The BEGIN Study Bifidobacterium Infantis to Newborns: Effects of Modulating the Gut Microbial Composition on Growth, Immune Function and Inflammatory Conditions - a Randomized Placebo-controlled Double-blinded Intervention Trial (BEGIN)

The BEGIN Study Bifidobacterium Infantis to Newborns: Effects of Modulating the Gut Microbial Composition on Growth, Immune Function and Inflammatory Conditions

The goal of The BEGIN Study, a randomized controlled double-blinded intervention trial, is to learn if probiotics, with Bifidobacterium longum subspecies infantis Bifin02 (B. infantis), given to healthy newborns can affect various health outcomes and to explore impacts of the infant gastrointestinal microbiome. The main questions it aims to answer are:

• Does B. infantis probiotics impact immune function and does it lower the number of bacterial infections and use of antibiotics?
• Does B. infantis probiotics impact overall health, development, growth and wellbeing?
• Does B. infantis probiotics impact inflammatory diseases, allergies and autoimmune diseases

Researchers will compare B. infantis probiotics to a placebo (a look-alike substance that contains no probiotic) to see if B. infantis colonization impact the human immunesystem and various clinical and biochemical health markers.

Participants (parents) will

• Orally administrate the B. infantis probiotic to their newborn child daily in three weeks from 7 days of age.
• Answer baseline and follow up questionnaires in a study app
• Take five stool samples from the child and one stool sample from the mother
• Collect a 4 week of passive dust sample at home (Electrostatic Dust fall Collector)
• Donate one dried bloodspot and one blood sample from their child

Study Overview

• Status: Recruiting
• Conditions: Healthy; Healthy Nutrition
• Intervention / Treatment: Dietary supplement: B. infantis; Dietary supplement: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mia E Sjørring, MD, PhD.stud; Phone Number: 60199810; Email: miasoe@rm.dk
• Study Contact Backup: Name: Marie T Philipsen, MD, PhD.stud; Phone Number: +45 53637369; Email: marie.tholstrup@rm.dk

Study Locations

• Denmark
  • Midtjylland
    • Herning, Midtjylland, Denmark, 7400
      • Recruiting
      • Regional Hospital Gødstrup
      • Contact: Marie T Philipsen, MD; Phone Number: +45 53637369; Email: marie_tholstrup@rm.dk
    • Horsens, Midtjylland, Denmark, 8700
      • Recruiting
      • Regional Hospital Horsens
      • Contact: Marie T Philipsen, MD; Phone Number: +45 53637369; Email: marie_tholstrup@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Infants born at term (above gestational week 37)
• Infants born in Region Midtjylland Denmark receiving a Danish CPR number.
• Parents age is above 18
• At least one parent holds a smartphone (for study app) and is able to fill out Danish questionaries
• Both legal parents are willing and able to provide written informed consent prior to participation, regarding both themselves and their future child.

Exclusion Criteria:

• Multiple pregnancy
• Child diagnosed with immune deficiency, renal, gastrointestinal, hepatic, or endocrine diseases
• Parents expecting to give other probiotics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: B. infantis; The investigational product to be tested is a Probio-Tec® I Stick-0.16 IF, containing 1.0 g of a standardized fine powder consisting of a food constituent, the freeze-dried culture of Bifidobacterium longum subsp. infantis Bifin02 (DSM33361). The infant dietary supplement is supposed to be mixed with a little human milk or clean water.	Dietary supplement: B. infantis; 1000 newborn children are randomized 50/50 to receive either B. infanits or placebo in a dietary supplement, for daily oral administration in three weeks from 7 days of age.; Other Names: Bifidobacterium longum subsp. infantis Bifin02 (DSM33361)
Placebo Comparator: Placebo; Identical looking placebo.	Dietary supplement: Placebo; Identical looking placebo (without any probiotics/B. infantis) for double-blinded daily oral administration in three weeks from 7 days of age.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prescriptions of antibiotics	Number of prescriptions of antibiotics among participants, as a measure of bacterial infections.	First assessment at 1 year and up to 18 years follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The intestinal microbiota and B. infantis colonization	Stool samples collected during the first year of life and tested with shutgun metagenomics, assessing the microbial composition..	1 year
Antibiotic resistance genes (ARGs)	Amount of Antibiotic resistance genes (ARGs) in participants microbial community in stool samples. Identification with shutgun metagenomics. Assessing the microbial composition and diversity.	1 year
Colic	Parents' observations registered in study app. Duration of crying in the first three months of life. Defined as Wessels criteria: Crying for three or more hours a day, three or more days a week, for three or more weeks.	3 months
Bowel function, stool consistency	Parents' observations registered in study app, related to their infant child's stool consistency measured at the Infant Stool Scale	3 months
Bowel function, stool frequency.	Parents' observations of their infant child's frequency of stool passings, registered in study app	3 months
Bowel function, laxatives	Parents' reported use of medical laxatives for their infant child, registered in study app and reported as amount of days using the laxative.	3 months
High sensitive C-reactive protein (hs-CRP)	Blood biomarker: Low-grade systemic inflammation. Unit of measurement: mg/l	1 year
Cluster of Differentiation 163" (CD163)	Blood biomarker: Macrophage-mediated inflammation and insulin-sensitivity. Unit of measurement: mg/l	1 year
Plasma Calprotectin	Blood biomarker: Intestinal inflammation. Unit of measurement: µg/l	1 year
Allergies, Immunoglobulin E (IgE)	Blood marker: Allergies. Specific IgE against the 11 most common inhalation allergens and IgE directed against Egg white, cow's milk, codfish, wheat, peanut and soybean. Unit of measurement: IU/l	1 year
Allergies	Self reported allergy symptoms	1 year
Growth, weight gain	Measured as weight gain in kilograms	First assessment at 1 year and up to 18 years follow-up
Growth	Growth velocity and weight-for-length z-scores, measured in kilograms and centimeters and combined for Z-scores.	First assessment at 1 year and up to 18 years follow-up
Growth, IGF-1 (Insulin-like Growth Factor-1)	Blood biomarker: Mediating the growth-promoting effects of growth hormone. Unit of measurement: µg/l	1 year
Body composition	Measured by air displacement plethysmography (ADP) (Pea Pod) estimating body fat	3 months
Body composition	Measured by air displacement plethysmography (ADP) (Pea Pod) estimating muscle mass.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital admissions	Number of hospital admissions. Registered at Landspatientregistret	First assessment at 1 year and up to 18 years follow-up
Febrile episodes	Number of days with a fever during the last month. A febrile episode is characterized as a body temperature at 38 degrees Celsius or above. Self-reported in a monthly questionnaire in study app.	1 year
Asthma Control Test	Participants reporting symptoms of astma or astmatic bronkitis, will be asked to complete the Asthma Control Test. The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma.	1 year, possible later follow-up
Asthmatic Bronchitis, prescriptions	Number of prescriptions of medicine for asthmatic bronchitis; Ventoline, Airomir, Flixotide, Aerobec, Montelukast / Singulair.	First assessment at 1 year
Asthmatic bronchitis, hospitalization	Number of hospitalizations due to asthmatic bronchitis.	First assessment at 1 year
Diaper rash	Atopic skin symptoms in diaper area. Self-reported by the childs parents as affected red skin, distribution in centimeters .	1 year
Rhinoconjunctivitis	Measured as Mini Rhinoconjunctivitis quality of life questionnaire Mini RQLQ, adjusted to infants. 14 questions in five domains (activity limitation, practical problems, nose symptoms, eye symptoms, and non-nose/ eye symptoms), scores for each question is ranging from 0 to 6, with 0 reflecting no affection and 6 reflecting maximum affection.	1 year
Obesity	Measured as number of participants diagnosed with Obesity	18 years
Metabolic syndrome	Measured as number of participants diagnosed with Metabolic syndrome	18 years
Diabetes	Measured as number of participants diagnosed with Diabetes	18 years
Inflammatory bowel disease	Measured as number of participants diagnosed with of Morbus Crohn and/or Colitis Ulcerosa.	18 years
Dried blood spot for metabolomics	The metabolomic method measures and compares large numbers of metabolites (for example shot chained fatty acids) present in the dried blood sample.	3 months and 1 year
Bloodsample analyzed with Singlecell PBMC method	Single cell sequencing is a method profiling the peripheral blood mononuclear cells (PBMC), by isolating memory B, T and B-cells	1 year
Child stool sample	Stool samples collected at week 1, 4, 13, 28 and 52 will by qPCR or shutgun metagenomics examine the gut microbiome.	1 year
Mother stool sample	A stool sample from the pregnant mother, preferably prior to or during birth. To analyze mothers microbial colonization, that may be transferred to the child, e.g during vaginal birth.	1 month
Mother HMO-secretor status	The type of Human Milk Oligosaccharides (HMO) section in mothers' breastmilk, will be determined to exploratively study the relationship between types of HMO's, mothers HMO-secretor status and effects of B.infantis.	1 month
Asthma	Number of participants with prescriptions of medicine for asthma	up to 18 years follow-up
Atopic disease (adjusted SCORAD grading)	Atopic symptoms, eczema, registered in study-app with description of episodes of atopic dermatitis (adjusted SCORAD grading). Disease intensity is calculated based on six characteristics: erythema, edema, oozing/crusts, excoriations, lichenification, and dryness. Each characteristic is given a score between 0 and 3, where 0 is absent and 3 is severe. The scores for each characteristic are added together for a total intensity score of up to 18.	First assessment at 1 year
Atopic disease, local steroids	Number of participants with prescriptions of local steroids to treat eczema.	First assessment at 1 year and up to 18 years follow-up

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; University of Copenhagen; Gødstrup Hospital; Statens Serum Institut; Technical University of Denmark; Regional Hospital Horsens
• Investigators: Principal Investigator: Sune Rubak, MD, Phd, Department of Paediatrics, Aarhus University Hospital (AUH) and Aarhus University; Principal Investigator: Kurt Kristensen, MD, Phd, Steno Diabetes Centre Aarhus and Department of Paediatrics (AUH) and and Aarhus University

Publications and helpful links

Helpful Links

• studywebsite for participants

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2043

Study Registration Dates

• First Submitted: May 22, 2024
• First Submitted That Met QC Criteria: June 10, 2024
• First Posted (Actual): June 11, 2024

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 30, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Child; Respiratory Tract Diseases; Immunology; Microbiota; Probiotics; Gastrointestinal Microbiome; Infant; Infections; Metabolism; Colic; Paediatrics; Growth and Development; Bifidobacterium longum subspecies infantis
• Other Study ID Numbers: BEGIN 2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Anonymized data that underlie the results reported in study articles (text, tables, figures, and appendices).

The laws related to the handling of personal data will be followed and results are processed in accordance with the General Data Protection Regulation (GDPR) and the Danish Data Protection Act (Databeskyttelsesforordningen and Databeskyttelsesloven).

• IPD Sharing Time Frame: After the study has been finalized
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No