Clinical trial NCT04769037: Supplementation With B. Infantis for Mitigation of Type 1 Diabetes Autoimmunity
Official title: "SINT1A" - Supplementation With B. Infantis for Mitigation of Type 1 Diabetes Autoimmunity - A Study of the Global Platform for the Prevention of Autoimmune Diabetes ("GPPAD")
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: Type 1 diabetes autoimmunity
celiac autoimmunity
respiratory infections
allergy
prevention
probiotic
B. infantis
Lead sponsor: Helmholtz Zentrum München
Sponsor class: INDUSTRY
Collaborators: name: Technical University of Munich
name: Kinderkrankenhaus auf der Bult
name: University Hospital Carl Gustav Carus
name: Skane University Hospital
name: Universitaire Ziekenhuizen KU Leuven
name: Medical University of Warsaw
name: Cambridge Biomedical Campus, Cambridge, UK
name: Royal Victoria Infirmary, Newcastle upon Tyne, UK
First posted: 2021-02-24
Enrollment: 1149
Sex: ALL
Minimum age (years): 7
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Investigator initiated, randomised, placebo-controlled, double-blind, multi-centre primary intervention study to assess whether daily administration of B. infantis EVC001 from age 7 days to 6 weeks (+14 days) until age 12 months (+ 14 days) to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.

Detailed description: The GPPAD-04 SINT1A study will evaluate whether early, regular supplementation with a daily dose of a probiotic can reduce the risk of developing beta-cell autoimmunity in children identified by GPPAD-02 as being genetically predisposed to developing type 1 diabetes. Children will be enrolled at age 7 days to 6 weeks (+14 days) and the study product (B. infantis EVC001 or Placebo) will be administered orally once per day from enrollment until age 12 months (+14 days).

The hypotheses is that administration of B. infantis may have a positive influence on the intestinal flora and thus have a regulating effect on the immune system. The study is designed to investigate whether pathogenic immune reactions as in type 1 diabetes but also in other diseases, such as celiac disease, can be reduced and if the disease can be prevented.

Children will be followed until age 3.5 - 6.5 years (2.5 - 5.5 years after end of treatment).

Throughout the study data will be collected by regular study visits, phone calls with the families and electronic questionaires.

Blood samples will be collected to investigate glucose, HbA1c, beta-cell autoantibodies, transglutaminase antibodies, vaccine responses, genetic susceptibility and mechanistic markers. Stool samples will be collected for further assessments such as colonization,microbiome, pH and calprotectin.

Exploratory outcomes (allergy, vaccine responses, stool microbiome, blood metabolomics, stool pH and calprotectin or site specific ancillary measurements) may be assessed or in part assessed on a portion of the participants after unblinding the study. They may not necessarily be included in the primary outcome analysis and publication.

GPPAD is committed to sharing of data in compliance with all applicable European and GPPAD Consortium Member State, Data Protection and Privacy Protection laws, rules and regulations.

Pseudonymized data of the GPPAD-04 SINT1A study will be available to the scientific community after the publication of the trial analysis, which is anticipated in 2028. The SINT1A data will be available upon request.

Eligibility criteria: Inclusion Criteria:

1. Infants between the ages of 7 days and 6 weeks (+14 days in case of illness or COVID-19 related issues or unexpected delay in result reporting) at the time of randomisation.
2. A 10% or higher genetic risk to develop multiple beta-cell autoantibodies by age 6 years:

   1. For infants without a first-degree family history of type 1 diabetes, high genetic risk is defined as a DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype and a genetic risk score that is in the upper 25th centile (\>14.4) or a DR3/DR4-DQ8 genotype with a GRS between the upper 50th (14.0) and 25th centile and a GG genotype at the rs3763305 SNP. These represent around 1% of all newborns.
   2. For infants with a first-degree family history of type 1 diabetes, high genetic risk is defined as having HLA DR4 and DQ8, and none of the following protective alleles: DRB1\*1501, DQB1\*0503, DRB1\*1303. These represent around 30% of infants with a first-degree family history of T1D.
3. Written informed consent signed by the custodial parent(s).-

Exclusion Criteria:

1. Any medical condition, concomitant disease or treatment that may interfere with the assessments or may jeopardize the participant's safe participation in the study, as judged by the Investigators.
2. Preterm delivery \< 36 weeks of gestation.
3. Proven immunodeficiency.
4. Any condition that could be associated with poor compliance.5. Diagnosis of diabetes at the time of recruitment

Primary outcomes:
measure: Persistent confirmed multiple beta-cell autoantibodies
timeFrame: Through study completion, up to 6.5 years
Secondary outcomes:
measure: Persistent confirmed beta-cell autoantibodies
timeFrame: Through study completion, up to 6.5 years
measure: Diabetes
timeFrame: Through study completion, up to 6.5 years
measure: Transglutaminase antibodies
timeFrame: Through study completion, up to 6.5 years
measure: Respiratory infection rate
timeFrame: 1 year
measure: Measurement of Safety parameters
timeFrame: from Baseline until 30 days after end of supplementation
Other outcomes:
measure: Allergy
timeFrame: Through study completion, up to 6.5 years
measure: Antibody response (IgG titres) to vaccines
timeFrame: at age 6 months (rotavirus) and at age 2 years (MMR)
measure: Alterations of the gut microbiome or blood metabolome
timeFrame: from baseline to age 12 months
measure: Stool pH
timeFrame: at age 6 months
measure: Stool calprotectin
timeFrame: at age 6 months
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven Faculty of Medicine, Catholic University of Leuven
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Technische Universität Dresden
city: Hannover
country: Germany
facility: AUF DER BULT, Kinder- und Jugendkrankenhaus
city: Munich
country: Germany
facility: Institute of Diabetes Research, Helmholtz Zentrum Munich, Germany, and Forschergruppe Diabetes, Technical University Munich (TUM), School of Medicine, Klinikum rechts der Isar
city: Warsaw
country: Poland
facility: Department of Paediatrics Medical University of Warsaw
city: Malmö
country: Sweden
facility: Lund University, Skane University Hospital SUS
city: Cambridge
country: United Kingdom
facility: University Department of Paediatrics, Cambridge Biomedical Campus
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary, Newcastle upon Tyne
Study officials:
References:
citation: Ziegler AG, Arnolds S, Kolln A, Achenbach P, Berner R, Bonifacio E, Casteels K, Elding Larsson H, Gundert M, Hasford J, Kordonouri O, Lundgren M, Oltarzewski M, Pekalski ML, Pfirrmann M, Snape MD, Szypowska A, Todd JA; GPPAD STUDY GROUP. Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol. BMJ Open. 2021 Nov 9;11(11):e052449. doi: 10.1136/bmjopen-2021-052449.