A randomised controlled trial of intranasal insulin to prevent type 1 diabetes: intranasal insulin trial II (INIT II)

Background: Insulin is a target of autoimmunity that destroys beta cells in type 1 diabetes (T1D). In the NOD mouse model of T1D, insulin delivered to the nasal mucosa induced regulatory T cells and decreased diabetes incidence. We reported two human trials demonstrating intranasal insulin was safe and elicited immune responses and tolerance to insulin. Here, we present intranasal insulin trial II (INIT II), which aimed to determine if intranasal insulin delayed or prevented the onset of T1D in individuals with sub-clinical disease.

Methods: Initially, >10,000 T1D relatives were screened; 2.2% were positive for autoantibodies ≥ 2 islet antigens (insulin, GAD65, IA-2). Following ‘staging’ to establish normal beta-cell function, 110 seropositive relatives (71 males, 39 females; median ages 11.4, 12.7 years) were randomized to 1.6mg and 16mg insulin dose and placebo arms. Their estimated 5-year risk of diabetes was 40%; the trial was powered to detect a decrease of 50%. Recruitment was slower than anticipated and the ‘low dose’ dose arm was ceased after it had enrolled 18 participants, but these continued to be followed. Treatment was self-administered as two 100μl spray doses per nostril, daily for one week then weekly for 1 year. Participants were followed 3-monthly in the first year, then 6-monthly for a further 4 years, or until diabetes.

Results: There were no serious treatment-related adverse events. All participants will complete 3-year follow-up by 01/10/18, at which time the median follow-up will be 57.5 months. Intranasal insulin led to a dose-related increase in serum insulin antibody concentrations, which peaked and then declined during ongoing treatment in the first year. This response is consistent with induction of immune tolerance but was not associated with change in rate of progression to diabetes. Results for the primary outcome, diabetes, will be presented.