Type 1 Diabetes Mellitus
Conditions
Keywords
immune tolerance, immunotherapy, antigen-specific tolerance, vaccine induced tolerance, Beta-cell function, T-cells, DPT-1, 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 multiple injections of GAD-Alum will preserve the body's own (endogenous) insulin production in patients who have been recently diagnosed with type 1 diabetes mellitus (T1DM).
Detailed description
Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part of the body which helps fight infections) mistakenly attacks and destroys the cells that produce insulin (islet cells found in the pancreas called islet cells). As these cells are destroyed, the body's ability to produce insulin decreases. Glutamic acid decarboxylase (GAD) is one of the major autoantigens (a protein that the immune system is reacting to) involved in the autoimmune process underlying T1DM. GAD-Alum is Recombinant human (rhGAD65) and is used as an antigen-specific immune modulator. Previous studies have shown that it may slow or prevent autoimmune destruction of pancreatic islet cells by introducing immune tolerance. By administering excess autoantigen, the body may stop its attack on its own cells that produce insulin. If the immune system's attack can be halted in a patient with recent onset T1DM, than residual insulin secretion may be maintained. This may be beneficial in decreasing acute and long-term diabetic complications as well as improving glucose control.
Interventions
DRUGGAD-Alum
Participants will receive 3 injections of 20 micrograms GAD-Alum subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart.
DRUGGAD-Alum and Aluminum hydroxide
Participants will receive 3 injections subcutaneously. The first two will contain 20 micrograms GAD-Alum vaccine and are given 4 weeks apart. The third injection will be Aluminum hydroxide alone and will be given 8 weeks after the second injection.
Participants will receive 3 injections of Aluminum hydroxide alone, subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)
National Center for Research Resources (NCRR)
American Diabetes Association
Juvenile Diabetes Research Foundation
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
3 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Age 3 to 45 years - Insulin dependent type 1-diabetes mellitus diagnosed within the previous 3 months * Stimulated C-peptide levels greater than or equal to 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) conducted 3 weeks from diagnosis of diabetes * Presence of GAD65 antibodies * At least one month from last immunization * Willing to comply with intensive diabetes management * If participant is a woman with reproductive potential, she must be willing to avoid pregnancy and have a negative pregnancy test * Willing to forgo routine clinical immunizations during the first 100 days after initial study drug administration
Exclusion criteria
* Immunodeficiency or clinically significant chronic lymphopenia * Active infection * Positive PPD test result * Pregnant or lactating or anticipating becoming pregnant for 24 months following first injection * Ongoing use of medications known to influence glucose tolerance * Require use of systemic immunosuppressant(s) * Serologic evidence of current or past HIV, Hep B, or Hep C infection * History of malignancies * Ongoing use of non-insulin pharmaceuticals to affect glycemic control * Participation in another clinical trial with a new chemical entity within the past 3 months * Complicating medical issues or abnormal clinical laboratory results that interfere with study conduct or cause increased risk including neurological, or clinically significant blood count abnormalities (such as lymphopenia, leukopenia, or thrombocytopenia) * History of epilepsy, head trauma or cerebrovascular accident or clinical * History of alcohol or drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One Year Visit | Based on mixed meal tolerance test (MMTT) conducted at the one 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. |
Countries
Canada, United States
Participant flow
Recruitment details
The original recruitment goal was to enroll 126 subjects. However, additional eligible subjects were identified during the screening process and 145 subjects were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| GAD-alum 3 injections of GAD-Alum vaccine
GAD-Alum: Participants will receive 3 injections of 20 micrograms GAD-Alum subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart. | 48 |
| GAD-alum Plus Alum 2 injections of GAD-Alum vaccine and one injection with Aluminum hydroxide alone
GAD-Alum: Participants will receive 3 injections subcutaneously. The first two will contain 20 micrograms GAD-Alum vaccine and are given 4 weeks apart. The third injection will be Aluminum hydroxide alone and will be given 8 weeks after the second injection. | 49 |
| Alum Alone 3 injections of Aluminum hydroxide alone
Aluminum hydroxide: Participants will receive 3 injections of Aluminum hydroxide alone, subcutaneously. The first two injections are given 4 weeks apart and the second and third are given 8 weeks apart. | 48 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Non-compliant | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | GAD-alum | GAD-alum Plus Alum | Alum Alone | Total |
|---|---|---|---|---|
| Age, Continuous | 17.8 years STANDARD_DEVIATION 10.3 | 14.8 years STANDARD_DEVIATION 8.7 | 16.6 years STANDARD_DEVIATION 9.2 | 16.4 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 14 Participants | 31 Participants | 19 Participants | 64 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 29 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 48 | 25 / 49 | 24 / 48 |
| serious Total, serious adverse events | 5 / 48 | 3 / 49 | 5 / 48 |
Outcome results
Primary
The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One 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: Based on mixed meal tolerance test (MMTT) conducted at the one year visit
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GAD-alum | The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One Year Visit | 0.448 nmol/L |
| GAD-alum Plus Alum | The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One Year Visit | 0.350 nmol/L |
| Alum Alone | The Primary Outcome is the Area Under the Stimulated C-peptide Curve (AUC) at the One Year Visit | 0.418 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: 0.98ANCOVA
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: 0.51ANCOVA