Pre-POINT-Early Study

NCT02547519 | Completed Phase 2 DMC

• 1 other identifier: 808040017
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• The activation of a CD4+ T cell immune response against insulin

  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.

  change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment

• The activation of an antibody response against insulin.

  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.

  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 (5)

• Gene expression of CD4+ T cell response to insulin.

  gene expression profile measurement on insulin-responsive CD4+ T cells at 12 months visit.

• Hypoglycemia

  Measured at baseline (visit 1) and at each subsequent change in dose (visits 2 and 3)

• 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.

Other Outcomes (1)

• Adverse events

  Duration of participation from study visit 1 until 12 months visit or drop out.

Study Arms (2)

oral insulin capsule (dose escalation using 3 dose strengths)

EXPERIMENTAL

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.

Drug: Oral Insulin

Placebo capsule

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Oral Insulin 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.

oral insulin capsule (dose escalation using 3 dose strengths)

Placebo DRUG

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

Placebo capsule

Eligibility Criteria

• Age: 6 Months - 2 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Technical University of Munich: lead
• Technische Universität Dresden: collaborator
• Ludwig-Maximilians - University of Munich: collaborator
• Helmholtz Zentrum München: collaborator
• German Center for Diabetes Research: collaborator

Study Sites (1)

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

München, 80804, Germany

Location

Related Publications (1)

• 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.

  PMID: 33515070 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus

Interventions

Insulin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Anette-G. Ziegler, Prof. Dr., MD

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

  PRINCIPAL INVESTIGATOR

• Ezio Bonifacio, Prof. Dr., PhD

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

  PRINCIPAL INVESTIGATOR

• Peter Achenbach, PD Dr., MD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2015
• First Posted: September 11, 2015
• Study Start: August 1, 2015
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: February 13, 2018

Record last verified: 2018-02

Locations

DE (1)