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 = 168) and 28.9% of placebo patients (n = 166
intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 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 = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39
95% confidence interval = 0.22-0.69
P = 0.002). 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.