Abnormal Glucose Tolerance, Type 1 Diabetes
Conditions
Keywords
prevention of type 1 diabetes, prevention of abnormal glucose tolerance
Brief 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.
Interventions
DRUGCTLA4-Ig (Abatacept)
Given as 30 minute IV infusion
DRUGPlacebo
Saline given as 30 minute IV infusion
Sponsors
Juvenile Diabetes Research Foundation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 45 Years
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Confirmed Abnormal Glucose Tolerance Test | 96 months | Measured by Oral Glucose Tolerance Test (OGTT): Abnormal Glucose Tolerance is primary endpoint and defined as: 1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and \< 126 mg/dL (7 mmol/L), or 2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and \< 200 (11.1 mmol/L), or 3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT) | 0 time to 30 months | To Determine whether treatment with Abatacept is superior to placebo with respect to C-peptide response to oral glucose tolerance |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abatacept IV Infusion CTLA4-Ig (Abatacept) will be administered as 14 (30 minute) infusions over one year (3 infusions every other week the first month; monthly for the following 11 months)
CTLA4-Ig (Abatacept): Given as 30 minute IV infusion | 101 |
| Placebo The placebo arm will receive 14 (30 minute) IV infusions (containing saline) given 3 times (every other week) the first month and monthly for the following 11 months.
Placebo: Saline given as 30 minute IV infusion | 111 |
| Total | 212 |
Baseline characteristics
| Characteristic | Abatacept IV Infusion | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 16.3 years | 15.6 years | 14.9 years |
| Autoantibodies positive Anti-GAD65 harmonized | 94 Participants | 198 Participants | 104 Participants |
| Autoantibodies positive Anti-IA-2 harmonized | 49 Participants | 110 Participants | 61 Participants |
| Autoantibodies positive Anti-ZnT8 | 47 Participants | 112 Participants | 65 Participants |
| Autoantibodies positive Autoantibodies (ICA) | 76 Participants | 155 Participants | 79 Participants |
| Autoantibodies positive Micro insulin | 4 Participants | 6 Participants | 2 Participants |
| Autoantibodies titer Anti-IA-2 harmonized | 2 titers | 9 titers | 23 titers |
| Autoantibodies titer Anti-ZnT8 | 0.013 titers | 0.027 titers | 0.041 titers |
| Autoantibodies titer Autoantibodies (ICA) | 40 titers | 40 titers | 40 titers |
| Autoantibodies titer GADA | 317 titers | 335 titers | 375 titers |
| Autoantibodies titer Micro insulin | 0.002 titers | 0.002 titers | 0.002 titers |
| Body Mass Index (BMI) | 22.7 kg/m^2 | 22.1 kg/m^2 | 21.6 kg/m^2 |
| Body Mass Index (BMI) Z-score | 0.668 Z-score | 0.623 Z-score | 0.582 Z-score |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 21 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants | 182 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 3 Participants |
| Glycated hemoglobin level | 5.1 percentage of glycated hemoglobin | 5.1 percentage of glycated hemoglobin | 5.1 percentage of glycated hemoglobin |
| HLA alleles present DR3 | 47 Participants | 107 Participants | 60 Participants |
| HLA alleles present DR4 | 60 Participants | 123 Participants | 63 Participants |
| HLA alleles present Missing | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) White | 91 Participants | 193 Participants | 102 Participants |
| Relationship to person with type 1 diabetes Identical twin | 1 Participants | 3 Participants | 2 Participants |
| Relationship to person with type 1 diabetes Offspring | 21 Participants | 35 Participants | 14 Participants |
| Relationship to person with type 1 diabetes Parent(s) | 14 Participants | 37 Participants | 23 Participants |
| Relationship to person with type 1 diabetes Second degree relative | 4 Participants | 10 Participants | 6 Participants |
| Relationship to person with type 1 diabetes Sibling and another first degree relative | 6 Participants | 15 Participants | 9 Participants |
| Relationship to person with type 1 diabetes Sibling(s) | 53 Participants | 109 Participants | 56 Participants |
| Relationship to person with type 1 diabetes Third degree relative | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 50 Participants | 107 Participants | 57 Participants |
| Sex: Female, Male Male | 51 Participants | 105 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 101 | 0 / 111 |
| other Total, other adverse events | 63 / 101 | 77 / 111 |
| serious Total, serious adverse events | 2 / 101 | 3 / 111 |
Outcome results
Primary
Time From Randomization to Confirmed Abnormal Glucose Tolerance Test
Measured by Oral Glucose Tolerance Test (OGTT): Abnormal Glucose Tolerance is primary endpoint and defined as: 1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and \< 126 mg/dL (7 mmol/L), or 2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and \< 200 (11.1 mmol/L), or 3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L)
Time frame: 96 months
Population: Relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abatacept IV Infusion | Time From Randomization to Confirmed Abnormal Glucose Tolerance Test | 89.2 months |
| Placebo | Time From Randomization to Confirmed Abnormal Glucose Tolerance Test | 71.6 months |
Secondary
Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT)
To Determine whether treatment with Abatacept is superior to placebo with respect to C-peptide response to oral glucose tolerance
Time frame: 0 time to 30 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Abatacept IV Infusion | Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT) | 2.16 nmol/L |
| Placebo | Change in C-peptide Concentration to Oral Glucose Tolerance Test (OGTT) | 2.07 nmol/L |