Pilot Study Using Oral Insulin at Early Age for Immune Efficacy in Primary Prevention of Type 1 Diabetes
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- The activation of a CD4+ T cell immune response against insulin
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 6 Months to 2 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Children aged 6 months to 2 years who have a first degree relative with type 1 diabetes, and have a HLA genotype that includes a HLA DR4-DQB1*0302 or HLA DR4-DQB1*0304 haplotype, and does not include one of the following alleles or haplotypes: DR 11, DR 12, DQB1*0602, DR7-DQB1*0303, DR14-DQB1*0503
- •and must be
- •Islet autoantibody negative at time of recruitment.
Exclusion Criteria
- •Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
- •Prior or current participation in another intervention trial.
- •Any condition that could be associated with poor compliance.
Arms & Interventions
oral insulin capsule (dose escalation using 3 dose strengths)
Dose 1 is 7.5 mg rH-insulin crystals; dose 2 is 22.5 mg rH-insulin crystals; dose 3 is 67.5 mg rH-insulin crystals. The insulin crystals are formulated together with filling substance (microcrystalline cellulose to a total weight of 200 mg) and contained in hard gelatine capsules. The study treatment will be given orally.
Intervention: Oral Insulin (Drug)
Placebo capsule
Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose).
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
The activation of a CD4+ T cell immune response against insulin
Time Frame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment
The primary outcome for immune efficacy is the activation of an immune response (antibody or CD4+ T cell) against insulin. Each participant will be categorized as reaching a response or not. A response is defined as a \>2-fold increase that reaches a stimulation index of \>3.0.
The activation of an antibody response against insulin.
Time Frame: change from baseline (visit 1) in antibodies measured as serum IgG binding to insulin (unit of measure, cpm) and salivary IgA binding to insulin (unit of measure, cpm) at 12 months of treatment
An antibody response is defined as an increase from baseline of \>10 cpm in serum IgG binding to insulin from baseline to 12 months, or a positive salivary IgA binding to insulin at 12 months.
Secondary Outcomes
- change in total IgE concentration(A change from baseline (visit 1) in total IgE concentration at 3 months of treatment,change from baseline (visit 1) in total IgE concentration at 6 months of treatment,change from baseline (visit 1) in total IgE concentration at 12 months of treatment)
- Study drug specific IgE(Baseline (visit 1) and end of treatment (12 months).)
- GAD and IA-2 autoantibodies(Measured at baseline where they must be negative, and at 3 months, 6 months, 9 months, and 12 months.)
- Hypoglycemia(Measured at baseline (visit 1) and at each subsequent change in dose (visits 2 and 3))
- Gene expression of CD4+ T cell response to insulin.(gene expression profile measurement on insulin-responsive CD4+ T cells at 12 months visit.)