CLINICAL TRIAL / NCT01773707
CTLA4-Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At -Risk for Type 1
- Interventional
- Active
- NCT01773707
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 outcomes.
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.
Gender
All
Age Group
6 Years to 45 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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).