Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
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.
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.
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.