| Outcome Measures: |
Primary: 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: Gene expression of single cells., 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., Gene expression profile measurement on insulin-responsive cells at 12 month visit|The change from baseline in insulin autoantibodies, 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., change from baseline to 3 months, 6, months, and 12 months|Number of circulating Insulin-tetramer positive T cells, 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., comparison at 9 month visit|CD4+ T cell responses to insulin, 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., comparison at 0, 3, 6, and 12 month visit|CD8+ T cell responses to insulin, 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., comparison at 0, 3, 6, and 12 month visit|Microbiome alpha diversity, beta diversity and taxanomic abundance, 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., comparison at 0, 6, and 12 month visits|Monocyte and T cell sub-populations, 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, comparison at 0, 3, 6, 9, and 12 month visits|Plasma inflammatory proteins, 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., comparison at 0, and 12 month visits|Transcriptome of peripheral blood mononuclear cells, 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., comparison at 0, and 12 month visits|Progression to diabetes, 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 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) | Other: Hypoglycemia, 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)., Measured at baseline (visit 1) and at subsequent change in dose (visits 2).|Adverse events, 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., 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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