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Lookup NU author(s): Dr George Mells, Professor David Jones, Professor James WasonORCiD, Shaun HiuORCiD, Dorcas KareithiORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Copyright © 2024 The Author(s).Objectives: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy. Methods: Patients randomized to OCA (5–10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score–weighted EC group was derived from a US healthcare claims database. Results: In the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68–1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22–0.69; P=0.001). No new safety signals were identified in the RCT. Conclusions: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.
Author(s): Kowdley KV, Hirschfield GM, Coombs C, Malecha ES, Bessonova L, Li J, Rathnayaka N, Mells G, Jones DE, Trivedi PJ, Hansen BE, Smith R, Wason J, Hiu S, Kareithi DN, Mason AL, Bowlus CL, Muller K, Carbone M, Berenguer M, Milkiewicz P, Adekunle F, Villamil A
Publication type: Article
Publication status: Published
Journal: American Journal of Gastroenterology
Year: 2024
Pages: epub ahead of print
Online publication date: 14/08/2024
Acceptance date: 02/04/2024
Date deposited: 02/09/2024
ISSN (print): 0002-9270
ISSN (electronic): 1572-0241
Publisher: Wolters Kluwer Health
URL: https://doi.org/10.14309/ajg.0000000000003029
DOI: 10.14309/ajg.0000000000003029
PubMed id: 39140490
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