Pre-POINT-Early Study
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 within the pancreatic islets of Langerhans. This process is identified by circulating
      islet autoantibodies to beta cell antigens, and is mediated by a lack of immunological
      self-tolerance. Self-tolerance is achieved by T cell exposure to antigen in the thymus or
      periphery in a manner that deletes autoreactive effector T cells or induces regulatory T
      cells. Immunological tolerance can be achieved by administration of antigen under appropriate
      conditions. Administration of oral 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.
    

Detailed description: 
      The purpose of the Pre-POINT-Early Study is to investigate and consolidate the finding from
      the preceding Pre-POINT Study, namely safety and immune efficacy at a daily dose of 67.5 mg
      oral insulin. Since younger children will be tested in Pre-POINT-Early, the 67.5 mg dose will
      be reached by dose escalation starting at 7.5 mg for 3 months followed by exposure to 22.5 mg
      for 3 months, and reaching the desired 67.5 mg dose, which is administered for 6 months in 22
      children.

      The active substance for oral application is human insulin, synthesized in a special
      non-disease-producing laboratory strain of Escherichia coli bacteria that has been
      genetically altered by the addition of the gene for human insulin production (Lilly
      Pharmaceuticals, Indianapolis, Indiana, USA). The physical, chemical and pharmaceutical
      properties of the human insulin have been well documented by the manufacturer. Oral Insulin
      will be applied as a capsule containing 7.5; 22.5 and 67.5 mg of the active substance
      together with filling substance cellulose. After oral administration insulin will be rapidly
      degraded by gastric acids. Enteric delivery and systemic availability is therefore unlikely
      and efficacy of active insulin is likely to be restricted to the oral mucosa.

      In human studies oral insulin administration was safe and without adverse side effects at
      doses between 2.5 and 7.5 mg per day. Additionally Bonifacio et al. have conducted and
      completed the Pre-POINT study, the first primary autoantigen vaccination dose-finding study
      in which children with high genetic risk for type 1 diabetes were administered insulin orally
      daily. Oral insulin at all tested doses (2.5 mg; 7.5 mg; 22.5 mg and 67.5 mg) in Pre-POINT
      was considered safe: None of the children who received study drug or placebo experienced
      hypoglycaemic episodes after administration of medication, and no allergic reactions were
      observed.

      The Pre-POINT-Early intended doses for oral application are 7.5, 22.5 and 67.5 mg per day.
      The aim of the study is to determine whether daily administration of oral insulin starting
      with dose 7.5 mg (3 months), moving to dose 22.5 mg (3 months) and to the highest dose of
      67.5 mg (6 months) insulin to young children aged 6 months to 2 years with high genetic risk
      for T1DM induces immune responses to insulin and/or proinsulin with features of immune
      regulation.
    

Intervention name(s): Oral Insulin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Total of 12 months treatment; dose escalation scheme: daily treatment with 7.5 mg or placebo for 3 months; increasing to daily treatment with 22.5 mg or placebo for the following 3 months; increasing to daily treatment with 67.5 mg or placebo for the last 6 months of the treatment period.; Total of 12 months treatment; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose).
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; oral insulin; oral tolerance; autoantigen; self tolerance; prevention; at risk for developing type 1 diabetes; juvenile diabetes