Type 1 Diabetes Mellitus
Conditions
Keywords
CTLA4-Ig, Abatacept, Beta-cell function, T-cells, DPT-1, treatment, treatment of type 1 diabetes, new onset type 1 diabetes, juvenile diabetes, T1D, diabetes mellitus, Type 1 diabetes TrialNet, TrialNet
Brief summary
The purpose of this study is to determine whether treatment with CTLA4-Ig (Abatacept) in individuals with new onset T1DM will improve insulin secretion (C-peptide production) compared to placebo.
Detailed description
Type 1 diabetes mellitus (T1DM) is a T-cell mediated autoimmune disease in which insulin-producing beta cells are completely or near completely destroyed resulting in life-long dependence on exogenous insulin. CTLA4-Ig (Abatacept) inhibits a crucial stimulatory pathway in the activation of T cells. By this mechanism, the drug is thought to arrest or slow the T cell mediated autoimmune destruction of beta-cells and preserve their function. At the time of clinical onset of T1DM, a significant amount of insulin producing beta cells are destroyed, but as many as 10-20% are still capable of insulin production. By using CTLA4-Ig close to the onset of T1DM, we hope to arrest or slow down the autoimmune destruction of these beta-cells and extend the endogenous insulin production. CTLA4-Ig regulates T cell function but does not deplete T cells. Therefore, its safety profile appears to be better than other immunosuppressive agents. Eligible participants will be randomized to the experimental or control groups. The experimental group will receive intravenous infusions of CTLA-4 Ig. The first infusion will occur at the time of randomization, followed by another infusion 2 and 4 weeks later. Subsequent infusions will be given monthly for two years during the treatment phase of the study. There is a total of 27 infusions during the treatment phase of the study. Participants in the control group will receive intravenous infusions of placebo according to the same schedule outlined above. Both groups will receive standard intensive diabetes treatment with insulin and dietary management. All participants randomized into the study will be seen at study site monthly for 24 months and then every 6 months for up to an additional 2 years. Participants will undergo assessments of their insulin production, immunologic status, overall health and well being and diabetes care.
Interventions
DRUGCTLA-4 Ig
Intravenous infusion of 10 mg/kg of CTLA-4 Ig every other week for the first two doses and then every 28 days for a total of 27 doses
OTHERPlacebo
Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Juvenile Diabetes Research Foundation
American Diabetes Association
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Age 6-45 2. Within 3 months (100 days) of diagnosis of T1DM based on ADA criteria 3. At least one diabetes-related autoantibody 4. Stimulated C-peptide level \>0.2 pmol/ml by MMTT conducted 21 days after diagnosis of T1DM and within 37 days of randomization 5. At least three months from last live immunization received and willing to forgo live vaccinations for three months following last dose of study treatment
Exclusion criteria
1. Immunodeficiency, chronic lymphopenia, active infection, positive PPD result or a history of malignancy 2. Serologic evidence of current or past HIV, Hepatitis B or C 3. Pregnancy, lactation, or intention of pregnancy while on study 4. Current use of immunosuppressive agents, or medications known to influence glucose tolerance or glycemic control 5. Current participation in another T1DM treatment study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 2 Year Visit | 2 years of follow up | The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CTLA-4 Ig Intravenous infusions of CTLA-4 Ig
CTLA-4 Ig: Intravenous infusion of 10 mg/kg of CTLA-4 Ig every other week for the first two doses and then every 28 days for a total of 27 doses | 77 |
| Placebo Intravenous infusions of placebo
Placebo: Intravenous infusions of placebo every other week for the first two doses and then every 28 days for a total of 27 doses | 35 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Travel issues | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | CTLA-4 Ig | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 13.9 years STANDARD_DEVIATION 6.9 | 13.7 years STANDARD_DEVIATION 5.3 | 13.9 years STANDARD_DEVIATION 6.4 |
| Sex: Female, Male Female | 36 Participants | 10 Participants | 46 Participants |
| Sex: Female, Male Male | 41 Participants | 25 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 77 | 26 / 35 |
| serious Total, serious adverse events | 11 / 77 | 7 / 35 |
Outcome results
Primary
Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 2 Year Visit
The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes.
Time frame: 2 years of follow up
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| CTLA-4 Ig | Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 2 Year Visit | 0.375 nmol/L |
| Placebo | Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 2 Year Visit | 0.266 nmol/L |
Comparison: The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.p-value: 0.0014ANCOVA