E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the immune efficacy, and treatment efficacy of daily high dose oral insulin (up to 67.5 mg) in children aged 2 years to 12 years with multiple islet autoantibodies in a secondary intervention study. Immune efficacy is defined as a change in the immune response to the treatment, which is associated with a reduction in the progression to dysglycemia or diabetes. Treatment efficacy is a treatment related reduction in the rate of progression to dysglycemia or diabetes. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal exclusion criteria |
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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. Immune response measures will be salivary IgA antibodies to insulin, blood CD4+ T responses to insulin, or autoantibodies to insulin (up to 12 months). Participants are categorized as immune responders if they show a change in at least one of these measures. If a treatment effect on responder status is observed in the first 90 participants, the analysis will proceed for all participants and the primary outcome of a change in immune response to insulin associated with reduced progression to dysglycemia or diabetes will be assessed in all participants. A co-primary outcome is to assess whether the treatment is associated with a reduced progression to dysglycemia or diabetes in all participants.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at baseline, 3 months-, 6 months-, 9 months and 12 months of treatment
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E.5.2 | Secondary end point(s) |
1. To determine whether daily administration of up to 67.5 mg insulin induces metabolic changes in blood of safety concern in autoantibody positive children aged 2 years to 12 years.
2. Evaluate if daily administration of up to 67.5 mg insulin to young autoantibody positive children aged 2 years to 12 years with multiple islet autoantibodies may reduce the rate of disease progression to the end point clinical type 1 diabetes.
3. Determine whether daily administration of up to 67.5 mg insulin is associated with a difference in the gene expression in insulin-responsive CD4+ T cells.*
4. Determine whether daily administration of up to 67.5mg insulin is associated with a difference in serum insulin autoantibodies.
5. Determine whether daily administration of up to 67.5 mg insulin increases the frequency of insulin tetramer positive CD4+ regulatory T cells compared to the placebo group.*
6. Determine whether daily administration of up to 67.5 mg insulin modifies CD4+ T cells responses to insulin.*
7. Determine whether daily administration of up to 67.5 mg insulin modifies CD8+ T cells responses to insulin.*
8. Determine whether daily administration of up to 67.5 mg insulin modifies microbiome alpha diversity, beta diversity or taxanomic abundance.*
9. Determine whether daily administration of up to 67.5 mg insulin modifies peripheral blood T cell or monocyte populations.
10. Determine whether daily administration of up to 67.5 mg insulin modifies plasma inflammatory markers.*
11. Determine whether daily administration of up to 67.5 mg insulin modifies the transcriptome of peripheral blood mononuclear cells.*
*These secondary outcomes may be assessed in only the first 90 participants. For all outcomes, analyses will also be stratified by INS genotype and HLA DR4.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
fasting blood glucose test; HbA1c: at baseline, 3 months-, 6 months-, 9 months and 12 months of treatment and during the follow-up phase: 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84 and 90 months
oral glucose tolerance test (measurement og blood glucose, insulin and c-peptide measurement before and 30, 60 & 120 min after administration of the study drug oral insulin or placebo): at baseline and 3 months of treatment
glucose tolerance test: at (screening) and 6 months and 12 months and during the follow-up phase: 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84 and 90 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial is the time when all outcome measurements are completed and all data available. Outcome measurements for immune response are complex and time-consuming. These measurements will first be conducted for the first 90 subjects only. Analysis of immune response for the first 90 subjects will be done after these 90 subjects have completed the initial study period (treatment phase). Based on this it will be determined if samples from all the remaining participants will also be tested.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 9 |