CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1
Condition: Abnormal Glucose Tolerance; Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Intolerance
Study type: Interventional
Phase: Phase 2

Summary: 
      The study is a 2-arm, multicenter, 1:1 randomized, placebo controlled clinical trial.

      All subjects will receive close monitoring for development of AGT or T1DM. Subjects will
      receive Abatacept or placebo and close monitoring for development of AGT or T1DM. To assess
      the safety, efficacy, and mode of action of Abatacept to prevent AGT and T1DM.

      The primary objective is to determine whether intervention with Abatacept will prevent or
      delay the development of AGT in at-risk autoantibody positive non-diabetic relatives of
      patients with T1DM.

      Secondary outcomes include: the effect of Abatacept on the incidence of T1DM; analyses of
      C-peptide and other measures from the OGTT; safety and tolerability; and mechanistic
      outcomes.
    

Detailed description: 
      Study Purpose and Rationale:

      In this study, relatives who are confirmed to have two or more antibodies, not including
      mIAA, and normal glucose tolerance will be eligible for randomization to experimental
      treatment or placebo groups with the aim to determine whether experimental treatment will
      prevent or delay the occurrence of abnormal glucose tolerance and type 1 diabetes mellitus.
      Individuals with normal glucose tolerance are earlier in the disease process; that is, have
      less beta cell destruction than those with abnormal glucose tolerance or frank diabetes, yet
      will inevitably progress to clinical disease and essentially complete beta cell loss.
      Treatment at this early stage in a population who will inevitably progress to type 1 diabetes
      provides the greatest opportunity for a clinically important impact on disease prevention.
      With abnormal glucose tolerance rather than diabetes as the primary endpoint, study
      participants, regulators, funders, and investigators will be able to determine whether the
      therapy can alter disease progression.

      Therefore, the rationale for this study is that individuals with immunologic markers of T1DM
      and normal glucose tolerance will inevitably develop clinical T1DM. Prior to development of
      clinical T1DM they will progress from normal glucose tolerance to abnormal glucose tolerance;
      and abnormal glucose tolerance results in clinical T1DM within 5 years in almost 80% of
      subjects. They have a condition that differs from overt diabetes only in the duration of the
      autoimmune process that results in beta cell destruction. Intervention early in the course of
      disease may be more effective than intervention in those with abnormal glucose tolerance or
      clinical T1DM.

      Description of Treatment Groups

      Subjects will be randomized to receive either Abatacept or placebo infusions along with close
      monitoring for abnormal glucose tolerance or diabetes. The infusions will be conducted at
      approved TrialNet clinical sites with appropriate facilities. All blood and serum samples for
      the primary and secondary outcome determinations will be sent to the Core Laboratories for
      analysis. Clinical laboratory studies may be done at the local sites.

      Participants will be randomly assigned in a 1:1 ratio (within the two strata defined by age
      at enrollment: <18 and 18 or older) to the following 2 groups:

        -  to receive Abatacept (intravenous infusion at 0, 2, and 4 weeks following randomization,
           and then every 28+/-7 days) thereafter for a total of 14 doses. Close monitoring for
           diabetes development through the duration of study.

        -  to receive placebo intravenous infusion at 0, 2, and 4 weeks following randomization and
           then every 28+/- 7 days thereafter for a total of 14 doses. Close monitoring for
           diabetes development through the duration of study.

      Treatment Assignment

      After participants sign the consent form, complete the screening visit(s), and meet all of
      the inclusion criteria and none of the exclusion criteria, participants will be randomized to
      receive either Abatacept and close monitoring or placebo with close monitoring.

      Participants will be randomized in equal allocations to each group. The randomization method
      will be stratified by TrialNet study site and whether the participant is less than 18 years
      of age or 18 years and older. This approach ensures that study site will not be a potential
      confounder. The TNCC will generate the randomization numbers and tables.

      Study Assessments

      During the course of the study, participants will frequently undergo assessments of their
      glucose tolerance status, insulin production, immunologic status, and overall health and
      well-being.

      Samples will be drawn for storage in the National Institute for Diabetes and Digestive and
      Kidney Disease (NIDDK) Repository and at TrialNet Laboratory Sites for future analysis
      related to T1DM.

      Study Duration

      The study has been designed to provide 80% power to detect a 40% risk reduction in the
      occurrence of abnormal glucose tolerance using a two-sided test at the 0.05 level after six
      years of study duration. A total of approximately 206 patients will be allocated in a 1:1
      ratio to the two groups.
    

Intervention name(s): CTLA4-Ig (Abatacept); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Given as 30 minute IV infusion; Saline given as 30 minute IV infusion
Other intervention name(s): Abatacept
Intervention MeSH terms: Abatacept
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: prevention of type 1 diabetes; prevention of abnormal glucose tolerance