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Abstract Details
Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome
Hepatol Commun. 2022 May 4. doi: 10.1002/hep4.1970. Online ahead of print.
2The Hospital for Sick Children, Toronto, Ontario, Canada.
3University of Michigan, Ann Arbor, Michigan, USA.
4Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA.
5Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
6Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
7Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Riley Hospital for Children, Indiana University, Indianapolis, Indiana, USA.
8Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
9Children's Hospital Los Angeles, Los Angeles, California, USA.
10Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA.
11Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA.
12Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Utah, and Intermountain Primary Children's Hospital, Salt Lake City, Utah, USA.
13Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
14Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh, School of Medicine and Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
15Department of Pediatrics-Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
Abstract
The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.