Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases—Examination of cholestatic liver disease in Alagille syndrome

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 investigatio...

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Published inHepatology communications Vol. 6; no. 8; pp. 1910 - 1921
Main Authors Shneider, Benjamin L., Kamath, Binita M., Magee, John C., Goodrich, Nathan P., Loomes, Kathleen M., Ye, Wen, Spino, Cathie, Alonso, Estella M., Molleston, Jean P., Bezerra, Jorge A., Wang, Kasper S., Karpen, Saul J., Horslen, Simon P., Guthery, Stephen L., Rosenthal, Philip, Squires, Robert H., Sokol, Ronald J.
Format Journal Article
LanguageEnglish
Published United States Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins 01.08.2022
John Wiley and Sons Inc
Wolters Kluwer Health/LWW
Subjects
Acids
Age
Alagille Syndrome - diagnosis
Ascites
Bile
Child
Cholestasis - diagnosis
Clinical trials
Cohort Studies
Drug development
Enrollments
Gallbladder diseases
Humans
Liver diseases
Liver transplants
Longitudinal studies
Natural history
Original
Prospective Studies
Pruritus
Pruritus - diagnosis
Rare Diseases
Vitamin deficiency
United States > US
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Summary: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. Prospective multi‐center longitudinal databases, which may require significant funding, provide critical biomedical information. It is possible to adapt entry criteria for completed and on‐going clinical trials to the participants in these registries, thereby generating a similar natural history cohort. Investment in prospective databases affords unique and invaluable real world data, serving as important comparators in the assessment of the safety and efficacy of novel agents investigated in rare diseases as demonstrated by this study in Alagille syndrome.
Bibliography:Funding information
Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL (supported by National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] DK62436 and National Center for Advancing Translational Sciences [NCATS] UL1TR001422): Estella Alonso, MD, Lee Bass, MD, Susan Kelly, RN, BSN, Mary Riordan, CCRP, Hector Melin‐Aldana, MD. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (supported by NIDDK DK62497 and NCATS UL1TR000077): Jorge Bezerra, MD, Kevin Bove, MD, James Heubi, MD, Alexander Miethke, MD, Greg Tiao, MD, Julie Denlinger, BSN, RN, Erin Chapman. Children’s Hospital Colorado, Aurora, CO (supported by NIDDK DK62453 and NCATS UL1TR002535): Ronald Sokol, MD, Amy Feldman, MD, Cara Mack, MD, Michael Narkewicz, MD, Frederick Suchy, MD, Shikha Sundaram, MD, Johan Van Hove, MD, Benigno Garcia, Mikaela Kauma, Kendra Kocher, CCRP, Matthew Steinbeiss, MS, CCRP, Mark Lovell, MD. The Children’s Hospital of Philadelphia, Philadelphia, PA (supported by NIDDK DK62481): Kathleen Loomes, MD, David Piccoli, MD, Elizabeth Rand, MD, Pierre Russo, MD, Nancy Spinner, PhD, Jessi Erlichman, MPH, Samantha Stalford, MPH, Dina Pakstis, Sakya King. Children’s Hospital of Pittsburgh, Pittsburgh, PA (supported by NIDDK DK62466 and NCATS UL1TR000005): Robert Squires, MD, Rakesh Sindhi, MD, Veena Venkat, MD, Kathy Bukauskas, RN, CCRC, Patrick McKiernan, MD, Lori Haberstroh, James Squires, MD, MS. UCSF Children’s Hospital, San Francisco, CA (supported by NIDDK DK62500 and NCATS UL1TR000004): Philip Rosenthal, MD, Laura Bull, PhD, Joanna Curry, Camille Langlois, Grace Kim, MD. Saint Louis University School of Medicine, St. Louis, MO (supported by NIDDK DK62453): Jeffery Teckman, MD, Vikki Kociela, BSN, CCRC, Rosemary Nagy, RDN, MBA, Shraddha Patel, PhD, Jacqueline Cerkoski, BSN. Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN (supported by NIDDK DK84536 and NCATS UL1TR001108): Jean P. Molleston, MD, Molly Bozic, MD, Girish Subbarao, MD, Ann Klipsch, RN, Cindy Sawyers, BSRT, Oscar Cummings, MD. Seattle Children’s Hospital, Seattle WA (supported by NIDDK DK84575 and NCATS UL1TR000423): Simon Horslen, MB, ChB, FRCPCH, Karen Murray, MD, Evelyn Hsu, MD, Kara Cooper, CCRC, Melissa Young, CCRC, Laura Finn, MD. The Hospital for Sick Children, Toronto, Ontario, Canada (supported by NIDDK DK103135): Binita Kamath, MD, Vicky Ng, MD, Claudia Quammie, CCRP, Juan Putra, MD, Deepika Sharma, MSc, Aishwarya Parmar, BSc. University of Utah, Salt Lake City, UT (supported by NIDDK DK103140): Stephen Guthery, MD, Kyle Jensen, MD, Ann Rutherford, Amy Lowichik, MD, PhD, Linda Book, MD, Rebecka Meyers, MD, Tyler Hall. Children’s Hospital Los Angeles, Los Angeles, CA (supported by NIDDK DK84538 and NCATS UL1TR000130): Kasper Wang, MD, Sonia Michail, MD, Danny Thomas, MD, Catherine Goodhue, CPNP, Rohit Kohli, MBBS, MS, Larry Wang, MD, PhD, Nisreen Soufi, MD, Daniel Thomas, MD. Children’s Healthcare of Atlanta, Atlanta, GA (supported by NIDDK DK062470 and NCATS UL1TR000454): Saul Karpen, MD, PhD, Nitika Gupta, MD, DCH, DNB, MRCPH, Rene Romero, Jr., MD, Miriam B. Vos, MD, MSPH, Rita Tory, MS, CCRP, John‐Paul Berauer, MD, Carlos Abramowsky, MD, Jeanette McFall, MPH. Texas Children’s Hospital, Houston, TX (supported by NIDDK DK103149): Benjamin Shneider, MD, Sanjiv Harpavat, MD, Paula Hertel, MD, Daniel Leung, MD, Mary Tessier, MD, Deborah Schady, MD, Laurel Cavallo, Diego Olvera, Christina Banks, Cynthia Tsai. King’s College Hospital, London, UK: Richard Thompson, BM, BCh, MRCP, MRCPCH. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD: Edward Doo, MD, Jay Hoofnagle, MD, Averell Sherker, MD, FRCP, Rebecca Torrance, RN, MSN, Sherry Hall, MS. Scientific Data Coordinating Center, Ann Arbor, MI (supported by NIDDK DK62456): John Magee, MD, Robert Merion, MD, FACS, Cathie Spino, DSc, Wen Ye, PhD.
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Funding informationAnn & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL (supported by National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] DK62436 and National Center for Advancing Translational Sciences [NCATS] UL1TR001422): Estella Alonso, MD, Lee Bass, MD, Susan Kelly, RN, BSN, Mary Riordan, CCRP, Hector Melin‐Aldana, MD. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (supported by NIDDK DK62497 and NCATS UL1TR000077): Jorge Bezerra, MD, Kevin Bove, MD, James Heubi, MD, Alexander Miethke, MD, Greg Tiao, MD, Julie Denlinger, BSN, RN, Erin Chapman. Children’s Hospital Colorado, Aurora, CO (supported by NIDDK DK62453 and NCATS UL1TR002535): Ronald Sokol, MD, Amy Feldman, MD, Cara Mack, MD, Michael Narkewicz, MD, Frederick Suchy, MD, Shikha Sundaram, MD, Johan Van Hove, MD, Benigno Garcia, Mikaela Kauma, Kendra Kocher, CCRP, Matthew Steinbeiss, MS, CCRP, Mark Lovell, MD. The Children’s Hospital of Philadelphia, Philadelphia, PA (supported by NIDDK DK62481): Kathleen Loomes, MD, David Piccoli, MD, Elizabeth Rand, MD, Pierre Russo, MD, Nancy Spinner, PhD, Jessi Erlichman, MPH, Samantha Stalford, MPH, Dina Pakstis, Sakya King. Children’s Hospital of Pittsburgh, Pittsburgh, PA (supported by NIDDK DK62466 and NCATS UL1TR000005): Robert Squires, MD, Rakesh Sindhi, MD, Veena Venkat, MD, Kathy Bukauskas, RN, CCRC, Patrick McKiernan, MD, Lori Haberstroh, James Squires, MD, MS. UCSF Children’s Hospital, San Francisco, CA (supported by NIDDK DK62500 and NCATS UL1TR000004): Philip Rosenthal, MD, Laura Bull, PhD, Joanna Curry, Camille Langlois, Grace Kim, MD. Saint Louis University School of Medicine, St. Louis, MO (supported by NIDDK DK62453): Jeffery Teckman, MD, Vikki Kociela, BSN, CCRC, Rosemary Nagy, RDN, MBA, Shraddha Patel, PhD, Jacqueline Cerkoski, BSN. Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN (supported by NIDDK DK84536 and NCATS UL1TR001108): Jean P. Molleston, MD, Molly Bozic, MD, Girish Subbarao, MD, Ann Klipsch, RN, Cindy Sawyers, BSRT, Oscar Cummings, MD. Seattle Children’s Hospital, Seattle WA (supported by NIDDK DK84575 and NCATS UL1TR000423): Simon Horslen, MB, ChB, FRCPCH, Karen Murray, MD, Evelyn Hsu, MD, Kara Cooper, CCRC, Melissa Young, CCRC, Laura Finn, MD. The Hospital for Sick Children, Toronto, Ontario, Canada (supported by NIDDK DK103135): Binita Kamath, MD, Vicky Ng, MD, Claudia Quammie, CCRP, Juan Putra, MD, Deepika Sharma, MSc, Aishwarya Parmar, BSc. University of Utah, Salt Lake City, UT (supported by NIDDK DK103140): Stephen Guthery, MD, Kyle Jensen, MD, Ann Rutherford, Amy Lowichik, MD, PhD, Linda Book, MD, Rebecka Meyers, MD, Tyler Hall. Children’s Hospital Los Angeles, Los Angeles, CA (supported by NIDDK DK84538 and NCATS UL1TR000130): Kasper Wang, MD, Sonia Michail, MD, Danny Thomas, MD, Catherine Goodhue, CPNP, Rohit Kohli, MBBS, MS, Larry Wang, MD, PhD, Nisreen Soufi, MD, Daniel Thomas, MD. Children’s Healthcare of Atlanta, Atlanta, GA (supported by NIDDK DK062470 and NCATS UL1TR000454): Saul Karpen, MD, PhD, Nitika Gupta, MD, DCH, DNB, MRCPH, Rene Romero, Jr., MD, Miriam B. Vos, MD, MSPH, Rita Tory, MS, CCRP, John‐Paul Berauer, MD, Carlos Abramowsky, MD, Jeanette McFall, MPH. Texas Children’s Hospital, Houston, TX (supported by NIDDK DK103149): Benjamin Shneider, MD, Sanjiv Harpavat, MD, Paula Hertel, MD, Daniel Leung, MD, Mary Tessier, MD, Deborah Schady, MD, Laurel Cavallo, Diego Olvera, Christina Banks, Cynthia Tsai. King’s College Hospital, London, UK: Richard Thompson, BM, BCh, MRCP, MRCPCH. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD: Edward Doo, MD, Jay Hoofnagle, MD, Averell Sherker, MD, FRCP, Rebecca Torrance, RN, MSN, Sherry Hall, MS. Scientific Data Coordinating Center, Ann Arbor, MI (supported by NIDDK DK62456): John Magee, MD, Robert Merion, MD, FACS, Cathie Spino, DSc, Wen Ye, PhD.
ISSN:2471-254X
2471-254X
DOI:10.1002/hep4.1970