Intervention on New Onset-T1D Children

Study Overview
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Brief Summary
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A pilot proof of concept clinical trial will be performed to demonstrate the restoration of gut barrier integrity by administration of beneficial anti-inflammatory gut microbial strains (Lactobacilli-enriched Vivomixx® probiotic) to new onset Type 1 Diabetes Children.

Detailed Description
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This is an interventional randomized, 2-arm, single-blind, single-center, placebo-controlled mechanistic clinical trial (1:1). One sachet of probiotic for children < 10 years old or two sachets for subjects > 10 years old dissolved into water or noncarbonated drinks will be administered every day for 90 consecutive days.The primary end point of the study will be the preservation of the residual insulin-producing beta-cell mass measured as the change in C-peptide values at 12 months after the beginning of treatment. Moreover, the investigators will collect blood samples for serological analysis (autoantibodies detection, measurement of biomarkers of gut barrier integrity) and immunological profiling; fecal samples for microbiome and metabolomic analysis. Finally the investigators will assess whether the response to Vivomixx® probiotic remains stable over a long-term period, that is in the absence of active treatment.

Official Title
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Assessing the Role of the Gut Microbiome and of the Intestinal Barrier Integrity in the Immune Pathogenesis of Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Dietary Supplement: Probiotic Vivomixx®
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of insulin-dependent type 1 diabetes Positive for at least one islet autoantibody (ICA, GADA, IA-2, IAA, ZnT8) No more than 3 months from first insulin injection ≥ 7 to < 18 year old Exclusion Criteria: Diagnosed with celiac disease, IBD or other intestinal inflammatory pathologies Diagnosed with tuberculosis, hepatitis B or C, HIV, or active EBV or CMV infection; significant cardiac disease; conditions associated with immune dysfunction or hematologic dyscrasia (including malignancy, lymphopenia, thrombocytopenia, or anemia); liver or renal dysfunction. Ongoing use of systemic medications other than insulin. Recent administration of antibiotics (1 months prior to treatment) Deemed unlikely or unable to comply with the protocol or have any complicating medical issues or abnormal clinical laboratory results that interfere with study conduct or cause increased risk.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Interventional, randomized (1:1), 2-arm, single-center, placebo controlled
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated<br>Probiotic name: Vivomixx® Form: powder Dosage: 4,4g/sachet with 450 billion of lactobacilli and bifidobacteria in a base of maltose Frequency: 1 sachet/day for children <10 year old or 2 sachets/day for children >10 year old Duration: 90 days | Dietary Supplement: Probiotic Vivomixx®<br>* The correct number of Vivomixx® sachets are given to parents with the indication to administer the dietary supplement as dissolved in drinking water or non-carbonated drinks.<br>* Other names: Visbiome®;|
| Placebo Comparator: Untreated<br>Product name: Placebo Form: powder Dosage: 4,4g/sachet containing maltose Frequency: 1 sachet/day for children <10 year old or 2 sachets/day for children >10 year old Duration: 90 days | Dietary Supplement: Placebo<br>* The correct number of Placebo sachets are given to parents with the indication to administer the dietary supplement as dissolved in drinking water or non-carbonated drinks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preservation of the residual insulin-producing beta cell mass | The primary outcome of the study will be the preservation of the residual insulin-producing beta-cell mass in newly diagnosed T1D patients that received the probiotic Vivomixx® in comparison to those receiving placebo. This parameter will be reported as the change in C-peptide values (ng/mL) before starting treatment (baseline) and 12 months after treatment initiation. | through study completion, an average of 1 year | 
| Glycemic control by Time-in-Range (TIR) monitoring | Glycemic control will be monitored in newly diagnosed T1D patients that received the probiotic Vivomixx® in comparison to those receiving placebo. This parameter will be reported as the change in TIR values (%) - that is the percentage of time in which blood glucose (blood sugar) remains in the safe target range of 70-180mg/dL - recorded before starting treatment (baseline) and 12 months after treatment initiation. | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut barrier integrity | The levels of zonulin and LBP will be measured in the serum before starting Vivomixx® or placebo administration (baseline), 3 months and 6 months after treatment initiation, as biomarkers used to determine the integrity of the intestinal epithelium in humans. | through study completion, an average of 1 year | 
| Gut microbiome profile | The gut microbiota composition will be analyzed on fecal samples collected before starting Vivomixx or placebo administration (baseline), 3 months and 6 months after treatment, 16S ribosomal RNA (rRNA) sequencing. | through study completion, an average of 1 year | 
| Measurement by flow cytometry of differences in the percentages of regulatory and inflammatory CD4 T cells | Changes in circulating regulatory and inflammatory CD4 T cell subsets (Treg, Th1, Th2, Th17) will be evaluated by flow cytometry of the expression of: CD4, FOXP3 (Treg) CD4, CRTH2 (Th2) CD4, Tbet (Th1) CD4, RORgt (Th17) Results will be expressed in term of percentage (%) of CD4 T cells expressing the molecules | through study completion, an average of 1 year | 
| Measurement by flow cytometry of differences in the percentages of MAIT cells and TCR gamma Delta T cells | Changes in circulating MAIT and TCR gammaDelta T cell subsets will be evaluated by flow cytometry of the expression of CD3, TCRgD, CD161, TCRva7.2 Results will be expressed in term of percentage (%) of cells expressing CD3, TCRgD molecules (that are TCRgammaDelta T cells) and CD3, CD161, TCRva7.2 molecules (that are MAIT cells) | through study completion, an average of 1 year | 
| Measurement by flow cytometry of differences in the percentages of innate lymphoid cells | Changes in circulating MAIT and TCR gammaDelta T cell subsets will be evaluated by flow cytometry of the expression of Lineage markers, c-kit, CRTH2 Results will be expressed in term of percentage (%) of Lineage-negative cells expressing c-kit or CRTH2 molecules. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiome, Intestinal barrier integrity