Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome
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 inv...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2022-08-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1970 |
| _version_ | 1797935609330794496 |
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| author | Benjamin L. Shneider Binita M. Kamath John C. Magee Nathan P. Goodrich Kathleen M. Loomes Wen Ye Cathie Spino Estella M. Alonso Jean P. Molleston Jorge A. Bezerra Kasper S. Wang Saul J. Karpen Simon P. Horslen Stephen L. Guthery Philip Rosenthal Robert H. Squires Ronald J. Sokol for the Childhood Liver Disease Research Network (ChiLDReN) |
| author_facet | Benjamin L. Shneider Binita M. Kamath John C. Magee Nathan P. Goodrich Kathleen M. Loomes Wen Ye Cathie Spino Estella M. Alonso Jean P. Molleston Jorge A. Bezerra Kasper S. Wang Saul J. Karpen Simon P. Horslen Stephen L. Guthery Philip Rosenthal Robert H. Squires Ronald J. Sokol for the Childhood Liver Disease Research Network (ChiLDReN) |
| author_sort | Benjamin L. Shneider |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T18:16:47Z |
| format | Article |
| id | doaj.art-4943757ba56340778b553a64b61dfc1f |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T18:16:47Z |
| publishDate | 2022-08-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-4943757ba56340778b553a64b61dfc1f2023-02-02T08:19:12ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-08-01681910192110.1002/hep4.1970Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndromeBenjamin L. Shneider0Binita M. Kamath1John C. Magee2Nathan P. Goodrich3Kathleen M. Loomes4Wen Ye5Cathie Spino6Estella M. Alonso7Jean P. Molleston8Jorge A. Bezerra9Kasper S. Wang10Saul J. Karpen11Simon P. Horslen12Stephen L. Guthery13Philip Rosenthal14Robert H. Squires15Ronald J. Sokol16for the Childhood Liver Disease Research Network (ChiLDReN)Baylor College of Medicine Houston Texas USAThe Hospital for Sick Children Toronto Ontario CanadaUniversity of Michigan Ann Arbor Michigan USAArbor Research Collaborative for Health Ann Arbor Michigan USADivision 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 USAUniversity of Michigan Ann Arbor Michigan USAUniversity of Michigan Ann Arbor Michigan USADivision of Gastroenterology, Hepatology, and Nutrition Ann & Robert H. Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago Illinois USADivision of Gastroenterology, Hepatology, and Nutrition Department of Pediatrics Riley Hospital for Children, Indiana University Indianapolis Indiana USACincinnati Children’s Hospital Medical Center Cincinnati Ohio USAChildren’s Hospital Los Angeles Los Angeles California USADivision of Gastroenterology, Hepatology, and Nutrition Department of Pediatrics Children’s Healthcare of Atlanta and Emory University School of Medicine Atlanta Georgia USADepartment of Pediatrics Seattle Children’s Hospital University of Washington School of Medicine Seattle WA USADivision of Gastroenterology, Hepatology and Nutrition Department of Pediatrics University of Utah, and Intermountain Primary Children’s Hospital Salt Lake City Utah USADepartment of Pediatrics University of California, San Francisco San Francisco California USADivision 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 USADepartment of Pediatrics‐Gastroenterology, Hepatology and Nutrition University of Colorado School of Medicine and Children’s Hospital Colorado Aurora Colorado USAAbstract 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.https://doi.org/10.1002/hep4.1970 |
| spellingShingle | Benjamin L. Shneider Binita M. Kamath John C. Magee Nathan P. Goodrich Kathleen M. Loomes Wen Ye Cathie Spino Estella M. Alonso Jean P. Molleston Jorge A. Bezerra Kasper S. Wang Saul J. Karpen Simon P. Horslen Stephen L. Guthery Philip Rosenthal Robert H. Squires Ronald J. Sokol for the Childhood Liver Disease Research Network (ChiLDReN) Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome Hepatology Communications |
| title | Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome |
| title_full | Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome |
| title_fullStr | Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome |
| title_full_unstemmed | Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome |
| title_short | Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome |
| title_sort | use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases examination of cholestatic liver disease in alagille syndrome |
| url | https://doi.org/10.1002/hep4.1970 |
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