PINIT Study: Primary Intranasal Insulin Trial
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): intranasal insulin; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Total of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter (formulation containing rH-insulin, benzalkonium chloride, glycerol and water); Total of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter placebo (formulation containing benzalkonium chloride, glycerol and water)
Intervention MeSH terms: Insulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Type 1 diabetes; T1D; diabetes mellitus; intranasal insulin; mucosal tolerance; autoantigen; self tolerance; prevention; at risk for developing type 1 diabetes; juvenile diabetes