Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls,Gastroenterology

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Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls
Gastroenterology ( IF 25.7 ) Pub Date : 2022-09-20 , DOI: 10.1053/j.gastro.2022.08.054
C Fiorella Murillo Perez ₁ , Holly Fisher ₂ , Shaun Hiu ₂ , Dorcas Kareithi ₂ , Femi Adekunle ₃ , Tracy Mayne ₃ , Elizabeth Malecha ₃ , Erik Ness ₃ , Adriaan J van der Meer ₄ , Willem J Lammers ₄ , Palak J Trivedi ₅ , Pier Maria Battezzati ₆ , Frederik Nevens ₇ , Kris V Kowdley ₈ , Tony Bruns ₉ , Nora Cazzagon ₁₀ , Annarosa Floreani ₁₀ , Andrew L Mason ₁₁ , Albert Parés ₁₂ , Maria-Carlota Londoño ₁₂ , Pietro Invernizzi ₁₃ , Marco Carbone ₁₄ , Ana Lleo ₁₅ , Marlyn J Mayo ₁₆ , George N Dalekos ₁₇ , Nikolaos K Gatselis ₁₇ , Douglas Thorburn ₁₈ , Xavier Verhelst ₁₉ , Aliya Gulamhusein ₁ , Harry L A Janssen ₂₀ , Rachel Smith ₂₁ , Steve Flack ₂₂ , Victoria Mulcahy ₂₂ , Michael Trauner ₂₃ , Christopher L Bowlus ₂₄ , Keith D Lindor ₂₅ , Christophe Corpechot ₂₆ , David Jones ₂ , George Mells ₂₇ , Gideon M Hirschfield ₁ , James Wason ₂₈ , Bettina E Hansen ₂₉ ,

Affiliation

Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Newcastle University, Newcastle upon Tyne, United Kingdom.
Intercept Pharmaceuticals, Morristown, New Jersey.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
University of Birmingham, Birmingham, United Kingdom.
Università degli Studi di Milano, Milan, Italy.
University Hospital Katholieke Universiteit Leuven, Leuven, Belgium.
Liver Institute Northwest, Seattle, Washington.
Department of Gastroenterology and Hepatology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
University of Padova, Padova, Italy.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Department of Medicine, Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain; European Reference Network on Hepatological Diseases, Barcelona, Spain.
European Reference Network on Hepatological Diseases, Barcelona, Spain; Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; San Gerardo Hospital, Monza, Italy.
University of Milano-Bicocca, Monza, Italy.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
Department of Medicine, Division of Digestive and Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas.
European Reference Network on Hepatological Diseases, Barcelona, Spain; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.
Royal Free London National Health Service Foundation Trust, London, United Kingdom.
Department of Hepatology, Ghent University Hospital, Ghent, Belgium.
Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
Cambridge Liver Unit, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom.
Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
Medical University of Vienna, Vienna, Austria.
University of California Davis, Sacramento, California.
Mayo Clinic, Scottsdale, Arizona.
Saint-Antoine University Hospital, Paris, France.
Addenbrooke's Hospital, Cambridge, United Kingdom.
Department of Biostatistics, Newcastle University, Newcastle upon Tyne, United Kingdom.
Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands, Toronto, Ontario, Canada; IHPME, University of Toronto, Toronto, Ontario, Canada.

Background & Aims

The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA–treated external controls.

Methods

Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis.

Results

During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10–0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12–0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03–1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09–1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21–0.85) including hepatic decompensation.

Conclusions

Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

中文翻译：

与真实世界的外部对照相比，在临床试验环境中接受奥贝胆酸治疗原发性胆汁性胆管炎的患者的无移植生存期更长

背景与目标

原发性胆汁性胆管炎 (PBC) 奥贝胆酸 (OCA) 国际疗效研究 (POISE) 随机、双盲、安慰剂对照试验表明，OCA 减少了与不良临床结果相关的生物标志物（即碱性磷酸酶、胆红素、天冬氨酸氨基转移酶、和谷丙转氨酶）在 PBC 患者中。本研究的目的是评估 POISE 试验和开放标签扩展与可比较的非 OCA 治疗的外部对照相比，OCA 患者首次发生肝移植或死亡的时间。

方法

使用在满足资格标准的第一个和最后一个日期（含）之间随机选择的索引日期，为来自 2 项注册研究（全球 PBC 和 UK-PBC）的符合 POISE 资格标准的外部对照患者生成倾向评分。由治疗的逆概率加权的 Cox 比例风险模型评估了死亡或肝移植的时间。额外的分析（仅限全球 PBC）将肝脏失代偿添加到复合终点，并评估了在有或没有肝硬化患者中的疗效。

结果

在 6 年的随访期间，POISE 队列中的 209 名受试者 (2.4%)、全球 PBC 对照组的 1381 名患者中的 135 名 (10.0%) 和英国的 2135 名患者中的 281 名有 5 名死亡或肝移植-PBC 控制 (13.2%)。POISE 与全球 PBC 的主要结果的风险比 (HR) 为 0.29（95% CI，0.10–0.83），POISE 与 UK-PBC 的主要结果的风险比 (HR) 为 0.30（95% CI，0.12–0.75）。在全球 PBC 研究中，肝硬化患者的 HR 为 0.20（95% CI，0.03-1.22），无肝硬化患者的 HR 为 0.31（95% CI，0.09-1.04）；HR 为 0.42（95% CI，0.21–0.85），包括肝脏失代偿。