Skip to content
type1.science
ObservationalRecruitingNCT00097292

TrialNet Pathway to Prevention

The backbone US/international screening and natural-history study that tests blood from relatives of people with T1D for islet autoantibodies, then monitors those who test positive. It defines and validates the stage 1/stage 2 framework of presymptomatic T1D and feeds nearly every modern prevention trial, including the one that led to teplizumab.

Primary endpoints

  • Development of clinical (stage 3) type 1 diabetes, by standard ADA diagnostic criteria
  • Progression of islet autoimmunity (seroconversion to one or more, then to multiple, islet autoantibodies)
  • Progression of dysglycemia on OGTT/HbA1c across presymptomatic stages

Results so far

Pooled and TrialNet cohort data show that risk is driven by how many islet autoantibodies a person has. Across childhood cohorts, ~70% of children with two or more autoantibodies developed clinical diabetes within 10 years versus ~14% with a single autoantibody and ~0.4% with none. TrialNet's own data refined this by age, autoantibody titer, genetics and metabolic testing, and the cohort directly identified the at-risk relatives enrolled in the trial that led to teplizumab (Tzield), the first therapy approved to delay type 1 diabetes onset.

The full picture

What it is and why it matters

TrialNet's Pathway to Prevention (also called the Natural History Study) is the long-running backbone study of type 1 diabetes (T1D) prevention research. Rather than testing a drug, it screens relatives of people with T1D for islet autoantibodies — immune markers that signal the body has begun attacking its own insulin-making cells — and then follows those who test positive over years to learn how, and how fast, the disease develops.1 It is the cohort from which nearly every US prevention trial draws its participants.2

This matters because T1D has a long silent phase. By the time symptoms appear, most insulin-producing cells are already gone. Pathway to Prevention proved that disease can be detected and staged years earlier, creating a window to intervene.1

Who it is for

It is open to relatives of someone with T1D who do not yet have diabetes. First-degree relatives (a child, sibling or parent) can join between ages 2 and 45; more distant relatives can join between ages 2 and 20.1 Screening is a simple blood test, done at home or at a site.

Design

This is an observational study — there is no randomization and no study drug. It began in 2004, is still recruiting, and aims to screen on the order of tens of thousands of relatives, with completion estimated for 2030.1 Screening looks for autoantibodies to GAD, insulin, IA-2 and ZnT8; people who test positive are offered repeat antibody testing plus glucose-tolerance (OGTT) and HbA1c monitoring to track progression.13

Key findings

The headline result is that the number of autoantibodies predicts risk. In pooled childhood cohorts, ~70% of children with two or more islet autoantibodies developed clinical diabetes within 10 years, versus ~14% with a single autoantibody and just ~0.4% with none.4 This finding underpins the now-standard definition of stage 1 (multiple autoantibodies, normal glucose) and stage 2 (autoantibodies plus dysglycemia) presymptomatic T1D.4 TrialNet data have since refined risk further using age, antibody titer, a genetic risk score and metabolic testing.53

Critically, this screening pipeline identified the high-risk relatives enrolled in the teplizumab (TN-10) trial — the study that showed an immune therapy can delay T1D onset, leading to teplizumab's approval as the first such drug.26

What it means / what's next

Pathway to Prevention turned T1D into a stageable, monitorable disease and made early intervention possible. Screening also lowers the risk of dangerous ketoacidosis at diagnosis by catching disease early.6 Ongoing work extends staging to adults, who progress differently from children.7

References

  1. U.S. National Library of Medicine. TrialNet Pathway to Prevention of T1D (NCT00097292). ClinicalTrials.gov (accessed 2026). https://clinicaltrials.gov/study/NCT00097292 ↩ ↩2 ↩3 ↩4 ↩5

  2. TrialNet. Teplizumab (Anti-CD3) Prevention Study. Type 1 Diabetes TrialNet (accessed 2026). https://www.trialnet.org/our-research/completed-studies/teplizumab ↩ ↩2

  3. Pribitzer S, et al. Beyond Stages: Predicting Individual Time Dependent Risk for Type 1 Diabetes. J Clin Endocrinol Metab (2024). https://doi.org/10.1210/clinem/dgae292 ↩ ↩2

  4. Ziegler AG, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA (2013). https://doi.org/10.1001/jama.2013.6285 ↩ ↩2

  5. Redondo MJ, et al. A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care (2018). https://doi.org/10.2337/dc18-0087 ↩

  6. Martinenghi S, et al. Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies and followed up in the TrialNet Pathway to Prevention study. Diabetologia (2025). https://doi.org/10.1007/s00125-025-06461-z ↩ ↩2

  7. Templeman EL, et al. Contrasting Adult and Pediatric Populations in a Cohort of At-Risk Relatives in The T1D TrialNet Pathway to Prevention Study. Diabetes Care (2025). https://doi.org/10.2337/dc25-0192 ↩