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The Combiotic-Study (GOLFIII)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02221687
Recruitment Status : Unknown
Verified August 2017 by HiPP GmbH & Co. Vertrieb KG.
Recruitment status was:  Active, not recruiting
First Posted : August 20, 2014
Last Update Posted : May 29, 2018
Sponsor:
Collaborator:
Biofortis Mérieux NutriSciences
Information provided by (Responsible Party):
HiPP GmbH & Co. Vertrieb KG

Brief 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.

Condition or disease Intervention/treatment Phase
Healthy Term Infants Dietary Supplement: Synbiotic formula Dietary Supplement: Control formula Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 540 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
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
Study Start Date : August 2014
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


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)



Primary Outcome Measures :
  1. (Cumulative) number of infectious diarrhea episodes per subject during the first year of life. [ Time Frame: one year ]

    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.



Secondary Outcome Measures :
  1. Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples [ Time Frame: 4 months ]
    Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile

  2. Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples [ Time Frame: 1 year ]
    Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile

  3. Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples [ Time Frame: 2 years ]
    Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile

  4. Analysis of fecal microbiota by molecular analysis from frozen stools in planned stool samples [ Time Frame: 3 years ]
    Levels of total lactobacilli, Lactobacillus fermentum species (and if possible the strain CECT 5716 will be quantified too), total bifidobacteria, enterobacteriaceae, clostridium difficile

  5. Analysis of fecal microbiota by molecular analysis from frozen stools in diarrhea samples [ Time Frame: 1 year ]
    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);

  6. Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples [ Time Frame: 4 months ]
    short chain fatty acids (SCFA): acetate, propionate, butyrate;

  7. Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples [ Time Frame: 1 year ]
    short chain fatty acids (SCFA): acetate, propionate, butyrate;

  8. Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples [ Time Frame: 2 years ]
    short chain fatty acids (SCFA): acetate, propionate, butyrate;

  9. Fecal pH and levels of short chain fatty acids (SCFA) in planned stool samples [ Time Frame: 3 years ]
    short chain fatty acids (SCFA): acetate, propionate, butyrate;

  10. Characteristics of bowel movements and stools [ Time Frame: 4 months ]

    - 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

  11. Characteristics of bowel movements and stools [ Time Frame: 6 months ]

    - 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

  12. Characteristics of bowel movements and stools [ Time Frame: 9 months ]

    - 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

  13. Characteristics of bowel movements and stools [ Time Frame: 1 year ]

    - 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

  14. Characteristics of bowel movements and stools [ Time Frame: 2 years ]

    - 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

  15. Characteristics of bowel movements and stools [ Time Frame: 3 years ]

    - 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

  16. Characteristics of bowel movements during diarrhea episodes [ Time Frame: 1 year ]

    - 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.

  17. Levels of fecal IgA and fecal calprotectin in planned stool samples [ Time Frame: 4 months ]
  18. Levels of fecal IgA and fecal calprotectin in planned stool samples [ Time Frame: 1 year ]
  19. Levels of fecal IgA and fecal calprotectin in planned stool samples [ Time Frame: 2 years ]
  20. Levels of fecal IgA and fecal calprotectin in planned stool samples [ Time Frame: 3 years ]
  21. Number and duration of infectious diseases [ Time Frame: 3 years ]
    Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;

  22. Number and duration of fever episodes; [ Time Frame: 3 years ]
  23. Number and duration of antibiotic treatment. [ Time Frame: 3 years ]
  24. Infants growth measured by anthropometric measurements [ Time Frame: 4 weeks ]
    weight, size, head circumference;

  25. Infants growth measured by anthropometric measurements [ Time Frame: 4 months ]
    weight, size, head circumference;

  26. Infants growth measured by anthropometric measurements [ Time Frame: 6 months ]
    weight, size, head circumference;

  27. Infants growth measured by anthropometric measurements [ Time Frame: 9 months ]
    weight, size, head circumference;

  28. Infants growth measured by anthropometric measurements [ Time Frame: 1 year ]
    weight, size, head circumference;

  29. Infants growth measured by anthropometric measurements [ Time Frame: 2 years ]
    weight, size, head circumference;

  30. Infants growth measured by anthropometric measurements [ Time Frame: 3 years ]
    weight, size, head circumference;

  31. Child's behavior [ Time Frame: 4 months ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  32. Child's behavior [ Time Frame: 6 months ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  33. Child's behavior [ Time Frame: 9 months ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  34. Child's behavior [ Time Frame: 1 year ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  35. Child's behavior [ Time Frame: 2 years ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  36. Child's behavior [ Time Frame: 3 years ]

    Assessed through a 3-day diary filled in by parents

    - Average sleep duration and crying duration per 24 hours;


  37. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 4 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  38. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 6 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  39. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 9 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  40. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 1 year ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  41. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 2 years ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  42. Minor gastrointestinal disorders (digestive tolerance) [ Time Frame: 3 years ]

    Assessed through a 3-day diary filled in by parents

    - average daily vomiting, regurgitation/reflux, flatulence, constipation (according to WHO definition);


  43. Suitability for daily use [ Time Frame: 4 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  44. Suitability for daily use [ Time Frame: 6 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  45. Suitability for daily use [ Time Frame: 9 months ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  46. Suitability for daily use [ Time Frame: 1 year ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  47. Suitability for daily use [ Time Frame: 2 years ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  48. Suitability for daily use [ Time Frame: 3 years ]

    Assessed through a 3-day diary filled in by parents

    - average daily consumption: drinking amounts and formula acceptance;


  49. Adverse events (AE) [ Time Frame: 4 months ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  50. Adverse events (AE) [ Time Frame: 6 months ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  51. Adverse events (AE) [ Time Frame: 9 months ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  52. Adverse events (AE) [ Time Frame: 1 year ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  53. Adverse events (AE) [ Time Frame: 2 years ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  54. Adverse events (AE) [ Time Frame: 3 years ]

    Assessed through a 3-day diary filled in by parents

    - Number of events, number of subjects showing adverse events, intensity and relationship of AE.


  55. Number and duration of fever episodes; [ Time Frame: 1 year ]
  56. Number and duration of antibiotic treatment. [ Time Frame: 1 year ]
  57. Number and duration of infectious diseases [ Time Frame: 1 year ]
    Especially: otitis media, infections of upper and lower respiratory tract and of urinary tract;


Other Outcome Measures:
  1. Microbiota results [ Time Frame: 1 year ]
    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. Urinary D-Lactate and creatinine [ Time Frame: 4 weeks ]
    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

  3. Urinary D-Lactate and creatinine [ Time Frame: 4 months ]
    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. Microbiota results [ Time Frame: 4 months ]
    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

  5. Microbiota results [ Time Frame: 2 years ]
    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

  6. Microbiota results [ Time Frame: 3 years ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 5 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02221687


Locations
Show Show 25 study locations
Sponsors and Collaborators
HiPP GmbH & Co. Vertrieb KG
Biofortis Mérieux NutriSciences
Investigators
Layout table for investigator information
Principal Investigator: Hugues Piloquet, Pediatrician
Layout table for additonal information
Responsible Party: HiPP GmbH & Co. Vertrieb KG
ClinicalTrials.gov Identifier: NCT02221687    
Other Study ID Numbers: 505564 - PEC10561
First Posted: August 20, 2014    Key Record Dates
Last Update Posted: May 29, 2018
Last Verified: August 2017
Keywords provided by HiPP GmbH & Co. Vertrieb KG:
synbiotic formula
infant formula
diarrhea