Author information

¹Liver Institute Northwest and Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA.

²Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

³Real World Evidence, Syneos Health, Morrisville, NC, USA.

⁴Intercept Pharmaceuticals, Morristown, NJ, USA.

⁵Department of Population Health Sciences, Duke University, Durham, NC, USA.

⁶Cambridge University Hospitals NHS Foundation Trust MRC Clinical Academic Research Partner, Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.

⁷Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

⁸National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

⁹Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, Netherlands.

¹⁰IHPME University of Toronto, Toronto, Ontario, Canada.

¹¹Toronto Centre for Liver Disease and TGHRI, University Health Network, Toronto, Ontario, Canada.

¹²Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

¹³Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.

¹⁴University of California Davis, Sacramento, CA, USA.

¹⁵Flinders Medical Centre, Adelaide, South Australia, Australia.

¹⁶University of Milano-Bicocca, Milano, Italy.

¹⁷La Fe University Hospital, IISLaFe, Ciberehd, University of Valencia, Valencia, Spain.

¹⁸Medical University of Warsaw, Warszawa, Poland.

¹⁹Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.

²⁰Intercept Pharmaceuticals, London, UK.

²¹Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Abstract

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.