Type 1 diabetes develops when fully activated T-cells attack beta cells in the pancreas, causing insulin production to shut down. In order for a T-cell to be fully active, a co-stimulatory signal is required. Abatacept (CTLA4-lg) prevents full T-cell activation by modulating co-stimulation. During the earlier stages of beta cell destruction individuals progress from normal glucose tolerance to abnormal glucose tolerance, a precursor to type 1 diabetes. Intervention in subjects with normal glucose tolerance may be more effective than in those with abnormal tolerance.

The purpose of the TrialNet 18 study was to determine whether Abatacept treatment prevented or delayed the development of abnormal glucose tolerance and type 1 diabetes mellitus in at-risk relatives of patients with type 1 diabetes. Since C-peptide production is directly related to insulin production, this study also used oral glucose tolerance testing to evaluate the effect of Abatacept on C-peptide response. Participants were randomized into either the Abatacept or placebo group. The groups received an intravenous infusion of their respective treatments at specific points during the course of the study. Subjects were regularly monitored and assessed for the development of abnormal glucose tolerance or diabetes.

The objective of the TrialNet 18 study was to determine the effect of Abatacept intervention on abnormal glucose tolerance in at-risk individuals. Additionally, the study determined whether treatment with Abatacept had an effect on C-peptide response to oral glucose tolerance testing.

Primary Outcome Measures: The time frame of the change from normal glucose tolerance to abnormal glucose tolerance was evaluated and compared between the two groups.

Secondary Outcome Measures: The time frame of the change in C-peptide response to Oral Glucose Tolerance Test will be evaluated and compared between the two groups.

Subjects must be age 6-45 years; a TrialNet Natural History/Pathway to Prevention Study participant; have normal glucose tolerance confirmed by Oral Glucose Tolerance Test within 7 weeks; have at least 2 confirmed diabetes-related autoantibodies, not including mIAA, present within 6 months prior to randomization; weigh at least 20kg (approx. 44lbs); the date of the last live immunization at least three months prior to study and forgo live vaccines until three months following study completion; and avoid pregnancy and undergo pregnancy testing before each infusion.

Individuals were excluded from the study if they have diabetes, abnormal glucose tolerance, or insulin autoantibodies (mIAA); a positive PPD or IGRA test, or previously treated TB; use immunosuppressive agents or medications that influence glucose tolerance; an active infection, including CMV and EBV; current or past HIV, Hepatitis B, or Hepatitis C infection; immunodeficiency or chronic lymphopenia; or are currently pregnant or lactating.

The TrialNet 18 study found that one year of abatacept treatment in individuals with stage 1 type 1 diabetes did not significantly delay progression to stage 2 or stage 3 diabetes, although it did cause expected immunological changes and improved insulin secretion. These results suggest abatacept may modify disease progression, but it did not meet the pre-set criteria for delaying diabetes in this population.