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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kong reports grants from Foundation Fighting Blindness and the National Institute of Allergy and Infectious Diseases during the conduct of the study. Dr Fujinami is a paid consultant of Astellas Pharma US, Inc. Dr Munoz reports grants from Foundation Fighting Blindness during the conduct of the study. Dr Ahmed reports grants from Foundation Fightling Blindness during the conduct of the study. Dr Elvin reports grants from Foundation Fightling Blindness during the conduct of the study. Dr Schönbach reports grants from German National Academy of Sciences during the conduct of the study. Dr Cheetham is a contractor for Foundation Fighting Blindness. Dr Scholl is a paid consultant of Boehringer Ingelheim Pharma KG, Daiichi Sankyo, Gerson Lehrman Group, Guidepoint, and Shire; a member of the Scientific Advisory Board of the Astellas Institute for Regenerative Medicine, GenSight Biologics SA, Intellia Therapeutics, ReNeuron Group Plc/Ora Inc, Vision Medicines; Data Monitoring and Safety Board/Committee of Genentech Inc/F. Hoffmann-La Roche Ltd, and ReNeuron Group Plc/Ora Inc; and is principal investigator of grants at the University of Basel (Universitätsspital Basel, USB) sponsored by Acucela Inc, NightstaRx Ltd, Novelion Therapeutics, Spark Therapeutics, Ltd Grants at USB are negotiated and administered by the institution (USB) that receives them on its proper accounts. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Johns Hopkins University and Bayer Pharma AG have an active research collaboration and option agreement. These arrangements have also been reviewed and approved by the USB in accordance with its conflict of interest policies. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor but may receive salary or other support from the institution to support their effort on the project(s). No other disclosures are reported.

Figures

Figure.. Best-Corrected Visual Acuity (BCVA) by Fovea Involvement and Genotype

A, Boxplots of BCVA showing the distributions of BCVA by fovea point lesion involvement status. B, Boxplots of baseline BCVA by genotype. In each boxplot, the lower and upper boundary of the box represents the first quartile (ie, 25th percentile) and the third quartile (ie, 75th percentile) of the data, respectively; the horizontal black line in the box is the median; the open circle in the box is the mean; the lower and upper whiskers are the lowest and highest values of the data that are not outliers. Any circle outside the whiskers is an outlier (ie, the data value is greater than 1.5 interquartile ranges away from the first and third quartiles). AF indicates autofluorescence; DDAF, definitely decreased AF; and QDAF, questionably decreased AF.