The Combiotic-Study

Healthy Term Infants Clinical Trial

— GOLFIII  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02221687
• Other study ID #: 505564 - PEC10561
• Status: Terminated
• Phase: N/A
• Start date: August 2014
• Est. completion date: April 2021

Study information

• Verified date: January 2022
• Source: HiPP GmbH & Co. Vertrieb KG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 540
• Est. completion date: April 2021
• Est. primary completion date: April 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 5 Weeks

Eligibility

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)

Related Conditions & MeSH terms

• Healthy Term Infants

Intervention

Dietary Supplement:
• Synbiotic formula
Standard milk formula enriched with a prebiotic fiber and a probiotic strain
• Control formula
Standard milk formula without pre and probiotic

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
HiPP GmbH & Co. Vertrieb KG	Biofortis Mérieux NutriSciences

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	(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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	4 months
Secondary	Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	1 year
Secondary	Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	2 years
Secondary	Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples	short chain fatty acids (SCFA): acetate, propionate, butyrate;	3 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Levels of fecal IgA and fecal calprotectin in planned stool samples		4 months
Secondary	Levels of fecal IgA and fecal calprotectin in planned stool samples		1 year
Secondary	Levels of fecal IgA and fecal calprotectin in planned stool samples		2 years
Secondary	Levels of fecal IgA and fecal calprotectin in planned stool samples		3 years
Secondary	Number and duration of infectious diseases	Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;	3 years
Secondary	Number and duration of fever episodes;		3 years
Secondary	Number and duration of antibiotic treatment.		3 years
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	4 weeks
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	4 months
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	6 months
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	9 months
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	1 year
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	2 years
Secondary	Infants growth measured by anthropometric measurements	weight, size, head circumference;	3 years
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	4 months
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	6 months
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	9 months
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	1 year
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	2 years
Secondary	Child's behavior	Assessed through a 3-day diary filled in by parents; - Average sleep duration and crying duration per 24 hours;	3 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	4 months
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	6 months
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	9 months
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	1 year
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	2 years
Secondary	Suitability for daily use	Assessed through a 3-day diary filled in by parents; - average daily consumption: drinking amounts and formula acceptance;	3 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number and duration of fever episodes;		1 year
Secondary	Number and duration of antibiotic treatment.		1 year
Secondary	Number and duration of infectious diseases	Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;	1 year