU 
Both eyes 
PI 
Principal investigator 
PRO 
Patient reported outcomes 
PROMISﬁ-29 
Patient-Reported Outcomes Measurement Information System 
QA 
Quality Assurance  
QC 
Quality Control  
RBM 
Risk-Based Monitoring  
RP 
Retinitis pigmentosa 
SAE 
Serious adverse event 
SD 
Standard deviation  
SD-OCT 
Spectral domain optical coherence tomography 
SP 
Static perimetry 
TALEN 
Transcription activator-like effector nuclease 
VA 
Visual acuity 
VF 
Visual Field 
VPA 
Valproic Acid 

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PROTOCOL SUMMARY 
ITEM  
DESCRIPTION  
Title 
Rate of Progression of PCDH15-Related Retinal Degeneration in Usher Syndrome 1F 
(RUSH1F) 
PrØcis  
This natural history study of patients with PCDH15 disease-causing variants will 
accelerate the development of outcome measures for clinical trials.  Sensitive, reliable 
outcome measures of retinal degeneration will greatly facilitate development of 
treatments for retinitis pigmentosa due to PCDH15 disease-causing variants.  
Together these approaches are expected to have an impact on understanding PCDH15 
related retinal degeneration, developing experimental treatment protocols, and 
assessing their effectiveness. 
The goals and expected impact of this natural history study are to: 
1. 
Describe the natural history of retinal degeneration in patients with biallelic 
disease-causing variants in the PCDH15 gene 
2. 
Contribute to the identification of sensitive structural and functional outcome 
measures to use for future multicenter clinical trials in PCDH15 related 
retinal degeneration  
3. 
Contribute to the identification of populations for future clinical trials of 
investigative treatments for PCDH15 related retinal degeneration 
Objectives  
1. 
Characterize the natural history of retinal degeneration associated with 
biallelic disease-causing variants in the PCDH15 gene over 4 years, as 
measured using functional, structural, and patient-reported outcome measures 
2. 
Explore whether structural outcome measures can be validated as surrogates 
for functional outcomes in individuals with biallelic disease-causing variants 
in the PCDH15 gene 
3. 
Explore possible risk factors (genotype, phenotype, environmental, and 
comorbidities) for progression of the outcome measures at 4 years in 
individuals with biallelic disease-causing variants in the PCDH15 gene 
4. 
Explore variability and symmetry of left and right eye outcomes over 4 years 
in individuals with biallelic disease-causing variants in the PCDH15 gene  
Study Design  
Multicenter, longitudinal, prospective natural history study. Participants will be 
assigned to one of two Vision Cohorts based on visual acuity (VA) and kinetic visual 
fields (VF). 
Number of Clinical Sites  
Approximately 10 
Endpoint  
Functional Outcomes:  
• 
VF sensitivity as measured by static perimetry with quantitative, topographic 
analysis (Hill of Vision) and assessed by a central reading center 
• 
Early Treatment of Diabetic Retinopathy Study (ETDRS) Best corrected visual 
acuity (BCVA) letter score as measured on the Electronic Visual Acuity (EVA) 
system or ETDRS charts. Berkeley Rudimentary Vision Test (BRVT) will be 
used for patients unable to see letters 
• 
Mean retinal sensitivity as measured by fundus-guided microperimetry (MP) and 
assessed by a central reading center at selected sites with requisite equipment 
• 
Full-field retinal sensitivity as measured by full-field stimulus threshold (FST) 
testing to blue, white and red stimuli 

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ITEM  
DESCRIPTION  
• 
Best corrected low luminance visual acuity (LLVA) letter score  
• 
Contrast sensitivity function (CSF) as measured by the CSV-1000E VectorVision 
chart 
 
Structural Outcomes:  
• 
Ellipsoid zone (EZ) area as measured by spectral domain optical coherence 
tomography (SD-OCT) and assessed by a central reading center 
• 
Explore qualitative categorization of Fundus Autofluorescence (FAF) pattern as 
assessed by a central reading center 
• 
Explore quantitative measures of FAF as assessed by a central reading center 
 
Patient Reported Outcomes (PRO):
 
• 
Adults (18 years or older) :  
o Michigan Retinal Degeneration Questionnaire (MRDQ)  
▪ 
The MRDQ is a patient reported outcomes instrument for Inherited 
Retinal Degeneration with 59 questions and contains seven domains 
which are; central vision, color vision, contrast sensitivity, 
photosensitivity, scotopic function, mesopic and photopic peripheral 
vision. 
 
o Patient-Reported Outcomes Measurement Information System (PROMISﬁ-
29) 
▪ 
The PROMISﬁ-29 questionnaire 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. 
 
• 
Children (less than 18 years) :  
o L. V. Prasad-Functional Vision Questionnaire (LVP-FVQ II) 
▪ 
The LVP-FVQ-II is a self-reported questionnaire with 23 
questions that will be administered to minor participants to 
assess self-reported functional vision problems. 
Population  
Key Eligibility Criteria:  
The entire list of eligibility criteria is in protocol section 2.3.1 and must be reviewed 
at the Screening Visit.  All eligibility criteria must be met to enroll into the genetic 
screening phase .  A key subset of those eligibility criteria includes the following.    
 
• 
Age ≥ 8 years of age 
• 
Clinical diagnosis of retinal dystrophy  
• 
Must meet one of the Genetic Screening Criteria: 
➢ Screening Group A:   At least 2 disease-causing variants  in the 
PCDH15 gene which are homozygous or heterozygous in trans , 
based on a report from a clinically certified lab (or a report from a 
research lab that has been pre-approved by the study Genetics 
Committee) 

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ITEM  
DESCRIPTION  
➢ Screening Group B:  Only 1 disease-causing variant  in the  
PCDH15 gene, based on a report from a clinically certified lab (or a 
report from a research lab which has been pre-approved by the study 
Genetics Committee) 
➢ Screening Group C:   At least 2 disease-causing variants  in the 
PCDH15 gene which are unknown phase , based on a report from a 
clinically certified lab (or a report from a research lab which has been 
pre-approved by the study Genetics Committee) 
 
Participants eligible upon initial screening will continue to the genetic screening 
phase. Following the genetic screening phase, to be eligible to enroll in the study 
cohort , the following must be documented: 
 
• 
Final Study Cohort Criteria: 
At least 2 disease-causing variants  in the 
PCDH15 gene which are homozygous or heterozygous in trans , based on a 
report from a clinically-certified lab (or a report from a research lab that has 
been pre-approved by the study Genetics Committee), and confirmed by a 
Central Genetics Auditor (CGA). 
 
Sample Size  
Recruitment will be tracked within Vision Cohort defined as follows.  Sample size 
rationale is detailed in protocol section 6.1. 
 
• 
Vision Cohort 1 : ~25 participants with the better eye  Screening Visit 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:   ~15 participants with the better eye  Screening Visit visual 
acuity ETDRS letter score of 19-53 [approximate Snellen equivalent 20/100 - 
20/400] or (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) 
 
The better eye is defined as the eye with better Screening Visit ETDRS VA.  If 
both eyes have the same VA (defined as the same Snellen equivalent), then the 
determination will be made at investigator discretion as the eye with better 
fixation or clearer ocular media to permit highest quality retinal imaging. 
 
The visual field (VF) is defined as a clinically determined kinetic VF III4e 
performed within the last 18 months prior to or including the Screening Visit date  
 
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 
 
Initial recruitment goals will be as follows:
 

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ITEM  
DESCRIPTION  
• 
40 participants enrolled into the study cohort  (Vision Cohorts 1 and 2, 
combined) 
 
If recruitment is not at a rate to meet the initial goals, an interim assessment of 
feasibility may be made by the FFB Consortium Executive Committee.  A minimum 
of 20 participants enrolled in Vision Cohorts 1 and 2 combined will be targeted. 
Participant Duration
 
From the time of screening until the 48-month visit: Approximately 51 Months 
• Screening- Baseline Visit (~ 3 months) 
• Baseline Visit – 48-month Follow-up Visit (~ 48 months) 
Protocol 
Overview/Synopsis  
1. Investigator reviews patient’s current genetic report as meeting one of the 
Genetic Screening Criteria and any other eligibility criteria that can be evaluated 
based on medical history 
2. Consent participant according to overseeing Institutional Review Board 
(IRB)/Ethics Committee (EC) requirements 
3. Obtain ID on study website to enroll into initial screening  
4. Complete a Screening Visit to determine eligibility, Vision Cohort and Genetic 
Screening Group. Participants meeting criteria to continue will enroll into the 
genetic screening phase .  (See flow chart in next section for details) 
5. Complete genetic screening according to the requirements for the given Genetic 
Screening Group.  Participants meeting criteria to continue will enroll int o the 
study cohort.  (See flow chart in next section for details) 
6. Participants who enroll into the study cohort  will return to the clinic within 90 
days of the Screening Visit date to start baseline testing, and no later than 30 
days after receiving confirmation of meeting final study cohort criteria
 from 
the CGA  
7. All participants who enroll into the study cohort  will return to the clinic at 12, 
24, 36 and 48 months from the baseline visit start date for follow-up visits.  
8. 
After the 48-month follow-up visit, participation in the study will be completed 
 

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SCHEMATIC OF STUDY DESIGN 
1 
 
2 
   
3 
 
4 
 
5 
  
6 
 
7 

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8 
 
9 

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SCHEDULE OF STUDY VISITS AND PROCEDURES  
10 
Visit Schedule  
11 
Visit 
Screening Baseline 
12M 
24M 
36M 
48M 
Visit Target Windows  
(up to Day 
-90) a 
(Day 0)b 
Wk 
52 ± 4c 
Wk 
104± 4c 
Wk 
156– 4c 
Wk 
208– 4c 
Participant-Level Procedures 
Informed Consent 
X 
 
 
 
 
 
Demographics/Screening Medical History (including pre-existing 
conditions, patient-reported daily activities and medications) 
X 
 
 
 
 
 
Concomitant Medications/Adverse Events  
 
X 
X 
X 
X 
X 
Patient Reported Outcomesg  (Adults: MRDQ and PROMISﬁ-
29; Children: LPV-FVQ II) 
 
X 
 
X 
 
X 
Audiology History 
 
X 
 
 
 
 
Pre-cochlear implant audiogram 
 
X 
 
 
 
 
Ocular Procedures - All testing performed in each eye  
Complete Ophthalmic Exame 
X 
 
X 
X 
X 
X 
Visual acuity (including refraction, ETDRS, BRVT if needed, 
LLVA if needed) 
X 
X h  
X 
X 
X 
X 
Contrast Sensitivity (VectorVision CSV-1000E) 
 
X 
X 
X 
X 
X 
SD-OCT with measurement of EZ area (Heidelberg Spectralis) 
 
X 
 X 
 X 
 X 
 X 
Axial Length and Corneal Curvature measurements 
 
X 
 
 
 
 
Near Infrared Reflectance Photos (Heidelberg Spectralis with 
55degree lens)i 
 
X 
 
 
 
 
Fundus Autofluorescence (Optos, where available)  
 
X 
X 
X 
X 
X 
Full-field Stimulus Threshold (Diagnosys Espion) 
 
X 
X 
X 
X 
X 
Static perimetry (Octopus 900 Pro)  
 
Xd  
X 
X 
X 
X 
Fundus guided microperimetry (MAIA)  
 
Xd 
X 
X 
X 
X 
Kinetic VF III4e for Vision Cohort definition only 
Xf 
 
 
 
 
 
a. 
All Screening Visit testing must be completed on the same day  
12 
b. 
Baseline Visit date (defined as the start date of all Baseline testing) must be no later than 30 days after receiving 
13 
confirmation of meeting final study cohort criteria
 from the CGA (and if possible, within 90 days of the Screening 
14 
Visit date).  All Baseline testing should be completed within 7 days of the Baseline Visit date, except PROs as 
15 
specified.  
16 
c. 
All Follow up visit testing must be completed on the same day, except PROs as specified. 
17 
d. 
For static perimetry and microperimetry, all Vision Cohort 1 and 2 participants will complete two tests at baseline. The 
18 
results will be compared according to the visual field criteria to determine if a third test is needed.   
19 
e. 
Ophthalmic exam includes slit-lamp biomicroscopy, indirect ophthalmoscopy and intraocular pressure (IOP).  IOP 
20 
measurements will be taken prior to pupil dilation and will take place at approximately the same time of the day at each 
21 
visit and with the same equipment 
22 
f. 
Kinetic VF III4e performed within the last 18 months prior to or including the Screening Visit date for Vision Cohort 
23 
determination only 
24 
g. 
May be completed in person or remotely any time within 6 months of the Baseline visit or  any time within the 
25 
allowable window of the associated visit window (not required to be the same day as the rest of the visit). 
26 
h. 
If the Baseline visit date is more than 90 days after the Screening Visit date, all Visual acuity procedures must also be 
27 
completed. 
28 
i. 
Required for all sites except with the exception of any site with equivalent equipment approved by the reading center 
29 
and operations committee. 
30 
 
31 
 
32 
 
33 

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Chapter 1:  Background Information
 
34 
1.1 Introduction  
35 
Usher syndrome (USH), is a neurosensory disease that impacts vision and hearing, inherited in 
36 
an autosomal recessive way. It is characterized by the combination of hearing impairment up to 
37 
deafness and retinal dystrophy (retinitis pigmentosa, RP), and in some cases vestibular and 
38 
olfactory deficits.1,2 The three main clinical subtypes known are USH1, USH2 and USH3. USH 
39 
type 1 (USH1) patients are born completely deaf. These patients experience other complications 
40 
such as delayed sitting and walking age due to vestibular problems. RP with night blindness is 
41 
typically diagnosed by 10 years of age. In USH2 patients, hearing impairment is less 
42 
pronounced, and the patients do not experience balance deficits. In most cases, this subtype does 
43 
not progress over time. Night blindness normally occurs later than in USH1.3 USH3 accounts for 
44 
2% of patients and found mostly in Finland and Ashkenazi Jews. In this type, the hearing 
45 
impairment is progressive, and a balance defect may be present.4,5  
46 
 
47 
USH1F is a subtype of USH1 caused by bi-allelic mutations of the USH1F gene, also called 
48 
protocadherin 15 (PCDH15). This gene has been localized in inner ear hair cell stereocilia and 
49 
outer segments of primates’ retinal photoreceptors; strong PCDH15 activity has been described 
50 
in cones, but also diffusely in rods through the whole photoreceptor layer.6 The majority of 
51 
PCDH15 mutations leading to USH1F are localized in the ectodomains of the protein, but not in 
52 
the transmembrane domain or the cytoplasmic domain, the latter two being probably important 
53 
outside of the hearing and visual system.  It is assumed that PCDH15 might have a role in the 
54 
morphogenesis and cohesion of stereocilia bundles and retinal photoreceptor cell maintenance or 
55 
function. Protocadherin 15 deficiency leads to functionally impaired cones and rods with 
56 
abnormally shaped outer segments.6,7  
57 
 
58 
PCDH15 has been linked to congenital deafness or its syndromic form USH1F.6,8 Additionally, 
59 
digenic inheritance of Usher syndrome USH1D/F has been described in patients with 
60 
heterozygous mutations in both CDH23 and PCDH15 genes.9 The prevalence of USH1 is around 
61 
1- 9 /100,000; the prevalence of USH1F is not precisely known due to its rarity but might be 
62 
around 10 % of all USH1 patients.2,10  
63 
 
64 
The current knowledge about the natural course of USH1F is limited, as no systematic 
65 
observational trials of the retinal phenotype have been published. The phenotype and fast time 
66 
course of the retinal degeneration in USH1F is comparable with the phenotype of USH1 in 
67 
general, which is characterized by profound pre-lingual deafness, vestibular ataxia, and 
68 
childhood onset of retinitis pigmentosa.11,12  
69 
 
70 
A large cohort of 268 USH patients in a multicenter European study TREATRUSH 
71 
(https://cordis.europa.eu/project/rcn/95259_en.html) was conducted to understand the genotype-
72 
phenotype correlations of USH and enabled some insight into the subgroups of phenotypes of 
73 
USH1. The analyses from this study indicated decay of visual fields and visual acuity as a 
74 
function of the patients’ age corresponds to the changes of the USH1 cohort in general.12  
75 
 
76 
Hearing loss is treatable with cochlear implants in many patients with USH1F. However, the 
77 
therapy for treating the retinal phenotype is still in preclinical research. Gene replacement 
78 

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therapy, similar as the first approved AAV (adeno associated virus) mediated subretinal gene 
79 
therapy for RPE65 retinitis pigmentosa, is not possible in USH1F due to the large size of the 
80 
PCDH15 gene.  
81 
 
82 
Gene-based therapies such as dual-vectors, gene editing or mini genes, and suppression of 
83 
several PCDH15 mutations by aminoglycosides have been examined. Aminoglycosides can 
84 
influence the translation of mRNA into protein by inhibiting ribosomal proofreading, thus, 
85 
leading to read-through of nonsense mutations. A partial read-through of PCDH15 nonsense 
86 
mutations leading to various levels of the full-length protein was shown by aminoglycosides in 
87 
vitro and ex vivo.13 However, more preclinical and clinical research is needed to determine 
88 
whether these approaches can restore vision in patients with USH1F or slow down the 
89 
degeneration process leading to blindness.  
90 
 
91 
The clinical research in therapy trials for other types of syndromic or non-syndromic RP shows 
92 
that valid readouts are one of the most important aspects of clinical trials. Morphological 
93 
readouts have improved with high resolution retinal imaging such as spectral domain OCT (SD-
94 
OCT) and became standard in clinical follow-ups and clinical trials due to its objectivity and 
95 
lower variability than psychophysical functional tests.14,15  
96 
 
97 
For functional tests of the retina, psychophysical examinations of visual fields and best corrected 
98 
visual acuity (BCVA) as well as contrast vision (or low luminance BCVA) are commonly used 
99 
but describing only foveal cone vision. Further, fundus guided mesopic microperimetry has been 
100 
used widely in clinical trials of inherited retinal degenerations. However, due to the mesopic 
101 
range of the stimuli, the method is not sensitive enough to test rod vision.17 Additionally, in 
102 
retinal degeneration with increasing dark-adapted rod thresholds, the mesopic testing is not able 
103 
to distinguish between the degenerating rod system and the healthy or degenerating cone system. 
104 
 
105 
With respect to the knowledge of the progression of the cone and rod degeneration and future 
106 
therapy approaches, a clear differentiation of the rod and cone function is desirable. Routinely 
107 
used objective readouts of the photoreceptors such as scotopic and photopic electro-retinography 
108 
(ERG) are usually non-recordable already in early stages of the retinal degeneration, including 
109 
RP in USH1 patients.18 Therefore, the full-field ERG is not a practical follow-up readout for the 
110 
natural course of USH1 or therapy interventions. A psychophysical test of the dark-adapted 
111 
thresholds, FST (full-field stimulus threshold) with chromatic stimuli is better suited to describe 
112 
the deterioration of the retinal progression even in late stages of RP.17,18  
113 
 
114 
Although these scotopic readouts are widely used, they do not possess the ability to show the 
115 
local retinotopy of the rod system. A method which can evaluate the local rod function is dark 
116 
adapted chromatic perimetry (DAC). This method has also earlier been applied in patients with 
117 
RP.19,20 A novel, shortened protocol for application in RP trials has been proposed recently with 
118 
duration of around 7 minutes, intervisit repeatability of 7.6 – 2.8 dB for cyan and 5.9 – 1.7 dB 
119 
for red stimuli and ability to detect the local rod rescue after gene therapy.22  
120 
 
121 
Further, novel diagnostic development has been introduced, enabling an objective, 
122 
retinotopically correct evaluation of the rod and cone system by analyzing the pupil response to 
123 
local stimuli.23 The chromatic pupil campimetry, although not broadly available, is a tool for 
124 

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evaluation of the function of both photoreceptors separately in an objective way, with a superior 
125 
intervisit repeatability compared to DAC.22  
126 
 
127 
In respect to the promising therapy approaches in RP, including the retinal phenotypes of USH1, 
128 
clinically acceptable tests of the local rod and cone function, supporting the morphological 
129 
evaluations such as OCT are needed. Only understanding the dynamic of the cone and rod 
130 
degeneration over time in a retinotopically correct manner can enable us to understand the 
131 
natural history of the disease and to evaluate eventual therapy safety and efficacy in the future 
132 
1.2 Scientific Rationale  for Study Design  
133 
A prospective natural history study is the gold standard for tracking the course of disease. The 
134 
knowledge of the course of patients with PCDH15 mutations will guide the planning of future 
135 
controlled treatment trials. Identifying the most sensitive and reliable outcome measures of 
136 
retinal degeneration will greatly facilitate development of treatments with maximum efficiency.  
137 
Together, these approaches are expected to have an impact on understanding PCDH15-related 
138 
retinal degeneration, developing investigational treatment protocols, and assessing their 
139 
effectiveness. 
140 
The goals and expected impact of this natural history study are to: 
141 
• 
Describe the natural history of retinal degeneration in patients with biallelic mutations in 
142 
the PCDH15 gene 
143 
• 
Contribute to the identification of sensitive structural and functional outcome measures to 
144 
use for future multicenter clinical trials in PCDH15-related retinal degeneration  
145 
• 
Contribute to the identification of populations for future clinical trials of investigative 
146 
treatments for PCDH15-related retinal degeneration 
147 
1.3 Study Objectives  
148 
1. Characterize the natural history of retinal degeneration associated with biallelic 
149 
pathogenic mutations in the PCDH15gene over 4 years, as measured using functional, 
150 
structural, and patient-reported outcome measures  
151 
2. Explore whether structural outcome measures can be validated as surrogates for 
152 
functional outcomes in individuals with biallelic pathogenic mutations in the PCDH15 
153 
gene 
154 
3. Explore possible risk factors (genotype, phenotype, environmental, and comorbidities) 
155 
for progression of the outcome measures at 4 years in individuals with biallelic 
156 
pathogenic mutations in the PCDH15 gene 
157 
4. Explore variability and symmetry of left and right eye outcomes over 4 years in 
158 
individuals with biallelic pathogenic mutations in the PCDH15 gene 
159 
1.4 General Considerations  
160 
The study is being conducted in compliance with the ethical principles that have their origin in 
161 
the Declaration of Helsinki, with the protocol described herein, and with the standards of Good 
162 
Clinical Practice (GCP). Employing a prospective longitudinal study design is advantageous 
163 
because it reflects a systematic method of data collection.  This study design incorporates several 
164 
strategies to minimize bias, detailed below, using considerations from “Rare Diseases: Natural 
165 

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History Studies for Drug Development: Guidance for Industry, Draft Guidance.24” These are 
166 
considered standard for treatment trials and will enhance the translation of the data from this 
167 
study to a treatment trial. 
168 
 
169 
• Establishing standardized testing procedures and specific required equipment for all 
170 
investigators, leading to greater consistency and precision in the information collected 
171 
• Training and certification of study staff who will perform the following procedures 
172 
related to the primary outcomes: SP, OCT, MP, FAF) by a Reading Center. The Reading 
173 
Center will grade test results in a uniform manner independently from study sites 
174 
• Use of standard, consistent definitions of pre-existing medical conditions, medications 
175 
and treatments, and adverse events (AEs) across all clinical sites 
176 
• A consistent schedule of follow-up visits for all participants with established visit time 
177 
frames 
178 
• A coordinating center (CC) is responsible for monitoring the conduct of the study to 
179 
ensure adherence to protocol  
180 

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Chapter 2:  Study Enrollment and Screening
 Visit 
181 
2.1 Participant Recruitment 
and Enrollment   
182 
Study participants will be recruited from approximately 10 clinical sites worldwide. All eligible 
183 
participants will be included without regard to gender, race, or ethnicity. Potential eligibility will 
184 
be assessed during a routine examination by an investigator prior to obtaining informed consent, 
185 
as part of usual care, through referrals from other providers or self-referral.   
186 
2.1.1 Participant Recruitment 
Goals and Strategy   
187 
Recruitment will be tracked within two Vision Cohorts defined as follows.  Sample size 
rationale is detailed in section 6.1.    
• Vision Cohort 1: ~25 participants with the better eye Screening Visit 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:  ~15 participants with the better eye Screening Visit visual acuity 
ETDRS letter score of 19-53 [approximate Snellen equivalent 20/100 - 20/400] or 
(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) 
 
 
The better eye is defined as the eye with better Screening Visit ETDRS VA.  If both eyes 
have the same VA (defined as the same Snellen equivalent), then the determination will be 
made at investigator discretion as the eye with better fixation or clearer ocular media to 
permit highest quality retinal imaging. 
 
The visual field (VF) is defined as the clinically determined kinetic VF III4e performed 
within the last 18 months prior to or including the Screening Visit date. 
 
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 
 
188 
The Foundation Fighting Blindness (FFB) Consortium Executive Committee will review 
189 
recruitment progress and feasibility at regular intervals.  Initial recruitment goals will be as 
190 
follows: 
191 
• 40 participants enrolled in to the study cohort (Cohorts 1 and 2, combined) 
192 
• If recruitment is not at a rate to meet the initial goals, an interim assessment of feasibility 
193 
may be made by the FFB Consortium Executive Committee. A minimum of 20 participants 
194 
enrolled in Vision Cohort 1 and Vision Cohort 2 combined will be targeted. 
195 
 
196 

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Participants will not be counted as 
enrolled into  the study  cohort  until initial screening and 
197 
genetic screening have been confirmed as a success (sections 2.3 and 2.4). This means that 
198 
more participants will be screened than noted above; the number and reasons for screen failures 
199 
will be tracked.  It is also possible that some participants will have completed the Screening Visit 
200 
and will be awaiting genetic confirmation at the time the enrolled numbers reach the goals 
201 
above; therefore, the final enrolled numbers may be larger. To limit over-enrollment, clinical 
202 
sites will be notified as the recruitment goals near completion, efforts will be made to accurately 
203 
predict numbers in the genetic screening queue, and consent and screening of participants which 
204 
could contribute to over-enrollment in a given Vision Cohort may be paused.   
205 
2.2 Informed Consent and Authorization Procedures
 
206 
Potential eligibility may be assessed as part of a routine care examination by an investigator prior 
207 
to obtaining informed consent, as part of usual care, by referral from another physician, or self-
208 
referral. Before completing any procedures or collecting any data that are not part of usual care, 
209 
written informed consent will be obtained, using consent documentation approved by the 
210 
overseeing IRB/ EC.  
211 
The study protocol will be discussed with the potential study participant by study staff.  The 
212 
potential study participant will be given the Informed Consent Form (ICF) to read. Potential 
213 
study participants with severe vision impairment may be presented with a Short Form, to be read 
214 
aloud by a clinical staff member if they prefer, following the overseeing IRB/ EC requirements. 
215 
Potential study participants will be encouraged to discuss the study with family members and 
216 
their personal physicians(s) before deciding whether to participate in the study.  
217 
As part of the informed consent process, each participant will be asked to sign an authorization 
218 
for release of personal information.  The investigator, or his or her designee, will review the 
219 
study-specific information that will be collected and to whom that information will be disclosed.  
220 
After speaking with the participant, questions will be answered about the details regarding 
221 
authorization.  
222 
A participant is considered enrolled into the initial screening
 when the ICF has been signed 
223 
and a participant ID has been obtained on the study website.    
224 
An immediate family member(s) of study participants may be asked to participate in family 
225 
member genetic testing as part of the genetic screening phase. In these cases, a family member(s) 
226 
will be asked to provide a saliva sample (described in section 2.4). An electronic consent form 
227 
will be reviewed and signed by the family member(s) in order to obtain permission to collect a 
228 
saliva sample. 
229 
2.3 Screening Visit  
230 
After the ICF has been signed, a potential participant will be evaluated for study eligibility 
231 
through the elicitation of a medical history, performance of ophthalmic tests as described below, 
232 
and genetic testing, if applicable.  The Screening Visit date will be the date the Screening Visit 
233 
testing procedures started.  All Screening Visit testing procedures will be completed on this date.    
234 

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2.3.1 Eligibility  Criteria  
235 
To be eligible to enroll into the genetic screening phase, a study participant must meet all the 
236 
inclusion criteria and none of the exclusion criteria at the Screening Visit.   
237 
2.3.1.1  Participant  Criteria  
238 
Participant Inclusion Criteria 
239 
Participants must meet all the following inclusion criteria at the Screening Visit in order to be 
240 
eligible to enroll into the genetic screening  phase . 
241 
1. Willing to participate in the study and able to communicate consent during the 
242 
consent process 
243 
2. Ability to return for all study visits over 48 months  
244 
3. Age ≥ 8 years  
245 
4. Not planning to enroll in an experimental clinical trial for the treatment of PCDH15 
246 
for the duration of this study  
247 
5. Must meet one of the Genetic Screening Criteria, defined below: 
248 
• Screening Group A:   At least 2 disease-causing variants  in the PCDH15 gene 
249 
which are homozygous or heterozygous in trans , based on a report from a 
250 
clinically certified lab (or a report from a research lab that has been pre-approved 
251 
by the Genetics Committee) 
252 
• Screening Group B:  Only 1 disease-causing variant  in the PCDH15  gene, 
253 
based on a report from a clinically certified lab (or a report from a research lab 
254 
which has been pre-approved by the Genetics Committee) 
255 
• Screening Group C:   At least 2 disease-causing variants  in the PCDH15  gene 
256 
which are unknown phase , based on a report from a clinically certified lab (or a 
257 
report from a research lab which has been pre-approved by the Genetics 
258 
Committee) 
259 
 
260 
Note pertaining to all Screening Groups: if a participant has a variant(s) of unknown 
261 
significance, he/she would still qualify if there is at least 1 disease-causing variant(s) on the 
262 
PCDH15 gene.Participant Exclusion Criteria 
263 
Participants must not meet any of the following exclusion criteria at the Screening Visit in order 
264 
to be eligible to enroll into the genetic screening  phase . 
265 
1. Mutations in genes that cause autosomal dominant retinitis pigmentosa (ADRP), X-
266 
linked retinitis pigmentosa (RP), or presence of biallelic mutations in autosomal 
267 
recessive RP/retinal dystrophy genes other than PCDH15  
268 
2. Expected to enter experimental treatment trial at any time during this study 
269 
3. History of more than 1 year of cumulative treatment, at any time, with an agent 
270 
associated with pigmentary retinopathy (including hydroxychloroquine, chloroquine, 
271 
thioridazine, and deferoxamine) 
272 
 
273 
Note: Pregnant women are not being specifically excluded from participation.  
274 
 
275 

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2.3.1.2 Ocular  Criteria  
276 
Ocular Inclusion Criteria 
277 
Both eyes must meet all the following at the Screening Visit for a participant to be eligible to 
278 
enroll into the genetic screening phase
. 
279 
1. Clinical diagnosis of retinal dystrophy 
280 
2. Clear ocular media and adequate pupil dilation to permit good quality photographic 
281 
imaging 
282 
 
283 
Ocular Exclusion Criteria 
284 
If either eye has any of the following at the Screening Visit, the participant is not eligible to 
285 
enroll into the genetic screening phase
. 
286 
1. Current vitreous hemorrhage  
287 
2. Current or any history of tractional or rhegmatogenous retinal detachment   
288 
3. Current or any history of (e.g., prior to cataract or refractive surgery) spherical 
289 
equivalent of the refractive error worse than -8 Diopters of myopia  
290 
4. History of intraocular surgery (e.g., cataract surgery, vitrectomy, penetrating 
291 
keratoplasty, or LASIK) within the last 3 months 
292 
5. Current or any history of confirmed diagnosis of glaucoma (e.g., based on 
293 
glaucomatous VF changes or nerve changes, or history of glaucoma filtering surgery) 
294 
6. Current or any history of retinal vascular occlusion or proliferative diabetic 
295 
retinopathy 
296 
7. History or current evidence of ocular disease that, in the opinion of the investigator, 
297 
may confound assessment of visual function 
298 
8. History or evidence of active treatment for retinitis pigmentosa that could affect the 
299 
progression of retinal degeneration, including: 
300 
a. Any use of ocular stem cell or gene therapy 
301 
b. Any treatment with ocriplasmin 
302 
c. Treatment with an ophthalmic oligonucleotide within the last 9 months (last 
303 
treatment date is less than 9 months prior to Screening Visit date) 
304 
d. Treatment with any other product within five times the expected half-life of 
305 
the product (time from last treatment date to Screening Visit date is at least 5 
306 
times the half-life of the given product) 
307 
e. Treatment with Ozurdex (dexamethasone), Iluvien or Yutiq (fluocinolone 
308 
acetonide) intravitreal implant 
309 
2.3.2 Screening Data Collection and Testing  
310 
The study design schematic at the beginning of the protocol shows the flow of the Screening 
311 
Visit.  The following procedures will be performed at the Screening Visit. The testing procedures 
312 
are detailed in the RUSH1F Clinical Site Manual of Procedures. An overview of the equipment 
313 
and technician requirements for all testing is in section 3.4. All ocular testing will be performed 
314 
in each eye, right eye (OD) first and then left eye (OS).   
315 
Participants meeting criteria to continue will be enrolled into the genetic screening  phase  
316 
(section 2.4). Otherwise, the participant will be an initial screen failure  (section 2.3.3). The 
317 
below information will be collected at the Screening Visit:    
318 

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1. Contact information (retained at the clinical site and not entered in the study database) 
319 
2. Inclusion and exclusion criteria assessment (criteria in sections 2.3.1.1 and 2.3.1.2) 
320 
3. Demographics (including sex, race, ethnicity) 
321 
4. A medical history will be elicited from the study participant and extracted from available 
322 
medical records, including patient-reported daily activities, pre-existing medical 
323 
conditions and medications 
324 
5. Complete ophthalmic exam. Exam will include slit-lamp biomicroscopy, indirect 
325 
ophthalmoscopy, and intraocular pressure (IOP).  IOP measurements will be taken prior 
326 
to pupil dilation 
327 
6. Genetic screening assessment (including number and phase of mutations in the PCDH15 
328 
gene, history of consanguinity, and collection of the source genetic report(s) available at 
329 
the clinical site)   
330 
➢ This includes an assessment that the participant meets one of the Genetic Screening 
331 
Criteria described in section 2.3.1.1.  If the participant does not meet the criteria for 
332 
one of the Genetic Screening Groups, then the remainder of procedures and testing 
333 
are not required.  Participant will be discontinued as an initial screen failure  per 
334 
section 2.3.3 
335 
7. Visual acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed)  
336 
➢  The VA letter score will determine whether LLVA or BRVT will be performed.  The 
337 
criteria are defined in the RUSH1F Clinical Site Manual of Procedures. 
338 
8. Kinetic VF III4e (or historical measurement performed within the last 18 months prior to 
339 
or including the Screening Visit date) Vision Cohort determination, based on eye with 
340 
better visual acuity and kinetic VF above (criteria in section 2.1.1) 
341 
➢ If the participant’s determined Vision Cohort is closed for enrollment, the remainder 
342 
of procedures and testing are not required.  Participant will be discontinued as an 
343 
initial screen failure  per section 2.3.3 
344 
2.3.3 Initial Screen Failures  
345 
Participants who do not meet criteria to continue as noted above will be discontinued as an 
346 
initial screen failure . The Screening Visit Form will still be completed, entering “Not Done” for 
347 
testing not finished. A Final Status Form will be completed, and the reason for screen failure will 
348 
be noted.  
349 
2.4 Genetic Screening  Phase  
350 
Participants passing the initial screening and enrolling into the Genetic Screening Phase will 
351 
complete the following genetic testing and/or review procedures, according to their Screening 
352 
Group (defined in section 2.3.1.1). The study design schematic at the beginning of the protocol 
353 
also summarizes the flow of the Genetic Screening Phase. More detailed procedures are specified 
354 
in the RUSH1F Clinical Site Manual of Procedures. 
355 
➢ All genetic reports noted below to be uploaded to the study website by the clinical site or 
356 
Central Lab may be available to and reviewed by the CC, associated clinical site, Central 
357 

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Lab, CGA, Genetics Committee, and investigators involved in oversight of the study 
358 
(which include the study chair, Operations Committee, and FFB Consortium Executive 
359 
Committee). All reports will be de-identified prior to uploading 
360 
Screening Group A  
361 
• The clinical site will upload supporting genetic documentation (including genetic reports) 
362 
onto the study website 
363 
• A CGA will review the genetic documentation provided by the clinical site to verify the 
364 
genetic screening data entry and appropriate documentation of the final study cohort 
365 
criteria  (section 2.5) of at least 2 disease-causing variants  in the PCDH15 gene which 
366 
are homozygous or heterozygous in trans .  Additional documentation may be requested 
367 
as needed to verify the final study cohort criteria
 and all genetic screening assessments 
368 
o If final study cohort criteria
 are verified, participant will be considered enrolled 
369 
into the study cohort  
370 
o Otherwise the participant will be a genetic screen failure  (section 2.4.1)      
371 
Screening Group B or C  
372 
• The clinical site will upload supporting genetic documentation (including genetic reports) 
373 
onto the study website 
374 
• Participants will be asked to provide a saliva sample, and approach at least 1 first-degree 
375 
relative to provide a saliva sample for additional genetic testing.  The first-degree 
376 
relative(s) will be provided with information on how to provide informed consent and 
377 
how to complete the saliva kit.   
378 
• The participant’s and first degree relative(s)’s samples will be shipped to and analyzed by 
379 
the Central Lab to conduct  retinal dystrophy panel genetic testing and determine the 
380 
presence and number of disease-causing variants on the PCDH15 gene (Screening Group 
381 
B only), and the phase of the alleles from the family member testing (Screening Groups B 
382 
and C).  The Central Lab will provide these assessments and its genetic report(s), which 
383 
will be uploaded to the study website 
384 
o If the Central Lab determines there are at least 2 disease-causing variants in the 
385 
PCDH15  gene which are homozygous or heterozygous in trans, the participant’s 
386 
reports will move forward to CGA review 
387 
o Otherwise the participant will be a genetic screen failure  (section 2.4.1) 
388 
• A CGA will review the reports provided by the clinical site and the Central Lab to verify 
389 
the genetic screening data entry and appropriate documentation of the final study cohort 
390 
criteria  (section 2.5) of at least 2 disease-causing variants  in the PCDH15  gene which 
391 
are homozygous or heterozygous in trans .  Additional documentation may be requested 
392 
as needed to verify the final study cohort criteria
 and all genetic screening assessments 
393 
o If final study cohort criteria
 are verified, the participant will be considered 
394 
enrolled into the study cohort
 
395 
o Otherwise the participant will be a genetic screen failure  (section 2.4.1) 
396 

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2.4.1 Genetic Screen Failures  
397 
Participants who do not meet criteria to continue as noted above will be discontinued as a 
398 
genetic screen failure . A Final Status Form will be completed, and the reason for screen failure 
399 
will be noted.  
400 
2.4.2 Genetics Committee Review  
401 
A Genetics Committee will review the genetic documentation of participants with verified final 
402 
study cohort criteria  and enrolled into the study cohort
 for interpretation/evaluation of 
403 
whether the PCDH15 mutations are causative of the disease (i.e., pathogenic, likely pathogenic). 
404 
Details of the process are described in the RUSH1F Monitoring Plan. Cases that are not 
405 
confirmed as disease- causing will remain in the study and will not be considered ineligible, 
406 
however their data may be analyzed separately from those with pathogenic mutations.    
407 
2.5  Participants Enrolled into the Natural History Study
 
408 
All participants meeting initial screening and eligibility criteria (section 2.3.1) who complete the 
409 
Genetic Screening Phase (section 2.4) and meet the final study cohort criteria
 (defined below) 
410 
will be considered enrolled into the study cohort 
and will complete the natural history study.  
411 
➢ Final Study Cohort Criteria
: At least 2 disease-causing variants  in the PCDH15 gene 
412 
which are homozygous or heterozygous in trans , based on a report from a clinically 
413 
certified lab (or a report from a research lab that has been pre-approved by the study 
414 
genetics committee), and confirmed by a CGA. 
415 

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Chapter 3:  Natural History Study  Procedures  
416 
3.1 Baseline Visit  
417 
Participants meeting criteria to enter the natural history study (section 2.5) will return for a 
418 
Baseline Visit date within thirty (30) days after receiving confirmation of meeting final study 
419 
cohort criteria from the CGA. The Baseline Visit date will be documented as the date testing 
420 
procedures began. All Baseline Visit testing procedures will be completed within seven (7) days 
421 
of the Baseline Visit date, except PROs as specified below.    
422 
 
423 
The testing procedures that are performed at the Screening Visit will serve as baseline measures 
424 
for the study and will not be completed again at the Baseline Visit. The only exception will be if 
425 
the Baseline Visit date is more than ninety (90) days after the Screening Visit date. The visual 
426 
acuity testing will need to be repeated (including refraction, ETDRS, LLVA if needed, BRVT if 
427 
needed) if the baseline visit is completed more than ninety (90) days from the screening visit.  
428 
3.2 Baseline Testing Procedures  
429 
The following procedures will be performed at the Baseline Visit.  The testing procedures are 
430 
detailed in the RUSH1F Clinical Site Manual of Procedures. An overview of the equipment 
431 
and certification requirements for all testing is in 
section 3.4.  All ocular testing will be 
432 
performed in each eye, OD first and then OS.   
433 
1. Medical updates, including new/changed adverse events, ocular procedures, and 
434 
medications  
435 
2. Audiology history  
436 
a. Participant-reported audiology history will be collected on the Audiology History 
437 
Information Form. This includes history of hearing loss, newborn screening 
438 
hearing, hearing aid use, cochlear implant use, history of ear infections, history of 
439 
ear surgery and balance disorders. 
440 
3. Audiogram (request the most recent pre-cochlear implant audiogram) 
441 
a. The most recent available audiogram prior to cochlear implant will be collected 
442 
on each participant including air conduction threshold and bone conduction 
443 
threshold. The Audiogram Results Form will be completed using the most recent 
444 
audiogram. The historical audiogram will be sent to the central study audiologist 
445 
reviewer, to confirm correct interpretation for the Results Form. 
446 
4. Patient Reported Outcomes  (Adults: MRDQ and PROMISﬁ-29; Children: LPV-FVQ II) 
447 
a. The PROs may be completed in person or remotely (phone or other remote 
448 
methods) any time within 6 months of the Baseline Visit (not required to be the 
449 
same day as the rest of the Baseline Visit). 
450 
5. Contrast sensitivity  
451 
6. SD-OCT 
452 
7. Axial Length and Corneal Curvature measurements 
453 
8. Near Infrared Reflectance Photos 
454 

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9. Full-field Stimulus Threshold 
455 
10. Fundus Autofluorescence (on Optos, where available) 
456 
11. Static perimetry  
457 
a. Two tests will be performed.  The clinical site will compare the certified 
458 
technician-determined mean sensitivity from test 1 versus test 2 
459 
o If the absolute value of the difference between the two tests is ≤ 2.4 dB, then 
460 
the participant passes static perimetry reliability criteria and a third test is not 
461 
needed 
462 
o If the absolute value of the difference between the two tests is > 2.4 dB then 
463 
the participant does not pass static perimetry reliability criteria, and a third test 
464 
is needed 
465 
12. Fundus-guided microperimetry 
466 
a. Two tests will be performed. The clinical site will compare the certified 
467 
technician-determined mean sensitivity from test 1 versus test 2 
468 
o If the absolute value of the difference between the two tests divided by the 
469 
average between them is ≤ 50% OR the absolute value of the difference 
470 
between the two tests is ≤ 0.5 dB, then the participant passes microperimetry 
471 
reliability criteria and a third test is not needed 
472 
o If the absolute value of the difference between the two tests divided by the 
473 
average between them is > 50% AND the absolute value of the difference 
474 
between the two tests is > 0.5 dB, then the participant does not pass 
475 
microperimetry reliability criteria and a third test is needed 
476 
3.3 Follow-up Visits  
477 
The Baseline Visit date is considered study day 0, from which follow-up visit windows are 
478 
timed.  The Follow-up Visit date will be the date the Follow-up Visit testing procedures started.  
479 
All Follow-up Visit testing procedures will be completed on the same date other than the PROs 
480 
required at the 24 Month and 48 Month Visits, which can be completed ± 6 weeks of the visits. 
481 
 
482 
Follow up visits will be conducted at: 
483 
Visit 
Target  
Target Window  
Allowable Window  
12 Month Visit  
52 Weeks  
– 4 Weeks 
– 6 Weeks 
24 Month Visit  
104 Weeks 
– 4 Weeks 
– 6 Weeks 
36 Month Visit  
156 Weeks  
– 4 Weeks 
– 6 Weeks 
48 Month Visit  
208 Weeks 
– 4 Weeks 
– 6 Weeks 
 
484 
Visits will be scheduled in the target window. If circumstances do not permit this, visits may be 
485 
scheduled to extend out to the allowable window without being considered a protocol deviation. 
486 

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The reason for scheduling outside of the target window must be documented on the visit form. 
487 
Visits that occur out of the allowable window will be used for analysis but will be documented as 
488 
protocol deviations. Details regarding when to consider a visit missed are specified in the 
489 
RUSH1F Clinical Site Manual of Procedures. 
490 
3.3.1 Follow-up Visit Testing Procedures  
491 
The following procedures will be performed at the Follow-up Visits as noted below.  The testing 
492 
procedures are detailed in the RUSH1F Clinical Site Manual of Procedures.  An overview of the 
493 
equipment and certification requirements for all testing is in section 3.4.  All ocular testing will 
494 
be performed in each eye, OD first and then OS.  
495 
 
496 
The following will be performed at the 12 Month, 24 Month, 36 Month, and 48 Month Visits 
497 
unless otherwise noted. 
498 
1. Medical updates, including new/changed AEs, ocular procedures, and medications  
499 
2. Patient Reported Outcomes at 24-Month and 48-Month visits only(Adults: MRDQ and 
500 
PROMISﬁ-29; Children: LPV-FVQ II) 
501 
a. The PROs may be completed in person or remotely (phone or other remote 
502 
methods) any time within the Allowable Window of the associated visit, (not 
503 
required to be the same day as the rest of the Follow up Visit). 
504 
3. Complete ophthalmic exam. Exam will include slit-lamp biomicroscopy, indirect 
505 
ophthalmoscopy, and intraocular pressure (IOP).  IOP measurements will be taken prior 
506 
to pupil dilation 
507 
4. Visual acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed)  
508 
a. The visual acuity letter score will determine whether LLVA or BRVT will be 
509 
performed.  The criteria are defined in the RUSH1F Clinical Site Manual of 
510 
Procedures 
511 
5. Contrast sensitivity 
512 
6. SD-OCT  
513 
7. Full-field Stimulus Threshold 
514 
8. Fundus Autofluorescence (on Optos, where available) 
515 
9. Static perimetry 
516 
10. Fundus-guided Microperimetry 
517 
3.3.2 Unscheduled Visits  
518 
Testing procedures at unscheduled visits are at investigator discretion. However, it is 
519 
recommended that procedures performed during these visits follow the standard protocol for 
520 
each procedure and be performed by certified personnel. Unscheduled visits will be recorded on 
521 
the FFB Consortium study website. Study images taken during unscheduled visits do not require 
522 
submission to the study website. 
523 

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3.4 Personnel and Equipment Requirements for Study Procedures
 
524 
The testing procedures are detailed in the RUSH1F Clinical Site Manual of Procedures. An 
525 
overview of the equipment and certification requirements for all testing are as follows. 
526 
Study Procedures  
Equipment Required  (if 
applicable)  
Who can Perform  
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: 
explanation/review of study with the 
potential participant and/or 
signature of ICF 
 
N/A 
Certified investigator/coordinator 
as permitted by the IRB/EC 
Signature of Informed Consent 
Form 
N/A 
Certified investigator/coordinator 
as permitted by the IRB/EC 
Data entry on study website 
Computer and internet 
connection 
Certified coordinator  
(or certified investigator with 
additional study website 
certification) 
Sample collection and shipping 
Study will provide necessary 
materials – detailed in 
RUSH1F Clinical Site 
Manual of Procedures 
Certified coordinator 
Collect information regarding 
medical history, demographics, 
adverse events, medications 
N/A 
Certified investigator/coordinator 
Patient Reported Outcomes 
Study will provide necessary 
materials – detailed in 
RUSH1F Clinical Site 
Manual of Procedures 
Certified investigator/coordinator 
Ocular Exam  
(including slit lamp biomicroscopy, 
indirect ophthalmoscopy and 
intraocular pressure IOP) 
Any equipment is acceptable 
Certified investigator 
Visual Acuity - Refraction 
N/A 
Clinical site personnel certified 
for refraction 
Visual Acuity - ETDRS 
EVA system (preferred) 
otherwise ETDRS charts 
Clinical site personnel certified 
for ETDRS 

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Visual Acuity - LLVA 
EVA system (preferred) 
otherwise ETDRS charts 
2.0 neutral density filter to be 
provided by study 
Clinical site personnel certified 
for performing ETDRS is also 
certified to perform LLVA 
Visual Acuity - BRVT 
BRVT charts provided by 
study 
Clinical site personnel certified 
for BRVT 
Contrast Sensitivity 
VectorVision CSV-1000E 
provided by study 
Clinical site personnel performing 
this testing do not require a study-
specific certification but must be 
trained and delegated by the PI 
per the SSDL 
SD-OCT 
Heidelberg Spectralis 
Clinical site personnel certified 
for SD-OCT 
Fundus Autofluorescence (on 
Optos) 
Optos (where available) 
 
Clinical site personnel certified 
for Fundus Autofluorescence on 
Optos 
Axial Length and Corneal Curvature Any equipment is acceptable 
Clinical site personnel performing 
this testing do not require a study-
specific certification but must be 
trained and delegated by the PI 
per the SSDL 
Near Infrared Reflectance Photos 
Heidelberg Spectralis ( with 
55degree lens)* 
Clinical site personnel certified 
for Near Infrared Photos 
FST 
Diagnosys Espion  
Clinical site personnel performing 
this testing do not require a study-
specific certification but must be 
trained and delegated by the PI 
per the SSDL 
Static Perimetry 
Octopus 900 Pro (GATE 
Protocol) 
Clinical site personnel certified 
for SP 
Fundus-guided Microperimetry 
MAIA 
Clinical site personnel certified 
for MP   
Kinetic Perimetry (historical) 
Any equipment is acceptable 
(Historical) Does not need to be 
performed by study certified 
personnel or recorded in the 
RUSH1F Study Staff Delegation 
Log 
*Required for all sites except with the exception of any site with equivalent equipment approved by the reading center and 
527 
operations committee.
528 

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Chapter 4:  Unanticipated Problems and 
Adverse Event  Reporting  
529 
4.1 Unanticipated Problems  
530 
Site investigators will promptly report to the CC all unanticipated problems meeting the criteria 
531 
below via the Unanticipated Problems eCRF. For this protocol, an unanticipated problem is an 
532 
incident, experience, or outcome that meets all the following criteria: 
533 
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
534 
that are described in the protocol related documents, such as the IRB/EC-approved 
535 
research protocol and informed consent document; and (b) the characteristics of the 
536 
subject population being studied 
537 
• Related or possibly related to participation in the research (possibly related means there is 
538 
a reasonable possibility that the incident, experience, or outcome may have been caused 
539 
by the procedures involved in the research) 
540 
• Suggests that the research places participants or others at a greater risk of harm than was 
541 
previously known or recognized (including physical, psychological, economic, or social 
542 
harm)   
543 
Sites will follow the overseeing IRB’s Unanticipated Problem reporting requirements as 
544 
applicable. The CC also will report to the IRB all unanticipated problems not directly involving a 
545 
specific site such as unanticipated problems that occur at the CC or at another participating entity 
546 
such as a laboratory. 
547 
4.2 Adverse Events  
548 
4.2.1 Definition  
549 
Adverse Event (AE):  Any untoward or unfavorable medical occurrence in a human subject, 
550 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
551 
symptom, or disease, temporally associated with the subject’s participation in the research, 
552 
whether or not considered related to the subject’s participation in the research (modified from the 
553 
definition of AEs in the Integrated Addendum to ICH E6 (R2)).24 
554 
 Serious Adverse Event (SAE):  Any untoward medical occurrence that: 
555 
• Results in death 
556 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
557 
have become life-threatening, is not necessarily considered a SAE) 
558 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
559 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
560 
ability to conduct normal life functions (sight threatening) 
561 
• Is a congenital anomaly or birth defect 
562 
• Is considered a significant medical event by the investigator based on medical judgment 
563 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
564 
prevent one of the outcomes listed above) 
565 

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4.2.2 Reportable Adverse Events  
566 
For this protocol, a reportable AE includes all events meeting the definition of an AE above. 
567 
All AEs—whether volunteered by the participant, discovered by study personnel during 
568 
questioning, or detected through examination, laboratory test, or other means—will be reported 
569 
on an AE form online.  
570 
The purpose of AE collection for the RUSH1F study will be to provide historical controls for 
571 
future clinical trials.  As a no greater than minimal risk study, AEs do not require any specific 
572 
reporting to regulatory or oversight bodies.  Each Principal Investigator is responsible for abiding 
573 
by any other reporting requirements specific to his/her IRB or equivalent ethics oversight 
574 
committee. 
575 
4.2.3 Relationship of Adverse Event to Study Procedure
 
576 
The study investigator will assess the relationship of any AE to be related or unrelated to a study 
577 
procedure by determining if there is a reasonable possibility that the AE may have been caused 
578 
by the procedure.  
579 
To ensure consistency of AE causality assessments, investigators will apply the following 
580 
general guideline when determining whether an AE is related: 
581 
Yes: 
582 
There is a plausible temporal relationship between the onset of the AE and a study procedure, 
583 
and the AE cannot be readily explained by the participant’s clinical state, intercurrent illness, or 
584 
concomitant therapies; and/or the AE follows a known pattern of response to a study procedure; 
585 
and/or the AE abates or resolves upon discontinuation of a study procedure and, if applicable, 
586 
reappears upon re-challenge. 
587 
No: 
588 
Evidence exists that the AE has an etiology other than a study procedure (e.g., preexisting 
589 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
590 
the AE has no plausible temporal relationship to a study procedure. 
591 
4.2.4 Severity (Intensity) of Adverse  Event  
592 
The severity (intensity) of an AE will be rated on a three-point scale: (1) mild, (2) moderate, or 
593 
(3) severe. A severity assessment is a clinical determination of the intensity of an event. Thus, a 
594 
severe AE is not necessarily serious.  For example, itching for several days may be rated as 
595 
severe, but may not be clinically serious. 
596 
1. MILD:  Usually transient, requires no special treatment, and does not interfere with the 
597 
participant’s daily activities 
598 
2. MODERATE:  Usually causes a low level of inconvenience, discomfort or concern to 
599 
the participant and may interfere with daily activities but is usually ameliorated by simple 
600 
therapeutic measures and participant is able to continue in study 
601 
3. SEVERE:  Interrupts a participant’s usual daily activities, causes severe discomfort, may 
602 
cause discontinuation of study drug, and generally requires systemic drug therapy or 
603 
other treatment 
604 

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4.3 Pregnancy Reporting  
605 
If a pregnancy occurs, the participant will remain in the study. The occurrence of pregnancy will 
606 
be reported to the Coordinating Center within seven (7) days of the site’s discovery of the 
607 
pregnancy (including at screening) and the Pregnancy Notification form will be completed 
608 
within seven (7) calendar days. Sites will collect concomitant medications throughout the 
609 
pregnancy. If an Adverse Event occurs as a result of the pregnancy, then the site will record the 
610 
Adverse Event on the Adverse Event form.  
611 
 
612 
613 

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Chapter 5:  Miscellaneous Considerations  
614 
5.1 Treatment s During the Study  
615 
5.1.1 Treatmen t for PCDH15 -Related Retinal Degeneration  
616 
Participants enrolled into the final study cohort will be asked to not enroll into experimental 
617 
treatment trials of underlying conditions related to PCDH15 mutations during the 4-year study 
618 
duration. Should a participant enroll into a treatment trial during participation, the Executive 
619 
Committee will decide as to their continuance in RUSH1F.   
620 
5.1.2 Treatment for Cystoid  Macular Edema  
621 
Participants enrolled into the final study cohort, who need to receive treatment for CME 
622 
during the study, may continue treatment. 
623 
5.1.3 Intraocular Surgical Procedures 
 
624 
Participants enrolled into the final study cohort
 who have intraocular surgery during the study 
625 
will have follow-up visits timed either before the surgery date or at least 3 months after the 
626 
surgery date. Clinical sites will make reasonable efforts to schedule the participant’s follow-up 
627 
visit as close to the visit target window as possible.   
628 
 
629 
5.2 Risks and Benefits  
630 
5.2.1 Risks and Discomforts  
631 
Most examination procedures are considered part of standard care for retinal degenerations.  This 
632 
study will be capturing some information about participants that include identifiable, personal 
633 
information, like date of birth (will be collected if permitted by site’s regulatory bodies). The 
634 
study has procedures in place to protect that information. However, there is a chance that a loss 
635 
of that protection could occur. This would be a loss of confidentiality. There are special efforts 
636 
being made to ensure that this does not happen. Otherwise, there are no known risks or 
637 
discomforts beyond those involved in standard clinical care for patients with retinal degeneration 
638 
involved in participation in this study, which involves systematically collecting information in a 
639 
prospective fashion.  
640 
The sections below summarize the risks and discomforts that may be involved in the usual care 
641 
of the patient during the period of prospective data collection. 
642 
• Risks associated with testing VA, KP, SP, Optos FAF, near infrared reflectance photos, 
643 
and PRO may include boredom and frustration, but no lasting adverse effects are 
644 
associated with these noninvasive tests 
645 
• Dilating eye drops will be used as part of the ophthalmic examination and before the SD-
646 
OCT, FST, and MP. Dilating eye drops may sting, cause light-sensitivity, or an allergic 
647 
reaction. There is a small risk of inducing a narrow-angle glaucoma attack from the pupil 
648 
dilation. However, all participants will have had prior pupil dilation usually on multiple 
649 
occasions and therefore the risk is extremely small.  If glaucoma occurs, treatment is 
650 
available. 
651 

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• IOP Examination: In rare instances, the cornea may be scratched during measurement of 
652 
intra-ocular pressure or use of a contact lens electrode.  An abrasion like this may be 
653 
painful, but it heals quickly with no lasting effects.  If a participant experiences a corneal 
654 
abrasion, a tear ointment may be administered, and an eye patch or gauze may be placed 
655 
over the eye 
656 
• The risks of genetic testing include emotional and psychological stress when patients may 
657 
learn they have a genetic disease that could be passed along to their children, if 
658 
information relating to the family, such as adoption and paternity, could be determined 
659 
from these tests. All the genetic testing information will be kept in confidential laboratory 
660 
documents and medical records. If data gathered through genetic testing is accidentally 
661 
released or stolen, it is possible that the information could become available to an insurer, 
662 
an employer, a relative, or someone else. There are discrimination protections in US 
663 
Federal Law and many State laws, however there is still a small chance that participants 
664 
could be harmed if a release occurred 
665 
5.2.2 Benefits  
666 
Study participants are not expected to benefit directly from participation in this study.  Subjects 
667 
participating in this study may benefit from close attention from the study personnel and PI.   
668 
The risks of participating in the study are outweighed by the benefits including increased 
669 
attention from the study personnel and the ability to contribute to increased understanding of the 
670 
natural history of PCDH15-related retinal degeneration and contribute to future development of 
671 
treatments. 
672 
5.3 Collection of Pre -Existing Conditions and Medications  
673 
Pre -Existing Co ndition : Any medical condition that is either present at screening, a chronic 
674 
disease, or a prior condition that could impact the participant’s health during the study (e.g., prior 
675 
myocardial infarction or stroke) will be recorded. 
676 
Medications : All medication for the treatment of chronic pre-existing conditions, medical 
677 
conditions, and/or AEs that the participant is currently taking at screening and during the study 
678 
will be recorded.  Nutraceuticals and preventative treatment also will be recorded. 
679 
5.4 Participant Compensation
 
680 
Participant compensation will be specified in the ICF. 
681 
5.5 Participant Withdrawal
 
682 
Participation in the study is voluntary, and a participant may withdraw at any time.  For 
683 
participants who withdraw, their data will be used up until the time of withdrawal. 
684 
5.6 Confidentiality  
685 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
686 
used instead of their name. Protected health information gathered for this study will be shared 
687 
with the FFB Consortium CC, the Jaeb Center for Health Research in Tampa, Florida, USA. De-
688 
identified participant information may also be provided to research sites involved in the study.
689 

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Chapter 6:  Statistical Consideration s 
690 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
691 
analysis plan will be written and finalized prior to the completion of the study.  The analysis plan 
692 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
693 
6.1 Sample Size  
694 
The sample size evaluation focuses on objective 1 of the study, to characterize the natural history 
695 
of retinal degeneration associated with biallelic pathogenic mutations in the PCDH15 gene over 
696 
4 years on both the structural and functional outcomes of interest.  Calculations to address 
697 
objective 3, explore possible risk factors associated with progression, are summarized.  A 
698 
justification of the selected sample size using percent change for the outcomes of interest is 
699 
outlined.  The precision of the between-eye correlation is also provided. 
700 
6.1.1 Sample Size Considerations for Evaluating Percent Change from Baseline to 4 Years 
701 
(All Outcomes)  
702 
Longitudinal changes on all outcome parameters being collected will be of interest.  Change 
703 
from baseline to 4 years will be evaluated for sample size purposes.  The power/sample size 
704 
calculations may be used to consider percent change on any outcome measure from baseline to 4 
705 
years.   
706 
Both eyes of a participant will be assessed for the main outcomes of interest.  Thus, if there are N 
707 
participants, 2N eyes will be available for analysis.  However, outcome measures from 2 eyes of 
708 
a person are typically strongly correlated (r ≥0.5).  The contribution of information in this case is 
709 
(2/(1+r)) instead of 2.  Values for the multiplier to the number of participants to obtain an 
710 
effective sample size are given below: 
711 
r 
Effective 
N 
0.0 
2.00 
0.1 
1.82 
0.2 
1.67 
0.3 
1.54 
0.4 
1.43 
0.5 
1.33 
0.6 
1.25 
0.7 
1.18 
0.8 
1.11 
0.9 
1.05 
1.0 
1.00 
 
712 

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One objective is to estimate the correlation between eyes for the outcome measures; therefore, 
713 
the value of the correlation is not known at the time of study design.  We assume here a 
714 
correlation of 0.8.  This assumption is conservative in that it requires a higher number of 
715 
participants that other plausible values of r.  
716 
The primary way sample size is evaluated is by considering the precision around the point 
717 
estimates for the outcome measures of interest.  Table 1 (including the table of specific values 
718 
corresponding to the graph) provides the half width of the 95% confidence interval (CI) for the 
719 
estimated mean percent change for combinations of the standard deviation (SD) of the 
720 
distribution of percent change and sample size.  The larger the SD, the wider the CI, meaning the 
721 
range of possible true values grows.    
722 
Table 1. Sample size versus half width of 95% confidence interval for the mean percent 
723 
change for varying standard deviation values 
724 
 
Effective Sample Size (N of participants)  
 
n=11 (10) 
n= 22 (20) 
n= 33 (30) 
n= 44 (40) 
n=55 (50) 
SD=20%  
12% 
8% 
7% 
6% 
5% 
SD=30%  
18% 
13% 
10% 
9% 
8% 
SD=40%  
24% 
17% 
14% 
12% 
11% 
SD=50%  
30% 
21% 
17% 
15% 
13% 
Note: Shaded columns correspond to the range of sample sizes feasible based on preliminary 
725 
patient counts and financial constraints 
726 
6.1.2 Sample Size Considerations for Comparing Percent Change from Baseline to 4 Years 
727 
within Subgroups of Interest (All Outcomes)
 
728 
Another important objective for this natural history study will be to explore the association of 
729 
possible risk factors with progression of various functional outcome variables (objective 3).  
730 
Figure 1 considers various expected SDs of the distribution of percent change from baseline to 4 
731 
years per eye and evaluates the power to detect varying differences in average percent change 
732 
from baseline to 4 years, comparing subgroups of various equally distributed sizes.  If subgroups 
733 
are not equally sized the detectable difference (with the same power) will be larger. Testing will 
734 
be performed with a Type I (α) error rate of 0.05.  
735 
Note: within subgroup point estimates and CIs will also be important.  Table 1 above can be 
736 
applied to potential subgroup sample sizes as well to consider the precision that would be 
737 
observed.   
738 
Figure 1.  Power to conclude there is a difference given varying true difference values, 
739 
population standard deviation, and sample size  
740 

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Effective sample size N= 11 (sample size = 10) 
 
 
Effective sample size N= 22 (sample size = 20)  
 
Effective sample size N= 33 (sample size=30) 
 
Effective sample size N= 44 (sample size = 40) 
 
 
 
741 
Power to conclude there is a difference, when true difference in mean percent change is x-axis 
742 
value. Assuming various sample size (subgroups close to equal distribution). 
743 
For example, with an effective sample size 22 and an effective sample size of 11 in each group, 
744 
to have power of 80% or more, the true difference needs to be approximately 1.25 SDs (a mean 
745 
difference of 25% if the SD of the percent change over 4 years 20%).  If the effective sample size 
746 
is 33, the true difference needs to be approximately 1.0 SD (a mean difference 20% if the SD of 
747 
the percent change over 4 years is 20%).  If the effective sample size is 44, the true difference 
748 
needs to be approximately 0.86 SDs (a mean difference 17% if the SD of the percent change over 
749 
4 years is 20%). Such mean differences are considered large. 
750 
 
751 
6.1.3 Sample Size Considerations for Precision of the Estimate of the Correlation between 
752 
Eyes 
753 
The intraclass correlation coefficient is used to assess the strength of correlation between eyes.  
754 
When both eyes have the same mean for the outcome measure, the intraclass correlation 
755 
coefficient is equal to the standard Pearson correlation coefficient (r).  The distribution of r is not 
756 
symmetric; therefore, CIs for the estimated correlation coefficient are not symmetric.  A 
757 
transformation of r (z = 0.5 * ln ((1+r)/1-r)) is used to create a variable that is asymptotically 
758 

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PAGE 39 OF 48 
distributed N (0, 1/(sqrt(N-3))) under the null hypothesis that r=0.  The table below provides the 
759 
95% CI for different estimates of r from the observed data.   
760 
Table 2. 95% Confidence Intervals for an Observed Value of r  
761 
 
762 
 
N of patients  
r 
n= 10  
n= 20  
n= 30  
n= 40  
n=50  
0.3     (-0.41,0.78)  
(-0.16,0.66)  
(-0.07,0.60)  
(-0.01,0.56)  
(0.02,0.53)  
0.4 
(-0.31,0.82)  
(-0.05,0.72)  
(0.05,0.66)  
(0.10,0.63)  
(0.14,0.61)  
0.5 
(-0.19,0.86)  
(0.07,0.77)  
(0.17,0.73)  
(0.22,0.70)  
(0.26,0.68)  
0.6 
(-0.05,0.89)  
(0.21,0.82)  
(0.31,0.79)  
(0.35,0.77)  
(0.39,0.75)  
0.7 
(0.13,0.92)  
(0.37,0.87)  
(0.45,0.85)  
(0.50,0.83)  
(0.52,0.82)  
0.8 
(0.34,0.95)  
(0.55,0.92)  
(0.62,0.90)  
(0.65,0.89)  
(0.67,0.88)  
0.9 
(0.62,0.98)  
(0.76,0.96)  
(0.80,0.95)  
(0.82,0.95)  
(0.83,0.94)  
Note: Shaded columns correspond to the range of sample sizes feasible based on preliminary 
763 
patient counts and financial constraints 
764 
 
765 
6.1.4 Final Sample Size Justification  
766 
Longitudinal changes in all outcome parameters being collected will be of interest for objectives 
767 
1 and 3.  Information on rates of decline for PCDH15, and for inherited retinal degenerations in 
768 
general, is very limited.  
769 
Data to consider for evaluating sa
mple size:  
770 
• Valproic Acid Protocol (VPA) Data (a phase II multiple site, randomized, placebo-
771 
controlled trial of oral valproic acid for ADRP) [Placebo group N=44; dataset can be 
772 
accessed at https://public.jaeb.org/ffb/stdy]  
773 
o Percent Change from Baseline to 1 year, Mean (SD): 
774 
▪ -0.3% (16%) OD 
775 
▪  -4.9% (17%) OS 
776 
• Natural history of 15 participants with EYS mutations (McGuigan/Jacobson, 2017)  
777 
o -5.7% per year for VA [8 participants] 
778 
o -5.8% for Inner Segment/Outer Segment (IS/OS) extent  
779 
• Natural history of 12 participants with EYS mutations (Miyata/Yoshimura, 2016) 
780 
o -5.2 –3.1% for IS/OS extent 
781 
Assumptions made:  
782 
• Expect average annual decline in the PCDH15 eyes will be 5% per year or 20% by 4 
783 
years  
784 
• True SD of percent change at 4 years is like VPA 1-year SD of approximately 20%  
785 

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If 30 patients or 33 effective eyes are recruited: With an effective sample size of 33, the half 
786 
width of a 95% CI around the point estimate for mean percent change would be 7%.  A 
787 
comparison of two equal-sized subgroups would have about 80% power to conclude there is a 
788 
difference if the true difference is 20%.  
789 
If 40 patients or 44 effective eyes are recruited: With an effective sample size of 44, the half 
790 
width of a 95% CI around the point estimate for mean percent change would be 6%.  A 
791 
comparison of two equal-sized subgroups would have about 80% power to conclude there is a 
792 
difference if the true difference is 17%.  
793 
For objective 4 of evaluating variability and symmetry, a sample size of 30 participants for 
794 
Vision Cohorts 1 and 2 will have a 95% CI of (0.17,0.73) when observed r equals to 0.5, and 
795 
(0.62,0.90) when observed r equals to 0.8.  A sample size of 40 participants for Vision Cohorts 1 
796 
and 2 will have a 95% CI of (0.22,0.70) when observed r equals to 0.5, and (0.65,0.89) when 
797 
observed r equals to 0.8.   
798 
Recruitment is anticipated to take 10 months from the time of study launch.  
799 
6.2 Data Analysis 
800 
The analysis plans below are written with respect to the majority of outcomes of interest. 
801 
Analyses will include data on both eyes for each participant, and confidence intervals will adjust 
802 
for correlation between 2 eyes of the same participant.     
803 
6.2.1 Primary Objectives Analyses 
804 
The primary objectives of the natural history study and brief analysis plan for each are as 
805 
follows.   
806 
1. Characterize the natural h
istory of retinal degeneration associated with biallelic disease
-
807 
causing variants in the PCDH15 gene over 4 years, as measured using functional, 
808 
structural, and patient
-reported outcome
 measures 
809 
a. Analysis plan for functional and structural measures
: The distribution of each 
810 
outcome at each visit will be summarized (including tabulating categorically, as 
811 
well as means, SDs, medians, quartiles, ranges; both the absolute change and 
812 
percent change will be evaluated
, tests performed multiple times will b
e analyzed 
813 
using average of all available tests). 
To determine the average annual rate of 
814 
progression in the population for each outcome, a repeated measure least squares 
815 
regression model will be fit using all available outcome data at baseline and all 
816 
annual visits. Multiple imputation will be used to impute the outcome values for 
817 
all missing time points (including participants who discontinue follow up prior to 
818 
48 months).  Secondary analyses using binary definitions of outcome measures 
819 
will also be explored in time to event analyses; Kaplan
-Meier estimates with 95% 
820 
confidence intervals will be calculated
.  
821 
b. Analysis plan for PRO measures:
 The scoring of each questionnaire will be 
822 
completed according to the procedures for each instrument and is detailed further 
823 
in a separate statistical analysis plan. Baseline scores will be cross tabulated with 
824 
categorical (severity of disease) versions of the outcome measures of interest at 
825 
baseline. Changes in scores will be cross tabulated with binary (progression of 
826 
disease) versions of the outcome measures of interest at the 24- and 48-month 
827 

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visits. A generalized linear model adjusted for baseline differences will be 
828 
explored. 
829 
2. Explore whether structural outcome measures can be validated as surrogates for 
830 
functional outcomes in individuals with biallelic pathogenic mutations in the 
PCDH15 
831 
gene 
832 
a. Analysis plan:  Scatterplots and Spearman correlation coefficients of changes in 
833 
SD-OCT EZ area versus 
VF progression from baseline to each visit will be 
834 
evaluated.   
835 
3. Explore possible risk factors (genotype, phenotype, environmental, and comorbidities) 
836 
for progression of the outcome measures at 4 years in individuals with biallelic 
837 
pathogenic mutations in the 
PCDH15 gene 
838 
• Analysis plan: The distribution of each outcome in terms of 
both absolute 
839 
change and percent change from baseline to 4 years will be summarized 
840 
(including tabulating categorically, as we
ll as means, standard deviations, 
841 
medians, quartiles), stratified by categorical levels of each potential risk factor 
842 
of interest (listed below).   Potential risk factors to evaluate include:
 
843 
o Phenotypic: 
844 
▪ Clinical diagnosis  
845 
▪ Age of onset of initial vision symptoms 
846 
▪ Gender  
847 
▪ Race/ethnicity 
848 
▪ Visual acuity 
849 
▪ Lens Status (phakic/pseudophakic/aphakic)
 
850 
▪ SD-OCT (as factors related to SP Hill Of 
Vision (HOV)) 
851 
• Presence of cysts 
 
852 
• Central subfield thickness
 
853 
 
854 
▪ MP 
855 
• Mean retinal sensitivity  
856 
 
857 
▪ SP (as factors related to 
SD-OCT EZ area) 
858 
• Volume of 30 degrees HOV 
 
859 
• Mean sensitivity   
860 
• Full field HOV  
861 
o Genotypic: 
862 
▪ Characterizations of the variants on the PCDH15 protein 
863 
o Environmental factors 
864 
▪ Smoking status at baseline 
865 
▪ Vitamin A use at baseline 
866 
▪ Docosahexaenoic acid (DHA) use at baseline 
867 
▪ Lutein use at baseline 
868 

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4. Evaluate variability of repeat perimetry testing and symmetry of left and right eye 
869 
outcomes over 4 years in individuals with biallelic pathogenic mutations in the PCDH15  
870 
gene 
871 
a. Analysis plan for variability of repeat perimetry testing at baseline:  Scatterplots 
872 
and Spearman correlation coefficients for pairs (first versus second) of testing 
873 
values for each repeated perimetry test.  Bland-Altman plots of difference versus 
874 
the mean value will be inspected. The intraclass correlation coefficient of the 
875 
values and the within-person variance will be estimated. 
876 
b. Analysis plan for the symmetry of left eye versus right eye:  At baseline and each 
877 
subsequent testing time, the symmetry of the test result values from the left and 
878 
right eyes will be assessed and the symmetry of the change from baseline from the 
879 
left and right eyes will be assessed for each follow-up visit. Bland-Altman plots of 
880 
the inter-eye difference versus the mean value will be inspected. The intraclass 
881 
correlation coefficient of the values will be estimated. 
882 
6.2.2 Interim Data Analysis  
883 
No formal interim analysis or “stopping guidelines” are planned for determining early stopping 
884 
according to statistical rules, as no intervention is being studied and thus early efficacy and 
885 
safety signals are not applicable.   
886 
Interim analyses will be planned for other reasons, including to evaluate data at baseline and 
887 
annual visits for reporting in preliminary manuscripts, as well as monitoring data for recruitment 
888 
and retention benchmarks, and quality assurance throughout the duration of the study.  The FFB 
889 
Consortium Executive Committee will review and oversee these data and their use in reporting.    
890 
 
 
891 

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Chapter 7:  Data Collection and Monitoring
 
892 
7.1 Case Report Forms and Other Data Collection  
893 
The main study data are collected on electronic case report forms (eCRFs). When data are 
894 
directly collected in eCRFs, this will be considered the source data. For any data points for which 
895 
the eCRF is not considered source (e.g., lab results which are transcribed from a printed report 
896 
into the eCRF), the original source documentation must be maintained in the participant’s study 
897 
chart or medical record. This source must be readily verifiable against the values entered 
898 
into eCRF.  Even where all study data are directly entered into the eCRFs at office visits, 
899 
evidence of interaction with a live subject must be recorded (e.g., office note, visit record, etc.) 
900 
and provided to the coordinating center for review.    
901 
The Central Lab will generate genetic reports from the retinal dystrophy genetic panel testing 
902 
and/or family member testing analysis as applicable. These reports will be uploaded to the FFB 
903 
Consortium study website and made available to the clinical site.  
904 
The CGA will review the genetic lab report(s) submitted by the clinical site during genetic 
905 
screening against the genetic eCRF data to ensure that the data entered by the clinical site are 
906 
consistent with the source(s) provided prior to the Baseline visit. The CGA will document his/her 
907 
verification of these genetic data on the FFB Consortium study website and the clinical site will 
908 
be notified of the results of the review. 
909 
In addition to providing interpretation/evaluation of whether or not the PCDH15  mutations are 
910 
causative of the disease on the FFB Consortium study website (see section 2.4.2), the Genetics 
911 
Committee will review and provide approval for the use of genetic reports from research labs to 
912 
be used for determining participant eligibility.  
913 
Reading Centers will conduct grading of the study data collected for MP, SD-OCT, Optos FAF, 
914 
and SP using the FFB Consortium study website. A Reading Center will conduct quality review 
915 
only of the first ERG obtained from each clinical site using the FFB Consortium study website. 
916 
These data will remain in the study database and will not be provided to the clinical site. 
917 
Each participating site will maintain appropriate medical and research records for this 
918 
trial, in compliance with International Council for Harmonisation of Technical 
919 
Requirements for Pharmaceuticals for Human Use (
ICH ) E6 and regulatory and 
920 
institutional requirements for the protection of confidentiality of participants.
 
921 
7.2 Study Records Retention  
922 
Study documents will be retained for a minimum of six (6) years from the date on which the CC 
923 
receives IRB approval to close the study. These documents will be retained for a longer period, 
924 
however, if required by local regulations. No records will be destroyed without the written 
925 
consent of the CC. It is the responsibility of the CC to inform the investigator when study 
926 
documents no longer need to be retained. 
927 
7.3 Quality Assurance and Monitoring
 
928 
Designated personnel from the CC will be responsible for maintaining quality assurance (QA) 
929 
and quality control (QC) systems to ensure that the clinical portion of the trial is conducted and 
930 
data are generated, documented and reported in compliance with the protocol, GCP and the 
931 

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applicable regulatory requirements, as well as to ensure that the rights and wellbeing of trial 
932 
participants are protected and that the reported trial data are accurate, complete, and verifiable.   
933 
Consistent with the Integrated Addendum to ICH E6 (R2)24, a risk-based monitoring (RBM) plan 
934 
will be developed and revised as needed during the study. This plan describes in detail who will 
935 
conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
936 
monitoring will be performed, and the distribution of monitoring reports. 
937 
As much as possible, remote monitoring will be performed in real-time with on-site monitoring 
938 
performed to evaluate the verity and completeness of the key site data.  Elements of the RBM 
939 
plan may include: 
940 
• Qualification assessment, training, and certification for sites and site personnel 
941 
• Oversight of IRB/EC coverage and informed consent procedures 
942 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
943 
review of entered data and edits, statistical monitoring, study closeout 
944 
• On-site monitoring (site visits): source data verification, site visit report 
945 
• Communications with site staff 
946 
• Participant retention and visit completion 
947 
• Quality control reports 
948 
• Management of noncompliance 
949 
• Documenting monitoring activities 
950 
• AE reporting  
951 
CC representatives or their designees may visit the study facilities at any time in order to 
952 
maintain current and personal knowledge of the study through review of the records, comparison 
953 
with source documents, observation and discussion of the conduct and progress of the study. The 
954 
investigational site will provide direct access to all trial related sites, source data/documents, and 
955 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
956 
regulatory authorities. 
957 
7.4 Protocol Deviations  
958 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
959 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
960 
or the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
961 
and implemented promptly. 
962 
The site PI and study staff delegated to study responsibilities are responsible for knowing and 
963 
adhering to their IRB/EC requirements.   
964 

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Chapter 8:  Ethics/Protection of Human Participants
 
965 
8.1 Ethical Standard  
966 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
967 
the Protection of Human Participants of Research codified in 45 Code of Federal Regulations 
968 
(CFR) Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
969 
8.2 Inst itutional Review Boards  and Ethics Committees  
970 
The protocol, ICF(s), recruitment materials, and all participant materials will be submitted to the 
971 
IRB or EC for review and approval. Approval of both the protocol and the ICF(s) must be 
972 
obtained before any participant is enrolled. Any amendment to the protocol will require review 
973 
and approval by the IRB or EC before the changes are implemented to the study. All changes to 
974 
the consent form will be IRB or EC approved; a determination will be made regarding whether 
975 
previously consented participants need to be re-consented.  
976 
8.3 Informed Consent Process  
977 
8.3.1 Consent Procedures and Documentation
 
978 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
979 
the study and continues throughout the individual’s study participation. All consent forms will be 
980 
IRB-or EC- approved and in the case of written consent, the participant will be given the 
981 
opportunity to carefully read and review the document.  For any form of consent presented 
982 
(written or verbal), the investigator or his/her designee (as approved by the IRB/EC) will explain 
983 
the research study to the participant and answer any questions that may arise.  All participants 
984 
will receive a verbal explanation in terms suited to their comprehension of the purposes, 
985 
procedures, and potential risks of the study and of their rights as research participants.  Extensive 
986 
discussion of risks and possible benefits of participation will be provided to the participants and 
987 
their families.  Participants will be asked to carefully consider the consent form presented to 
988 
them and have any questions answered prior to signing. 
989 
Participants will have the opportunity to discuss the study with their surrogates or think about it 
990 
prior to agreeing to participate.  Participants must sign the ICF prior to any procedures being 
991 
done specifically for the study. Participants may withdraw consent at any time throughout the 
992 
course of the trial.  A copy of the ICF will be given to participants for their records.  The rights 
993 
and welfare of participants will be protected by emphasizing to them that the quality of their 
994 
medical care will not be adversely affected if they decline to participate in this study. 
995 
8.3.2 Participant and Data Confidentiality
 
996 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, the 
997 
funder(s) and their agents.  This confidentiality is extended to cover genetic tests in addition to 
998 
the clinical information relating to participants.  Therefore, the study protocol, documentation, 
999 
data, and all other information generated will be held in strict confidence.  No information 
1000 
concerning the study, or the data will be released to any unauthorized third party without prior 
1001 
written approval of the sponsor. 
1002 

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The CC, other authorized vendors or representatives of the funder, representatives of the 
1003 
IRBs/ECs, or regulatory agencies may inspect all documents and records required to be 
1004 
maintained by the investigator, including but not limited to medical records (office, clinic, or 
1005 
hospital) for the participants in this study.  The clinical study site will permit access to such 
1006 
records. 
1007 
The study participant’s contact information will be securely stored at each clinical site for 
1008 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1009 
secure location for as long a period as dictated by the reviewing IRB/EC, institutional policies, or 
1010 
sponsor requirements. 
1011 
Study participant research data, which is for purposes of statistical analysis and scientific 
1012 
reporting, will be transmitted to and stored at the FFB Consortium CC, located at the Jaeb Center 
1013 
for Health Research in Tampa, Florida.  This will not include the participant’s contact or 
1014 
identifying information, unless otherwise specified in the informed consent form.  Rather, a 
1015 
unique study identification number will identify individual participants and their research data.  
1016 
The study data entry and study management systems used by clinical sites and by the FFB 
1017 
Consortium CC research staff will be secured and password protected.  At the end of the study, 
1018 
all study databases will be de-identified and archived at the FFB Consortium CC. 
1019 
8.4 Stored Specimens  
1020 
With the participant’s approval and as approved by the IRB/ECs, de-identified biological 
1021 
samples collected for genetic testing in screening groups B and C will be stored at Blueprint 
1022 
Genetics until the FFB Study Team notifies them in writing to destroy the samples. We expect 
1023 
the samples to be destroyed one (1) year after the end of the study.   
1024 
 
1025 

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Chapter 9:  References  
1026 
1. 
Zrada SE, Braat K, Doty RL, Laties AM. Olfactory loss in Usher syndrome: Another 
1027 
sensory deficit? Am J Med Genet. 1996;64(4):602-603. 
1028 
2. 
Petit C. Usher Syndrome: From Genetics to Pathogenesis. Annu Rev Genomics Hum 
1029 
Genet. 2001;2(1):271-297. 
1030 
3. 
Fakin A, Jarc-Vidmar M, Glavac D, Bonnet C, Petit C, Hawlina M. Fundus 
1031 
autofluorescence and optical coherence tomography in relation to visual function in 
1032 
Usher syndrome type 1 and 2. Vision Res. 2012;75:60-70. 
1033 
4. 
Pakarinen L, Tuppurainen K, Laippala P, Mäntyjärvi M, Puhakka H. The 
1034 
ophthalmological course of Usher syndrome type III. Int Ophthalmol. 1995;19(5):307-
1035 
311. 
1036 
5. 
Ness SL, Ben-Yosef T, Bar-Lev A, et al. Genetic homogeneity and phenotypic variability 
1037 
among Ashkenazi Jews with Usher syndrome type III. J Med Genet. 2003;40(10):767. 
1038 
6. 
Ahmed ZM, Riazuddin S, Ahmad J, et al. PCDH15 is expressed in the neurosensory 
1039 
epithelium of the eye and ear and mutant alleles are responsible for both USH1F and 
1040 
DFNB23. Hum Mol Genet. 2003;12(24):3215-3223. 
1041 
7. 
Schietroma C, Parain K, Estivalet A, et al. Usher syndrome type 1–associated cadherins 
1042 
shape the photoreceptor outer segment. J Cell Biol. 2017;216(6):1849-1864. 
1043 
8. 
Ahmed ZM, Riazuddin S, Aye S, et al. Gene structure and mutant alleles of PCDH15: 
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nonsyndromic deafness DFNB23 and type 1 Usher syndrome. Hum Genet. 
1045 
2008;124(3):215-223. 
1046 
9. 
Zheng QY, Yan D, Ouyang XM, et al. Digenic inheritance of deafness caused by 
1047 
mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum 
1048 
Mol Gen. 2004;14(1):103-111. 
1049 
10. 
Ben-Yosef T, Ness SL, Madeo AC, et al. A Mutation of PCDH15 among Ashkenazi Jews 
1050 
with the Type 1 Usher Syndrome. N Engl J of Med. 2003;348(17):1664-1670. 
1051 
11. 
Jacobson SG, Cideciyan AV, Aleman TS, et al. Usher syndromes due to MYO7A, 
1052 
PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Hum Mol 
1053 
Genet. 2008;17(15):2405-2415. 
1054 
12. 
Stingl K, Kurtenbach A, Hahn G, et al. Full-field electroretinography, visual acuity and 
1055 
visual fields in Usher syndrome: a multicentre European study. Doc Ophthalmol. 
1056 
2019;139(2):151-160. 
1057 
13. 
Rebibo-Sabbah A, Nudelman I, Ahmed ZM, Baasov T, Ben-Yosef T. In vitro and ex vivo 
1058 
suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher 
1059 
syndrome. Hum Genet. 2007;122(3-4):373-381. 
1060 
14. 
Birch DG, Locke KG, Felius J, et al. Rates of decline in regions of the visual field 
1061 
defined by frequency-domain optical coherence tomography in patients with RPGR-
1062 
mediated X-linked retinitis pigmentosa. Ophthalmology. 2015;122(4):833-839. 
1063 
15. 
Hariri AH, Zhang HY, Ho A, et al. Quantification of Ellipsoid Zone Changes in Retinitis 
1064 
Pigmentosa Using en Face Spectral Domain–Optical Coherence Tomography. JAMA 
1065 
Ophthalmology. 2016;134(6):628-635. 
1066 
16. 
Han RC, Gray JM, Han J, Maclaren RE, Jolly JK. Optimisation of dark adaptation time 
1067 
required for mesopic microperimetry. Br J Ophthalmol. 2019;103(8):1092. 
1068 

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17. 
Stingl KT, Kuehlewein L, Weisschuh N, et al. Chromatic Full-Field Stimulus Threshold 
1069 
and Pupillography as Functional Markers for Late-Stage, Early-Onset Retinitis 
1070 
Pigmentosa Caused by CRB1 Mutations. Transl Vis Sci Technol. 2019;8(6):45-45. 
1071 
18. 
Birch DG, Cheng P, Duncan JL, et al. The RUSH2A Study: Best-Corrected Visual 
1072 
Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds 
1073 
at Baseline. Transl Vis Sci Technol. 2020;9(11):9-9. 
1074 
19. 
Bennett LD, Klein M, Locke KG, Kiser K, Birch DG. Dark-Adapted Chromatic 
1075 
Perimetry for Measuring Rod Visual Fields in Patients with Retinitis Pigmentosa. Transl 
1076 
Vis Sci Technol. 2017;6(4):15-15. 
1077 
20. 
Jacobson SG, Voigt WJ, Parel J-M, et al. Automated Light- and Dark- Adapted Perimetry 
1078 
for Evaluating Retinitis Pigmentosa. Ophthalmology. 1986;93(12):1604-1611. 
1079 
21. 
Stingl K, Nowomiejska K, Kuehlewein L, et al. Clinical protocols for the evaluation of 
1080 
rod function. Ophthalmologica. 2020. 
1081 
22. 
Kelbsch C, Stingl K, Kempf M, et al. Objective Measurement of Local Rod and Cone 
1082 
Function Using Gaze-Controlled Chromatic Pupil Campimetry in Healthy Subjects. 
1083 
Transl Vis Sci Technol. 2019;8(6):19-19. 
1084 
23. 
Rare diseases: Natural History Studies for Drug Development: Guidance for Industry, 
1085 
Draft Guidance. In: U.S Department of Health and Human Services Food and Drug 
1086 
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1087 
24. 
Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice: E6(R2). In: 
1088 
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1089 
 
1090