Gyrate Atrophy Ocular and Systemic Study
Conditions: Gyrate Atrophy, Gyrata of Choroid and Retina; Atrophy, Ornithine-δ-aminotransferase, OAT, Chorioretinal Degeneration
Sponsor: Jaeb Center for Health Research

Protocol Identifying Number: GYROS
Funded by: Foundation Fighting Blindness and Conquering Gyrate Atrophy 
Foundation
Version Number: 1.2
28-Nov-2022

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Protocol Identifying Number: GYROS
Version Number: v1.2
28-Nov-2022
GYROS Protocol Co-Chair
Name, degree
Mandeep Singh, M.D.
Signature/Date
GYROS Protocol Co-Chair
Name, degree
David Valle, M.D.
Signature/Date
JCHR GYROS Protocol Director (Sponsor)
Name, degree
Allison Ayala, MS
Signature/Date
FFB Representative (Funder)
Name, degree
Todd Durham, PhD.
Signature/Date
Statistician
Name, degree
Maureen Maguire, PhD, FARVO
Signature/Date

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TABLE OF CONTENTS
CHAPTER 1: BACKGROUND INFORMATION .............................................................................................19 
1.1 Introduction .......................................................................................................................................19 
1.1.1 Clinical ........................................................................................................................................19 
1.1.2 Metabolism..................................................................................................................................19 
1.1.3 Molecular.....................................................................................................................................20 
1.2 Treatment...........................................................................................................................................20 
1.2.1 Arginine Restricted Diet (ARD)..................................................................................................20 
1.2.2 Pyridoxine Supplementation .......................................................................................................21 
1.2.3 Creatine Supplementation ...........................................................................................................22 
1.2.4 Proline Supplementation .............................................................................................................22 
1.2.5 Lysine Supplementation..............................................................................................................22 
1.3 Rationale............................................................................................................................................22 
1.4 Study Objective .................................................................................................................................23 
1.5 Potential Risks and Benefits..............................................................................................................23 
1.5.1 Known Potential Risks ................................................................................................................23 
1.5.2 Known Potential Benefits............................................................................................................24 
1.5.3 Risk Assessment..........................................................................................................................24 
1.6 General Considerations......................................................................................................................24 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING ..............................................................................26 
2.1 Participant Recruitment and Enrollment ...........................................................................................26 
2.1.1 Participant Recruitment Goals and Strategy................................................................................26 
2.1.1.1 Target Study Sample Size...................................................................................................26 
2.1.1.2 Participant Recruitment.......................................................................................................27 
2.1.1.3 Participant Enrollment ........................................................................................................27 
2.2 Informed Consent and Authorization Procedures..............................................................................27 
2.3 Screening Visit ..................................................................................................................................28 
2.3.1 Eligibility Criteria........................................................................................................................28 
2.3.1.1 Participant Inclusion Criteria ..............................................................................................28 
2.3.1.2 Ocular Inclusion Criteria.....................................................................................................29 
2.3.1.3 Participant Exclusion Criteria.............................................................................................29 
2.3.1.4 Ocular Exclusion Criteria....................................................................................................29 
2.3.2 Screening Data Collection and Testing .......................................................................................30 
2.3.3 Initial Screen Failures..................................................................................................................32 
2.4 Genetic Screening Phase ...................................................................................................................32 

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2.4.1.1 Genetic Screen Failures ......................................................................................................32 
2.4.1.2 Genetics Committee Review...............................................................................................32 
2.5 Final Study Cohort Criteria ...............................................................................................................32 
CHAPTER 3: BASELINE VISIT....................................................................................................................34 
3.1 Baseline Visit.....................................................................................................................................34 
3.2 Food Record and Blood Sample Collection ......................................................................................34 
3.3 Baseline Procedures...........................................................................................................................35 
3.3.1 Baseline Data Collection and Testing Cohorts 1 & 2..................................................................35 
3.3.2 Baseline Data Collection and Testing Cohort 3 ..........................................................................36 
CHAPTER 4: FOLLOW-UP VISITS ..............................................................................................................38 
4.1 Follow-up Visits ................................................................................................................................38 
4.2 Target Timelines................................................................................................................................38 
4.3 Food Record and Blood Sample Collection ......................................................................................39 
4.4 Follow-up Procedures........................................................................................................................40 
4.4.1 Follow-up Data Collection and Testing Cohorts 1 & 2...............................................................40 
4.4.2 Follow-up Data Collection and Testing Cohort 3 .......................................................................42 
4.4.3 Unscheduled Visits......................................................................................................................43 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES .................................................................44 
5.1 Study Procedure Requirements .........................................................................................................44 
5.2 Questionnaires ...................................................................................................................................48 
CHAPTER 6: UNANTICIPATED PROBLEM AND ADVERSE EVENT REPORTING.......................................50 
6.1 Unanticipated Problems.....................................................................................................................50 
6.2 Adverse Events..................................................................................................................................50 
6.2.1 Definitions...................................................................................................................................50 
6.2.2 Reportable Adverse Events .........................................................................................................51 
6.2.3 Relationship of Adverse Event to Study Procedure ....................................................................51 
6.2.4 Severity (Intensity) of Adverse Event .........................................................................................52 
6.2.5 Expectedness ...............................................................................................................................52 
6.2.6 Coding of Adverse Events...........................................................................................................52 
6.2.7 Outcome of Adverse Event .........................................................................................................52 
6.3 Timing of Event Reporting................................................................................................................53 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS...................................................................................54 
7.1 New or ongoing Medical Conditions and Medications .....................................................................54 
7.1.1 Pre-Existing Condition................................................................................................................54 
7.1.2 Medical Conditions during the study ..........................................................................................54 

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7.1.3 Medications .................................................................................................................................54 
7.2 Prohibited Medications, Treatments, and Procedures .......................................................................54 
7.2.1 Prohibited Medications and Treatment for OAT-Related Retinal 
Degeneration ........................................................................................................................................54 
7.2.2 Intraocular Surgical Procedures ..................................................................................................55 
7.2.3 Treatment for Cystoid Macular Edema (CME)...........................................................................55 
7.3 Pregnancy Reporting .........................................................................................................................55 
7.4 Participant Compensation..................................................................................................................55 
7.5 Participant Withdrawal......................................................................................................................55 
7.6 Confidentiality...................................................................................................................................55 
CHAPTER 8: STATISTICAL CONSIDERATIONS..........................................................................................56 
8.1 Statistical and Analytical...................................................................................................................56 
8.2 Sample Size .......................................................................................................................................56 
8.2.1 Sample Size Considerations for Evaluating Percent Change from Baseline 
to four (4) Years All Outcomes.........................................................................................................56 
8.2.2 Sample Size Considerations for Comparing Percent Change from Baseline 
to four (4) Years within Subgroups of Interest All Outcomes...........................................................57 
8.2.3 Sample Size Considerations for Precision of the Estimate of the Correlation 
Between Structure-based, Function-based, and Metabolic-based Outcomes and of 
the Correlation Between Eyes ..............................................................................................................59 
8.2.4 Final Sample Size Justification ...................................................................................................60 
8.3 Data Analysis.....................................................................................................................................61 
8.3.1 Primary Objective Analysis.........................................................................................................61 
CHAPTER 9: DATA COLLECTION AND MONITORING..............................................................................64 
9.1 Case Report Forms and Other Data Collection .................................................................................64 
9.1.1 Central Lab..................................................................................................................................64 
9.1.2 Research Lab...............................................................................................................................64 
9.1.3 Central Genetics Auditor (CGA).................................................................................................64 
9.1.4 Genetics Committee ....................................................................................................................64 
9.1.5 The Johns Hopkins Institute for Clinical and Translational Research (ICTR) 
Research Nutrition................................................................................................................................65 
9.1.6 Reading Centers ..........................................................................................................................65 
9.2 Study Records Retention ...................................................................................................................65 
9.3 Quality Assurance and Monitoring....................................................................................................65 
9.4 Protocol Deviations ...........................................................................................................................66 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS............................................................67 
10.1 Ethical Standard...............................................................................................................................67 

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10.2 Institutional Review Boards ............................................................................................................67 
10.3 Informed Consent Process...............................................................................................................67 
10.3.1 Consent Procedures and Documentation...................................................................................67 
10.3.2 Participant and Data Confidentiality .........................................................................................67 
10.3.3 Future Use of Stored Specimens and Data ................................................................................68 
10.3.4 Future Use of Ocular Images.....................................................................................................68 
CHAPTER 11: REFERENCES.......................................................................................................................69 

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LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
AE
Adverse Event
ARD
Arginine Restricted Diet 
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
EC
Ethics Committee
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
GA
Gyrate Atrophy
ICF
Informed consent form
ICH
International Committee of Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
IOP
Intraocular Pressure
IRB
Institutional Review Board
KKI
Kennedy Krieger Institute
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
OAT
ornithine- -aminotransferase 
OCTA
Optical coherence tomography angiography 
OD
Right Eye
OS
Left Eye
OU
Both eyes
PI
Principal investigator
PRO
Patient reported outcomes

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ABBREVIATION
DEFINITION
PROMIS®-29
Patient-Reported Outcomes Measurement Information System
PSC
Posterior sub-capsular 
QA
Quality Assurance 
QC
Quality Control 
RBM
Risk-Based Monitoring 
RP
Retinitis pigmentosa
RPE
Retinal pigment epithelium 
SAE
Serious adverse event
SD
Standard deviation 
SD-OCT
Spectral domain optical coherence tomography
SP
Static perimetry
VA
Visual acuity
ViSIO-PRO
Visual Symptom and Impact Outcomes Patient Reported Outcome
VF
Visual Field
VPA
Valproic Acid

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PROTOCOL SUMMARY
ITEM 
DESCRIPTION 
Title
GYROS: Gyrate Atrophy Ocular and Systemic Study   
Précis
Gyrate atrophy (GA) is a rare inherited chorioretinal degeneration that is 
associated with hyperornithinemia, an inborn error of metabolism caused by 
autosomal recessive mutations in the ornithine aminotransferase (OAT) gene. GA
is characterized by childhood-onset nyctalopia and sharply demarcated areas of 
chorioretinal atrophy that initially involve the midperipheral fundus. The atrophic 
areas typically coalesce and enlarge towards the posterior pole in the second and 
third decades of life, leading to severe visual field constriction and vision loss if 
left untreated. The current standard care treatment of GA is an arginine restricted 
diet that is implemented in practice using dietary protein restriction with essential 
amino acid supplementation. However, dietary treatment is highly burdensome on 
patients and negatively impacts quality of life such that only about ~20% of 
patients can comply. Strict adherence to dietary protein restriction (particularly 
through adolescence), essential amino acid supplementation, and nutritional 
management of body weight especially during intercurrent illness and pregnancy 
are among the challenges of treatment. Periods of suboptimal dietary control led to 
plasma ornithine elevation and progressive chorioretinal degeneration. To facilitate 
a future interventional gene therapy clinical trial, there is a need to evaluate natural 
history of and the relationship between potential clinical trial outcome measures.
Objectives
The objectives of the OAT gene natural history study are as follows: 
1.
Natural History 
a.
Characterize the natural history of retinal degeneration associated 
with disease-causing OAT variants in the presence of standard care 
dietary treatment regimens over four (4) years, using functional, 
structural, and patient-reported outcome measures.
b.
Characterize the natural history of ornithine levels associated with 
disease-causing OAT variants in the presence of standard care 
dietary treatment regimens over four (4) years.
c.
Determine within-patient variability of ornithine levels associated 
with disease-causing OAT variants in the presence of standard care 
dietary treatment regimens over four (4) years.
d.
Evaluate inter-eye correlation of ocular measures.
2.
Metabolic-Structure-Function Relationships
a.
Explore relationship of structural outcomes with functional 
outcomes in individuals with disease-causing OAT variants. 
b.
Explore relationship of plasma ornithine levels with structural and 
functional outcomes in individuals with disease-causing OAT
variants. 
3.
Identify Rapid Progressors
a.
Explore possible risk factors (genotype, phenotype, 
environmental, comorbidities, and dietary therapy/supplements) 
for progression of the functional, structural, and patient-reported 
outcome measures over four (4) years in individuals with disease-
causing OAT variants.
b.
Explore possible risk factors (genotype, phenotype, 
environmental, comorbidities, and dietary therapy/supplements) 

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ITEM 
DESCRIPTION 
for ornithine levels over four (4) years in individuals with 
disease-causing OAT variants.
Impact
The expected impact of the OAT gene natural history study is to inform a future 
interventional clinical trial design and implementation, including the following:
1.
Determine within-patient variability of ornithine levels.
2.
Develop quantitative measures of progression of the area of preserved 
retina and establish its reproducibility, sensitivity to change, and 
relationship with other measures.
3.
Establish rates of progression of retinal degeneration on all functional, 
structural, and patient-reported outcome measures, and determine which 
measures are most sensitive to change. 
4.
Determine primary time points and duration for a planned future treatment 
trial.
5.
Use variability and inter-eye correlation of outcomes for trial sample size 
calculations.
6.
Identify candidates for the future trial, including eligibility criteria based 
on risk factors and cut points for severity of disease most likely to benefit
from treatment.
7.
Establish study procedures and workflows for practical implementation of 
the same testing procedures in a future trial.
Study Design
Multicenter, longitudinal, prospective natural history study. Participants will be 
assigned to one (1) of three (3) Vision Cohorts based on visual acuity (VA) and 
kinetic visual fields (VF).
Number of Sites
Approximately 12
Outcomes
Structural Outcomes:
Key Assessments
Test
Equipment
Reading 
Center
Primary: Quantitative 
measures of progression 
of the area of preserved 
retina and of the area of 
lesions in standardized 
regions*
Fundus
autofluorescence 
(FAF)
Optos
Yes
Primary: Use with FAF 
for assessments noted 
above  
Ultra-Widefield Color 
Photography
Optos
Yes
Ellipsoid zone (EZ) area
Spectral domain optical 
coherence tomography 
(SD-OCT)
Heidelberg 
Spectralis
Yes
Presence and type of 
cataract (posterior 
subcapsular and cortical 
cataract) **
Red reflex photography
Digital camera 
capable of 
capturing 
external eye 
photos 
Megapixels of 
>=3MP 
Magnification 
of 30-40 degrees 
Digital camera 
export in PNG, 
TIF, DICOM or 
BMP
Yes

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ITEM 
DESCRIPTION 
Foveal avascular zone 
(FAZ) area and macular 
vessel density
OCTA
Ancillary test at subset of 
sites
Pre-
Approved 
list
Yes
*Other approaches to grading methods may be explored
**Ocular exam by investigator will include clinical grading of presence of nuclear sclerosis 
cataract.
Functional Outcomes:
Key Assessments
Test
Equipment
Reading 
Center
Visual field sensitivity 
measured with 
quantitative topographic 
analysis (Hill of Vision)
Static Perimetry
Octopus 900 Pro Yes
Early Treatment of 
Diabetic Retinopathy 
Study (ETDRS) best 
corrected visual acuity 
(BCVA) letter score
Visual Acuity
Electronic 
Visual Acuity 
(EVA) system 
or ETDRS 
charts 
N/A
Low visual acuity test -
for participants unable to 
see ETDRS letters
Low Visual 
Acuity 
Berkeley 
Rudimentary 
Vision Test 
(BRVT)
N/A
ETDRS best corrected low 
luminance visual acuity 
letter score 
Low Luminance 
Visual Acuity 
(LLVA)
Electronic 
Visual Acuity 
(EVA) system 
or ETDRS 
charts
N/A
Mean macular sensitivity
Fundus-Guided 
Microperimetry
MAIA 
Yes
Full-field retinal 
sensitivity
Full-field stimulus 
threshold (FST) 
testing to blue, 
white, and red 
stimuli
Diagnosys 
Espion 
No
Metabolic Outcomes:
Primary: Plasma ornithine level; obtained by fasting plasma amino acids 
panel and evaluated by a central lab
Primary: Blood spot ornithine level; obtained by fasting blood spot test amino 
acids panel and evaluated by a central lab
Secondary: Proline, lysine, glutamine, glutamate, arginine, and related 
metabolite: creatine and its precursor guanidinoacetate; obtained by fasting 
plasma amino acids panel and evaluated by a central lab
Patient Reported Outcomes (PRO):
Adults 18 years or older:

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ITEM 
DESCRIPTION 
o Michigan Retinal Degeneration Questionnaire (MRDQ)
o Visual Symptom and Impact Outcomes Patient Reported Outcome 
(ViSIO-PRO)
o Patient-Reported Outcomes Measurement Information System 
(PROMIS®-29)
Adolescents 12-17 years:
o Visual Symptom and Impact Outcomes Patient Reported Outcome (ViSIO-
PRO)
o L. V. Prasad-Functional Vision Questionnaire (LVP-FVQ II)
Risk Factors of 
Interest
Body weight and height
Assessment of B6 supplements and daily arginine and protein intake, based on 
patient-reported food record sheet evaluated by central expert dietician review.
Biochemical validation of new and rare variants in OAT gene, based on skin 
biopsy evaluated by a central lab.
Population
Key Eligibility Criteria: 
The complete list of eligibility criteria is in Chapter 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.
1.
2. Clinical diagnosis of retinal dystrophy
3. Must meet one of the Genetic Screening Criteria:
At least 2 disease-causing variants in the OAT 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),
OR
At least 2 disease-causing variants in the OAT gene with unknown
phase, 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 must meet both of the following phenotype 
criteria:
(1) Classic fundus appearance of gyrate atrophy (based on 
investigator discretion), AND
(2) Elevated ornithine levels >300 µmol/L (documented on any 
prior lab report).
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: Must meet one of the Genetic Screening 
Criteria and have the genetic criteria confirmed by a Central Genetics 
Auditor (CGA).
Sample Size and 
Recruitment
Sample size rationale is detailed in Chapter 8.2. Recruitment will be tracked with 
approximate distribution in three (3) Vision Cohorts. A goal of at least forty-five
(45) participants will be enrolled, with approximately twenty-five (25) in Vision 
Cohort 1, fifteen (15) in Vision Cohort 2, and five (5) in Vision Cohort 3.

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ITEM 
DESCRIPTION 
Phase
Natural History Study
Vision Cohort 
Groups
Vision Cohort Definitions
All participants will be designated into one of the following Vision Cohorts based 
on data entered at the Screening Visit. See Section 2.1.1.1 Target Study Sample 
Size for the detailed definitions.
VF diameter
every meridian
VF diameter <10° in 
any meridian
20/80 or better
Vision Cohort 1
Vision Cohort 2
20/100-20/400
Vision Cohort 2
Vision Cohort 2
20/500 or worse
Vision Cohort 3
Vision Cohort 3
Participant 
Duration
From the time of screening until the forty-eight (48) month visit: Approximately 
fifty-one (51) Months.
Screening Baseline Visit, sixty (60) days
Baseline Visit forty-eight (48) month Follow-up Visit, forty-eight (48) 
months.
Study Duration 
(planned)
Sixty-one (61) months from first enrollment until last participant visit
Protocol 
Overview/
Synopsis
1.
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.
a.
See flow chart in next section for details.
5.
Complete genetic screening, including review of genetic reports by CGA. 
Participants meeting criteria to continue will enroll into the study cohort.
a.
See flow chart in next section for details.
6.
Participants who enroll into the study cohort will return to the clinic within 
sixty (60) days of the Screening Visit date to start baseline testing, and no later 
than two (2) weeks after receiving confirmation of meeting final study cohort 
criteria from the CGA.
7.
Participants 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, for all three (3)
Vision Cohorts, will be completed.

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SCHEMATIC OF STUDY ENROLLMENT

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SCHEMATIC OF GENETIC SCREENING PHASE

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SCHEDULE OF STUDY VISITS AND PROCEDURES: VISION COHORT 1 &
VISION COHORT 2
Visit
Screening
Baseline
12M
24M
36M
48M
Visit Target Windows
(Up to Day
-60) a
(Day 0)b
Wk
52 ± 4c
Wk
104± 4c
Wk
156± 4c
Wk
208± 4c
Participant-Level Procedures
Informed Consent / Eligibility Assessment
X
Demographics/Screening Medical History (including pre-existing conditions, 
symptomology history, patient-reported daily activities, and medications)
X
Determination of Vision Cohort
X
3mm punch skin biopsyi
X
Concomitant Medications 
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
Patient Reported Outcomes (PROMIS-29, MRDQ, ViSIO-PRO, LVP-FVQ II)h
X
X
X
Ocular Procedures - All testing performed in each eye
Complete Ophthalmic Examf
X
X
X
X
X
Intraocular Pressureg
X
X
X
X
X
Visual acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed)
X
X
X
X
X
SD-OCT volume scans (Heidelberg Spectralis)
X
X
X
X
X
SD-OCT vertical and horizontal scans (Heidelberg Spectralis)
X
X
X
X
X
Axial Length and Corneal Curvature measurements
X
X
X
Fundus Autofluorescence (FAF) (Optos)
X
X
X
X
X
Ultra-Widefield Color Photo (Optos)
X
X
X
X
X
Optical coherence tomography angiography (OCTA)j
X
X
X
X
X
Red reflex photo k
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
Xe
a.
All Screening Visit testing must be completed on the same day (except for kinetic VF, as noted below).
b.
Baseline Visit date (defined as the start date of all Baseline testing) must be no later than two (2) weeks after receiving confirmation 
of meeting final study cohort criteria from the CGA. All Baseline testing must be completed within ten (10) days of the Baseline 
Visit date, except PROs as specified.
c.
All Follow up visit testing must be completed on the same day, except PROs as specified.
d.
For static perimetry and microperimetry, all Vision Cohort 1 and 2 participants will complete two (2) tests at baseline. The results 
will be compared according to the visual field criteria to determine if a third test is needed.
e.
Historical measurement performed within the last eighteen (18) months prior to the Screening Visit. If a historical measurement is
not available, then perform the Kinetic VF III4e at the Screening Visit.
f.
Ophthalmic exam includes slit-lamp biomicroscopy and indirect ophthalmoscopy. Whenever possible the site should make its best 
effort to ensure that the exam takes place at approximately the same time of the day at each visit and with the same equipment.
g.
IOP measurements will be taken prior to pupil dilation.
h.
PROs may be completed in person or remotely any time within six (6) months of the Baseline visit or  any time within the allowable 
window of the associated visit window (not required to be the same day as the rest of the visit). Required PROs depend on age, see 
outcomes grid.
i.
Collected by certified investigator; sent to JHU/KKI Biochemical Genetics Lab.
j.
If site does not have the equipment that would be required for the ancillary study, then participation in this test will be waived, with 
approval from the Coordinating Center. Site must use a pre-approved equipment for this test.
k.
Digital camera capable of capturing external eye photos, Megapixels of >=3MP, Magnification of 30-40 degrees, Digital camera 
export in PNG, TIF, DICOM or BMP.

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SCHEDULE OF STUDY VISITS AND PROCEDURES: VISION COHORT 3
Visit
Screening
Baseline
12M
24M
36M
48M
Visit Target Windows
(Up to Day
-60) a
(Day 0)b
Wk
52 ± 4c
Wk
104± 4c
Wk
156± 4c
Wk
208± 4c
Participant-Level Procedures
Informed Consent / Eligibility Assessment
X
Demographics/Screening Medical History (including pre-existing conditions, 
symptomology history, patient-reported daily activities, and medications)
X
Determination of Vision Cohort
X
3mm punch skin biopsy h
X
Concomitant Medications 
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
Patient Reported Outcomes (PROMIS-29, MRDQ, ViSIO-PRO, LVP-FVQ II)g
X
X
X
Ocular Procedures - All testing performed in each eye
Complete Ophthalmic Exame
X
X
X
X
X
Intraocular Pressuref
X
X
X
X
X
Visual acuity (including refraction, ETDRS, BRVT if needed, LLVA if needed)
X
X
X
X
X
SD-OCT volume scans (Heidelberg Spectralis)
X
X
X
X
X
SD-OCT vertical and horizontal scans (Heidelberg Spectralis)
X
X
X
X
X
Axial Length and Corneal Curvature measurements
X
X
X
Fundus Autofluorescence (FAF) (Optos)
X
X
X
X
X
Ultra-Widefield Color Photo (Optos)
X
X
X
X
X
Optical coherence tomography angiography (OCTA)i
X
X
X
X
X
Red reflex photo j
X
X
X
X
X
Full-field Stimulus Threshold (Diagnosys Espion)
X
X
X
X
X
Kinetic VF III4e for Vision Cohort definition only
Xd
a.
All Screening Visit testing must be completed on the same day (except for kinetic VF, as noted below).
b.
Baseline Visit date (defined as the start date of all Baseline testing) must be no later than two (2) weeks after receiving confirmation of 
meeting final study cohort criteria from the CGA). All Baseline testing must be completed within ten (10) days of the Baseline Visit 
date, except PROs as specified.
c.
All Follow up visit testing must be completed on the same day, except PROs as specified.
d.
Historical Kinetic VF III4e if available. Kinetic VF III4e does not need to be performed at screening if a historical measurement is not 
available.
e.
Ophthalmic exam includes slit-lamp biomicroscopy and indirect ophthalmoscopy. Whenever possible the site should make its best 
effort to ensure that the exam takes place at approximately the same time of the day at each visit and with the same equipment.
f.
IOP measurements will be taken prior to pupil dilation.
g.
PROs may be completed in person or remotely any time within six (6) months of the Baseline visit or  any time within the allowable 
window of the associated visit window (not required to be the same day as the rest of the visit). Required PROs depend on age, see 
outcomes grid.
h.
Collected by certified investigator; sent to JHU/KKI Biochemical Genetics Lab.
i.
If site does not have the equipment that would be required for the ancillary study, then participation in this test will be waived, with 
approval from the Coordinating Center. Site must use a pre-approved equipment for this test.
j.
Digital camera capable of capturing external eye photos, Megapixels of >=3MP, Magnification of 30-40 degrees, Digital camera export 
in PNG, TIF, DICOM or BMP.

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FOOD RECORD AND SAMPLE COLLECTION SCHEDULE FOR ALL 
VISION COHORTS
Screening
Baseline
4M
8M
12M
16M
20M
24M
28M
32M
36M
40M
44M
48M
Clinical site coordinator 
contacts participant a
X
X
X
X
X
X
X
X
X
X
X
X
X
Three-day food record a
X
X b
X b
X b
X b
X b
X b
X b
X b
X b
X b
X b
X
Target Windows for 
Sample Collection
Wk 
17 ± 4
Wk 
34 ± 4
Wk 
52 ± 4
Wk 
69 ± 4
Wk 
86 ± 4
Wk 
104 ± 4
Wk 
121 ± 4
Wk 
138 ± 4
Wk 
156 ± 4
Wk 
173 ± 4
Wk 
190 ± 4
Wk 
208 ± 4
Fasting plasma amino 
acidsc
X
X (2)
X
X
X
X
Fasting blood spot amino 
acidsd
X
Xd
Xd
X
Xd
Xd
X
Xd
Xd
X
Xd
Xd
X
Request Albumin Lab 
Recordse
X
X
X
X
X
Body Weight
X
X
X
X
X
Height f
X
X
X
X
X
a.
The Pre-Sample Participant Telephone Contact should occur four (4)
ten (10) days prior to scheduled sample collection date.
Food record should occur for three (3) days leading up to the sample collection date. For at-home samples, the Post-Sample 
Collection Telephone Call should be completed within one (1) day after the scheduled sample collection date.
b.
The Food Record is only collected if the participant is on an arginine-restricted diet. If the participant is not following an
arginine-restricted diet, then the food record will not be recorded and collected. See Section 4.3 Food Record and Blood 
Sample Collection for more details.
c.
Baseline only: two (2) fasting plasma samples collected on two (2) different days, within ten (10) days of Baseline Visit date. 
d.
Participant and/or caretaker administered remotely. Samples will be collected on all participants.
e.
The albumin labs will be requested only 
if the participant is on an arginine-restricted diet.
f.
Height will be measured annually in participants less than twenty-one (21) years of age at enrollment, otherwise height will 
only be collected at the Baseline Visit. 

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Chapter 1: Background Information
1
1.1 Introduction
2
Gyrate atrophy (GA) of the choroid and retina (GA, OMIM 258870) is a rare and slowly
3
progressive chorioretinal degeneration that leads to severe loss of vision. The prevalence of GA 
4
is thought to be approximately 1 in 1,500,000 live births worldwide, but in certain populations 
5
(e.g., Finns) is as high as 1:50,000 live births. Inherited as an autosomal recessive trait, the 
6
primary defect in GA is deficiency of the mitochondrial matrix enzyme, ornithine- -
7
aminotransferase (OAT) resulting from biallelic loss of function mutations in the OAT gene 
8
located at 10q26. OAT deficiency accounts for the hyperornithinemia (plasma levels are ~15-fold
9
increased over normal) present in all GA children and adults ingesting an unrestricted diet.
10
1.1.1 Clinical
11
The early symptoms of GA include myopia and reduced night vision in late childhood. Disease 
12
progression is characterized by progressive visual field constriction, visual acuity loss, and 
13
reduced daytime vision that invariably culminate in functional and legal blindness by mid-
14
adulthood. Visual disability is typically severe and is associated with difficulties in educational, 
15
vocational, mental, and personal aspects of life. Ophthalmologic exam reveals a pathognomonic
16
pattern of chorioretinal degeneration starting as punctate lesions in the mid-periphery which 
17
gradually enlarge forming sharply demarcated circular areas of atrophy often with
18
hyperpigmented margins. Within the circular areas, the atrophy involves the photoreceptor cell 
19
layer, retinal pigment epithelium (RPE), and choroid. The full field electroretinogram (ERG) 
20
amplitudes are typically reduced by the second decade of life. Over the ensuing decades, the 
21
atrophic lesions increase in number and size, coalescing to form scalloped margins and 
22
progressing toward the posterior pole of the eye. Patients can also develop cystoid macular 
23
edema (CME) usually in the third decade or beyond. In all patients, posterior sub-capsular (PSC) 
24
cataracts develop toward the end of the second decade of life. Aside from their ocular phenotype, 
25
GA patients are healthy. Although, they can have abnormal electroencephalograms (EEGs).
26
However, the frequency of seizures is not increased. Some have mild proximal muscle weakness 
27
that is not of clinical consequence.
28
1.1.2 Metabolism
29
OAT is a pyridoxal phosphate (vitamin B6) dependent homohexameric transaminase, which 
30
catalyzes the reversible conversion of ornithine 
-
-pyrroline-5-
31
carboxylate (P5C) and glutamate. Each OAT monomer has a pyridoxal phosphate covalently 
32
bound to lysine 292. P5C is in non-enzymatic equilibrium with glutamate semialdehyde (GSA) 
33
and is an intermediate in the synthesis of glutamate and proline. When arginine levels (derived 
34
from the breakdown of dietary or endogenous protein) are adequate, the net flux of the OAT
35
reaction is in the direction of P5C synthesis1. When dietary arginine is inadequate, the net flux 
36
reverses to favor ornithine synthesis. Thus, the OAT reaction serves an anapleurotic function for 
37
the urea cycle and serves a necessary function for de novo arginine synthesis. Loss of this 
38
anapleurotic function explains why a few infants with GA present with arginine deficiency and 
39
neonatal hyperammonemia1. OAT activity is expressed in many cell types including high levels 
40
in the RPE but is low to undetectable in photoreceptors2. Deficiency of OAT was shown to be the 
41

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primary defect in GA by our group in 1977.3 OAT activity in GA patient fibroblasts is < 5% of 
42
control values2.
43
1.1.3 Molecular
44
The OAT gene and cDNA were cloned in 1988 and shortly thereafter the first disease producing 
45
mutation was identified4-6. Since then, more than seventy-five (75) disease causing loss of 
46
function variants have been identified2,7. As with other rare autosomal recessive conditions, the 
47
frequency of certain disease producing variants is enriched in certain populations. For example, 
48
in Finland where GA is 5- to 10-fold more frequent than in other populations, most patients are 
49
homozygous for the OAT- L402P allele reflecting a founder effect in the ancestors of modern-
50
day Finns6. A few OAT disease alleles encode a Vitamin B6 mutant enzyme, most of these are 
51
missense variants near the B6 binding lysine 292, e.g. A226V2,8.
52
Interestingly, ornithine levels are increased in a second, rare, autosomal recessive inborn error, 
53
the Hyperornithinemia- Hyperammonemia-Homocitrullinuria syndrome (HHHS, OMIM 
54
238970). The plasma ornithine values in these patients range from 200-
55
generally lower than those observed in GA. HHHS patients have episodic hyperammonemia 
56
often with a degree of intellectual disability and spasticity. More than 100 patients have been 
57
reported and only one is known to have retinal abnormalities but without the funduscopic change 
58
characteristic of GA9. It has been shown that the primary defect in HHHS is loss of function 
59
mutations in the SLC25A15 gene which encodes ORC1 (aka ORNT1), the inner mitochondrial 
60
membrane carrier protein that transports ornithine from the cytosol into the mitochondrial matrix 
61
in exchange for matrix citrulline plus H+, an essential step for normal functioning of the urea 
62
cycle10,11.
63
1.2 Treatment
64
Development of treatment of GA has been hampered by several factors:
65
The disorder is quite rare so that almost no centers have adequate numbers of patients to 
66
compare the course of treated versus non-treated individuals.
67
The patients come to medical attention at different ages and given the high allelic 
68
heterogeneity, often have different OAT genotypes.
69
There is currently no pathophysiologic model explaining the unique sensitivity of the 
70
retina to this inborn error of ornithine metabolism.
71
The progress of the untreated disease is slow and there are no systemic manifestations of 
72
hyperornithinemia. As an example, patients on diet therapy did not notice any acute 
73
negative consequences of going off-diet.
74
There is no well-studied cohort of untreated patients available for comparison to a treated 
75
group.
76
Despite these challenges, several approaches have been recently reviewed12.
77
1.2.1 Arginine Restricted Diet (ARD)
78
When the basic defect in GA was identified, it was determined that since ornithine is derived 
79
from arginine released by the breakdown of dietary or endogenous protein, a diet which 
80

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maintains adequate nutrition but in which natural protein was restricted should reduce ornithine 
81
accumulation. Due to the severity of the required protein restriction, essential amino acids (EAA) 
82
were added to the diet to avoid deficiencies of these amino acids and care was taken to provide 
83
adequate calories, minerals, and vitamins13-16. This approach was shown to reduce ornithine 
84
aintained by some patients for 
85
years with no ill effects. Ultimately, > 25 patients started this diet; most found compliance 
86
difficult and only a few were able to maintain reduce levels of ornithine for greater than five (5)
87
years17. Evaluation of the consequences of systemically reduce ornithine levels on the progress 
88
of the retinal degeneration was challenging for the reasons described above. However, based on 
89
fundus photos, visual acuity measures, and other tests, in patients followed over five (5) years or 
90
more it was concluded that reduction of plasma ornithine slowed or even stopped the retinal 
91
degeneration17.
92
This clinical impression was supported by two additional lines of evidence, one in patients and 
93
the other in a mouse model of GA. First, as described above, there is substantial heterogeneity in 
94
the rate of progression of GA, which is explained in part by allelic heterogeneity in the OAT
95
mutations causing GA. To confirm this, intra- vs inter-familial variation was compared in the 
96
ocular phenotype in six (6) GA sibling pairs and found that the ocular phenotypes of siblings 
97
were more similar than those of unrelated GA patients of a similar age. From this observation, it
98
was reasoned that in families with multiple affected siblings, the older could serve as the best 
99
control for the younger. In two (2) families, both siblings were placed, one older and one 
100
younger, on an ARD at the same time. The severity of the younger sibling to that of the older 
101
was compared when the younger reached the age of the older at the time of institution of an 
102
ARD. In both families, the retinal phenotype of the younger, who had been on an ARD for 5-7
103
years by the time they reached the age of diagnosis of the older (untreated at that point) was far 
104
less severe. This observation strongly supported the hypothesis that reduction of ornithine 
105
accumulation is beneficial18. Second, using gene targeting, a knockout mouse model of GA was 
106
produced.1 Post-weaning, homozygous OAT null mice had hyperornithinemia to an extent like
107
human GA patients. Their ERG, retinal histology and ultrastructure were normal at two (2)
108
months of age but by age six (6) months these parameters were clearly abnormal and by twelve 
109
(12) months of age they had unrecordable ERGs and a severe generalized retinal degeneration19.
110
By contrast, GA mice placed on an ARD at two (2) months of age maintained near normal 
111
plasma ornithine levels and at twelve (12) months of age had normal ERGs and completely 
112
normal retinal histology and ultrastructure20. These unambiguous results strongly indicate that 
113
systemic correction of ornithine accumulation prevents retinal degeneration in GA. As described 
114
above, however, an ARD poses an adherence challenge and only ~20% of patients can comply,
115
and all require careful and repeated evaluation to ensure adequate nutrition.
116
1.2.2 Pyridoxine Supplementation
117
For many inherited enzyme deficiencies involving vitamin B6-dependent enzymes (all 
118
transaminases, many decarboxylases), a fraction of the patients exhibited some improvement 
119
when treated with pyridoxine, vitamin B6, a precursor of pyridoxal phosphate, the active form of 
120
the vitamin. Normal pyridoxine intake is ~ 1mg/day while the therapeutic dose ranges from 200 
121
500 mg/day. This approach is completed initially on all new GA patients, instructing them to 
122
maintain their usual diet and defining a response as a > 30% reduction in ornithine levels. Using
123
these criteria, < 10% of patients respond. In those patients for whom skin fibroblasts are 
124
available, B6 responsivity in the OAT activity assays was also evaluated. The B6 responsive 
125

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patients identified have not exhibited a complete correction of ornithine levels, and for those 
126
whose
was recommended8.
127
1.2.3 Creatine Supplementation
128
The first step in the creatine biosynthetic pathway is catalyzed by arginine: glycine
129
amidinotransferase (AGAT), a cytosolic enzyme that is inhibited by ornithine, one of the 
130
reaction products. For this reason, hyperornithinemic GA patients have less than 10% of normal 
131
levels of plasma creatine and its degradation product, creatinine21. However, trials with creatine 
132
therapy have not prevented progression of the retinal degeneration22-24 and patients with inborn 
133
errors of creatine biosynthesis and similar reductions in creatine do not have retinal 
134
degeneration24. These observations have reduced enthusiasm for creatine treatment.
135
1.2.4 Proline Supplementation
136
Plasma proline levels are normal in GA, but some studies have indicated that proline is an 
137
important energy source for RPE cells and largely is derived from ornithine in a pathway that 
138
depends on OAT activity2,25. Proline crosses the blood brain barrier poorly2 and dietary 
139
supplementation with proline has been tried in GA with no beneficial effect.  However, this 
140
approach may be worth additional studies, especially if advances in understanding the 
141
pathophysiology of GA support a role for reduced proline consumption by the RPE.
142
1.2.5 Lysine Supplementation
143
Plasma lysine levels are reduced in GA patients with a mean near the lower limit of normal.2
144
This is because ornithine and lysine share a common dibasic amino acid transporter in the kidney 
145
and the high levels of ornithine compete with lysine to increase renal losses of lysine. If lysine 
146
levels could be maintained at high, supra-normal levels it should be possible to increase urinary 
147
losses of ornithine. Evidence from GA mice and GA patients indicates that this approach works 
148
but requires high doses of oral lysine which many (most) patients do not tolerate. Moreover, to 
149
be effective, lysine levels must be maintained at supra-normal levels which could have 
150
detrimental consequences over the long-term.
151
1.3 Rationale
152
The treatment for GA that has produced clearly positive results is systemic reduction of ornithine 
153
with an ARD. This diet is challenging and only a small fraction of patients can maintain the diet.
154
The results, to date, support the hypothesis that ornithine is directly involved in pathophysiology 
155
and that systemic reduction is sufficient for a therapeutic benefit. Pyridoxine supplementation 
156
treatment should be beneficial in those patients who have B6-responsive OAT mutations 
157
regardless of the pathophysiological mechanism and all patients merit a trial with clear criteria 
158
for a beneficial effect (>30% decrease in plasma ornithine on an unrestricted diet). To date, 
159
depending on OAT genotype, only a few GA patients respond. There is little or no evidence 
160
supporting the other therapeutic approaches currently. A well-controlled natural history study 
161
would be extremely valuable for future therapeutic trials.
162
There is limited information from previous natural history studies of patients with GA12,26. The 
163
available information is based on cross-sectional data from small numbers of patients, or from 
164
longitudinal studies that are either short term treatment studies or natural history studies with 
165
outcomes based on outdated imaging and visual function methodology17.
166

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1.4 Study Objective
167
Natural History - Characterize the natural history of ornithine levels and retinal degeneration 
168
(RD) associated with disease-causing OAT variants in the presence of standard care dietary 
169
treatment regimens over 4 years.
170
Metabolic-Structure-Function Relationships - Explore the relationships between structural 
171
and functional RD outcome measures and plasma ornithine levels.
172
Identify Rapid Progressors
Explore the relationship of possible risk factors (genotype, 
173
phenotype, environmental, comorbidities, and standard care dietary regimen) with severity and 
174
progression of metabolic, functional, structural, and patient-reported outcomes.
175
1.5 Potential Risks and Benefits
176
1.5.1 Known Potential Risks
177
Most examination procedures are considered part of standard care for retinal degenerations. This
178
study will be capturing information about participants that includes identifiable, personal 
179
180
in place to protect that information. However, there is a chance that a loss of that protection 
181
could occur. This would be a loss of confidentiality. There are special efforts being made to 
182
ensure that this does not happen. 
183
The sections below summarize the risks and discomforts that may occur during the period of
184
prospective data collection.
185
Risks associated with testing visual acuity (VA), kinetic perimetry (KP), microperimetry 
186
(MP), static perimetry (SP), Optos fundus autofluorescence (FAF), Optos Color Photos,
187
red reflectance photos, Optical coherence tomography angiography (OCT-A), and patient 
188
reported outcome (PRO) questionnaires may include boredom and frustration. However,
189
no lasting adverse effects are associated with these noninvasive tests
190
Dilating eye drops will be used as part of the ophthalmic examination and before the
191
spectral domain optical coherence tomography (SD-OCT), full-field stimulus threshold 
192
(FST), and MP. Dilating eye drops may sting, cause light-sensitivity, or an allergic 
193
reaction. There is a small risk of inducing a narrow-angle glaucoma attack from the pupil 
194
dilation. However, all participants will have had prior pupil dilation, usually on multiple 
195
occasions. Therefore, the risk is extremely small. If glaucoma occurs, treatment is 
196
available.
197
Intraocular Pressure (IOP) Examination: In rare instances, the cornea may be 
198
scratched during measurement of IOP. An abrasion like this may be painful, but it heals 
199
quickly with no lasting effects. If a participant experiences a corneal abrasion, ophthalmic
200
ointment may be administered, and an eye patch or gauze may be placed over the eye.
201
Venipuncture: Blood draws can cause common mild reactions including pain, bruising, 
202
or redness at the sampling site. Less common reactions include bleeding from the 
203
sampling site, formation of a small blood clot or swelling of the vein and surrounding 
204
tissues, and fainting. The risk of local infection is less than 1 in 1000.
205

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Fingerstick Risks: About two (2) drops of blood will be removed by fingerstick for 
206
measuring ornithine, amino acid, and arginine. Pain is common at the time of lancing. In 
207
about 1 in 10 cases, a small amount of bleeding under the skin will produce a bruise. A 
208
small scar may persist for several weeks. The risk of local infection is less than 1 in 1000.
209
Skin biopsy: Complications associated with a three (3) mm punch biopsy of the skin 
210
include a brief sting when the local anesthetic (numbing medicine) is injected at the 
211
biopsy site, the possibility of local bleeding and bruising, pain, infection, allergic reaction 
212
to the numbing medicine used in the procedure, or damage to the structures beneath the 
213
skin site (such as an artery or a nerve). A small scar may persist for several years.
214
1.5.2 Known Potential Benefits
215
Study participants are not expected to benefit directly from participation in this study. 
216
1.5.3 Risk Assessment
217
The known potential risks above, except for venipuncture, fingerstick collection and skin biopsy,
218
are standard-of-care procedures that do not pose additional risks to participate in the study.
219
The venipuncture is needed to collect plasma samples to monitor the ornithine levels in
220
relation to progression of Gyrate Atrophy.
221
A fingerstick blood spot collection is needed to obtain a blood spot sample. This will 
222
determine if this procedure is comparable to the plasma sample collection in evaluating 
223
the ornithine levels over time.
224
A skin biopsy is an incisional procedure of the skin. The potential complications include 
225
localized bleeding, scarring, bruising, pain, redness, swelling, and damage to nerves and
226
blood vessels. These complications are rare, and when they occur, are mild and self-
227
limiting. This procedure will be used to collect the p
s cells, which are 
228
fibroblasts. These cells will be used to measure the activity of the 
OAT
229
enzyme and the response to vitamin B6. The research goal is to understand the impact of 
230
OAT mutations on plasma ornithine levels and retinal degeneration. The skin biopsy is 
231
necessary to quantify OAT enzyme activity in each participant as it is not possible to 
232
derive this information from the blood sample, thus providing direct confirmation on the 
233
pathogenicity and functional severity of the mutation in each subject. This information 
234
will inform the analysis of the plasma ornithine and retinal degeneration outcome 
235
measures for the duration of this trial and will complement the development of dietary 
236
guidelines for treatment trials in slowing the progression of Gyrate Atrophy. The cells 
237
can be stored frozen indefinitely with participant consent. These cells can be re-cultured 
238
to perform additional studies as needed to provide a better understanding of Gyrate 
239
Atrophy.
240
1.6 General Considerations
241
The study is being conducted in compliance with the policies described in the study policies 
242
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
243
the protocol described herein, and with the standards of Good Clinical Practice (GCP).
244

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Employing a prospective longitudinal study design is advantageous because it reflects a 
245
systematic method of data collection. This study design incorporates several strategies to 
246
History 
247
Studies for Drug Development: Guidance for Industry, Draft Guidance.27 These are considered 
248
standard for treatment trials and will enhance the translation of the data from this study to a 
249
treatment trial.
250
Establishing standardized testing procedures and specific required equipment for all 
251
investigators, leading to greater consistency and precision in the information collected.
252
Training and certification of study staff who will perform primary outcome procedures by
253
a Reading Center. The Reading Center will grade test results in a uniform manner 
254
independently from study sites.
255
Use of standard, consistent definitions of pre-existing medical conditions, medications 
256
and treatments, and adverse events (AEs) across all clinical sites.
257
A consistent schedule of follow-up visits for all participants with established visit time 
258
frames.
259
A coordinating center (CC) is responsible for monitoring the conduct of the study to 
260
ensure adherence to protocol.
261
When feasible, data will be directly collected in electronic case report forms, which will 
262
be considered the source data.
263

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Chapter 2: Study Enrollment and Screening
264
2.1 Participant Recruitment and Enrollment
265
Enrollment will proceed with the goal of at least forty-five (45) participants completing the trial. 
266
Approximately fifty (50) individuals may be enrolled in the study to achieve this goal. 
267
Participants who have signed consent and started the Screening process may be permitted to 
268
continue into the trial, if eligible, even if the enrollment goal has been reached.
269
Study participants will be recruited from approximately twelve (12) clinical sites worldwide. All
270
eligible participants will be included without regard to gender, race, or ethnicity. The primary 
271
recruitment strategy will be from the patients referred from the Investigators. However, 
272
recruitment materials may be made available at retinal disorder websites upon IRB approval.
273
The target population for GYROS will be patients with GA associated with disease-causing 
274
variants in the OAT gene. The male: female distribution of patients with OAT-related retinal 
275
degeneration is expected to be approximately 1:1, therefore both genders will be eligible to 
276
enroll. Additionally, OAT-related retinal degeneration affects patients of all racial and ethnic 
277
groups, thus enrollment will be conducted without regard to race or ethnicity. 
278
It is expected that GYROS enrollment will be representative of the population of patients with 
279
gyrate atrophy associated with disease-causing variants in the OAT gene, including those under 
280
the age of eighteen (18). GA can impact individuals in the first or second decade of life, 
281
therefore it is important that children are included in this natural history study to characterize the
282
natural history of retinal degeneration in patients with gyrate atrophy.     
283
2.1.1 Participant Recruitment Goals and Strategy
284
2.1.1.1 Target Study Sample Size
285
Recruitment will be tracked by three (3) vision cohorts defined below. Reference Chapter 6.1 
286
Sample size for the rationale.
287
Vision Cohort 1
Approximately 
Twenty-five (25) 
participants
Criteria that must be met in the better eye* at the Screening Visit: 
o visual acuity ETDRS letter score of 54 or more (approximate Snellen 
equivalent 20/80 or better) and visual field** diameter 10 degrees or 
more in every meridian of the central field
Vision Cohort 2
Approximately 
Fifteen (15) 
participants
Criteria that must be met in the better eye* at the Screening Visit:
o visual acuity ETDRS letter score of 19-53 (approximate Snellen 
equivalent 20/100 - 20/400)
OR
o visual acuity ETDRS letter score of 54 or more (approximate Snellen 
equivalent 20/80 or better) and visual field** diameter less than 10 
degrees in any meridian of the central field.
Vision Cohort 3
Approximately 
Five (5) 
participants
Criteria that must be met in the better eye* at the Screening Visit:
o visual acuity ETDRS letter score of 18 or less (approximate Snellen 
equivalent 20/500 or worse).

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*Better eye 
definition 
The better eye is defined as the eye with the better Screening Visit ETDRS 
visual acuity. However, if both eyes have the same visual acuity, which is 
defined as the same Snellen equivalent, then the determination will be made 
at investigator discretion. In this scenario, the investigator will consider the 
eye with better fixation or clearer ocular media to permit highest quality 
retinal imaging.
**Visual Field 
The visual field (VF) is defined as the clinically determined kinetic VF 
III4e performed within the last 18 months prior to the Screening Visit or 
performed on the day of the Screening Visit.
288
VF diameter
every meridian
VF diameter <10° in 
any meridian
20/80 or better
Vision Cohort 1
Vision Cohort 2
20/100-20/400
Vision Cohort 2
Vision Cohort 2
20/500 or worse
Vision Cohort 3
Vision Cohort 3
289
2.1.1.2 Participant Recruitment
290
The Foundation Fighting Blindness (FFB) Consortium Executive Committee will review 
291
recruitment progress and feasibility at regular intervals. 
292
293
Initial recruitment goals will include forty-five (45) participants enrolled into the study vision 
294
cohorts 1, 2, and 3 combined. If recruitment is not at a rate to meet the initial goals, an interim 
295
assessment of feasibility may be made by the FFB Consortium Executive Committee. A 
296
minimum of forty (40) participants enrolled in Vision Cohorts 1 and 2 combined will be targeted.
297
2.1.1.3 Participant Enrollment
298
Participants will not be counted as enrolled into the study cohort until Initial Screening
299
and Genetic Screening have been confirmed. This means that potentially more participants 
300
will be screened. The number and reasons for screen failures will be tracked. It is possible that 
301
participants will have completed the screening visit and will be awaiting genetic confirmation at 
302
the time the enrolled numbers reach the goals above. Therefore, the final enrolled numbers may 
303
be larger. To limit over-enrollment, clinical sites will be notified as the recruitment goals near 
304
completion and efforts will be made to accurately predict numbers in the genetic screening 
305
queue.
306
2.2 Informed Consent and Authorization Procedures
307
Study participants must be age of majority to consent for themselves, e.g., at least eighteen (18)
308
years of age in the US. For potential participants who are minors, e.g., under eighteen (18) years 
309
of age in the US, a parent/legal guardian (referred to 
310
with the Informed Consent Form to read and will be given the opportunity to ask questions. 
311
P
n Assent Form to 
312
read and discuss with their parents and study personnel. If the parents and child agree 
313

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to participate, the Informed Consent Form and Child Assent Form will be signed. A copy of the 
314
consent form will be provided to the participant and their parents, and another copy will be 
315
added t
316
The study protocol will be discussed with the potential study participant by study staff. The 
317
potential study participant will be given the Informed Consent Form to read. Potential study 
318
participants will be encouraged to discuss the study with family members and their personal 
319
physician(s) before deciding whether to participate in the study.
320
As part of the informed consent process, each participant will be asked to sign an authorization 
321
for release of personal information. The investigator, or his or her designee, will review the 
322
study-specific information that will be collected and to whom that information will be disclosed. 
323
After speaking with the participant, questions will be answered about the details regarding
324
authorization.
325
A participant is considered enrolled into the initial screening when the ICF has been signed 
326
and a participant ID has been obtained on the study website.
327
Participants who become age of majority, e.g., eighteen (18) years of age in the US, during the
328
study will need to re-consent with an adult Informed Consent Form.
329
2.3 Screening Visit 
330
After the ICF has been signed, a potential participant will be evaluated for study eligibility 
331
through the elicitation of a medical history, performance of ophthalmic tests as described below, 
332
and genetic testing, if applicable. The Screening Visit date will be the date the Screening Visit 
333
testing procedures started. All Screening Visit testing procedures will be completed on this date.
334
2.3.1 Eligibility Criteria
335
To be eligible to enroll into the genetic screening phase, a study participant must meet all the 
336
inclusion criteria and none of the exclusion criteria at the Screening Visit.
337
2.3.1.1 Participant Inclusion Criteria
338
Participants must meet all the following inclusion criteria at the Screening Visit to be eligible to 
339
enroll into the genetic screening phase.
340
1. Willing to participate in the study and able to communicate consent during the 
341
consent process.
342
2. Willing and able to complete all study visit assessments at each visit over the forty-
343
eight (48) month study period.
344
3.
345
4. Adult participants must have the capacity to consent on their own behalf. 
346
5. Must meet one (1) of the Genetic Screening Criteria below:
347
At least 2 disease-causing variants in the OAT gene which are 
348
homozygous or heterozygous in trans, based on a report from a 
349
clinically certified lab, or a report from a research lab that has been pre-
350
approved by the study Genetics Committee.
351
352
OR
353

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354
At least 2 disease-causing variants in the OAT gene with unknown 
355
phase, based on a report from a clinically certified lab, or a report from a 
356
research lab that has been pre-approved by the study Genetics Committee,
357
AND must meet both of the following phenotype criteria:
358
1. Classic fundus appearance of gyrate atrophy (based on 
359
investigator discretion) AND
360
2. Elevated ornithine levels >300 µmol/L (documented on any 
361
prior lab report).
362
2.3.1.2 Ocular Inclusion Criteria
363
Participant must meet the following criteria at the Screening Visit to enroll into the genetic 
364
screening phase.
365
6. Both eyes must have a clinical diagnosis of retinal dystrophy
366
7. Both eyes must permit good quality photographic imaging (for example, but not 
367
limited to, clear ocular media, adequate pupil dilation, stable fixation).
368
2.3.1.3 Participant Exclusion Criteria
369
Participants must not meet any of the following exclusion criteria at the Screening Visit to be 
370
eligible to enroll into the genetic screening phase.
371
1. Single pathogenic or likely pathogenic genetic variants known to be associated with 
372
autosomal dominant retinitis pigmentosa/retinal dystrophy (AD, heterozygous), X-
373
linked retinitis pigmentosa/retinal dystrophy (XL, hemizygous), or mitochondrial 
374
inheritance.
375
2. Expected to enter experimental treatment trial at any time during this study.
376
3. History of more than one (1) year of cumulative treatment, at any time, with an agent 
377
associated with pigmentary retinopathy, including amiodarone, chloroquine, 
378
deferoxamine, hydroxychloroquine, pentosan polysulfate, tamoxifen, and 
379
deferoxamine.
380
Note: Since this is a Natural History Study collecting data on the progression of GA, pregnant 
381
women will not be specifically excluded from participation.
382
2.3.1.4 Ocular Exclusion Criteria
383
If either eye has any of the following ocular exclusion criteria at the Screening Visit, then the
384
participant is not eligible to enroll into the genetic screening phase.
385
4. Current vitreous hemorrhage. 
386
5. Current complications of pathological myopia (for example, but not limited to,
387
myopic maculopathy including atrophy, scar, choroidal neovascularization, schisis) 
388
that could inhibit imaging studies of gyrate atrophy-related chorioretinal degeneration 
389
or assessment of visual function.
390
6. History of intraocular surgery (for example, but not limited to cataract surgery, 
391
vitrectomy, penetrating keratoplasty, or LASIK) within the last 3 months.
392

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7. Current or any history of confirmed diagnosis of glaucoma (for example, but not 
393
limited to glaucomatous VF changes or nerve changes, or history of glaucoma 
394
filtering surgery).
395
8. Current or any history of retinal vascular occlusion or proliferative diabetic 
396
retinopathy.
397
9. Any clinically significant cystoid macular edema, as determined by the Investigator, 
398
that is not stable three (3) months before screening; use of chronic, prophylactic 
399
treatment with topical or oral agents (for example, but not limited to, dorzolamide) is 
400
allowed.
401
10. History or current evidence of ocular disease that, in the opinion of the investigator, 
402
may confound assessment of visual function (for example, but not limited to,
403
tractional or rhegmatogenous retinal detachment, any vitreoretinal surgery, retinal 
404
vascular occlusion, proliferative diabetic retinopathy).
405
11. The following medications and treatments are prohibited as they can affect 
406
progression of retinitis pigmentosa or confound the assessments. The participant must 
407
not have received or plan to receive the following treatments.
408
i. Any use of ocular stem cell or gene therapy:
409
ii. Any treatment with ocriplasmin.
410
iii. Treatment with Ozurdex (dexamethasone), Iluvien or Yutiq (fluocinolone 
411
acetonide) intravitreal implant.
412
12. The following medications and treatments are excluded within the specified 
413
timeframe:
414
i. Treatment with an ophthalmic oligonucleotide within the last 9 months (last 
415
treatment date is less than 9 months prior to Screening Visit date).
416
ii. Treatment with any other product for retinal dystrophy within five times the 
417
expected half-life of the product (time from last treatment date to Screening 
418
Visit date is at least 5 times the half-life of the given product). 
419
iii. Treatment that can alter VA between Screening and Baseline (e.g., 
420
periorbital injections.
421
2.3.2 Screening Data Collection and Testing
422
Please reference the schematic of study design at the beginning of the protocol for the flow of the 
423
study visit procedures. The following procedures will be performed at the Screening Visit. The 
424
testing procedures are detailed in the GYROS Clinical Site Manual of Procedures. An 
425
overview of the equipment and technician requirements for all testing is in Chapter 5.1 Study 
426
Procedure Requirements. All ocular testing will be performed in each eye, right eye (OD) first 
427
and then left eye (OS). Screening procedures will last approximately four (4) hours.
428
429
Participants meeting criteria to continue will be enrolled into the genetic screening phase.
430
Otherwise, the participant will be an initial screen failure.
431
432
The following procedures will be performed, data collected, eligibility criteria checked, and 
433
documented at the Screening Visit.
434
1. Inclusion and exclusion criteria assessed
435
2. Demographics: date of birth, sex, race, and ethnicity
436

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3. Contact information: this will be retained at the site and not entered on the study database
437
4. Medical history: will be elicited from the study participant and extracted from available 
438
medical records, including patient-reported daily activities, pre-existing medical 
439
conditions, and medications.
440
Participant will sign a release of medical information form to collect medical 
441
records and laboratory records.
442
5. Concomitant medications
443
6. Genetic screening assessment, including number and phase of mutations in the OAT gene, 
444
history of consanguinity, and collection of the source genetic report(s) available at the 
445
clinical site.
446
This includes an assessment that the participant meets one of the Genetic 
447
Screening Criteria. If the participant does not meet the criteria for one of the 
448
Genetic Screening Criteria, then the remainder of procedures and testing are not 
449
required. The participant will be discontinued as an initial screen failure.
450
7. Complete ophthalmic examination to include:
451
Slit lamp biomicroscopy
452
Indirect ophthalmoscopy
453
8. IOP
454
IOP measurements will be taken prior to pupil dilation.
455
9. VA (including refraction, ETDRS, BRVT if needed, LLVA if needed).
456
The VA letter score will determine whether LLVA or BRVT will be performed.
457
The criteria are defined in the GYROS Clinical Site Manual of Procedures.
458
10. Kinetic VF III4e 
459
Vision Cohort 1 and 2: Historical measurement performed within the last 
460
eighteen (18) months prior to the Screening Visit. If a historical measurement is 
461
not available, then perform the Kinetic VF III4e at the Screening Visit.
462
Vision Cohort 3: Collect the most recent historical measurement prior to the 
463
Screening Visit, if available. Kinetic VF III4e does not need to be performed at 
464
screening if a historical measurement is not available.
465
11. Determination of Vision Cohort
466
467
remainder of procedures and testing are not required. Participant will be 
468
discontinued as an initial screen failure.
469
12. Sample Collection
470
The Site Personnel will collect one (1) fasting plasma sample.
471

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2.3.3 Initial Screen Failures
472
Participants who do not meet criteria to continue as noted above will be discontinued as an
473
initial screen failure
474
testing not finished. A Final Status Form will be completed, and the reason for screen failure will 
475
be noted.
476
2.4 Genetic Screening Phase
477
Participants passing the initial screening and enrolling into the Genetic Screening Phase will 
478
submit their genetic lab reports for CGA review. The schematic of study design at the beginning 
479
of the protocol summarizes the flow of the Genetic Screening Phase. Reference the GYROS 
480
Clinical Site Manual of Procedures for detailed procedures.
481
All genetic reports will be uploaded to the FFB study website by the clinical site. These reports 
482
may be reviewed by the CC, associated clinical site, Central Genetics Auditor (CGA), Genetics 
483
Committee, and investigators involved in the oversight of the study (which includes the study 
484
chair, Operations Committee, and Executive Committee). All genetic reports will be de-
485
identified and redacted of all personal data prior to uploading on the FFB study website.
486
The clinical site will upload supporting genetic documentation, including the genetic reports, on
487
the FFB study website. The CGA will review the genetic documentation provided by the clinical 
488
site to verify the genetic screening data entry and appropriate documentation of the Genetic 
489
Screening Criteria. Additional documentation may be requested as needed to verify the Genetic 
490
Screening Criteria and all genetic screening assessments.
491
If Genetic Screening Criteria are verified, then the participant will be considered 
492
enrolled into the study cohort.
493
If the final study cohort is not verified, then the participant will be a genetic screen 
494
failure.
495
2.4.1.1 Genetic Screen Failures
496
Participants who do not meet criteria to continue in the study will be discontinued as a genetic 
497
screen failure. A Final Status Form will be completed, and the reason for screen failure will be 
498
indicated.
499
2.4.1.2 Genetics Committee Review
500
A Genetics Committee will review the genetic documentation of participants with verified final 
501
study cohort criteria and enrolled into the study cohort for interpretation and evaluation of 
502
whether the OAT mutations are causative of the disease (i.e., pathogenic, likely pathogenic). 
503
Cases that are not confirmed as disease causing will remain in the study and will not be 
504
considered ineligible. However, their data may be analyzed separately from those with 
505
pathogenic mutations.
506
2.5 Final Study Cohort Criteria
507
The Final Study Cohort Criteria is participants that meet one of the Genetic Screening 
508
Criteria, and have the genetic criteria confirmed by a Central Genetics Auditor (CGA).
509

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Participants that meet the initial screening and eligibility criteria, who complete the Genetic 
510
Screening Phase, and who meet the final study cohort criteria will be considered enrolled into 
511
the study cohort. These participants should complete the natural history study.
512
513

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Chapter 3: Baseline Visit
514
3.1 Baseline Visit 
515
Participants meeting criteria to enter the natural history study will return for a Baseline Visit
516
within sixty (60) days after receiving confirmation of meeting final study cohort criteria from 
517
the CGA. 
518
519
The Baseline Visit date will be documented as the date testing procedures began. All Baseline 
520
Visit testing procedures will be completed within ten (10) days of the Baseline Visit date, unless
521
specified below.
522
3.2 Food Record and Blood Sample Collection
523
All participants will complete the food record and blood sample collection as described below.
524
(1) Participant Contact
525
The Clinical Site Coordinator will contact the participants (via phone or other 
526
remote interface) four (4) to ten (10) days prior to the first of the two (2)
527
scheduled sample collection date. The Pre-Sample Collection Telephone 
528
Call will include instructions and reminders of:
529
o
The two (2) sample collection dates.
530
o
Fasting instructions.
531
o
Food record collection instructions.
532
(2) Food Record 
533
The participant will complete a food record to document their daily 
534
consumption during the following period:
535
o
Begin three (3) days prior to the first sample collection date
536
o
End one (1) day prior to the last sample collection date
537
The participant will digitally send (e-mail or text) a picture of the food record 
538
documentation and either mail the original food tracking record to the site or 
539
bring it to the site at their Baseline Visit.
540
The Clinical Site Coordinator will enter the data from the food record on the 
541
FFB Study Website. 
542
A Central Dietitian Reviewer (CDR) will review food record on FFB Study 
543
Website to determine nutritional content. This information will be 
544
documented on the FFB Study Website.
545
(3) Sample Collection
546
Site Personnel will collect the following:
547
o
Two (2) fasting plasma samples on two (2) different days, within ten 
548
(10) days of the Baseline Visit date.
549

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o
One (1) fasting blood spot fingerstick on the same day as one of the 
550
fasting plasma samples.
551
All samples will be shipped to the Kennedy Krieger Institute
552
(KKI).
553
The Clinical Site Coordinator would request the most recent lab records with 
554
an albumin result if the participant indicated they are currently on an arginine-
555
restricted diet.
556
3.3 Baseline Procedures
557
The following procedures will be performed at the Baseline Visit. The testing procedures are 
558
detailed in the GYROS Clinical Site Manual of Procedures. An overview of the equipment 
559
and certification requirements for all testing is in Chapter 5.1: Study Procedure 
560
Requirements. All ocular testing will be performed in each eye, OD first and then OS. Baseline
561
procedures will last approximately seven (7) eight (8) hours. Baseline procedures will span 
562
over ten (10) days.
563
3.3.1 Baseline Data Collection and Testing Cohorts 1 & 2
564
1. Medical updates to include:
565
New or changed adverse events (AEs)
566
New ocular procedures
567
New or changed medications
568
Request medical records and laboratory records if applicable.
569
2. Patient Reported Outcomes 
570
Adults: PROMIS®-29, MRDQ, ViSIO-PRO
571
Adolescents: LPV-FVQ II, ViSIO-PRO
572
Children: LPV-FVQ II
573
The PROs may be completed in person or remotely (phone or other remote 
574
methods) any time within six (6) months of the Baseline Visit (not required to 
575
be the same day as the rest of the Baseline Visit).
576
3. Skin biopsy (3mm punch skin biopsy)
577
Ship to Johns Hopkins University Department of Genetic Medicine Research Lab 
578
4. Spectral Domain Optical Coherence Tomography (SD-OCT)
579
Volume Scan 
580
Vertical and Horizontal Scan 
581
5. Axial Length and Corneal Curvature Measurements
582
6. Fundus Autofluorescence
583
7. Widefield color photo
584

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8. Optical coherence tomography angiography (OCTA)
585
Ancillary test; may be waived with approval from the Coordinating Center
586
9. Red reflex photo
587
10. Full field Stimulus Threshold (FST)
588
11. Static perimetry
589
Two (2) tests will be performed. The clinical site will compare the certified 
590
technician determined mean sensitivity from test one (1) versus test two (2).
591
(a)
592
then the participant passes static perimetry reliability criteria. A third test 
593
is not needed.
594
595
(b) If the absolute value of the difference between the two tests is > 2.4 dB, 
596
then the participant does not pass static perimetry reliability criteria. A 
597
third test will be required.
598
12. Fundus guided microperimetry 
599
Two (2) tests will be performed. The clinical site will compare the certified 
600
technician determined mean sensitivity from test one (1) versus test two (2).
601
(a) If the absolute value of the difference between the two tests divided by 
602
of the 
603
604
the microperimetry reliability criteria. A third test is not needed.
605
606
(b) If the absolute value of the difference between the two tests divided by 
607
the average between them is > 50% AND the absolute value of the 
608
difference between the two tests is > 0.5 dB, then the participant does not 
609
pass microperimetry reliability criteria. A third test will be required.
610
13. Measurements to include:
611
Weight
612
Height
613
3.3.2 Baseline Data Collection and Testing Cohort 3
614
1. Medical updates to include
615
New or changed adverse events (AEs)
616
New ocular procedures
617
New or changed medications
618
Request medical records and laboratory records if applicable.
619
2. Patient Reported Outcomes 
620
Adults: PROMIS®-29, MRDQ, ViSIO-PRO
621

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Adolescents: LPV-FVQ II, ViSIO-PRO
622
Children: LPV-FVQ II
623
The PROs may be completed in person or remotely (phone or other remote 
624
methods) any time within six (6) months of the Baseline Visit (not required to 
625
be the same day as the rest of the Baseline Visit).
626
3. Skin biopsy (3mm punch skin biopsy)
627
Ship to Johns Hopkins University Department of Genetic Medicine Research Lab 
628
4. Spectral Domain Optical Coherence Tomography (SD-OCT)
629
Volume Scan 
630
Vertical and Horizontal Scan 
631
5. Axial Length and Corneal Curvature Measurements
632
6. Fundus Autofluorescence
633
7. Widefield color photo
634
8. Optical coherence tomography angiography (OCTA)
635
Ancillary test; may be waived with approval from the Coordinating Center
636
9. Red reflex photo
637
10. Full field Stimulus Threshold (FST)
638
11. Measurements to include:
639
Weight
640
Height
641
642

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Chapter 4: Follow-up Visits
643
4.1 Follow-up Visits 
644
Follow-up Visits for all vision cohorts will occur annually. The Baseline Visit date is considered 
645
study day zero (0) from which follow-up visit windows are timed. The Follow-up Visit date will 
646
be the date the Follow-up Visit testing procedures started. All Follow-up Visit testing procedures 
647
will be completed on the same date other than the PROs as noted in Section 4.4 Follow-up
648
Procedures.
649
4.2 Target Timelines
650
Target dates and windows for each study Follow-up Visit for all vision cohorts are shown below.
651
Dates and windows are timed from Baseline Visit Date. Visits will be scheduled in the target 
652
window.
653
Table 4-1. Schedule for Follow-up Visits
654
VISIT SCHEDULE 
TARGET DATE 
TARGET 
WINDOW  
(AROUND TARGET 
DATE) 
12 Month Visit 
52 Weeks 
± 4 Weeks
24 Month Visit 
104 Weeks
± 4 Weeks
36 Month Visit 
156 Weeks 
± 4 Weeks
48 Month Visit 
208 Weeks
± 4 Weeks
655
Table 4-2. Schedule for Remote Blood Spot Collection
656
BLOOD SPOT 
SCHEDULE 
TARGET DATE 
TARGET 
WINDOW  
(AROUND TARGET 
DATE) 
4 Months
17 Weeks
± 4 Weeks
8 Months
34 Weeks
± 4 Weeks
16 Months
69 Weeks
± 4 Weeks
20 Months
86 Weeks
± 4 Weeks
28 Months
121 Weeks
± 4 Weeks
32 Months
138 Weeks
± 4 Weeks
40 Months
173 Weeks
± 4 Weeks
44 Months
190 Weeks
± 4 Weeks
The goal will be for all participants to complete all scheduled visits. However, participants who,
657
because of unforeseen circumstances, are unable or unwilling to return for all follow-up visits 
658
will be permitted to return for key visits only as an alternative to withdrawal from the study. 
659

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Additional office visits may occur as needed.
660
4.3 Food Record and Blood Sample Collection
661
All participants will be asked to complete the blood sample collection as described below.
662
Clinical Site Coordinators will complete a Pre-Sample Collection Telephone Call four (4) to 
663
ten (10) days prior to the scheduled sample collection date. For at-home samples, the Post-
664
Sample Collection Telephone Call should be completed within one (1) day after the scheduled 
665
sample collection date. Reference the GYROS Clinical Site Manual of Procedures for more 
666
details.
667
(1) Participant Contact
668
The Clinical Site Coordinator will contact the participants (via phone or other 
669
remote interface) four (4) to ten (10) days prior to the scheduled sample 
670
collection date. The Pre-Sample Collection Telephone Call will include 
671
instructions and reminders of:
672
o
The next sample collection date.
673
o
Fasting instructions.
674
o
Food record collection instructions (if applicable; see Food Record 
675
instructions below).
676
For at-home sample collections the Clinical Site Coordinator will contact the 
677
participants (via phone or other remote interface) after the scheduled sample 
678
collection date, within one (1) day preferred. The Post-Sample Collection 
679
Telephone Call will include the collection of:
680
o
Information on the
.
681
o
Completion of the blood spot sample.
682
o
Completion of the Food Record.
683
(2) Food Record 
684
Participants who indicated following an arginine-restricted diet at
685
Screening will be asked to complete a food record every four (4) months
686
between Baseline and the 48M visit.
687
o
If a participant initiates an arginine-restricted diet after Screening, the 
688
participant will complete a food record every four (4) months going
689
forward.
690
o
If a participant following an arginine-restricted diet at screening stops 
691
following an arginine-restricted diet at any point in the study, the
692
participant will continue to complete the food record every four (4)
693
months.
694
ALL participants will complete the food record for the 48M visit.
695
The participants will complete the food record every day for three (3) days 
696
prior to the fasting sample collection.
697

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The participant will digitally send (e-mail or text) a picture of the food record
698
to the site and either mail the original food record document to the site or
699
bring it to the site at their next visit.
700
The Clinical Site Coordinator will transcribe the data from the food record on 
701
the FFB Study Website. 
702
A Central Dietitian Reviewer (CDR) will review food record on FFB Study
703
Website to determine nutritional content. This information will be entered into 
704
the FFB Study Website.
705
(3) Sample Collection
706
At the annual Follow-up Visits, the Clinical Site Personnel will collect one 
707
(1) fasting plasma sample on all participants and ship to KKI. The sample 
708
collection procedures are detailed in the GYROS Clinical Site Manual of 
709
Procedures.
710
At the annual Follow-up Visits, the Clinical Site Personnel will collect one 
711
(1) fasting blood spot fingerstick on all participants and ship to KKI. The 
712
sample collection procedures are detailed in the GYROS Clinical Site Manual 
713
of Procedures.
714
At the annual Follow-up Visits, the Clinical Site Coordinator would request
715
the most recent lab records with an albumin result if the participant indicated 
716
they are currently on an arginine-restricted diet.
717
Every four (4) months between annual Follow-up Visits, one (1) fasting
718
blood spot fingerstick will be collected on all participants. The participant or 
719
caretaker will collect the sample and ship to the central laboratory, KKI. The 
720
blood spot collection kits and instructions will be provided. The sample 
721
collection procedures are detailed in the GYROS Clinical Site Manual of 
722
Procedures.
723
4.4 Follow-up Procedures
724
The following procedures will be performed at the Follow-Up Visits, unless otherwise specified.
725
The testing procedures are detailed in the GYROS Clinical Site Manual of Procedures. An
726
overview of the equipment and certification requirements for all testing is in Chapter 5.1: Study 
727
Procedure Requirements. All ocular testing will be performed in each eye, OD first and then 
728
OS. Follow-up visit procedures will last approximately seven (7) eight (8) hours.
729
4.4.1 Follow-up Data Collection and Testing Cohorts 1 & 2
730
1. Medical updates to include:
731
New or changed adverse events (AEs)
732
New ocular procedures
733
New or changed medications
734
Request medical records and laboratory records if applicable.
735
2. Patient Reported Outcomes
736

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Complete at 24-Month and 48-Month Follow-up Visits Only
737
Adults: PROMIS®-29, MRDQ, ViSIO-PRO
738
Adolescents: LPV-FVQ II, ViSIO-PRO
739
Children: LPV-FVQ II
740
The PROs may be completed in person or remotely (phone or other remote 
741
methods) any time within the Allowable Window of the associated visit, (not 
742
required to be the same day as the rest of the Follow up Visit).
743
3. Complete ophthalmic examination to include:
744
Slit lamp biomicroscopy
745
Indirect ophthalmoscopy
746
4. IOP
747
IOP measurements will be taken prior to pupil dilation.
748
5. VA (including refraction, ETDRS, BRVT if needed, LLVA if needed)
749
The visual acuity letter score will determine whether LLVA or BRVT will be 
750
performed. The criteria are defined in the GYROS Clinical Site Manual of 
751
Procedures.
752
6. SD-OCT
753
Volume Scan 
754
Vertical and Horizontal Scan 
755
7. Axial Length and Corneal Curvature Measurements
756
Complete at 24-Month and 48-Month Follow-up Visits Only
757
8. Fundus Autofluorescence
758
9. Widefield color photo
759
10. OCTA
760
Ancillary test; may be waived with approval from the Coordinating Center
761
11. Red reflex photo
762
12. Full field Stimulus Threshold test (FST)
763
13. Static perimetry
764
14. Fundus guided microperimetry 
765
15. Measurements to include:
766
Weight
767
Height
768
Measured annually in participants <21 years of age at enrollment.
769

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PAGE 42 OF 70
4.4.2 Follow-up Data Collection and Testing Cohort 3
770
1. Medical updates to include
771
New or changed adverse events (AEs)
772
New ocular procedures
773
New or changed medications
774
Request medical records and laboratory records if applicable
775
2. Patient Reported Outcomes
776
Complete at 24-Month and 48-Month Follow-up Visits Only
777
Adults: PROMIS®-29, MRDQ, ViSIO-PRO
778
Adolescents: LPV-FVQ II, ViSIO-PRO
779
Children: LPV-FVQ II
780
The PROs may be completed in person or remotely (phone or other remote 
781
methods) any time within the Allowable Window of the associated visit, (not 
782
required to be the same day as the rest of the Follow up Visit).
783
3. Complete ophthalmic examination to include:
784
Slit lamp biomicroscopy
785
Indirect ophthalmoscopy
786
4. IOP
787
IOP measurements will be taken prior to pupil dilation.
788
5. VA (including refraction, ETDRS, BRVT if needed, LLVA if needed)
789
The visual acuity letter score will determine whether LLVA or BRVT will be 
790
performed. The criteria are defined in the GYROS Clinical Site Manual of 
791
Procedures.
792
6. SD-OCT
793
Volume Scan
794
Vertical and Horizontal Scan 
795
7. Axial Length and Corneal Curvature Measurements
796
Complete at 24-Month and 48-Month Follow-up Visits Only 
797
8. Fundus Autofluorescence
798
9. Widefield color photo
799
10. OCTA
800
Ancillary test; may be waived with approval from the Coordinating Center
801
11. Red reflex photo
802
12. FST
803

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13. Measurements to include:
804
Weight
805
Height
806
Measured annually in participants <21 years of age at enrollment.
807
4.4.3 Unscheduled Visits
808
Testing procedures at unscheduled visits are at the investigator
discretion. However, it is 
809
recommended that procedures performed during these visits follow the standard protocol for 
810
each procedure and be performed by certified personnel. Unscheduled visits will be recorded on 
811
the FFB Consortium study website. Study images taken during unscheduled visits do not require 
812
submission to the study website.
813
814

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Chapter 5: Testing Procedures and Questionnaires
815
5.1 Study Procedure Requirements
816
The study procedure instructions are detailed in the GYROS Clinical Site Manual of 
817
Procedures. An overview of the equipment and certification requirements for all testing are 
818
provided in the table below.
819
Study Procedures
Description
Equipment 
Required
(If applicable)
Site Personnel 
Delegation
Investigator taking overall 
responsibility for a visit 
Oversees that consent process was 
performed in accordance with 
IRB/EC requirements; signs off on all 
eCRFs for a participant, eCRF edits, 
and protocol deviations.
N/A
Certified 
investigator
Coordinator taking 
responsibility for the visit 
Oversees the data entry aspect of the 
visit; addresses protocol queries and 
signs off on deviations.
N/A
Certified 
coordinator
Informed Consent Form 
(ICF) Process
Explanation/review of study with the 
potential participant and/or signature 
of ICF.
N/A
Certified 
investigator as 
permitted by the 
IRB/EC
Signature of Informed 
Consent Form
The participant and/or LAR sign the 
ICF. The person obtaining the ICF 
will also sign.
N/A
Certified 
investigator as 
permitted by the 
IRB/EC
Data entry on study 
website
Data collected from the study 
participant will be directly entered on 
the FFB Study Website (strongly 
encouraged) or written on the paper 
CRF and transcribed on the FFB 
Study Website within seven (7) days.
Computer and 
internet 
connection
Certified 
coordinator or 
certified 
investigator with 
additional study 
website 
certification 
Collect information 
regarding medical history, 
demographics, adverse 
events, medications
Sites will collect medical history, 
demographic information, adverse 
events, and medications from the 
participant during each visit. This 
information can be confirmed by 
requesting medical records if needed.
N/A
Certified 
investigator or 
coordinator
Patient Reported 
Outcomes 
There will be a total of four (4) 
questionnaires. Three (3) for adults 
and one (1) two (2) for minors
depending on their age.
Study will 
provide
Certified 
investigator or 
coordinator
Ocular Exam 
Including slit lamp biomicroscopy 
and indirect ophthalmoscopy
Any equipment 
is acceptable
Certified 
investigator
IOP
Measurement of the fluid pressure 
inside the eye. 
Any equipment 
is acceptable
Clinical site 
personnel 
performing this 
test does not 
require a study 

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Study Procedures
Description
Equipment 
Required
(If applicable)
Site Personnel 
Delegation
specific 
certification. 
However, they 
must be trained 
and delegated by 
the PI per the 
SSDL.
Visual Acuity Refraction 
Refraction is done as a routine part of 
an eye exam to achieve best corrected 
visual acuity measures
N/A
Clinical site 
personnel 
certified for 
refraction
Visual Acuity ETDRS 
Traditional measure of central visual 
function that represents foveal cone 
function,
EVA system, 
ETDRS charts
Clinical site 
personnel 
certified for 
ETDRS
Visual Acuity LLVA 
LLVA tests vision function in low 
luminance conditions.
EVA system, or 
ETDRS charts
2.0 neutral 
density filter to 
be provided by 
study
Clinical site 
personnel 
certified for 
performing 
ETDRS is also 
certified to 
perform LLVA
Visual Acuity BRVT 
BRVT incorporates a three-level 
hierarchy for visual acuity testing
better suited for low vision 
participants.
BRVT charts 
provided by 
study
Clinical site 
personnel 
certified for 
BRVT
Spectral Domain Optical 
Coherence Tomography -
Volume Scan 
Scans provide objective, non-
invasive measures of retinal structure, 
including loss of inner/outer segment 
junction and have been shown to 
correlate with visual function in eyes 
with retinal degeneration 
Heidelberg 
Spectralis
Clinical site 
personnel 
certified for SD-
OCT
Spectral Domain Optical 
Coherence Tomography -
Vertical and Horizontal 
Scan
Scans provide objective, non-
invasive measures of retinal structure, 
including loss of inner/outer segment 
junction and have been shown to 
correlate with visual function in eyes 
with retinal degeneration 
Heidelberg 
Spectralis
Clinical site 
personnel 
certified for SD-
OCT and 
vertical and 
horizontal scan
OCTA
Provides information on foveal 
avascular zone enlargement and 
decreased macular vascular density
Site must use 
pre-approved 
device.
Clinical site 
personnel 
certified for 
OCTA
Axial Length and Corneal 
Curvature
Axial length measures the distance 
between the anterior and posterior 
poles of the eye.
Corneal curvature determines the 
power of the cornea.
Any equipment 
is acceptable
Clinical site 
personnel 
performing this 
test does not 
require a study 

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PAGE 46 OF 70
Study Procedures
Description
Equipment 
Required
(If applicable)
Site Personnel 
Delegation
specific 
certification. 
However, they 
must be trained 
and delegated by 
the PI per the 
SSDL.
Fundus Autofluorescence
Captures areas of absent 
autofluorescence which corresponds 
with areas of chorioretinal atrophy 
seen on clinical exam
Optos
Clinical site 
personnel 
certified for 
widefield fundus 
autofluorescence
Widefield color photo 
(UWF color)
Complementary imaging modality 
that delineates the borders of the 
atrophic lesions classically associated 
with GA
Optos
Clinical site 
personnel 
certified for 
widefield color 
photo
Red reflex photo  
Captures the area and severity of 
posterior subcapsular cataracts 
commonly associated with GA
Digital camera 
capable of 
capturing 
external eye 
photos, 
Megapixels of 
>=3MP, 
Magnification 
of 30-40
degrees, Digital 
camera export 
in PNG, TIF, 
DICOM or 
BMP
Clinical site 
personnel 
certified for red 
reflex photo
Full field Stimulus 
Threshold test (FST)
Measures rod- and cone-mediated 
parts of the visual field
Diagnosys 
Espion
Clinical site 
personnel 
performing this 
test does not 
require a study 
specific 
certification. 
However, they 
must be trained 
and delegated by 
the PI per the 
SSDL.
Static perimetry (SP)
A static field of vision test involves 
illuminating an object that does not
to evaluate the vision in this manner.
Octopus 900 
Pro (GATE 
Protocol)
Clinical site 
personnel 
certified for SP

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Study Procedures
Description
Equipment 
Required
(If applicable)
Site Personnel 
Delegation
Fundus guided 
microperimetry (MP)
This test will map out how bright a 
spot needs to be for the participant to 
be see it at specific locations inside 
the eye. 
MAIA
Clinical site 
personnel 
certified for MP
Kinetic Perimetry (KP)
A kinetic visual field test involves 
moving an object in and out of a 
to find the 
Any equipment 
is acceptable
Does not need to 
be performed by 
study certified 
personnel or 
recorded on the 
GYROS Study 
Staff Delegation
Log as this is a 
historical test.
Three (3) day food record 
A three-day food record is designed 
to get an accurate description of a 
Source provided 
by the study
Certified 
investigator or 
coordinator
Blood sample collection: 
Fasting plasma 
amino acids
The Amino Acids Analysis, Plasma 
is a blood test that measures 36 
amino acids and intermediary 
metabolites. 
N/A
Does not need to 
be performed by 
study certified 
personnel or 
recorded on the 
GYROS Study
Staff Delegation 
Log.
Blood sample processing: 
Fasting plasma 
amino acids
During centrifugation, the barrier gel 
rises to separate the heavier cell mass 
from the lighter liquid portion.
Calibrated 
centrifuge
Certified 
investigator,
coordinator, or 
appropriately 
trained
laboratory staff
Measurements: 
Weight
Height
Collect the participants height and 
weight using a calibrated scale in the 
office. BMI is automatically 
calculated on the FFB Study Website.
Calibrated scale
Certified 
investigator or 
coordinator
Skin Biopsy (3mm punch 
skin biopsy)
The skin is performed by stabilizing 
the area with the thumb and 
forefinger and stretched slightly 
perpendicular to the skin tension 
lines. A punch is held perpendicular 
to the skin, and is rotated into the 
skin with a firm, constant pressure.
Kit provided by 
the study
Certified 
investigator
Participant Contact 
Reminders to complete the 
three (3) day food record
The Clinical Site Coordinator will 
complete a Pre-Sample Collection 
Telephone Call to the participants 
(via phone or other remote interface) 
four (4) to ten (10) days prior to the 
scheduled sample collection date.
N/A
Certified 
investigator or 
coordinator

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Study Procedures
Description
Equipment 
Required
(If applicable)
Site Personnel 
Delegation
The Clinical Site Coordinator will 
complete a Post-Sample Collection 
Telephone Call for at-home samples 
within one (1) day after the scheduled 
sample collection date.
Food Record Collection 
and transcription of data 
on the FFB Study Website.
The Clinical Site Coordinator will
collect and transcribe the data from 
the food record on the FFB Study 
Website
N/A
Certified 
investigator or 
coordinator
5.2 Questionnaires
820
The following questionnaires will be administered in the study by a certified investigator or 
821
coordinator. Each questionnaire takes about fifteen (15) minutes to administer.
822
Questionnaire
Type 
Description
Vision 
Cohort
Age
Michigan Retinal 
Degeneration 
Questionnaire 
(MRDQ)
Vision 
Function
The MRDQ is a psychometrically 
validated patient-reported outcome 
measure for inherited retinal 
degenerations questionnaire which 
consists of fifty-nine (59) questions 
measuring seven (7) unidimensional 
domains: central vision, color vision, 
contrast sensitivity, scotopic 
function, photopic peripheral vision, 
mesopic peripheral vision, and 
photosensitivity.
All
Adults >= 18 
years
PROMIS-29®
(Patient-Reported 
Outcomes 
Measurement 
Information 
System®)
Global 
physical, 
mental, 
and
social 
health
The PROMIS®-29 contains items 
from seven PROMIS domains: 
depression; anxiety; physical 
function; pain interference; fatigue; 
sleep disturbance; and ability to 
participate in social roles and 
activities. The seven domains cover 
the most relevant areas of self-
reported health for most people with 
chronic illness. There is also one 11-
point rating scale for pain intensity.
All
Adults >= 18 
years
Visual Symptom 
and Impact 
Outcomes Patient 
Reported Outcome 
(ViSIO-PRO)
Vision 
Function 
and
HRQoL
The ViSIO-PRO is an instrument 
designed to assess visual function 
symptoms, impacts on functional 
vision, and impacts on wider health-
related quality of life (HRQoL). It 
has been designed for completion by 
adolescents (12-17) and adults (18 +) 
with retinitis pigmentosa (RP).
All
Adolescents 
(12-17) and 
Adults (18+)
L. V. Prasad-
Functional Vision 
Vision 
Function
The LVP-FVQ-II questionnaire 
consists of twenty-three (23) 
All
Children 
(<18 years)

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PAGE 49 OF 70
Questionnaire 
(LVP-FVQ II)
questions. The questionnaire is used 
to assess self-reported difficulties in 
performing daily tasks in children 
with visual impairment.
823

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Chapter 6: Unanticipated Problem and
824
Adverse Event Reporting
825
6.1 Unanticipated Problems
826
Site investigators will promptly report all unanticipated problems meeting the criteria below on 
827
an eCRF. Sites overseen by the JCHR IRB must report Unanticipated Problems to the IRB 
828
within seven (7) calendar days of recognition. For this protocol, an unanticipated problem is an 
829
incident, experience, or outcome that meets all the following criteria:
830
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
831
procedures that are described in the protocol related documents, such as the IRB-
832
approved research protocol and informed consent document; and (b) the 
833
characteristics of the subject population being studied.
834
Related or possibly related to participation in the research (possibly related means 
835
there is a reasonable possibility that the incident, experience, or outcome may have 
836
been caused by the procedures involved in the research).
837
Suggests that the research places participants or others at a greater risk of harm than 
838
was previously known or recognized (including physical, psychological, economic, or 
839
social harm).
840
The CC will report to the IRB all unanticipated problems not directly involving a specific site 
841
such as unanticipated problems that occur at the CC or at another participating entity such as a 
842
laboratory. 
843
These instances must be reported to the JCHR IRB within seven (7) calendar days of recognition. 
844
The Director of the Human Research Protection Program (HRPP) will report to the appropriate 
845
regulatory authorities and applicable relying IRBs if the JCHR IRB determines that the event
846
indeed meets the criteria of an Unanticipated Problem that requires further reporting to fulfill the 
847
reporting obligations of the HRPP.
848
6.2 Adverse Events
849
6.2.1 Definitions
850
Adverse Event (AE): Any untoward medical occurrence, including laboratory findings,
851
associated with study procedures whether the event is considered related. Progression of GA
852
retinal dystrophy including new or worsening of anticipated clinical signs or symptoms, which 
853
are collected and assessed as unequivocally associated with the disease progression should NOT 
854
be reported as AEs unless the disease progression is greater than anticipated in the natural course 
855
of the disease.
856
Serious Adverse Event (SAE): Any untoward medical occurrence that results in any of the 
857
following outcomes:
858
Death.
859
A life-threatening adverse event: (a non-life-threatening event which, had it been 
860
more severe, might have become life-threatening, is not necessarily considered a 
861
serious adverse event).
862

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Inpatient hospitalization or prolongation of existing hospitalization.
863
A persistent or significant disability/incapacity or substantial disruption of the ability 
864
to conduct normal life functions.
865
A congenital anomaly or birth defect.
866
An important medical event that may not result in death, be life-threatening, or require 
867
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
868
may jeopardize the patient or subject and may require medical and surgical intervention to 
869
prevent one of the outcomes listed in this definition. 
870
Note: As this is a Natural History Study, the Investigator(s) will make the categorical 
871
determinations of Adverse Events, as described above, and will report each determination to the 
872
Coordinating Center, as per data collection.
873
6.2.2 Reportable Adverse Events
874
For this protocol, a reportable adverse event includes all events meeting the definition of an 
875
adverse event.
876
All reportable Adverse Events whether volunteered by the participant, discovered by study 
877
personnel during questioning, or detected through ophthalmological examination, laboratory test, 
878
or other means will be reported on an adverse event form online.
879
The purpose of AE collection for the GYROS study will be to provide historical controls for 
880
future clinical trials. As a no greater than minimal risk study, AEs do not require any specific 
881
reporting to regulatory or oversight bodies. However, each Principal Investigator is responsible 
882
for abiding by any other reporting requirements specific to their IRB or equivalent ethics 
883
oversight committee
884
6.2.3 Relationship of Adverse Event to Study Procedure
885
The study investigator will assess the relationship of any adverse event to be related or unrelated 
886
to a study procedure by determining if there is a reasonable possibility that the adverse event 
887
may have been caused by the study procedure. 
888
To ensure consistency of adverse event causality assessments, investigators should apply the 
889
following general guideline when determining whether an adverse event is related:
890
Yes
891
There is a plausible temporal relationship between the onset of the adverse event and the study 
892
proce
893
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
894
of response to the study procedure; and/or the adverse event abates or resolves upon 
895
discontinuation of the study procedure.
896
No
897
Evidence exists that the adverse event has an etiology other than the study procedure (e.g., 
898
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
899
medication); and/or the adverse event has no plausible temporal relationship to study procedure.
900

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6.2.4 Severity (Intensity) of Adverse Event
901
A severity assessment is a clinical determination of the intensity of an event. Thus, a severe 
902
adverse event is not necessarily serious. For example, itching for several days may be rated as 
903
severe, but may not be clinically serious. 
904
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) 
905
moderate, or (3) severe.
906
1. MILD: Usually transient, requires no special treatment, and does not interfere with 
907
908
2. MODERATE: Usually causes a low level of inconvenience, discomfort or concern 
909
to the participant and may interfere with daily activities but is usually ameliorated by 
910
simple therapeutic measures and participant is able to continue in study.
911
3. SEVERE:
and causes severe 
912
discomfort.
913
6.2.5 Expectedness
914
As this is a Natural History Study, the expectedness for a serious adverse event will not be 
915
assessed.
916
6.2.6 Coding of Adverse Events
917
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
918
enter a preliminary MedDRA code
919
6.2.7 Outcome of Adverse Event
920
The outcome of each reportable adverse event will be classified by the investigator as follows:
921
1. RECOVERED/RESOLVED (COMPLETE RECOVERY)
The participant 
922
recovered from the AE/SAE without sequelae. Record the AE/SAE stop date.
923
2. RECOVERED/RESOLVED WITH SEQUELAE
AE/SAE where the subject 
924
recuperated but retained pathological conditions resulting from the prior disease or 
925
injury. Record the AE/SAE stop date.
926
3. FATAL
A fatal outcome is defined as the SAE that resulted in death. Only the 
927
event that was the cause of death should be reported as fatal. AEs/SAEs that were 
928
ongoing at the time of death; however, were not the cause of death, will be recorded 
929
930
4. ONGOING NOT RECOVERED/NOT RESOLVED
An ongoing AE/SAE is 
931
defined as an ongoing event with an undetermined outcome.
932
An ongoing outcome will require follow-up by the site to determine the outcome
933
of the AE/SAE.
934
The outcome of an ongoing event at the time of death that was not the cause of 
935
recorded 
936
as the stop date.
937

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5. ONGOING (MEDICALLY STABLE)
AE/SAE is ongoing, but medically stable. 
938
For example, a chronic condition where no further change is expected.
939
If any reported adverse events are ongoing when a participant completes the study (or 
940
withdraws), they will be followed until they are either resolved, or have no prospect of 
941
improvement or change, even after the participant has completed all applicable study 
942
visits/contacts. For all other adverse events, data collection will end at the time the participant 
943
completes the study. 
944
Note: participants should continue to receive appropriate medical care for an adverse event after 
945
their participation in the study ends.
946
If a participant is lost to follow up and participant outcome cannot be determined, outcome 
947
classification will be the last known outcome.
948
6.3 Timing of Event Reporting
949
Investigator(s) are responsible for reporting Adverse Events on the electronic case report form 
950
(eCRF) through the study website in a timely manner.
951
Each Principal Investigator (PI) is responsible for reporting serious study-related adverse events 
952
and abiding by any other reporting requirements specific to his/her Institutional Review Board 
953
(IRB) or Ethics Committee (EC). Where the JCHR IRB is the overseeing IRB, sites must report 
954
all serious, related adverse events regardless of whether they are expected/anticipated and 
955
regardless of whether they are fatal or life-threatening within seven (7) calendar days.
956
957

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Chapter 7: Miscellaneous Considerations
958
7.1 New or ongoing Medical Conditions and Medications
959
7.1.1 Pre-Existing Condition
960
Any medical condition that is either present at screening, a chronic disease, or a prior condition 
961
during the study (e.g., prior myocardial infarction or 
962
stroke).
963
7.1.2 Medical Conditions during the study
964
In addition to conditions meeting the reporting requirements for an adverse event or as described 
965
above, the following medical conditions should also be reported: (1) new diagnosis of a chronic 
966
disease (i.e., not present at the time of enrollment), and (2) any medical condition that could 
967
968
assessment. These will be reported as adverse events. See Chapter 6.2 Adverse Events for more 
969
detail.
970
7.1.3 Medications
971
All medication for the treatment of chronic pre-existing conditions, medical conditions, and/or 
972
adverse events that the participant is currently taking at screening and during the study should be 
973
recorded. Nutraceuticals and preventative treatments that are of interest to the study will be 
974
recorded.
975
7.2 Prohibited Medications, Treatments, and Procedures
976
7.2.1 Prohibited Medications and Treatment for OAT-Related Retinal Degeneration
977
Participants who are enrolled into the final study cohort should not receive IRD treatments 
978
during the study. This includes enrolling into an experimental treatment trial of underlying 
979
conditions related to OAT mutations during the 4-year study duration. However, if the 
980
participants enroll in a treatment trial the Executive Committee will be consulted and will 
981
determine if the participant may continue in the study.
982
Examples of prohibited medications and treatments include, but are not limited to the following:
983
use of ocular stem cell or gene therapy
984
ocriplasmin
985
ophthalmic oligonucleotide
986
Ozurdex (dexamethasone)
987
Iluvien or
988
Yutiq (fluocinolone acetonide) intravitreal implant
989
Amiodarone, chloroquine, deferoxamine, hydroxychloroquine, pentosan polysulfate, 
990
tamoxifen, thioridazine
991

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7.2.2 Intraocular Surgical Procedures 
992
Participants enrolled into the final study cohort, who have intraocular surgery during the study,
993
will have follow-up visits timed either before the surgery date or at least three (3) months after 
994
-
995
up visit as close to the visit target window as possible.
996
7.2.3 Treatment for Cystoid Macular Edema (CME)
997
Participants enrolled into the final study cohort, who need to receive treatment for CME 
998
during the study, may do so with an oral or topical dorzolamide, topical nonsteroidal or 
999
injectable corticosteroid, but not a steroid implant.
1000
7.3 Pregnancy Reporting
1001
If a pregnancy occurs, the participant will remain in the study. The occurrence of pregnancy will 
1002
be reported to the Coordinating Center within seven (7) days of the site
1003
pregnancy (including at screening) and the Pregnancy Notification form will be completed 
1004
within seven (7) calendar days. Sites will collect concomitant medications throughout the 
1005
pregnancy. If an Adverse Event occurs because of the pregnancy, then the site will record the 
1006
Adverse Event on the Adverse Event form.
1007
7.4 Participant Compensation
1008
Participant compensation will be specified in the informed consent form.
1009
7.5 Participant Withdrawal
1010
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1011
participants who withdraw, their data will be used up until the time of withdrawal.
1012
7.6 Confidentiality
1013
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1014
used instead of their name. Protected health information gathered for this study will be shared 
1015
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1016
participant information may also be provided to research sites involved in the study.
1017

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Chapter 8: Statistical Considerations
1018
8.1 Statistical and Analytical 
1019
The approach to sample size and statistical analyses are summarized below. The analysis plan 
1020
synopsis in this chapter contains the framework of the anticipated final analysis plan.
1021
8.2 Sample Size
1022
The sample size evaluation focuses on objective 1a of the study, to characterize the natural 
1023
history of retinal degeneration associated with disease-causing OAT variants in the presence of 
1024
standard care dietary treatment regimens over four (4) years, using functional, structural, and 
1025
patient-reported outcome measures. A justification of the selected sample size using percent 
1026
change for the outcomes of interest is outlined. The precision of estimates and of the correlation 
1027
between structure-based, function-based, and metabolic-based outcomes involved in objective 
1028
two (2) and of the correlation between eyes in the outcomes is also provided. Calculations to 
1029
address objective three (3), explore risk factors associated with progression (i.e., compare 
1030
subgroups for dichotomous risk factors), are summarized.
1031
8.2.1 Sample Size Considerations for Evaluating Percent Change from Baseline to four
1032
(4) Years All Outcomes
1033
Longitudinal changes on all outcome parameters being collected will be examined with the 
1034
change in preserved retina being of particular interest. Change from baseline to four (4) years 
1035
will be evaluated for sample size purposes, although statistical analyses will include the data 
1036
from each annual visit. The power and sample size calculations below may be used to consider 
1037
percent change on any outcome measure from baseline to four (4) years.
1038
Both eyes of a participant will be assessed for the main outcomes of interest. Thus, if there are N 
1039
participants, 2N eyes will be available for analysis. However, outcome measures from two (2)
1040
e contribution of information from 
1041
the two (2) eyes in this case is (2/(1+r)) instead of two (2). Values for the multiplier to the 
1042
number of participants to obtain an effective sample size are given below:
1043
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

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0.9
1.05
1.0
1.00
The correlation between eyes (inter-eye correlation) for each outcome measure will be estimated 
1044
during the study and is not known at the time of study design. We assume here a correlation of 
1045
0.8. This assumption is conservative in that it requires a higher number of participants than lower 
1046
plausible values of r. 
1047
The primary way sample size is evaluated is by considering the precision around the point 
1048
estimates for the percent change in the outcome measures over four (4) years. Table 6.1 provides 
1049
the half width of the 95% confidence interval (CI) for the estimated mean percent change per 
1050
year for combinations of the standard deviation (SD) of the distribution of percent change and 
1051
sample size. The larger the SD, the wider the CI, meaning the range of possible true values 
1052
grows.
1053
Table 6.1. Sample size versus half width of 95% confidence interval for the mean percent 
1054
change for varying standard deviation values.
1055
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: The shaded column corresponds to the sample size deemed feasible based on preliminary patient counts 
1056
and financial constraints. Forty (40) participants from Vision Cohorts 1 and 2 will be followed for 
1057
progression.
1058
8.2.2 Sample Size Considerations for Comparing Percent Change from Baseline to four
1059
(4) Years within Subgroups of Interest All Outcomes
1060
Another objective for this natural history study will be to explore the association of risk factors 
1061
with progression of various functional outcome variables (objective 3). Figure 6.1 considers 
1062
various expected SDs of the distribution of percent change from baseline to four (4) years per 
1063
eye and evaluates the power to detect varying differences in average percent change from 
1064
baseline to four (4) years, comparing subgroups of various equally distributed sizes. If subgroups 
1065
are not equally sized the smallest detectable difference (with the same power) will be larger. 
1066
1067
Note: within subgroup point estimates and Cis will also be important. Table 6.1 above can be 
1068
applied to potential subgroup sample sizes as well to consider the precision that would be 
1069
observed.
1070

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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)
Figure 6.1. Power to conclude there is a difference given varying true difference values, population standard 
1071
deviation, and sample size.
1072
For the graphs is Figure 6.1, the y-axis if for the power to conclude that there is a difference 
1073
when the true difference in mean percent change is the x-axis value. Each of the four graphs is 
1074
for a different total sample size with the number of eyes in each of the two subgroups being 
1075
approximately fifty percent (50%). Forty (40) participants from Vision Cohorts 1 and 2 will be 
1076
followed.
1077
For example, with an effective sample size of twenty-two (22) and an effective sample size of 
1078
eleven (11) in each subgroup, to have power of 80% or more, the true difference needs to be 
1079
approximately 1.25 SDs (a mean difference of 25% if the SD of the percent change over four (4) 
1080
years 20%). If the effective sample size is thirty-three (33), the true difference needs to be
1081
approximately 1.0 SD (a mean difference 20% if the SD of the percent change over four (4) 
1082
years is 20%). If the effective sample size is forty-four (44), the true difference needs to be 
1083
approximately 0.86 SDs (a mean difference 17% if the SD of the percent change over four (4) 
1084
years is 20%). Such mean differences are considered large.
1085

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8.2.3 Sample Size Considerations for Precision of the Estimate of the Correlation 
1086
Between Structure-based, Function-based, and Metabolic-based Outcomes and of the 
1087
Correlation Between Eyes
1088
The Pearson correlation coefficient (r) can be used to assess the correlation between two 
1089
different outcome measures. The distribution of r is not symmetric; therefore, CIs for the 
1090
estimated correlation coefficient are not symmetric. A transformation of r (z = 0.5 * ln ((1+r)/1-
1091
r)) is used to create a variable that is asymptotically distributed N (0, 1/(sqrt(N-3))) under the 
1092
null hypothesis that r=0.
1093
The intraclass correlation coefficient is used to assess the strength of agreement between eyes.
1094
When both eyes have the same mean for the outcome measure, the intraclass correlation 
1095
coefficient is equal to the standard Pearson correlation coefficient (r). The table below provides 
1096
the 95% CI for different estimates of r from the observed data.
1097
Table 6.2A. 95% Confidence Intervals for an Observed Value of the Correlation between 
1098
Outcome Measures.
1099
Effective sample size
r
n= 11
n= 22
n= 33
n= 44
n=55
0.3
(-0.37,0.76)
(-0.14,0.64)
(-0.05,0.58)
(0.00,0.55)
(0.04,0.52)
0.4
(-0.26,0.81)
(-0.03,0.70)
(0.07,0.65)
(0.12,0.62)
(0.15,0.60)
0.5
(-0.14,0.85)
(0.10,0.76)
(0.19,0.72)
(0.24,0.69)
(0.27,0.68)
0.6
(0.00,0.88)
(0.24,0.82)
(0.32,0.78)
(0.37,0.76)
(0.40,0.75)
0.7
(0.17,0.92)
(0.39,0.87)
(0.47,0.84)
(0.51,0.83)
(0.53,0.81)
0.8
(0.38,0.95)
(0.57,0.91)
(0.63,0.90)
(0.66,0.89)
(0.68,0.88)
0.9
(0.65,0.97)
(0.77,0.96)
(0.81,0.95)
(0.82,0.94)
(0.83,0.94)
Table 6.2B. 95% Confidence Intervals for an Observed Value of the Inter-eye Correlation.
1100
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)

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Note: The shaded column corresponds to the sample size deemed feasible based on preliminary patient counts 
1101
and financial constraints. Forty (40) participants from Vision Cohorts 1 and 2 will be followed and used for 
1102
assessing inter-eye correlation of change in outcome measures over time.
1103
8.2.4 Final Sample Size Justification
1104
Longitudinal changes in all outcome parameters being collected will be of interest for objectives 
1105
one (1) and three (3). Information on rates of decline using the proposed outcome measures for 
1106
OAT variants does not exist.12,26 Information on rates of decline for inherited retinal 
1107
degenerations in general is limited.
1108
Data to consider for evaluating sample size:
1109
Valproic Acid Protocol (VPA) Data (phase II multiple sites, randomized, placebo-
1110
controlled trial of oral valproic acid for ADRP) [Placebo group N=44; dataset can be 
1111
accessed at https://public.jaeb.org/ffb/stdy]
1112
o
Percent Change from Baseline to 1 year, Mean (SD):
1113
-0.3% (16%) OD
1114
-4.9% (17%) OS
1115
Assumptions made:
1116
Expect average annual decline due to OAT will be 5% per year or 20% by four (4) years.
1117
True SD of percent change at four (4) years is like VPA 1-year SD of approximately 
1118
20%.
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
For the objective of evaluating the correlation between outcomes, an effective sample 
1129
size of thirty-three (33) participants for Vision Cohorts 1 and 2 will have a 95% CI of 
1130
(0.19,0.72) when the observed r equals 0.5, and (0.63,0.90) when the observed r equals 
1131
0.8.
1132
1133
1134
1135
1136
1137
1138
1139
1140
1141

JAEB CENTER FOR HEALTH RESEARCH
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1142
1143
1144
1145
8.3 Data Analysis
1146
The analysis plans below are written with respect to most outcomes of interest. Analyses will 
1147
include data on both eyes for each participant, and confidence intervals will be adjusted for 
1148
correlation between two (2) eyes of the same participant.
1149
8.3.1 Primary Objective Analysis
1150
The primary objectives of the natural history study and brief analysis plan for each are as 
1151
follows.
1152
1. Natural History
1153
(a) Characterize the natural history of retinal degeneration associated with 
1154
disease-causing OAT variants over four (4) years, as measured using 
1155
functional, structural, and patient-reported outcome measures.
1156
1157
i.
Functional and structural measures: The distribution of each 
1158
outcome at each visit will be summarized (including tabulating 
1159
categorically, as well as means, SDs, medians, quartiles, ranges; both 
1160
the absolute change and percent change will be evaluated, tests 
1161
performed multiple times per visit will be analyzed using the average 
1162
of all available tests). To determine the average annual rate of 
1163
progression in the population for each outcome, a mixed effects model 
1164
will be fit using all available outcome data at baseline and all annual 
1165
visits. Both the correlation in outcomes over time and the correlation 
1166
in outcomes between eyes will be accommodated by the model.28
1167
Mixed models adequately accommodate missing values when missing 
1168
values are missing at random (MAR). A second method of 
1169
accommodating missing values will be through multiple imputation for 
1170
the outcome values for all missing time points (including participants 
1171
who discontinue follow up prior to forty-eight (48) months).
1172
Secondary analyses using binary definitions of outcome measures will 
1173
also be explored in time to event analyses; Kaplan-Meier estimates 
1174
with 95% confidence intervals will be calculated.
1175
1176
ii.
PRO measures: The scoring of each questionnaire will be completed 
1177
according to the procedures recommended by the developers of the 
1178
questionnaire for each instrument. Baseline scores will be cross 
1179
tabulated with categorical (severity of disease) versions of the outcome 
1180
measures of interest at baseline. Changes in scores will be cross 
1181
tabulated with binary (progression of disease) versions of the outcome 
1182
measures of interest at the 24- and 48-month visits. A generalized 
1183
linear model adjusted for baseline differences will be explored.
1184

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Partially completed questionnaires will be managed using methods
1185
recommended by the developers of the specific questionnaire. When 
1186
no questionnaire is completed, we will use statistical methods that 
1187
mitigate the impact of missing data, specifically, mixed effects 
1188
regression models and multiple imputation for the outcome values for 
1189
all missing time points.
1190
1191
(b) Characterize the natural history of ornithine levels associated with disease-
1192
causing OAT variants in the presence of standard care dietary treatment 
1193
regimens over four (4) years.
1194
1195
i.
Longitudinal annual measures of ornithine will be explored by 
1196
graphing the values for everyone
1197
detect any linear trend in time with mixed effects models.
1198
1199
(c) Determine within-patient variability of ornithine levels associated with 
1200
disease-causing OAT variants in the presence of standard care dietary 
1201
treatment regimens over four (4) years.
1202
i.
The within-person standard deviation of ornithine levels will be 
1203
estimated for the group of patients using a mixed effects model.
1204
Models will be based on levels from blood dot tests and from plasma 
1205
testing over the four (4) years to determined long -term variability and 
1206
on levels from blood dot tests over periods of six (6) months and of 
1207
twelve (12) months to determine short-term variability. The coefficient 
1208
of repeatability will be calculated to estimate the difference from 
1209
baseline that would need to be exceeded to indicate that a treatment 
1210
was causing an effect beyond random variability.
1211
2. Metabolic, Structure, and Function Relationships
1212
(a) Evaluate cross-sectional associations at baseline and each annual visit with 
1213
scatterplots and Spearman correlation coefficients. Evaluate the association of 
1214
changes in each outcome measure with changes the other outcome measures 
1215
at each visit with scatter plots and Spearman correlation coefficients. Use 
1216
mixed effects regression models to evaluate the association of change in each 
1217
outcome measure with changes in each of the other outcome measures. With 
1218
so many outcomes and only forty (40) patients, results will be interpreted 
1219
cautiously because of both low powers to detect clinically meaningful 
1220
associations and elevated Type I error rates due to multiple comparisons.
1221
3. Identify Rapid Progressors
1222
(a) The distribution of each outcome in terms of both absolute change and percent 
1223
change from baseline to four (4) years will be summarized (including 
1224
tabulating categorically, as well as means, standard deviations, medians, 
1225
quartiles), stratified by categorical levels of each potential risk factor of 
1226
interest (listed below). Potential risk factors to evaluate include phenotypic 
1227
factors including the baseline level of each of the structural and functional 
1228

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measures and ornithine level, genotype, and adherence to the arginine-
1229
restricted diet as noted below. Univariable regression models of each outcome 
1230
measure will be fit for each of the potential risk factors. With so many
1231
potential risk factors and outcomes and only forty (40) patients, results will be 
1232
interpreted cautiously because of both low powers to detect clinically 
1233
meaningful differences and elevated Type I error rates due to multiple 
1234
comparisons.
1235
1236
i.
Phenotypic:
1237
Age of onset of initial vision symptoms
1238
Gender 
1239
Race/ethnicity
1240
Body weight/BMI
1241
Lens Status (phakic/pseudophakic/aphakic) and area of 
1242
subcapsular cataract on red reflex photos
1243
Baseline foveal avascular zone (FAZ) area and macular vessel 
1244
density on OCTA
1245
Baseline visual acuity 
1246
Baseline low luminance visual acuity
1247
Baseline area of preserved retina on fundus autofluorescence 
1248
and color photos
1249
Baseline full Hill of Vision (HOV) on static perimetry
1250
Baseline mean sensitivity on static perimetry
1251
Baseline mean retinal sensitivity on microperimetry
1252
Baseline full-field stimulus (FST) levels
1253
Baseline ERG amplitude and timing
1254
Baseline ellipsoid zone (EZ) area on OCT
1255
Baseline ornithine level
1256
1257
ii.
Genotypic
1258
Characterizations of the OAT variants
1259
1260
iii.
Environmental Factors
1261
Adherence to arginine-restricted diet
1262
Smoking
1263
1264

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Chapter 9: Data Collection and Monitoring
1265
9.1 Case Report Forms and Other Data Collection 
1266
The main study data are collected on electronic case report forms (eCRFs). When data are 
1267
directly collected in electronic case report forms, this will be considered the source data. 
1268
However, it is recommended that a progress note is completed to document the events of the 
1269
visit. For any data points for which the eCRF is not considered source (e.g., lab results that are 
1270
transcribed from a printed report into the eCRF), the original source documentation must be 
1271
edical record. This source must be readily 
1272
verifiable against the values entered into eCRF. Even where all study data are directly entered 
1273
into the eCRFs at office visits, evidence of interaction with a live subject must be recorded (e.g., 
1274
office note, visit record, etc.) and provided to the coordinating center for review.
1275
Each participating site will maintain appropriate medical and research records for this trial, in 
1276
compliance with International Council for Harmonisation of Technical Requirements for 
1277
Pharmaceuticals for Human Use (ICH) E6 and regulatory and institutional requirements for the 
1278
protection of confidentiality of participants.
1279
9.1.1 Central Lab
1280
The Kennedy Krieger Institute, Central Lab, will complete an analysis from the fasting amino 
1281
acid panel, and blood spot collection. The lab will directly enter the laboratory results on the FFB 
1282
Study Website.
1283
Results for ornithine and arginine will be provided for the site.
1284
9.1.2 Research Lab
1285
The Johns Hopkins University Department of Genetic Medicine Research Lab will receive the 
1286
skin biopsy samples to grow fibroblasts. The tissue sample analysis will be entered directly in the
1287
FFB Study Website.
1288
9.1.3 Central Genetics Auditor (CGA)
1289
The CGA will review the genetic lab report(s) submitted by the clinical site during genetic 
1290
screening against the genetic eCRF data to ensure that the data entered by the clinical site are 
1291
consistent with the source(s) provided prior to the Baseline visit. The CGA will document his/her 
1292
verification of these genetic data on the FFB Consortium study website and the clinical site will 
1293
be notified of the results of the review.
1294
9.1.4 Genetics Committee
1295
In addition to providing evaluation of whether the OAT mutations are causative of the disease on 
1296
the FFB Consortium study website, the Genetics Committee will review and provide approval 
1297
for the use of genetic reports from research labs to be used for determining participant eligibility. 
1298

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9.1.5 The Johns Hopkins Institute for Clinical and Translational Research (ICTR)
1299
Research Nutrition
1300
The site will enter the food record documentation on the FFB Study Website. ICTR will review 
1301
the three (3) day food records and analyze for arginine, vitamin A, and vitamin B6 intake. Total 
1302
protein and caloric intake will be documented as well. ICTR will enter the nutrition analysis 
1303
assessment data directly on the FFB Study Website.
1304
9.1.6 Reading Centers
1305
Reading Centers will conduct grading of the study data collected using the FFB Consortium
1306
study website. The Reading Centers will provide the graded data through a data transfer or by 
1307
entering the graded data on the study website. These data will remain in the study database and 
1308
will not be provided to the clinical site.
1309
9.2 Study Records Retention
1310
Each participating site will maintain appropriate medical and research records for this trial, in 
1311
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1312
confidentiality of participants.
1313
Study documents will be retained for a minimum of six (6) years from the date on which the CC 
1314
receives IRB approval to close the study. These documents should be retained for a longer 
1315
period, however, if required by local regulations. No records will be destroyed without the 
1316
written consent of the sponsor. It is the responsibility of the sponsor to inform the investigator 
1317
when these documents no longer need to be retained.
1318
9.3 Quality Assurance and Monitoring
1319
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1320
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1321
conducted and data are generated, documented and reported in compliance with the protocol, 
1322
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1323
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1324
accurate, complete, and verifiable.
1325
A risk-based monitoring (RBM) plan will be developed and revised as needed during the study, 
1326
A Risk-
1327
.29 Study conduct and monitoring will conform 
1328
with 21 Code of Federal Regulations (CFR) 312.30 This plan describes in detail who will conduct 
1329
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
1330
will be performed, and the distribution of monitoring reports.
1331
The data of most importance for monitoring at the site are participant eligibility and adverse 
1332
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1333
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1334
verity and completeness of the key site data. Elements of the RBM may include:
1335
Qualification assessment, training, and certification for sites and site personnel
1336
Oversight of Institutional Review Board (IRB) coverage and informed consent 
1337
procedures
1338

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Central (remote) data monitoring: validation of data entry, data edits/audit trail, 
1339
protocol review of entered data and edits, statistical monitoring, study closeout
1340
On-site monitoring (site visits): source data verification, site visit report
1341
Communications with site staff
1342
Patient retention and visit completion
1343
Quality control reports
1344
Management of noncompliance
1345
Documenting monitoring activities
1346
Adverse event reporting and monitoring
1347
Coordinating Center representatives or their designees may visit the study facilities at any time to
1348
maintain current and personal knowledge of the study through review of records, comparison 
1349
with source documents, observation and discussion of the conduct and progress of the study. The 
1350
investigational site will provide direct access to all trial-related sites, source data/documents, and 
1351
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
1352
regulatory authorities.
1353
9.4 Protocol Deviations
1354
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1355
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
1356
the study site staff.
1357
A significant (or major) deviation is any deviation that departs from the established materials in 
1358
such a way that it poses an increase in the risk to the study participants, adversely affects the 
1359
welfare, rights, or safety of the research study participants, or negatively influences the scientific 
1360
study integrity. As a result of significant deviations, corrective and preventive actions are to be 
1361
developed by the site and implemented promptly.
1362
The site PI and study staff are responsible for knowing and adhering to their IRB/EC
1363
requirements. 
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Chapter 10: Ethics/Protection of Human Participants
1365
10.1 Ethical Standard
1366
The Principal Investigator (PI) will ensure that this study is conducted in full conformity with 
1367
Regulations for the Protection of Human Participants of Research in accordance with ICF 
1368
E6/GCP, EC requirements, and local laws and regulations, as applicable.
1369
10.2 Institutional Review Boards
1370
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1371
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1372
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1373
require review and approval by the IRB before the changes are implemented to the study. All
1374
changes to the consent form will be IRB approved; a determination will be made regarding 
1375
whether previously consented participants need to be re-consented.
1376
10.3 Informed Consent Process
1377
10.3.1 Consent Procedures and Documentation
1378
1379
the study and continues throughout the 
. Extensive discussion of 
1380
risks and benefits of participation will be provided to the participants and their families. Consent 
1381
forms will be IRB-approved, and the participant will be asked to read and review the document.
1382
The investigator will explain the research study to the participant and answer any questions that 
1383
may arise. All participants will receive a verbal explanation in terms suited to their 
1384
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1385
research participants. Participants will have the opportunity to carefully review the written 
1386
consent form and ask questions prior to signing.
1387
The participants will have the opportunity to discuss the study with their surrogates or think 
1388
about it prior to agreeing to participate. The participant will sign the informed consent document 
1389
prior to any procedures being done specifically for the study. The participants may withdraw 
1390
consent at any time throughout the course of the trial. A copy of the informed consent document 
1391
will be given to the participants for their records. The rights and welfare of the participants will 
1392
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1393
affected if they decline to participate in this study.
1394
10.3.2 Participant and Data Confidentiality
1395
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1396
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1397
samples and genetic tests in addition to the clinical information relating to participants.
1398
Therefore, the study protocol, documentation, data, and all other information generated will be 
1399
held in strict confidence. No information concerning the study, or the data will be released to any 
1400
unauthorized third party without prior written approval of the sponsor.
1401
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1402
regulatory agencies or company supplying study product may inspect all documents and records 
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required to be maintained by the investigator, including but not limited to, medical records 
1404
(office, clinic, or hospital) for the participants in this study. The clinical study site will permit 
1405
access to such records.
1406
1407
internal use during the study. At the end of the study, all records will continue to be kept in a 
1408
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1409
sponsor requirements.
1410
Study participant research data, which is for purposes of statistical analysis and scientific 
1411
reporting, will be transmitted to and stored at the FFB Consortium Coordinating Center, located 
1412
at the Jaeb Center for Health Research in Tampa, FL.
1413
contact or identifying information, unless otherwise specified in the informed consent form.
1414
Rather, individual participants and their research data will be identified by a unique study 
1415
identification number. The study data entry and study management systems used by clinical sites 
1416
and by the FFB Consortium Coordinating Center research staff will be secured and password 
1417
protected. At the end of the study, all study databases will be de-identified and archived at the 
1418
FFB Consortium Coordinating Center.
1419
10.3.3 Future Use of Stored Specimens and Data
1420
-identified biological skin
1421
fibroblasts and blood samples collected for analysis will be stored at The Kennedy Krieger 
1422
Institute until the FFB Study Team notifies them in writing to destroy the samples. The blood
1423
samples will be destroyed one (1) year after the end of the study. The skin biopsy samples will 
1424
1425
10.3.4 Future Use of Ocular Images
1426
Data collected for this study will be analyzed and stored at the FFB Coordinating Center and the 
1427
Reading Centers. After the study is completed, the archived data will be transmitted to and stored 
1428
at the FFB Consortium Coordinating Center, under the supervision of Allison Ayala, for use by 
1429
other researchers including those outside of the study. Permission to transmit data to the FFB 
1430
Consortium Coordinating Center will be included in the informed consent. This data will contain 
1431
images of the retina, which are considered identifiable, but no directly identifying information 
1432
will be share, such as name, as described in the consent forms.
1433
During the conduct of the study, an individual participant can choose to withdraw consent to 
1434
have their ocular images stored for future research. However, withdrawal of consent will not be 
1435
possible after the study is completed.
1436
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Chapter 11: References
1438
1439
1.
Wang T, Lawler AM, Steel G, Sipila I, Milam AH, Valle D. Mice lacking ornithine-
1440
delta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal 
1441
degeneration. Nat Genet. 1995;11(2):185-190.
1442
2.
Valle D, Simell O. The Hyperornithinemias. In: Valle DL, Antonarakis S, Ballabio A, 
1443
Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited 
1444
Disease. New York, NY: McGraw-Hill Education; 2019.
1445
3.
Valle D, Kaiser-Kupfer MI, Del Valle LA. Gyrate atrophy of the choroid and retina: 
1446
deficiency of ornithine aminotransferase in transformed lymphocytes. Proceedings of the 
1447
National Academy of Sciences of the United States of America. 1977;74(11):5159-5161.
1448
4.
Mitchell GA, Brody LC, Looney J, et al. An initiator codon mutation in ornithine-delta-
1449
aminotransferase causing gyrate atrophy of the choroid and retina. The Journal of clinical 
1450
investigation. 1988;81(2):630-633.
1451
5.
Mitchell GA, Looney JE, Brody LC, et al. Human ornithine-delta-aminotransferase. 
1452
cDNA cloning and analysis of the structural gene. The Journal of biological chemistry. 
1453
1988;263(28):14288-14295.
1454
6.
Mitchell GA, Brody LC, Sipila I, et al. At least two mutant alleles of ornithine delta-
1455
aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proceedings of 
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the National Academy of Sciences of the United States of America. 1989;86(1):197-201.
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7.
Brody LC, Mitchell GA, Obie C, et al. Ornithine delta-aminotransferase mutations in 
1458
gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 
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1992;267(5):3302-3307.
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8.
Michaud J, Thompson GN, Brody LC, et al. Pyridoxine-responsive gyrate atrophy of the 
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choroid and retina: clinical and biochemical correlates of the mutation A226V. Am J Hum 
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Genet. 1995;56(3):616-622.
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9.
Lemay JF, Lambert MA, Mitchell GA, et al. Hyperammonemia-hyperornithinemia-
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homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic 
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examination of six patients. J Pediatr. 1992;121(5 Pt 1):725-730.
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10.
Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia-
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homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial 
1468
ornithine transporter. Nat Genet. 1999;22(2):151-158.
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11.
Palmieri F, Scarcia P, Monné M. Diseases Caused by Mutations in Mitochondrial Carrier 
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Genes SLC25: A Review. Biomolecules. 2020;10(4).
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12.
Balfoort BM, Buijs MJN, Ten Asbroek A, et al. A review of treatment modalities in 
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gyrate atrophy of the choroid and retina (GACR). Mol Genet Metab. 2021;134(1-2):96-
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116.
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13.
Valle D, Walser M, Brusilow S, Kaiser-Kupfer MI, Takki K. Gyrate atrophy of the 
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choroid and retina. Biochemical considerations and experience with an arginine-restricted 
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diet. Ophthalmology. 1981;88(4):325-330.
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14.
Kaiser-Kupfer MI, de Monasterio F, Valle D, Walser M, Brusilow S. Visual results of a 
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long-term trial of a low-arginine diet in gyrate atrophy of choroid and retina. 
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Ophthalmology. 1981;88(4):307-310.
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15.
Valle D, Walser M, Brusilow SW, Kaiser-Kupfer M. Gyrate atrophy of the choroid and 
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retina: amino acid metabolism and correction of hyperornithinemia with an arginine-
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deficient diet. J Clin Invest. 1980;65(2):371-378.
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16.
Kaiser-Kupfer MI, de Monasterio FM, Valle D, Walser M, Brusilow S. Gyrate atrophy of 
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the choroid and retina: improved visual function following reduction of plasma ornithine 
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by diet. Science. 1980;210(4474):1128-1131.
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17.
Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. Use of an arginine-restricted diet to 
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slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol. 
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2004;122(7):982-984.
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18.
Kaiser-Kupfer MI, Caruso RC, Valle D. Gyrate atrophy of the choroid and retina. Long-
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term reduction of ornithine slows retinal degeneration. Arch Ophthalmol. 
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1991;109(11):1539-1548.
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19.
Wang T, Milam AH, Steel G, Valle D. A mouse model of gyrate atrophy of the choroid 
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and retina. Early retinal pigment epithelium damage and progressive retinal degeneration. 
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J Clin Invest. 1996;97(12):2753-2762.
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20.
Wang T, Steel G, Milam AH, Valle D. Correction of ornithine accumulation prevents 
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retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. 
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Proceedings of the National Academy of Sciences of the United States of America. 
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2000;97(3):1224-1229.
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21.
Sipilä I, Simell O, Arjomaa P. Gyrate atrophy of the choroid and retina with 
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hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine. J Clin 
1501
Invest. 1980;66(4):684-687.
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22.
Vannas-Sulonen K, Sipilä I, Vannas A, Simell O, Rapola J. Gyrate atrophy of the choroid 
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and retina. A five-year follow-up of creatine supplementation. Ophthalmology.
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1985;92(12):1719-1727.
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23.
Heinänen K, Näntö-Salonen K, Komu M, et al. Creatine corrects muscle 31P spectrum in 
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gyrate atrophy with hyperornithinaemia. Eur J Clin Invest. 1999;29(12):1060-1065.
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24.
Hanna-El-Daher L, Braissant O. Creatine synthesis and exchanges between brain cells: 
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What can be learned from human creatine deficiencies and various experimental models? 
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Amino Acids. 2016;48(8):1877-1895.
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25.
Du J, Zhu S, Lim RR, Chao JR. Proline metabolism and transport in retinal health and 
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disease. Amino Acids. 2021;53(12):1789-1806.
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26.
Elnahry AG, Elnahry GA. Gyrate Atrophy of the Choroid and Retina: A Review. 
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European Journal of Ophthalmology. 2021:11206721211067333.
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Food and Drug Administration. Rare Diseases: Natural History Studies for Drug 
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Ying GS, Maguire MG, Glynn RJ, Rosner B. Tutorial on Biostatistics: Longitudinal 
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Food and Drug Administration. Guidance for Industry Oversight of Clinical 
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