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Fr1da Insulin Intervention

This study is currently recruiting participants.
Verified November 2016 by Technische Universität München
Sponsor:
ClinicalTrials.gov Identifier:
NCT02620072
First Posted: December 2, 2015
Last Update Posted: November 11, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Technische Universität Dresden
Ludwig-Maximilians - University of Munich
Helmholtz Zentrum München
The Leona M. and Harry B. Helmsley Charitable Trust
Information provided by (Responsible Party):
Technische Universität München
November 29, 2015
December 2, 2015
November 11, 2016
December 2015
June 2021   (Final data collection date for primary outcome measure)
(1) Immune response: The activation of a protective immune response against insulin (immune responder status) and (2) Immune efficacy: rate of progression to dysglycemia in immune responders vs. non-responders [ Time Frame: (1) change from baseline in CD4+ T cell response measured as a stimulation index at 12 months after the end of treatment and (2) comparison of the rate of progression to dysglycemia at end of FU (12 mon. after treatment in last enrolled partic.) ]

Study includes two co-primary outcomes:

Analysis of co-primary outcomes is hierarchical. Order of hierarchy: 1st: immune response. If significant, analysis will proceed to 2nd: immune efficacy.

(1) Immune response: children will be categorized as having or not having response to insulin during treatment. Outcome is positive when a child has one or more of the following three responses at one or more times points during follow-up:

  1. a pos. salivary IgA-IAA (at 3-, 6-, 12 months)
  2. a >2-fold increase in CD4+ T cell response to insulin (at 3-, 9-, 12 months)
  3. a >2-fold increase in number of circulating Insulin-tetramer pos. CD4+CD25+FOXP3+ T cells (at 6 months).

Number between placebo- and study drug responder will be compared.

(2) Immune efficacy: comparing progression rates in children with without change in immune response to insulin, regardless of treatment group. Comparison will be made using the Cox regression at the 0.05 level, two-sided.

The activation of a protective 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 ]

An immune response to the study drug is the primary outcome of the trial. Children will be categorized as having a response to insulin or not having a response to insulin during treatment. The primary outcome is positive when a child has one or more of the following three responses at one or more times points during follow-up:

  1. A positive salivary IgA-IAA (measured at 3 months, 6 months, 12 months)
  2. A >2-fold increase in the CD4+ T cell response to insulin (measured at 3 months, 9 months, 12 months)
  3. A >2-fold increase in the number of circulating Insulin-tetramer positive CD4+CD25+FOXP3+ T cells (measured at 6 months).

The number of children responding between the placebo and study drug treated groups will be compared.

Complete list of historical versions of study NCT02620072 on ClinicalTrials.gov Archive Site
  • Gene expression of single cells. [ Time Frame: Gene expression profile measurement on insulin-responsive cells at 12 month visit ]
    The FOXP3 signature/IFNG signature ratio of the insulin responsive cells will be compared between the placebo and study drug treated children. In addition the gene expression of all analyzed genes will be compared between the placebo and study drug treated groups using tSNE.
  • The change from baseline in IgG-binding to insulin [ Time Frame: change from baseline to 3 months, 6, months, and 12 months ]
    The change in IgG-binding to insulin will be measured by radio-binding assay. It will be compared between placebo and study drug treated children at the 3 months, 6 months, and 12 months time points using ANOVA and normalized data.
  • The change from baseline in IgG4-binding to insulin [ Time Frame: change from baseline to 3 months, 6, months, and 12 months ]
    The change in IgG4-binding to insulin will be measured by radio-binding assay. It will be compared between placebo and study drug treated children at the 3 months, 6 months, and 12 months time points using ANOVA and normalized data.
  • Number of circulating Insulin-tetramer positive T cells [ Time Frame: comparison at 9 month visit ]
    The number of circulating Insulin-tetramer positive CD4+CD25+FOXP3+ T cells (measured at 9 months) will be compared between placebo and study drug treated children using ANOVA.
  • Progression to diabetes [ Time Frame: Measured at baseline (visit 1) and at each subsequent visit of the treatment phase (visits 2, 3, 4, 5) and observational follow-up of 24 to 54 months after the one year treatment (visits 6, 7, 8, 9, 10, 11, 12, 13, 14) ]
    Progression to diabetes will be monitored and compared between placebo and study drug treated children using the Cox regression at the 0.05 level, two-sided. With 220 children randomized over a 30 month period, and a study duration of 66 month, the study will have 86% power to detect a 50% reduction in the rate of progression to diabetes at a two-sided alpha of 0.05.
  • Gene expression of single cells. [ Time Frame: Gene expression profile measurement on insulin-responsive cells at 12 month visit ]
    The FOXP3 signature/IFNG signature ratio of the insulin responsive cells will be compared between the placebo and study drug treated children. In addition the gene expression of all analyzed genes will be compared between the placebo and study drug treated groups using tSNE.
  • The change from baseline in IgG-binding to insulin [ Time Frame: change from baseline to 3 months, 6, months, and 12 months ]
    The change in IgG-binding to insulin will be measured by radio-binding assay. It will be compared between placebo and study drug treated children at the 3 months, 6 months, and 12 months time points using ANOVA and normalized data.
  • The change from baseline in IgG4-binding to insulin [ Time Frame: change from baseline to 3 months, 6, months, and 12 months ]
    The change in IgG4-binding to insulin will be measured by radio-binding assay. It will be compared between placebo and study drug treated children at the 3 months, 6 months, and 12 months time points using ANOVA and normalized data.
  • Number of circulating Insulin-tetramer positive T cells [ Time Frame: comparison at 9 month visit ]
    The number of circulating Insulin-tetramer positive CD4+CD25+FOXP3+ T cells (measured at 9 months) will be compared between placebo and study drug treated children using ANOVA.
  • Progression to dysglycemia within treatment period [ Time Frame: Measured at baseline (visit 1) and at each subsequent visit (visit 2, visit 3, visit 4 and visit 5) ]
    Progression to dysglycemia within 12 months of treatment will be monitored and compared between placebo and study drug treated children using Fisher's exact test.
  • Hypoglycemia [ Time Frame: Measured at baseline (visit 1) and at subsequent change in dose (visits 2). ]
    Metabolic changes within two hours after receiving study drug. This will be performed at the first administration of oral insulin or placebo at each new dose (visit 1 and visit 2). At these visits, blood glucose concentrations will be measured at 0 minutes, 30 minutes, 60 minutes, and 120 minutes after receiving study drug to determine whether the treatment induces hypoglycaemia which is defined as <50 mg/dl (<2.8 mmol/L).
  • Adverse events [ Time Frame: Duration of participation from study visit 1 until the end of the study (min. 36 months, max. 66 months) or drop out ]
    Adverse events are reported throughout the period of participation of each participant. Analysis will compare the number and frequency of adverse events during treatment with study drug (total and during each dose period) to the number and frequency of adverse events in the placebo treated children.
  • Hypoglycemia [ Time Frame: Measured at baseline (visit 1) and at subsequent change in dose (visits 2). ]
    Metabolic changes within two hours after receiving study drug. This will be performed at the first administration of oral insulin or placebo at each new dose (visit 1 and visit 2). At these visits, blood glucose concentrations will be measured at 0 minutes, 30 minutes, 60 minutes, and 120 minutes after receiving study drug to determine whether the treatment induces hypoglycaemia which is defined as <50 mg/dl (<2.8 mmol/L).
  • Adverse events [ Time Frame: Duration of participation from study visit 1 until 12 months visit or drop out ]
    Adverse events are reported throughout the period of participation of each participant. Analysis will compare the number and frequency of adverse events during treatment with study drug (total and during each dose period) to the number and frequency of adverse events in the placebo treated children.
 
Fr1da Insulin Intervention
Mechanistic Study Using Oral Insulin for Immune Efficacy in Secondary Prevention of Type 1 Diabetes
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.

Type 1 diabetes (T1D) is a disease that predominantly affects children. T1D is preceded by islet autoimmunity, which often starts in early childhood and which has a peak incidence at around 1 to 2 years of age. Previous studies show that multiple islet autoantibodies indicate a point of limited return in the path to T1D. Every year, around 10% of multiple islet autoantibody positive children progress from islet autoantibody positivity to symptomatic T1D. Thus, therapy and intervention is needed to change the inevitable path to insulin dependence. Treated should be initiated early when most beta cells are still intact and when the autoimmune process is less advanced may be more effective.

Administration of oral insulin in multiple islet autoantibody-positive children offers the potential for immunological tolerance against beta cells and thereby protect against progression to T1D. Previous studies in rodents had indicated that mucosal administration of insulin is effective in inducing regulatory immune responses that can prevent autoimmune diabetes. Mouse studies indicated that the dose of oral insulin is important. In human studies oral insulin administration shows an excellent safety profile, without adverse side effects at doses between 2.5 and 7.5 mg per day (1-3). The administration of oral insulin (7.5 mg per day) to prediabetic ICA and IAA positive first degree relatives of T1D patients within the DPT-1 study showed no significant beneficial effect in the intention to treat analysis. A sub-analysis of the data, however, showed significant benefit in those relatives with higher titer IAA.

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 tested doses (2.5 mg; 7.5 mg; 22.5 mg and 67.5 mg) showed five of six children exposed to a dose of 67.5 mg insulin had evidence of an antibody or T cell response to insulin. The response differed to the typical responses seen in children who develop diabetes in that the antibody responses were of weak affinity and the T cell responses had a preponderance of cells with regulatory T cell phenotypes (37). These results are also encouraging from a safety viewpoint and indicate that oral exposure to insulin at doses that are approximately equivalent to efficacious doses in rodents may promote tolerance in children.

A secondary prevention study using 7.5 mg oral insulin administered daily is currently conducted by the TrialNet Study Group, and includes the Forschergruppe Diabetes, Klinikum rechts der Isar der Technischen Universität München as a study site. Autoantibody, normoglycemic subjects aged 3 to 45 years are treated with oral insulin. In this currently conducted trial there have been no safety issues reported thus far.

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 mg of the active substance together with filling substance cellulose and a dose escalation to 67.5 mg of the active substance together with filling substance cellulose. After ingestion, most of the insulin will be 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.

The Fr1da Insulin Intervention Study intends doses for oral application at 7.5 mg and 67.5 mg per day. The aim of the study is to determine whether daily administration of up to 67.5 mg insulin to young children aged 2 years to 12 years with multiple islet autoantibodies alters the immune responses to insulin over an intervention period of 12 months and whether an altered immune response is associated with protection from developing dysglycemia

The immune response to oral insulin treatment has not yet been demonstrated to indicate protection from disease. To address this, the Fr1da Insulin Intervention Study included dysglycemia as a co-primary outcome in the trial, through novel data indicating that dysglycemia is a valid outcome on the path to type 1 diabetes. Once such dysglycemia is present in multiple autoantibody positive subjects, there is an average time of 2 years to clinical symptomatic diabetes.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Diabetes Mellitus, Type 1
  • Drug: 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 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.
  • Other: Placebo
    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.
  • Experimental: oral insulin capsule (dose escalation using 2 dose strengths)
    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.
    Intervention: Drug: Oral Insulin
  • Placebo Comparator: Placebo capsule
    Daily administration of placebo capsules containing filling substance (microcrystalline cellulose).
    Intervention: Other: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
220
June 2021
June 2021   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Written informed consent signed by either parent(s) or legal guardian(s).
  2. Children aged 2 years to 12 years.
  3. 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).
  4. Normoglycemia assessed by oral glucose tolerance test (OGTT).
  5. Participation in an observational study that regularly monitors diabetes development

Exclusion Criteria:

Participants meeting any of the following criteria will NOT be eligible for inclusion into the study:

  1. dysglycaemia or overt hyperglycemia (diabetes)
  2. Concomitant disease or treatment that may interfere with assessment or cause immunosuppression, as judged by the investigators.
  3. Current participation in another intervention trial.
  4. Any condition that could be associated with poor compliance.
Sexes Eligible for Study: All
2 Years to 12 Years   (Child)
Yes
Contact: Anette-G. Ziegler, Prof. Dr. +49 89 3187 ext 2896 anette-g.ziegler@helmholtz-muenchen.de
Germany
 
 
NCT02620072
808040019
Yes
Not Provided
Not Provided
Technische Universität München
Technische Universität München
  • Technische Universität Dresden
  • Ludwig-Maximilians - University of Munich
  • Helmholtz Zentrum München
  • The Leona M. and Harry B. Helmsley Charitable Trust
Principal Investigator: Anette-G. Ziegler, Prof. Dr., MD Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München
Study Chair: Ezio Bonifacio, Prof. Dr., PhD Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden
Principal Investigator: 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
Study Chair: Christiane Winkler, Dr., PhD Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München
Technische Universität München
November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP