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Phase 3CompletedNCT00419562

TN-07: Oral insulin for prevention in autoantibody-positive relatives

A large international Phase 3 trial (TrialNet) testing whether a daily oral insulin capsule could delay or prevent type 1 diabetes in autoantibody-positive relatives of people with the disease. Overall it did not delay diabetes, but a pre-specified subgroup with the most rapidly failing insulin response appeared to benefit — keeping the idea of antigen-specific immune tolerance alive.

Primary endpoints

  • Time to onset of type 1 diabetes (clinical diagnosis) in the primary study group — relatives with multiple autoantibodies and a preserved first-phase insulin response
  • Diabetes incidence rate per year in that primary stratum

Results so far

Over a median 2.7 years of follow-up, oral insulin did not delay or prevent type 1 diabetes in the main study group (diabetes in 28.5% on oral insulin vs 33% on placebo; hazard ratio 0.87, P=.21). However, in a pre-specified subgroup with a weaker first-phase insulin response (secondary stratum 1, n=55), diabetes was diagnosed in 48.1% on oral insulin vs 70.3% on placebo, and time to diabetes was significantly longer (HR 0.45, P=.006). Later post-hoc analyses found a similar signal in participants with high IA-2 autoantibody levels (HR 0.62, P=.012) and in carriers of the HLA DR4-DQ8 genetic type (HR 0.59, P=.027). The drug was safe, with no significant study-related adverse events.

The full picture

What was tested, and why it matters

Type 1 diabetes develops when the immune system attacks the insulin-making cells in the pancreas. Years before any symptoms, that attack shows up as islet autoantibodies in the blood — so relatives of people with type 1 diabetes can be screened and flagged as "at risk."1 TN-07 asked a hopeful question: if you feed the immune system a small daily dose of insulin by mouth, can you gently retrain it to tolerate insulin instead of attacking it — and so delay or prevent the disease?1 Oral insulin is digested, not absorbed as a hormone, so the goal was immune "tolerance," not blood-sugar lowering.1

Who it was for

The trial enrolled relatives of people with type 1 diabetes who already had at least two islet autoantibodies (including insulin autoantibodies) but whose glucose tests were still normal — people in the silent, pre-symptomatic stages of the disease.1 Participants ranged from young children to adults (ages 3–45; median enrollment age about 8 years).2

How it was designed

TN-07 was a Phase 3, randomized, triple-masked, placebo-controlled trial run across nine countries (Canada, the US, Australia, New Zealand, the UK, Italy, Sweden, Finland, and Germany).12 In total 560 people were randomized to either 7.5 mg of oral insulin daily or a matching placebo.1 They were sorted into groups based on their antibody profile and insulin-response strength; the main analysis group had 389 participants, followed for a median of 2.7 years.1

The key results

In the main study group, oral insulin did not delay type 1 diabetes: diabetes developed in 28.5% on oral insulin versus 33% on placebo (hazard ratio 0.87; P=.21 — not significant).1 Across the whole cohort the result was likewise not significant.1

But one pre-specified subgroup stood out — relatives whose insulin response was already weakening (secondary stratum 1, n=55). There, diabetes occurred in 48.1% on oral insulin versus 70.3% on placebo, and time to diabetes was significantly longer (HR 0.45; P=.006).1 Oral insulin was safe, with no significant study-related adverse events.1

What it means and what's next

The headline was negative — oral insulin as used here does not prevent type 1 diabetes — but the subgroup signal kept the antigen-tolerance idea alive.1 Later analyses of TN-07 data sharpened the picture: participants with high IA-2 autoantibody levels (HR 0.62; P=.012) and carriers of the HLA DR4-DQ8 genetic type (HR 0.59; P=.027) appeared to have their diabetes delayed, suggesting a specific "endotype" that may respond to oral insulin.3 The lesson shaping today's prevention research: the right therapy may need to be matched to the right person, identified early by their antibodies and genetics.3

References

  1. Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ; Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group. Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. JAMA (2017);318(19):1891–1902. https://pmc.ncbi.nlm.nih.gov/articles/PMC5798455/ ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9 ↩10 ↩11 ↩12

  2. National Institute of Diabetes and Digestive and Kidney Diseases (TrialNet). Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus (TN07). ClinicalTrials.gov, NCT00419562. https://clinicaltrials.gov/study/NCT00419562 ↩ ↩2

  3. Zhao LP, Papadopoulos GK, Skyler JS, et al. Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07). Diabetes Care (2024);47(9):1608–1616. https://doi.org/10.2337/dc24-0573 ↩ ↩2