Stargardt Disease
Conditions
Keywords
genetic testing, ABCA4, Stargardt, retina, retinal degeneration
Brief summary
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. Participants will be recruited from each Investigator's own patient population as the study requires the availability of both multiyear retrospective data, as well as ongoing prospectively collected data. A concurrent ancillary study (SMART study) is also being conducted with a subset of the prospective study patients during their regular ProgSTAR study visits to expand the collection of retinal images to include microperimetry measurements gathered under scotopic (low light) conditions.
Interventions
None listed
Sponsors
United States Department of Defense
Foundation Fighting Blindness
Study design
Observational model
CASE_ONLY
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provide a signed informed consent form and authorization allowing the disclosure and use of protected health information. * 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. * 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. * The primary study eye must have clear ocular media and adequate pupillary dilation to permit good quality fundus autofluorescence (FAF) and Spectral-Domain optical coherence tomography (sd-OCT) imaging in the opinion of the investigator. * Be able to cooperate in performing the examinations. * Be willing to undergo ocular examinations once every 6 months for up to 24 months. * Be at least six years old. * Both eyes can be included if inclusion criteria are fulfilled for both eyes.
Exclusion criteria
* Ocular disease, such as choroidal neovascularization, glaucoma and diabetic retinopathy, in either eye that may confound assessment of the retina morphologically and functionally. * Intraocular surgery in the primary study eye within 90 days prior to baseline visit. * 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. * 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. * Any systemic disease with a limited survival prognosis (e.g. cancer, severe/unstable cardiovascular disease). * 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. * Evidence of significant uncontrolled concomitant diseases such as cardiovascular, neurological, pulmonary, renal, hepatic, endocrine or gastro-intestinal disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Yearly Progression Rate of Atrophic Lesions Using Fundus Autofluorescence (FAF) Images | 2-12 years | Yearly increase in area of decreased auto-fluorescence (DAF) which is defined as the sum of definite and questionable decreased auto-fluorescence |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Yearly Rate of Visual Acuity Loss | 2-12 years | Yearly change of visual acuity. Visual acuity measures of best-corrected or presenting VA extracted from medical record charts. Prospective cohort is best-corrected visual acuity using Early-Treatment Diabetic Retinopathy study methods |
| Difference in the Rate of Retinal Sensitivity Change Per Year Between Photopic and Scotopic Micro-perimetry Testing | 2 years | Difference in the yearly rate of change in retinal sensitivity under photopic and scotopic conditions. Sensitivity tested with a Nidek MP-1. Scotopic sensitivity was obtained using a 40 points test pattern, and photopic sensitivity was obtained using a 68 points test pattern in a subset of Prospective cohort patients |
| Yearly Rate of Loss of Overall Retinal Thickness | Participants followed at Baseline, 6 months, 12 months and 24 months | Yearly decrease of overall retinal thickness using spectral domain optical coherence tomography (SD-OCT) scans from a 20° x 20° scan area centered on the fovea. Data are only available for the Prospective cohort. |
| Yearly Rate of Loss of Retinal Sensitivity as Measured by Scotopic Microperimetry (MP) | 2 years | The yearly rate of change in retinal sensitivity. Sensitivity tested with a Nidek MP-1 machine using a modified Humphrey 10-2 grid. The sensitivity was the average sensitivity from a 68-points test pattern (Prospective cohort only) |
| Yearly Rate of Loss of the Inner Ring Retinal Thickness | Participants followed at Baseline, 6 months, 12 months and 24 months | Yearly decrease of the inner ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Inner ring defined as ETDRS fields 5-8. Data are only available for the Prospective cohort. |
| Yearly Rate of Loss of the Central Ring Retinal Thickness | Participants followed at Baseline, 6 months, 12 months and 24 months | Yearly decrease of the central ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Central area defined as ETDRS fields 9. Data are only available for the Prospective cohort. |
| Yearly Rate of Loss of Outer Ring Retinal Thickness | Participants followed at Baseline, 6 months, 12 months and 24 months | Yearly decrease of outer ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Outer ring defined as ETDRS fields 1-4. |
Countries
France, Germany, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Retrospective Cohort Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT)) | 251 |
| Prospective Cohort Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry. | 259 |
| Total | 510 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Total Study - Prospective | Death | 0 | 1 |
| Total Study - Prospective | Lost to Follow-up | 0 | 8 |
| Total Study - Prospective | No show | 0 | 1 |
| Total Study - Prospective | Not available at time of visit | 0 | 5 |
| Total Study - Prospective | Protocol Violation | 0 | 1 |
| Total Study - Prospective | Withdrawal by Subject | 0 | 13 |
Baseline characteristics
| Characteristic | Retrospective Cohort | Prospective Cohort | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 69 Participants | 51 Participants | 120 Participants |
| Age, Categorical >=65 years | 3 Participants | 7 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants | 201 Participants | 380 Participants |
| Race/Ethnicity, Customized Race Asian/Indian | 10 Participants | 10 Participants | 20 Participants |
| Race/Ethnicity, Customized Race Black or African American | 14 Participants | 20 Participants | 34 Participants |
| Race/Ethnicity, Customized Race Don't know/missing | 46 Participants | 4 Participants | 50 Participants |
| Race/Ethnicity, Customized Race More than one race | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White/Middle Eastern | 174 Participants | 222 Participants | 396 Participants |
| Region of Enrollment France | 49 participants | 48 participants | 97 participants |
| Region of Enrollment Germany | 33 participants | 44 participants | 77 participants |
| Region of Enrollment United Kingdom | 79 participants | 30 participants | 109 participants |
| Region of Enrollment United States | 90 participants | 137 participants | 227 participants |
| Sex: Female, Male Female | 149 Participants | 141 Participants | 290 Participants |
| Sex: Female, Male Male | 102 Participants | 118 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 251 | 1 / 259 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Yearly Progression Rate of Atrophic Lesions Using Fundus Autofluorescence (FAF) Images
Yearly increase in area of decreased auto-fluorescence (DAF) which is defined as the sum of definite and questionable decreased auto-fluorescence
Time frame: 2-12 years
Population: Eyes of participants with at least 2 visits with gradable fundus auto-fluorescence images with atrophic lesions present
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Progression Rate of Atrophic Lesions Using Fundus Autofluorescence (FAF) Images | 0.35 mm^2/year |
| Prospective Cohort | Yearly Progression Rate of Atrophic Lesions Using Fundus Autofluorescence (FAF) Images | 0.64 mm^2/year |
Secondary
Difference in the Rate of Retinal Sensitivity Change Per Year Between Photopic and Scotopic Micro-perimetry Testing
Difference in the yearly rate of change in retinal sensitivity under photopic and scotopic conditions. Sensitivity tested with a Nidek MP-1. Scotopic sensitivity was obtained using a 40 points test pattern, and photopic sensitivity was obtained using a 68 points test pattern in a subset of Prospective cohort patients
Time frame: 2 years
Population: Photopic microperimetry was obtained in a subset of patients, in a single designated study eye
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Prospective Cohort | Difference in the Rate of Retinal Sensitivity Change Per Year Between Photopic and Scotopic Micro-perimetry Testing | -0.78 dB/year |
Secondary
Yearly Rate of Loss of Outer Ring Retinal Thickness
Yearly decrease of outer ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Outer ring defined as ETDRS fields 1-4.
Time frame: Participants followed at Baseline, 6 months, 12 months and 24 months
Population: All visits of eligible eyes of the 258 participants with gradable thickness in the outer ring. Only OCT scans with adequate and fair quality are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Rate of Loss of Outer Ring Retinal Thickness | -2.84 microns/year |
Secondary
Yearly Rate of Loss of Overall Retinal Thickness
Yearly decrease of overall retinal thickness using spectral domain optical coherence tomography (SD-OCT) scans from a 20° x 20° scan area centered on the fovea. Data are only available for the Prospective cohort.
Time frame: Participants followed at Baseline, 6 months, 12 months and 24 months
Population: All visits of eligible eyes of the 258 participants with gradable overall thickness. Only OCT scans with adequate and fair quality are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Rate of Loss of Overall Retinal Thickness | -2.85 microns/year |
Secondary
Yearly Rate of Loss of Retinal Sensitivity as Measured by Scotopic Microperimetry (MP)
The yearly rate of change in retinal sensitivity. Sensitivity tested with a Nidek MP-1 machine using a modified Humphrey 10-2 grid. The sensitivity was the average sensitivity from a 68-points test pattern (Prospective cohort only)
Time frame: 2 years
Population: Microperimetry data are available for only the Prospective cohort at centers with required equipment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Prospective Cohort | Yearly Rate of Loss of Retinal Sensitivity as Measured by Scotopic Microperimetry (MP) | -0.76 dB/year |
Secondary
Yearly Rate of Loss of the Central Ring Retinal Thickness
Yearly decrease of the central ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Central area defined as ETDRS fields 9. Data are only available for the Prospective cohort.
Time frame: Participants followed at Baseline, 6 months, 12 months and 24 months
Population: All visits of eligible eyes of the 258 participants with gradable thickness in the inner ring. Only OCT scans with adequate and fair quality are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Rate of Loss of the Central Ring Retinal Thickness | -2.24 microns/year |
Secondary
Yearly Rate of Loss of the Inner Ring Retinal Thickness
Yearly decrease of the inner ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Inner ring defined as ETDRS fields 5-8. Data are only available for the Prospective cohort.
Time frame: Participants followed at Baseline, 6 months, 12 months and 24 months
Population: All visits of eligible eyes of the 258 participants with gradable thickness in the inner ring. Only OCT scans with adequate and fair quality are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Rate of Loss of the Inner Ring Retinal Thickness | -3.20 microns/year |
Secondary
Yearly Rate of Visual Acuity Loss
Yearly change of visual acuity. Visual acuity measures of best-corrected or presenting VA extracted from medical record charts. Prospective cohort is best-corrected visual acuity using Early-Treatment Diabetic Retinopathy study methods
Time frame: 2-12 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Retrospective Cohort | Yearly Rate of Visual Acuity Loss | 0.030 logMAR/year |
| Prospective Cohort | Yearly Rate of Visual Acuity Loss | 0.011 logMAR/year |