The Combiotic-Study

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy Term Infants

Intervention / Treatment
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* Dietary Supplement: Synbiotic formula
* Dietary Supplement: Control formula


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 3 Weeks
Maximum Age: 5 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Synbiotic formula<br>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<br>* Standard milk formula enriched with a prebiotic fiber and a probiotic strain<br>|
| Placebo Comparator: Control formula<br>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<br>* Standard milk formula without pre and probiotic<br>|
| No Intervention: Breast-fed group<br>- 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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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synbiotic formula, infant formula, diarrhea