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Phase 3CompletedNCT00004984

DPT-1: Diabetes Prevention Trial-Type 1 (parenteral and oral insulin)

A landmark NIH prevention trial that screened over 100,000 relatives of people with type 1 diabetes to test whether giving insulin (by injection or by mouth) before diagnosis could delay or prevent the disease. Neither approach worked overall, but a subgroup signal from the oral-insulin arm seeded the later TrialNet oral insulin study (TN-07).

Primary endpoints

  • Diagnosis of type 1 diabetes (development of clinical diabetes), assessed by oral glucose tolerance testing every 6 months
  • Annualized rate of / cumulative incidence of progression to type 1 diabetes

Results so far

Neither approach prevented type 1 diabetes overall. In the injected-insulin trial (339 high-risk relatives), diabetes developed in 69 of the insulin group versus 70 of the observation group, with nearly identical yearly progression rates (15.1% vs 14.6%) and no overall benefit (relative risk 0.96). In the oral-insulin trial (372 relatives), diabetes developed in 44 on oral insulin versus 53 on placebo (6.4% vs 8.2% per year; hazard ratio 0.764, not significant, P=0.189). However, in a pre-specified subgroup with high insulin autoantibody levels, oral insulin appeared to slow progression (6.2% vs 10.4% per year; hazard ratio 0.566, P=0.015) - a hypothesis-generating signal that motivated a follow-up trial.

The full picture

What was tested and why it matters. The Diabetes Prevention Trial-Type 1 (DPT-1) asked a bold question: if you find people who are on the path to type 1 diabetes before they get sick, can giving them insulin early teach the immune system to stand down and delay or prevent the disease?1 This was one of the first large trials to test prevention using the body's own target molecule (insulin) as a kind of "tolerance" therapy.2

Who it was for. DPT-1 enrolled close relatives of people with type 1 diabetes, because they carry higher genetic risk. Researchers screened more than 84,000 relatives for the injected-insulin study and over 100,000 for the oral-insulin study, looking for islet-cell antibodies (an early sign of immune attack), then narrowed down with genetic, immune, and metabolic tests to find those most likely to progress.34 Eligible relatives were ages 3-45 (first-degree) or 3-20 (second-degree).5

Design. DPT-1 was really two NIH-funded, randomized Phase 3 trials run in parallel across 15 sites in the US and Canada.5 Higher-risk relatives (over 50% projected 5-year risk) were randomized to low-dose injected insulin (with annual intravenous insulin infusions) or to close observation - 339 people, followed a median of 3.7 years.3 Intermediate-risk relatives with insulin autoantibodies were randomized to an oral insulin capsule (7.5 mg/day) or placebo - 372 people, followed a median of 4.3 years.4 The goal in both was to see who developed diabetes, checked every 6 months.34

Key results. Neither approach prevented diabetes overall. Injected insulin: 69 cases vs 70 in the observation group; yearly progression 15.1% vs 14.6% (relative risk 0.96).3 Oral insulin: 44 cases vs 53 on placebo (6.4% vs 8.2% per year; hazard ratio 0.764, not statistically significant).4 But in a subgroup with high insulin-autoantibody levels, oral insulin appeared to slow progression (6.2% vs 10.4% per year; hazard ratio 0.566, P=0.015).4

What it means / what's next. DPT-1 proved that large-scale prevention trials in at-risk relatives are feasible and mapped the natural history of type 1 diabetes before diagnosis.6 The oral-insulin subgroup signal was promising enough to seed a dedicated follow-up trial in TrialNet (the oral insulin study, TN-07).4

References

  1. Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med (2002), via PubMed. https://pubmed.ncbi.nlm.nih.gov/12037147/ ↩

  2. Pozzilli P. The DPT-1 trial: a negative result with lessons for future type 1 diabetes prevention. Diabetes Metab Res Rev (2002), via PubMed. https://doi.org/10.1002/dmrr.316 ↩

  3. Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346:1685-1691 (2002), via PubMed. https://pubmed.ncbi.nlm.nih.gov/12037147/ ↩ ↩2 ↩3 ↩4

  4. Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial-Type 1. Diabetes Care 28:1068-1076 (2005), via PubMed. https://pubmed.ncbi.nlm.nih.gov/15855569/ ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  5. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The Diabetes Prevention Trial of Type 1 Diabetes (DPT-1). ClinicalTrials.gov (NCT00004984). https://clinicaltrials.gov/study/NCT00004984 ↩ ↩2

  6. Wilson DM, Buckingham B. Prevention of type 1a diabetes mellitus. Pediatr Diabetes 2:17-24 (2001), via PubMed. https://doi.org/10.1046/j.1399-543x.2001.00000.x ↩