TY - JOUR
T1 - COBALT
T2 - A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls
AU - Kowdley, Kris V.
AU - Hirschfield, Gideon M.
AU - Coombs, Charles
AU - Malecha, Elizabeth S.
AU - Bessonova, Leona
AU - Li, Jing
AU - Rathnayaka, Nuvan
AU - Mells, George
AU - Jones, David E.
AU - Trivedi, Palak J.
AU - Hansen, Bettina E.
AU - Smith, Rachel
AU - Wason, James
AU - Hiu, Shaun
AU - Kareithi, Dorcas N.
AU - Mason, Andrew L.
AU - Bowlus, Christopher L.
AU - Muller, Kate
AU - Carbone, Marco
AU - Berenguer, Marina
AU - Milkiewicz, Piotr
AU - Adekunle, Femi
AU - Villamil, Alejandra
N1 - Publisher Copyright:
©2023 Komodo Health, Inc. All rights reserved.
PY - 2025/2/1
Y1 - 2025/2/1
N2 - INTRODUCTION: 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 patients with PBC 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 5 168) and 28.9% of placebo patients (n 5 166; intent-to-treat analysis hazard ratio [HR] 5 1.01, 95% confidence interval 5 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 and as-treated analyses shifted the HR to favor OCA. In the EC (n 5 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR 5 0.39; 95% confidence interval 5 0.22–0.69; P 5 0.001). No new safety signals were identified in the RCT. DISCUSSION: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat 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.
AB - INTRODUCTION: 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 patients with PBC 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 5 168) and 28.9% of placebo patients (n 5 166; intent-to-treat analysis hazard ratio [HR] 5 1.01, 95% confidence interval 5 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 and as-treated analyses shifted the HR to favor OCA. In the EC (n 5 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR 5 0.39; 95% confidence interval 5 0.22–0.69; P 5 0.001). No new safety signals were identified in the RCT. DISCUSSION: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat 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.
UR - https://www.scopus.com/pages/publications/85201796621
U2 - 10.14309/ajg.0000000000003029
DO - 10.14309/ajg.0000000000003029
M3 - Article
C2 - 39140490
AN - SCOPUS:85201796621
SN - 0002-9270
VL - 120
SP - 390
EP - 400
JO - American Journal of Gastroenterology
JF - American Journal of Gastroenterology
IS - 2
ER -