The TrialNet (TN20) study was a two-arm, multi-center, randomized, open-labeled clinical trial designed to assess the effects of varying doses and schedules of oral insulin on immunological and metabolic markers in relatives at risk for type 1 diabetes (T1D).

Participants were from the TrialNet Natural History/Pathway to Prevention (TN01) study, had a relative with T1D, and were positive for insulin autoantibodies and at least one other autoantibody. All participants received an active treatment of recombinant insulin in capsules of either 67.5 mg daily or 500 mg every other week. Participants visited the study site up to 11 times over one year for blood tests and other study procedures. During the beginning treatment phase, there were two visits one month apart for those given the 67.5 mg dose, and three visits two weeks apart to titrate the dose for those in the 500 mg treatment group. There were three additional treatment visits at months 2, 3, and 6, as well as four additional visits for follow-up at months 7, 8, 9, and 12. The primary outcome was the change in immune function as assessed by change in level or quality of T-lymphocyte or autoantibody biomarkers measured between 13 and 26 weeks compared to the baseline.

The main objective of this study was to learn more about the immune effects of oral insulin using different doses, and to ascertain additional scientific information about oral insulin and gain a better understanding of how much oral insulin should be given to produce a more favorable immune response that could help delay or prevent T1D.

The primary outcome measure was change in immune function (from 13 and 26 weeks after first dose versus baseline), assessed by level or quality of T-lymphocyte or autoantibody biomarkers of beta cell specific immune response as measured by change in CD4 auto-antigen specific ELISPOTs for IFN-g and IL-17, and cD8 peptide-HLA multimers (Q-dots).

Inclusion criteria:

• Participants in the TrialNet Natural History/Pathway to Prevention Study (TN01)
• A relative of a proband with T1D
• Between ages 3-45 years with normal Oral Glucose Tolerance Test (OGTT) or between ages 3-7 years with an abnormal OGTT
• Confirmed positive for insulin autoantibodies within previous six months
• Confirmed positive for one or more other autoantibodies on two separate occasions within the past six months

Exclusion criteria:

• Diagnosed with T1D
• History of treatment with insulin or oral hypoglycemic agent
• History of therapy with immunosuppressive drugs or non-physiologic glucocorticoids within the past two years for a period of more than three months
• Ongoing use of medications known to influence glucose tolerance
• Pregnant or intending to become pregnant while on study or lactating

The TN20 results found that oral insulin did not delay or prevent T1D in individuals at high risk for T1D. However, the study proved that it is possible to identify and enroll individuals at high risk for T1D in large randomized clinical trials, indicating that future research can be accomplished in the efforts of preventing the development of T1D in these high risk groups.