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Intervention on New Onset-T1D Children

Primary Purpose

Type 1 Diabetes

Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Probiotic Vivomixx®
Placebo
Sponsored by
IRCCS San Raffaele
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 1 Diabetes focused on measuring Gut microbiome, Intestinal barrier integrity

Eligibility Criteria

7 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Autoimmune Pathogenesis UnitRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treated

Untreated

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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
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)
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.

Full Information

First Posted
November 21, 2022
Last Updated
March 10, 2023
Sponsor
IRCCS San Raffaele
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1. Study Identification

Unique Protocol Identification Number
NCT05767450
Brief Title
Intervention on New Onset-T1D Children
Official Title
Assessing the Role of the Gut Microbiome and of the Intestinal Barrier Integrity in the Immune Pathogenesis of Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 16, 2022 (Actual)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
IRCCS San Raffaele

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
Keywords
Gut microbiome, Intestinal barrier integrity

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Interventional, randomized (1:1), 2-arm, single-center, placebo controlled
Masking
Participant
Masking Description
Participants will be randomized in blind (by a computer) in 1:1 allocations. Participants enrolled in both arms and their parents wil be blinded to treatment as sachets provided will be identical as will be the visual aspect and taste of the Vivomixx probiotic.
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treated
Arm Type
Experimental
Arm Description
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
Arm Title
Untreated
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Dietary Supplement
Intervention Name(s)
Probiotic Vivomixx®
Other Intervention Name(s)
VSL#3, Visbiome®
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Preservation of the residual insulin-producing beta cell mass
Description
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.
Time Frame
through study completion, an average of 1 year
Title
Glycemic control by Time-in-Range (TIR) monitoring
Description
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.
Time Frame
through study completion, an average of 1 year
Secondary Outcome Measure Information:
Title
Gut barrier integrity
Description
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.
Time Frame
through study completion, an average of 1 year
Title
Gut microbiome profile
Description
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.
Time Frame
through study completion, an average of 1 year
Title
Measurement by flow cytometry of differences in the percentages of regulatory and inflammatory CD4 T cells
Description
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
Time Frame
through study completion, an average of 1 year
Title
Measurement by flow cytometry of differences in the percentages of MAIT cells and TCR gamma Delta T cells
Description
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)
Time Frame
through study completion, an average of 1 year
Title
Measurement by flow cytometry of differences in the percentages of innate lymphoid cells
Description
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.
Time Frame
through study completion, an average of 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marika Falcone, MD
Phone
00390226434890
Email
falcone.marika@hsr.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marika Falcone
Organizational Affiliation
IRCCS San Raffaele
Official's Role
Principal Investigator
Facility Information:
Facility Name
Autoimmune Pathogenesis Unit
City
MIlan
ZIP/Postal Code
20132
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marika Falcone
Phone
+390226434890
Email
falcone.marika@hsr.it

12. IPD Sharing Statement

Citations:
PubMed Identifier
26779542
Citation
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.
Results Reference
result
PubMed Identifier
16973917
Citation
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.
Results Reference
result
PubMed Identifier
23990830
Citation
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.
Results Reference
result

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Intervention on New Onset-T1D Children

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