PracticeUpdate: Conference Series | ADC 2018

Update on Intranasal Insulin Trial II (INIT II) to Prevent Type 1 Diabetes

Data show that, while nasal insulin induced an immune response, it did not halt progression to T1D. BY THE PRACTICEUPDATE EDITORIAL TEAM A ustralian researchers are leading a multinational, randomized con- trolled trial on the use of intranasal insulin to prevent the onset of type 1 dia- betes (T1D) in individuals with subclinical disease. The Intranasal Insulin Trial II (INIT II) will see all participants completing a 3-year follow-up in October 2018, at which time the median follow-up will be 57.5 months. “Previous non-obese diabetic (NOD) mouse model studies have shown that insulin delivered to the nasal mucosa induced regulatory T cells and decreased diabetes incidence,” said Leonard Harrison, MBBS, MD, DSc, FRACP, FRCPA, FAHMS, of the Walter and Eliza Hall Institute of Medical Research and the Royal Melbourne Hospital in Melbourne, Australia. He added that two human trials had shown that intranasal insulin was safe and elicited immune responses and tolerance to insulin. Against this background, INIT II was performed to determine if intranasal insulin delayed or prevented the onset of T1D in at-risk children and young adults. The trial screened over 10,000 people with T1D relatives and found 2.2% had at least two autoantibodies directed at two or more islet antigens (insulin, GAD65, IA-2). The individuals were staged through first-phase insulin response and glucose tolerance. The trial experienced quite a large dropout, according to Professor Harrison. Around 110 participants were randomized to a "low dose" or a higher dose of insulin or placebo. The estimated 5-year risk of diabetes was 40%; the trial was powered to detect a decrease of 50%. The low-dose arm was eventually discontinued, but its 18 participants con- tinue to be followed. The characteristics by treatment arm were generally similar. About 41 people (38%) developed diabetes. Comparing charac- teristics of those who developed diabetes and thosewho had not, Professor Harrison

insulin group. However, Professor Harrison remarked that he did not know why the placebo group had a low incidence of T1D. “Unfortunately, we do not know – we are intrigued by this finding.” The trial showed that intranasal insulin was safe and induced immune response, but this did not translate to a change in the development of T1D. Professor Harrison noted the importance of beginning treatment early in the dis- ease course to prevent diabetes. He said researchers are now studying nasal and oral insulin in children who are not yet autoantibody positive but are genetically at risk for T1D. oral insulin in children who are not yet autoantibody positive but are genetically at risk for T1D. " " …researchers are now studying nasal and

said the age of the former group was sig- nificantly lower. “The lower the age, the more rapidly they progressed to T1D,” he added. Insulin antibody concentrations were similar between the diabetes and non-di- abetes groups directed at two or more. HLA phenotype was significantly more frequent among those who developed diabetes, which was to be expected. No serious treatment-related adverse events were reported. Speaking about the response, Professor Harrison said intranasal insulin led to a dose-related increase in serum insulin antibody concentrations, which peaked and then declined during ongoing treat- ment in the first year. “This is quite unusual for an antibody response,” he said. “We think this is consistent with the induction of immune tolerance to exogenous insulin.” What was of concern to the researchers was the incidence of diabetes by treat- ment arm, said Professor Harrison. In the placebo group, 30% developed diabetes over a median follow-up of 1385 days ver- sus 61% in the low-dose intranasal insulin group and 36% in high-dose intranasal

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ADC 2018 • PRACTICEUPDATE CONFERENCE SERIES