Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Randomised Blinded Phase 2 Trial

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells.  The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes.  Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial.  Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia.  Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site.  The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975.   Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016.  45 patients were assigned to imatinib, 22 to placebo.  The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test).  In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping.   Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes.  Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975.   Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG 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 medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.