Safety and Efficacy of Infant Formulas Supplemented With Pre- and Probiotic(s) (CLARA)

Safety and Efficacy of Starter Infant Formula, Follow-up Formula and Growing-up Milk Supplemented With Pre- and Probiotic(s): a Double-blind, Randomized, Controlled Trial

This is a randomized, controlled, multicenter, double-blind study of healthy term infants. The primary objective of the trial is to demonstrate the safety of a a starter infant formula supplemented with pre- and probiotic(s) by comparing the growth of infants randomized to the experimental formula versus the control formula from enrolment to 4 months of age.

Study Overview

• Status: Active, not recruiting
• Conditions: Healthy Infants
• Intervention / Treatment: Other: Experimental formulas (EF); Other: Control formulas (CF); Other: Breast feeding (BF)

Detailed Description

This is a randomized, controlled, multicenter, double-blind study of healthy term infants, consisting of two randomized formula-fed arms (control and experimental formulas) and a non-randomized breast-fed reference group.

The population under investigation are healthy infants aged ≤14 days at enrollment. The planned sample size for formula-fed infants is 236 (118 per study group). A non-randomized breastfed reference group of 90 healthy, term, exclusively breastfed infants up to 4 months will also be enrolled.

Study formulas are administrated orally, ad libitum, from enrollment until 15 months of age.

The primary objective of the trial is to demonstrate the safety of a starter infant formula supplemented with pre- and probiotic(s) by comparing the growth (weight gain, g/day) of infants randomized to the experimental formula versus the control formula from enrolment to 4 months of age.

In addition fecal microbiome, fecal metabolic profile, fecal markers of immune and gut health, blood markers of immune health (in a subset of 60 infants/group), GI tolerance, bone index (subset of 40 infants/group), other anthropometric measurements, dietary pattern and infant illness and infection outcomes will be assessed/measured.

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • AZ Sint-Jan Brugge-Oostende AV
  • Brussel, Belgium, 1090
    • Universitair Ziekenhuis Brussel
  • Hasselt, Belgium, 3500
    • Kinderartsen Huis
  • Liège, Belgium, 4000
    • CHC-Groupe santé, Clinique MontLégia
  • Liège, Belgium, 4000
    • CHU de Liège - CHR de la Citadelle
• France
  • Amiens, France, 80054
    • CHU Amiens-Picardie
  • Bron, France, 69677
    • Hopital Femme Mere Enfant
  • Lyon, France, 69004
    • Hôpital de la Croix Rousse
  • Nantes, France
    • CHU de Nantes
  • Rouen, France, 76031
    • CHU Charles Nicolle
  • Tours, France, 37044
    • Hôpital Bretonneau, CHRU de Tours
• Germany
  • Rostock, Germany, 18059
    • Klinikum Südstadt Rostock
  • Spandau, Germany, 13589
    • Evangelisches Waldkrankenhaus Spandau
• Spain
  • Castellón De La Plana, Spain
    • Hospital Vithas Castellón
  • Córdoba, Spain, 14004
    • Reina Sofia University Hospital
  • Sevilla, Spain, 41014
    • Instituto Hispalense de Pediatría, Unidad de Investigación
  • Valencia, Spain
    • Hospital Vithas Valencia
  • Valencia, Spain
    • Quironsalud Valencia Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 weeks (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Evidence of personally signed and dated informed consent document indicating that the infant's parent(s)/ legally accepted representatives LAR have been informed of all pertinent aspects of the study.
2. Infants whose parent(s)/LAR have reached the legal age of majority in the countries where the study is conducted.
3. Infants whose parent(s)/LAR are willing and able to comply with scheduled visits, and the requirements of the study protocol.
4. Infants whose parent(s)/LAR are able to be contacted directly by telephone throughout the study.

5. Infants must meet all of the following inclusion criteria to be eligible for enrollment into the study:

   1. Healthy term infant (≥37 weeks of gestation)
   2. At enrollment visit, post-natal age ≤14 days/0.5 months
   3. Birth weight ≥ 2500g and ≤ 4500g.
   4. For formula-fed groups, infants must be exclusively consuming and tolerating a cow's milk infant formula at time of enrollment and their parent(s)/LAR must have independently elected, before enrollment, not to breastfeed.
   5. For the breastfed group, infants must have been exclusively consuming breast milk since birth, and their parent(s)/LAR must have made the decision to continue exclusively breastfeeding until at least 4 months of age.

Exclusion Criteria:

1. Infants with conditions requiring infant feedings other than those specified in the protocol.

2. Infants who have a medical condition or history that could increase the risk associated with study participation or interfere with the interpretation of study results, including:

   1. Evidence of major congenital malformations (e.g., cleft palate, extremity malformation)
   2. Suspected or documented systemic or congenital infections (e.g., human immunodeficiency virus, cytomegalovirus, syphilis)
   3. Previous or ongoing severe medical or laboratory abnormality (acute or chronic) which, in the judgment of the investigator, would make the infant inappropriate for entry into the study. Of note, children who are normally healthy but at the time of enrollment suffering from acute illness in a minor condition which are common in childhood and do not require some of the exclusionary medication mentioned below can be enrolled.
3. Infants who are presently receiving or have received prior to enrollment any of the following: medication(s) or supplement(s) which are known or suspected to affect the following: fat digestion, absorption, and/or metabolism (e.g., pancreatic enzymes); stool microbiota and characteristics (e.g., oral or systemic antibiotics, glycerin suppositories, bismuth-containing medications, docusate, Maltsupex, or lactulose); growth (e.g. insulin or growth hormone); gastric acid secretion.
4. Currently participating or having participated in another clinical trial since birth.
5. Subjects or subjects' parent(s) or legal representative who are not willing and not able to comply with scheduled visits and the requirements of the study protocol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental formulas (EF) group; Starter infant formula, follow-up infant formula and growing-up milk (partially hydrolyzed bovine whey protein) supplemented with pre- and probiotic(s)	Other: Experimental formulas (EF); First age formula administered orally ad libitum until 6 months of age, switch to second age formula until 12 months and finally to growing-up milk from 12 to 15 months
Active Comparator: Control formulas (CF) group; Starter infant formula, follow-up infant formula and growing-up milk (partially hydrolyzed bovine whey protein) not supplemented	Other: Control formulas (CF); First age formula administered orally ad libitum until 6 months of age, switch to second age formula until 12 months and finally to growing-up milk from 12 to 15 months
Active Comparator: Breastfed (BF) group; Breast milk	Other: Breast feeding (BF); Exclusive breast feeding up to 4 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Weight gain measured as mean daily weight gain in g/day	From baseline (≤14 days) to 4 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bifidobacteria abundance	Bifidobacteria abundance	At 90 days (3 months of age)
Fecal microbiome	Overall fecal microbiota composition, diversity, different bacteria taxa and microbiota community types assessed using next generation sequencing (NGS) technology	Stool sample collected at ≤14 days (baseline), 3, 6, 12 and 15 months of age
Fecal metabolic profile: fecal pH	Fecal pH	Stool sample collected at ≤14 days (baseline), 3, 6, 12 and 15 months of age
Fecal metabolic profile: fecal organic acids	Fecal organic acids (such as, but not restricted to lactate, including indole-lactate, L- and D-lactate, propionate, butyrate, acetate, valerate, and total fecal organic acids)	Stool sample collected at ≤14 days (baseline), 3, 6, 12 and 15 months of age
Fecal markers of immune health and gut barrier	Fecal markers of immune health and gut barrier such as total secretory IgA (sIgA), lipocalin-2, calprotectin, and α-1-antitrypsin assessed by ELISA.	Stool sample collected at ≤14 days (baseline), 3, 6, 12 and 15 months of age
Fecal cytokine profile	Fecal cytokine profile (such as but not restricted to: IL-6, IL-8, IL-1b, IL-22, IFN-γ) using multiplex assays	Stool sample collected at ≤14 days (baseline), 3, 6, 12 and 15 months of age
Blood markers of immune health	Vaccine specific antibodies assessed by ELISA and Immuno-phenotyping in a subset of 120 infants (60/group)	At 4 months of age
GI-related behavior: stool frequency	Stool frequency recorded via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behavior: stool consistency	Stool consistency recorded via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behavior: incidence of spitting	Incidence of spitting recorded via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behavior: incidence of flatulence	Incidence of flatulence via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behavior: crying time	Crying time via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behavior: sleep time	Sleep time via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
GI-related behaviour: volume of formula consumed	Volume of formula consumed at each feeding or the number of breast milk feedings recorded via the GI Symptom and Behavior Diary	Retrospective 1-day (at baseline) and prospective for 3 days prior to 1, 2, 3, 4, 6, 9, 12 and 15 months of age
Infant Gastrointestinal Symptom Index	GI symptoms via the Infant Gastrointestinal Symptom Questionnaire (IGSQ-13)	At baseline, 1, 2, 3, 4, 6, 9, 12 and 15 months of infant age
Bone index	Bone index measurement will be conducted using a non-invasive and radiation-free ultra-sound sonometer in a subset of 80 children (40/group)	At baseline, 3, 6, 9, 12 and 15 months of infant age
Additional growth parameters: weight	Weight in grams and corresponding weight-for-age Z-score according WHO growth standards	At infant age ≤14 days (baseline), 1, 2, 3, 4, 6, 9, 12 and 15 months of age
Additional growth parameters: length	Length in centimeters and corresponding length-for-age Z-score according WHO growth standards	At infant age ≤14 days (baseline), 1, 2, 3, 4, 6, 9, 12 and 15 months of age
Additional growth parameters:head circumference	Head circumference in centimeters and corresponding head circumference-for-age Z-score according WHO growth standards	At infant age ≤14 days (baseline), 1, 2, 3, 4, 6, 9, 12 and 15 months of age
Additional growth parameters: Body Mass Index	BMI (kg/m2) and corresponding BMI-for-age Z-score according WHO growth standards	At infant age ≤14 days (baseline), 1, 2, 3, 4, 6, 9, 12 and 15 months of age
Dietary pattern	Data collected using a food frequency questionnaire including key food groups for infants and young children	At infant age 6, 9, 12 and 15 months
Absenteeism (infant and parent)	Time away from daycare (infant) or work (parent) will be recorded during occurrences of illness / infection using a calendar-based electronic Infant Illness Diary (IID)	Data collected continuously from enrollment until 15 months of age

Collaborators and Investigators

• Sponsor: Société des Produits Nestlé (SPN)

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2021
• Primary Completion (Actual): July 31, 2023
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: July 5, 2021
• First Submitted That Met QC Criteria: July 5, 2021
• First Posted (Actual): July 15, 2021

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 20.12.INF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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