Second Generation Human Milk Oligosaccharides Blend Study

Not Applicable

Completed

• Conditions: Healthy Infants
• Interventions: Other: Breast-feeding; Other: Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides; Other: Standard Starter Infant Formula, Follow-up Formula, and Growing-up Milk

• Registration Number: NCT03722550
• Lead Sponsor: Société des Produits Nestlé (SPN)

Brief Summary

The aim of this trial is to show that infants fed these new formulas, containing a blend of 5 Human Milk Oligosaccharides (HMOs), allow for growth in line with infants fed formulas without HMOs.

There will be different groups in the trial: three formula-fed groups and a breastfed group.

Detailed Description

These 5 HMOs are identical to the ones found naturally in human milk. They are natural prebiotics (or complex sugars) with potential health benefits. Prebiotics are natural compounds that help the establishment of beneficial gut bacteria (such as bifidobacteria), while preventing bad bacteria from doing harm. Supplementing diets with certain prebiotics has been shown to be well tolerated in adults and infants and to provide potential benefits.Therefore, the trial also aims to understand if consuming HMOs supplemented formulas could strengthen immunity and prevent common illnesses (for example, respiratory illnesses) in infants and toddlers. Furthermore, stool frequency and consistency will be monitored, so as to evaluate digestive tolerance to the formula.

Study Timeline

• Study Start: 2018-09-19
• Study First Submitted: 2018-09-27
• Study First Submitted QC: 2018-10-24
• Study First Posted: 2018-10-29
• Primary Completion: 2021-11-05
• Study Completion: 2022-01-19
• Status Verified: 2022-02
• Last Update Submitted: 2022-02-16
• Last Update Posted: 2022-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 789

Inclusion Criteria

1. Evidence of personally signed and dated informed consent document indicating that the infant's parent(s)/Legally Acceptable Representative has been informed of all pertinent aspects of the study.

2. Infants whose parent(s)/Legally Acceptable Representative have reached the legal age of majority in the countries where the study is conducted.

3. Infants whose parent(s)/Legally Acceptable Representative are willing and able to comply with scheduled visits, and the requirements of the study protocol.

4. Infants whose parent(s)/Legally Acceptable Representative are able to be contacted directly by telephone throughout the study.

5. Infants whose parent(s)/Legally Acceptable Representative have a working freezer.

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

   1. Healthy term (37-42 weeks of gestation) infant at birth.
   2. At enrollment visit, post-natal age ≥ 7 days and ≤ 21 days (date of birth = day 0, 0.25 - 0.75 months old).
   3. At enrollment, birth weight ≥ 2500g and ≤ 4500g.
   4. For formula-fed group, infants must be exclusively consuming and tolerating a cow's milk infant formula at time of enrollment and their parent(s)/Legally Acceptable Representative must have independently elected, before enrollment, not to breastfeed.
   5. For breastfed group, infants must have been exclusively consuming breast milk since birth, and their parent(s)/Legally Acceptable Representative must have made the decision to continue exclusively breastfeeding until at least 4 month of age.

Exclusion Criteria

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

2. Infants receiving complementary foods or liquids defined as 4 or more teaspoons per day or approximately 20 g per day of complementary foods or liquids at or prior to enrollment.

3. 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. History of admission to the Neonatal Intensive Care Unit (NICU), with the exception of admission for jaundice phototherapy.
   4. Other 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.

4. 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 characteristics (e.g., glycerin suppositories, bismuth-containing medications, docusate, Maltsupex, or lactulose); growth (e.g. insulin or growth hormone); gastric acid secretion; or any study outcomes.

5. Currently participating or having participated in another clinical trial since birth

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Breastfed Group	Breast-feeding	Non-randomized Breastfed reference group
Test Group 1	Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides	Starter Infant Formula (same as Control Group) supplemented with 1.5g/L of Human Milk Oligosaccharides, Follow-up Formula (same as Control Group) supplemented with 0.5g/L of Human Milk Oligosaccharides, and Growing-up Milk (same as Control Group) supplemented with 0.4g/L of Human Milk Oligosaccharides
Control Group	Standard Starter Infant Formula, Follow-up Formula, and Growing-up Milk	Standard Starter Infant Formula, Standard Follow-up Formula, and Standard Growing-up Milk
Test Group 2	Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides	Starter Infant Formula (same as Control Group) supplemented with 2.5g/L of Human Milk Oligosaccharides, Follow-up Formula (same as Control Group) supplemented with 0.5g/L of Human Milk Oligosaccharides, and Growing-up Milk (same as Control Group) supplemented with 0.4g/L of Human Milk Oligosaccharides

Primary Outcome Measures

Name	Time	Method
To compare recurrent incidences of illness of infants between the groups	From Study Day 1 to 15 months of age	To compare recurrent incidences of illness (specifically lower and upper respiratory tract illnesses including bronchitis/bronchiolitis), of infants randomized to Test Groups (TG1 or TG2) versus Control Group (CG)
To compare the growth of infants between the groups	From Study Day 1 to 4 months of age	To compare the growth (weight gain, g/day) of infants randomized to Test Groups (TG1 or TG2) versus Control Group (CG)

Secondary Outcome Measures

Name	Time	Method
Absenteeism: Time away from daycare (infant) or work (parent)	From enrollment until 15 months of age	Time away from daycare (infant) or work (parent)
Blood Markers of immune health	At 6 months of age	Plasma and peripheral blood mononuclear cells, Extracellular in vivo and ex vivo circulating cytokine levels will be measured in plasma
Gastrointestinal tolerance	Stool sample collected at infant age less than 0.75, 3, 6, 12, and 15 months of age (a subset of 105 infants per formula group; 90 breastfed infants)	Stool patterns (stool frequency and consistency), Gastrointestinal symptoms, Gastrointestinal-related behaviors, and milk intake will be combined to report the gastrointestinal tolerance
Anthropometric measurements: Weight	From enrollment until 15 months of age	Weight measurements in grams to report anthropometric measurements.
Anthropometric measurements: Length	From enrollment until 15 months of age	Length measurements in centimeters to report anthropometric measurements.
Anthropometric measurements: Head circumference	From enrollment until 15 months of age	Head circumference measurements in centimeters to report anthropometric measurements.
Breastmilk collection for Human Milk Oligosaccharides profile analysis (breastfeeding mothers only)	At Study Day 90 +/- 5 days	A small sample of milk (1ml) will be hand pumped, collected in an Eppendorf tube and stored frozen
Anthropometric measurements: World Health Organization (WHO) growth standard calculated z-scores	From enrollment until 15 months of age	WHO growth standard z-scores including weight-for-age, length-for-age, weight-for-length, head-circumference-for-age, BMI-for-age and weight velocity will be calculated and combined to report anthropometric measurements.
Standard adverse events (AEs) reporting for safety assessment	From the time the informed consent form has been signed at enrollment infant age less than 21 days or 0.75 months through the 2 weeks post-study telephone contact at infant age 464 days	Reported adverse events (AEs) and Serious Adverse Events (SAEs) include type, incidence, severity, seriousness and relation to feeding
Vital signs: Body temperature	From enrollment until 15 months of age	Body temperature in Celsius degree will also be measured to report vital signs
Bone index measurement	From enrollment until 15 months of age	Bone index measurement will be conducted using a non-invasive and radiation-free ultra-sound sonometer measuring bone transmission time and speed of sound at the radius and tibia site, including also the measurement of the femur and radius length
Infant illness and infection outcomes	at different stages of feeding 1st age Infant Formula, 2nd age Follow-up Formula, and 3rd age Growing-up Milk when applicable	Specific parent-reported infant illness symptoms and physician confirmed diagnoses of lower respiratory tract infection (LRTI), upper respiratory tract infection (URTI), total respiratory tract infection (TRTI), gastrointestinal infection (GII), ear illness \[including: otitis media (OM), ear infection, ear inflammation, and ear pain\], and fever will be combined to report infant illness and infection outcomes (Episode, incidence, duration, severity, and recurrence)
Fecal microbiome composition, diversity, community type	Stool sample collected at infant age less than 0.75, 3, 6, 12, and 15 months of age (a subset of 105 infants per formula group; 90 breastfed infants)	Fecal microbiota composition, diversity, and microbiota community type will be assessed using cutting-edge next generation sequencing technology and combined to report the Fecal microbiome
Fecal metabolic profile	Stool sample collected at infant age less than 0.75, 3, 6, 12, and 15 months of age (a subset of 105 infants per formula group; 90 breastfed infants)	Measures of fecal metabolism will be combined to report fecal metabolic profile (fecal pH, fecal organic acids, as well as additional targeted/untargeted metabolomics and cell-based functional assays)
Cognitive and behavioral outcomes	At 15 months of age	Assessment at 15 months through the use of the MacArthur-Bates Communicative Development Inventories (MCDI) and the Early Childhood Behavior Questionnaire (ECBQ), two parent-reported questionnaires that evaluate early language/vocabulary and development of communication skills, that will be combined to report the cognitive and behavioral outcomes
Anthropometric measurements: BMI	From enrollment until 15 months of age	BMI measurements in kg/m\^2 to report anthropometric measurements.
Vital signs: Heart rate	From enrollment until 15 months of age	Heart rate in beasts per minute will also be measured to report vital signs
Dietary pattern	From 6 months of age until 15 months of age	Dietary pattern will be evaluated using a Food frequency questionnaire including sixteen key food groups for infants and young children
Medication use (specifically antimicrobials and antipyretics)	From enrollment until 15 months of age	Medication type and duration of intake will be combined to report the medication use
Markers of immune and gut health	Stool sample collected at infant age less than 0.75, 3, 6, 12, and 15 months of age (a subset of 105 infants per formula group; 90 breastfed infants)	Fecal markers of immune and gut health will include secretory immunoglobulin A IgA \[total\], alpha-1 antitrypsin, and calprotectin.
DNA Genotyping of fucosyltransferase 2 and 3 (secretor status)	At Study Day 60 +/- 5 days	Association between secretor status and illnesses/infections via microbiome modulation will be evaluated.
Vital signs: Infant respiration	From enrollment until 15 months of age	Infant respiration in breaths per minute will also be measured to report vital signs

Trial Locations

Locations (34)

Clinical Vitae Sp z o.o. Poradnia Podstawowej Opieki Zdrowotnej; 🇵🇱 Gdańsk, Poland

Grażyna Jasieniak-Pinis ATOPIA Niepubliczny Zakład Opieki Zdrowotnej Poradnie Specjalistyczne; 🇵🇱 Kraków, Poland

Szpital Uniwersytecki nr 2; 🇵🇱 Bydgoszcz, Poland

Diagnostic-consultative center Ritam TR'' OOD; 🇧🇬 Stara Zagora, Bulgaria

Centrum Medyczne Pratia Warszawa; 🇵🇱 Warsaw, Poland

Sveti Ivan Rilski - Chudotvorets; 🇧🇬 Blagoevgrad, Bulgaria

University Hospital Deva Maria, Department for Naonatology; 🇧🇬 Burgas, Bulgaria

Multiprofile Hospital for Active Treatment Sveti Ivan Rilski Kozloduy,Department of Pediatrics; 🇧🇬 Kozloduy, Bulgaria

University Multiorofile Hospital for active treatment Sveti Georgi EAD, Pediatric clinic; 🇧🇬 Plovdiv, Bulgaria

Multiprofile Hospital for Active Treatment City Clinic - Sveti Georgi EOOD,Department of Paediatrics; 🇧🇬 Montana, Bulgaria

Multiprofile Hospital for Active treatment- Ruse AD, Department of Paediatrics; 🇧🇬 Ruse, Bulgaria

Medical Center Excelsior; 🇧🇬 Sofia, Bulgaria

Medical Center-1-Sevlievo EOOD; 🇧🇬 Sevlievo, Bulgaria

1st Pediatric Consultative Clinic; 🇧🇬 Sofia, Bulgaria

Medical Centre - Izgrev EOOD; 🇧🇬 Sofia, Bulgaria

Alitera-Med-Medical Center EOOD; 🇧🇬 Sofia, Bulgaria

SMA Dr Stefan Banov; 🇧🇬 Stara Zagora, Bulgaria

Dr. Kenessey Albert Kórház-Rendelőintézet Csecsemő és Gyermekosztály; 🇭🇺 Balassagyarmat, Hungary

Clinexpert Kft.; 🇭🇺 Budapest, Hungary

Clinexpert Gyöngyös Egészségügyi Szolgáltató Kft.; 🇭🇺 Gyöngyös, Hungary

Futurenest Kft.; 🇭🇺 Miskolc, Hungary

Kanizsai Dorottya Kórház Csecsemő és Gyermekgyógyászati Osztály; 🇭🇺 Nagykanizsa, Hungary

Házi Gyermekorvosi Rendelő / Babadoki Kft.; 🇭🇺 Szeged, Hungary

Poliklinika Ginekolo.-Poloznicza; 🇵🇱 Białystok, Poland

Mentaház Magánorvosi Központ Kft.; 🇭🇺 Székesfehérvár, Hungary

Csolnoky Ferenc Kórház; 🇭🇺 Veszprém, Hungary

Gdańskie Centrum Zdrowia Sp. Z o.o; 🇵🇱 Gdańsk, Poland

Centrum Medyczne Plejady; 🇵🇱 Kraków, Poland

Uniwersytecki Szpital Dziecięcy w Lublinie; 🇵🇱 Lublin, Poland

Centrum Medyczne PROMED; 🇵🇱 Kraków, Poland

Korczowski Bartosz Gabinet Lekarski; 🇵🇱 Rzeszów, Poland

Centrum Medyczne Pratia Ostrolęka; 🇵🇱 Ostrołęka, Poland

ALERGO-MED Specjalistyczna Przychodnia Lekarska Sp. Z o.o; 🇵🇱 Tarnów, Poland

Centrum Innowacyjnych Terapii Sp. z o.o.; 🇵🇱 Piaseczno, Poland