PMID- 34214479 OWN - NLM STAT- MEDLINE DCOM- 20210827 LR - 20230330 IS - 2213-8595 (Electronic) IS - 2213-8587 (Print) IS - 2213-8587 (Linking) VI - 9 IP - 8 DP - 2021 Aug TI - Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. PG - 502-514 LID - S2213-8587(21)00139-X [pii] LID - 10.1016/S2213-8587(21)00139-X [doi] AB - BACKGROUND: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0.2 nmol L(-1) on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 x 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). FINDINGS: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0.095 (90% CI -0.003 to 0.191; p=0.048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. INTERPRETATION: A 26-week course of imatinib preserved beta-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required. FUNDING: Juvenile Research Diabetes Foundation. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Gitelman, Stephen E AU - Gitelman SE AD - University of California San Francisco, San Francisco, CA, USA. Electronic address: Stephen.Gitelman@ucsf.edu. FAU - Bundy, Brian N AU - Bundy BN AD - University of South Florida, Tampa, FL, USA. FAU - Ferrannini, Ele AU - Ferrannini E AD - CNR Institute of Clinical Physiology, Pisa, Italy. FAU - Lim, Noha AU - Lim N AD - Immune Tolerance Network, Bethesda, MD, USA. FAU - Blanchfield, J Lori AU - Blanchfield JL AD - Benaroya Research Institute, Seattle, WA, USA. FAU - DiMeglio, Linda A AU - DiMeglio LA AD - Indiana University School of Medicine, Indianapolis, IN, USA. FAU - Felner, Eric I AU - Felner EI AD - Emory University, Atlanta, GA, USA. FAU - Gaglia, Jason L AU - Gaglia JL AD - Section on Immunology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. FAU - Gottlieb, Peter A AU - Gottlieb PA AD - Barbara Davis Center, University of Colorado, Aurora, CO, USA. FAU - Long, S Alice AU - Long SA AD - Benaroya Research Institute, Seattle, WA, USA. FAU - Mari, Andrea AU - Mari A AD - CNR Institute of Neurosciences, Padua, Italy. FAU - Mirmira, Raghavendra G AU - Mirmira RG AD - University of Chicago, Chicago, IL, USA. FAU - Raskin, Philip AU - Raskin P AD - University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Sanda, Srinath AU - Sanda S AD - University of California San Francisco, San Francisco, CA, USA. FAU - Tsalikian, Eva AU - Tsalikian E AD - University of Iowa, Iowa City, IA, USA. FAU - Wentworth, John M AU - Wentworth JM AD - Walter and Eliza Hall Institute and Royal Melbourne Hospital, Melbourne, VIC, Australia. FAU - Willi, Steven M AU - Willi SM AD - Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA. FAU - Krischer, Jeffrey P AU - Krischer JP AD - University of South Florida, Tampa, FL, USA. FAU - Bluestone, Jeffrey A AU - Bluestone JA AD - University of California San Francisco, San Francisco, CA, USA. CN - Gleevec Trial Study Group LA - eng SI - ClinicalTrials.gov/NCT01781975 GR - UM1 AI109565/AI/NIAID NIH HHS/United States GR - UL1 TR002537/TR/NCATS NIH HHS/United States GR - UL1 TR001108/TR/NCATS NIH HHS/United States GR - UL1 TR000004/TR/NCATS NIH HHS/United States GR - U01 DK127786/DK/NIDDK NIH HHS/United States GR - R01 DK060581/DK/NIDDK NIH HHS/United States GR - UL1 TR001878/TR/NCATS NIH HHS/United States GR - P30 DK097512/DK/NIDDK NIH HHS/United States GR - P30 DK036836/DK/NIDDK NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210629 PL - England TA - Lancet Diabetes Endocrinol JT - The lancet. Diabetes & endocrinology JID - 101618821 RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Protein Kinase Inhibitors) RN - 8A1O1M485B (Imatinib Mesylate) SB - IM CIN - Lancet Diabetes Endocrinol. 2021 Aug;9(8):475-476. PMID: 34214480 MH - Adolescent MH - Adult MH - Biomarkers/analysis MH - Blood Glucose/analysis MH - Diabetes Mellitus, Type 1/*drug therapy/pathology MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - Imatinib Mesylate/*therapeutic use MH - Male MH - Middle Aged MH - Prognosis MH - Protein Kinase Inhibitors/*therapeutic use MH - Young Adult PMC - PMC8494464 MID - NIHMS1740518 COIS- Declaration of interests SEG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Caladrius, Intrexon, Janssen, Provention Bio, and Tolerion. JLG has consulted for Vertex Pharmaceuticals and Regeneron Pharmaceuticals, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PAG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk, and Pfizer, and is co-founder and chief medical officer for ImmunoMolecular Therapeutics. RGM has a patent application for DNA methylation in inflammatory disease. SMW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals and Medtronic, and a data and safety monitoring board for the US National Institutes of Health (NIH). All other authors declare no competing interests. FIR - Barr, Mayalin IR - Barr M FIR - Blanchfield, J Lori IR - Blanchfield JL FIR - Bluestone, Jeffrey A IR - Bluestone JA FIR - Buchanan, Jeanne IR - Buchanan J FIR - Bundy, Brian N IR - Bundy BN FIR - Cabbage, Joanne IR - Cabbage J FIR - Coleman, Peter IR - Coleman P FIR - De La Vega, Monica IR - De La Vega M FIR - DiMeglio, Linda A IR - DiMeglio LA FIR - Evans-Molina, Carmella IR - Evans-Molina C FIR - Felner, Eric I IR - Felner EI FIR - Ferrannini, Ele IR - Ferrannini E FIR - Ferrara, Christine IR - Ferrara C FIR - Gaglia, Jason L IR - Gaglia JL FIR - Gitelman, Stephen E IR - Gitelman SE FIR - Gottlieb, Peter A IR - Gottlieb PA FIR - Healy, Felicity IR - Healy F FIR - Higgins, Laurie IR - Higgins L FIR - Hildinger, Megan IR - Hildinger M FIR - Jenkins, Margaret IR - Jenkins M FIR - Kayton Bryant, Nora IR - Kayton Bryant N FIR - Kinderman, Amanda IR - Kinderman A FIR - Koshy, Nisha IR - Koshy N FIR - Kost, Brianne IR - Kost B FIR - Krischer, Jeffrey P IR - Krischer JP FIR - Krishfield, Suzanne IR - Krishfield S FIR - Kucheruk, Olena IR - Kucheruk O FIR - Lim, Noha IR - Lim N FIR - Lindsley, Karen IR - Lindsley K FIR - Long, S Alice IR - Long SA FIR - Mantravadi, Manasa IR - Mantravadi M FIR - Mari, Andrea IR - Mari A FIR - Mesfin, Shelley IR - Mesfin S FIR - Michels, Aaron IR - Michels A FIR - Migre, Mary Ellen IR - Migre ME FIR - Minnock, Pantea IR - Minnock P FIR - Mirmira, Raghavendra G IR - Mirmira RG FIR - Mohammed-Nur, Elham IR - Mohammed-Nur E FIR - Nelson, Jennifer IR - Nelson J FIR - Nursing, Ashvin IR - Nursing A FIR - O'Donnell, Ryan IR - O'Donnell R FIR - Olivos, Diana IR - Olivos D FIR - Parker, Melissa IR - Parker M FIR - Raskin, Philip IR - Raskin P FIR - Redl, Leanne IR - Redl L FIR - Reed, Nicole IR - Reed N FIR - Resnick, Brittany IR - Resnick B FIR - Sanda, Srinath IR - Sanda S FIR - Sayre, Peter IR - Sayre P FIR - Serti, Elisavet IR - Serti E FIR - Sims, Emily IR - Sims E FIR - Smith, Karen IR - Smith K FIR - Soppe, Carol IR - Soppe C FIR - Stuart, Fiona IR - Stuart F FIR - Szubowicz, Sarah IR - Szubowicz S FIR - Tansey, Michel IR - Tansey M FIR - Terrell, Jennifer IR - Terrell J FIR - Tersey, Sarah IR - Tersey S FIR - Torok, Christine IR - Torok C FIR - Tsalikian, Eva IR - Tsalikian E FIR - Watson, Kelly IR - Watson K FIR - Wentworth, John M IR - Wentworth JM FIR - Wesch, Rebecca IR - Wesch R FIR - Willi, Steven IR - Willi S FIR - Woerner, Stephanie IR - Woerner S EDAT- 2021/07/03 06:00 MHDA- 2021/08/28 06:00 PMCR- 2022/08/01 CRDT- 2021/07/02 20:10 PHST- 2021/01/25 00:00 [received] PHST- 2021/05/06 00:00 [revised] PHST- 2021/05/10 00:00 [accepted] PHST- 2021/07/03 06:00 [pubmed] PHST- 2021/08/28 06:00 [medline] PHST- 2021/07/02 20:10 [entrez] PHST- 2022/08/01 00:00 [pmc-release] AID - S2213-8587(21)00139-X [pii] AID - 10.1016/S2213-8587(21)00139-X [doi] PST - ppublish SO - Lancet Diabetes Endocrinol. 2021 Aug;9(8):502-514. doi: 10.1016/S2213-8587(21)00139-X. Epub 2021 Jun 29.