Natural History of Progression of Atrophy Secondary to Stargardt Disease: Retrospective, and Prospective Longitudinal Observational Study Incl. Ancillary SMART Study- Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease
Conditions: Stargardt Disease
Sponsor: Foundation Fighting Blindness

 
 Date:  October 8, 2013 
Principal Investigator:  Hendrik P. N. Scholl, M.D., M.A. 
Application Number: NA_00088107 
Study Title:  
SMART Study: Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease 
 
JHM IRB - eForm A – Protocol 
 
 
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1. 
Abstract 
a. Provide no more than a one-page research abstract briefly stating the problem, the research hypothesis, 
and the importance of the research. 
 
Stargardt disease [1] is responsible for 7% of all retinal dystrophies and affects 1 in 10,000 people. The typical 
onset occurs during the first two decades of life, which makes it the most common form of juvenile macular 
degeneration with an estimated incidence of 10 – 12.5 per 100,000.  STGD has been associated with 
considerable clinical and genetic heterogeneity, nearly two thirds of the cases are caused by several mutations 
in the ABCA4 gene [2, 3] with predominantly autosomal recessive inheritance [4]. A minor percentage have 
been associated with mutations in the ELOVL4 and PROM1 genes [5, 6] and was linked to autosomal dominant 
Stargardt-like phenotypes [7], which usually have later onset[8].  
In STGD, the visual acuity impairment is accompanied by atrophic-appearing lesions in the macula and 
presence of yellow-white lesions at the level of the retinal pigment epithelium (RPE), also known as “fundus 
flecks”. Histologically, these fundus flecks are characterized by sub-retinal deposition of lipofuscin-like material 
mainly formed from the abnormal photoreceptors’ visual cycle [9-12]. Multiple lines of evidence indicate that 
the toxic effect of lipofuscin accumulation in the RPE is responsible for the RPE cells death [13-15]. Following the 
RPE loss, photoreceptor cells (rods and cones) degenerate rapidly [16] as their maintenance is largely 
dependent on RPE cells.  
It was surprising that first reports of ABCA4 expression found its presence in rod but not in cone photoreceptors 
[17]. Such findings contradicted the STGD most common clinical manifestations, which are primarily related to 
cones dysfunction. Only few years later, it was shown by immunofluorescence microscopy and Western blot 
analysis that ABCA4 is also expressed in the fovea, and so, both cones and rods express the defective gene [18]. 
Studies with electroretinography (ERG) confirmed the findings of ABCA4 expression in both types of 
photoreceptors by showing abnormal electro-activity of cone and rods. For example, Scholl and collaborators 
have found that L and M-cone driven ERG exhibit phase and amplitude alterations in STGD [19]. Others studies 
with ERG have also demonstrated ERG rod dysfunction [20], although important variability in the degree of cone 
and rods dysfunction are frequently seen across STGD patients. The association between clinical phenotype and 
ERG phenotype has been previously attempted by some investigators [20]. A study conducted by Simonelli et al 
has shown reasonable correlation between clinical appearance and full-field ERG findings, however, such 
association was not supported by a later study with a larger cohort of patients [21].  
Moreover, the marked phenotype (clinical appearance) variability, variable autosomal traits and large 
amount of mutations involving the ABCA4 gene make the correlation between gene mutations and phenotype 
a challenge for retina physicians. Furthermore, the differential impairment of rods and cones activity during the 
natural course of STGD is yet to be fully understood. It is possible that rod photoreceptors show the earliest 
functional decline, show regional variability of dysfunction and different rate of progression as compared to 
cones dysfunction. Such aspects may play important role in possible therapeutic targeting, clinical trial planning 
and outcomes interpretations. Whereas ERG is capable of detecting the differential rod and cone’s electrical 
activities, it cannot be precisely correlated with focal anatomical changes and distinguish macular lesions. 
 A relatively novel technology, the automated fundus related perimetry technology (also known as 
microperimetry-MP), constitutes a surplus tool to assess retinal function, in this case sensitivity, with the advantage 
of precisely correlating the retinal sensitivity to the anatomical changes seen in scanning laser ophthalmoscope 
(SLO) images and autofluorescence images. In the last 5 years, many studies using MP have reported cross-
sectional findings of retinal sensitivity impairment in STGD [22-25]. The majority of these findings were based on 
the evaluation of microperimetric mesopic response (cones and rods response combined) without any 
consideration to differential activity and impairment of the two types of photoreceptors during the natural 
course of the disease.   
More recently, Crossland and colleagues followed by Birch and colleagues have described and validated 
protocols to measure rod sensitivity using a modified MP-1 [26, 27], which may allow, for the first time, the precise 
evaluation of rod function and its correlation with morphologic damage in the natural history of STGD.  

 
 
Ultimately, the understanding of the differential impairment of the cone and rods photoreceptors, through 
microperimetry findings, may establish consistent and reliable parameters to monitor patients and investigate 
potential treatments for STGD, which thus far, has not been available for patients with ABCA4-related retinal 
disease. 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Through a multicenter prospective cohort study on the natural history of STDG (the ProgStar Study), this 
ancillary study has the main objective of investigating the rod photoreceptors’ sensitivity during the natural 
course of the disease.  
 
The primary objective is: 
 
• To assess the yearly rate of progression of STGD using macular sensitivity under scotopic testing 
conditions.  
 
The secondary objectives are: 
 
• To correlate scotopic microperimetric changes with anatomical status/progression as determined 
by visual acuity, ERG, optical coherence tomography (OCT) and autofluorescence images. 
• To determine the variability of the test.  
• To determine the earliest functional deficits in STGD 
• To establish the best microperimetric parameters to monitor patients with STGD. 
 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, drug or 
device, and any other relevant information to justify the research) 
 
Device: NIDEK MP-1S (NIDEK Technologies Srl, Italy; holding company, NIDEK Co., Ltd. Japan) 
 
In 2002, Nishida and colleagues described for the first time an automated measuring system for fundus 
perimetry [28]. The MP-1 microperimeter produced by NIDEK Technologies was the first commercial 
microperimeter garnished with a true eye-track system, replacing the manual correction for eye movements 
which allowed accurate quantification of sensitivity and spatial location of the points tested [29, 30]. 
The device is composed of an infrared fundus camera, which acquires real-time fundus images in up to 45 
deg of view (768 × 576 pixels resolution). A liquid crystal display (LCD) with set luminance of 1.27cd/m2 (4abs) 
presents the fixation target and the stimuli, which is generated and controlled by a computer [31]. At the end 
of the exam, a conventional fundus camera captures a standard full color image. The built-in software 
superimposes the visual field map onto the retinal image, providing the spatial correlation between the 
anatomic landmarks and visual sensitivity maps [30, 32, 33]. The perimeter software also allows customization of 
the test parameters, the overlay of the fixation test results onto the fundus image, re-test of the same area 
scanned in a previous visit and automated comparison between exams. 
The MP-1 received FDA 510(k) clearance in September 28 of 2006 (510k No. K023719) and was classified as a 
class II device. It has been approved for color retinography, fixation exam, fundus-related MP and visual 
rehabilitation.  
Normative data has been published by Springer and co-authors [34] and Midena and collaborators [35] 
facilitating the interpretation of results obtained in diseased individuals. In addition, Chen and colleagues 
contributed with information regarding the test-retest variability of MP in patients with macular retinopathy as 
measured by the MP-1 [36]. In 2011, Crossland and colleagues validated for the first time a protocol for MP 
evaluation under scotopic conditions [26].  Fixation patterns have also been described in patients with various 
macular diseases using the MP-1 microperimeter [31, 37-40]. 
Physicians interested in the study of psychophysical parameters rapidly incorporated the technology 
employed in the MP-1, contributing vast literature over the last decade. Moreover, macular sensitivity and 
fixation stability have become measures to evaluate patients in clinical routine. Also, low vision rehabilitation 
could be enhanced with training sessions for fixation relocation [40].  
MP has been shown to be a good tool to enhance the understanding of functional impairment in STGD. The 
information gathered from this proposed study should provide guidance and support to the identification of 
the most appropriate clinical outcome measures for anticipated clinical trials. 
 
4. 
Study Procedures 
 
This study will assess the scotopic macular sensitivity determined by rod cells using controlled fundus perimetry 
under dark-adapted conditions. This test will be performed in addition to the standard of clinical care tests 
required in the IRB approved prospective ProgStar-02 Study (JHU IRB NA# 00081134). Only one eye will be 
enrolled in the SMART study. In case both eyes are eligible and are enrolled in the ProgStar-02 study, the 

 
 
principal investigator (PI) will chose one eye (study eye - SE) to participate in the SMART study. The following SE 
selection criteria are recommended, although the final decision will be at the PI’s discretion: 
 
è Recommended SE selection criteria: 
a) The eye that has the smaller lesion within the range defined in the ProgStar-02 protocol 
b) The eye that has the better vision in terms of best-corrected visual acuity (BCVA)  
c) The eye that has the better fixation stability, which is defined by the smaller bivariate contour ellipse 
area (BCEA). 
 
 
a. Study design, including the sequence and timing of study procedures  (distinguish research procedures 
from those that are part of routine care). Study duration and number of study visits required of research 
participants. 
 
This is a prospective longitudinal observational study. The study shall utilize up to 12 clinical sites to collect 
prospective longitudinal observations on up to 70 participants.  To qualify for this study, participants be 
enrolled in the IRB approved ProgStar Study.  The scotopic MP will be the sole non-standard of care procedure 
executed at each visits.  
 
 
The study will collect data every 6 months over a 24 months period. Therefore, 5 visits will take place during 
the study (baseline, months 6, 12, 18 and 24). If enrollment and prospective evaluation of an eligible patient in 
the ProgStar-02 study started significantly earlier than the start of the SMART study, then it is possible that only 18 
months of follow-up will be available. The last ProgStar-02 visit should also be the last SMART study visit. Each 
visit, all patients will undergo microperimetric examination under scotopic condition in addition to the 
standard of care procedures included in the ProgStar Study protocol, which are described below:  
• 
best-corrected visual acuity,  
• 
complete ophthalmic exam (including dilated fundoscopy),  
• 
autofluorescence imaging,  
• 
MP and  
• 
spectral-domain optical coherence tomography (SD-OCT) will be performed).  
 
The ProgStar study results will be sent by the participating centers to the Dana Center for of Preventative 
Ophthalmology of the Wilmer Eye Institute, the Johns Hopkins University, Baltimore, for evaluation, with 
exception of the results of MP, autofluorescence and optical coherence tomography, which will be sent to a 
central reading center at the Doheny Eye Institute, Los Angeles, California. 
 
This is a natural history study. There will be no treatments being investigated in this trial. 
 
b. Blinding, including justification for blinding or not blinding the trial, if applicable. N/A 
c. 
Justification of why participants will not receive routine care or will have current therapy stopped. N/A 
d. Justification for inclusion of a placebo or non-treatment group. N/A 
e. 
Definition of treatment failure or participant removal criteria. N/A 
f. 
Description of what happens to participants receiving therapy when study ends or if a participant’s 
participation in the study ends prematurely. N/A 
 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion criteria:  
 
• 
A mandatory inclusion criteria for the index ancillary study is being a participant of the IRB 
approved ProgStar Study (JHU IRB NA# 00081134). In the ProgStar Study, the study participants are 
required to meet the following inclusion criteria: 
1. 
Provide a signed informed consent form and authorization allowing the disclosure and use 
of protected health information. 
2. 
The designated primary study eye must have at least one well-demarcated area of 
atrophy as imaged by fundus autofluorescence with a minimum diameter of 300 microns 
and all lesions together must add to less than or equal to 12 mm2 (equivalent to no more 
than 5 disc areas in a least one eye) and a BCVA of 20 ETDRS letters (20/400 Snellen 
equivalent) or better. 
3. 
Two (2) pathogenic mutations confirmed present, in the ABCA4 gene. If only one ABCA4 
allele contains a pathogenic mutation, the patient shall have a typical Stargardt 
phenotype, namely at least one eye must have flecks at the level of the retinal pigment 
epithelium typical for STGD. 

 
 
4. 
The primary study eye must have clear ocular media and adequate pupillary dilation to 
permit good quality FAF and sd-OCT imaging in the opinion of the investigator.  
5. 
Be able to cooperate in performing the examinations. 
6. 
Be willing to undergo ocular examinations once every 6 months for up to 24 months. 
7. 
Be at least six years old.  
8. 
Both eyes can be included if inclusion criteria are fulfilled for both eyes. 
 
In addition, candidates of the ProgStar study that meet any of the following exclusion criteria 
shall not be enrolled in any of the ProgStar study neither in the index ancillary study: 
 
1. 
Ocular disease, such as choroidal neovascularization, glaucoma and diabetic 
retinopathy, in either eye that may confound assessment of the retina morphologically 
and functionally. 
2. 
Intraocular surgery in the primary study eye within 90 days prior to baseline visit. 
3. 
Current or previous participation in an interventional study to treat STGD such as gene 
therapy or stem cell therapy. Current participation in a drug trial or previous participation 
in a drug trial within six months before enrollment. The use of oral supplements of vitamins 
and minerals are permitted although the current use of Vitamin A supplementation shall 
be documented. 
4. 
The site Principal Investigator may declare any patient at their site ineligible to participate 
in the study for a sound medical reason prior to the patient’s enrollment into the study. 
5. 
Any systemic disease with a limited survival prognosis (e.g. cancer, severe/unstable 
cardiovascular disease). 
6. 
Any condition that would make adherence to the examinationinterfere with the patient 
attending their regular follow-up visits schedule of once every 6 months for up to 24 
months difficult or unlikely, e.g. personality disorder, use of major tranquilizers such as 
Haldol or Phenothiazine, chronic alcoholism, Alzheimer’s Disease or drug abuse. 
7. 
Evidence of significant uncontrolled concomitant diseases such as cardiovascular, 
neurological, pulmonary, renal, hepatic, endocrine or gastro-intestinal disorders. 
 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Degeneration of the photoreceptors and underlying RPE in STGD typically occurs close to and within the 
macula center, leading to bilateral central atrophy.  
MP is a valuable tool to perform a systematic and quantitative evaluation of the macular sensitivity to 
different intensities of light and at the same time to correlate the functional findings to anatomical 
changes. The Nidek MP device has a built-in eye-tracking system and permits the precise re-test of 
previous scanned areas [31]. In addition, this technology can provide quantitative analysis of gaze 
fixation, a known parameter of visual quality, which can be affected by the growth of central atrophy in 
patients with STGD.  
The microperimeter manufactured by Nidek (MP-1, NIDEK Technologies Srl, Italy) MP-1 has been used 
since 2002 in research and clinical settings [28, 29] and has normative and disease data available. The 
device created the standards for automated fundus related perimeter and stands as the most common 
microperimeter found in retina services. At this time, the Nidek MP-1 is the only microperimeter that has 
been adapted to scoptopic MP with validated protocols [41][35]. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA approved 
indications or if doses or routes of administration or participant populations are changed. N/A 
c. 
Justification and safety information if non-FDA approved drugs without an IND will be administered. N/A  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 9 
 
Date: _ June 11, 2013  
Principal Investigator: _ Hendrik P. N. Scholl, M.D., M.A. 
Application Number: ___________ 
 
 
7. 
Study Statistics 
a. Primary outcome variable. 
Change in macular sensitivity measured under scotopic conditions. 
 
b. Secondary outcome variables. N/A 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Sample Size and Power: 
 
The ancillary study will follow the statistical standards imposed by the ProgStar Study protocol.  
 
In the ProgStar Study, a feasibility survey was undertaken prior to establishing the study protocol. The survey 
consisted  of  a  questionnaire  that  was  sent  to  the  participating  centers  to  determine  how  many  study 
candidates might be available at each center for this prospective study. 
 
The primary outcome of the study is the yearly growth in the area of the atrophic lesion as measured by 
fundus  auto-fluorescence.   A  recent  paper  by  Chen  et  al  [29]  reported  that  in  a  group  of  24  STGD 
participants with well defined atrophic lesions at baseline, the mean yearly growth of the lesion was 0.94 
mm2 ± 0.87.  
 
The  reliability  of  measuring  areas  of  geographic  atrophy  using  
images  taken  with  a  confocal  scanning 
laser  ophthalmoscopy  has  been  described  by  Deckert  et  al  [35].  Using  2  different  readers  to  examine 
images from 34 eyes, the mean difference in area affected for the proposed quantification algorithm was 
0.12mm2 with a 95% confidence interval (0.02, 0.22). 
 
Using  the  above  parameters  as  a  
reference,  we  calculated  the  power  to  detect  yearly  progression  for 
sample  sizes  between  120  and  240  participants,  with  standard  deviations  between  0.9  and  1.1,  and 
expected progression rates of 0.40 and 0.50 mm2 per year (Figure 5).  A clinically meaningful progression 
rate should be greater than the variability of the measurement.  The power calculations were set to test for 
progression rates above 0.2 mm2 which is the estimate of the upper bound of the difference that could be 
attributable solely to measurement error.   
  
Figure 5: Power calculations for expected progressions rates of 0.40 and 0.50 mm2 per year 
 
A sample size of 170 achieves 80% power to detect a difference of 0.2 between the null hypothesis mean 
of 0.2 mm2 (measurement error) and the alternative hypothesis mean progression of the lesion of 0.4 mm2 
with an estimated standard deviation of 0.9 and a significance level = 0.05 using a two-sided Wilcoxon 
test (Figure 5 (a)). Similarly, if the expected standard deviation increases to 1.0 we need 200 participants to 
achieve the same level of power.  When the expected progression rate is ≥0.50 mm2, a sample size of 120 
participants achieves more than 80% to detect differences beyond the expected measurement error, for 
standard deviations ≤1.1 (Figure 5 (b)).  
 
 
Statistical Analyses 
 
Estimating the yearly growth in the area of the atrophic lesion as measured by fundus auto-fluorescence: 
 
First exploratory analysis looking at the baseline, six, and twelve months overall distribution of the outcome 
will be performed, outliers and inconsistent measures will be identified and reviewed. Let Yiv represent the 
area (or a transformation to achieve normality; e.g. square root) of the ith individual at visit v for v=0, 1, 2, 
3,  4  for  the  baseline,  6  months,  12  months,  18  months  and  24  months  visits,  respectively.  In  order  to 
determine the average rate of progression in the population, an appropriate approach will be to allow for 
each individual to have his/her own intercept and slope and to average them to achieve the overall rate 
of decline. This is accomplished with a random coefficients regression model of the form:  
Yiv=(µ+ai)+(Δ+bi)v+γZiv+ eiv; where a
i~N(0,σ12), b
i~N(0,σ22), cov(ai,bi)= σ 
12 and eiv~N(0,σ2). 
 
The  a
i and  bi are  the  random  departures  of  the  
line  for  the  
ith individual  from  the  population  
line  with 
intercept µ  and  slope Δ.  The  e
iv are  the  within  individual  departures  from  the  line  of  the  repeated 
measurements  taken  on  the  
ith individual  at  times  0,  6,12,  18  and  24  months.  
  Z
iv represents  a  vector  of 
factors that could to be related to progression such as age and use of vitamin A supplementation. 

 
 
 
The estimate of Δ and its standard error will provide the six-month progression of the lesions. In addition, to 
explore whether progression may be different for different initial levels, we will carry out the analysis in 
strata of baseline severity. 
 
A similar approach to will be used to examine progression overtime for the secondary outcomes: retinal 
thinning, loss of photoreceptors, loss of retinal sensitivity, and changes of BCVA. 
 
Scatterplots with lowess smooth average curves will be used to explore the relationship between variables. 
A linear mixed model will be then used to analyze and quantify the association between the different 
variables. 
 
Baseline demographic characteristics are: date of birth, age, sex, and race. Randomization is not 
applicable. 
 
 
 
Data Set Descriptions 
 
Study Population: patients with STGD enrolled into the study shall have had previous genetic testing and a 
finding of at least 2 pathogenic mutations in the ABCA4 gene. If only one ABCA4 allele containing a 
pathogenic mutation is detected, a patient may be enrolled if they have a typical Stargardt phenotype, 
i.e. at least one eye must have flecks at the level of the retinal pigment epithelium typical of STGD. 
 
Data Sets for Endpoint Analyses: the final data set will include all participant visits. Most of the participants 
will complete 5 visits. Participants lost to follow-up after the six month visit shall be included but will only 
partially contribute to the estimation of the progression rates. 
 
Handling of Missing Data: the random effects methods described in section 7.2 do not require all 
individuals to have all the five visits. Individuals who are lost to follow up will partially contribute to the 
analysis and will be appropriately weighted by the maximum likelihood approach. To rule out informative 
censoring (i.e., fast progressors having less visits with available data) we will perform sensitivity analysis 
restricting to those with complete data. Were it to be necessary, we will explore multiple imputation 
methods to complete the trajectories shorter than two years. 
 
 Interim Analysis: an interim analysis of the study data is planned after all participants have completed their 
12-month visit. 
 
d. Early stopping rules. 
 
 
This is an observational study of the natural course of STGD. All devices included in the study are used in 
standard of clinical care for patients affected by STGD. Therefore, no study-specific safety events are 
anticipated. 
 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
This study is an observational study of the natural course of STGD that will include data from the results of 
both psychophysical examinations (visual acuity testing and microperimetry) and retinal imaging 
examinations (optical coherence tomography and fundus autofluorescence), which are an integral part 
of current standard of clinical Care that is routine in patients with STGD. The risk to participants will not 
exceed the risks associated with the current standard of clinical care examinations. The protocol for 
scotopic microperimetry does not use any range of the light spectrum that could cause known harm to 
patients with STGD or would put the patients above minimal risks. 
 
b. Steps taken to minimize the risks. N/A 
c. 
Plan for reporting unanticipated problems or study deviations. 
 
Protocol Deviations:  
 
This study shall be conducted according to this written protocol except in the case of an emergency 
where immediate intervention based on the judgment of the investigator (or a responsible, appropriately 
trained professional designated by the investigator) is essential for the protection, safety, and well-being of 
the participant. In the event of a significant deviation from the protocol as a result of an emergency, 
accident, or mistake, the investigator or designee must contact the Study Director, as soon as possible, by 
telephone.  A joint decision will then be made regarding the participant’s continuation in the study and 

 
 
the decision documented by the investigator and the Study Director and reviewed by the monitor.  In 
addition, the investigator must notify the IRB to the extent necessary under GCP and local requirements. 
The sponsor, the Foundation Fighting Blindness Clinical Research Institute shall be notified of any protocol 
deviations and shall forward a detailed report any serious deviations to HRPO immediately.  Any non-
serious deviations shall be reported to HRPO as part of the annual study progress report. 
All unanticipated problems involving risk to participants or others related to participation in the study 
should be promptly reported to the Principal Investigator’s office by phone (410-614-6908). 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality.  
 
Although microperimetry under scotopic condition is not a standard MP protocol used in regular clinic 
visits of patients with ABCA4 related retinopathies, microperimetry exam is considered a standard of care 
procedure. The risks that would be associated with breach of confidentiality in scoptopic microperimetry 
would not be higher than any other standard of care procedures.  
If the results of the each individual’s procedures conducted during the time period of patients’ 
participation in this study, including any clinically significant abnormal findings, if requested, will be shared 
with that study participants or their his/her primary care provider at any time during throughout the study 
since study participation is part of standard clinical care and authorized by the patient. 
 
e. 
Financial risks to the participants. 
 
The costs associated with microperimetry examinations under scotopic conditions will be covered by the 
study sponsor Foundation Fighting Blindness Clinical Research Institute. Therefore, patients are not 
expected to be exposed to financial risks. 
 
 
9. 
Benefits 
a. Description of the probable benefits for the participant and for society. 
 
There would be no direct benefit to the participant from being in this study. However, the knowledge 
gained from this study may establish novel and reliable parameters to follow and investigate potential 
treatment for STGD.   
 
 
10. 
Payment and Remuneration 
a. Detail compensation for participants including possible total compensation, proposed bonus, and any 
proposed reductions or penalties for not completing the protocol. 
 
Compensation will not be provided to the study participants in this study. 
 
11. 
Costs 
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will pay for 
them. 
 
The microperimetry examinations under scotopic conditions will be financially supported by the 
Foundation Fighting Blindness Clinical Research Institute. 
 
 
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families with Stargardt disease. Ophthalmic Res 2005, 37(3):159-167. 
21. 
Oh KT, Weleber RG, Stone EM, Oh DM, Rosenow J, Billingslea AM: Electroretinographic findings in patients with 
Stargardt disease and fundus flavimaculatus. Retina 2004, 24(6):920-928. 
22. 
Mori F, Ishiko S, Kitaya N, Takamiya A, Sato E, Hikichi T, Yoshida A: Scotoma and fixation patterns using scanning 
laser ophthalmoscope microperimetry in patients with macular dystrophy. Am J Ophthalmol 2001, 132(6):897-
902. 
23. 
Anastasakis A, McAnany JJ, Fishman GA, Seiple WH: Clinical value, normative retinal sensitivity values, and 
intrasession repeatability using a combined spectral domain optical coherence tomography/scanning laser 
ophthalmoscope microperimeter. Eye (Lond) 2011, 25(2):245-251. 
24. 
Testa F, Rossi S, Sodi A, Passerini I, Di Iorio V, Della Corte M, Banfi S, Surace EM, Menchini U, Auricchio A et al: 
Correlation between photoreceptor layer integrity and visual function in patients with Stargardt disease: 
implications for gene therapy. Invest Ophthalmol Vis Sci 2012, 53(8):4409-4415. 
25. 
Park SP, Chang S, Allikmets R, Smith RT, Burke TR, Gregory-Roberts E, Tsang SH: Disruption in Bruch membrane in 
patients with Stargardt disease. Ophthalmic Genet 2012, 33(1):49-52. 
26. 
Crossland MD, Luong VA, Rubin GS, Fitzke FW: Retinal specific measurement of dark-adapted visual function: 
validation of a modified microperimeter. BMC Ophthalmol 2011, 11:5. 
27. 
Birch DG, Wen Y, Locke K, Hood DC: Rod sensitivity, cone sensitivity, and photoreceptor layer thickness in 
retinal degenerative diseases. Invest Ophthalmol Vis Sci 2011, 52(10):7141-7147. 
28. 
Nishida Y, Murata T, Yoshida K, Sawada T, Kani K: An automated measuring system for fundus perimetry. Jpn J 
Ophthalmol 2002, 46(6):627-633. 
29. 
Rohrschneider K, Springer C, Bultmann S, Volcker HE: Microperimetry--comparison between the micro 
perimeter 1 and scanning laser ophthalmoscope--fundus perimetry. Am J Ophthalmol 2005, 139(1):125-134. 
30. 
Shah VA, Chalam KV: Values for macular perimetry using the MP-1 microperimeter in normal subjects. 
Ophthalmic Res 2009, 41(1):9-13. 
31. 
Midena E, Radin PP, Pilotto E, Ghirlando A, Convento E, Varano M: Fixation pattern and macular sensitivity in 
eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration. A 
microperimetry study. Semin Ophthalmol 2004, 19(1-2):55-61. 
32. 
Sawa M, Gomi F, Toyoda A, Ikuno Y, Fujikado T, Tano Y: A microperimeter that provides fixation pattern and 
retinal sensitivity measurement. Jpn J Ophthalmol 2006, 50(2):111-115. 
33. 
Midena E, Vujosevic S, Convento E, Manfre A, Cavarzeran F, Pilotto E: Microperimetry and fundus 
autofluorescence in patients with early age-related macular degeneration. Br J Ophthalmol 2007, 91(11):1499-
1503. 
34. 
Springer C, Bultmann S, Volcker HE, Rohrschneider K: Fundus perimetry with the Micro Perimeter 1 in normal 
individuals: comparison with conventional threshold perimetry. Ophthalmology 2005, 112(5):848-854. 
35. 
Midena E, Vujosevic S, Cavarzeran F: Normal values for fundus perimetry with the microperimeter MP1. 
Ophthalmology 2010, 117(8):1571-1576, 1576 e1571. 
36. 
Chen FK, Patel PJ, Xing W, Bunce C, Egan C, Tufail AT, Coffey PJ, Rubin GS, Da Cruz L: Test-retest variability of 
microperimetry using the Nidek MP1 in patients with macular disease. Invest Ophthalmol Vis Sci 2009, 
50(7):3464-3472. 
37. 
Crossland MD, Dunbar HM, Rubin GS: Fixation stability measurement using the MP1 microperimeter. Retina 
2009, 29(5):651-656. 
38. 
Finger RP, Charbel Issa P, Fimmers R, Holz FG, Rubin GS, Scholl HP: Reading performance is reduced by 
parafoveal scotomas in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2009, 50(3):1366-
1370. 

 
 39. 
Schmitz-Valckenberg S, Ong EE, Rubin GS, Peto T, Tufail A, Egan CA, Bird AC, Fitzke FW: Structural and 
functional changes over time in MacTel patients. Retina 2009, 29(9):1314-1320. 
40. 
Tarita-Nistor L, Gonzalez EG, Markowitz SN, Steinbach MJ: Plasticity of fixation in patients with central vision loss. 
Vis Neurosci 2009, 26(5-6):487-494. 
41. 
Crossland MD, Engel SA, Legge GE: The preferred retinal locus in macular disease: toward a consensus 
definition. Retina 2011, 31(10):2109-2114. 
 
 
 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
1 
FOUNDATION FIGHTING BLINDNESS 
CLINICAL RESEARCH INSTITUTE 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Project Title 
 
The Natural History of the Progression of Atrophy Secondary to Stargardt Disease: A 
Prospective Longitudinal Observational Study 
 
 Amendment 1.0 
Protocol No.:   
 
 
 
FFBCRI-PROGSTAR-02 
IND No.: 
 
 
 
 
N/A 
Drug Development Phase: 
 
 
N/A 
Issue Date: 
3/11/2013 
 
Study Director and Principal Investigator  
 
Hendrik P.N. Scholl, M.D., M.A. 
The Dr. Frieda Derdeyn Bambas Professor of Ophthalmology 
Wilmer Eye Institute 
Johns Hopkins University School of Medicine 
748 Maumenee Building 
1800 Orleans St 
Baltimore, MD 21287-9277 
Phone: +1 (443) 287-5495 
e-mail: hscholl1@jhmi.edu 
Fax: +1 (410) 614-2186 
FWA-Number: FWA00006087 
 
Study Site Locations 
 
Greater Baltimore Medical Center 
Janet S. Sunness, M.D. 
Medical Director 
Hoover Low Vision Rehabilitation Services  
Greater Baltimore Medical Center 
6569 North Charles Street, PPW504 
Baltimore, MD 21204 
Phone: +1 (443) 849-2658 
e-mail: jsunness@gbmc.org 
Fax: +1 (443) 849-2631 
FWA-Number: FWA00003849 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
2 
 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
3 
 
Hospital University of Pennsylvania 
Artur Cideciyan, Ph.D., 
Center for Hereditary Retinal Degenerations 
Scheie Eye Institute, Room 601 
Myrin Circle, 51 N. 39th Street 
Philadelphia, PA 19104 
Phone: +1 (215) 662 9986 
email:cideciya@mail.med.upenn.edu 
Fax: +1 (215) 662 9388 
FWA-Number: FWA00004028 
 
Retina Foundation of the Southwest 
David G. Birch, Ph.D. 
Retina Foundation of the Southwest 
9600 N. Central Expressway 
Dallas, TX 75231 
Phone: +1 (214) 363-3911 
e-mail: dbirch@retinafoundation.org 
Fax: +1 (214) 363-4538 
FWA-Number: FWA00005004 
 
University of Utah 
Paul S. Bernstein, M.D., Ph.D., 
Moran Eye Center 
University of Utah School of Medicine 
65 Mario Capecchi Drive 
Salt Lake City, UT 84132 
Phone: +1 (801) 581-2352 
e-mail:  paul.bernstein@hsc.utah.edu 
FWA-Number: FWA00003745 
 
Cole Eye Institute at Cleveland Clinic 
Elias Traboulsi, M.D. 
Mail Code i32  
9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: +1 (216) 444-7152 
e-mail: traboue@ccf.org 
Fax: +1 (216) 445-8475 
FWA-Number: FWA00005367 
 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
4 
 
Centre de Recherche Institut de la Vision Paris 
José-Alain Sahel, M.D. 
Centre de Recherche Institut de la Vision Paris 
UMR_S968 INSERM / UPMC / CHNO des Quinze-Vingts 
17 rue Moreau 
75012 Paris 
France 
Phone: +33 1 53 46 25 04 
e-mail:  j.sahel@gmail.com 
FWA-Number: FWA00005831 
 
Universitaetsklinikum Tuebingen (Eberhard-Karls University Hospital) 
Eberhart Zrenner, M.D. 
Institute for Ophthalmic Research 
Center for Ophthalmology 
Schleichstr. 12-16 
72076 Tübingen 
Germany 
Phone: +49 (7071) 2984 786 
e-mail:  ez@uni-tuebingen.de 
Fax: +49 (7071) 2950 38 
FWA-Number: FWA00000781 
 
Moorfields Eye Hospital, NHS Foundation Trust 
Michel Michaelides, M.D., F.R.C.Ophth. 
UCL Institute of Ophthalmology 
11-43 Bath Street 
London, EC1V 9EL 
United Kingdom 
Phone: +44 20 7566 2255 
 e-mail: michel.michaelides@ucl.ac.uk 
FWA-Number: FWA00010199 
 
Clinical Data and Biostatistics Coordination 
 
Sheila West, Ph.D. 
El-Maghraby Professor of Preventive Ophthalmology 
Dana Center for Preventive Ophthalmology 
Wilmer Eye Institute, Room 129 
600 North Wolfe Street 
Baltimore, MD  21287 
Phone: +1 (410) 955-2606 
e-mail: shwest@jhmi.edu 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
5 
Fax: +1 (410) 955-0096 
 
Clinical Laboratory 
 
N/A 
 
Central Reading Center 
 
Srinivas R. Sadda, M.D., 
Associate Professor of Ophthalmology 
Director, Medical Retina Unit 
Ophthalmic Imaging Unit, Doheny Image Reading Center 
Doheny Eye Institute 
Keck School of Medicine 
University of Southern California 
1450 San Pablo Street DEI 3615 
Los Angeles, CA 90033 
Phone: +1 (323) 442-6503 
e-mail: ssadda@doheny.org 
Fax: +1 (323) 442-6460 
FWA-Number: FWA00005904 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
6 
Protocol Synopsis 
Name of Sponsor:  Foundation Fighting Blindness 
Clinical Research Institute 
Name of Product:  
N/A 
Protocol #: CRI-PROGSTAR-02 
IND#: N/A 
Protocol Title: 
The Natural History of the Progression of Atrophy Secondary to 
Stargardt Disease (STGD): A Prospective Longitudinal 
Observational Study 
Clinical Phase:  
N/A – Natural History Study 
Treatment 
Indication:  
N/A 
Objectives: 
The primary objective is: 
• To assess the yearly rate of progression of STGD using the 
growth of atrophic lesions as measured by fundus 
autofluorescence (FAF) imaging. 
The secondary objectives are: 
• To assess the yearly rate of progression of STGD using the rate 
of retinal thinning and the rate of loss of photoreceptors as 
measured by spectral-domain optical coherence tomography 
(sd-OCT) 
• To assess the yearly rate of loss of retinal sensitivity as 
measured by microperimetry 
• To assess the yearly rate of visual acuity changes using the 
Early Treatment Diabetic Retinopathy Study (ETDRS) visual 
acuity protocol 
• To correlate the presence and progression of morphological 
abnormalities in FAF and sd-OCT images with visual function 
as measured by microperimetry and visual acuity. 
• 
To perform exploratory analysis that examines factors 
associated with effects on STGD progression, such as the use 
of vitamin A supplementation and mutations in the ABCA4 
gene 
Study Design: 
Prospective longitudinal observational study over a period of 24 
months. 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
7 
Name of Sponsor:  Foundation Fighting Blindness 
Clinical Research Institute 
Name of Product:  
N/A 
Protocol #: CRI-PROGSTAR-02 
IND#: N/A 
Participant 
Population: 
Up to a total of 250 (minimum of 150) patients, including males 
and females age 6 years and older affected by STGD that have an 
atrophic lesion in at least one eye with a minimum diameter of at 
least 300 microns, and a sum of all lesions less than or equal to 12 
mm2 (five disc areas). 
Test Product, Dose, 
Mode of 
Administration: 
N/A 
Outcome Variables 
• Growth of atrophic lesions as measured by FAF imaging 
performed at 12 and 24 months. 
• Rate of retinal thinning and photoreceptor loss as measured by 
sd-OCT at 12 and 24 months. 
• Loss of retinal sensitivity as measured by microperimetry at 12 
and 24 months. 
• 
Change of best-corrected visual acuity by using the ETDRS 
protocol at 12 and 24 months. 
Study Duration: 
Participant: 24 months involvement with data collection every 6 
months. 
Total duration of study including patient enrollment and data 
analysis: 36 months. 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
8 
Table of Contents 
 
 
Protocol Synopsis ...........................................................................................6 
Table of Contents ...........................................................................................8 
1 
Introduction ........................................................................................ 15 
1.1 
Background.....................................................................................................16 
1.2 
Treatment Strategies .......................................................................................19 
1.3 
Known and Potential Risks ............................................................................20 
1.3.1 
Foreseeable Risks ...........................................................................................20 
1.3.2 
Risk Management and Emergency Response.................................................21 
1.3.2.1 
Minimization of Risk ......................................................................................21 
1.3.2.2 
Response to Risk ............................................................................................21 
1.3.2.3 
Research Injury Compensation.......................................................................21 
1.3.2.4 
Precautions and Preventive Measures ............................................................21 
1.3.3 
Known and Potential Benefits ........................................................................21 
2 
Study Rationale and Objectives ....................................................... 22 
2.1 
Study Rationale ..............................................................................................22 
2.2 
Study Objectives .............................................................................................22 
3 
Study Design ....................................................................................... 23 
3.1 
Type/Design of Study .....................................................................................24 
3.2 
Study Treatments ............................................................................................24 
3.3 
Study Population ............................................................................................24 
3.3.1 
Recruitment Methods .....................................................................................24 
3.3.2 
Recruitment Process .......................................................................................24 
3.3.3. 
Volunteer Compensation ................................................................................25 
3.3.4. 
Recruitment Materials ....................................................................................25 
3.4 
Eligibility Criteria ...........................................................................................25 
3.4.1 
Informed Consent/Assent ...............................................................................25 
3.4.2 
Disclosure of DOD Sponsorship and Access to Research Records ...............26 
3.4.3 
Inclusion Criteria ............................................................................................27 
3.4.4 
Exclusion Criteria ...........................................................................................28 
3.5 
Primary and Secondary Outcome Variables...................................................29 
3.6 
Measures to Minimize/Avoid Bias .................................................................29 
3.6.1 
Blinding ..........................................................................................................29 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
9 
3.6.2 
Study Data ......................................................................................................30 
3.7 
Schedule of Data Collection ...........................................................................31 
3.7.1.1. 
Screening/Baseline (Day 0) ............................................................................31 
3.7.1.2. 
Follow-up visits ..............................................................................................32 
3.7.2. 
Safety Assessments ........................................................................................33 
3.7.2.1. 
Adverse Events ...............................................................................................33 
3.7.2.2. 
Clinical Laboratory Data ................................................................................33 
3.7.2.3. 
Evaluations .....................................................................................................33 
3.7.2.4. 
Labs Performing Evaluations and Special Precautions ..................................34 
3.7.2.5. 
Sharing Research Results ...............................................................................34 
3.7.3. 
Endpoints ........................................................................................................34 
3.7.3.1. 
Primary Statistical Endpoint ...........................................................................34 
3.7.3.2. 
Secondary Statistical Endpoints .....................................................................34 
3.7.4. 
End of Study ...................................................................................................35 
3.8. 
Withdrawal Criteria, and Procedures .............................................................35 
3.9. 
Screen Failures ...............................................................................................35 
3.10. 
Definition of Completed .................................................................................35 
3.11. 
Definition of Lost to Follow-up .....................................................................36 
3.12. 
Participant Compliance ..................................................................................36 
3.13. 
Protocol Deviations ........................................................................................36 
3.14. 
Protocol Modifications ...................................................................................36 
4. 
Study Personnel ................................................................................. 37 
4.1. 
Roles and Responsibilities of Key Study Personnel.......................................37 
4.2. 
Conflict of Interest ..........................................................................................39 
5. 
Prohibited Medications ..................................................................... 39 
6. 
Evaluation of Adverse Events ........................................................... 39 
7. 
Statistical Analysis ............................................................................. 39 
7.1. 
Sample Size and Power ..................................................................................39 
7.2. 
Statistical Analyses .........................................................................................40 
7.3. 
Baseline Demographic Characteristics ...........................................................41 
7.4. 
Data Set Descriptions .....................................................................................42 
7.5. 
Handling of Missing Data ..............................................................................42 
7.6. 
Safety Analyses ..............................................................................................42 
7.7. 
Study Drug Compliance .................................................................................42 
7.8. 
Interim Analysis .............................................................................................42 
8. 
Study Product Management ............................................................. 42 
9. 
Data Handling and Records Management ...................................... 43 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
10 
9.1. 
Data Collection ...............................................................................................43 
9.1.1. 
Volunteer Identification..................................................................................44 
9.1.2. 
Confidentiality ................................................................................................44 
9.1.3. 
Access .............................................................................................................45 
9.1.4. 
Reporting Requirements .................................................................................45 
9.2. 
Source Documents ..........................................................................................45 
9.3. 
File Management at the Study Site .................................................................46 
9.4. 
Records Retention at the Study Site ...............................................................46 
9.5. 
Data Management Considerations ..................................................................46 
9.5.1. 
Database Design and Creation........................................................................46 
9.5.2. 
Data Coding ....................................................................................................46 
9.5.3. 
Data Transfer ..................................................................................................46 
9.5.4. 
Data Validation ...............................................................................................47 
9.5.5. 
Database Lock ................................................................................................47 
10. Quality Control and Quality Assurance .......................................... 47 
10.1. 
Monitoring ......................................................................................................47 
10.2. 
Auditing ..........................................................................................................48 
11. Ethics and Responsibility .................................................................. 48 
11.1. 
Clinical Study Report .....................................................................................48 
12. Confidentiality .................................................................................... 49 
13. Amendment Policy ............................................................................. 49 
14. References ........................................................................................... 50 
Appendix 1 - Agreement............................................................................. 53 
Appendix 2 – Additional Institutions and Personnel Involved With the 
Study ................................................................................................... 54 
Appendix 3 – Biosketches of Key Personnel ............................................ 55 
Appendix 4 – Electronic Clinical Report Form (eCRF) ......................... 56 
 
List of In-text Tables 
 
Table 3.4.3-1 
Inclusion Criteria ......................................................... 27 
Table 3.4.4-1 
Exclusion Criteria ........................................................ 28 
Table 3.6.2 
Study Data………….....................................................29 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
11 
List of Abbreviations and Definitions of Terms 
 
Abbreviations 
AE 
AF 
AHRPO 
Adverse event 
Autofluorescence 
Army Human Research Protection Office 
BCVA 
Best Corrected Visual Acuity 
CFR 
CO 
COR 
Code of Federal Regulations 
Contract Officer 
Contract Officer Representative 
CRF 
CRI 
Case Report Form 
Clinical Research Institute 
eCRF 
cSLO 
DOD 
Electronic Clinical Report Form 
Confocal Scanning Laser Ophthalmoscopy 
Department of Defense 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FFB 
Foundation Fighting Blindness 
FFB CRI 
Foundation Fighting Blindness Clinical Research Institute 
GCP 
HRPO 
HSPS 
Good Clinical Practice 
Human Research Protections Office 
Human Subjects Protection Scientist 
ICH 
International Conference on Harmonization 
ID 
Identification 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MP 
Microperimetry 
mmHg 
millimeters of Mercury 
N/A 
OC 
Not Applicable 
Observed cases  
sd-OCT 
Spectral Domain Optical Coherence Tomography 
STGD 
USAMRMC 
Stargardt Disease 
US Army Medical Research and Materiel Command 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
12 
WOCBP 
Women of Child Bearing Potential 
 
Definition of Terms 
 
Research - A systematic investigation, including the development, testing and evaluation of 
an idea, designed to develop or contribute to generalizable knowledge.  Activities that meet 
this definition constitute research whether or not they are conducted or supported under a 
program that is considered research for other purposes.  For example, some demonstration and 
service programs may include research activities. 
 
Clinical Investigation - Any experiment in which a drug or therapy is administered, 
dispensed, or used for treating one or more human participant.  This definition applies to 
research involving the use of FDA-regulated products.  Even if a clinical investigation does 
not meet the definition of research, it is participant to the same regulations as research. 
 
Human Participant - A living individual about whom an investigator is conducting research, 
obtains data, through intervention or interaction with the individual, or identifiable private 
information. 
 
Human Anatomical Substances - Any human organs, tissues, cells, or body fluids including 
but not limited to blood/sera (finger stick, ear stick, venipuncture, etc.), hair, nails, teeth, skin, 
sputum or cells gathered from mouth washing, nasal or oral swabs, placenta or amniotic fluid. 
   
Individually Identifiable Private Information - Private information includes information 
about behavior that occurs in a context in which an individual can reasonably expect that no 
observation or recording is taking place.  This information has been provided for specific 
purposes by an individual and the individual can reasonably expect that private information 
will not be made public (for example, a medical record).  Individually identifiable means that 
the identity of the participant is known or that their identity may readily be ascertained by the 
investigator or that their identity is associated with the information.  
    
 Protected Health Information (PHI) - Any individually identifiable health information held 
by a covered entity, as defined in the Health Insurance Portability and Accountability Act 
(HIPAA). 
 
Covered Entity - An organization engaged in the treatment of patients, responsible for 
obtaining payment for such treatment, or engaged in other healthcare operations where PHI is 
electronically exchanged.  
  
Authorization - Written permission from an individual allowing a Covered Entity to use or 
disclose specified PHI for a particular purpose (such as research).  
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
13 
Minimal Risk - The probability and magnitude of harm or discomfort in the research are not 
anticipated to be greater in and of themselves than those ordinarily encountered in daily life, 
or during the performance of routine physical and psychological examinations or tests.  
 
Legally Authorized Representative (LAR) - An individual or judicial or other body 
authorized under applicable law to consent on behalf of a potential participant to the 
participant’s participation in the procedure(s) involved in the research.  NOTE:  State law 
defines who may act as an LAR. The Institutional Review Board (IRB) of record should be 
consulted for guidance regarding who can serve as an LAR for research at the research site.  
 
USAMRMC Supported Research - For the purpose of this document USAMRMC supported 
research includes but is not limited to: (1) Research funded (through grant, contract, 
cooperative agreement, military interdepartmental purchase request, etc.) by the USAMRMC 
and (2) Research managed (technical management and/or funds management) by the 
USAMRMC as directed by Congress (e.g., Telemedicine and Advanced Technology Research 
Center (TATRC)). 
 
Institutional Review Board (IRB) of Record - The IRB listed on an Institution’s Assurance 
of Compliance that assumes responsibility for review and oversight of a research protocol on 
behalf of the institution.  An IRB of record from each institution engaged in the research must 
review and approve the protocol; therefore, there can be more than one IRB of record for a 
protocol.  An IRB Authorization Agreement between two IRBs of Record allows one IRB of 
record to defer to another.   
 
Research Proposal - A research plan submitted to the DOD funding agency in response to a 
solicitation.  The proposal provides an overview of all proposed work to be performed and 
provides the rationale explaining why the institution should be awarded funds to complete the 
work.  A proposal may consist of multiple research projects conducted under separate 
protocols at one or more institutions. 
  
Research Protocol - A comprehensive, detailed, and specific plan of action for the execution 
of research on human participants  
   
Award - A financial agreement such as a grant, contract, or cooperative agreement between 
the Federal Government and an institution. 
  
Scientific Review – An independent, documented review that objectively evaluates the 
scientific merit of a research proposal or protocol.  Refer to the HRPO Policies and 
Procedures document on the HRPO website for additional information on scientific reviews.   
 
Contract Officer (CO) – A federal government employee authorized to negotiate awards and 
commit funds on behalf of the U.S. Government.  
  
Contract Specialist - A federal government employee assigned to assist the CO with award 
related issues.  The contract specialist is the primary point of contract for award related issues.  

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
14 
  
Contract Officer’s Representative (COR) - A federal government employee assigned by the 
CO to manage the technical aspects and performance of an award on behalf of the DOD 
program office responsible for oversight of the research.  The COR may serve as the Grant 
Manager or Project Manager or may have assistance from other personnel within the DOD 
program office in executing COR responsibilities. 
  
Human Subjects Protection Scientist (HSPS) - A federal government employee or 
contractor within the HRPO responsible for assisting investigators with the HRPO review and 
approval process.  The HSPS is the investigator’s primary point of contact for questions 
regarding the human research review process and other issues related to human subjects 
protection. 
  
Army Human Research Protection Office (AHRPO) - The office that reports to the 
Assistant Surgeon General, Force Projection and is responsible for human research policy, 
education, and oversight for the U S Army.  The AHRPO administers DOD Assurances of 
Compliance. 
   
Informed Consent - Informed consent is an ongoing process that provides the participant, or 
legally authorized representative (LAR), with sufficient details about a study so that he/she 
can make a voluntary decision about participation.  Often a written consent form is employed 
to facilitate initial discussion of a study, and includes descriptions of study procedures, 
potential risks and benefits, and other pertinent information.  Informed consent is an ongoing, 
interactive process and the participant’s voluntary decision about continuing to take part in the 
trial should be reassessed throughout the study. 
 
Enrollment - To register, enter, screen, randomize, or otherwise formally initiate a 
participant’s participation in a study.  Informed consent precedes enrollment.  The number of 
participant consented may differ from the number of participants enrolled in a study (e.g., a 
participant may give consent to participate in a study but may be determined to be ineligible 
upon screening; commonly called a “screen failure”).  
  
Screening - A process of actively assessing a potential participant for inclusion in a study 
based on compatibility with pre-determined inclusion/exclusion criteria, ability and 
willingness to complete the study, and other factors.  Screening that does not access, collect, 
or record a participant’s protected health information may take place before informed consent 
is obtained.  However, informed consent must be obtained prior to screening procedures that 
use protected health information or involve procedures that a participant would not normally 
undergo.   

Protocol No. FFBCRI-PROGSTAR-02 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
15 
1 Introduction 
Stargardt disease (STGD1; OMIM: 248200), initially described by the German 
ophthalmologist Karl Stargardt in 1909, is predominantly an autosomal recessively inherited 
disorder, although an autosomal dominant Stargardt-like phenotype has also been described 
[1]. Stargardt disease is the most common form of juvenile macular degeneration with an 
estimated incidence of 10 – 12.5 per 100,000 and about 95% of cases are caused by mutations 
in the ABCA4 gene [2, 6] that lead to an autosomal recessive inherited disorder, although an 
autosomal dominant Stargardt-like phenotype [3] has also been described associated with 
mutations in the ELOVL4 and PROM1 genes [4, 5]. 
 
Patients with STGD develop a progressive impairment of visual acuity, which begins most 
frequently within the first or second decades of life [7]. However some patients do not lose 
visual acuity until the fourth or even fifth decade of life. The loss of acuity is accompanied by 
atrophic-appearing lesions within the macula and the presence of yellow-white lesions about 
the retinal pigment epithelium (RPE), which are referred to as “fundus flecks”. The fundus 
changes apparent clinically are caused by excess accumulation of lipofuscin in the RPE 
(Figure 1).  RPE lipofuscin is a heterogeneous material composed of a mixture of lipids, 
proteins, and different fluorescent compounds [8]. The natural autofluorescent properties of 
lipofuscin have led to the use of confocal scanning laser ophthalmoscopy (cSLO), and 
autofluorescence (AF) imaging, as convenient, noninvasive methods for determining the 
distribution of lipofuscin in human participants. [9-11]. 
 
Figure 1: 
 
 
 
Figure 1:  AF images of both eyes of a patient with bilateral central atrophy of the RPE. Stars: fixation 
loci determined individually in each eye. The contrast of each grayscale image is uniformly stretched 
for better visibility of features [12]. 
 

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1.1 
Background 
Any new therapeutic clinical studies must be able to compare the intervention to the natural 
history of the disease in a longitudinal study.  Therefore, the natural history of the disease in 
the patients to be treated must be understood. Any clinical outcome measures must be 
accurate, reproducible and have acceptably small intra- and inter-observer variability. For 
surrogate measures, the FDA states that “validated surrogate markers are those for which 
evidence has been established that a drug-induced effect on the surrogate predicts the desired 
effect on the clinical outcome of interest” [13].  
 
Degeneration of the photoreceptors and underlying retinal pigment epithelium (RPE) in 
STGD, as measured by standard histology and sd-OCT imaging, typically occurs close to and 
within the macula [14] (Figure 2). Multiple lines of evidence indicate that lipofuscin 
accumulation in the RPE is responsible for RPE cell death [15-17], most probably by 
facilitating apoptosis and damage to lysosomal membranes [15]. Following RPE loss, 
photoreceptor cells degenerate rapidly [18] because of their dependence on RPE cells for the 
maintenance and the removal of shed photoreceptor outer segments. 
 
Figure 2: 
 
 
Figure 2: (A) A Fundus Autofluorescence (FAF) image of a Stargardt patient’s retina. The diameter of 
the central area of “absent FAF” corresponds to geographic atrophy seen clinically with a larger 
diameter of “abnormal FAF” visible. (B) An sd-OCT image through the fovea of a normal control eye. 
(C) An sd-OCT image showing the extent of the transverse loss of the inner segment-outer segment 
junction of the photoreceptors in the foveal region. (D) A comparison of the measurements obtained 
from FAF in (A) and sd-OCT in (C). [14]  
 
During the part of the visual cycle that occurs in the discs of the outer segment of 
photoreceptors, opsin bound 11-cis-retinal is converted by light into all-trans retinal.  This 
conformational change triggers a signaling cascade and is followed by the release of all-trans-

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retinal, which must then be recycled back to 11-cis-retinal.  Since rhodopsin is a trans-
membrane protein, the all-trans retinal is released into the membrane where it can either 
diffuse to the cytoplasmic face of the disc membrane, where a cytoplasmic retinol 
dehydrogenase starts the recycling process, or it remains in the disc membrane where it can be 
covalently modified by membrane lipids to form N-retinylidene-phosphatidylethanolamine 
(NRPE), which can be trapped within the membrane or the lumenal side of the disc.  To be 
recycled, NRPE must be transported across the disc membrane to the cytoplasm for 
dehydrogenation. 
 
Both in vitro and in vivo studies of the ABCA4 knockout mouse model, support the hypothesis 
that the ABCA4 protein is an outwardly directed “flippase” that transports all-trans retinal and 
NRPE to the cytoplasmic side of the disc membrane [19] (Figure 3).  In the absence of 
ABCA4 activity, the membrane trapped all-trans retinal and NRPE do not get removed for 
recycling [19] [20, 21]. If their concentration increases, as may occur during high levels of 
illumination or a failure of the flippase (Stargardt disease) to transport them away to the 
cytoplasm, NRPE and all-trans-retinal can react to form A2-dihydropyridine-ethanolamine 
(A2E-PE) [19, 22]. 
 
Photoreceptor outer segment membranes are renewed in a circadian cycle by the RPE that 
endocytose the distal 10% of each rod outer segment each day [17] for digestion in the RPE 
lysosomes. In Stargardt disease, the endocytosed outer segments contain elevated quantities of 
A2E-PE which are hydrolyzed within the lysosomes to generate elevated levels of A2E and 
related bisretinoids.  These are components of lipofuscin that are to be elevated in Stargardt 
disease [23-27].  Studies suggest that elevated levels of these metabolites are not handled 
efficiently and become toxic, leading to the A2E-mediated cell death seen in Stargardt 
disease. This mechanism of RPE cell death is consistent with the studies of the ABCA4 knock 
out mouse model that exhibit abundant lipofuscin accumulation, and elevated A2E levels that 
lead to eventual RPE cell death [24]. 
 

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Figure 3: 
 
 
Figure 3: Scheme of visual cycle.  The cell at the top of the diagram represents the distal tip of a rod 
outer segment.  The cell at the bottom of the diagram represents part of the RPE cell that endocytoses 
the distal segment of the photoreceptor and degrades it inside the lysosome. Excess accumulation of 
A2-PE leads to excess accumulation of A2E within the RPE lysosome that leads to A2E-mediated cell 
death. [25] 

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Consistent with this mechanism, a reduction of the daily light load on the retina should reduce 
production of A2E, and this is observed in ABCA4 knock-out mice reared in darkness [24]. 
 
1.2 
Treatment Strategies 
At present there are no FDA-approved treatments for ABCA4-related retinal diseases.  There is 
a phase I gene therapy clinical trial in progress and a number of preclinical studies of 
compounds designed to reduce the formation of A2-PE, which may slow or prevent 
progression of the disease (Figure 4).  What is currently unclear is whether a treatment 
strategy employed after significant accumulation of lipofuscin has already occurred will be 
able to effectively decrease the lipofuscin content and thereby save RPE and photoceptor 
cells. However, none of the treatments will be able to restore visual function to areas of the 
retina that have already undergone RPE, choriocapillaris, and photoreceptor cell loss. While a 
promising intervention, gene therapy can only be effective if the target cells are still viable. 
Therefore the initial primary therapeutic intent is to slow or halt the progression of retinal 
degeneration.  
 
Figure 4: 
 
Figure 4: Scheme of Vitamin A Visual Cycle 
 
Gene Therapy 
Given that STGD is caused by the loss of function of the ABCA4 protein, transfecting the 
wild type ABCA4 gene into the nucleus of photoreceptor cells may improve the retinoid flow 
in the visual cycle, prevent further abnormal accumulation of lipofuscin in RPE cells, and 
slow the disease process in patients with STGD.  This may be particularly therapeutic with 
early intervention before there is extensive cell loss. 
 

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There is currently one phase I/II gene therapy clinical trial for the product Stargen developed 
by Oxford BioMedica.  The therapy consists of a single subretinal injection of a genetically 
engineered lentivirus (the Equine Infectious Anaemia Virus, EIAV) carrying a single copy of the 
wild type ABCA4 gene.  This is a dose escalation study enrolling up to 28 participants with 
Stargardt disease, with the primary outcome measures being the incidence of adverse events 
over 48 weeks and the number and percentage of patients with treatment emergent adverse 
events.  The secondary outcome measures are a delay in retinal degeneration and changes 
from baseline function relative to the contralateral eye utilizing retinal analytical techniques.  
To date the trial has reported no significant adverse events.  
 
Pharmacologic and Other Interventions 
There are many different therapeutic approaches in the preclinical research stage for Stargardt 
disease.  These include: stem cell therapies; dietary supplementations; molecules that slow the 
visual cycle thereby limiting the rate that all-trans-retinal can be generated; molecules that 
chelate the all-trans retinal in the membrane; derivatives of 11-cis-retinal such as deuterated 
forms that markedly slow the formation of A2-PE; molecules that stimulate the activity of an 
impaired ABCA4 protein; molecules that restrict the amount of retinal that can reach the 
retina; molecules that remove the lipofuscin from the RPE cells before it can have a toxic 
effect; molecules targeting A2E; optogenetics and visual prosthetics [26, 27]. 
 
1.3 
Known and Potential Risks  
This study is an observational study of the natural course of STGD that will include data from 
the results of  both psychophysical examinations (visual acuity testing, fundus photography, 
and microperimetry) and retinal imaging examinations (optical coherence tomography and 
fundus autofluorescence), which are an integral part of current Standard or Care that is routine 
in patients with STGD. The risk to participants will not exceed the risks associated with the 
current standard of clinical care examinations.  
 
1.3.1 
Foreseeable Risks 
There are no anticipated risks associated with this observational study. The risks associated 
with ophthalmic procedures that are part of the current standard of care for STGD patients 
include redness of the eye, and discomfort or allergic reaction to topical medications used to 
dilate the pupil prior to visual function tests. High blood pressure, cardiac dysrhythmias and 
closed angle glaucoma may be exacerbated by some of these medications and light sensitivity 
may be experienced when the pupil is dilated. These risks are not attributable to participation 
in this trial but to the standard of care procedures encountered at all of the patients’ follow-up 
visits with their ophthalmologist. 
 
The data from a full-field electroretinogram may be collected during the study from any 
participants that have not had this exam within the last five years.  A rare side effect of this 
exam is corneal abrasion arising from the placement of electrodes required for testing.  
 

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All these tests and the frequency of assessments are part of the current standard of care for 
patients with STGD. 
 
1.3.2 
Risk Management and Emergency Response 
1.3.2.1 
Minimization of Risk 
The participants will be informed of the information to be collected in the study by one of the 
delegated study staff members, in a language the participant can understand. Participants will 
be informed that they may withdraw from the study at any time, for any reason without 
jeopardizing their future treatment. Participants will be given full information regarding the 
procedure results involved. All procedures related to the study will be performed by trained 
and licensed medical and health professionals at their own ophthalmologist’s facility. In the 
unlikely event of an adverse event associated with the study, immediate medical care will be 
provided. Adverse events will be reported to the IRBs and DOD as required by clinical trial 
regulations, to ensure the safety of participants. 
 
The study will be compliant with the relevant parts of 45 CFR and the ICH GCP Guidelines. 
 
1.3.2.2 
Response to Risk 
The study is an observational study of the natural course of STGD. Therefore, all participants 
in this trial will experience minimal risk not exceeding the risk of a standard of care 
examination of psychophysical examinations (visual acuity testing and microperimetry), 
retinal imaging (optical coherence tomography, fundus photography and fundus 
autofluorescence), and electroretinography.  
 
1.3.2.3 
Research Injury Compensation 
Due to the observational design of this study and collection of data from standard of care 
procedures, no research injuries are expected. 
 
1.3.2.4 
Precautions and Preventive Measures 
Due to the observational design of the natural course, no study specific preventive measures 
and precautions are needed. 
 
1.3.3 
Known and Potential Benefits 
There is no direct benefit to participants in this study, although they may conceivably be good 
candidates for future studies of emerging STGD therapies. Participants in this study are not 
experimental subjects as there is neither a study intervention nor is the interaction with the 
participant for the primary purpose of obtaining data regarding the effect of an intervention or 
interaction; as such, LARS consent/child assent will be allowed in the study and children may 
be enrolled. Data resulting from this natural history study may influence the clinical design of 

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future trials designed to evaluate therapies for treating Stargardt disease.  As such, this study 
may support work that leads to benefit for some patients in the long term. 
 
2 Study Rationale and Objectives 
2.1 
Study Rationale 
Although STGD is the most prevalent form of juvenile-onset macular dystrophy, with an 
estimated incidence of 10 – 12.5 per 100,000, it is still relatively rare and there is very limited 
information available about the natural course of the disease in larger numbers of STGD 
patients. The information currently available is predominantly based on individual reports of 
patient data collected from single centers [28, 29].  However, this limited data clearly points 
to a disease which is very heterogeneous with significant variation in the age of onset and rate 
of progression, and limited clear correlations between phenotype and genotype [30, 31]. These 
limitations highlight the urgent need for a multi-center study that documents the natural 
course of the disease. The information gathered from this proposed study should provide 
guidance and support to the identification of the most appropriate clinical outcome measures 
for anticipated clinical trials. It may also be used to identify and support the validation of 
surrogate clinical trial endpoints that are offered by recent technological advances in retinal 
imaging capabilities, such as fundus autofluorescence (FAF) and spectral-domain optical 
coherence tomography (sd-OCT). 
 
2.2 
Study Objectives 
Stargardt disease is currently an incurable and untreatable macular dystrophy that causes 
severe visual loss in children and young adults, thereby causing enormous morbidity with 
economic, psychological, emotional, and social implications. There are no FDA approved 
therapeutic treatments for this disease. Therefore, the objective of this study is to collect 
natural history data from a large population of children and adults in order to evaluate possible 
efficacy measures for planned clinical trials. 
 
Primary objective: 
• To assess the yearly rate of progression of STGD using the growth of atrophic lesions 
as measured by fundus autofluorescence (FAF) imaging. 
 
Secondary objectives: 
• To assess the yearly rate of progression of STGD using spectral-domain optical 
coherence tomography (sd-OCT) to measure the rates of retinal thinning and the loss 
of photoreceptors. 
• To assess the yearly rate of loss of retinal sensitivity as measured by microperimetry. 

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• To assess the yearly rate of visual acuity changes as measured by best corrected visual 
acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) 
protocol [32]. 
• To correlate the presence and progression of morphological abnormalities in FAF and 
sd-OCT images with visual function as measured by microperimetry and visual acuity. 
• To perform exploratory analysis of factors associated with STGD progression, such as 
participant’s use of vitamin A supplementation and mutations in the ABCA4 gene. 
 
3 Study Design 
The study shall utilize up to 14 clinical sites to collect prospective longitudinal observations 
on up to 250 participants (minimum of 150).  Participants must present with atrophic lesions 
secondary to STGD, in at least one eye.  The study shall take place over a 24 month period 
that includes data collection from the procedures conducted at a patients’ physician visit that 
will be designated as the baseline visit and subsequently from the patients’ following four six- 
month, regular follow-up visits (months six, 12, 18 and 24).  
Each of the study investigators has indicated that the information that will be available at each 
visit will include: best-corrected visual acuity, a complete ophthalmic exam (including dilated 
fundoscopy), autofluorescence imaging, microperimetry and spectral-domain optical 
coherence tomography (sd-OCT). Results will be sent by the participating centers to the Dana 
Center for Preventative Ophthalmology of the Wilmer Eye Institute, the Johns Hopkins 
University, Baltimore, for evaluation, with exception of the microperimetry, autofluorescence 
and optical coherence tomography, which will be sent to a central reading center at the 
Doheny Eye Institute, Los Angeles, California. 
 
Primary outcome measure: 
• Yearly rate of progression of STGD as reflected by the growth of atrophic lesions 
measured by FAF imaging. 
 
Secondary outcome measures: 
• Yearly rate of progression of STGD as reflected by the rate of retinal thinning and 
photoreceptor loss as measured by sd-OCT 
• Yearly rate of loss of retinal sensitivity as measured by microperimetry 
• Yearly changes in the best corrected visual acuity (BCVA) assessed using the Early 
Treatment Diabetic Retinopathy Study (ETDRS) protocol. 
• Correlation of the presence and/or progression of morphological abnormalities in FAF 
and sd-OCT images with visual function as measured by microperimetry and BCVA. 
• Exploratory analysis to examine factors associated with disease progression, such as 
participant’s use of vitamin A supplementation and mutations in the ABCA4 gene. 
 
At each follow-up visit, any changes in medical and ophthalmic history as well as vitamin A 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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supplementation will be recorded.  
 
3.1 
Type/Design of Study  
This is a prospective longitudinal observational study. 
 
3.2 
Study Treatments 
This is a natural history study. There are no treatments being investigated in this trial. 
 
3.3 
Study Population 
The study population shall consist of up to 250 Stargardt disease patients (minimum of 150 
patients) recruited at up to 14 clinical centers across the US and Europe.  Participants must be 
at least six years old, able to cooperate in performing the examinations and be willing to 
attend their regular 6 month follow-up visits for up to 24 months. There are no limitations 
regarding race, ethnicity or sex. 
 
The participants must present with atrophic lesions secondary to STGD with a minimum 
diameter of 300 microns and all lesions together must add to less than or equal to 12 mm2 
(equivalent to no more than 5 disc areas) in a least one eye. Participants must have been 
previously genotyped to participate in the study and have at least 2 confirmed pathogenic 
mutations in the ABCA4 gene. If only one ABCA4 allele contains a pathogenic mutation, then 
the patient needs to show a typical phenotype, i.e. at least one eye must have flecks at the 
level of the retinal pigment epithelium typical for STGD. Best-corrected visual acuity 
(BCVA) must be 20 ETDRS letters (20/400 Snellen equivalent) or better.  
 
3.3.1 
Recruitment Methods 
The investigators at each of the centers will review their own clinical patient databases and 
contact their patients. 
 
3.3.2 
Recruitment Process 
The investigators at each of the clinical centers will identify potential study patients from their 
own patient populations. Potential study participants who demonstrate an interest in 
participating in the study will receive an explanation of the terms, and requirements of the 
study, in language they can understand, from an investigator in the research team. They will 
also receive a written copy of the Informed Consent Form to read and share with family or 
friends prior to their screening visit. Subsequently, an investigator or a qualified designee will 
answer questions and request the patient's permission to participate in the study. Participants 
who sign a study-specific patient informed consent form approved by the local Institutional 
Review Board will then be scheduled for an evaluation with their doctor to determine their 
eligibility.  
 

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For participants younger than 18 years of age, parental/LAR consent and patient assent will 
both be obtained prior to participation in this study. 
 
3.3.3. 
Volunteer Compensation 
This observational study collects information on the natural course of STGD and all 
examinations are part of the standard clinical care. Compensation will not be provided to the 
study participants. 
 
3.3.4. 
Recruitment Materials 
No centrally prepared recruitment or advertising materials are planned for this study. 
 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent/Assent 
When individuals are identified in-person as potential study participants, the investigator will 
provide information about the study, and confirm contact information. The investigator or 
other designated study staff will obtain and document informed consent from appropriate, 
interested patients.  
 
Potential study participants who demonstrate an interest in participating in the study will 
receive an explanation of the terms, and requirements of the study from the research team in a 
language they can understand. They will receive a copy of the Informed Consent Form to read 
and share with family or friends, if they prefer, prior to their screening visit. An investigator 
or designated site study staff member will answer any questions or concerns that the potential 
participants may raise and request the patient's permission to participate in the study. Each site 
will provide adequate time for the patient to make a decision whether to participate in the 
study. When the potential participant is a minor (less than 18 years of age), parental/LAR 
consent and minor participant assent will be obtained following the same procedures outlined 
in the previous paragraph. The minor participant will be provided with an age appropriate 
assent form and given a chance to freely choose whether to participate in the study. 
 
Following the initial study consent/assent, study participants will be asked at each follow-up 
visit to confirm their continued consent to continue their participation in the study. 
 
Care will be taken to ensure that the mental capacity of potential volunteers is properly 
assessed during each follow-up visit, as uncontrolled concomitant diseases such as 
neurological disorders are exclusion criteria.  
 
Study candidates who cannot give their own consent to participate will only be enrolled into 
the study after consent is obtained from the individual’s Legally Authorized Representative 
(LAR).  Children shall receive an additional assent form written in age appropriate language 
for them to read, and will only be enrolled into the study following consent by their 

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individual’s Legally Authorized Representative (LAR).  Site investigators will consult with 
their local institutional review boards for guidance regarding who may serve as an LAR. 
 
For study candidates who are illiterate or unable to understand the written consent form, the 
consent form will be read and explained to them in the presence of a witness. The candidate 
must sign or mark the form in an individually unique manner, such as with a thumbprint, to 
indicate their agreement to participate.  The witness present during the presentation must also 
sign the form to attest that the content of the written consent form was conveyed accurately to 
the study candidate. 
 
If a study candidate is not fluent in the primary language of the host country of the study site, 
all documentation including the consent form and any site information sheets approved by the 
local IRB shall be translated into their native language by a certified translator and the 
translation approved by the local HRPO.  Plans shall also be made and approved to ensure a 
qualified translator is available during the consent process, baseline and all follow-up visits to 
address any concerns or ensure they provide continuing consent to study participation. 
 
When consent is obtained in a language other than English, the foreign language version of 
the consent form will be an accurate translation of the English version of the consent form.  
 
Written informed consent shall be obtained from all participants or their LAR before any 
study-related participation. However, investigators may discuss in general the availability of 
the study and the general entry criteria with a potential participant candidate without obtaining 
consent.  
 
The investigator has both an ethical and legal responsibility to ensure that each participant 
study candidate being considered for inclusion in this study is given a full explanation of the 
protocol. This shall be documented on the written informed consent form approved by the 
same Institutional Review Board (IRB) responsible for approving this protocol.  
 
Once the appropriate essential information has been provided to the participant and fully 
explained by the investigator, or a qualified designee, and the participant understands the 
implications of participating, the IRB-approved written informed consent/assent form(s) will 
be signed and dated by the participant and the person obtaining consent (investigator or 
designee), and by any other parties required by the site’s local IRB. The participant shall be 
given a copy of the signed informed consent form.  The original signed informed consent 
form shall be kept on file by the investigator; the time length will be determined by the local 
IRB. All of the above mentioned activities shall be completed prior to the participant’s 
participation in the trial. 
 
3.4.2 
Disclosure of DOD Sponsorship and Access to Research Records 
The informed consent form shall include a statement that discloses that the DOD is supporting 
the research and that representatives of the USAMRMC have the authority to review research 

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11 March 2013 
 
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records of any study participant.  Study candidates have a right to decline participation in 
research based on the source of the funding.   
 
3.4.3 
Inclusion Criteria 
Study participants are required to meet the following inclusion criteria: 
 
Table 3.4.3-1 
Inclusion Criteria 
1. 
Provide a signed informed consent form and authorization allowing the 
disclosure and use of protected health information. 
2. 
The designated primary study eye must have at least one well-demarcated area of 
atrophy as imaged by fundus autofluorescence with a minimum diameter of 300 
microns and all lesions together must add to less than or equal to 12 mm2 
(equivalent to no more than 5 disc areas in a least one eye) and a BCVA of 20 
ETDRS letters (20/400 Snellen equivalent) or better. 
3. 
Two (2) pathogenic mutations confirmed present, in the ABCA4 gene. If only 
one ABCA4 allele contains a pathogenic mutation, the patient shall have a typical 
Stargardt phenotype, namely at least one eye must have flecks at the level of the 
retinal pigment epithelium typical for STGD. 
4. 
The primary study eye must have clear ocular media and adequate pupillary 
dilation to permit good quality FAF and sd-OCT imaging in the opinion of the 
investigator.  
5. 
Be able to cooperate in performing the examinations. 
6. 
Be willing to undergo ocular examinations once every 6 months for up to 24 
months. 
7. 
Be at least six years old.  
8. 
Both eyes can be included if inclusion criteria are fulfilled for both eyes. 
 
 

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3.4.4 
Exclusion Criteria 
Study candidates shall be excluded if they meet any of the following exclusion criteria: 
 
Table 3.4.4-1 
Exclusion Criteria 
Exclusion Criteria 
1. 
Ocular disease, such as choroidal neovascularization, glaucoma and diabetic 
retinopathy, in either eye that may confound assessment of the retina 
morphologically and functionally. 
2. 
Intraocular surgery in the primary study eye within 90 days prior to baseline visit. 
3. 
Current or previous participation in an interventional study to treat STGD such as 
gene therapy or stem cell therapy. Current participation in a drug trial or previous 
participation in a drug trial within six months before enrollment. The use of oral 
supplements of vitamins and minerals are permitted although the current use of 
Vitamin A supplementation shall be documented. 
4. 
The site Principal Investigator may declare any patient at their site ineligible to 
participate in the study for a sound medical reason prior to the patient’s enrollment 
into the study. 
5. 
Any systemic disease with a limited survival prognosis (e.g. cancer, 
severe/unstable cardiovascular disease). 
6. 
Any condition that would interfere with the patient attending their regular follow-
up visits every 6 months for up to 24 months, e.g. personality disorder, use of 
major tranquilizers such as Haldol or Phenothiazine, chronic alcoholism, 
Alzheimer’s Disease or drug abuse. 
7. 
Evidence of significant uncontrolled concomitant diseases such as cardiovascular, 
neurological, pulmonary, renal, hepatic, endocrine or gastro-intestinal disorders. 
 

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3.5 
Primary and Secondary Outcome Variables 
The primary outcome variable for the ProgSTAR study is the yearly rate of progression of 
STGD as reflected by the growth of atrophic lesions measured by FAF imaging.  
 
The secondary outcome variables are:  
• Yearly rate of progression of STGD using spectral-domain optical coherence 
tomography (sd-OCT) to measure the rates of retinal thinning and the loss of 
photoreceptors. 
• Yearly rate of loss of retinal sensitivity as measured by microperimetry 
• Yearly change in best corrected visual acuity (BCVA) by using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) protocol. 
• Correlation of the presence and/or progression of morphological abnormalities in 
FAF and sd-OCT images with visual function as measured by microperimetry and 
BCVA. 
• Exploratory analysis to examine factors associated with disease progression, such as 
participant’s use of vitamin A supplementation and mutations in the ABCA4 gene. 
 
3.6 
Measures to Minimize/Avoid Bias 
Data from all sites will be sent, using a standardized, de-identified electronic clinical report 
form (eCRF), to a central data management center at the Dana Center for Preventive 
Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 
except in the case of data from retinal imaging procedures and microperimetry, which will be 
sent to a central reading center at the Doheny Eye Institute, Keck School of Medicine, 
University of Southern California for further processing.  Each center shall undertake 
standardized collection of all data. Ophthalmic outcome data from the microperimetry, sd-
OCT and fundus autofluorescence assessments will be electronically submitted from the site 
to the appropriate reading center via secure data upload through the reading center internet 
website.  
 
Once processed and analyzed by the appropriate reading center, all data will be transferred 
electronically from the reading center to the Dana Center system via a secure transfer process. 
Only coded identifiers will be used to identify participants. 
 
3.6.1 
Blinding 
Not applicable. 
 
 

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3.6.2 
Study Data 
 
 
1: Ophthalmic examination includes slit lamp examination, cataract grading, and dilated 
fundus examination 
2: In selected centers  
3: Only if a full-field ERG was not performed within the past 5 years. 
4: If qualified, patients may exit the study before Visit 5 to participate in an investigational 
treatment study for STGD 
 
 
Table 3.6.2  
Study Data 
ASSESSMENT/ 
PROCEDURE DATA 
COLLECTION POINTS 
BASELINE 
Visit 1 
DAY 0 
VISIT 2 
MONTH 
6 
VISIT 3 
MONTH 
12 
VISIT 4 
MONTH 
18 
VISIT 5 
MONTH 
24 
Informed consent, medical 
history, genotype 
information, demographics 
X 
 
 
 
 
Inclusion/Exclusion 
criteria assessed 
X 
 
 
 
 
ETDRS BCVA Data 
X 
X 
X 
X 
X 
Ophthalmic fundus exam 1 
Data 
X 
X 
X 
X 
X 
Autofluorescence imaging 
Data 
X 
X 
X 
X 
X 
Microperimetry2 Data 
X 
X 
X 
X 
X 
sd-OCT Data 
X 
X 
X 
X 
X 
Changes in medical and 
ophthalmic history Data 
X 
X 
X 
X 
X 
Vitamin A 
supplementation Data 
X 
X 
X 
X 
X 
Full-field 
electroretinogram3 Data 
X 
 
 
 
 
Exit from study4 
 
 
 
 
X 

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3.7 
Schedule of Data Collection 
Screening and baseline visits may be combined into one visit if the inclusion criteria are 
fulfilled and the exclusion criteria do not apply. Follow-up visits will be approximately 6, 12, 
18, and 24 months after baseline visit. For these follow-up visits, a time window of ± five (5) 
weeks around the calculated, expected date of the follow-up visit is acceptable for the data to 
be included for that time point. 
 
3.7.1.1. 
Screening/Baseline (Day 0) 
The Screening/Baseline visit consists of the entering of data resulting from examinations and 
procedures performed as part of Standard of Care during the participant’s scheduled follow-
up ophthalmology visit: 
 
1. An explanation of the study and providing a copy of the consent forms (if not mailed 
ahead of the visit) to the study candidate 
2. Signing of the informed consent for the study 
3. Completion of a medical and ophthalmic history 
4. Recording and documentation of demographic information 
5. Recording and documentation of vitamin A supplement use 
6. Recording and documentation of genetic mutations in the ABCA4 gene 
7. Measurement of refraction and best-corrected visual acuity (BCVA) using the Early 
Treatment Diabetic Retinopathy Study (ETDRS) Testing Protocol [32] 
8. Microperimetry  
9. Ophthalmic examination 
10. Spectral-domain optical coherence tomography 
11. Fundus autofluorescence 
 
The order of the examinations may be changed by the investigator and examinations may be 
performed on different days. 
 
Description of Standard of Care examinations and procedures the investigators will utilize to 
obtain data that will be collected for this study include: 
Refraction and best-corrected visual acuity (BCVA) according to the Early Treatment 
Diabetic Retinopathy Study protocol [32]: 
Visual acuity is measured at a distance of one or four meters. A separate sequence of letters 
is used for each eye. Patients are encouraged to read each letter, and instructed to guess if 
unsure. The vision score is then calculated. 
 
Fundus-Autofluorescence (FAF) and spectral-domain optical coherence tomography 
(sd-OCT): 
Images of patient’s eyes are recorded using sd-OCT, and scanning laser ophthalmoscopy 
(cSLO) in order to acquire fundus autofluorescence images. The computer driven cameras 
used in these techniques use a beam of light to take images.  

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Microperimetry: 
Patients undergo an examination of the retinal central visual field using Microperimetry. 
During this procedure patients press a button when they see a little light spot on a screen of a 
special computer monitor. This technique uses a beam of light to take images and the test 
takes about 30 minutes. 
 
Full-Field Electroretinogram (FF-ERG): 
With pupils dilated, patients remain in a darkened room for at least 20 minutes. Then, 
electrodes are placed close to the cornea, through the use of special contact lenses, to record 
the electrical response of the retina to light stimuli in a manner similar to an 
electrocardiogram recording. 
 
Full field ERGs are performed according to ISCEV standards [33]. A standard for four 
different types of response measured include: 
1. Rod response in the dark adapted eye 
2. Maximal/combined response in the dark adapted eye 
3. Cone response 
4. Response to flicker 
 
If an acceptable ERG was performed within the last 5 years, the test result will be used for 
the study data evaluation by the site investigators. The ERG is not generally recommended to 
be repeated if a previous ERG of more than 5 years ago was documented as unrecordable 
(absent responses) at that time. 
 
An ophthalmic examination to diagnose the typical clinical appearance of STGD will aid in 
confirming eligibility for the study. 
 
In order to participate in the study, all patients must have documentation of two (2) 
pathogenic mutations confirmed in the ABCA4 gene from previously completed genetic 
testing. If only one ABCA4 allele contains a pathogenic mutation, the patient should have a 
typical Stargardt phenotype, namely at least one eye must have flecks at the level of the 
retinal pigment epithelium typical for STGD.  The genetic testing will have been previously 
completed and outside the scope of this study. 
 
Before any study-related data is collected, the participants will have all imaging procedures 
explained to them, as well as what information from their procedure will be included in the 
study.  Study participants must sign and date all appropriate informed consent forms before 
any data for the study is collected. 
 
3.7.1.2. 
Follow-up visits 
The follow-up visits consist of the entry of data resulting from the following Standard of 
Care examinations and procedures obtained from the patients’ regular follow-up visits: 

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1. Confirm that the participant wishes to continue in the study 
2. Review and documentation of changes in medical and ophthalmic history  
3. Documentation of vitamin A supplement use 
4. Refraction and best-corrected visual acuity (BCVA) using the Early Treatment 
Diabetic Retinopathy Study (ETDRS) Testing Protocol [32] 
5. Microperimetry  
6. Ophthalmic examination 
7. Spectral-domain optical coherence tomography 
8. Fundus autofluorescence 
 
The data from the visits will be utilized in the study even if the order of the examinations 
change from visit to visit or between the practices of the different investigators, and the 
examinations are performed on different days (as long as the time window is respected). 
 
3.7.2. 
Safety Assessments 
Due to the observational design of the natural course study, no study specific safety 
assessments are needed. 
 
3.7.2.1. 
Adverse Events 
Due to the observational design of the natural course study, no adverse events are expected. 
 
3.7.2.2. 
Clinical Laboratory Data 
Not applicable 
 
3.7.2.3. 
Evaluations 
During each participant’s visit to the clinic, a clinician participating in the study will record 
“study progress notes” to document all significant observations. At a minimum, this 
documentation will contain: 
• The informed consent process, including any revised consents 
• The date of the visit and the corresponding Visit, Day, or Week in the study schedule 
• The genetic information at baseline 
• Any comments made by the participant about the study, including any significant 
medical findings 
• Any changes in Vitamin A supplement use 
• A general reference to the procedures completed 
• The signature (or initials) and date of all clinicians who made an entry in the progress 
notes 
• The evaluation of refraction and best corrected visual acuity according to ETDRS 
• The evaluation of full-field electroretinogram in at least one eye at baseline (or within 
the past five years) 
• The evaluation of microperimetry test and recording of mean sensitivity 

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• The evaluation of spectral-domain optical coherence tomography (sd-OCT)  
• The evaluation of fundus autofluorescence 
• A summary of the ophthalmologic exam including status of the anterior segment of 
the eyes, including the cornea, anterior chamber, iris and grading cataract, and dilated 
fundus exam 
 
In addition, any contact with the participant via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as described 
above. Information from the study progress notes and other source documents will be 
promptly transcribed to eCRFs for transmission to the Coordinating Center. Any changes to 
information in the study progress notes, other source documents, and CRFs will be properly 
tracked. 
 
3.7.2.4. 
Labs Performing Evaluations and Special Precautions 
Not applicable 
 
3.7.2.5. 
Sharing Research Results 
As the data collected during study participation in this observational study is collected from 
standard clinical care ophthalmologist visits, the results of each individual’s procedures 
conducted during the time period of patients’ participation in this study, including any 
clinically significant abnormal findings, will be shared with that study participant or his/her 
primary care provider throughout the study.  
 
3.7.3. 
Endpoints 
3.7.3.1. 
Primary Statistical Endpoint  
The primary endpoint is the rate of growth of atrophic lesions as measured by FAF imaging, 
calculated at 12 and 24 months. 
 
3.7.3.2. 
Secondary Statistical Endpoints 
The secondary endpoints are: 
• Rate of retinal thinning and photoreceptor loss as measured by sd-OCT calculated at 
12 and 24 months. 
• Loss of retinal sensitivity as measured by microperimetry calculated at 12 and 24 
months. 
• Change of best-corrected visual acuity by using the ETDRS protocol calculated at 12 
and 24 months. 
 

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3.7.4. 
End of Study 
The End-of-Study date for each participant is defined as the last date of contact with the 
participant, or the last date an attempt was made to contact the participant, recorded on the 
follow-up CRF page. Typically, the End-of-Study date will be the date of the 24 month 
follow up visit. 
 
3.8. 
Withdrawal Criteria, and Procedures 
All participants have the right to withdraw from the study at any time, for any reason, 
without prejudice.  The investigator may discontinue any participant’s participation when in 
the investigator’s judgment it is necessary for any reason.  This can include the failure of a 
participant to comply with the protocol or when the investigator considers withdrawal is in 
the best interest of the participant. 
 
When a participant is withdrawn from participation in the study, or if the study is terminated 
prematurely, the investigator will collect all data from previous study visits at the last 
scheduled visit, or will request that the participant return for a follow-up visit.  All 
measurements will be recorded in the source documents and on the electronic clinical report 
form. 
 
When a participant decides to withdraw study consent, an investigator at the site will attempt 
to contact the participant and determine the reason that led the participant to the decision.  
When known, the reasons for withdrawal shall be fully evaluated and recorded appropriately 
in source documents and the eCRF. 
 
If the study sponsor, the Foundation Fighting Blindness Clinical Research Institute (FFB 
CRI), discontinues the study for any reason, such reasons will be thoroughly documented in 
the source documents and eCRFs, and all local study site IRB’s and HRPO will be notified 
immediately. 
 
3.9. 
Screen Failures 
A screen failure participant candidate is a study candidate who has provided written informed 
consent for participation but who is not entered into the study. 
 
3.10. 
Definition of Completed 
The study period is defined as the time period during which participants are evaluated for the 
primary and secondary objectives of the study. Participants who complete all follow-up 
studies and are evaluated at the last scheduled visit of their study period will be defined as 
having completed the study. 
 

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3.11. 
Definition of Lost to Follow-up 
Study participants who miss a follow-up study visit and cannot be contacted after multiple 
contacts at different times of day during a period of 10 days, and who do not have a known 
reason for discontinuation (e.g., withdrew consent) will be classified as “lost to follow-up”. 
 
3.12. 
Participant Compliance 
Not applicable. 
 
3.13. 
Protocol Deviations 
This study shall be conducted according to this written protocol except in the case of an 
emergency where immediate intervention based on the judgment of the investigator (or a 
responsible, appropriately trained professional designated by the investigator) is essential for 
the protection, safety, and well-being of the participant. In the event of a significant deviation 
from the protocol as a result of an emergency, accident, or mistake, the investigator or 
designee must contact the Study Director, as soon as possible, by telephone.  A joint decision 
will then be made regarding the participant’s continuation in the study and the decision 
documented by the investigator and the Study Director and reviewed by the monitor.  In 
addition, the investigator must notify the IRB to the extent necessary under GCP and local 
requirements. The sponsor, the Foundation Fighting Blindness Clinical Research Institute 
shall be notified of any protocol deviations and shall forward a detailed report any serious 
deviations to HRPO immediately. Any non-serious deviations shall be reported to HRPO as 
part of the annual study progress report. 
 
3.14. 
Protocol Modifications 
No changes shall be made to this protocol by site principal investigators or any other site 
staff without prior written consent and approval from the Study Director, the Sponsor [the 
Foundation Fighting Blindness Clinical Research Institute (FFB CRI)], their respective IRBs, 
and HRPO. Amendments shall be submitted to the IRBs for review and approval prior to 
implementation. Any permanent change to the protocol, whether an overall change or a study 
center specific change(s), must be treated as a protocol amendment. Any amendment to the 
protocol that is deemed necessary as the study progresses will be fully discussed by the 
investigator(s). Except for administrative amendments, investigators must await IRB 
approval of protocol amendments before implementing the change(s). Administrative 
amendments are defined as amendments that do not affect the safety of the research 
participants, the scope of the investigation, or the quality of the trial. However, if a protocol 
amendment is required to eliminate an apparent and immediate hazard to participants, the 
amendment should be implemented immediately, and the IRB notified within 5 days.  
 
Any deviation to the protocol that may have an effect on the safety or rights of the participant 
or the integrity of the study must be reported to the local IRBs and to the USAMRMC ORP 

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HRPO as soon as the deviation is identified. Any corrective actions taken to avoid future 
deviations shall be included in the report. 
 
All unanticipated problems involving risk to participants or others related to participation in 
the study should be promptly reported by phone (301-619-2165), by email 
(hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office of 
Research Protections, Human Research Protection Office.  A complete written report will 
follow the initial notification.  In addition to the methods above, the complete report will be 
sent to the U.S. Army Medical Research and Materiel Command, ATTN: MCMR-ZB-PH, 
504 Scott Street, Fort Detrick, Maryland 21702-5012. 
 
When, in the judgment of the chair of the local IRB and the investigators, the amendment to 
the protocol substantially alters the study design and/or increases the potential risk to the 
participant, the current approved written informed consent form shall be revised and if 
applicable, the participants shall be asked to sign a new written informed consent. 
 
Major modifications to the research protocol and any modifications that could potentially 
increase risk to participants will be submitted by the Sponsor to the USAMRMC ORP HRPO 
for approval prior to implementation. All other amendments will be submitted by the Sponsor 
with the continuing review report to the USAMRMC ORP HRPO for acceptance.  
 
4. 
Study Personnel 
4.1. 
Roles and Responsibilities of Key Study Personnel 
Hendrik P.N. Scholl, M.D., M.A, is the Study Director and the Principal Investigator at the 
Wilmer Eye Institute site. His responsibilities include: the overall study design; coordination 
and execution of the study; analysis of the data; review of any protocol deviations; and 
dissemination of the study findings. Dr. Scholl will also submit the study protocol to the local 
IRB, obtain informed consent and be responsible for: obtaining the medical history of 
participants; performing scheduled ophthalmic study visits; documenting the clinical visits; 
resolving any data concerns; and overall oversight of the protocol at the Wilmer Eye Institute 
site. 
 
Janet Sunness, M.D. is the site Principal Investigator at the Greater Baltimore Medical Center 
site. She will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; performing scheduled 
ophthalmic study visits; documenting the clinical visits; resolving any data concerns; and 
overall oversight of the protocol at Greater Baltimore Medical Center. 
 
Artur Cideciyan, Ph.D. is the site Principal Investigator at the Hospital University of 
Pennsylvania, Scheie Eye Institute. He will submit the study protocol to the local IRB, obtain 
informed and be responsible for: obtaining the medical history of participants; performing 

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scheduled ophthalmic study visits; documenting the clinical visits; resolving any data 
concerns; and overall oversight of the protocol at Scheie Eye Institute. 
 
Elias Traboulsi, M.D. is the site Principal Investigator at Cleveland Clinic's Cole Eye 
Institute. He will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; performing scheduled 
ophthalmic study visits; documenting the clinical visits; resolving any data concerns; and 
overall oversight of the protocol at Cleveland Clinic's Cole Eye Institute. 
 
José-Alain Sahel, M.D. is the site Principal Investigator at the Centre de Recherche Institut 
de la Vision Paris. He will submit the study protocol to the local IRB, obtain informed 
consent and be responsible for: obtaining the medical history of participants; performing 
scheduled ophthalmic study visits; documenting the clinical visits; resolving any data 
concerns; and overall oversight of the protocol at the Centre de Recherche Institut de la 
Vision, Paris. 
 
Eberhart Zrenner, M.D. is the site Principal Investigator at the University Eye Hospital 
Tübingen. He will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; performing scheduled 
ophthalmic study visits; documenting the clinical visits; resolving any data concerns; and 
overall oversight of the protocol at University Eye Hospital Tübingen. 
 
Michel Michaelides, M.D., F.R.C.Ophth. is the site Principal Investigator at the Moorfields 
Eye Hospital NHS Foundation Trust. He or designated members of the research team will: 
submit the study protocol to the local IRB and obtain informed consent; be responsible for 
obtaining the medical history of participants, performing scheduled ophthalmic study visits, 
documenting the clinical visits and resolving any data concerns. He will have overall 
oversight of the protocol at Moorfields Eye Hospital NHS Foundation Trust. 
 
Paul S. Bernstein, MD, PhD is the site Principal Investigator at the University of Utah, 
School of Medicine, Moran Eye Center. He will submit the study protocol to the local IRB, 
obtain informed consent and be responsible for: obtaining the medical history of participants; 
performing scheduled ophthalmic study visits; documenting the clinical visits; resolving any 
data concerns; and overall oversight of the protocol at the University of Utah. 
 
David G. Birch, PhD is the site Principal Investigator at the Retina Foundation of the 
Southwest. He will submit the study protocol to the local IRB, obtain informed consent and 
be responsible for: obtaining the medical history of participants; performing scheduled 
ophthalmic study visits; documenting the clinical visits; resolving any data concerns; and 
overall oversight of the protocol at the Retina Foundation of the Southwest. 
 
Sheila West, Ph.D., is Director of the Dana Center for Preventive Ophthalmology at the 

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Wilmer Eye Institute. She will lead the data management coordinating center activities 
associated with this study and be responsible for study site monitoring, data collection and 
management, and statistical analysis of the study data. 
 
Srinivas R. Sadda, M.D. is Associate Professor of Ophthalmology and Director of the 
Doheny Image Reading Center at the Keck School of Medicine, University of Southern 
California. He will lead the image collection and reading, and imaging analysis of the study 
data arising from retinal imaging and microperimetry. 
 
4.2. 
Conflict of Interest 
As this protocol does not support the development of a drug, device, or other intellectual 
property, there is no immediate concern about conflict of interest.  If any concerns arise, 
conflict of interest statements will be obtained on a case-by-case basis. 
 
5. Prohibited Medications 
Study participants may use any systemic medications that are necessary.  However, study 
participants shall not participate in, or take concomitant therapy, to treat Stargardt disease.  
Study candidates who have previously participated in an interventional study for Stargardt 
disease are also excluded – see study exclusion criteria. 
 
6. Evaluation of Adverse Events 
Not applicable. 
7. Statistical Analysis 
7.1. 
Sample Size and Power 
Prior to establishing this study protocol, a feasibility survey was undertaken. The survey 
consisted of a questionnaire that was sent to the participating centers to determine how many 
study candidates might be available at each center for this prospective study. 
 
The primary outcome of the study is the yearly growth in the area of the atrophic lesion as 
measured by fundus auto-fluorescence.  A recent paper by Chen et al [34] reported that in a 
group of 24 STGD participants with well defined atrophic lesions at baseline, the mean 
yearly growth of the lesion was 0.94 mm2 ± 0.87.  
 
The reliability of measuring areas of geographic atrophy using images taken with a confocal 
scanning laser ophthalmoscopy has been described by Deckert et al [35]. Using 2 different 
readers to examine images from 34 eyes, the mean difference in area affected for the 
proposed quantification algorithm was 0.12mm2 with a 95% confidence interval (0.02, 0.22). 
 

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Using the above parameters as a reference, we calculated the power to detect yearly 
progression for sample sizes between 120 and 240 participants, with standard deviations 
between 0.9 and 1.1, and expected progression rates of 0.40 and 0.50 mm2 per year (Figure 
5).  A clinically meaningful progression rate should be greater than the variability of the 
measurement.  The power calculations were set to test for progression rates above 0.2 mm2 
which is the estimate of the upper bound of the difference that could be attributable solely to 
measurement error.   
(a)
Expected progression rate
0.40mm2 per year
(b)
Expected progression rate
0.50 mm2 per year
*Assuming  that test retest differences could be as high as 0.2 
Power to detect progression rates for a range of sample sizes and standard deviations 
with a two-sided significance level α=0.05*
0.9
1.0
1.1
Power
Std Dev
Sample size
0.4
0.6
0.8
1.0
100
150
200
250
0.9
1.0
1.1
Power
Std Dev
Sample size
0.4
0.6
0.8
1.0
100
150
200
250
 
Figure 5: Power calculations for expected progressions rates of 0.40 and 0.50 mm2 per year 
 
A sample size of 170 achieves 80% power to detect a difference of 0.2 between the null 
hypothesis mean of 0.2 mm2 (measurement error) and the alternative hypothesis mean 
progression of the lesion of 0.4 mm2 with an estimated standard deviation of 0.9 and a 
significance level α= 0.05 using a two-sided Wilcoxon test (Figure 5 (a)). Similarly, if the 
expected standard deviation increases to 1.0 we need 200 participants to achieve the same 
level of power.  When the expected progression rate is ≥0.50 mm2, a sample size of 120 
participants achieves more than 80% to detect differences beyond the expected measurement 
error, for standard deviations ≤1.1 (Figure 5 (b)).  
 
7.2. 
Statistical Analyses 
Estimating the yearly growth in the area of the atrophic lesion as measured by fundus 
auto-fluorescence: 
 
First exploratory analysis looking at the baseline, six, and twelve months overall distribution 
of the outcome will be performed, outliers and inconsistent measures will be identified and 
reviewed. Let Yiv represent the area (or a transformation to achieve normality; e.g. square 

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41 
root) of the ith individual at visit v for v=0, 1, 2, 3, 4 for the baseline, 6 months, 12 months, 18 
months and 24 months visits, respectively. In order to determine the average rate of 
progression in the population, an appropriate approach will be to allow for each individual to 
have his/her own intercept and slope and to average them to achieve the overall rate of 
decline. This is accomplished with a random coefficients regression model of the form:  
Yiv=(µ+ai)+(Δ+bi)v+γZiv+ eiv; where ai~N(0,σ1
2), bi~N(0,σ2
2), cov(ai,bi)= σ 12 and 
eiv~N(0,σ2). 
 
The ai and bi are the random departures of the line for the ith individual from the population 
line with intercept µ and slope Δ. The eiv are the within individual departures from the line of 
the repeated measurements taken on the ith individual at times 0, 6,12, 18 and 24 months.  Ziv 
represents a vector of factors that could to be related to progression such as age and use of 
vitamin A supplementation. 
 
The estimate of Δ and its standard error will provide the six month progression of the lesions. 
In addition, to explore whether progression may be different for different initial levels, we 
will carry out the analysis in strata of baseline severity. 
 
A similar approach to will be used to examine progression overtime for the secondary 
outcomes: retinal thinning, loss of photoreceptors, loss of retinal sensitivity, and changes of 
BCVA. 
 
7.3. 
Baseline Demographic Characteristics 
Baseline demographic characteristics are: date of birth, age, sex, and race. Randomization is 
not applicable. 
 

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7.4. 
Data Set Descriptions 
Study Population  
Patients with STGD enrolled into the study shall have had previous genetic testing and a 
finding of at least 2 pathogenic mutations in the ABCA4 gene. If only one ABCA4 allele 
containing a pathogenic mutation is detected, a patient may be enrolled if they have a typical 
Stargardt phenotype, i.e. at least one eye must have flecks at the level of the retinal pigment 
epithelium typical of STGD. 
 
Data Sets for Endpoint Analyses 
The final data set will include all participant visits. Most of the participants will complete 5 
visits. Participants lost to follow-up after the six month visit shall be included but will only 
partially contribute to the estimation of the progression rates. 
 
7.5. 
Handling of Missing Data 
The random effects methods described in section 7.2 do not require all individuals to have all 
the five visits. Individuals who are lost to follow up will partially contribute to the analysis 
and will be appropriately weighted by the maximum likelihood approach. To rule out 
informative censoring (i.e., fast progressors having less visits with available data) we will 
perform sensitivity analysis restricting to those with complete data. Were it to be necessary, 
we will explore multiple imputation methods to complete the trajectories shorter than two 
years. 
 
7.6. 
Safety Analyses 
This is an observational study of the natural course of STGD. All investigations included are 
part of standard of clinical care for patients affected by STGD. Therefore, no study-specific 
safety events are anticipated. 
 
7.7. 
Study Drug Compliance 
Not applicable  
 
7.8. 
Interim Analysis 
An interim analysis of the study data is planned after all participants have completed their 12 
month visit. 
 
8. Study Product Management 
Not applicable 
 

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9. Data Handling and Records Management 
Any questions about the protocol or eCRFs will be referred to the sponsor or its 
representatives, by the Dana Center. 
 
9.1. 
Data Collection 
Study Forms 
Most patient data are collected on paper and kept at each individual clinic center. Therefore, 
in this study, paper copies of the study forms shall be created from an electronic clinical 
report form (eCRF) that was developed specifically for the study using REDCap software 
(Appendix 4, Data Collection forms). Once the paper study forms have been completed with 
patient data, the clinical investigator shall review the data for accuracy and sign their 
signature to approve the forms.  
 
Once the data are approved by the investigator, the clinic coordinator will log into REDCap 
using a unique user id and password. When entering a new study participant, the coordinator 
must first fill out the eligibility form that assigns a unique ID to the participant. If the clinic 
coordinator is entering data for a participant already enrolled in the study, the coordinator 
must first enter the participant’s ID, and then select the appropriate form.  Data are 
subsequently entered into the forms using 100% double data entry.  
 
The programs developed in REDCap contain a series of data checks within each form to 
check that: 
a) All entries are within the allowed range. 
b) There is internal consistency (i.e., skip patterns) within each form. 
c) Duplicate entries do not occur. 
d) All required fields are entered; if not, the record is flagged as incomplete. 
e) Double data entry is completed after the first entry to ensure the integrity of the data. 
f) Any reports created indicate any missing or incomplete records. 
g)  Reports are issued to help the Clinic Coordinator manage upcoming appointments, 
and follow-up with missed appointments. 
h) All data entries and changes are logged in an electronic audit trail that tracks who 
made the change, on what date and time the change was made, and the field name(s) 
and value(s) of the change. The system also logs any changes made to the structure of 
the forms by the DCPO DCC. 
 
There are two methods planned in order to transfer imaging data to the Central Reading 
Center. This is described in detail in a separate standard operating procedure. Generally, 
imaging data are not compressed.  
Option 1: The Reading Center has its own secure servers where images are to be downloaded 
directly from the clinic centers  
Option 2: Create a CD-DVD to be mailed to the reading center 
 

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During each participant’s visit to the clinic, a study clinician will record progress notes to 
document all significant observations.  At a minimum, these notes will contain: 
• Documentation of the informed consent process, including any revised consents 
• The date of the visit and the corresponding Visit, Day, or Week in the study schedule 
• Any comments made by the participant about the study, including any significant 
medical findings 
• A general reference to the procedures completed 
• A dated signature, or initials, of all clinicians who made an entry in the progress 
notes. 
 
In addition, any contact with the participant via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as described 
above. 
 
Information from the study progress notes and other source documents will be promptly and 
legibly transcribed to eCRFs for transmission to the data management center. 
 
Any changes to information in the study progress notes, other source documents, and CRFs 
will be initialed and dated on the day the change is made by a site study staff member 
authorized to make the change.  Changes will be made by striking a single line through 
erroneous data, and clearly entering the correct data (e.g., wrong data right data).  If the 
reason for the change is not apparent, a brief explanation for the change shall be written in 
the source documentation by the clinician.  Correction fluid shall not be used at any time. 
 
9.1.1. Volunteer Identification 
Each center shall de-identify patient data. Patient data shall be encoded by a five-digit code 
number: the first two numbers shall indicate the number of the study center and the last three 
numbers shall label the patients in an ascending ordinal scale (for example, following 
patient’s enrollment on the study). Data shall be collected using electronic clinical report 
form (e-CRF) and shall be centrally managed at the Dana Center for Preventive 
Ophthalmology. 
 
9.1.2. Confidentiality 
The data collected during the study are part of standard clinical care. Charts shall be secured 
to protect privacy of patients and maintain confidentiality. Clinical data shall be entered on 
electronic Case Report Forms (eCRFs) for transmission to the coordinating center in 
accordance with the procedures specified in the current Manual of Standard Operating 
Procedures (SOPs) for this trial. Data on eCRFs transmitted to the coordinating center shall 
correspond to, and be supported by, source documentation maintained at the site. All study 
forms and records transmitted to the coordinating center shall carry only coded identifiers 
such that personal identifying information is not transmitted to the coordinating center. 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
45 
 
The Johns Hopkins Biostatistics Center (JHBC) servers that host the data are protected by 
both a hardware firewall and a web application firewall. In addition, they have multi-level 
intrusion detection, network security audits, and secondary hardware on standby for 
immediate replacement. JHBC administrators connect to the REDCap servers for system 
administration using a VPN connection and a two-factor authentication method. All data 
transmitted between the client browser and REDCap web servers are encrypted using an SSL 
connection. JHBC system administrators regularly monitor server logs and services to ensure 
that the servers are secured. They also ensure that server updates are applied in a timely 
manner and that the data are regularly backed up and stored securely off-site. 
 
Ophthalmic outcome data from the microperimetry, sd-OCT and fundus autofluorescence 
assessments will be submitted electronically from the site to the Reading Center via secure 
data upload. 
 
Once processed and analyzed by the Reading Center, the data will be transferred 
electronically from the Reading Center to the Dana Center system via a secure transfer 
process. Only coded identifiers will be used to identify participants.  
 
9.1.3. Access 
At each site, the site investigator and the personnel designated by him shall have access to 
source documents. De-identified data shall be collected at the Data Coordinating Center at 
Johns Hopkins. All site investigators, their designated personnel, study staff at Johns 
Hopkins University and study staff at the reading center shall have access to the database of 
de-identified data.  
 
Representatives of the USAMRMC and FFB CRI have the authority to review research 
records. 
 
9.1.4. Reporting Requirements 
The investigators of each site shall take care to meet the requirements for reporting sensitive 
information to state or local authorities. For example the investigators might seek guidance 
from their institutional review boards when considering how to report information such as 
positive human immunodeficiency virus (HIV) status, hepatitis or tuberculosis test results, 
illegal residency, child or spouse abuse, or participation in other illegal activities. 
 
9.2. 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents shall include, but are not limited to, progress notes, 
electronic data, screening logs, study worksheets, and data recorded from automated 
instruments.  All source documents pertaining to this study shall be maintained by the 
investigators and made available for inspection by authorized persons. 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
46 
 
9.3. 
File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the ICH GCP Guideline. 
 
9.4. 
Records Retention at the Study Site 
The investigator shall take responsibility for maintaining adequate and accurate electronic or 
hard copy source documents of all observations and data generated during this study, 
including any data quality queries received from the data management center.  Such 
documentation is participant to inspection by FFB CRI and relevant agencies, such as 
USAMRMC.  If the investigator withdraws from the study, all study related records shall be 
transferred to a mutually agreed upon designee.  Notice of such transfer will be given to FFB 
CRI in writing.  
 
The investigator shall not dispose of any records relevant to this without written permission 
from FFB CRI and providing FFB CRI the opportunity to collect such records. Generally, 
records are kept for a minimum of ten years 
 
9.5. 
Data Management Considerations 
Data will be stored in the REDCap system (section 9.1).  
 
Every effort shall be made to ensure that data management practices adhere to international 
standardization of the following data management procedures.   
 
9.5.1. Database Design and Creation 
An appropriate database shall be designed and created within a validated Clinical Data 
Management System (CDMS). This database shall be designed to store the data recorded on 
the CRFs and shall ensure a one-to-one mapping between the CRF and the electronic copy 
stored in the system (section 9.1). 
 
9.5.2. Data Coding 
Upon completion of CRF data entry, a secondary, in-house clinical review shall be 
conducted. Adverse event coding shall be undertaken using the current version of the 
MedDRA dictionary (version 12.1). The version of this dictionary will remain the same 
throughout the study. 
 
9.5.3. Data Transfer 
Data shall be transferred to the Dana Center of Preventive Ophthalmology, Wilmer Eye 
Institute of the Johns Hopkins University, Baltimore, Maryland.  The transfer shall be 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
47 
electronic and shall happen on a defined schedule, in a data format mutually agreed upon by 
the Dana Center of Preventive Ophthalmology (study central data management center). 
 
9.5.4. Data Validation 
After the data have been entered and verified, various edit checks shall be performed to 
ensure the accuracy, integrity and validation of the database against the CRFs. 
Inconsistencies that arise from these edit checks shall be resolved with the investigator or 
designee. 
 
9.5.5. Database Lock 
Upon completion of the trial and completion of data entry, verification and validation, the 
database shall be locked and write access removed. 
 
10. Quality Control and Quality Assurance  
10.1. Monitoring 
The Data Coordinating Center shall undertake on-site monitoring of study data for the 
duration of the study. These clinical site monitoring visits shall be conducted regularly during 
the two-year study conduct phase. The anticipated monitoring visit schedule for each site will 
be based on the time of the enrollment of the first study participant at the site and includes: 
one evaluation/initiation visit prior to the start of study procedures, one visit 3 months 
following enrollment of the first participant at the site or when at least 5 participants have 
been enrolled, and a second visit at 14 months or when the first five participants have 
completed their first annual follow-up visit. Other clinical site monitoring visits shall be 
conducted on an as-needed basis.  It is anticipated that remote data monitoring of randomly 
determined data points will be completed by the Data Coordinating Center. 
 
The Data Coordinating Center may also conduct study site visits, on the sponsor’s behalf.  
The study shall be monitored in compliance with the relevant parts of 45 CFR and according 
to the ICH GCP Guidelines. Site visits shall include, but are not limited to, verifying the 
presence of required documents, verifying the informed consent process, and comparing case 
report forms with source documents. Each investigator agrees to participate in site visits 
conducted at a reasonable time in a reasonable manner. Regulatory authorities may also audit 
the investigator during or after the study.  If a regulatory authority announces an audit, the 
investigator should contact the sponsor immediately, and must fully cooperate with these 
audits within a reasonable time in a reasonable manner. 
 
The knowledge of any pending compliance inspection or visit by the DHHS-OHRP, or other 
government agency concerning clinical investigation or research, the issuance of Inspection 
Reports, warning letters or actions taken by any Regulatory Agencies including legal or 
medical actions and any instances of serious or continuing noncompliance with the 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
48 
regulations or requirements shall be reported immediately to the Study Director, FFB CRI, 
and USAMRMC ORP HRPO.  
 
FFB CRI has ethical, legal, and scientific obligations to carefully follow this study in a 
detailed and orderly manner in accordance with established research and GCP principles.  As 
part of a concerted effort to fulfill these obligations, FFB CRI’s or its designee’s monitors 
shall visit the center during the study in addition to maintaining frequent telephone and 
written communications. 
 
10.2. Auditing 
FFB CRI may conduct audits at the study site(s).  Audits shall include, but are not limited to, 
verifying the presence of required documents, verifying the informed consent process, and 
comparing the case report forms with source documents.  The investigator agrees to 
participate with such audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study.  If 
a regulatory authority announces an audit, the investigator should contact FFB CRI 
immediately, and must fully cooperate with the audits within a reasonable time in a 
reasonable manner. 
 
11. Ethics and Responsibility 
This study shall be conducted in compliance with this study protocol, the ICH GCP 
Guidelines, the applicable regulatory requirements, and the current Declaration of Helsinki. 
 
11.1. Clinical Study Report 
A yearly continuing review report shall be submitted to the local IRB(s) by each of the 
clinical sites, if required by the host country.  A copy of this report and IRB approval 
notification shall be submitted to the HRPO and WIRB by the Sponsor as soon as these 
documents become available. In host countries that do not require an annual IRB report, the 
site will prepare and submit an annual report summary to the Sponsor to submit to WIRB and 
HRPO, per HRPO guidelines.  A copy of the approved final study report and the central IRB 
approval notification shall also be submitted to the HRPO by the Sponsor as soon as 
available. 
 
The report shall include a discussion of the study objectives, methodology, clinical 
observations and conclusions in relation to the study objectives. 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
49 
12. Confidentiality 
All information generated in this study shall be considered highly confidential and shall not 
be disclosed to any persons not directly concerned with the study without written prior 
permission from FFB CRI.  However, authorized HRPO representatives, regulatory officials, 
and FFB CRI personnel (or their representatives) shall be allowed full access to inspect and 
copy the records.  All participants’ materials collected shall be used solely in accordance 
with this protocol, unless otherwise agreed to in writing by FFB CRI. Participants shall be 
identified only by their unique participant numbers in CRFs. However, their full names may 
be made known to a regulatory agency or other authorized officials, if necessary. 
Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command. These 
representatives are authorized to review research records as part of their responsibility to 
protect human research volunteers. Research records will be stored in a confidential manner 
so as to protect the confidentiality of participant information. 
 
13. Amendment Policy 
The investigator shall not make any changes to this protocol without prior written consent 
from FFB CRI and subsequent approval by the IRB.  Any permanent change to the protocol, 
whether it is an overall change or a change for specific study center(s), shall be handled as a 
protocol amendment.  Any amendment to the protocol that appears indicated as the study 
progresses shall be fully discussed between the investigator(s), the study director and FFB 
CRI.  If agreement is reached regarding the need for an amendment, it shall be written by 
FFB CRI.  The written amendment shall be submitted to the study central IRB identified with 
this responsibility (WIRB); upon approval by WIRB, each of the clinical sites will submit the 
amendment to their local IRB for review and approval.  Except for ‘administrative 
amendments’, investigators shall await IRB approval of protocol amendments before 
implementing any change(s).  Administrative amendments are defined as amendments that 
have no effect on the safety of the research participants, the scope of the investigation, or 
quality of the trial. However, a protocol change intended to eliminate an apparent immediate 
hazard to participants should be implemented immediately, and the IRB notified within 5 
days.  FFB CRI shall submit protocol amendments to the HRPO or other regulatory agencies, 
as required. 
 
When, in the judgment of the chairman of the local IRB, the investigators, the study director 
and/or FFB CRI, the amendment to the protocol substantially alters the study design and/or 
increases the potential risk to the participant, the currently approved written informed 
consent form shall require similar modification.  In such cases, a new informed consent shall 
be obtained from participants enrolled in the study before expecting continued participation. 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
50 
 
14. References 
 
1. Stargardt, K., Ueber familiaere, progressive Degeneration in der Makulagegend des 
Auges. Graefes Arch Clin Exp Ophthalmol, 1909. 71: p. 534-549. 
2. Allikmets, R., et al., A photoreceptor cell-specific ATP-binding transporter gene (ABCR) 
is mutated in recessive Stargardt macular dystrophy. Nat Genet, 1997. 15(3): p. 236-46. 
3. Zhang, K., et al., A 5-bp deletion in ELOVL4 is associated with two related forms of 
autosomal dominant macular dystrophy. Nat Genet, 2001. 27(1): p. 89-93. 
4. Walia, S. and G.A. Fishman, Natural history of phenotypic changes in Stargardt macular 
dystrophy. Ophthalmic Genet, 2009. 30(2): p. 63-8. 
5. Walia, S., G.A. Fishman, and R. Kapur, Flecked-retina syndromes. Ophthalmic Genet, 
2009. 30(2): p. 69-75. 
6. Riviero-Alvarez, R., et al., Frequency of ABCA4 mutations in 278 Spanish controls: an 
insight into the prevalence of autosomal recessive Stargardt's disease. Br J Ophthalmol, 
2009. 93(10): p. 1359-64. 
7. Fishman, G.A., et al., Visual acuity loss in patients with Stargardt's macular dystrophy. 
Ophthalmology, 1987. 94(7): p. 809-14. 
8. Kennedy, C.J., P.E. Rakoczy, and I.J. Constable, Lipofuscin of the retinal pigment 
epithelium: a review. Eye (Lond), 1995. 9 ( Pt 6): p. 763-71. 
9. Delori, F.C., et al., In vivo fluorescence of the ocular fundus exhibits retinal pigment 
epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci, 1995. 36(3): p. 718-29. 
10. Cideciyan, A.V., et al., Reduced-illuminance autofluorescence imaging in ABCA4-
associated retinal degenerations. J Opt Soc Am A Opt Image Sci Vis, 2007. 24(5): p. 
1457-67. 
11. Holz, F.G., et al., Inhibition of lysosomal degradative functions in RPE cells by a retinoid 
component of lipofuscin. Invest Ophthalmol Vis Sci, 1999. 40(3): p. 737-43. 
12. Cideciyan, A.V., et al., ABCA4-associated retinal degenerations spare structure and 
function of the human parapapillary retina. Invest Ophthalmol Vis Sci, 2005. 46(12): p. 
4739-46. 
13. Katz, R., Biomarkers and surrogate markers: an FDA perspective. NeuroRx, 2004. 1(2): 
p. 189-95. 
14. Gomes, N.L., et al., A comparison of fundus autofluorescence and retinal structure in 
patients with Stargardt disease. Invest Ophthalmol Vis Sci, 2009. 50(8): p. 3953-9. 
15. Davies, S., et al., Photocytotoxicity of lipofuscin in human retinal pigment epithelial 
cells. Free Radic Biol Med, 2001. 31(2): p. 256-65. 
16. Boulton, M., et al., The photoreactivity of ocular lipofuscin. Photochem Photobiol Sci, 
2004. 3(8): p. 759-64. 
17. Sparrow, J.R. and M. Boulton, RPE lipofuscin and its role in retinal pathobiology. Exp 
Eye Res, 2005. 80(5): p. 595-606. 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
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18. Bok, D., G.S. Hageman, and R.H. Steinberg, Repair and replacement to restore sight. 
Report from the Panel on Photoreceptor/Retinal Pigment Epithelium. Arch Ophthalmol, 
1993. 111(4): p. 463-71. 
19. Parish, C.A., et al., Isolation and one-step preparation of A2E and iso-A2E, fluorophores 
from human retinal pigment epithelium. Proc Natl Acad Sci U S A, 1998. 95(25): p. 
14609-13. 
20. Molday, R.S. and L.L. Molday, Identification and characterization of multiple forms of 
rhodopsin and minor proteins in frog and bovine rod outer segment disc membranes. 
Electrophoresis, lectin labeling, and proteolysis studies. J Biol Chem, 1979. 254(11): p. 
4653-60. 
21. Sun, H. and J. Nathans, ABCR: rod photoreceptor-specific ABC transporter responsible 
for Stargardt disease. Methods Enzymol, 2000. 315: p. 879-97. 
22. Saari, J.C., et al., Reduction of all-trans-retinal limits regeneration of visual pigment in 
mice. Vision Res, 1998. 38(10): p. 1325-33. 
23. Ben-Shabat, S., et al., Biosynthetic studies of A2E, a major fluorophore of retinal 
pigment epithelial lipofuscin. J Biol Chem, 2002. 277(9): p. 7183-90. 
24. Mata, N.L., J. Weng, and G.H. Travis, Biosynthesis of a major lipofuscin fluorophore in 
mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl 
Acad Sci U S A, 2000. 97(13): p. 7154-9. 
25. Lewis, R.A. and J.R. Lupski, Macular degeneration: the emerging genetics. Hosp Pract 
(Minneap), 2000. 35(6): p. 41-50, 56-8. 
26. Ma, L., et al., C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological 
retinal degeneration in a mouse model of Stargardt disease. J Biol Chem, 2011. 286(10): 
p. 7966-74. 
27. Kaufman, Y., L. Ma, and I. Washington, Deuterium enrichment of vitamin A at the C20 
position slows the formation of detrimental vitamin A dimers in wild-type rodents. J Biol 
Chem, 2011. 286(10): p. 7958-65. 
28. Rotenstreich, Y., G.A. Fishman, and R.J. Anderson, Visual acuity loss and clinical 
observations in a large series of patients with Stargardt disease. Ophthalmology, 2003. 
110(6): p. 1151-8. 
29. Prokofyeva, E., et al., An epidemiological approach for the estimation of disease onset in 
Central Europe in central and peripheral monogenic retinal dystrophies. Graefes Arch 
Clin Exp Ophthalmol, 2009. 247(7): p. 885-94. 
30. Westeneng-van Haaften, S.C., et al., Clinical and Genetic Characteristics of Late-onset 
Stargardt's Disease. Ophthalmology, 2012. 119(6): p. 1199-210. 
31. Burke, T.R., et al., Familial discordance in Stargardt disease. Mol Vis, 2012. 18: p. 227-
33. 
32. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy 
Study report number 1. Early Treatment Diabetic Retinopathy Study research group. 
Arch Ophthalmol, 1985. 103(12): p. 1796-806. 
33. Marmor, M.F., et al., ISCEV Standard for full-field clinical electroretinography (2008 
update). Doc Ophthalmol, 2009. 118(1): p. 69-77. 
34. Chen, B., et al., Analysis of autofluorescent retinal images and measurement of atrophic 
lesion growth in Stargardt disease. Exp Eye Res, 2010. 91(2): p. 143-52. 

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35. Deckert, A., et al., Automated analysis of digital fundus autofluorescence images of 
geographic atrophy in advanced age-related macular degeneration using confocal 
scanning laser ophthalmoscopy (cSLO). BMC Ophthalmol, 2005. 5: p. 8. 
 

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Appendix 1 - Agreement 
Agreement Signatures 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, and 
scientific information necessary to conduct this study. I shall personally conduct the study as 
described herein and in FFB CRI’s Clinical Research Agreement. 
 
I shall provide copies of the protocol to all physicians, nurses, and other professional 
personnel responsible to me who participate in the study.  I shall discuss the protocol with 
them to assure myself that they are sufficiently informed about the endpoint parameters and 
the conduct of the study in general to perform the study correctly. I am aware that this 
protocol must be approved by the local IRB responsible for my Clinical Study Facility and 
that IRB approval is required prior to commencement of this study. I agree to adhere strictly 
to the attached protocol unless it is amended in the manner set forth in Paragraph 1 of FFB 
CRI’s Clinical Research Agreement.  In that case, I agree to adhere strictly to the amended 
protocol. I agree that clinical data entered on case report forms by me and my staff shall be 
used by FFB CRI in various ways, such as for submission to governmental regulatory 
authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable.  I agree to allow monitors and auditors, or their designees, full access to 
all medical records at the research facility for participants screened or enrolled in the study. 
 
I agree to provide all participants with informed consent forms, as required by government 
and ICH regulations.  I agree to report to FFB CRI any adverse experiences in accordance 
with the terms of FFB CRI, or designee’s, Clinical Research Agreement and FDA 
regulations, 45 CFR 312.64.  I further agree to provide all required information regarding 
financial certification or disclosure to FFB CRI for all investigators and sub-investigators in 
accordance with the terms of FDA regulation 45 CFR 54.  I understand that participation in 
the protocol involves a commitment to publish the data from this study in a cooperative 
publication prior to publication of efficacy and safety results on an individual basis. 
 
 
 
 
Signature 
 
 
Date 
Site Principal Investigator 
 
Signature 
 
 
Date 
Hendrik P.N. Scholl, M.D., M.A. 
Study Director 
 
 
 
Signature 
 
 
Date 
Sheila West, Ph.D. 
Study Biostatistician 
 
Signature 
 
 
Date 
Patricia Zilliox, Ph.D., Pharm.D. 
Sponsor Representative 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
11 March 2013 
 
54 
Appendix 2 – Additional Institutions and Personnel Involved With the 
Study 
Sponsor: 
Foundation Fighting Blindness Clinical Research Institute 
Patricia Zilliox, Ph.D.  
Project Officer 
7168 Columbia Gateway Drive 
Suite 100 
Columbia, MD 21046  
Phone: +1 (410) 423-0581 
email: pzilliox@fightblindness.org 
Fax: +1 (410) 872-0574 
FWA: 00014475 
 
Judith Chiostri, M.S. 
Project Manager 
7168 Columbia Gateway Drive 
Suite 100 
Columbia, MD 21046  
Phone: +1 (410) 423-0582 
email: jchiostri@fightblindness.org 
Fax: +1 (410) 872-0574 
 
Expert Advisor: 
The Chicago Lighthouse for People Who are Blind or Visually Impaired 
Gerald Fishman, M.D. 
The Chicago Lighthouse for People Who are Blind or Visually Impaired 
1850 W. Roosevelt Road 
Chicago, IL 60608 
Phone: +1 (312) 666-1331 
e-mail: Gerald.Fishman@chicagolighthouse.org 
Fax: +1 (312) 243-8539 
FWA-Number: FWA00017514 
 
 

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11 March 2013 
 
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Appendix 3 – Biosketches of Key Personnel 
 
The biosketches of Key Personnel are attached. 
 
 

Protocol No. FFBCRI-PROGSTAR-02 
 
 
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11 March 2013 
 
56 
Appendix 4 – Electronic Clinical Report Form (eCRF) 
 
Print version of the electronic clinical report forms are attached 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
1 
FOUNDATION FIGHTING BLINDNESS 
CLINICAL RESEARCH INSTITUTE 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Project Title 
 
The Natural History of the Progression of Atrophy Secondary to Stargardt Disease: 
A Retrospective Longitudinal Observational Study 
 
Protocol No.:   
 
 
 
FFBCRI-PROGSTAR-01 
IND No.: 
 
 
 
 
N/A 
Drug Development Phase: 
 
 
N/A 
Issue Date: 
03/21/2013 
 
Study Director and Principal Investigator  
 
Hendrik P.N. Scholl, M.D., M.A. 
The Dr. Frieda Derdeyn Bambas Professor of Ophthalmology 
Wilmer Eye Institute 
Johns Hopkins University School of Medicine 
748 Maumenee Building 
1800 Orleans St 
Baltimore, MD 21287-9277 
Phone: +1 (443) 287-5495 
e-mail: hscholl1@jhmi.edu 
Fax: +1 (410) 614-2186 
FWA-Number: FWA00006087 
 
Study Site Locations 
 
Greater Baltimore Medical Center 
Janet S. Sunness, M.D. 
Medical Director 
Hoover Low Vision Rehabilitation Services  
Greater Baltimore Medical Center 
6569 North Charles Street, PPW504 
Baltimore, MD 21204 
Phone: +1 (443) 849-2658 
e-mail: jsunness@gbmc.org 
Fax: +1 (443) 849-2631 
FWA-Number: FWA00003849 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
2 
University of Pennsylvania 
Artur Cideciyan, Ph.D., 
Center for Hereditary Retinal Degenerations 
Scheie Eye Institute, Room 601 
Myrin Circle, 51 N. 39th Street 
Philadelphia, PA 19104 
Phone: +1 (215) 662 9986 
email: cideciya@mail.med.upenn.edu 
Fax: +1 (215) 662 9388 
FWA-Number: FWA00004028 
 
Retina Foundation of the Southwest 
David G. Birch, Ph.D. 
Retina Foundation of the Southwest 
9600 N. Central Expressway 
Dallas, TX 75231 
Phone: +1 (214) 363-3911 
e-mail: dbirch@retinafoundation.org 
Fax: +1 (214) 363-4538 
FWA-Number: FWA00005004 
 
University of Utah 
Paul S. Bernstein, M.D., Ph.D., 
Moran Eye Center 
University of Utah School of Medicine 
65 Mario Capecchi Drive 
Salt Lake City, UT 84132 
Phone: +1 (801) 581-2352 
e-mail:  paul.bernstein@hsc.utah.edu 
FWA-Number: FWA00003745 
 
Cole Eye Institute at Cleveland Clinic 
Elias Traboulsi, M.D. 
Mail Code i32  
9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: +1 (216) 444-7152 
e-mail: traboue@ccf.org 
Fax: +1 (216) 445-8475 
FWA-Number: FWA00005367 
 
Centre de Recherche Institut de la Vision Paris 
José-Alain Sahel, M.D. 
Centre de Recherche Institut de la Vision Paris 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
3 
UMR_S968 INSERM / UPMC / CHNO des Quinze-Vingts/ Centre de Référence 
Maladies Rares 
17 rue Moreau 
75012 Paris 
France 
Phone: +33 1 53 46 25 04 
e-mail:  j.sahel@gmail.com 
FWA-Number: FWA00005831 
 
Universitaetsklinikum Tuebingen (Eberhard-Karls University Hospital) 
Eberhart Zrenner, M.D. 
Institute for Ophthalmic Research 
Center for Ophthalmology 
Schleichstr. 12-16 
72076 Tübingen 
Germany 
Phone: +49 (7071) 2984 786 
e-mail:  ez@uni-tuebingen.de 
Fax: +49 (7071) 2950 38 
FWA-Number: FWA00000781 
 
Moorfields Eye Hospital, NHS Foundation Trust 
Michel Michaelides, M.D., F.R.C.Ophth. 
UCL Institute of Ophthalmology 
11-43 Bath Street 
London, EC1V 9EL 
United Kingdom 
Phone: +44 20 7608 6864 
 e-mail: michel.michaelides@ucl.ac.uk 
FWA-Number: FWA00010199 
 
Clinical Data and Biostatistics Coordination 
 
Sheila West, Ph.D. 
El-Maghraby Professor of Preventive Ophthalmology 
Dana Center for Preventive Ophthalmology 
Wilmer Eye Institute, Room 129 
600 North Wolfe Street 
Baltimore, MD  21287 
Phone: +1 (410) 955-2606 
e-mail: shwest@jhmi.edu 
Fax: +1 (410) 955-0096 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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Clinical Laboratory 
 
N/A 
 
Central Reading Center 
 
Srinivas R. Sadda, M.D., 
Associate Professor of Ophthalmology 
Director, Medical Retina Unit 
Ophthalmic Imaging Unit, Doheny Image Reading Center 
Doheny Eye Institute 
Keck School of Medicine 
University of Southern California 
1450 San Pablo Street DEI 3615 
Los Angeles, CA 90033 
Phone: +1 (323) 442-6503 
e-mail: ssadda@doheny.org 
Fax: +1 (323) 442-6460 
FWA-Number: FWA00005904 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
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Protocol Synopsis 
Name of Sponsor:  Foundation Fighting Blindness 
Clinical Research Institute 
Name of Product:  
N/A 
Protocol #:  
FFBCRI-PROGSTAR-01 
IND#: N/A 
Protocol Title: 
The Natural History of the Progression of Atrophy Secondary 
to Stargardt Disease (STGD): A Retrospective Longitudinal 
Observational Study 
Clinical Phase:  
N/A – Natural History Study 
Treatment 
Indication:  
N/A 
Objectives: 
The primary objective is: 
• To assess the yearly rate of progression of STGD using 
the growth or the development of atrophic lesions as 
measured by fundus autofluorescence (FAF) imaging. 
The secondary objectives are: 
• To assess the yearly rate of progression of STGD using 
the rate of retinal thinning and the rate of loss of 
photoreceptors as measured by spectral-domain optical 
coherence tomography (sd-OCT). 
• To assess the yearly rate of loss of retinal sensitivity as 
measured by microperimetry. 
• To assess the yearly rate of best-corrected visual acuity 
changes. 
• To correlate the presence and progression of 
morphological abnormalities in FAF and sd-OCT 
images with visual function as measured by 
microperimetry and visual acuity. 
• 
To perform exploratory analysis that examines factors 
associated with effects on STGD progression, such as 
the use of vitamin A supplementation and mutations in 
the ABCA4 gene. 
Study Design: 
Retrospective longitudinal observational study over a period of 
at least 24 months, and up to 60 months. 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
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Name of Sponsor:  Foundation Fighting Blindness 
Clinical Research Institute 
Name of Product:  
N/A 
Protocol #:  
FFBCRI-PROGSTAR-01 
IND#: N/A 
Participant 
Population: 
Up to a total of 250 (minimum of 150) patients, including 
males and females age 6 years and older affected by STGD 
that have an atrophic lesion in at least one eye with a minimum 
diameter of at least 300 microns, and a sum of all lesions areas 
less than or equal to 12 mm2 (five disc areas) at the most 
recent visit. Participants must have been previously genotyped 
to participate in the study and have at least 2 confirmed 
pathogenic mutations in the ABCA4 gene. If only one ABCA4 
allele contains a pathogenic mutation, then the patient needs to 
show a typical phenotype, i.e. at least one eye must have flecks 
at the level of the retinal pigment epithelium typical for STGD. 
Test Product, Dose, 
Mode of 
Administration: 
N/A 
Outcome variables: 
• Growth or development of atrophic lesions as measured 
by FAF imaging over a period of at least 24 months, and 
up to 60 months. 
• Rate of retinal thinning and photoreceptor loss as 
measured by sd-OCT over a period of at least 24 months, 
and up to 60 months. 
• Loss of retinal sensitivity as measured by microperimetry 
over a period of at least 24 months, and up to 60 months. 
• 
Change of best-corrected visual acuity over a period of at 
least 24 months, and up to 60 months. 
Study Duration: 
Total duration of study including patient enrollment and data 
analysis: 12 months. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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Table of Contents 
 
 
Protocol Synopsis ........................................................................................... 5 
Table of Contents ........................................................................................... 7 
1 
Introduction ........................................................................................ 14 
1.1 
Background.....................................................................................................15 
1.2 
Treatment Strategies .......................................................................................18 
1.3 
Known and Potential Risks ............................................................................19 
1.3.1 
Foreseeable Risks ...........................................................................................19 
1.3.2 
Risk Management and Emergency Response.................................................19 
1.3.2.1 
Minimization of Risk ......................................................................................19 
1.3.2.2 
Response to Risk ............................................................................................20 
1.3.2.3 
Research Injury Compensation.......................................................................20 
1.3.2.4 
Precautions and Preventive Measures ............................................................20 
1.3.3 
Known and Potential Benefits ........................................................................20 
 
2 
Study Rationale and Objectives ........................................................ 20 
2.1 
Study Rationale ..............................................................................................20 
2.2 
Study Objectives .............................................................................................21 
 
3 
Study Design ........................................................................................ 21 
3.1 
Type/Design of Study .....................................................................................23 
3.2 
Study Treatments ............................................................................................24 
3.3 
Study Population ............................................................................................24 
3.3.1 
Recruitment Methods .....................................................................................24 
3.3.2 
Recruitment Process .......................................................................................24 
3.3.3. 
Volunteer Compensation ................................................................................25 
3.3.4. 
Recruitment Materials ....................................................................................25 
3.4 
Eligibility Criteria ...........................................................................................25 
3.4.1 
Informed Consent/Assent ...............................................................................25 
3.4.2 
Disclosure of DOD Sponsorship and Access to Research Records ...............26 
3.4.3 
Inclusion Criteria ............................................................................................26 
3.4.4 
Exclusion Criteria ...........................................................................................28 
3.5 
Primary and Secondary Outcome Variables...................................................29 
3.6 
Measures to Minimize/Avoid Bias .................................................................29 
3.6.1 
Blinding ..........................................................................................................29 
3.6.2 
Study Data ......................................................................................................30 
3.7 
Data collection ................................................................................................31 
3.7.1. 
Safety Assessments ........................................................................................32 
3.7.1.1. 
Adverse Events ...............................................................................................32 

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21 March 2013 
 
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3.7.1.2. 
Clinical Laboratory Data ................................................................................32 
3.7.1.3. 
Evaluations .....................................................................................................32 
3.7.1.4. 
Labs Performing Evaluations and Special Precautions ..................................32 
3.7.1.5. 
Sharing Research Results ...............................................................................33 
3.7.2. 
Endpoints ........................................................................................................33 
3.7.2.1. 
Primary Statistical Endpoint ...........................................................................33 
3.7.2.2. 
Secondary Statistical Endpoints .....................................................................33 
3.8. 
Withdrawal Criteria, and Procedures .............................................................33 
3.9. 
Definition of Completed .................................................................................33 
3.10. 
Participant Compliance ..................................................................................34 
3.11. 
Protocol Deviations ........................................................................................34 
3.12. 
Protocol Modifications ...................................................................................34 
 
4. 
Study Personnel .................................................................................. 35 
4.1. 
Roles and Responsibilities of Key Study Personnel.......................................35 
4.2. 
Conflict of Interest ..........................................................................................37 
 
5. 
Prohibited Medications ...................................................................... 37 
 
6. 
Evaluation of Adverse Events ............................................................ 37 
7. 
Statistical Analysis .............................................................................. 37 
7.1. 
Sample Size and Power ..................................................................................37 
7.2. 
Statistical Analyses .........................................................................................38 
7.3. 
Demographic Characteristics..........................................................................39 
7.4. 
Data Set Descriptions .....................................................................................39 
7.5. 
Handling of Missing Data ..............................................................................39 
7.6. 
Safety Analyses ..............................................................................................39 
7.7. 
Study Drug Compliance .................................................................................39 
7.8. 
Interim Analysis .............................................................................................39 
 
8. 
Study Product Management .............................................................. 40 
9. 
Data Handling and Records Management ....................................... 40 
9.1. 
Data Collection ...............................................................................................40 
9.1.1. 
Volunteer Identification..................................................................................41 
9.1.2. 
Confidentiality ................................................................................................41 
9.1.3. 
Access .............................................................................................................42 
9.1.4. 
Reporting Requirements .................................................................................42 
9.2. 
Source Documents ..........................................................................................42 
9.3. 
File Management at the Study Site .................................................................43 
9.4. 
Records Retention at the Study Site ...............................................................43 
9.5. 
Data Management Considerations ..................................................................43 
9.5.1. 
Database Design and Creation........................................................................43 
9.5.2. 
Data Coding ....................................................................................................43 

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21 March 2013 
 
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9.5.3. 
Data Transfer ..................................................................................................44 
9.5.4. 
Data Validation ...............................................................................................44 
9.5.5. 
Database Lock ................................................................................................44 
 
10. Quality Control and Quality Assurance ........................................... 44 
10.1. 
Monitoring ......................................................................................................44 
10.2. 
Auditing ..........................................................................................................45 
 
11. Ethics and Responsibility ................................................................... 45 
11.1. 
Clinical Study Report .....................................................................................45 
 
12. Confidentiality .................................................................................... 45 
13. Amendment Policy .............................................................................. 46 
14. References ............................................................................................ 47 
Appendix 1 - Agreement ............................................................................. 50 
Appendix 2– Additional Institutions and Personnel Involved With the 
Study .................................................................................................... 51 
Appendix 3 – Biosketches of Key Personnel ............................................. 52 
Appendix 4 – Electronic Clinical Report Form (eCRF) .......................... 53 
 
List of In-text Tables 
 
Table 3.4.3-1 
Inclusion Criteria ...........................................................................27 
Table 3.4.4-1 
Exclusion Criteria ..........................................................................28 
Table 3.6.2 
Study Procedures…....................... ................................................30 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
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List of Abbreviations and Definitions of Terms 
 
Abbreviations 
AE 
AF 
AHRPO 
Adverse event 
Autofluorescence 
Army Human Research Protection Office 
BCVA 
Best Corrected Visual Acuity 
CFR 
CO 
COR 
Code of Federal Regulations 
Contract Officer 
Contract Officer Representative 
CRF 
CRI 
Case Report Form 
Clinical Research Institute 
eCRF 
cSLO 
DOD 
Electronic Clinical Report Form 
Confocal Scanning Laser Ophthalmoscopy 
Department of Defense 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus Autofluorescence 
FDA 
Food and Drug Administration 
FFB 
Foundation Fighting Blindness 
FFB CRI 
Foundation Fighting Blindness Clinical Research Institute 
GCP 
HRPO 
HSPS 
Good Clinical Practice 
Human Research Protections Office 
Human Subjects Protection Scientist 
ICH 
International Conference on Harmonization 
ID 
Identification 
IRB 
IS-OS 
Institutional Review Board 
Inner Segment – Outer Segment junction of photoreceptor cells 
LOCF 
Last Observation Carried Forward 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MP 
Microperimetry 
mmHg 
Millimeters of Mercury 
N/A 
OC 
Not Applicable 
Observed cases  
sd-OCT 
Spectral Domain Optical Coherence Tomography 
STGD 
USAMRMC 
Stargardt Disease 
US Army Medical Research and Materiel Command 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
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WOCBP 
Women of Child Bearing Potential 
 
Definition of Terms 
 
Research - A systematic investigation, including the development, testing and evaluation 
of an idea, designed to develop or contribute to generalizable knowledge.  Activities that 
meet this definition constitute research whether or not they are conducted or supported 
under a program that is considered research for other purposes.  For example, some 
demonstration and service programs may include research activities. 
 
Clinical Investigation - Any experiment in which a drug or therapy is administered, 
dispensed, or used for treating one or more human participant.  This definition applies to 
research involving the use of FDA-regulated products.  Even if a clinical investigation 
does not meet the definition of research, it is participant to the same regulations as 
research. 
 
Human Participant - A living individual about whom an investigator is conducting 
research, obtains data through intervention or interaction with the individual, or 
identifiable private information. 
 
Human Anatomical Substances - Any human organs, tissues, cells, or body fluids 
including but not limited to blood/sera (finger stick, ear stick, venipuncture, etc.), hair, 
nails, teeth, skin, sputum or cells gathered from mouth washing, nasal or oral swabs, 
placenta or amniotic fluid. 
   
Individually Identifiable Private Information - Private information includes 
information about behavior that occurs in a context in which an individual can reasonably 
expect that no observation or recording is taking place.  This information has been 
provided for specific purposes by an individual and the individual can reasonably expect 
that private information will not be made public (for example, a medical record).  
Individually identifiable means that the identity of the participant is known or that their 
identity may readily be ascertained by the investigator or that their identity is associated 
with the information.  
    
Protected Health Information (PHI) - Any individually identifiable health information 
held by a covered entity, as defined in the Health Insurance Portability and Accountability 
Act (HIPAA). 
 
Covered Entity - An organization engaged in the treatment of patients, responsible for 
obtaining payment for such treatment, or engaged in other healthcare operations where 
PHI is electronically exchanged.  
  
Authorization - Written permission from an individual allowing a Covered Entity to use 
or disclose specified PHI for a particular purpose (such as research).  

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Minimal Risk - The probability and magnitude of harm or discomfort in the research are 
not anticipated to be greater in and of themselves than those ordinarily encountered in 
daily life, or during the performance of routine physical and psychological examinations 
or tests.  
 
Legally Authorized Representative (LAR) - An individual or judicial or other body 
authorized under applicable law to consent on behalf of a potential participant to the 
participant’s participation in the procedure(s) involved in the research.  NOTE:  State law 
defines who may act as an LAR. The Institutional Review Board (IRB) of record should 
be consulted for guidance regarding who can serve as an LAR for research at the research 
site.  
 
USAMRMC Supported Research - For the purpose of this document USAMRMC 
supported research includes but is not limited to: (1) Research funded (through grant, 
contract, cooperative agreement, military interdepartmental purchase request, etc.) by the 
USAMRMC and (2) Research managed (technical management and/or funds 
management) by the USAMRMC as directed by Congress (e.g., Telemedicine and 
Advanced Technology Research Center (TATRC)). 
 
Institutional Review Board (IRB) of Record - The IRB listed on an Institution’s 
Assurance of Compliance that assumes responsibility for review and oversight of a 
research protocol on behalf of the institution.  An IRB of record from each institution 
engaged in the research must review and approve the protocol; therefore, there can be 
more than one IRB of record for a protocol.  An IRB Authorization Agreement between 
two IRBs of Record allows one IRB of record to defer to another.   
 
Research Proposal - A research plan submitted to the DOD funding agency in response 
to a solicitation.  The proposal provides an overview of all proposed work to be performed 
and provides the rationale explaining why the institution should be awarded funds to 
complete the work.  A proposal may consist of multiple research projects conducted under 
separate protocols at one or more institutions. 
  
Research Protocol - A comprehensive, detailed, and specific plan of action for the 
execution of research on human participants.  
   
Award - A financial agreement such as a grant, contract, or cooperative agreement 
between the Federal Government and an institution. 
  
Scientific Review – An independent, documented review that objectively evaluates the 
scientific merit of a research proposal or protocol.  Refer to the HRPO Policies and 
Procedures document on the HRPO website for additional information on scientific 
reviews.   
 

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Contract Officer (CO) – A federal government employee authorized to negotiate awards 
and commit funds on behalf of the U.S. Government.  
  
Contract Specialist - A federal government employee assigned to assist the CO with 
award related issues.  The contract specialist is the primary point of contract for award 
related issues.  
  
Contract Officer’s Representative (COR) - A federal government employee assigned by 
the CO to manage the technical aspects and performance of an award on behalf of the 
DOD program office responsible for oversight of the research.  The COR may serve as the 
Grant Manager or Project Manager or may have assistance from other personnel within 
the DOD program office in executing COR responsibilities. 
  
Human Subjects Protection Scientist (HSPS) - A federal government employee or 
contractor within the HRPO responsible for assisting investigators with the HRPO review 
and approval process.  The HSPS is the investigator’s primary point of contact for 
questions regarding the human research review process and other issues related to human 
subjects protection. 
  
Army Human Research Protection Office (AHRPO) - The office that reports to the 
Assistant Surgeon General, Force Projection and is responsible for human research policy, 
education, and oversight for the U S Army.  The AHRPO administers DOD Assurances of 
Compliance. 
   
Informed Consent - Informed consent is an ongoing process that provides the participant, 
or legally authorized representative (LAR), with sufficient details about a study so that 
he/she can make a voluntary decision about participation.  Often a written consent form is 
employed to facilitate initial discussion of a study, and includes descriptions of study 
procedures, potential risks and benefits, and other pertinent information.  Informed 
consent is an ongoing, interactive process and the participant’s voluntary decision about 
continuing to take part in the trial should be reassessed throughout the study. 
 
Enrollment - To register, enter, screen, randomize, or otherwise formally initiate a 
participant’s participation in a study.  Informed consent precedes enrollment.  The number 
of participant consented may differ from the number of participants enrolled in a study 
(e.g., a participant may give consent to participate in a study but may be determined to be 
ineligible upon screening; commonly called a “screen failure”).  
  
Screening - A process of actively assessing a potential participant for inclusion in a study 
based on compatibility with pre-determined inclusion/exclusion criteria, ability and 
willingness to complete the study, and other factors.  Screening that does not access, 
collect, or record a participant’s protected health information may take place before 
informed consent is obtained.  However, informed consent must be obtained prior to 
screening procedures that use protected health information or involve procedures that a 
participant would not normally undergo.   

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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1 Introduction 
Stargardt disease (STGD1; OMIM: 248200), initially described by the German 
ophthalmologist Karl Stargardt in 1909, is an autosomal recessive inherited disorder, 
although an autosomal dominant Stargardt-like phenotype has also been described [1]. 
Stargardt disease is the most common form of juvenile macular degeneration with an 
estimated incidence of 10 – 12.5 per 100,000 and is caused by mutations in the ABCA4 
gene [2]. An autosomal dominant Stargardt-like phenotype [3] has also been described 
associated with mutations in the ELOVL4, PROM1 and PRPH2 genes [4, 5]. 
 
Patients with STGD develop a progressive impairment of visual acuity, which begins most 
frequently within the first or second decades of life [6]. However some patients do not 
lose visual acuity until the fourth or even fifth decade of life. The loss of acuity is 
accompanied by atrophic-appearing lesions within the macula and the presence of yellow-
white lesions at the level of the retinal pigment epithelium (RPE), which are referred to as 
“fundus flecks”. The fundus changes apparent clinically are caused by excess 
accumulation of lipofuscin in the RPE (Figure 1).  RPE lipofuscin is a heterogeneous 
material composed of a mixture of lipids, proteins, and different fluorescent compounds 
[7]. The natural autofluorescent properties of lipofuscin have led to the use of confocal 
scanning laser ophthalmoscopy (cSLO), and autofluorescence (AF) imaging, as 
convenient, noninvasive methods for determining the distribution of lipofuscin in human 
participants. [8-10]. 
 
Figure 1: 
 
 
 
Figure 1:  AF images of both eyes of a patient with bilateral central atrophy of the RPE. Stars: fixation loci 
determined individually in each eye. The contrast of each grayscale image is uniformly stretched for better 
visibility of features [11]. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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1.1 
Background 
Any new therapeutic clinical studies must be able to compare the intervention to the 
natural history of the disease in a longitudinal study.  Therefore, the natural history of the 
disease in the patients to be treated must be understood. Any clinical outcome measures 
must be accurate, reproducible and have acceptable intra- and inter-observer variability. 
For surrogate measures, the FDA states that “validated surrogate markers are those for 
which evidence has been established that a drug-induced effect on the surrogate predicts 
the desired effect on the clinical outcome of interest” [12].  
 
Degeneration of the photoreceptors and underlying retinal pigment epithelium (RPE) in 
STGD, as measured by standard histology and sd-OCT imaging, typically occurs close to 
or within the macula [13] (Figure 2). Photoreceptors degenerate either primarily due to 
accumulation of toxic retinoids within outer segments [14, 15] or secondarily following 
RPE loss because of their dependence on RPE cells for the maintenance and the removal 
of shed photoreceptor outer segments [16]. Multiple lines of evidence indicate that 
lipofuscin accumulation in the RPE is associated with RPE cell death [17-19], most 
probably by facilitating apoptosis and damage to lysosomal membranes [17].  
 
 
Figure 2: 
 
 
Figure 2: The complementary nature of FAF and sd-OCT imaging. (A) A Fundus Autofluorescence (FAF) 
image of a Stargardt patient’s retina. The diameter of the central area of “absent FAF” corresponds to 
geographic atrophy seen clinically with a larger diameter of “abnormal FAF” visible. (B) An sd-OCT image 
through the fovea of a normal control eye. (C) An sd-OCT image showing the extent of the transverse loss 
of the inner segment-outer segment junction of the photoreceptors in the foveal region. (D) A comparison of 
the measurements obtained from FAF in (A) and sd-OCT in (C). [13]  
 
During the part of the visual cycle that occurs in the discs of the outer segment of 
photoreceptors, opsin bound 11-cis-retinal is converted by light into all-trans-retinal.  This 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
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conformational change triggers a signaling cascade.  The all-trans-retinal is then released 
from opsin and, must be recycled back to 11-cis-retinal to maintain light responsiveness.  
Since rhodopsin is a trans-membrane protein, the all-trans-retinal is released into the 
membrane where it can either diffuse to the cytoplasmic face of the disc membrane, where 
a cytoplasmic retinol dehydrogenase starts the recycling process, or it remains in the disc 
membrane where it can be covalently modified by membrane lipids to form N-
retinylidene-phosphatidylethanolamine (NRPE), which can be trapped within the 
membrane or the lumenal side of the disc.  To be recycled, trapped NRPE must be 
transported across the disc membrane to the cytoplasm for dehydrogenation. 
 
Both in vitro and in vivo studies of the ABCA4 knockout mouse model support the 
hypothesis that the ABCA4 protein is an outwardly directed “flippase” that transports all-
trans-retinal and NRPE to the cytoplasmic side of the disc membrane [20, 21] (Figure 3).  
In the absence of ABCA4 activity, the membrane trapped all-trans-retinal and NRPE do 
not get removed for recycling [22] [23, 24]. If their concentration increases, as may occur 
during high levels of illumination or a lack of flippase activity (Stargardt disease), NRPE 
and all-trans-retinal can react to form A2-dihydropyridine-ethanolamine (A2E-PE) [22, 
25]. Accumulation of bisretinoids within the outer segments is believed to be toxic to 
photoreceptors [14, 15]. 
 
Photoreceptor outer segment membranes are renewed in a circadian cycle by the RPE cells 
that endocytose the distal 10% of each rod outer segment each day [16] and digest them in 
lysosomes. In Stargardt disease, the endocytosed outer segments contain elevated 
quantities of A2E-PE which are hydrolyzed within the lysosomes to generate elevated 
levels of A2E and related bisretinoids.  These are components of lipofuscin that are known 
to be elevated in Stargardt disease [26].  Studies suggest that elevated levels of these 
metabolites are not handled efficiently and become toxic, leading to the A2E-mediated 
cell death seen in Stargardt disease. This mechanism of RPE cell death is consistent with 
the studies of the ABCA4 knockout mouse model that exhibits abundant lipofuscin 
accumulation, and elevated A2E levels that lead to eventual RPE cell death and 
subsequent photoreceptor loss [27]. 
 

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Figure 3: 
 
 
Figure 3: Scheme of the visual cycle.  The cell at the top of the diagram represents the distal tip of a rod 
outer segment.  The cell at the bottom of the diagram represents part of the RPE cell that endocytoses the 
distal segment of the photoreceptor and degrades it inside the lysosome. Excess accumulation of A2-PE 
leads to excess accumulation of A2E within the RPE lysosome that leads to A2E-mediated cell death. [20] 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Consistent with this mechanism, a reduction of the daily light load on the retina would be 
predicted to reduce production of A2E, and this is observed in ABCA4 knockout mice 
reared in darkness [27]. However more recent results have shown continued accumulation 
of A2E in the dark [28] suggesting a role in 11-cis-retinal in A2E generation. 
 
1.2 
Treatment Strategies 
At present there are no FDA-approved treatments for ABCA4-related retinal diseases.  
There is a phase I/IIa gene therapy clinical trial in progress.  There are also a number of 
preclinical studies of compounds designed to reduce the formation of A2-PE or A2E-
related toxicity, which may slow or prevent progression of the disease (Figure 4).  What is 
currently unclear is whether a treatment strategy employed after significant accumulation 
of lipofuscin has already occurred will be able to effectively decrease the lipofuscin 
content and thereby save RPE and photoceptor cells. However, none of these treatments 
will be able to restore visual function to areas of the retina that have already undergone 
RPE, choriocapillaris, and photoreceptor cell loss.  Stem cell therapy may be able to 
address this concern, but the technology is still several years from the clinic.  While a 
promising intervention, gene therapy can only be effective if the target cells are still 
viable. Therefore the initial primary therapeutic intent is to slow or halt the progression of 
retinal degeneration.  
 
Figure 4: 
 
Figure 4: Scheme of Vitamin A Visual Cycle 
 
Gene Therapy 
Given that STGD is caused by the loss of function of the ABCA4 protein, transfecting the 
wild type ABCA4 gene into the nucleus of photoreceptor cells may improve the retinoid 
flow in the visual cycle, prevent further abnormal accumulation of lipofuscin in RPE cells, 
and slow the disease process in patients with STGD.  This may be particularly therapeutic 
with early intervention before there is extensive cell loss. 
 

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There is currently one phase I/IIa gene therapy clinical trial for the product Stargen 
developed by Oxford BioMedica.  The therapy consists of a single subretinal injection of a 
genetically engineered lentivirus (the Equine Infectious Anaemia Virus, EIAV) carrying a 
single copy of the wild type ABCA4 gene.  This is a dose escalation study enrolling up to 
28 participants with Stargardt disease, with the primary outcome measures being the 
incidence of adverse events over 48 weeks and the number and percentage of patients with 
treatment emergent adverse events.  The secondary outcome measures are a delay in 
retinal degeneration and changes from baseline function relative to the contralateral eye 
utilizing retinal analytical techniques.  To date the trial has reported no significant adverse 
events.  
 
Pharmacologic and Other Interventions 
There are many different therapeutic approaches in the preclinical research stage for 
Stargardt disease.  These include: stem cell therapies; dietary supplementations; molecules 
that slow the visual cycle thereby limiting the rate that all-trans-retinal can be generated; 
molecules that chelate the all-trans-retinal in the membrane; derivatives of 11-cis-retinal 
such as deuterated forms that markedly slow the formation of A2-PE; molecules that 
stimulate the activity of an impaired ABCA4 protein; molecules that restrict the amount of 
retinal that can reach the retina; molecules that remove the lipofuscin from the RPE cells 
before it can have a toxic effect; molecules targeting A2E; optogenetics and visual 
prosthetics [29, 30]. 
 
1.3 
Known and Potential Risks  
This study is a retrospective observational study of the natural course of STGD and 
therefore no risks are involved. 
 
1.3.1 
Foreseeable Risks 
Due to the retrospective design of the study, there are no foreseeable risks to the 
participants. 
 
1.3.2 
Risk Management and Emergency Response 
1.3.2.1 
Minimization of Risk 
The participants will be informed of the risks and consequences of the study by one of the 
delegated study staff members, in a language the participant can understand. Participants 
will be informed that they may withdraw from the study at any time, for any reason 
without jeopardizing their future treatment. Participants will be given full information 
regarding the study protocol.  
 
The study will be compliant with the relevant parts of 45 CFR and the ICH GCP 
Guidelines. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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1.3.2.2 
Response to Risk 
N/A  
 
1.3.2.3 
Research Injury Compensation 
N/A 
 
1.3.2.4 
Precautions and Preventive Measures 
N/A 
 
1.3.3 
Known and Potential Benefits 
There is no direct benefit to participants in this study, although they may conceivably be 
good candidates for future studies of emerging STGD therapies. Participants in this study 
are not experimental subjects as there is neither a study intervention nor is the interaction 
with the participant for the primary purpose of obtaining data regarding the effect of an 
intervention or interaction; as such, LARS consent/child assent will be allowed in the 
study and children may be enrolled. Data resulting from this natural history study may 
influence the clinical design of future trials designed to evaluate therapies for treating 
Stargardt disease.  As such, this study may support work that leads to benefit for some 
patients in the long term. 
 
2 Study Rationale and Objectives 
2.1 
Study Rationale 
Although STGD is the most prevalent form of juvenile-onset macular dystrophy, with an 
estimated incidence of 10 – 12.5 per 100,000, it is still relatively rare and there is very 
limited information available about the natural course of the disease in larger numbers of 
STGD patients. In one study, initiation and longitudinal progression of dysfunction in the 
peripheral retinal regions was used to provide quantitative severity scale for specific 
ABCA4 mutations [31]. There is less information currently available about the progression 
of macular disease and it is predominantly based on individual reports of patient data 
collected from single centers [32, 33].  However, this limited data clearly points to a 
disease which is very heterogeneous with significant variation in the age of onset and rate 
of progression, and limited clear correlations between phenotype and genotype [34, 35]. 
These limitations highlight the urgent need for a multi-center study that documents the 
natural course of the macular disease. The information gathered from this proposed study 
should provide guidance and support to the identification of the most appropriate clinical 
outcome measures for anticipated clinical trials. It may also be used to identify and 
support the validation of surrogate clinical trial endpoints that are offered by recent 
technological advances in retinal imaging capabilities, such as fundus autofluorescence 
(FAF) and spectral-domain optical coherence tomography (sd-OCT). 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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2.2 
Study Objectives 
Stargardt disease is currently an incurable and untreatable macular dystrophy that causes 
severe visual loss in children and young adults, thereby causing enormous morbidity with 
economic, psychological, emotional, and social implications. There are no FDA approved 
therapeutic treatments for this disease. Therefore, the objective of this study is to collect 
natural history data from a large population of children and adults in order to evaluate 
possible efficacy measures for planned clinical trials. 
 
 
Primary objective: 
• To assess the yearly rate of progression of STGD using the growth or the 
development of atrophic lesions as measured by fundus autofluorescence (FAF) 
imaging. 
 
Secondary objectives: 
• To assess the yearly rate of progression of STGD using spectral-domain optical 
coherence tomography (sd-OCT) to measure the rates of retinal thinning and the 
loss of photoreceptors. 
• To assess the yearly rate of loss of retinal sensitivity as measured by 
microperimetry. 
• To assess the yearly rate of best-corrected visual acuity changes. 
• To correlate the presence and progression of morphological abnormalities in FAF 
and sd-OCT images with visual function as measured by microperimetry and 
visual acuity. 
• To perform exploratory analysis of factors associated with STGD progression, 
such as participant’s use of vitamin A supplementation and mutations in the 
ABCA4 gene. 
 
3 Study Design 
The study shall utilize data from up to 14 clinical sites to collect retrospective longitudinal 
observations on up to 250 participants (minimum of 150).  Participants must present with 
atrophic lesions secondary to STGD, in at least one eye at the most recent visit.  The study 
shall take place over a 12 months period including patient enrollment and data analysis.  
Each of the study investigators has indicated that the information that will be available at 
each visit will include: data of at least two, up to three previous visits over a period of at 
least 24 months, up to 60 months, including visual acuity, complete ophthalmic exam 
recordings (including dilated fundoscopy), autofluorescence imaging, microperimetry and 
spectral-domain optical coherence tomography (sd-OCT). The screening visit of the 
prospective FFBCRI-PROGSTAR-02 study can serve as one visit. The study visits with 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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study procedures are summarized in Table 3.6.2 and graphically shown in Figure 5. In 
brief, if a patient is being screened for the prospective FFBCRI-PROGSTAR-02 study that 
visit can serve as the baseline visit for this retrospective (FFBCRI-PROGSTAR-01) study. 
If the patient participates in the prospective FFBCRI-PROGSTAR-02 study, the screening 
visit serves as “visit 1” of the prospective FFBCRI-PROGSTAR-02 study and 
simultaneously as the “visit -1” of the retrospective FFBCRI-PROGSTAR-01 study 
described herein if they have also been seen previously for at least 24 months, up to 60 
months.  
 
 
Figure 5: Overview to show the difference in possible datasets in the retrospective FFBCRI-PROGSTAR-01 
Study, depending on number of available visits.  01 Study: the retrospective study.  02 Study: the 
prospective FFBCRI-PROGSTAR-02 Study.  
 
Results will be sent by the participating centers to the Dana Center for Preventative 
Ophthalmology of the Wilmer Eye Institute, the Johns Hopkins University, Baltimore, for 
evaluation, with the exception of the microperimetry, autofluorescence and optical 
coherence tomography, which will be sent to a central reading center at the Doheny Eye 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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Institute, Los Angeles, California. 
 
Primary outcome measure: 
• Yearly rate of progression of STGD as reflected by the growth or the development 
of atrophic lesions measured by FAF imaging. Because patients have to have an 
atrophic lesion at the most recent visit, it is possible that they had no detectable 
lesion at earlier visits. Therefore, there are distinct scenarios as illustrated in Figure 
6: 
 
 
Figure 6: Possible scenarios regarding the presence or the development of atrophic lesions as the primary 
outcome measure.  
 
Secondary outcome measures: 
• Yearly rate of progression of STGD as reflected by the rate of retinal thinning and 
photoreceptor loss as measured by sd-OCT. 
• Yearly rate of loss of retinal sensitivity as measured by microperimetry. 
• Yearly changes in best-corrected visual acuity. 
• Correlation of the presence and/or progression of morphological abnormalities in 
FAF and sd-OCT images with visual function as measured by microperimetry and 
best-corrected visual acuity. 
• 
Exploratory analysis to examine factors associated with disease progression, such 
as participant’s use of vitamin A supplementation and mutations in the ABCA4 
gene. 
 
3.1 
Type/Design of Study  
This is a retrospective, longitudinal, observational, study. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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3.2 
Study Treatments 
This is a natural history study. There are no treatments being investigated in this trial. 
 
3.3 
Study Population 
The study population shall consist of up to 250 Stargardt disease patients, with a minimum 
of 150 patients, recruited at up to 14 clinical centers across the US and Europe.  
Participants must be at least six years old at study enrollment. There are no limitations 
regarding race, ethnicity, or sex. 
 
The participants must present with atrophic lesions secondary to STGD with a minimum 
diameter of 300 microns and the area of all lesions together must add to less than or equal 
to 12 mm2 and must represent no more than 5 disc areas in a least one eye at the most 
recent visit (which can coincide with the screening visit of the PROGSTAR 02 study). 
Participants must have been genotyped to participate in the study and have at least 2 
confirmed pathogenic mutations in the ABCA4 gene. If only one ABCA4 allele contains a 
pathogenic mutation, then for inclusion in this study the patient must show a typical 
phenotype, i.e. at least one eye must have flecks at the level of the retinal pigment 
epithelium typical for STGD.  
 
3.3.1 
Recruitment Methods 
The investigators at each of the centers will review their own clinical patient databases and 
contact their patients. 
 
3.3.2 
Recruitment Process 
The investigators at each of the clinical centers will identify potential study patients from 
their own patient populations. Potential study participants who demonstrate an interest in 
participating in the study will receive an explanation of the terms, and requirements of the 
study, in language they can understand, from an investigator in the research team. They 
will also receive a written copy of the Informed Consent Form to read and share with 
family or friends prior to their screening visit. Subsequently, an investigator or a qualified 
designee will answer questions and request the patient's permission to participate in the 
study. Participants will sign a study-specific patient informed consent form approved by 
the local Institutional Review Board.  
 
For participants younger than 18 years of age, parental/LAR consent and patient assent 
will both be obtained prior to participation in this study. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.3.3. 
Volunteer Compensation 
This observational study collects existing information on the natural course of STGD and 
all examinations were part of the standard clinical care. Compensation will not be 
provided to the study participants. 
 
3.3.4. 
Recruitment Materials 
No centrally prepared recruitment or advertising materials are planned for this study. 
Recruitment materials such as telephone scripts or written letters may be prepared by 
individual sites. 
 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent/Assent 
When individuals are identified in-person as potential study participants, the investigator 
will provide information about the study, and confirm contact. The investigator or other 
designated study staff will obtain and document informed consent from appropriate, 
interested patients.  
 
Potential study participants who demonstrate an interest in participating in the study will 
receive an explanation of the terms and requirements of the study from the research team 
in a language they can understand. They will receive a copy of the Informed Consent 
Form to read and share with family or friends. An investigator or designated site study 
staff member will answer any questions or concerns that the potential participants may 
raise and request the patient's permission to participate in the study. Each site will provide 
adequate time for the patient to make a decision whether to participate in the study. When 
the potential participant is a minor (less than 18 years of age), parental consent/LAR and 
minor participant assent will be obtained following the same procedures outlined in the 
previous paragraph. The minor participant will be provided with an age appropriate assent 
form and given a chance to freely choose whether to participate in the study. 
 
Study candidates who cannot give their own consent to participate will only be enrolled 
into the study after consent is obtained from the individual’s Legally Authorized 
Representative (LAR).  Children shall receive an additional assent form written in age 
appropriate language for them to read, and will only be enrolled into the study following 
consent by their individual’s Legally Authorized Representative (LAR).  Site investigators 
will consult with their local institutional review boards for guidance regarding who may 
serve as an LAR. 
 
For study candidates who are illiterate or unable to understand the written consent form, 
the consent form will be read and explained to them in the presence of a witness. The 
candidate must sign or mark the form in an individually unique manner, such as with a 
thumbprint, to indicate their agreement to participate.  A witness may also sign the form to 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
26 
attest that the content of the written consent form was conveyed accurately to the study 
candidate. 
 
If a study candidate is not fluent in the primary language of the host country of the study 
site, all documentation including the consent form and any site information sheets 
approved by the local IRB shall be translated into their native language by a certified 
translator and the translation approved by the local IRB and HRPO.  Plans shall also be 
made and approved to ensure a qualified translator is available during the consent process, 
baseline and all follow-up visits to address any concerns or ensure they provide continuing 
consent to study participation. 
 
When consent is obtained in a language other than English, the foreign language version 
of the consent form will be a certified accurate translation of the English version of the 
consent form.  
 
Written informed consent shall be obtained from all participants or their LAR before any 
data will be collected for study use. However, investigators may discuss in general the 
availability of the study and the general entry criteria with a potential participant candidate 
without obtaining consent.  
 
The investigator has both an ethical and legal responsibility to ensure that each participant 
study candidate being considered for inclusion in this study is given a full explanation of 
the protocol. This shall be documented on the written informed consent form approved by 
the same Institutional Review Board (IRB) responsible for approving this protocol.  
 
Once the appropriate essential information has been provided to the participant and fully 
explained by the investigator, or a qualified designee, and the participant understands the 
implications of participating, the IRB-approved written informed consent/assent form(s) 
will be signed and dated by the participant and the person obtaining consent (investigator 
or designee), and by any other parties required by the site’s local IRB. The participant 
shall be given a copy of the signed informed consent form.  The original signed informed 
consent form shall be kept on file by the investigator; the time length will be determined 
by the local IRB. All of the above mentioned activities shall be completed prior to the 
participant’s participation in the trial. 
 
3.4.2 
Disclosure of DOD Sponsorship and Access to Research Records 
The informed consent form shall include a statement that discloses that the DOD is 
supporting the research and that representatives of the USAMRMC have the authority to 
review research records of any study participant.  Study candidates have a right to decline 
participation in research based on the source of the funding.   
 
3.4.3 
Inclusion Criteria 
Study participants are required to meet the following inclusion criteria: 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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21 March 2013 
 
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Table 3.4.3-1 
Inclusion Criteria 
1. 
Provide a signed informed consent/assent form and authorization allowing the 
disclosure and use of protected health information. 
2. 
The study eye must have at least one well-demarcated area of atrophy as imaged 
by fundus autofluorescence with a minimum diameter of 300 microns and the 
area of all lesions together must add to less than or equal to 12 mm2 (equivalent 
to no more than 5 disc areas in a least one eye) at the most recent visit. 
3. 
Two (2) or more pathogenic mutations confirmed present, in the ABCA4 gene. If 
only one ABCA4 allele contains pathogenic mutation(s), the patient shall have a 
typical Stargardt phenotype, namely at least one eye must have flecks at the level 
of the retinal pigment epithelium typical for STGD. 
4. 
Sufficient quality of imaging and psychophysical procedures in the opinion of 
the investigator.  
5. 
Patients have been followed for at least two (2) visits over a period of at least 24 
months, up to 60 months, and had at least two examinations (same at all visits 
out of: Fundus Autofluorescence obtained with a Heidelberg Engineering 
instrument (e.g. HRA2, Spectralis); sd-OCT obtained with the Heidelberg 
Spectralis; Microperimetry obtained with the Nidek MP-1). 
6. 
Be at least six years old at the most recent visit (“visit -1”).  
7. 
Both eyes can be included if inclusion criteria are fulfilled for both eyes. 
 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.4.4 
Exclusion Criteria 
Study candidates shall be excluded if they meet any of the following exclusion criteria: 
 
Table 3.4.4-1 
Exclusion Criteria 
Exclusion Criteria 
1. 
Ocular disease, such as choroidal neovascularization, glaucoma and diabetic 
retinopathy, in either eye that may confound assessment of the retina 
morphologically and functionally. 
2. 
Intraocular surgery in the primary study eye within 90 days prior to baseline visit. 
3. 
Current or previous participation in an interventional study to treat STGD such as 
gene therapy or stem cell therapy. Current participation in a drug trial or previous 
participation in a drug trial within six months before enrollment. The use of oral 
supplements of vitamins and minerals are permitted although the use of Vitamin A 
supplementation shall be documented if available. 
4. 
The site Principal Investigator may declare any patient at their site ineligible to 
participate in the study for a sound medical reason prior to the patient’s enrollment 
into the study. 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.5 
Primary and Secondary Outcome Variables 
The primary outcome variable for the ProgSTAR study is the yearly rate of progression of 
STGD as reflected by the growth or the development of atrophic lesions measured by FAF 
imaging.  
 
The secondary outcome variables are:  
• Yearly rate of progression of STGD using spectral-domain optical coherence 
tomography (sd-OCT) to measure the rates of retinal thinning and the loss of 
photoreceptors. 
• Yearly rate of loss of retinal sensitivity as measured by microperimetry. 
• Yearly change in best corrected visual acuity (VA). 
• Correlation of the presence and/or progression of morphological abnormalities in 
FAF and sd-OCT images with visual function as measured by microperimetry and 
BCVA. 
• Exploratory analysis to examine factors associated with disease progression, such as 
participant’s use of vitamin A supplementation and mutations in the ABCA4 gene. 
 
3.6 
Measures to Minimize/Avoid Bias 
Data from all sites will be sent, using a standardized, de-identified electronic clinical report 
form (eCRF), to a central data management center at the Dana Center for Preventive 
Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 
except in the case of data from retinal imaging procedures and microperimetry, which will be 
sent to a central reading center at the Doheny Eye Institute, Keck School of Medicine, 
University of Southern California for further processing.  Each center shall have undertaken 
standardized collection of all data. Ophthalmic outcome data from the microperimetry, sd-
OCT and fundus autofluorescence assessments will be electronically submitted from the site 
to the appropriate reading center via secure data upload through the reading center internet 
website.  
 
Once processed and analyzed by the appropriate reading center, all data will be transferred 
electronically from the reading center to the Dana Center system via a secure transfer process. 
Only coded identifiers will be used to identify participants. 
 
3.6.1 
Blinding 
Not applicable. 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.6.2 
Study Data 
 
See also Fig. 5 where it is explained that there will be two to four datasets (“visits”) per 
patient. 
 
 
 
Table 3.6.2  
Study Data 
ASSESSMENT/DATA 
COLLECTION POINTS 
VISIT -4 (if 
applicable) 
VISIT -3 (if 
applicable) 
VISIT 
-2 
Visit -1 (if Patient has 
Screening Visit of 
FFBCRI-PROGSTAR 02 
(Best-corrected) visual acuity 
data 
X 
X 
X 
X 
Ophthalmic fundus exam data 
X 
X 
X 
X 
Autofluorescence imaging data 
and/or 
X 
X 
X 
X 
Microperimetry data and/or 
X 
X 
X 
X 
sd-OCT data 
X 
X 
X 
X 
Vitamin A supplementation 
data recorded if available 
X 
X 
X 
X 

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21 March 2013 
 
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3.7 
 Data collection 
The Screening consists of review of existing data obtained through the following procedures: 
 
Medical and ophthalmic history: 
 
1. Recording and documentation of demographic information 
2. Recording and documentation of vitamin A supplement use 
3. Recording and documentation of genetic mutations in the ABCA4 gene 
 
 
Description of Standard of Care examinations and procedures the investigators had utilized to 
obtain data that had been collected for this study include: 
 
Best-corrected Visual acuity (VA): 
Visual acuity was measured at a distance of one or four meters using an ETDRS chart. 
Patients were encouraged to read each letter, and instructed to guess if unsure. 
 
Fundus-Autofluorescence (FAF) and spectral-domain optical coherence tomography (sd-
OCT): 
Images of patient’s eyes were recorded using sd-OCT, and scanning laser ophthalmoscopy 
(cSLO) in order to acquire fundus autofluorescence images. The computer driven cameras 
used in these techniques used a beam of light to take images.  
 
Microperimetry: 
Patients had undergone an examination of the retinal central visual field using 
microperimetry. During this procedure patients had to press a button when they saw a little 
light spot on a screen of a special computer monitor.  
 
An ophthalmic examination will be used to determine if the participant exhibits the typical 
clinical appearance of STGD in assessing eligibility for the study. 
 
In order to participate in the study, all patients must have documentation of two (2) 
pathogenic mutations confirmed in the ABCA4 gene from previously completed genetic 
testing. If only one ABCA4 allele contains a pathogenic mutation(s), the patient should have a 
typical Stargardt phenotype, namely at least one eye must have flecks at the level of the 
retinal pigment epithelium typical for STGD.  The genetic testing will have been previously 
completed and outside the scope of this study. 
 
The data from the visits will be utilized in the study even if the order of the examinations 
change from visit to visit or between the practices of the different investigators, and the 
examinations are performed on different days as long as all measurements were completed 
within a time window of ± five (5) weeks of each other. 
 

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3.7.1. 
Safety Assessments 
Due to the observational design of the natural course study, no study specific safety 
assessments are needed. 
 
3.7.1.1. 
Adverse Events 
Due to the observational design of the natural course study, no adverse events are expected. 
 
3.7.1.2. 
Clinical Laboratory Data 
Not applicable 
 
3.7.1.3. 
Evaluations 
A member of the study group participating in the study will document all significant 
observations. At a minimum, this documentation will contain: 
• The informed consent process, including any revised consents 
• The date of the visit and evidence that the required measurements were performed 
within 5 weeks of each other 
• The genetic information at time of enrollment 
• Whether the patient with one affected allele presents with typical Stargardt disease 
the basis for that conclusion 
• Any comments made by the participant about the study, including any significant 
medical findings 
• Any Vitamin A supplement use if available 
• A general reference to the provided procedures 
• The signature (or initials) and date of all clinicians who made an entry in the progress 
notes 
• The evaluation of (best-corrected) visual acuity 
• The evaluation of microperimetry test and recording of mean sensitivity and/or 
• The evaluation of spectral-domain optical coherence tomography (sd-OCT) and/or 
• The evaluation of fundus autofluorescence 
• A summary of the ophthalmologic exam including status of the anterior segment of 
the eyes, including the cornea, anterior chamber, iris and grading cataract, and dilated 
fundus exam 
 
In addition, any contact with the participant via telephone or other means that provides 
significant clinical information will also be documented as described above. Information 
from the study progress notes and other source documents will be promptly transcribed to 
eCRFs for transmission to the Coordinating Center. Any changes to information in the study 
progress notes, other source documents, and CRFs will be properly tracked. 
 
3.7.1.4. 
Labs Performing Evaluations and Special Precautions 
Not applicable 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.7.1.5. 
Sharing Research Results 
As the data collected in this observational study is collected from standard clinical care 
ophthalmologist visits, the results of each individual’s procedures conducted, including any 
clinically significant abnormal findings, will be shared with that study participant or his/her 
primary care provider.  
 
3.7.2. 
Endpoints 
3.7.2.1. 
Primary Statistical Endpoint  
The primary endpoint is the rate of the growth or the development of atrophic lesions as 
measured by FAF imaging calculated over a period of at least 24months, up to 60 months. 
 
3.7.2.2. 
Secondary Statistical Endpoints 
The secondary endpoints are: 
 
• Rate of retinal thinning and photoreceptor loss as measured by sd-OCT calculated 
over a period of at least 24 months, up to 60 months. 
• Loss of retinal sensitivity as measured by microperimetry calculated over a period of 
at least 24 months, up to 60 months. 
• Change of best-corrected visual acuity by using the ETDRS protocol calculated over 
a period of at least 24 months, up to 60 months. 
 
3.8. 
Withdrawal Criteria, and Procedures 
All participants have the right to withdraw from the study at any time, for any reason, 
without prejudice. When known, the reasons for withdrawal shall be fully evaluated and 
recorded appropriately in source documents and the eCRF. 
 
If the study sponsor, the Foundation Fighting Blindness Clinical Research Institute (FFB 
CRI), discontinues the study for any reason, such reasons will be thoroughly documented in 
the source documents and eCRFs, and all local study site IRB’s and HRPO will be notified 
immediately. 
 
3.9. 
Definition of Completed 
The study period is defined as the time period during which participants are evaluated for the 
primary and secondary objectives of the study. Participants who have been followed for at 
least two (2) visits and were followed over a period of at least 24 months, up to 60 months 
and had at least two examinations (same data at all visits: Fundus Autofluorescence obtained 
with a Heidelberg Engineering instrument; SD-OCT obtained with the Heidelberg Spectralis; 
microperimetry obtained with the Nidek MP-1) shall be defined as having completed the 
study. 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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3.10. 
Participant Compliance 
Not applicable. 
 
3.11. 
Protocol Deviations 
This study shall be conducted according to this written protocol. In the event of a significant 
deviation from the protocol as a result of an emergency, accident, or mistake, the investigator 
or designee must contact the Study Director, as soon as possible, by telephone.  A joint 
decision will then be made regarding the participant’s continuation in the study and the 
decision documented by the investigator and the Study Director and reviewed by the monitor.  
In addition, the investigator must notify the IRB to the extent necessary under GCP and local 
requirements. The sponsor, the Foundation Fighting Blindness Clinical Research Institute 
shall be notified of any protocol deviations and shall forward a detailed report any serious 
deviations to HRPO immediately. Any non-serious deviations shall be reported to HRPO as 
part of the annual study progress report. 
 
3.12. 
Protocol Modifications 
No changes shall be made to this protocol by site principal investigators or any other site 
staff without prior written consent and approval from the Study Director, the Sponsor [the 
Foundation Fighting Blindness Clinical Research Institute (FFB CRI)], their respective IRBs, 
and HRPO. Amendments shall be submitted to the IRBs for review and approval prior to 
implementation. Any permanent change to the protocol, whether an overall change or a study 
center specific change(s), must be treated as a protocol amendment. Any amendment to the 
protocol that is deemed necessary as the study progresses will be fully discussed by the 
investigator(s). Except for administrative amendments, investigators must await IRB 
approval of protocol amendments before implementing the change(s). Administrative 
amendments are defined as amendments that do not affect the safety of the research 
participants, the scope of the investigation, or the quality of the trial. However, if a protocol 
amendment is required to eliminate an apparent and immediate hazard to participants, the 
amendment should be implemented immediately, and the IRB notified within 5 days.  
 
Any deviation to the protocol that may have an effect on the safety or rights of the participant 
or the integrity of the study must be reported to the local IRBs and to the USAMRMC ORP 
HRPO as soon as the deviation is identified. Any corrective actions taken to avoid future 
deviations shall be included in the report. 
 
All unanticipated problems involving risk to participants or others related to participation in 
the study should be promptly reported by phone (301-619-2165), by email 
(hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office of 
Research Protections, Human Research Protection Office. A complete written report will be 
provided to HRPO following the initial notification.  In addition to the methods above, the 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
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complete report will be sent to the U.S. Army Medical Research and Materiel Command, 
ATTN: MCMR-ZB-PH, 504 Scott Street, Fort Detrick, Maryland 21702-5012. 
 
When, in the judgment of the chair of the local IRB and the investigators, the amendment to 
the protocol substantially alters the study design and/or increases the potential risk to the 
participant, the current approved written informed consent form shall be revised and if 
applicable, the participants shall be asked to sign a new written informed consent. 
 
Major modifications to the research protocol and any modifications that could potentially 
increase risk to participants will be submitted by the Sponsor to the USAMRMC ORP HRPO 
for approval prior to implementation. All other amendments will be submitted by the Sponsor 
with the continuing review report to the USAMRMC ORP HRPO for acceptance.  
 
4. 
Study Personnel 
4.1. 
Roles and Responsibilities of Key Study Personnel 
Hendrik P.N. Scholl, M.D., M.A, is the Study Director and the Principal Investigator at the 
Wilmer Eye Institute site. His responsibilities include: the overall study design; coordination 
and execution of the study; analysis of the data; review of any protocol deviations; and 
dissemination of the study findings. Dr. Scholl will also submit the study protocol to the local 
IRB, obtain informed consent and be responsible for: obtaining the medical history of 
participants; documenting findings obtained at previous clinical visits from patient charts; 
resolving any data concerns; and overall oversight of the protocol at the Wilmer Eye Institute 
site. 
 
Janet Sunness, M.D. is the site Principal Investigator at the Greater Baltimore Medical Center 
site. She will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; documenting findings obtained 
at previous clinical visits from patient charts; resolving any data concerns; and overall 
oversight of the protocol at Greater Baltimore Medical Center. 
 
Artur Cideciyan, Ph.D. is the site Principal Investigator at the University of Pennsylvania, 
Scheie Eye Institute. He will submit the study protocol to the local IRB, obtain informed and 
be responsible for: obtaining the medical history of participants; documenting findings 
obtained at previous clinical visits from patient charts; resolving any data concerns; and 
overall oversight of the protocol at Scheie Eye Institute. 
 
Elias Traboulsi, M.D. is the site Principal Investigator at Cleveland Clinic's Cole Eye 
Institute. He will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; documenting findings obtained 
at previous clinical visits from patient charts; resolving any data concerns; and overall 
oversight of the protocol at Cleveland Clinic's Cole Eye Institute. 
 

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José-Alain Sahel, M.D. is the site Principal Investigator at the Centre de Recherche Institut 
de la Vision(Center for Rare Diseases, Hôpital Quinze-Vingts) Paris. He will submit the 
study protocol to the local IRB, obtain informed consent and be responsible for: obtaining the 
medical history of participants; documenting findings obtained at previous clinical visits 
from patient charts; resolving any data concerns; and overall oversight of the protocol at the 
Centre de Recherche Institut de la Vision, Paris. 
 
Eberhart Zrenner, M.D. is the site Principal Investigator at the University Eye Hospital 
Tübingen. He will submit the study protocol to the local IRB, obtain informed consent and be 
responsible for: obtaining the medical history of participants; documenting findings obtained 
at previous clinical visits from patient charts; resolving any data concerns; and overall 
oversight of the protocol at University Eye Hospital Tübingen. 
 
Michel Michaelides, M.D., F.R.C.Ophth. is the site Principal Investigator at the Moorfields 
Eye Hospital NHS Foundation Trust. He or designated members of the research team will: 
submit the study protocol to the local IRB and obtain informed consent; be responsible for 
obtaining the medical history of participants, documenting findings obtained at previous 
clinical visits from patient charts. He will have overall oversight of the protocol at 
Moorfields Eye Hospital NHS Foundation Trust. 
 
Paul S. Bernstein, MD, PhD is the site Principal Investigator at the University of Utah, 
School of Medicine, Moran Eye Center. He will submit the study protocol to the local IRB, 
obtain informed consent and be responsible for: obtaining the medical history of participants; 
documenting findings obtained at previous clinical visits from patient charts; resolving any 
data concerns; and overall oversight of the protocol at the University of Utah. 
 
David G. Birch, PhD is the site Principal Investigator at the Retina Foundation of the 
Southwest. He will submit the study protocol to the local IRB, obtain informed consent and 
be responsible for: obtaining the medical history of participants; documenting findings 
obtained at previous clinical visits from patient charts; resolving any data concerns; and 
overall oversight of the protocol at the Retina Foundation of the Southwest. 
 
Sheila West, Ph.D., is Director of the Dana Center for Preventive Ophthalmology at the 
Wilmer Eye Institute. She will lead the data management coordinating center activities 
associated with this study and be responsible for study site monitoring, data collection and 
management, and the statistical analysis of the study data. 
 
Srinivas R. Sadda, M.D. is Associate Professor of Ophthalmology and Director of the 
Doheny Image Reading Center at the Keck School of Medicine, University of Southern 
California. He will lead the image collection, reading, and imaging analysis of the study data 
arising from retinal imaging and microperimetry. 
 

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4.2. 
Conflict of Interest 
As this protocol does not support the development of a drug, device, or other intellectual 
property, there is no immediate concern about conflict of interest.  If any concerns arise, 
conflict of interest statements will be obtained on a case-by-case basis. 
 
5. Prohibited Medications 
Study participants may use any systemic medications that are necessary.  However, study 
participants should not participate or have participated in, or taken concomitant therapy, to 
treat Stargardt disease within six months before the observation period.  Study candidates 
who have participated in an interventional study for Stargardt disease before the end of the 
retrospective observation period are also excluded – see study exclusion criteria. 
 
6. Evaluation of Adverse Events 
Not applicable. 
7. Statistical Analysis 
7.1. 
Sample Size and Power 
Prior to establishing this study protocol, a feasibility survey was undertaken. The survey 
consisted of a questionnaire that was sent to the participating centers to determine how many 
study candidates might be available at each center for this prospective study. 
 
The primary outcome of the study is the yearly growth in the area of the atrophic lesion as 
measured by fundus auto-fluorescence.  A recent paper by Chen et al [36] reported that in a 
group of 24 STGD participants with well defined atrophic lesions at baseline, the mean 
yearly growth of the lesion was 0.94 mm2 ± 0.87.  
 
The reliability of measuring areas of geographic atrophy using images taken with a confocal 
scanning laser ophthalmoscopy has been described by Deckert et al [37]. Using 2 different 
readers to examine images from 34 eyes, the mean difference in area affected for the 
proposed quantification algorithm was 0.12mm2 with a 95% confidence interval (0.02, 0.22). 
 
Using the above parameters as a reference, we calculated the power to detect yearly 
progression for sample sizes between 120 and 240 participants, with standard deviations 
between 0.9 and 1.1, and expected lesion progression rates of 0.40 and 0.50 mm2 per year 
(Figure 7).  A clinically meaningful progression rate should be greater than the variability of 
the measurement.  The power calculations were set to test for lesion progression rates above 
0.2 mm2 which is the estimate of the upper bound of the difference that could be attributable 
solely to measurement error.   

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Figure 7: Power calculations for expected lesion progressions rates of 0.40 and 0.50 mm2 per year 
 
A sample size of 170 achieves 80% power to detect a difference of 0.2 between the null 
hypothesis mean of 0.2 mm2 (measurement error) and the alternative hypothesis mean 
progression of the lesion of 0.4 mm2 with an estimated standard deviation of 0.9 and a 
significance level α= 0.05 using a two-sided Wilcoxon test (Figure 5 (a)). Similarly, if the 
expected standard deviation increases to 1.0 we need 200 participants to achieve the same 
level of power.  When the expected progression rate is ≥0.50 mm2, a sample size of 120 
participants achieves more than 80% to detect differences beyond the expected measurement 
error, for standard deviations ≤1.1 (Figure 5 (b)).  
 
7.2. 
Statistical Analyses 
Estimating the yearly growth in the area of the atrophic lesion as measured by fundus 
auto-fluorescence: 
 
First exploratory analysis looking at the overall distribution of the outcome at all visits will 
be carried out, outliers and inconsistent measures will be identified and reviewed. 
By design, the interval between visits will be variable. For each individual, a slope will be 
estimated using the available data points by fitting a regression line to the data points. For 
example, if the ith subject contributes with 3 visits the times ti0, ti,-1, ti,-2 with outcome 
observations yi0, yi,-1, yi,-2 will be used to estimate the slope bi, which will be obtained from 
the regression yik=a+bitik. (k=0,-1,-2). Once the data from each individual has been used to 
estimate the slope (b), the second stage of the analysis will be to explore which 
exposures/risk factors determine the heterogeneity of the slopes. Using the slope as the 
outcome, multivariate regression models will be constructed to identify factors correlating 
(a)
Expected progression rate
0.40mm2 per year
(b)
Expected progression rate
0.50 mm2 per year
*Assuming  that test retest differences could be as high as 0.2 
Power to detect progression rates for a range of sample sizes and standard deviations 
with a two-sided significance level α=0.05*
0.9
1.0
1.1
Power
Std Dev
Sample size
0.4
0.6
0.8
1.0
100
150
200
250
0.9
1.0
1.1
Power
Std Dev
Sample size
0.4
0.6
0.8
1.0
100
150
200
250

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with progression. Specifically, the correlation to progression of age, severity at first visit, and 
use of vitamin A supplementation will be examined. 
 
A similar approach to will be used to examine progression over time for the secondary 
outcomes: retinal thinning, loss of photoreceptors, loss of retinal sensitivity, and changes of 
BCVA. 
 
7.3. 
Demographic Characteristics 
Demographic characteristics are: date of birth, age, sex, and race. Randomization is not 
applicable. 
 
7.4. 
Data Set Descriptions 
Study Population  
Patients with STGD enrolled into the study shall have had previous genetic testing and a 
finding of at least 2 pathogenic mutations in the ABCA4 gene. However, if only one ABCA4 
allele containing a pathogenic mutation is detected, a patient may be enrolled if they have a 
typical Stargardt phenotype, i.e. at least one eye must have flecks at the level of the retinal 
pigment epithelium typical of STGD. 
 
Data Sets for Endpoint Analyses 
The possible final data sets are illustrated in Figure 5.  
 
7.5. 
Handling of Missing Data 
A requirement for inclusion to the study is that the subject has information on the main 
outcome for all the eligible visits. We do not expect missing data for the main outcomes 
because of the study design. 
 
7.6. 
Safety Analyses 
This is an observational study of the natural course of STGD. All investigations included 
were part of standard of clinical care for patients affected by STGD. Therefore, no study-
specific safety events are anticipated. 
 
7.7. 
Study Drug Compliance 
Not applicable  
 
7.8. 
Interim Analysis 
An interim analysis of the study data is not planned. 
 

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8. Study Product Management 
Not applicable 
 
9. Data Handling and Records Management 
Any questions about the protocol or eCRFs will be referred to the sponsor or its 
representatives, by the Dana Center. 
 
9.1. 
Data Collection 
Study Forms 
Most patient data are collected on paper and kept at each individual clinic center. Therefore, 
in this study, paper copies of the study forms shall be created from an electronic clinical 
report form (eCRF) that was developed specifically for the study using REDCap software 
(Appendix 4, Data Collection forms). Once the paper study forms have been completed with 
patient data, the clinical investigator shall review the data for accuracy and sign their 
signature to approve the forms.  
 
Once the data are approved by the investigator, the clinic coordinator will log into REDCap 
using a unique user id and password. When entering a new study participant, the coordinator 
must first fill out the eligibility form that assigns a unique ID to the participant. If the clinic 
coordinator is entering data for a participant already enrolled in the study, the coordinator 
must first enter the participant’s ID, and then select the appropriate form.  Data are 
subsequently entered into the forms using 100% double data entry.  
 
The programs developed in REDCap contain a series of data checks within each form to 
check that: 
a) All entries are within the allowed range. 
b) There is internal consistency (i.e., skip patterns) within each form. 
c) Duplicate entries do not occur. 
d) All required fields are entered; if not, the record is flagged as incomplete. 
e) Double data entry is completed after the first entry to ensure the integrity of the data. 
f) Any reports created indicate any missing or incomplete records. 
g)  Reports are issued to help the Clinic Coordinator manage upcoming appointments, 
and follow-up with missed appointments. 
h) All data entries and changes are logged in an electronic audit trail that tracks who 
made the change, on what date and time the change was made, and the field name(s) 
and value(s) of the change. The system also logs any changes made to the structure of 
the forms by the DCPO DCC. 
 
There are two methods planned in order to transfer imaging data to the Central Reading 
Center. This is described in detail in a separate standard operating procedure. Generally, 
imaging data are not compressed.  

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Option 1: The Reading Center has its own secure servers, where images are to be directly 
uploaded by the clinic centers  
Option 2: Create a CD-DVD to be mailed to the reading center 
 
A member of the study group will document all significant observations.  At a minimum, 
these notes will contain: 
• Documentation of the informed consent process, including any revised consents 
• The date of the visit and the corresponding Visit, Day, or Week in the study schedule 
• A general reference to the procedures completed 
• A dated signature, or initials, of all clinicians who made an entry in the progress 
notes. 
 
In addition, any contact with the participant via telephone or other means that provides 
significant clinical information will also be documented. 
 
Information from the study progress notes and other source documents will be promptly and 
legibly transcribed to eCRFs for transmission to the data management center. 
 
Any changes to information in the study progress notes, other source documents, and CRFs 
will be initialed and dated on the day the change is made by a site study staff member 
authorized to make the change.  Changes will be made by striking a single line through 
erroneous data, and clearly entering the correct data (e.g., wrong data right data).  If the 
reason for the change is not apparent, a brief explanation for the change shall be written in 
the source documentation by the clinician.  Correction fluid shall not be used at any time. 
 
9.1.1. Volunteer Identification 
Each center shall de-identify patient data. Patient data shall be encoded by a five-digit code 
number: the first two numbers shall indicate the number of the study center and the last three 
numbers shall label the patients in an ascending ordinal scale (for example, following 
patient’s enrollment on the study). Data shall be collected using electronic clinical report 
form (e-CRF) and shall be centrally managed at the Dana Center for Preventive 
Ophthalmology. 
 
9.1.2. Confidentiality 
The data collected during the study had been obtained at the study sites as part of standard 
clinical care. Charts shall be secured to protect privacy of patients and maintain 
confidentiality. Clinical data shall be entered on electronic Case Report Forms (eCRFs) for 
transmission to the coordinating center in accordance with the procedures specified in the 
current Manual of Standard Operating Procedures (SOPs) for this trial. Data on eCRFs 
transmitted to the coordinating center shall correspond to, and be supported by, source 
documentation maintained at the site. All study forms and records transmitted to the 

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coordinating center shall carry only coded identifiers such that personal identifying 
information is not transmitted to the coordinating center. 
 
The Johns Hopkins Biostatistics Center (JHBC) servers that host the data are protected by 
both a hardware firewall and a web application firewall. In addition, they have multi-level 
intrusion detection, network security audits, and secondary hardware on standby for 
immediate replacement. JHBC administrators connect to the REDCap servers for system 
administration using a VPN connection and a two-factor authentication method. All data 
transmitted between the client browser and REDCap web servers are encrypted using an SSL 
connection. JHBC system administrators regularly monitor server logs and services to ensure 
that the servers are secured. They also ensure that server updates are applied in a timely 
manner and that the data are regularly backed up and stored securely off-site. 
 
Ophthalmic outcome data from the microperimetry, sd-OCT and fundus autofluorescence 
assessments will be submitted electronically from the site to the Reading Center via secure 
data upload. 
 
Once processed and analyzed by the Reading Center, the data will be transferred 
electronically from the Reading Center to the Dana Center system via a secure transfer 
process. Only coded identifiers will be used to identify participants.  
 
9.1.3. Access 
At each site, the site investigator and the personnel designated by him shall have access to 
source documents. De-identified data shall be collected at the Data Coordinating Center at 
Johns Hopkins. All site investigators, their designated personnel, study staff at Johns 
Hopkins University and study staff at the reading center shall have access to the database of 
de-identified data.  
 
Representatives of the USAMRMC and FFB CRI have the authority to review research 
records. 
 
9.1.4. Reporting Requirements 
The investigators of each site shall take care to meet the requirements for reporting sensitive 
information to state or local authorities. For example the investigators might seek guidance 
from their institutional review boards when considering how to report information such as 
positive human immunodeficiency virus (HIV) status, hepatitis or tuberculosis test results, 
illegal residency, child or spouse abuse, or participation in other illegal activities. 
 
9.2. 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation.  Source documents shall include, but are not limited to, progress notes, 
electronic data, screening logs, study worksheets, and data recorded from automated 

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instruments.  All source documents pertaining to this study shall be maintained by the 
investigators and made available for inspection by authorized persons. 
 
9.3. 
File Management at the Study Site 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with Section 8 of the ICH GCP Guideline. 
 
9.4. 
Records Retention at the Study Site 
The investigator shall take responsibility for maintaining adequate and accurate electronic or 
hard copy source documents of all observations and data generated during this study, 
including any data quality queries received from the data management center.  Such 
documentation is subject to inspection by FFB CRI and relevant agencies, such as 
USAMRMC.  If the investigator withdraws from the study, all study related records shall be 
transferred to a mutually agreed upon designee.  Notice of such transfer will be given to FFB 
CRI in writing.  
 
The investigator shall not dispose of any records relevant to this study without written 
permission from FFB CRI and without providing FFB CRI the opportunity to collect such 
records. Generally, records are kept for a minimum of ten years 
 
9.5. 
Data Management Considerations 
Data will be stored in the REDCap system (section 9.1).  
 
Every effort shall be made to ensure that data management practices adhere to international 
standardization of the following data management procedures.   
 
9.5.1. Database Design and Creation 
An appropriate database shall be designed and created within a validated Clinical Data 
Management System (CDMS). This database shall be designed to store the data recorded on 
the CRFs and shall ensure a one-to-one mapping between the CRF and the electronic copy 
stored in the system (section 9.1). 
 
9.5.2. Data Coding 
Upon completion of CRF data entry, a secondary, in-house clinical review shall be 
conducted. Adverse event coding shall be undertaken using the current version of the 
MedDRA dictionary (version 12.1). The version of this dictionary will remain the same 
throughout the study. 
 

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9.5.3. Data Transfer 
Data shall be transferred to the Dana Center of Preventive Ophthalmology, Wilmer Eye 
Institute of the Johns Hopkins University, Baltimore, Maryland.  The transfer shall be 
electronic and shall happen on a defined schedule, in a data format mutually agreed upon by 
the Dana Center of Preventive Ophthalmology (study central data management center). 
 
9.5.4. Data Validation 
After the data have been entered and verified, various edit checks shall be performed to 
ensure the accuracy, integrity and validation of the database against the CRFs. 
Inconsistencies that arise from these edit checks shall be resolved with the investigator or 
designee. 
 
9.5.5. Database Lock 
Upon completion of the trial and completion of data entry, verification and validation, the 
database shall be locked and write access removed. 
 
10. Quality Control and Quality Assurance  
10.1. Monitoring 
The Data Coordinating Center shall undertake on-site monitoring of study data for the 
duration of the study. These clinical site monitoring visits shall be conducted during the 6-
months study conduct phase. Other clinical site monitoring visits shall be conducted on an 
as-needed basis.  It is anticipated that remote data monitoring of randomly determined data 
points will be completed by the Data Coordinating Center. 
 
The Data Coordinating Center may also conduct study site visits, on the sponsor’s behalf.  
The study shall be monitored in compliance with the relevant parts of 45 CFR and according 
to the ICH GCP Guidelines. Site visits shall include, but are not limited to, verifying the 
presence of required documents, verifying the informed consent process, and comparing case 
report forms with source documents. Each investigator agrees to participate in site visits 
conducted at a reasonable time in a reasonable manner. Regulatory authorities may also audit 
the investigator during or after the study.  If a regulatory authority announces an audit, the 
investigator should contact the sponsor immediately, and must fully cooperate with these 
audits within a reasonable time in a reasonable manner. 
 
The knowledge of any pending compliance inspection or visit by the DHHS-OHRP, or other 
government agency concerning clinical investigation or research, the issuance of Inspection 
Reports, warning letters or actions taken by any Regulatory Agencies including legal or 
medical actions and any instances of serious or continuing noncompliance with the 

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regulations or requirements shall be reported immediately to the Study Director, FFBCRI, 
and USAMRMC ORP HRPO.  
 
FFB CRI has ethical, legal, and scientific obligations to carefully follow this study in a 
detailed and orderly manner in accordance with established research and GCP principles.  As 
part of a concerted effort to fulfill these obligations FFB CRI study monitors or its designee 
shall visit the center during the study in addition to maintaining frequent telephone and 
written communications. 
 
10.2. Auditing 
FFB CRI may conduct audits at the study site(s).  Audits shall include, but are not limited to, 
verifying the presence of required documents, verifying the informed consent process, and 
comparing the case report forms with source documents.  The investigator agrees to 
participate with such audits conducted at a reasonable time in a reasonable manner. 
 
Regulatory authorities worldwide may also audit the investigator during or after the study.  If 
a regulatory authority announces an audit, the investigator should contact FFB CRI 
immediately, and must fully cooperate with the audits within a reasonable time in a 
reasonable manner. 
 
11. Ethics and Responsibility 
This study shall be conducted in compliance with this study protocol, the ICH GCP 
Guidelines, the applicable regulatory requirements, and the current Declaration of Helsinki. 
 
11.1. Clinical Study Report 
A review report shall be submitted to the local IRB(s) by each of the clinical sites, if required 
by the host country.  A copy of this report and IRB approval notification shall be submitted 
to the HRPO by the sites as soon as these documents become available. In host countries that 
do not require an annual IRB report, the site will prepare and submit an annual report 
summary to HRPO, per HRPO guidelines.  A copy of the approved final study report and the 
central IRB approval notification shall also be submitted to the HRPO by the Sponsor as 
soon as available. 
 
The report shall include a discussion of the study objectives, methodology, clinical 
observations and conclusions in relation to the study objectives. 
 
12. Confidentiality 
All information generated in this study shall be considered highly confidential and shall not 
be disclosed to any persons not directly concerned with the study without written prior 

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permission from FFB CRI.  However, authorized HRPO representatives, regulatory officials, 
and FFB CRI personnel (or their representatives) shall be allowed full access to inspect and 
copy the records.  All participants’ materials collected shall be used solely in accordance 
with this protocol, unless otherwise agreed to in writing by FFB CRI. Participants shall be 
identified only by their unique participant numbers in CRFs. However, their full names may 
be made known to a regulatory agency or other authorized officials, if necessary. 
 
Accurate and complete study records will be maintained and made available to 
representatives of the U.S. Army Medical Research and Materiel Command. These 
representatives are authorized to review research records as part of their responsibility to 
protect human research volunteers. Research records will be stored in a confidential manner 
so as to protect the confidentiality of participant information. 
13. Amendment Policy 
The investigator shall not make any changes to this protocol without prior written consent 
from FFB CRI and subsequent approval by the IRB and HRPO.  Any permanent change to 
the protocol, whether it is an overall change or a change for specific study center(s), shall be 
handled as a protocol amendment.  Any amendment to the protocol that appears indicated as 
the study progresses shall be fully discussed between the investigator(s), the study director 
and FFB CRI.  If agreement is reached regarding the need for an amendment, it shall be 
written by FFB CRI.  The written amendment shall be submitted to the study central IRB 
identified with this responsibility (WIRB); upon approval by WIRB, to HRPO and then to 
each of the clinical sites will submit the amendment to their local IRB for review and 
approval.  Except for ‘administrative amendments’, investigators shall await IRB approval of 
protocol amendments before implementing any change(s).  Administrative amendments are 
defined as amendments that have no effect on the safety of the research participants, the 
scope of the investigation, or quality of the trial. However, a protocol change intended to 
eliminate an apparent immediate hazard to participants should be implemented immediately, 
and the IRB notified within 5 days.  FFB CRI shall submit protocol amendments to the 
HRPO, or other regulatory agencies, as required. 
 
When, in the judgment of the chairman of the local IRB, HRPO, the investigators, the study 
director and/or FFB CRI, the amendment to the protocol substantially alters the study design 
and/or increases the potential risk to the participant, the currently approved written informed 
consent form shall require similar modification.  In such cases, a new informed consent shall 
be obtained from participants enrolled in the study before expecting continued participation. 

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14. References 
 
1. 
Stargardt, K., Ueber familiaere, progressive Degeneration in der Makulagegend 
des Auges. Graefes Arch Clin Exp Ophthalmol, 1909. 71: p. 534-549. 
2. 
Allikmets, R., et al., A photoreceptor cell-specific ATP-binding transporter gene 
(ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet, 1997. 
15(3): p. 236-46. 
3. 
Zhang, K., et al., A 5-bp deletion in ELOVL4 is associated with two related forms 
of autosomal dominant macular dystrophy. Nat Genet, 2001. 27(1): p. 89-93. 
4. 
Walia, S. and G.A. Fishman, Natural history of phenotypic changes in Stargardt 
macular dystrophy. Ophthalmic Genet, 2009. 30(2): p. 63-8. 
5. 
Walia, S., G.A. Fishman, and R. Kapur, Flecked-retina syndromes. Ophthalmic 
Genet, 2009. 30(2): p. 69-75. 
6. 
Fishman, G.A., et al., Visual acuity loss in patients with Stargardt's macular 
dystrophy. Ophthalmology, 1987. 94(7): p. 809-14. 
7. 
Kennedy, C.J., P.E. Rakoczy, and I.J. Constable, Lipofuscin of the retinal pigment 
epithelium: a review. Eye (Lond), 1995. 9 ( Pt 6): p. 763-71. 
8. 
Delori, F.C., et al., In vivo fluorescence of the ocular fundus exhibits retinal 
pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci, 1995. 
36(3): p. 718-29. 
9. 
Cideciyan, A.V., et al., Reduced-illuminance autofluorescence imaging in 
ABCA4-associated retinal degenerations. J Opt Soc Am A Opt Image Sci Vis, 
2007. 24(5): p. 1457-67. 
10. 
Holz, F.G., et al., Inhibition of lysosomal degradative functions in RPE cells by a 
retinoid component of lipofuscin. Invest Ophthalmol Vis Sci, 1999. 40(3): p. 737-
43. 
11. 
Cideciyan, A.V., et al., ABCA4-associated retinal degenerations spare structure 
and function of the human parapapillary retina. Invest Ophthalmol Vis Sci, 2005. 
46(12): p. 4739-46. 
12. 
Katz, R., Biomarkers and surrogate markers: an FDA perspective. NeuroRx, 
2004. 1(2): p. 189-95. 
13. 
Gomes, N.L., et al., A comparison of fundus autofluorescence and retinal 
structure in patients with Stargardt disease. Invest Ophthalmol Vis Sci, 2009. 
50(8): p. 3953-9. 
14. 
Maeda, A., et al., Involvement of all-trans-retinal in acute light-induced 
retinopathy of mice. J Biol Chem, 2009. 284(22): p. 15173-83. 
15. 
Chen, Y., et al., Mechanism of all-trans-retinal toxicity with implications for 
stargardt disease and age-related macular degeneration. J Biol Chem, 2012. 
287(7): p. 5059-69. 
16. 
Bok, D., G.S. Hageman, and R.H. Steinberg, Repair and replacement to restore 
sight. Report from the Panel on Photoreceptor/Retinal Pigment Epithelium. Arch 
Ophthalmol, 1993. 111(4): p. 463-71. 

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17. 
Davies, S., et al., Photocytotoxicity of lipofuscin in human retinal pigment 
epithelial cells. Free Radic Biol Med, 2001. 31(2): p. 256-65. 
18. 
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21 March 2013 
 
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8. 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
50 
Appendix 1 - Agreement 
Agreement Signatures 
 
I have read and understand the protocol and agree that it contains all the ethical, legal, 
and scientific information necessary to conduct this study. I shall personally conduct the 
study as described herein and in FFB CRI’s Clinical Research Agreement. 
 
I shall provide copies of the protocol to all physicians, nurses, and other professional 
personnel responsible to me who participate in the study.  I shall discuss the protocol with 
them to assure myself that they are sufficiently informed about the endpoint parameters 
and the conduct of the study in general to perform the study correctly. I am aware that 
this protocol must be approved by the local IRB responsible for my Clinical Study 
Facility and that IRB approval is required prior to commencement of this study. I agree to 
adhere strictly to the attached protocol unless it is amended in the manner set forth in 
Paragraph 1 of FFB CRI’s Clinical Research Agreement.  In that case, I agree to adhere 
strictly to the amended protocol. I agree that clinical data entered on case report forms by 
me and my staff shall be used by FFB CRI in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered 
from other research sites, whenever applicable.  I agree to allow monitors and auditors, or 
their designees, full access to all medical records at the research facility for participants 
screened or enrolled in the study. 
 
I agree to provide all participants with informed consent forms, as required by 
government and ICH regulations.  I agree to report to FFB CRI any adverse experiences 
in accordance with the terms of FFB CRI, or designee’s, Clinical Research Agreement 
and FDA regulations, 45 CFR 312.64.  I further agree to provide all required information 
regarding financial certification or disclosure to FFB CRI for all investigators and sub-
investigators in accordance with the terms of FDA regulation 45 CFR 54.  I understand 
that participation in the protocol involves a commitment to publish the data from this 
study in a cooperative publication prior to publication of efficacy and safety results on an 
individual basis. 
 
 
 
 
Signature 
 
 
Date 
Site Principal Investigator 
 
Signature 
 
 
Date 
Hendrik P.N. Scholl, M.D., M.A. 
Study Director 
 
 
 
Signature 
 
 
Date 
Sheila West, Ph.D. 
Study Biostatistician 
 
Signature 
 
 
Date 
Patricia Zilliox, Ph.D. 
Sponsor Representative 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
51 
Appendix 2– Additional Institutions and Personnel Involved With the Study 
Sponsor: 
Foundation Fighting Blindness Clinical Research Institute 
Patricia Zilliox, Ph.D.  
Project Officer/PI 
7168 Columbia Gateway Drive 
Suite 100 
Columbia, MD 21046  
Phone: +1 (410) 423-0581 
email: pzilliox@fightblindness.org 
Fax: +1 (410) 872-0574 
FWA: 00014475 
 
Judith Chiostri, M.S. 
Project Manager 
7168 Columbia Gateway Drive 
Suite 100 
Columbia, MD 21046  
Phone: +1 (410) 423-0582 
email: jchiostri@fightblindness.org 
Fax: +1 (410) 872-0574 
 
Expert Advisor: 
The Chicago Lighthouse for People Who are Blind or Visually Impaired 
Gerald Fishman, M.D. 
The Chicago Lighthouse for People Who are Blind or Visually Impaired 
1850 W. Roosevelt Road 
Chicago, IL 60608 
Phone: +1 (312) 666-1331 
e-mail: Gerald.Fishman@chicagolighthouse.org 
Fax: +1 (312) 243-8539 
FWA-Number: FWA00017514 
 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
52 
Appendix 3 – Biosketches of Key Personnel 
 
The biosketches of Key Personnel are attached. 
 
 

Protocol No.FFBCRI-PROGSTAR-01 
 
 
Confidential and Proprietary 
Foundation Fighting Blindness Clinical Research Institute 
21 March 2013 
 
53 
Appendix 4 – Electronic Clinical Report Form (eCRF) 
 
Print version of the electronic clinical report forms are attached