|
PLD |Abstract Library |
![Abstract Library](/images/AbstractLibBanner.jpg) |
|
The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors. |
Abstract Details |
![Back](/images/BackBtn.jpg) |
|
|
|
|
|
|
|
Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA |
|
|
|
|
|
Hepatology. 2023 Dec 25. doi: 10.1097/HEP.0000000000000727. Online ahead of print.
Bettina E Hansen 1 2 3, Shannon M Vandriel 4, Pamela Vig 5, Will Garner 5, Douglas B Mogul 5, Kathleen M Loomes 6, David A Piccoli 6, Elizabeth B Rand 6, Irena Jankowska 7, Piotr Czubkowski 7, Dorota Gliwicz-Miedzinska 7, Emmanuel M Gonzales 8, Emmanuel Jacquemin 8, Jérôme Bouligand 9, Lorenzo D'Antiga 10, Emanuele Nicastro 10, Henrik Arnell 11, Björn Fischler 12, Étienne Sokal 13, Tanguy Demaret 13, Susan Siew 14, Michael Stormon 14, Saul J Karpen 15, Rene Romero 15, Noelle H Ebel 16, Jeffrey A Feinstein 17, Amin J Roberts 18, Helen M Evans 18, Shikha S Sundaram 19, Alexander Chaidez 19, Winita Hardikar 20, Sahana Shankar 21, Ryan T Fischer 22, Florence Lacaille 23, Dominique Debray 24, Henry C Lin 25, M Kyle Jensen 26, Catalina Jaramillo 26, Palaniswamy Karthikeyan 27, Giuseppe Indolfi 28, Henkjan J Verkade 29, Catherine Larson-Nath 30, Ruben E Quiros-Tejeira 31, Pamela L Valentino 32, Maria Rogalidou 33, Antal Dezsofi 34, James E Squires 35, Kathleen Schwarz 36, Pier Luigi Calvo 37, Jesus Quintero Bernabeu 38 39, Andréanne N Zizzo 40, Gabriella Nebbia 41, Pinar Bulut 42, Ermelinda Santos-Silva 43, Rima Fawaz 44, Silvia Nastasio 45, Wikrom Karnsakul 46, María Legarda Tamara 47, Cristina Molera Busoms 48, Deirdre Kelly 49, Thomas Damgaard Sandahl 50, Carolina Jimenez-Rivera 51, Jesus M Banales 52, Quais Mujawar 53
|
|
|
|
|
Author information
- 1Toronto General Hospital University Health Network, Toronto, ON, Canada.
- 2Institute of Health Policy, Management and Evaluation, Toronto, ON, Canada.
- 3Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands.
- 4The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, ON, Canada.
- 5Mirum Pharmaceuticals, Inc., Foster City, CA, USA.
- 6The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, PA, USA.
- 7The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland.
- 8Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques (AVB-CG), FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Faculté de Médecine Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hépatinov, Université Paris-Saclay, Orsay, France.
- 9Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay, Assistance PubliqueHôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France.
- 10Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy.
- 11Astrid Lindgren Children's Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- 12Astrid Lindgren Children's Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Stockholm, Sweden.
- 13Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium.
- 14The Children's Hospital at Westmead, Department of Gastroenterology, Sydney, NSW, Australia.
- 15Children's Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, Georgia.
- 16Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
- 17Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, CA, USA.
- 18Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand.
- 19Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
- 20Royal Children's Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Vic, Australia.
- 21Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India.
- 22Children's Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, MO, USA.
- 23Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
- 24Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
- 25Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, OR, USA.
- 26University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, Salt Lake City, UT, USA.
- 27Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK.
- 28Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy.
- 29University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, The Netherlands.
- 30University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, MN, USA.
- 31Children's Hospital & Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, NE, USA.
- 32Gastroenterology & Hepatology Division, Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, WA, USA.
- 33Division of Gastroenterology & Hepatology, "Agia Sofia" Children's Hospital, First Department of Pediatrics, University of Athens, Athens, Greece.
- 34First Department of Paediatrics, Semmelweis University, Budapest, Hungary.
- 35University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, PA, USA.
- 36University of California San Diego, Rady Children's Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, CA, USA.
- 37Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy.
- 38Hospital Universitari Vall d'Hebron, Pediatric Hepatology and Liver Transplant Department, Barcelona, Spain.
- 39Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- 40Children's Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, ON, Canada.
- 41Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy.
- 42Phoenix Children's Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, AZ, USA.
- 43Centro Hospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal.
- 44Yale University School of Medicine, Department of Pediatrics, New Haven, CT, USA.
- 45Boston Children's Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, & Nutrition, Boston, MA, USA.
- 46Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, MD, USA.
- 47Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain.
- 48Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
- 49Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, UK.
- 50Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
- 51Children's Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, ON, Canada.
- 52Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute - Donostia University Hospital, Universidad del País Vasco (UPV/EHU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain.
- 53University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, MB, Canada.
- 54Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China.
- 55Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, South Korea.
- 56Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina.
- 57Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.
- 58Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa.
- 59Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand.
- 60Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
- 61Koç University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey.
- 62Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India.
- 63Pediatric Gastroenterology Department, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, DF, Brazil.
- 64Pediatric Gastroenterology Service, Hospital da Criança Santo Antônio, Universidade Federal de Ciências da Saúde de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, RS, Brazil.
- 65Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, Tennessee.
- 66Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey.
- 67Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas.
- 68Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland.
- 69Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil.
- 70Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, Netherlands.
- 71Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida.
- 72Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa.
- 73University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, NY, USA.
- 74University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia.
- 75Swiss Pediatric Liver Center, Division of Pediatric Specialties, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland.
- 76Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
- 77Harvard Medical School, Massachusetts General Hospital for Children, Boston, MA, USA.
- 78Institute of Liver Studies, King's College London, London, UK.
Abstract
Background and aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is the first-approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the Global ALagille Alliance (GALA) study.
Approach and results: Maralixibat trials comprise 84 patients with ALGS with≤6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids (sBA) could not be included in the GALA filtering criteria as these are routinely performed in clinical practice. Index time was determined via maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival (EFS), defined as time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin (TB), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT) were balanced between groups with no statistical differences. EFS in the maralixibat cohort was significantly better than the GALA cohort (hazard ratio 0.305; 95% CI, 0.189-0.491; p<0.0001). Multiple sensitivity and subgroup analyses (including sBA availability) showed similar findings.
Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves EFS in patients with ALGS.
|
|
|
|
|
|
|
|
|
|
|
|
|