- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02620072
Fr1da Insulin Intervention
Mechanistic Study Using Oral Insulin for Immune Efficacy in Secondary Prevention of Type 1 Diabetes
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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 or diabetes and whether oral insulin treatment reduces the rate of progression to dysglycemia or diabetes.
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Deutschland (deu)
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München, Deutschland (deu), Germany, 80804
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
Participants meeting any of the following criteria will NOT be eligible for inclusion into the study:
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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.
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Placebo Comparator: Placebo capsule
Daily administration of placebo capsules containing filling substance (microcrystalline cellulose).
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Immune response to insulin
Time Frame: change from baseline (visit 1) to 12 months of treatment
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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.
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change from baseline (visit 1) to 12 months of treatment
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Dysglycemia or diabetes
Time Frame: every 6 months up to at least 24 months after baseline
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Dysglycemia is determined through Oral Glucose Tolerance Test (OGTT): Dysglycemia is defined as:
Diabetes is defined as:
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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Gene expression of single cells.
Time Frame: Gene expression profile measurement on insulin-responsive cells at 12 month visit
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The FOXP3 signature/IFNG signature ratio of the insulin responsive T-cells will be compared between the placebo and study drug treated children.
In addition the expression for a panel of genes in insulin-responsive T cells will be compared between the placebo and study drug treated children.
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Gene expression profile measurement on insulin-responsive cells at 12 month visit
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The change from baseline in insulin autoantibodies
Time Frame: change from baseline to 3 months, 6, months, and 12 months
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The change in insulin autoantibodies 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.
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change from baseline to 3 months, 6, months, and 12 months
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Number of circulating Insulin-tetramer positive T cells
Time Frame: comparison at 9 month visit
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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.
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comparison at 9 month visit
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CD4+ T cell responses to insulin
Time Frame: comparison at 0, 3, 6, and 12 month visit
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The CD4+ T cell response is measured by proliferation assay and will be compared between the placebo and study drug treated children at baseline, 3, 6, and 12 months.
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comparison at 0, 3, 6, and 12 month visit
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CD8+ T cell responses to insulin
Time Frame: comparison at 0, 3, 6, and 12 month visit
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The CD8+ T cell response is measured by proliferation assay and will be compared between the placebo and study drug treated children at baseline, 3, 6, and 12 months.
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comparison at 0, 3, 6, and 12 month visit
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Microbiome alpha diversity, beta diversity and taxanomic abundance
Time Frame: comparison at 0, 6, and 12 month visits
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The alpha diversity, beta diversity and taxanomic abundance is measured in stool samples using 16S and metagenomic methods and will be compared between the placebo and study drug treated children at baseline, 6, and 12 months.
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comparison at 0, 6, and 12 month visits
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Monocyte and T cell sub-populations
Time Frame: comparison at 0, 3, 6, 9, and 12 month visits
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Flow cytometry performed on peripheral blood mononuclear cells to identify monocyte and T cell subpopulations and activated cells based on surface and intracellular markers.
The populations will be compared between the placebo and study drug treated children at baseline, 3, 6, 9, and 12 months visits
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comparison at 0, 3, 6, 9, and 12 month visits
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Plasma inflammatory proteins
Time Frame: comparison at 0, and 12 month visits
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A panel of inflammation proteins measured in plasma by OLINK technology.
The quantitative values will be compared between the placebo and study drug treated children at baseline and 12 months.
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comparison at 0, and 12 month visits
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Transcriptome of peripheral blood mononuclear cells
Time Frame: comparison at 0, and 12 month visits
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The transcriptome of isolated peripheral blood mononuclear cells is measured by RNA seq at baseline and at the 12 month visit.
Differentially expressed genes (DEG) and pathway analysis of DEG will be compared between the placebo and study drug treated children at baseline, and 12 months, and between baseline and 12 month visits in study drug and placebo treated children.
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comparison at 0, and 12 month visits
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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)
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Diabetes is defined as:
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. For each secondary outcome, analyses will also be stratified by INS genotype and HLA DR4. |
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)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Hypoglycemia
Time Frame: Measured at baseline (visit 1) and at subsequent change in dose (visits 2).
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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).
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Measured at baseline (visit 1) and at subsequent change in dose (visits 2).
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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
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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.
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Duration of participation from study visit 1 until the end of the study (min. 36 months, max. 66 months) or drop out
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- 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
Publications and helpful links
General Publications
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 808040019
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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