PINIT Study: Primary Intranasal Insulin Trial

Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. Administration of mucosal insulin in islet autoantibody-negative children who are genetically predisposed for T1D offers the potential for inducing immunological tolerance to beta cells and thereby protect against the development of islet autoimmunity and T1D. Intranasal insulin has the advantage that whole protein will be exposed at the mucosa. Therefore, the available dose of insulin when administered intranasally is likely to be consistent between individuals. On this basis, the investigators aim to conduct a placebo-controlled, double-blind/double-masked primary intervention pilot trial (PINIT Study) of intranasal insulin treatment in islet autoantibody negative children to test immune efficacy and safety in the primary prevention setting. This pilot will help to develop and design a Phase III study aiming to test efficacy of preventing islet autoimmunity and T1D.

Hypothesis: The hypothesis is that intranasal administration of insulin will induce protective immune responses and prevent T1D-autoimmunity, and the development of T1D.

Objectives: To determine whether intranasal administration of 440 IU insulin to children with high genetic risk for T1D will induce likely protective IgG or IgA antibody responses to insulin, and/or T-cell responses to insulin and/or proinsulin.

Intranasal insulin will be applied as a fine aerosol spray to the back of the nose. The insulin formulation and method of administration of intranasal insulin is designed to stimulate local mucosal immunity to insulin as an antigenic protein. Without an absorption enhancer, such as a surfactant, intranasal insulin is not anticipated to have systemic hormonal effects. The presentation is a multi-dose spray device with nasal actuator in a brown glass vial designed to deliver 50 μl spray doses to the nasal mucosa.

The PINIT Study is designed as a randomized, placebo-controlled, double-blind, multicenter, primary intervention pilot phase II study, in which intranasal insulin will be administered daily for the first seven days and once per week thereafter. The study will include 38 islet autoantibody negative children with the HLA DR3/4-DQ8 genotype or with a first degree relative with T1D and at least one HLA DR4-DQ8 haplotype and no protective HLA DR-DQ alleles or haplotypes. These 38 children will be randomized to either insulin or placebo in a 1:1 ratio. The study will be monitored by an external Data Safety Monitoring Committee (DSMB).

Recruitment will be carried out German wide and will be organized by clinical centers in Munich and Dresden. PINIT will determine the immune bioavailability of mucosal insulin to the immune system in the age group of 1 year to 7 years and assess safety of treatment with intranasal insulin at a single dose (440 IU).

Primary outcome - immune efficacy: The primary outcome is immune efficacy measured by the activation of an immune response (antibody or CD4+ T cell) against insulin.

Additional outcomes are:

* safety assessed by blood glucose concentrations in the first 2 hours after receiving study drug to determine whether the treatment induces hypoglycaemia, and the development of islet autoantibodies to GAD and IA-2 and ZnT8 is assessed at 3 and 6 months after commencing treatment.
* mechanistic T cell studies to determine the characteristics of any T cell response to insulin.
* Flow cytometry to measure T cell and monocyte subpopulations
* RNA seq on peripheral blood mononuclear cells
* Serum inflammatory markers

Comparisons between treatment groups will be performed on the whole cohort and also separately on the participants by the type 1 diabetes susceptible INS genotype, and after stratification for age and SIGLEC1 (CD169) positivity of monocytes.

Time schedule: The recruitment phase will run over a period of 12 months. Enrolled participants will be treated for 6 months. First patient first visit (FPFV) occured in May 2018 and the last patient last visit (LPLV) occured on 18. August 2020. The overall end of trial time point is defined as the time when all mechanistic assays and measurement of lab values including T-cell stimulation tests have been completed. This is expected by end of February 2021.

Eligibility Criteria:
Inclusion Criteria:

1. Children aged 1 year to 7 years (randomization must be performed prior to 8th birthday) who

   * have the HLA DR3-DQB1\*0201/DR4-DQB1\*0302 or the HLA DR3-DQB1\*0201/DR4-DQB1\*0304 genotype or
   * have a first degree relative with type 1 diabetes, and have a HLA genotype that includes the HLA DR4-DQB1\*0302 or HLA DR4-DQB1\*0304 haplotype, and does not include one of the following alleles DR 11, DR 12, DQB1\*0602, or haplotypes DR7-DQB1\*0303, DR14-DQB1\*0503, DR13-DQB1\*0603 and must be
2. Islet autoantibody negative (autoantibodies against insulin, GAD, IA-2 and ZnT8) at time of screening.

Exclusion Criteria:

1. Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
2. Any condition that could be associated with poor compliance.
3. Any defect or pathology of nasal passage, which would preclude application of the intranasal spray.
4. Any moderate to severe intolerance to ingredients of the investigational medicinal product.