Clinical trial NCT02547519: Pre-POINT-Early Study
Official title: Pilot Study Using Oral Insulin at Early Age for Immune Efficacy in Primary Prevention of Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: Type 1 diabetes
T1D
diabetes mellitus
oral insulin
oral tolerance
autoantigen
self tolerance
prevention
at risk for developing type 1 diabetes
juvenile diabetes
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
Collaborators: name: Technische Universität Dresden
name: Ludwig-Maximilians - University of Munich
name: Helmholtz Zentrum München
name: German Center for Diabetes Research
First posted: 2015-09-11
Enrollment: 44
Sex: ALL
Minimum age (years): 6
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: The activation of a CD4+ T cell immune response against insulin
timeFrame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment
measure: The activation of an antibody response against insulin.
timeFrame: 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
Secondary outcomes:
measure: Gene expression of CD4+ T cell response to insulin.
timeFrame: gene expression profile measurement on insulin-responsive CD4+ T cells at 12 months visit.
measure: Hypoglycemia
timeFrame: Measured at baseline (visit 1) and at each subsequent change in dose (visits 2 and 3)
measure: change in total IgE concentration
timeFrame: 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
measure: Study drug specific IgE
timeFrame: Baseline (visit 1) and end of treatment (12 months).
measure: GAD and IA-2 autoantibodies
timeFrame: Measured at baseline where they must be negative, and at 3 months, 6 months, 9 months, and 12 months.
Other outcomes:
measure: Adverse events
timeFrame: Duration of participation from study visit 1 until 12 months visit or drop out.
Locations:
city: München
country: Germany
facility: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München
Study officials:
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
name: Anette-G. Ziegler, Prof. Dr., MD
role: PRINCIPAL_INVESTIGATOR
affiliation: DFG-Center for Regenerative Therapies Dresden, Dresden University of Technology
name: Ezio Bonifacio, Prof. Dr., PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
name: Peter Achenbach, PD Dr., MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel-Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia. 2021 May;64(5):1079-1092. doi: 10.1007/s00125-020-05376-1. Epub 2021 Jan 30.