GPPAD-POInT (Global Platform of Autoimmune Diabetes - Primary Oral Insulin Trial)

The GPPAD-POInT Study is designed as a randomized, placebo-controlled, double blind, multicentre, multinational primary prevention phase IIb study aiming to induce immune tolerance to beta-cell autoantigens through regular exposure to oral insulin for a period of 29 to 32 months. The hypothesis is that regular exposure to oral insulin throughout the period in life where beta-cell autoimmunity usually initiates will tolerize against insulin and train the body's immune system to recognize the treatment product without reacting adversely to it in a manner seen in children who develop T1D. This immune tolerance induction therapy would reduce the likelihood of beta-cell autoimmunity. The study objective is to determine whether daily administration of oral insulin from age 4 months - 7 months until age 3.00 years to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies and diabetes in childhood.

The GPPAD-POInT-Study aims to determine whether daily administration of oral insulin to children from age 4 months - 7 months with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies and diabetes in childhood. The purpose of the GPPAD-POInT-Study is to induce immune tolerance to beta-cell autoantigens through regular exposure to oral insulin for a period of 29 to 32 months. Together with the results of the Pre-POINT-Early Study, this phase IIb study aims to investigate and consolidate the findings from the pilot Pre-POINT Study, namely safety and immune efficacy at a daily dose of 67.5 mg oral insulin. Since babies and young children will be tested in the GPPAD-POInT-Study, the 67.5 mg dose will be reached by dose escalation starting at 7.5 mg for 2 months, followed by exposure to 22.5 mg for 2 months, and reaching the desired 67.5 mg dose. The GPPAD-POInT-Study aims to recruit 1040 children into the trial.

The active substance for oral application is human insulin. Oral Insulin will be applied as a capsule containing 7.5, 22.5 and 67.5 mg of the active substance together with filling substance microcrystalline cellulose.

Eligibility Criteria:
Inclusion Criteria:

1. Infant between the ages of 4 months and 7 months at the time of randomization.

2. A high genetic risk (\>10%) to develop beta-cell autoantibodies by age 6 years:

1. For infants without a first degree family history of type 1 diabetes, high genetic risk is defined as a DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype, and a genetic risk score that is \>14.4.
2. For infants with a first degree family history of type 1 diabetes, high genetic risk is defined as having HLA DR4 and DQ8, and none of the following protective alleles: DRB1\*1501, DQB1\*0503.
3. Solid foods introduced into diet of infant
4. Written informed consent signed by the custodial parent(s).

Exclusion Criteria:

1. Concomitant disease or treatment that may interfere with the assessments, as judged by the investigators.
2. Any condition that could be associated with poor compliance.
3. Any medical condition or medical condition coexisting, which, in the opinion of the investigator, may jeopardize the participant's safe participation in the study.
4. Diagnosis of diabetes at the time of recruitment.
5. Participation in another clinical trial.