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

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.

Figure 1.. Theoretical Trial of Glaucoma Treatment

Power to detect differences in normal and glaucoma change rates by study length and number of observations with fixed total sample size of 150 participants (75 per group, both eyes included). The variance components (ie, random effect and error variances) and effect sizes (ie, difference in change rates) are set equal to the model estimates derived from the 2-year trial with observations 3 months apart (effect size of 0.32 dB/year for visual field [VF] 24-2 mean deviation [MD] and 0.54 μm/year for global retinal nerve fiber layer [RNFL] thickness). Study lengths to achieve 80% power are given in blue.

Figure 2.. Effect Sizes Associated With a Range of Sample Sizes for Visual Field (VF) 24-2 Mean Deviation (MD)

Detectable VF 24-2 MD effect sizes for glaucoma studies of varying sample size (assuming both eyes are included), follow-up, and observation frequency.

Figure 3.. Effect Sizes Associated With a Range of Sample Sizes for Retinal Nerve Fiber Layer (RFNL) Thickness

Detectable RNFL thickness effect sizes for glaucoma studies of varying sample size (assuming both eyes are included), follow-up, and observation frequency.