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Phase 2TerminatedNCT03428945

TN-22: Hydroxychloroquine in stage 1 at-risk individuals

A TrialNet prevention trial testing whether the inexpensive oral immune-modulating drug hydroxychloroquine could slow the earliest stage of type 1 diabetes in people with two or more islet autoantibodies but still-normal blood sugar. It was stopped early for futility: the drug did not delay progression. An instructive negative result, though it left intriguing signals on autoantibodies.

Primary endpoints

  • Time from randomization to development of confirmed abnormal glucose tolerance (stage 2) or clinical type 1 diabetes (stage 3), assessed by oral glucose tolerance test every 6 months for up to 4 years

Results so far

The trial was stopped early for futility after a median follow-up of about 23 months: hydroxychloroquine did not delay progression. Median time to abnormal glucose tolerance or diabetes was 19.7 months on the drug versus 18.8 months on placebo, and the hazard ratio was 0.95 (95% CI 0.56-1.61) -- essentially no difference. Thirty-four drug-treated and seventeen placebo participants progressed. The drug was safe, with no retinal toxicity on annual eye exams. Preplanned secondary analyses did show signals -- a transient drop in glucose response at month 6 and lower anti-GAD and anti-insulin autoantibody titers plus less acquisition of new autoantibodies in the drug arm -- but these did not translate into clinical benefit.

The full picture

What was tested, and why it matters

Type 1 diabetes (T1D) doesn't begin the day someone needs insulin. Years earlier, the immune system starts attacking the insulin-making cells, a process you can detect through "islet autoantibodies" in the blood. People with two or more of these antibodies but still-normal blood sugar are in stage 1 T1D — almost all of them will eventually develop the clinical disease.1 TrialNet's TN-22 trial asked a hopeful, practical question: could hydroxychloroquine — a cheap, decades-old oral pill used for malaria and lupus that calms parts of the immune response — slow that hidden attack and buy people more time before their blood sugar started to climb?2

Who it was for

The trial enrolled 273 people aged 3 and older who already had two or more islet autoantibodies but normal glucose tolerance.2 They were drawn from TrialNet's large screening program, which finds at-risk relatives of people with T1D before symptoms appear.3

How it was designed

This was a phase 2, double-blind, randomized, placebo-controlled trial run across the United States, Canada, Australia, the United Kingdom, and parts of Europe.3 Participants were assigned 2-to-1 to hydroxychloroquine (5 mg/kg per day, up to 400 mg) or an identical placebo, and tracked with glucose tolerance tests every six months for up to four years.2 It was funded by the NIH's NIDDK with the Juvenile Diabetes Research Foundation.3

The key results

After a median follow-up of about 23 months, an independent safety board stopped the trial early for futility — the drug simply wasn't working.2 The median time to abnormal glucose tolerance or diabetes was 19.7 months on hydroxychloroquine versus 18.8 months on placebo, with a hazard ratio of 0.95 (95% CI 0.56–1.61): essentially no difference.4 Thirty-four people on the drug and seventeen on placebo progressed.2 Reassuringly, the drug was safe, including on the annual eye exams that hydroxychloroquine requires.2 Intriguingly, preplanned secondary analyses found that the drug arm had lower anti-GAD and anti-insulin antibody titers and acquired fewer new autoantibodies — a real immune effect that never translated into clinical benefit.2

What it means and what's next

TN-22 is an honest, instructive negative result: a gentle, low-cost oral immune modulator was not enough to bend the course of early T1D.2 It helped clarify that meaningfully delaying progression — as the antibody therapy teplizumab later did at stage 2 — likely needs more targeted intervention.1

References

  1. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care (2015). https://diabetesjournals.org/care/article/38/10/1964/37642 ↩ ↩2

  2. Libman I, Bingley PJ, Becker D, et al.; Type 1 Diabetes TrialNet Study Group. Hydroxychloroquine in Stage 1 Type 1 Diabetes. Diabetes Care (2023);46(11):2035–2043. https://pmc.ncbi.nlm.nih.gov/articles/PMC10620539/ ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8

  3. National Institute of Diabetes and Digestive and Kidney Diseases. Hydroxychloroquine in Individuals At-risk for Type 1 Diabetes Mellitus (TN-22), NCT03428945. ClinicalTrials.gov (2024). https://clinicaltrials.gov/study/NCT03428945 ↩ ↩2 ↩3

  4. Libman I, Bingley PJ, Becker D, et al. Hydroxychloroquine in Stage 1 Type 1 Diabetes. Diabetes Care (2023). https://doi.org/10.2337/dc23-1096 ↩