Ascending Doses of Crofelemer Powder for Oral Solution in Pediatric Microvillus Inclusion Disease (MVID)

Summary

A study that will evaluate the safety, tolerability and preliminary efficacy of multiple ascending doses of crofelemer, compared to placebo, using a randomized cross-over design within each dose level, when administered to participants with MVID receiving parenteral support (PS, defined as TPN with or without supplementary IV fluid requirements). Blinded study drug will be administered as a novel crofelemer formulation, Crofelemer Powder for Oral Solution, or a matching placebo powder formulation for oral solution. Assigned study drug will be reconstituted and administered orally (or enterally) three times daily (TID) as a concentrated liquid formulation in each of the three dose levels.

Timeline

Start

2025-05-01

Primary completion

2026-12

Completion

2026-12

Publications

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• Background Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of monogenic intestinal epithelial disorders. Hum Genet. 2023 May;142(5):613-654. doi: 10.1007/s00439-022-02501-5. Epub 2022 Nov 23.
• Background Canani RB, Castaldo G, Bacchetta R, Martin MG, Goulet O. Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol. 2015 May;12(5):293-302. doi: 10.1038/nrgastro.2015.44. Epub 2015 Mar 17.
• Background Berni Canani R, Terrin G, Cardillo G, Tomaiuolo R, Castaldo G. Congenital diarrheal disorders: improved understanding of gene defects is leading to advances in intestinal physiology and clinical management. J Pediatr Gastroenterol Nutr. 2010 Apr;50(4):360-6. doi: 10.1097/MPG.0b013e3181d135ef.
• Background Bowman DM, Kaji I, Goldenring JR. Altered MYO5B Function Underlies Microvillus Inclusion Disease: Opportunities for Intervention at a Cellular Level. Cell Mol Gastroenterol Hepatol. 2022;14(3):553-565. doi: 10.1016/j.jcmgh.2022.04.015. Epub 2022 Jun 1.
• Background Gao JJ, Tan M, Pohlmann PR, Swain SM. HALT-D: A Phase II Evaluation of Crofelemer for the Prevention and Prophylaxis of Diarrhea in Patients With Breast Cancer on Pertuzumab-Based Regimens. Clin Breast Cancer. 2017 Feb;17(1):76-78. doi: 10.1016/j.clbc.2016.08.005. Epub 2016 Aug 27.
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• Background Groisman GM, Amar M, Livne E. CD10: a valuable tool for the light microscopic diagnosis of microvillous inclusion disease (familial microvillous atrophy). Am J Surg Pathol. 2002 Jul;26(7):902-7. doi: 10.1097/00000478-200207000-00008.
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• Background Knowles BC, Roland JT, Krishnan M, Tyska MJ, Lapierre LA, Dickman PS, Goldenring JR, Shub MD. Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease. J Clin Invest. 2014 Jul;124(7):2947-62. doi: 10.1172/JCI71651. Epub 2014 Jun 2.
• Background Chowdhury AI, Phillips JF. Predicting contraceptive use in Bangladesh: a logistic regression analysis. J Biosoc Sci. 1989 Apr;21(2):161-8. doi: 10.1017/s0021932000017855.
• Background Leng C, Rings EHHM, de Wildt SN, van IJzendoorn SCD. Pharmacological and Parenteral Nutrition-Based Interventions in Microvillus Inclusion Disease. J Clin Med. 2020 Dec 23;10(1):22. doi: 10.3390/jcm10010022.
• Background Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP. Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study. HIV Clin Trials. 2013 Nov-Dec;14(6):261-73. doi: 10.1310/hct1406-261.
• Background Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant irritable bowel syndrome patients. Digestion. 2008;78(4):180-6. doi: 10.1159/000185719. Epub 2008 Dec 18.
• Background Muller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, Ponstingl H, Partsch J, Rollinghoff B, Kohler H, Berger T, Lenhartz H, Schlenck B, Houwen RJ, Taylor CJ, Zoller H, Lechner S, Goulet O, Utermann G, Ruemmele FM, Huber LA, Janecke AR. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008 Oct;40(10):1163-5. doi: 10.1038/ng.225. Epub 2008 Aug 24.
• Background Nee J, Salley K, Ludwig AG, Sommers T, Ballou S, Takazawa E, Duehren S, Singh P, Iturrino J, Katon J, Lee HN, Rangan V, Lembo AJ. Randomized Clinical Trial: Crofelemer Treatment in Women With Diarrhea-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2019 Dec;10(12):e00110. doi: 10.14309/ctg.0000000000000110.
• Background Overeem AW, Posovszky C, Rings EH, Giepmans BN, van IJzendoorn SC. The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Dis Model Mech. 2016 Jan;9(1):1-12. doi: 10.1242/dmm.022269.
• Background Patel TS, Crutchley RD, Tucker AM, Cottreau J, Garey KW. Crofelemer for the treatment of chronic diarrhea in patients living with HIV/AIDS. HIV AIDS (Auckl). 2013 Jul 15;5:153-62. doi: 10.2147/HIV.S30948. Print 2013.
• Background Phillips AD, Szafranski M, Man LY, Wall WJ. Periodic acid-Schiff staining abnormality in microvillous atrophy: photometric and ultrastructural studies. J Pediatr Gastroenterol Nutr. 2000 Jan;30(1):34-42. doi: 10.1097/00005176-200001000-00015.
• Background Pohlmann PR, Graham D, Wu T, Ottaviano Y, Mohebtash M, Kurian S, McNamara D, Lynce F, Warren R, Dilawari A, Rao S, Mainor C, Swanson N, Tan M, Isaacs C, Swain SM. HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane. Breast Cancer Res Treat. 2022 Dec;196(3):571-581. doi: 10.1007/s10549-022-06743-9. Epub 2022 Oct 25.
• Background Ruemmele FM, Schmitz J, Goulet O. Microvillous inclusion disease (microvillous atrophy). Orphanet J Rare Dis. 2006 Jun 26;1:22. doi: 10.1186/1750-1172-1-22.
• Background Terrin G, Tomaiuolo R, Passariello A, Elce A, Amato F, Di Costanzo M, Castaldo G, Canani RB. Congenital diarrheal disorders: an updated diagnostic approach. Int J Mol Sci. 2012;13(4):4168-4185. doi: 10.3390/ijms13044168. Epub 2012 Mar 29.
• Background Thiagarajah JR, Verkman AS. Chloride channel-targeted therapy for secretory diarrheas. Curr Opin Pharmacol. 2013 Dec;13(6):888-94. doi: 10.1016/j.coph.2013.08.005. Epub 2013 Aug 27.
• Background Tradtrantip L, Namkung W, Verkman AS. Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. doi: 10.1124/mol.109.061051. Epub 2009 Oct 6.
• Background van der Velde KJ, Dhekne HS, Swertz MA, Sirigu S, Ropars V, Vinke PC, Rengaw T, van den Akker PC, Rings EH, Houdusse A, van Ijzendoorn SC. An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations. Hum Mutat. 2013 Dec;34(12):1597-605. doi: 10.1002/humu.22440. Epub 2013 Oct 16.
• Background Weale AR, Edwards AG, Bailey M, Lear PA. Intestinal adaptation after massive intestinal resection. Postgrad Med J. 2005 Mar;81(953):178-84. doi: 10.1136/pgmj.2004.023846.
• Background Wiegerinck CL, Janecke AR, Schneeberger K, Vogel GF, van Haaften-Visser DY, Escher JC, Adam R, Thoni CE, Pfaller K, Jordan AJ, Weis CA, Nijman IJ, Monroe GR, van Hasselt PM, Cutz E, Klumperman J, Clevers H, Nieuwenhuis EE, Houwen RH, van Haaften G, Hess MW, Huber LA, Stapelbroek JM, Muller T, Middendorp S. Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology. 2014 Jul;147(1):65-68.e10. doi: 10.1053/j.gastro.2014.04.002. Epub 2014 Apr 12.

Drugs

Indications