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

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 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. 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.