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Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma

Montesano, G; Garway-Heath, DF; Rabiolo, A; De Moraes, CG; Ometto, G; Crabb, DP; (2023) Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma. Translational Vision Science and Technology , 12 (10) , Article 20. 10.1167/tvst.12.10.20. Green open access

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Abstract

Purpose: The purpose of this study was to evaluate the power of trend-based visual field (VF) progression end points against long-term development of event-based end points accepted by the US Food and Drug Administration (FDA). Methods: One eye from 3352 patients with ≥10 24-2 VFs (median = 11 years) follow-up were analyzed. Two FDA-compatible criteria were applied to these series to label “true-progressed” eyes: ≥5 locations changing from baseline by more than 7 dB (FDA-7) or by more than the expected test-retest variability (GPA-like) in 2 consecutive tests. Observed rates of progression (RoP) were used to simulate trial-like series (2 years) randomly assigned (1000 times) to a “placebo” or a “treatment” arm. We simulated neuroprotec-tive “treatment” effects by changing the proportion of “true progressed” eyes in the two arms. Two trend-based methods for mean deviation (MD) were assessed: (1) linear mixed model (LMM), testing average difference in RoP between the two arms, and (2) time-to-progression (TTP), calculated by linear regression as time needed for MD to decline by predefined cutoffs from baseline. Power curves with 95% confidence intervals were calculated for trend and event-based methods on the simulated series. Results: The FDA-7 and GPA-like progression was achieved by 45% and 55% of the eyes in the clinical database. LMM and TTP had similar power, significantly superior to the event-based methods, none of which reached 80% power. All methods had a 5% false-positive rate. Conclusions: The trend-based methods can efficiently detect treatment effects defined by long-term FDA-compatible progression. Translational Relevance: The assessment of the power of trend-based methods to detect clinically relevant progression end points.

Type: Article
Title: Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1167/tvst.12.10.20
Publisher version: https://doi.org/10.1167/tvst.12.10.20
Language: English
Additional information: Copyright © 2023 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International License.
Keywords: Humans, Eye, Glaucoma, Neuroprotection, United States, Visual Fields, Randomized Controlled Trials as Topic
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10183813
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