CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1
CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1 Diabetes
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
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.
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.
During the course of the study, participants will frequently undergo assessments of their
glucose tolerance status, insulin production, immunologic status, and overall health and
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.
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.
- Participant in TrialNet Natural History/Pathway to Prevention Study and thus, a
relative of a proband with T1DM.
- Between the ages of 1-45 years at the time of enrollment in TN01 and age ≥ 6 at time
of randomization in this trial.
- Willing to provide Informed Consent or have a parent or legal guardian provide
informed consent if the subject is <18 years of age.
- Normal glucose tolerance by OGTT confirmed within 7 weeks (no more than 52 days) of
baseline (visit 0). If previous abnormal glucose tolerance, has had two consecutive
OGTTs with normal glucose tolerance.
1. Fasting plasma glucose < 110 mg/dL (6.1 mmol/L), and
2. 2 hour plasma glucose <140 mg/dL (7.8 mmol/L), and
3. 30, 60, or 90 minute value on OGTT< 200mg/dL (11.1 mmol/L)
- At least two diabetes-related autoantibodies confirmed to be present on two
occasions, not including mIAA. Confirmation of 2 positive autoantibodies must occur
within the six months prior to randomization, but the confirmation does not have to
involve the same 2 autoantibodies.
- Weight ≥ 20 kg at Baseline Visit.
- If a female participant with reproductive potential, willing to avoid pregnancy and
undergo pregnancy testing prior to each infusion.
- At least three months from date of last live immunization.
- Willing to forgo live vaccines while receiving treatment on study and for three
months following last study drug administration.
- Abnormal Glucose Tolerance or Diabetes
1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L), or
2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L), or
3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)
- Insulin autoantibodies (mIAA).
- Are immunodeficient or have clinically significant chronic lymphopenia.
- Have an active infection at time of randomization.
- Have a positive PPD test result or history of previously treated TB, or positive
interferon-gamma release assay (IGRA) test.
- Be currently pregnant or lactating, or anticipate getting pregnant within 3 months of
the last study drug administration.
- Use of medications known to influence glucose tolerance.
- Require use of other immunosuppressive agents.
- Have serologic evidence of current or past HIV, Hepatitis B (positive for Hepatitis B
core antibody or surface antigen), or Hepatitis C infection.
- Have serological evidence of current CMV infection.
- Have evidence of active EBV infection.
- Have any complicating medical issues or abnormal clinical laboratory results that
interfere with study conduct or cause increased risk. These include pre-existing
cardiac disease, COPD, neurological, or blood count abnormalities (such as
lymphopenia, leukopenia, or thrombocytopenia).