Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes

Abstract

• Introduction: Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is ATG, Thymoglobuline®, encouraging further exploration in lower age groups. Methods and analysis: MELD-ATG is a phase 2, multi-centre, randomised, double-blind, placebo-controlled, multi-arm parallel-group trial in participants 5-25 years diagnosed with T1D within 3–9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over 2 consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test (MMTT) at 12 months for 2.5mg/kg ATG arm versus the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on 1) stimulated C-peptide, 2) HbA1c, 3) daily insulin dose, 4) time in range by intermittent continuous glucose monitoring (CGM) measures, 5) fasting and stimulated dry blood spot (DBS) C-peptide measurements. Ethics and dissemination: MELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA grant agreement (www.innodia.eu).