Pre-POINT-Early Study

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

44 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-08-31

Study Completion Date

2017-12-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Diabetes Mellitus, Type 1

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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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.

Group Type EXPERIMENTAL

Oral Insulin

Intervention Type DRUG

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.

Placebo capsule

Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose).

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Total of 12 months treatment; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose).

Interventions

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Oral Insulin

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.

Intervention Type DRUG

Placebo

Total of 12 months treatment; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose).

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. 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
2. Islet autoantibody negative at time of recruitment.

Exclusion Criteria

1. Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
2. Prior or current participation in another intervention trial.
3. Any condition that could be associated with poor compliance.

Minimum Eligible Age

6 Months

Maximum Eligible Age

2 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Anette-G. Ziegler, Prof. Dr., MD

Role: PRINCIPAL_INVESTIGATOR

Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München

Ezio Bonifacio, Prof. Dr., PhD

Role: PRINCIPAL_INVESTIGATOR

DFG-Center for Regenerative Therapies Dresden, Dresden University of Technology

Peter Achenbach, PD Dr., MD

Role: PRINCIPAL_INVESTIGATOR

Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München