Diabetes Mellitus, Type 1
Conditions
Keywords
oral insulin, autoantigen, self tolerance, oral tolerance, Diabetes Prevention Trial - 1 (DPT-1), prevention, at risk for developing type 1 diabetes, juvenile diabetes, Type 1 diabetes (T1D), diabetes mellitus, Type 1 diabetes TrialNet, TrialNet
Brief summary
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). As these cells are destroyed, the body's ability to produce insulin decreases. There is evidence suggesting that repeated oral administration of an autoantigen (the same protein that the immune system is reacting to) may introduce a protective immunity and cause the immune system to stop its attack. An earlier, large scale study was done to see if oral insulin could delay or prevent the development of Type 1 diabetes in relatives at risk for developing Type 1 diabetes. The overall results showed that for the entire study population, oral insulin did not delay or prevent Type 1 diabetes. However, an analysis that was done after the conclusion of the trial suggested a potential beneficial effect in a subgroup of participants. The participants who seemed to benefit from oral insulin had higher levels of insulin autoantibodies which are directed against insulin itself ( called mIAA). The Type 1 Diabetes TrialNet study group will further explore the potential role of oral insulin to delay or prevent Type 1 diabetes in a similar group of people. The study will also include a secondary group of individuals at different levels of risk than those in the primary cohort to gather information for future studies.
Detailed description
Eligible participants will be randomized to receive either oral insulin (7.5 mg of recombinant human insulin crystals) or placebo daily. All participants randomized into this study will be seen at a study site for a follow-up evaluation, three and six months after randomization, and every six months thereafter. Participants will be contacted by phone between 6-monthly clinic visits to assess changes in diabetes status, medication compliance and adverse events. These phone contacts will occur approximately 3 months from the date of the participants previous clinic visit. At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. As the primary outcome measure, subjects will be followed until development of type 1 diabetes or the conclusion of the study. The trial is expected to last approximately 7-8 years or until the required amount of information is gathered.
Interventions
DRUGOral Insulin
7.5 mg oral insulin or placebo given before breakfast on a daily basis.
DRUGPlacebo
Placebo capsule designed to match active drug
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
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Have a proband with Type 1 diabetes mellitus (T1DM). A proband is an individual diagnosed with diabetes before age 40 and started on insulin therapy within 1-year of diagnosis. Probands considered to have type 1 diabetes by their physician who do not meet this definition will be referred to the TrialNet Eligibility Committee. 2. If the proband is a parent, sibling or a child, the study participant must be 3 -45 years of age. If the proband is a second or third degree relative (i.e. niece, nephew, aunt, uncle, grandparent, cousin, or half-sibling), the study participant must be 3-20 years of age. 3. Willing to sign Informed Consent Form. 4. Oral glucose tolerance test (OGTT) performed within 7 weeks prior to randomization in which: * fasting plasma glucose \< 110 mg/dL (6.1 mmol/l), and * 2 hour plasma glucose \< 140 mg/dL (7.8 mmol/l) 5. mIAA confirmed positive within the previous six months. 6. Two samples with at least one autoantibody other than mIAA positive within the previous six months.
Exclusion criteria
1. Does not satisfy the above inclusion criteria. Subjects with mIAA positive but no other autoantibodies positive are not eligible for randomization. 2. Has severe active disease, e.g. chronic active hepatitis, severe cardiac, pulmonary, renal, hepatic, immune deficiency and/or disease that is likely to limit life expectancy or lead to therapies such as immunosuppression during the time of the study. 3. Prior participation in a trial for prevention of T1DM, e.g. nicotinamide, insulin, immunosuppressive drugs. 4. History of treatment with insulin or oral hypoglycemic agent. 5. History of therapy with immunosuppressive drugs or glucocorticoids within the past two years for a period of more than three months. 6. Ongoing use of medications known to influence glucose, i.e. sulfonylureas, growth hormone, metformin, anticonvulsants, thiazide or potassium depleting diuretics, beta adrenergic blockers, niacin. Subjects on such medications should be changed to a suitable alternative, if available, and will become eligible one month after medication is discontinued. 7. Pregnant or intends to become pregnant while on study or lactating. 8. Deemed unlikely or unable to comply with the protocol. 9. OGTT that reveals Diabetes, Impaired Glucose Tolerance (IGT), or Impaired Fasting Glucose (IFG). Diabetes is defined by: * fasting plasma glucose ³ 126 mg/dL (7 mmol/l), OR * 2 hour plasma glucose ³ 200 mg/dL (11.1 mmol/l) IGT is defined by: * fasting plasma glucose \< 126 mg/dL (7 mmol/l), and * 2 hour plasma glucose 140-199 mg/dL (7.8 - 11mmol/l), IFG is defined by: * fasting plasma glucose 110-125 mg/dL (6.1-6.9 mmol/l) AND * 2 hour plasma glucose \< 140 mg/dL (7.8 mmol/l) 10. Subject has HLA DQA1\*0102, DQB1\*0602 haplotype.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo | Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years | Primary outcome is reported as the rate of type 1 diabetes per year among the primary stratum; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo | Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years | Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 2; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up. |
| Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo | Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years | Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 3+4; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up. |
Countries
Australia, Canada, Finland, Italy, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Insulin 7.5 mg oral insulin capsules given before breakfast on a daily basis. | 283 |
| Placebo Placebo capsule designed to mimic appearance of treatment capsule | 277 |
| Total | 560 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 12 | 13 |
| Overall Study | Participant Institutionalized | 1 | 0 |
| Overall Study | Withdrawal by Subject | 20 | 18 |
Baseline characteristics
| Characteristic | Total | Placebo | Oral Insulin |
|---|---|---|---|
| Age, Continuous | 8.2 years | 8.2 years | 8.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 25 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 508 Participants | 252 Participants | 256 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Self-Reported Race African American | 17 Participants | 9 Participants | 8 Participants |
| Race/Ethnicity, Customized Self-Reported Race Asian/Pacific Islander | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Self-Reported Race Not Reported | 32 Participants | 13 Participants | 19 Participants |
| Race/Ethnicity, Customized Self-Reported Race White | 501 Participants | 249 Participants | 252 Participants |
| Region of Enrollment Australia | 11 Participants | 4 Participants | 7 Participants |
| Region of Enrollment Canada | 32 Participants | 15 Participants | 17 Participants |
| Region of Enrollment Finland | 9 Participants | 5 Participants | 4 Participants |
| Region of Enrollment Germany | 15 Participants | 6 Participants | 9 Participants |
| Region of Enrollment Italy | 14 Participants | 7 Participants | 7 Participants |
| Region of Enrollment New Zealand | 8 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Sweden | 8 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United Kingdom | 12 Participants | 6 Participants | 6 Participants |
| Region of Enrollment United States | 453 Participants | 227 Participants | 226 Participants |
| Sex: Female, Male Female | 220 Participants | 107 Participants | 113 Participants |
| Sex: Female, Male Male | 340 Participants | 170 Participants | 170 Participants |
| Stratum 1 | 389 Participants | 186 Participants | 203 Participants |
| Stratum 2 | 55 Participants | 27 Participants | 28 Participants |
| Stratum 3 | 114 Participants | 63 Participants | 51 Participants |
| Stratum 4 | 2 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 283 | 0 / 277 |
| other Total, other adverse events | 150 / 283 | 133 / 277 |
| serious Total, serious adverse events | 0 / 283 | 0 / 277 |
Outcome results
Primary
Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo
Primary outcome is reported as the rate of type 1 diabetes per year among the primary stratum; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up.
Time frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Insulin | Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo | 0.088 Proportion with diabetes/year |
| Placebo | Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo | 0.102 Proportion with diabetes/year |
Secondary
Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo
Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 3+4; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up.
Time frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Population: Combine stratum 3 (mIAA Confirmed, ICA Not Confirmed, ICA512+ OR GAD65ab+, high functioning beta cells) and stratum 4 (mIAA Confirmed, ICA Not Confirmed, ICA512+ OR GAD65ab+, low functioning beta cells)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Insulin | Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo | 0.051 Proportion with diabetes/year |
| Placebo | Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo | 0.047 Proportion with diabetes/year |
Secondary
Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo
Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 2; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up.
Time frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Population: Stratum 2: mIAA Confirmed, (ICA Confirmed) OR (ICA Not Confirmed AND ICA512+ AND GAD65ab+), low functioning beta cells
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Insulin | Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo | 0.181 Proportion with diabetes/year |
| Placebo | Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo | 0.341 Proportion with diabetes/year |