The Combiotic-Study (GOLFIII)

Evaluation of the Efficacy and Safety of an Infant Formula Containing Synbiotics and Its Effects on the Incidence of Infectious Diseases in the Infant Gut : a Double-blind, Randomized, Controlled Interventional Study

The primary objective of this study is to demonstrate that a synbiotic formula, fed for the duration of the first year of life (infant and follow-on formula) reduces the incidence rate of episodes of infectious diarrhea in infants during the first year of life compared to a standard infant formula.

Study Overview

• Status: Terminated
• Conditions: Healthy Term Infants
• Intervention / Treatment: Dietary supplement: Synbiotic formula; Dietary supplement: Control formula

• Study Type: Interventional
• Enrollment (Actual): 540
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Charente-Maritime
    • Gemozac, Charente-Maritime, France, 17260
      • Elie JABBOUR
    • La Rochelle, Charente-Maritime, France, 17000
      • Christophe VIEL
  • Isère
    • Grenoble, Isère, France, 38043
      • C.I.C Pédiatrique - C.H.U. de Grenoble - Hôpital Couple-Enfant
  • Loire-Atlantique
    • Nantes, Loire-Atlantique, France, 44093
      • C.I.C pédiatrique - C.H.U. de Nantes - Hôpital Mère-Enfant
  • Maine-et-Loire
    • Angers, Maine-et-Loire, France, 49000
      • Alain PALOMBA
    • Angers, Maine-et-Loire, France, 49000
      • Christophe RONDEAU
    • Angers, Maine-et-Loire, France, 49000
      • Damien GODIN
    • Angers, Maine-et-Loire, France, 49000
      • Daniel GOMBAUD
    • Angers, Maine-et-Loire, France, 49000
      • Jean-François FOUCAULT
    • Angers, Maine-et-Loire, France, 49000
      • Michel LAMBERT
    • Angers, Maine-et-Loire, France, 49000
      • Nolwenn RONCERAY
    • Angers, Maine-et-Loire, France, 49000
      • Philippe REMAUD
    • Angers, Maine-et-Loire, France, 49000
      • Pierre-André FERRAND
    • Angers, Maine-et-Loire, France, 49000
      • Vanessa BERNAND
    • Angers, Maine-et-Loire, France, 49100
      • Francisco MARTINEZ-CORTES
    • Angers, Maine-et-Loire, France, 49120
      • Damien GUILLON
    • Becon Les Granits, Maine-et-Loire, France, 49370
      • Christine REGIMBART
    • Montreuil, Maine-et-Loire, France, 49460
      • Antoine LEPELLETIER
    • Segre, Maine-et-Loire, France, 49500
      • Benoit DAGUZAN
    • Tierce, Maine-et-Loire, France, 49125
      • Didier NOURRY
    • Tierce, Maine-et-Loire, France, 49125
      • Philippe IGIGABEL
  • Mayenne
    • Laval, Mayenne, France, 53000
      • Alain BATY
    • Laval, Mayenne, France, 53000
      • Christian DUROY
    • Laval, Mayenne, France, 53000
      • François RICHARD
    • Laval, Mayenne, France, 53000
      • Patrick ROBERT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 weeks to 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy term infants
• Female or male gender
• Gestational age between 37 and 41 weeks completed (= 41 weeks + 6 days)
• Age at time of V1 visit : 4 +/- 7 days
• Birth weight between 2500 ans 4200g, with regular weight gain (≥ 150g / week)
• Two legal representatives (parent(s) / guardian(s)) who are capable of and willing to comply with the protocol and have signed the informed consent in accordance with legal requirements.
• at least one of the legal representatives is affiliated to with a social security scheme.

Additionnaly , criteria of inclusion in one of the formula-fed groups or in the breast-fed group, respectively, are the following:

• To be included in one of the formula arm, infants will have to be exclusively formula-fed (no breast milk meal) at the time of V1 visit (randomization).

or

• To be included in the breastfeeding arm, infants will have to be exclusively breast-fed (no more than one formula meal per day) at V1 visit (randomization) and its mother will have to be willing to pursue exclusive breastfeeding at least until the infant will be 4-month old.

Exclusion Criteria:

• Intensive care during at least the first 14 days of life
• Neonatal health problems, such as: respiratory distress, asphyxia, hypoglycemia, sepsis, NEC (necrotizing enterocolitis),...
• Clinical evidence of chronic illness or gastrointestinal disorders such as : GER (Gastrooesophageal Reflux), gastroenteritis,...
• Known metabolic disorders, such as diabetes, lactose intolerance,....
• Known immune deficiency
• Subjects recommended to receive formula with hydrolized protein (e.g. children with allergy risk)
• Subject under oral antibiotic treatment at V1 visit
• Participation in another biomedical study
• Whose legal representatives have psychological or linguistic incapability to sign the informed consent form
• Reasons to presume that parents are unable to meet the study plan requirements (e.g. impossibility to contact study representatives in case of emergency, drug addiction etc)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Synbiotic formula; Synbiotic formula : standard formula enriched with a prebiotic fiber and a probiotic strain Dose : variable number of powder scoops, adapted to the infant's age and weight, and addition of the defined amount of water, according to the Dose and Drinking Amount table. Route : oral, ad libitum Duration of product intake: Synbiotic IF : 5 months of consumption (from the inclusion until 6 months completed of age); Synbiotic FoF: 6 months of consumption (from 6 to 12 months of age)	Dietary supplement: Synbiotic formula; Standard milk formula enriched with a prebiotic fiber and a probiotic strain
Placebo Comparator: Control formula; Control formula : standard formula without pre and probiotic Dose : variable number of powder scoops, adapted to the infant's age and weight, and addition of the defined amount of water according to the Dose and Drinking Amount table. Route: oral, ad libitum Duration of product intake: Control IF : 5 months of consumption (from the inclusion until 6 months completed of age); Control FoF : 6 months of consumption (from 6 to 12 months of age)	Dietary supplement: Control formula; Standard milk formula without pre and probiotic
No Intervention: Breast-fed group; - Breast milk as exclusive feeding (no more than one formula meal per day), from birth until at least 4 months of age. Then, when the mother decides to stop breastfeeding, the infants can consume any formula on parent's choice respecting forbidden products list. Dose: Breast milk : on demand Route : oral, ad libitum Duration of product intake: Breast milk : at least 4 month (from birth until at least 4 months of age)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Cumulative) number of infectious diarrhea episodes per subject during the first year of life.	Difference between formula groups are evaluated via incidence rate based on number of subjects. In formula-fed infants, diarrhea is defined as three or more loose or watery stools in 24 hours with or without fever or vomiting (according to WHO and ESPGHAN definition). For breast-fed infants, a change in stool consistency versus previous stool consistency is more indicative of diarrhea than stool number. Diarrhea episode is considered as ended as soon as 2 consecutive non-watery stools are observed or no stools are observed in 24 hours.	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples	Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile	4 months
Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples	Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile	1 year
Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples	Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile	2 years
Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples	Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile	3 years
Analysis of fecal microbiota by molecular analysis from frozen stools in diarrhea samples	levels of potential pathogens causing diarrhea including rotavirus, norovirus, Salmonella enterica, Campylobacter jejuni, Clostridium difficile, Clostridium perfringens, Escherichia coli (potential pathogenic bacteria will be screened only in case of negative testing for viruses on sample collected within 72 hours after beginning of the diarrhea episode);	1 year
Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	4 months
Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	1 year
Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	2 years
Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	3 years
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	4 months
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	6 months
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	9 months
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	1 year
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	2 years
Characteristics of bowel movements and stools	- assessed through a 3-day diary filled in by parents; average daily number of bowel movements;; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) (using the validated scale for preterm and term infants proposed by Bekkali N, et al., 2009), and especially; average daily incidence of loose or watery stools (category A, subscale 'consistency' on Bekkali scale);; dominant stool color per visit	3 years
Characteristics of bowel movements during diarrhea episodes	- assessed through a diary filled in by parents during diarrhea episodes; average daily number of bowel movements per diarrhea episode;; average duration (number of days) of diarrhea episodes;; total number of days with diarrhea, within the first year of age (between V1 and V5);; (average daily) Infant Stool Form scores consistency (4-point scale), amount (4-point scale) and color (6 categories) per diarrhea episode.	1 year
Levels of fecal IgA and fecal calprotectin in planned stool samples		4 months
Levels of fecal IgA and fecal calprotectin in planned stool samples		1 year
Levels of fecal IgA and fecal calprotectin in planned stool samples		2 years
Levels of fecal IgA and fecal calprotectin in planned stool samples		3 years
Number and duration of infectious diseases	Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;	3 years
Number and duration of fever episodes;		3 years
Number and duration of antibiotic treatment.		3 years
Infants growth measured by anthropometric measurements	weight, size, head circumference;	4 weeks
Infants growth measured by anthropometric measurements	weight, size, head circumference;	4 months
Infants growth measured by anthropometric measurements	weight, size, head circumference;	6 months
Infants growth measured by anthropometric measurements	weight, size, head circumference;	9 months
Infants growth measured by anthropometric measurements	weight, size, head circumference;	1 year
Infants growth measured by anthropometric measurements	weight, size, head circumference;	2 years
Infants growth measured by anthropometric measurements	weight, size, head circumference;	3 years
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	4 months
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	6 months
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	9 months
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	1 year
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	2 years
Child's behavior	Assessed through a 3-day diary filled in by parents - Average sleep duration and crying duration per 24 hours;	3 years
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	4 months
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	6 months
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	9 months
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	1 year
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	2 years
Minor gastrointestinal disorders (digestive tolerance)	Assessed through a 3-day diary filled in by parents - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);	3 years
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	4 months
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	6 months
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	9 months
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	1 year
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	2 years
Suitability for daily use	Assessed through a 3-day diary filled in by parents - average daily consumption: drinking amounts and formula acceptance;	3 years
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	4 months
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	6 months
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	9 months
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	1 year
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	2 years
Adverse events (AE)	Assessed through a 3-day diary filled in by parents - Number of events, number of subjects showing adverse events, intensity and relationship of AE.	3 years
Number and duration of fever episodes;		1 year
Number and duration of antibiotic treatment.		1 year
Number and duration of infectious diseases	Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiota results	Phyla and families of bacteria in planned stools using 16S taxonomical metasequencing compared to the control formula in a sub-group of 96 infants only	1 year
Urinary D-Lactate and creatinine	To assess change in the urinary lactate and creatinine (in a subgroup of 96 infants only) via ratio after 3 months of consumption of the supplemented infant formula, compared to the control formula	4 weeks
Urinary D-Lactate and creatinine	To assess change in the urinary lactate and creatinine (in a subgroup of 96 infants only) via ratio after 3 months of consumption of the supplemented infant formula, compared to the control formula	4 months
Microbiota results	Phyla and families of bacteria in planned stools using 16S taxonomical metasequencing compared to the control formula in a sub-group of 96 infants only	4 months
Microbiota results	Phyla and families of bacteria in planned stools using 16S taxonomical metasequencing compared to the control formula in a sub-group of 96 infants only	2 years
Microbiota results	Phyla and families of bacteria in planned stools using 16S taxonomical metasequencing compared to the control formula in a sub-group of 96 infants only	3 years

Collaborators and Investigators

• Sponsor: HiPP GmbH & Co. Vertrieb KG
• Collaborators: Biofortis Mérieux NutriSciences
• Investigators: Principal Investigator: Hugues Piloquet, Pediatrician

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: August 19, 2014
• First Submitted That Met QC Criteria: August 19, 2014
• First Posted (Estimate): August 20, 2014

Study Record Updates

• Last Update Posted (Actual): January 20, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: diarrhea; infant formula; synbiotic formula
• Other Study ID Numbers: 505564 - PEC10561