TrialNet 09: Effects of CTLA-4 IG (Abatacept) on the Progression of Type 1 Diabetes in New Onset Subjects (TN09)

General Description

The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. Therefore, this multicenter, double-blind, randomized, controlled trial evaluated the effect of abatacept in subjects with recently diagnosed type 1 diabetes mellitus. Subjects were randomly assigned in a 2:1 ratio to receive either the experimental treatment of 30 minute intravenous infusion of 10 mg/kg of CTLA-4 Ig (abatacept) or an intravenous saline solution (placebo). The treatments were administered on days 1, 14, 28, and then every 28 days for a total of 27 doses over 700 days. All subjects received intensive diabetes management with the goal of achieving excellent glycemic control. 2 hour mixed meal tolerance tests (MMTT) were performed at 3, 6, 12 and 18 months. Four hour MMTTs were performed at baseline and at 24 months. Safety and efficacy were assessed over a two year follow-up period.

Objectives

The primary objective was to assess if co-stimulation modulation with abatacept, by blocking the generation of autoagressive T-lymphocytes, would halt or slow autoimmune beta cell destruction leading to preservation of C-peptide secretion in recently diagnosed patients with type 1 diabetes mellitus.

Outcome Measure

The primary outcome was comparison of the area under the curve of stimulated C-peptide response over the first 2 hours of the 4 hour MMTTs conducted at the 24 month visit and baseline. Secondary outcomes included slope of C-peptide over time, difference between groups in incidence of loss of peak C-peptide to < 0•2 pmol/ml, differences in HbA1c and insulin dose over time, and safety.

Criteria

Eligible subjects were 6 to 45 years old with an insulin dependent type 1 diabetes mellitus diagnosis within the previous 100 days. Additional criteria included the presence of at least one diabetes related autoantibody, stimulated C-peptide levels of at least 0.2 pmol/ml as assessed by a MMTT, at least three months since last live immunization, and willingness to forgo live vaccines for three months after the last study treatment dose.

Outcome

Co-stimulation modulation with abatacept slowed reduction in beta cell decline . The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. The initial treatment effect was sustained during the monthly administration of abatacept over 24 months, and also persisted for at least one year after treatment was stopped.