Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial,The Lancet Gastroenterology & Hepatology

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Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial
The Lancet Gastroenterology & Hepatology ( IF 35.7 ) Pub Date : 2022-07-01 , DOI: 10.1016/s2468-1253(22)00093-0
Richard J Thompson ₁ , Henrik Arnell ₂ , Reha Artan ₃ , Ulrich Baumann ₄ , Pier Luigi Calvo ₅ , Piotr Czubkowski ₆ , Buket Dalgic ₇ , Lorenzo D'Antiga ₈ , Özlem Durmaz ₉ , Björn Fischler ₁₀ , Emmanuel Gonzalès ₁₁ , Tassos Grammatikopoulos ₁₂ , Girish Gupte ₁₃ , Winita Hardikar ₁₄ , Roderick H J Houwen ₁₅ , Binita M Kamath ₁₆ , Saul J Karpen ₁₇ , Lise Kjems ₁₈ , Florence Lacaille ₁₉ , Alain Lachaux ₂₀ , Elke Lainka ₂₁ , Cara L Mack ₂₂ , Jan P Mattsson ₁₈ , Patrick McKiernan ₁₃ , Hasan Özen ₂₃ , Sanjay R Rajwal ₂₄ , Bertrand Roquelaure ₂₅ , Mohammad Shagrani ₂₆ , Eyal Shteyer ₂₇ , Nisreen Soufi ₂₈ , Ekkehard Sturm ₂₉ , Mary Elizabeth Tessier ₃₀ , Henkjan J Verkade ₃₁ , Patrick Horn ₁₈

Affiliation

Institute of Liver Studies, King's College London, London, UK.
Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Department of Paediatric Gastroenterology, Akdeniz University, Antalya, Turkey.
Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.
Paediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy.
Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey.
Department of Paediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
Istanbul University Istanbul Faculty of Medicine, Department of Paediatric Gastroenterology and Hepatology, Istanbul, Turkey.
Department of Paediatrics, CLINTEC, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U1193, Paris, France.
Institute of Liver Studies, King's College London, London, UK; Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital NHS Trust, London, UK.
Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Department of Gastroenterology, Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital and University Medical Centre, Utrecht, Netherlands.
Department of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada.
Paediatrics Department, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Albireo Pharma, Boston, MA, USA.
Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D'hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France.
Children's Hospital, Department of Paediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany.
Paediatrics Department, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK.
APHM, Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone Enfants, Marseille, France.
Department of Liver and SB Transplant and Hepatobiliary-Paediatric Surgery, King Faisal Specialist Hospital and Research Centre-Organ Transplant Centre and College Of Medicine-Alfaisal University, Riyadh, Saudi Arabia.
Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel.
Paediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany.
Department of Paediatrics, Section of Paediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine-Texas Children's Hospital, Houston, TX, USA.
Department of Paediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Centre Groningen, Groningen, Netherlands.

Background

Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC.

Methods

Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238.

Findings

Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5−15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5−41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6−48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients.

Interpretation

In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC.

Funding

Albireo Pharma.

中文翻译：

Odevixibat 治疗进行性家族性肝内胆汁淤积症：一项随机、安慰剂对照的 3 期试验

背景

进行性家族性肝内胆汁淤积症 (PFIC) 是一组遗传性小儿肝病，由影响胆汁分泌的基因突变引起。我们旨在评估 odevixibat（一种回肠胆汁酸转运蛋白抑制剂）与安慰剂对 PFIC 儿童的影响。

方法

符合这项为期 24 周、随机、双盲、已完成的 3 期研究的患者是诊断为 PFIC1 或 PFIC2 且在筛查时出现瘙痒和血清胆汁酸升高的儿科门诊患者。使用基于网络的交互式系统将患者随机分配（1:1:1）至每天一次口服安慰剂、odevixibat 40 μg/kg 或 odevixibat 120 μg/kg。随机化以 6 个块大小进行，并按 PFIC 类型和患者年龄分层；患者、临床医生和研究人员对治疗分配不知情。患者被纳入全球 33 个站点之一。评估了两个主要终点：24 周内阳性瘙痒评估的比例（PPA；即护理人员使用 Albireo 观察者报告结果 [ObsRO] PRUCISION 工具评估的搔痒评分≤1 或 ≥1 分），第 24 周时血清胆汁酸反应（即血清胆汁酸从基线降低 ≥70% 或浓度≤70 μmol/L）的患者比例。在随机分配的接受一剂或多剂的患者中分析疗效和安全性研究药物。该研究已在 ClinicalTrials.gov 注册，NCT03566238。

发现

2018 年 6 月 21 日至 2020 年 2 月 10 日期间，62 名患者（中位年龄 3·2 [范围 0·5-15·9] 岁）被随机分配至安慰剂组（n=20），奥维昔巴 40 μg/kg 每天(n=23)，或 odevixibat 120 μg/kg 每天 (n=19)。模型调整的（最小二乘）平均 PPA 比例在 odevixibat 组中显着高于安慰剂组（联合 odevixibat 组为 55% [SE 8] [每天 40 μg/kg 组为 58%，每天 120 μg/kg 组为 52%） kg/d 组]与安慰剂组 30% [SE 9]；模型调整平均差 25·0% [95% CI 8·5−41·5]；p=0·0038)。与安慰剂组相比，使用奥德维昔布的患者血清胆汁酸反应的百分比也显着升高（联合奥德维昔巴组 42 名患者中的 14 名 [33%] [每天 40 μg/kg 组 10 名，120 μg/kg 组 4 名）每天组] vs安慰剂组中没有 20 人；调整分层因素[PFIC类型]，比例差异为30·7％[95％CI 12·6-48·8；p=0·0030])。最常见的治疗中出现的不良事件 (TEAE) 是腹泻或频繁排便（奥维昔巴组 42 例中的 13 例 [31%]与安慰剂组 20 例中的 2 例 [10%]）和发热（42 例中的 12 例 [29%]与5例[25%] 的 20); 42 名 odevixibat 治疗患者中的 3 名 (7%) 和 20 名安慰剂治疗患者中的 5 名 (25%) 发生了严重的 TEAE。