INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double-blind, randomised controlled trials (INVESTDIA)

Abstract

Aims: β-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP - 1) analogue liraglutide in three early stages of type 1 diabetes.

Methods: We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10-14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed.

Conclusions: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic β-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate.

Trial registration: NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial).

Keywords: diabetes prevention; glucagon-like peptide 1 analogue; islet autoantibody; liraglutide; type 1 diabetes.

FIGURE 1

Overview of the design and recruitment for three parallel type 1 diabetes prevention trials testing incretin‐based therapy in islet autoantibody positive participants at various stages of type 1 diabetes. ¹See ref [5, 6]; ²See ref [4]; ³Primary endpoint assessed before and at the end of intervention; ⁴IAA (insulin autoantibody), GADA (glutamic acid decarboxylase antibody), IA‐2A (insulinoma‐associated protein 2 antibody), ZnT8A (zinc transporter 8 antibody).