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

Not Applicable

Completed

• Conditions: Healthy Infants
• Interventions: Other: Control formulas (CF); Other: Breast feeding (BF); Other: Experimental formulas (EF)

• Registration Number: NCT04962594
• Lead Sponsor: Société des Produits Nestlé (SPN)

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-07-05
• Study First Submitted QC: 2021-07-05
• Study First Posted: 2021-07-15
• Study Start: 2021-09-02
• Primary Completion: 2023-07-31
• Study Completion: 2024-04-04
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-12
• Last Update Posted: 2024-06-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 318

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control formulas (CF) group	Control formulas (CF)	Starter infant formula, follow-up infant formula and growing-up milk (partially hydrolyzed bovine whey protein) not supplemented
Breastfed (BF) group	Breast feeding (BF)	Breast milk
Experimental formulas (EF) group	Experimental formulas (EF)	Starter infant formula, follow-up infant formula and growing-up milk (partially hydrolyzed bovine whey protein) supplemented with pre- and probiotic(s)

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (18)

AZ Sint-Jan Brugge-Oostende AV; 🇧🇪 Brugge, Belgium

Universitair Ziekenhuis Brussel; 🇧🇪 Brussel, Belgium

Kinderartsen Huis; 🇧🇪 Hasselt, Belgium

CHU Amiens-Picardie; 🇫🇷 Amiens, France

Hôpital Femme Mère Enfant; 🇫🇷 Bron, France

Hôpital de la Croix Rousse; 🇫🇷 Lyon, France

CHU Charles Nicolle; 🇫🇷 Rouen, France

CHU de Nantes; 🇫🇷 Nantes, France

Klinikum Südstadt Rostock; 🇩🇪 Rostock, Germany

Hôpital Bretonneau, CHRU de Tours; 🇫🇷 Tours, France

Hospital Vithas Castellón; 🇪🇸 Castellón De La Plana, Spain

Reina Sofía University Hospital; 🇪🇸 Córdoba, Spain

Instituto Hispalense de Pediatría, Unidad de Investigación; 🇪🇸 Sevilla, Spain

Hospital Vithas Valencia; 🇪🇸 Valencia, Spain

Quironsalud Valencia Hospital; 🇪🇸 Valencia, Spain

Evangelisches Waldkrankenhaus Spandau; 🇩🇪 Spandau, Germany

CHC-Groupe santé, Clinique MontLégia; 🇧🇪 Liège, Belgium

CHU de Liège - CHR de la Citadelle; 🇧🇪 Liège, Belgium