COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

Fecha de publicación: 14/08/2024 Fecha Ahead of Print: 14/08/2024

Autores de IIS La Fe

Marina Berenguer Haym

Autor

Participantes ajenos a IIS La Fe

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
Milkiewicz P
Adekunle F
Villamil A

Grupos

Hepatología, Cirugia Hepatobiliopancreática y Trasplantes

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.

Datos de la publicación

ISSN/ISSNe:: 0002-9270, 1572-0241
Tipo:: Article
Páginas:: 390-400
DOI:: 10.14309/ajg.0000000000003029
PubMed:: 39140490
Enlace a otro recurso:: www.scopus.com
Factor de Impacto:: 2,683 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

No hay documentos

Métricas

Filiaciones

Kowdley KV:: Liver Institute Northwest and Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA
Hirschfield GM:: Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Coombs C:: Real World Evidence, Syneos Health, Morrisville, NC, USA
Malecha ES:: Intercept Pharmaceuticals, Morristown, NJ, USA
Bessonova L:: Intercept Pharmaceuticals, Morristown, NJ, USA
Li J:: Intercept Pharmaceuticals, Morristown, NJ, USA
Rathnayaka N:: Department of Population Health Sciences, Duke University, Durham, NC, USA
Mells G:: Cambridge University Hospitals NHS Foundation Trust MRC Clinical Academic Research Partner, Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
Jones DE:: Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
Trivedi PJ:: National 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
Hansen BE:: Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, Netherlands

IHPME University of Toronto, Toronto, Ontario, Canada

Toronto Centre for Liver Disease and TGHRI, University Health Network, Toronto, Ontario, Canada
Smith R:: Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Wason J:: Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
Hiu S:: Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
Kareithi DN:: Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
Mason AL:: Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Bowlus CL:: University of California Davis, Sacramento, CA, USA
Muller K:: Flinders Medical Centre, Adelaide, South Australia, Australia
Carbone M:: University of Milano-Bicocca, Milano, Italy
Berenguer M:: Instituto de Investigación. La Fe University Hospital, IISLaFe, Ciberehd, University of Valencia, Valencia, Spain
Milkiewicz P:: Medical University of Warsaw, Warszawa, Poland

Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
Adekunle F:: Intercept Pharmaceuticals, London, UK
Villamil A:: Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

Keywords

Adult; Aged; Ascites; Chenodeoxycholic Acid; Double-Blind Method; Female; Humans; Liver Cirrhosis, Biliary; Liver Transplantation; Male; Middle Aged; Treatment Outcome; alanine aminotransferase; albumin; alkaline phosphatase; aspartate aminotransferase; bilirubin; obeticholic acid; chenodeoxycholic acid; obeticholic acid; abdominal pain; adult; Article; ascites; clinical outcome; constipation; controlled study; crossover procedure; decompensated liver cirrhosis; double blind procedure; drug safety; drug tolerability; female; follow up; headache; hospitalization; human; intention to treat analysis; liver graft; major clinical study; male; middle aged; Model For End Stage Liver Disease Score; nausea; peripheral edema; portal hypertension; primary biliary cirrhosis; propensity score; randomized controlled trial; rhinopharyngitis; sensitivity analysis; treatment switching; upper abdominal pain; aged; biliary cirrhosis; clinical trial; drug therapy; etiology; liver transplantation; multicen

Campos de Estudio

Cita

Cita Bibliográfica