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Estimated Utility of the Short-term Assessment of Glaucoma Progression Model in Clinical Practice

Educational Objective
To describe the design for the Short-term Assessment of Glaucoma Progression model and provide guidance on sample size and power calculations for shorter clinical trials.
1 Credit CME
Key Points

Question  Can a study design that evaluates current clinical practice assess glaucomatous change in a shorter than usual study period in patients with glaucoma?

Findings  In this cohort study of 178 eyes from 97 patients with glaucoma, with testing every 3 months, clinically relevant rates of retinal nerve fiber layer and visual field mean deviation change were detected in 18 months. Assuming moderate differences in the rates of change and testing every 3 months, sufficient power was demonstrated for glaucoma therapy trials with 18 months follow-up.

Meaning  In this study using frequent testing and the rate of change in retinal nerve fiber layer thickness or visual field mean deviation as the end point, the results suggest that clinical trials of glaucoma therapy can be completed within a relatively short time frame.

Abstract

Importance  Clinical trials of glaucoma therapies focused on protecting the optic nerve have required large sample sizes and lengthy follow-up to detect clinically relevant change due to its slow rate of progression. Whether shorter trials may be possible with more frequent testing and use of rate of change as the end point warrants further investigation.

Objective  To describe the design for the Short-term Assessment of Glaucoma Progression (STAGE) model and provide guidance on sample size and power calculations for shorter clinical trials.

Design, Setting, and Participants  A cohort study of patients with mild, moderate, or advanced open-angle glaucoma recruited from the Diagnostic Innovations in Glaucoma Study at the University of California, San Diego. Enrollment began in May 2012 with follow-up for every 3 months for 2 years after baseline examination. Follow-up was concluded in September 2016. Data were analyzed from July 2019 to January 2021. Visual fields (VF) and optic coherence tomography (OCT) scans were obtained at baseline and for 2 years with visits every 3 months.

Exposures  Glaucoma was defined as glaucomatous appearing optic discs classified by disc photographs in at least 1 eye and/or repeatable VF damage at baseline.

Main Outcomes and Measures  Longitudinal rates of change in retinal nerve fiber layer (RNFL) thickness and VF mean deviation (MD) are estimated in study designs of varying length and observation frequency. Power calculations as functions of study length, observation frequency, and sample size were performed.

Results  In a total referred sample of 97 patients with mild, moderate, or advanced glaucoma (mean [SD] age, 69 [11.4] years; 50 [51.5%] were female; 19 [19.6%]), over the 2-year follow-up, the mean VF 24-2 MD slope was −0.32 dB/y (95% CI, −0.43 to −0.21 dB/y) and the mean RNFL thickness slope was −0.54 μm/y (95% CI, −0.75 to −0.32 μm/y). Sufficient power (80%) to detect similar group differences in the rate of change in both outcomes was attained with total follow-up between 18 months and 2 years and fewer than 300 total participants.

Conclusions and Relevance  In this cohort study, results from the STAGE model with reduction of the rate of progression as the end point, frequent testing, and a moderate effect size, suggest that clinical trials to test efficacy of glaucoma therapy can be completed within 18 months of follow-up and with fewer than 300 participants.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: April 19, 2021.

Published Online: June 10, 2021. doi:10.1001/jamaophthalmol.2021.1812

Corresponding Author: Robert N. Weinreb, MD, Shiley Eye Institute, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0946 (rweinreb@ucsd.edu).

Author Contributions: Mr Proudfoot and Dr Zangwill had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Mr Proudfoot and Dr Zangwill had equal contributions as co–first authors.

Concept and design: Proudfoot, Zangwill, Bowd, Belghith, Dirkes, Weinreb.

Acquisition, analysis, or interpretation of data: Proudfoot, Zangwill, Moghimi, Saunders, Hou, Belghith, Medeiros, Williams-Steppe, Acera, Dirkes, Weinreb.

Drafting of the manuscript: Proudfoot, Zangwill, Weinreb.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Proudfoot, Moghimi, Belghith.

Obtained funding: Zangwill, Weinreb.

Administrative, technical, or material support: Zangwill, Saunders, Hou, Medeiros, Williams-Steppe, Acera, Dirkes, Weinreb.

Supervision: Zangwill, Bowd, Medeiros, Weinreb.

Conflict of Interest Disclosures: Dr Zangwill reported grants from Heidelberg Engineering (equipment and research support), grants from Carl Zeiss Meditec (equipment and research support), nonfinancial support from Optovue Inc (research equipment), nonfinancial support from Topcon Inc (equipment support), and grants from the National Eye Institute during the conduct of the study; personal fees from Idx (consultant) outside the submitted work; in addition, Dr Zangwill had a patent for UCSD issued by Carl Zeiss Meditec. Dr Medeiros reported grants from Novartis, grants from AbbVie, grants from Carl Zeiss Meditec, personal fees from Reichert, and grants from Heidelberg Engineering during the conduct of the study. Dr Weinreb reported grants from National Eye Institute, other from Carl Zeiss Meditec (equipment support, patent), nonfinancial support from Centervue (equipment support), nonfinancial support from Genentech Research (support), nonfinancial support from Heidelberg Engineering (equipment support), nonfinancial support from Konan (research or equipment support), nonfinancial support from Optovue (equipment support), nonfinancial support from Bausch & Lomb (research support), personal fees from Aerie Pharmaceuticals (consultant), personal fees from Allergan (consultant), personal fees from Eyenovia (consultant), and other from Toromedes (patent) during the conduct of the study. No other disclosures were reported.

Funding/Support: Genentech Inc, National Institutes of Health/National Eye Institute grants EY029058, EY011008, EY019869, EY027510, and EY026574, core grant P30EY022589; an unrestricted grant from Research to Prevent Blindness (New York, NY) and participant retention incentive grants in the form of glaucoma medication at no cost from Novartis/Alcon Laboratories Inc, Allergan, Akorn, and Pfizer Inc.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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