Fr1da Insulin Intervention

NCT02620072 | Completed Phase 2 DMC

• 1 other identifier: 808040019
• Study Type: interventional
• Target: 220
• Locations: 1 country
• Sites: 1

Brief Summary

Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. The process of autoimmune destruction 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. Evidence is now emerging in humans that these approaches may be effective in chronic inflammatory diseases such as multiple sclerosis and allergy. Administration of oral insulin in multiple islet autoantibody-positive children offers the potential for inducing immunological tolerance to beta cells and thereby protect against further development progression to type 1 diabetes.

Conditions

Stage 1 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; dysglycemia

Outcome Measures

Primary Outcomes (2)

• Immune response to insulin

  Immune response measures will be salivary IgA antibodies to insulin, blood CD4+ T cell responses to insulin, and autoantibodies to insulin. Participants are categorized as immune responders if they show a change in at least one of these measures from baseline to 12 months. The number and frequency of immune responders will be compared between the placebo and study drug treatedchildren. If a treatment effect on responder status is observed in the first 90 participants (two-tailed p value \<0.05), the responder status will be measured for the remaining participants and the progression to dysglycemia or diabetes will be compared between immune responders and non-responders using Cox proportional hazards model.

  change from baseline (visit 1) to 12 months of treatment

• Dysglycemia or diabetes

  Dysglycemia is determined through Oral Glucose Tolerance Test (OGTT): Dysglycemia is defined as: 1. Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L) and \< 126 mg/dL (7 mmol/L), or 2. 2 hour plasma glucose ≥ 140 mg/dL (7.8 mmol/L) and \< 200 (11.1 mmol/L), or 3. 30, 60, 90 minute plasma glucose during OGTT ≥ 200 mg/dL (11.1 mmol/L) Diabetes is defined as: 1. random blood glucose value ≥200 mg/dl (11.1 mmol/L), or 2. fasting blood glucose value ≥126 mg/dl (7 mmol/L), or 3. a 2-hour plasma glucose ≥200 mg/dl (11.1 mmol/L) measured by Oral Glucose Tolerance Test Cox proportional hazards model will be used to compare development of dysglycemia or diabetes between the placebo and study drug treated children. For each primary outcome, analyses will also be performed separately in children with the susceptible INS genotype and children with the HLA DR4 allele.

  every 6 months up to at least 24 months after baseline

Secondary Outcomes (10)

• Gene expression of single cells.

  Gene expression profile measurement on insulin-responsive cells at 12 month visit

• The change from baseline in insulin autoantibodies

  change from baseline to 3 months, 6, months, and 12 months

• Number of circulating Insulin-tetramer positive T cells

  comparison at 9 month visit

• CD4+ T cell responses to insulin

  comparison at 0, 3, 6, and 12 month visit

• CD8+ T cell responses to insulin

  comparison at 0, 3, 6, and 12 month visit

Other Outcomes (2)

• Hypoglycemia

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

• Adverse events

  Duration of participation from study visit 1 until the end of the study (min. 36 months, max. 66 months) or drop out

Study Arms (2)

oral insulin capsule (dose escalation using 2 dose strengths)

EXPERIMENTAL

Dose 1 is 7.5 mg rH-insulin crystals; dose 2 is 67.5 mg rH-insulin crystals. Insulin crystals are formulated together with filling substance (microcrystalline cellulose to a total weight of 200 mg) contained in hard gelatine capsules given orally.

Drug: Oral Insulin

Placebo capsule

PLACEBO COMPARATOR

Daily administration of placebo capsules containing filling substance (microcrystalline cellulose).

Other: 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 67.5 mg or placebo for the following 9 months of the treatment period. Follow-up will continue for 24 months after the last administration of treatment.

oral insulin capsule (dose escalation using 2 dose strengths)

Placebo OTHER

Total of 12 months intervention period; daily administration of insulin or placebo capsules containing filling substance (microcrystalline cellulose). Follow-up will continue for 24 months after the last administration of treatment.

Placebo capsule

Eligibility Criteria

• Age: 2 Years - 12 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Written informed consent signed by either parent(s) or legal guardian(s).
• Children aged 2 years to 12 years.
• Positive for at least two islet autoantibodies out of autoantibodies to glutamic acid decarboxylase (GAD65), to insulin (IAA), autoantibodies to IA-2 (IA2A), or autoantibodies to zink transporter 8 (ZnT8A) (time between screening sample collection and randomization must not exceed 90 days).
• Normoglycemia assessed by oral glucose tolerance test (OGTT).
• Participation in an observational study that regularly monitors diabetes development

You may not qualify if:

• dysglycaemia or overt hyperglycemia (diabetes)
• Concomitant disease or treatment that may interfere with assessment or cause immunosuppression, as judged by the investigators.
• 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

Study Sites (1)

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

München, Deutschland (deu), 80804, Germany

Location

Related Publications (1)

• Jacobsen LM, Schatz DA. Insulin immunotherapy for pretype 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2021 Aug 1;28(4):390-396. doi: 10.1097/MED.0000000000000648.

  PMID: 34091488 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

  PRINCIPAL INVESTIGATOR

• Ezio Bonifacio, Prof. Dr., PhD

  Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden

  STUDY CHAIR

• Peter Achenbach, PD. Dr., MD

  Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München

  PRINCIPAL INVESTIGATOR

• Katharina Warncke, Dr., MD

  Forschergruppe Diabetes, Klinikum rechts der Isar, Techn. Universität München and Kinderklinik München Schwabing, Klinik u. Poliklinik f. Kinder- und Jugendmedizin, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar der Techn. Universität München

  PRINCIPAL INVESTIGATOR

• Christiane Winkler, Dr., PhD

  Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München

  STUDY CHAIR

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: November 29, 2015
• First Posted: December 2, 2015
• Study Start: December 11, 2015
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: October 8, 2024

Record last verified: 2024-10

Locations

DE (1)