TN-22: Hydroxychloroquine in stage 1 at-risk individuals
What this study tests
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.
Editorial review: .
Registry checked: 2026-09-17. Registry’s own update: 2024-04-09.
Most recent recorded citation date: 2023-11-01. Only explicit date metadata is included; an undated citation may be newer. This does not mean every claim was reviewed on that date.
Trial status, labels and access can change between reviews. How we review the evidence · How to read the evidence
Evidence at a glance
- Who can enter the study?
- For people aged 3 and older already enrolled in TrialNet's Pathway to Prevention screening study who had two or more islet autoantibodies on two samples but still had normal glucose tolerance on an oral glucose tolerance test (i.e., stage 1 T1D). Weight had to be at least 12 kg. People with abnormal glucose tolerance, existing diabetes, G6PD deficiency, prior retinopathy, or a prolonged QT interval were excluded. Registered eligibility ↗Enrollment criteria describe who may enter. They do not establish who was analyzed or the denominator for a reported result.
- Reported benefit and results
- 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. No safety concern, including retinal toxicity, was identified during trial follow-up; this does not establish risk-free use. 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.Read the result sources and their limitations →
- Important harms
- Read the reported results, safety discussion and original sources. A separate harms summary is not available; this does not establish safety.
- Research access and approval
- Study regions: United States, United Kingdom, European Union, Canada, Australia. A trial listing does not establish product approval or current recruitment at a particular site. Check the study’s current entry requirements.
- What remains uncertain?
- Read the full discussion and original sources for study limitations. Planned endpoints and completion dates are not results.
Research status alone does not establish approval, clinical benefit or local availability.
Australian sites in the registry
- Royal North Shore Hospital, St Leonards, New South Wales — Site status not reported
- Women's and Children's Hospital, Adelaide, North Adelaide, South Australia — Site status not reported
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria — Site status not reported
- Perth Children's Hospital, Perth, Western Australia — Site status not reported
Overall recruitment does not imply availability at every site. Confirm eligibility and local recruitment with the study team.
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
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 No safety concerns were identified during this trial, including its annual eye examinations; this does not establish that hydroxychloroquine is risk-free.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 The result applies to this drug and stage 1 population. It does not establish which other immune therapies will work or fail.1
Sources
- [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) · Peer-reviewed study
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).
- [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 · Peer-reviewed study
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.
- [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) · Trial registry
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).
- [4]Hydroxychloroquine in Stage 1 Type 1 Diabetes. · Peer-reviewed study · 2023-11-01
Libman I, Bingley PJ, Becker D, et al. Hydroxychloroquine in Stage 1 Type 1 Diabetes. Diabetes Care (2023).