Intervention on New Onset-T1D Children

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

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.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Dietary supplement: Probiotic Vivomixx®; Dietary supplement: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marika Falcone, MD; Phone Number: 00390226434890; Email: falcone.marika@hsr.it

Study Locations

• Italy
  • MIlan, Italy, 20132
    • Recruiting
    • Autoimmune Pathogenesis Unit
    • Contact: Marika Falcone; Phone Number: +390226434890; Email: falcone.marika@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treated; 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®; 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.; Other Names: VSL#3; Visbiome®
Placebo Comparator: Untreated; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Principal Investigator: Marika Falcone, IRCCS San Raffaele

Publications and helpful links

General Publications

• Dolpady J, Sorini C, Di Pietro C, Cosorich I, Ferrarese R, Saita D, Clementi M, Canducci F, Falcone M. Oral Probiotic VSL#3 Prevents Autoimmune Diabetes by Modulating Microbiota and Promoting Indoleamine 2,3-Dioxygenase-Enriched Tolerogenic Intestinal Environment. J Diabetes Res. 2016;2016:7569431. doi: 10.1155/2016/7569431. Epub 2015 Dec 8.
• Caballero-Franco C, Keller K, De Simone C, Chadee K. The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G315-22. doi: 10.1152/ajpgi.00265.2006. Epub 2006 Sep 14.
• Korpela R, Niittynen L. Probiotics and irritable bowel syndrome. Microb Ecol Health Dis. 2012 Jun 18;23. doi: 10.3402/mehd.v23i0.18573. eCollection 2012.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2022
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: November 21, 2022
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 14, 2023

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: November 27, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Gut microbiome; Intestinal barrier integrity
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: RF-2019-123-70721

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No