This study was testing a medication, hydroxychloroquine (HCQ), to assess safety and effectiveness to prevent individuals at risk of type 1 diabetes (T1D) from progressing to type 1 diabetes. HCQ is approved by the U.S. Food and Drug Administration as a treatment for malaria, lupus, and rheumatoid arthritis. HCQ has been used extensively for treatment of autoimmune disease in adults, children, and during pregnancy. This medication has not previously been studied as a treatment to prevent T1D.

The goal of this study was to learn if HCQ can help prevent or delay progression from normal glucose tolerance (Stage 1) to abnormal glucose tolerance (Stage 2) or type 1 diabetes (Stage 3). The study was a 2-arm, double-blinded, multicenter, 2:1 randomized, placebo-controlled clinical trial. Subjects received hydroxychloroquine or placebo and close monitoring for progression of T1D.

The objective of this prevention study was to test if hydroxychloroquine can delay or prevent early stage T1D (Stage 1) from progressing to abnormal glucose tolerance (Stage 2) and ultimately prevent clinical diagnosis (Stage 3).

The primary outcome was the time from treatment assignment to changes in glucose tolerance. The time to development of abnormal glucose tolerance or the diagnosis of type 1 diabetes was measured to identify these changes.

• Participants in TrialNet Pathway to Prevention Study (TN01)
• Age 3 years or older at time of randomization
• Willing to provide informed consent
• Normal glucose tolerance by OGTT within 7 weeks of baseline
• Two or more diabetes-related autoantibodies present on two separate samples
• Weight of 12 kg or greater at screening
• If a female participant with reproductive potential, willing to avoid pregnancy and undergo pregnancy testing prior to randomization and at each study visit
• Anticipated ability to swallow study medication

• Abnormal glucose tolerance or diabetes
• History of treatment with insulin or other diabetes therapies
• Ongoing use of medications known to influence glucose tolerance
• Use of medications known to have untoward interactions with hydroxychloroquine
• Hypersensitivity to 4-aminoquinoline compounds
• G6PD deficiency
• History of retinopathy
• Active infection at time of randomization
• Current or past HIV, Hepatitis B, or Hepatitis C infection, or other complicating medical issues
• Deemed unlikely or unable to comply with the protocol or have any complicating medical issues, including disease previously or likely in the future to require immunosuppression, or abnormal clinical laboratory results that interfere with study conduct or cause increased risk.
• Pregnant or breastfeeding

The unadjusted hazard ratio, describing the time to confirmed abnormal OGTT or T1D, was 0.95 (95% CI 0.56–1.61), showing no meaningful difference between the treatment and placebo groups. After conducting an interim analysis and data safety monitoring board review, study enrollment was stopped because of futility, and subgroup analyses found that neither age, BMI z score, autoantibodies, nor HLA type had a significant effect on the primary outcome measure. Overall, the trial concluded that hydroxychloroquine did not delay or prevent progression from stage 1 to stage 2 or 3 type 1 diabetes.