Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14

Purpose: Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS. Design: Multicenter, international, prospective cohort study: ProgStar Study. Methods: Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS). Results: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = −1.33; P < .001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461). Conclusions: In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

BACKGROUND/AIMS: To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency. METHODS: 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele. RESULTS: 211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants. CONCLUSIONS: There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants

Visual Acuity Change over 12 Months in the Prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: ProgStar Report Number 6

PURPOSE: To estimate the yearly rate of change of best-corrected visual acuity (BCVA) and the risk of loss 1 line or more over 1 year and to identify risk factors for BCVA loss in patients with Stargardt disease (STGD1). DESIGN: Multicenter, prospective cohort study. PARTICIPANTS: Two hundred fifty-nine patients (489 eyes) with molecularly confirmed STGD1 enrolled at 9 centers in the United States and Europe. METHODS: Participants were followed up every 6 months, and data at the baseline and 6- and 12-month visits were analyzed. Best-corrected visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Standardized reporting forms were used to collect participants' characteristics and clinical observations. Linear mixed effects models were used to estimate the rate of BCVA loss. Linear models with generalized estimating equations were used to identify risk factors for BCVA loss of 1 line or more over 1 year. MAIN OUTCOME MEASURES: Change in BCVA over 1 year. RESULTS: Cross-sectional analysis at baseline showed that earlier symptom onset and longer duration since onset was associated with worse BCVA. Longitudinal analysis showed no overall significant change of BCVA within 12 months, but the rate of BCVA change was significantly different by baseline BCVA (P < 0.001). The BCVA of eyes with baseline BCVA of 20/25 or better declined at a rate of 2.8 ETDRS letters per year (P = 0.10), eyes with baseline BCVA between 20/25 and 20/70 declined at a rate of 2.3 ETDRS letters per year (P = 0.002), eyes with baseline BCVA between 20/70 and 20/200 declined at a rate of 0.8 ETDRS letters per year (P = 0.08), and eyes with baseline BCVA worse than 20/200 showed a significant improvement of 2.3 ETDRS letters per year (P < 0.001). Overall, 12.9% of eyes lost 1 line or more, and the risk of such BCVA loss was different by baseline BCVA level (P = 0.016). Smoking and vitamin A use was not associated significantly with baseline BCVA, nor with rate of BCVA loss over 1 year. CONCLUSIONS: Change in BCVA in STGD1 patients over a 12-month period was small, but varied depending on baseline BCVA. Given the slow change during 1 year, BCVA is unlikely to be a sensitive outcome measure for STGD1 treatment trials with 1 year's duration

The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1)

BACKGROUND/AIMS: To describe the design and baseline characteristics of patients enrolled in the multicenter, prospective natural history study of Stargardt disease type 4. METHODS: Fifteen eligible patients aged 6 years and older at baseline, harboring disease-causing variants in the PROM1 gene, and with specified ocular lesions were enrolled. They were examined at baseline using a standard protocol, with 6 monthly follow-up visits for a 2-year period including best-corrected ETDRS visual acuity, spectral-domain optical coherence tomography, fundus autofluorescence (FAF), mesopic and scotopic microperimetry (MP). Areas of definitely decreased FAF (DDAF) and questionably decreased FAF were outlined and quantified on FAF images. RESULTS: Amongst the 15 patients (29 eyes) that were enrolled at 5 centers in the USA and Europe, 10 eyes (34.5%) had areas of DDAF with an average lesion area of 3.2 ± 3.5 mm2 (range 0.36-10.39 mm2) at baseline. The mean retinal sensitivity of the posterior pole derived from mesopic MP was 8.8 ± 5.8 dB. CONCLUSIONS: Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterization of the natural history of disease and the exploration of the utility of several modalities to track progression and therefore to potentially be used in future interventional clinical trials

Progression of Visual Acuity and Fundus Autofluorescence in Recent-Onset Stargardt Disease: ProgStar Study Report #4

PURPOSE: To investigate the impact of areas of decreased fundus autofluorescence (AF) on visual acuity (VA) in molecularly confirmed Stargardt disease (STGD1) with recent symptom onset, and investigate the association between these structural and functional measures over time. DESIGN: Prospective, international, multicenter observational study of Stargardt disease. PARTICIPANTS: Sixty-four patients (124 eyes) aged ≥6 years at first study visit, with onset of symptoms ≤2 years before the first visit. METHODS: AF images were graded for the presence and areas of definitely decreased AF (DDAF), questionably decreased AF (QDAF), and total decreased AF (DAF). First-visit images were also graded for presence of these lesions and for the presence of increased AF in the fovea. VA was measured as best-corrected or presenting acuity and converted to logarithm of the minimum angle of resolution (logMAR). Cross-sectional associations were measured using linear models with generalized estimating equations. Longitudinal linear mixed effects models were used to estimate yearly progression rates of VA and AF lesion areas. Main outcome measures were rate of change in VA and rate of change of decreased AF area. RESULTS: In cross-sectional analyses at baseline, VA was not significantly associated with area of DDAF (P = 0.86), or QDAF (P = 0.11), but was significantly associated with lesion involvement in the fovea (P < 0.001). The VA change rate was 0.054 logMAR/year (P < 0.001) and depended on initial level of VA (faster loss was observed in those with 20/30 to 20/70 at first visit, 0.114 logMAR/year, 95% confidence interval = 0.090-0.138). Growth of DDAF depended on the size of the lesion at first visit, with larger DDAF having faster growth. Regression of QDAF area over time was associated with significantly larger growth in DDAF (P < 0.001), suggesting that QDAF areas may lose further AF signal over time. The increase in area of DDAF, or total decreased AF, was not associated with change in VA (P = 0.62, and P = 0.27, respectively). CONCLUSIONS: In recent-onset STGD1, the rate of VA loss was not significantly associated with the rate of increase in area of DDAF, QDAF, or DAF. For DDAF, the growth rate depended on the initial size of the lesion, a finding that will be helpful in stratifying these patients for intervention

Visual Acuity Change Over 24 Months and its Association With Foveal Phenotype and Genotype in Individuals With Stargardt Disease: ProgStar Study Report No. 10

Importance: Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials. Objective: To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1. Design, Setting, and Participants: This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years. Exposures: Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations). Main Outcomes and Measures: Rate of BCVA change per year. Results: The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, -1.2 to 1.35) letters per year (P = .89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (P < .001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up. Conclusions and Relevance: A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time

Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5

IMPORTANCE: Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. OBJECTIVE: To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)–binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 μm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017. EXPOSURES Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves. MAIN OUTCOMES AND MEASURES: Incidence of atrophic lesions as determined by fundus autofluorescence. RESULTS: The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P = .01). CONCLUSIONS AND RELEVANCE: An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

IMPORTANCE: Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. OBJECTIVE: To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. EXPOSURES: Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable. MAIN OUTCOMES AND MEASURES: Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence. RESULTS: A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion. CONCLUSIONS AND RELEVANCE: In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size

The progression of Stargardt Disease as determined by fundus autofluorescence over a 24-month period (ProgStar Report No. 17)

PURPOSE: To estimate the progression rate of atrophic lesions in Stargardt disease derived from fundus autofluorecence (FAF). DESIGN: International, multicenter, prospective cohort study. METHODS: 259 participants aged ≥6 years with disease-causing variants in the ABCA4 gene, were enrolled from nine centers and followed over a 24 month period. FAF images were obtained every 6 months and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified. Progression rates were estimated from linear mixed models with time as the independent variable. RESULTS: 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24-months. The overall estimated progression of DDAF was 0.74 (confidence interval (CI) 0.64 - 0.85; p<.0001) mm2/year, and of DAF was 0.64 (CI 0.57 - 0.71) mm2/year over a 24 month period in univariate analysis. Growth rates were strongly dependent on baseline lesion area. After square root transformation, DDAF growth rate was not dependent on baseline lesion radius (p=0.11), whereas DAF growth rate was dependent (p<.0001). Genotype was not found to significantly impact growth rate of DDAF or DAF lesions. CONCLUSIONS: FAF may serve as a convenient monitoring tool and suitable endpoint for interventional clinical trials that aim to slow disease progression. DDAF and DAF lesion sizes at baseline are strong predicting factors for lesion area growth and can be partially accounted for by square root transformation

Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 12-Month Period: ProgStar Report No. 11

Importance: Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. Objective: To estimate the progression rate of atrophic lesions in the prospective Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study over a 12-month period. Design, Setting, and Participants: This multicenter prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017. Patients who were affected by Stargardt disease, aged 6 years and older at baseline, and harboring disease-causing variants of the ABCA4 gene were enrolled at 9 centers in the United States, United Kingdom, and continental Europe. Data analysis occurred from November 2016 to January 2017. Exposures: Autofluorescence images obtained with a standard protocol were sent to a central reading center, and areas of definitely decreased autofluorescence, questionably decreased autofluorescence, and the total combined area of decreased autofluorescence were outlined and quantified. Progression rates were estimated from linear mixed models with time as the independent variable. Main Outcomes and Measures: Yearly rate of progression, using the growth of atrophic lesions measured by autofluorescence imaging. Results: A total of 259 study participants (488 eyes; 230 individuals [88.8%] were examined in both eyes) were enrolled (mean [SD] age at first visit, 33.3 [15.1] years; 118 [54.4%] female). Gradable images were available for evaluation for 480 eyes at baseline and 454 eyes after 12 months. At baseline, definitely decreased autofluorescence was present in 306 eyes, and the mean (SD) lesion size was 3.93 (4.37) mm2. The mean total area of decreased autofluorescence at baseline was 4.07 (4.04) mm2. The estimated progression of definitely decreased autofluorescence was 0.76 (95% CI, 0.54-0.97) mm2 per year (P < .001), and the total area of both questionably and definitely decreased autofluorescence was 0.64 (95% CI, 0.50-0.78) mm2 per year (P < .001). Both progression rates depended on initial lesion size. Conclusions and Relevance: In Stargardt disease, autofluorescence imaging may serve as a monitoring tool and definitely decreased autofluorescence and total area as outcome measures for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size