2649-P: Population-Normed Z-scores for Body Composition Enhance Sensitivity and Effect Size: Analysis of a Phase 2 RCT Testing Anti-GDF8 and Anti-Activin A on Top of Semaglutide (COURAGE)

Introduction and Objective: Body composition depends on weight, age, sex, height, and race, confounding comparisons across weight-loss interventions. A population-norming approach can provide weight, age, height, sex, and race-corrected z-scores for total lean mass (TLM) and fat mass (TFM). Z-scores were assessed in the COURAGE trial (NCT06299098), which tested the efficacy of semaglutide vs semaglutide with trevogrumab (anti-GDF8) with or without garetosmab (anti-activin A) for weight, TFM loss, and TLM preservation. Methods: The NHANES dataset (n = 26,125) was used to model the distributions of TLM and TFM as functions of covariates. Z-scores for TLM and TFM were inferred for each participant in the COURAGE study at baseline and week 26 (n = 599). Differences across treatment arms in change-from-baseline (CFB) z-scores were assessed with a mixed-model approach similar to the primary analysis of the trial (TFM and TLM percent CFB). Results: Statistical significance (CFB vs semaglutide alone) was met for TLM and TFM z-scores for all trevogrumab groups with and without garetosmab (Fig. 1). The CFB z-score had a larger effect size than the TLM and TFM percent CFB, which was not significant for TFM in the trevogrumab 200 mg group. Conclusion: Z-scores account for differences in weight loss across arms, yielding a larger effect size and greater sensitivity to group differences than percent CFB. Disclosure Q. Nguyen: Employee; Current; Regeneron Pharmaceuticals Inc. J. Lyu: None. J. Grimsby: Employee; Current; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Current; Regeneron Pharmaceuticals Inc. O. Mosenzon: Employee; Current; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Current; Regeneron Pharmaceuticals Inc. J. Lighter: None. R.A. Calle: Employee; Current; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Current; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Ended; Pfizer Inc. J.G. Raya: Employee; Current; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Current; Regeneron Pharmaceuticals Inc.