Second Generation Human Milk Oligosaccharides Blend Study

Growth, Safety and Efficacy of a Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides: a Double-blind, Randomized, Controlled Trial

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 789
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Sveti Ivan Rilski - Chudotvorets
  • Burgas, Bulgaria, 8000
    • University Hospital Deva Maria, Department for Naonatology
  • Kozloduy, Bulgaria, 3320
    • Multiprofile Hospital for Active Treatment Sveti Ivan Rilski Kozloduy,Department of Pediatrics
  • Montana, Bulgaria, 3400
    • Multiprofile Hospital for Active Treatment City Clinic - Sveti Georgi EOOD,Department of Paediatrics
  • Plovdiv, Bulgaria, 4002
    • University Multiorofile Hospital for active treatment Sveti Georgi EAD, Pediatric clinic
  • Ruse, Bulgaria, 7000
    • Multiprofile Hospital for Active treatment- Ruse AD, Department of Paediatrics
  • Sevlievo, Bulgaria, 5400
    • Medical Center-1-Sevlievo EOOD
  • Sofia, Bulgaria, 1407
    • Medical Center Excelsior
  • Sofia, Bulgaria, 1404
    • 1st Pediatric Consultative Clinic
  • Sofia, Bulgaria, 1612
    • Medical Centre - Izgrev EOOD
  • Sofia, Bulgaria, 1618
    • Alitera-Med-Medical Center EOOD
  • Stara Zagora, Bulgaria, 6000
    • Diagnostic-consultative center Ritam TR'' OOD
  • Stara Zagora, Bulgaria, 6000
    • SMA Dr Stefan Banov
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Dr. Kenessey Albert Kórház-Rendelőintézet Csecsemő és Gyermekosztály
  • Budapest, Hungary, 1033
    • Clinexpert Kft.
  • Gyöngyös, Hungary, 3200
    • Clinexpert Gyöngyös Egészségügyi Szolgáltató Kft.
  • Miskolc, Hungary, 3527
    • Futurenest Kft.
  • Nagykanizsa, Hungary, 8800
    • Kanizsai Dorottya Kórház Csecsemő és Gyermekgyógyászati Osztály
  • Szeged, Hungary, 6723
    • Házi Gyermekorvosi Rendelő / Babadoki Kft.
  • Székesfehérvár, Hungary, 8000
    • Mentaház Magánorvosi Központ Kft.
  • Veszprém, Hungary, 8200
    • Csolnoky Ferenc Korhaz
• Poland
  • Białystok, Poland, 15-435
    • Poliklinika Ginekolo.-Poloznicza
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2
  • Gdańsk, Poland, 80-180
    • Clinical Vitae Sp z o.o. Poradnia Podstawowej Opieki Zdrowotnej
  • Gdańsk, Poland, 80-542
    • Gdańskie Centrum Zdrowia Sp. Z o.o
  • Kraków, Poland, 31-411
    • Centrum Medyczne Promed
  • Kraków, Poland, 30-363
    • Centrum Medyczne Plejady
  • Kraków, Poland, 31-159
    • Grażyna Jasieniak-Pinis ATOPIA Niepubliczny Zakład Opieki Zdrowotnej Poradnie Specjalistyczne
  • Lublin, Poland, 20-093
    • Uniwersytecki Szpital Dzieciecy w Lublinie
  • Ostrołęka, Poland, 07-410
    • Centrum Medyczne Pratia Ostrolęka
  • Piaseczno, Poland, 05-500
    • Centrum Innowacyjnych Terapii Sp. z o.o.
  • Rzeszów, Poland, 35-302
    • Korczowski Bartosz Gabinet Lekarski
  • Tarnów, Poland, 33-100
    • Alergo-Med Specjalistyczna Przychodnia Lekarska sp. z o.o
  • Warsaw, Poland, 01-868
    • Centrum Medyczne Pratia Warszawa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 3 weeks (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Control Group; Standard Starter Infant Formula, Standard Follow-up Formula, and Standard Growing-up Milk	Other: Standard Starter Infant Formula, Follow-up Formula, and Growing-up Milk; Standard Study formulas are administered orally, ad libitum, from enrollment until 15 months of age
EXPERIMENTAL: Test Group 1; 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	Other: Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides; Study formulas are administered orally, ad libitum, from enrollment until 15 months of age
EXPERIMENTAL: Test Group 2; 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	Other: Starter Infant Formula, Follow-up Formula, and Growing-up Milk Supplemented With a Blend of Five Human Milk Oligosaccharides; Study formulas are administered orally, ad libitum, from enrollment until 15 months of age
ACTIVE_COMPARATOR: Breastfed Group; Non-randomized Breastfed reference group	Other: Breast-feeding; Exclusive Breast-feeding up to 4 months of age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the growth of infants between the groups	To compare the growth (weight gain, g/day) of infants randomized to Test Groups (TG1 or TG2) versus Control Group (CG)	From Study Day 1 to 4 months of age
To compare recurrent incidences of illness of infants between the groups	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)	From Study Day 1 to 15 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant illness and infection outcomes	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)	at different stages of feeding 1st age Infant Formula, 2nd age Follow-up Formula, and 3rd age Growing-up Milk when applicable
Medication use (specifically antimicrobials and antipyretics)	Medication type and duration of intake will be combined to report the medication use	From enrollment until 15 months of age
Absenteeism: Time away from daycare (infant) or work (parent)	Time away from daycare (infant) or work (parent)	From enrollment until 15 months of age
Fecal microbiome composition, diversity, community type	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	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 metabolic profile	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)	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)
Markers of immune and gut health	Fecal markers of immune and gut health will include secretory immunoglobulin A IgA [total], alpha-1 antitrypsin, and calprotectin.	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)
Blood Markers of immune health	Plasma and peripheral blood mononuclear cells, Extracellular in vivo and ex vivo circulating cytokine levels will be measured in plasma	At 6 months of age
Gastrointestinal tolerance	Stool patterns (stool frequency and consistency), Gastrointestinal symptoms, Gastrointestinal-related behaviors, and milk intake will be combined to report the 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)
Cognitive and behavioral outcomes	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	At 15 months of age
DNA Genotyping of fucosyltransferase 2 and 3 (secretor status)	Association between secretor status and illnesses/infections via microbiome modulation will be evaluated.	At Study Day 60 +/- 5 days
Breastmilk collection for Human Milk Oligosaccharides profile analysis (breastfeeding mothers only)	A small sample of milk (1ml) will be hand pumped, collected in an Eppendorf tube and stored frozen	At Study Day 90 +/- 5 days
Anthropometric measurements: Weight	Weight measurements in grams to report anthropometric measurements.	From enrollment until 15 months of age
Anthropometric measurements: Length	Length measurements in centimeters to report anthropometric measurements.	From enrollment until 15 months of age
Anthropometric measurements: Head circumference	Head circumference measurements in centimeters to report anthropometric measurements.	From enrollment until 15 months of age
Anthropometric measurements: BMI	BMI measurements in kg/m^2 to report anthropometric measurements.	From enrollment until 15 months of age
Anthropometric measurements: World Health Organization (WHO) growth standard calculated z-scores	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.	From enrollment until 15 months of age
Vital signs: Infant respiration	Infant respiration in breaths per minute will also be measured to report vital signs	From enrollment until 15 months of age
Vital signs: Heart rate	Heart rate in beasts per minute will also be measured to report vital signs	From enrollment until 15 months of age
Vital signs: Body temperature	Body temperature in Celsius degree will also be measured to report vital signs	From enrollment until 15 months of age
Standard adverse events (AEs) reporting for safety assessment	Reported adverse events (AEs) and Serious Adverse Events (SAEs) include type, incidence, severity, seriousness and relation to feeding	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
Bone index measurement	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	From enrollment until 15 months of age
Dietary pattern	Dietary pattern will be evaluated using a Food frequency questionnaire including sixteen key food groups for infants and young children	From 6 months of age until 15 months of age

Collaborators and Investigators

• Sponsor: Nestlé
• Investigators: Principal Investigator: Aleksander Krasnow, Lek. Med., Gdańskie Centrum Zdrowia Sp. z o.o.; Principal Investigator: Wiesław Olechowski, Dr n.med., Alergo-Med Specjalistyczna Przychodnia Lekarska Sp. Z O.O.; Principal Investigator: Sylwia Korzyńska, MD, Centrum Medyczne Pratia Ostrolęka; Principal Investigator: Anna Płoszczuk, Dr. n.med., Prywatna Praktyka Lekarska Gabinet Pediatryczno-Alergologiczny Anna Płoszczuk; Principal Investigator: Magdalena Sidorowicz, Dr., Centrum Medyczne Pratia Warszawa; Principal Investigator: Grażyna Jasieniak-Pinis, Lek. Med., ATOPIA Niepubliczny Zakład Opieki Zdrowotnej Poradnie Specjalistyczne; Principal Investigator: Bartosz Korczowski, PhD MD Dr, Korczowski Bartosz Gabinet Lekarski; Principal Investigator: Piotr Korbal, Dr., Szpital Uniwersytecki nr 2 Im. Dr Jana Biziela w Bydgoszczy Oddział Kliniczny Noworodków, Wcześniaków z Intensywną Terapią Noworodka wraz z; Principal Investigator: Marta Żołnowska, Lek. Med., Centrum Medyczne Plejady; Principal Investigator: Bogusław Cimoszko, Lek. Med., Clinical Vitae Sp z o.o. Poradnia Podstawowej Opieki Zdrowotnej; Principal Investigator: Wanda Furmaga-Jabłonska, Prof., Uniwersytecki Szpital Dzieciecy w Lublinie; Principal Investigator: Marzena Nowak, Dr., Centrum Medyczne Promed; Principal Investigator: Georgios Marek Vasilopoulos, Dr., Centrum Innowacyjnych Terapii Sp. z o.o.; Principal Investigator: Viktor Bauer, MD, Dr. Kenessey Albert Korhaz-Rendelointezet; Principal Investigator: Robert Simkó, MD, Futurenest Kft.; Principal Investigator: István Laki, MD, Kanizsai Dorottya Korhaz; Principal Investigator: Éva Kovács, MD, Házi Gyermekorvosi Rendelő / Babadoki Kft.; Principal Investigator: Éva Szabó, MD, Csolnoky Ferenc Korhaz; Principal Investigator: István Tokodi, MD, Mentaház Magánorvosi Központ Kft.; Principal Investigator: Zsuzsanna Tengelyi, MD, Clinexpert Kft.; Principal Investigator: Katalin Fister, MD, Clinexpert Gyöngyös Egészségügyi Szolgáltató Kft.; Principal Investigator: Anton Bilev, MD, MC ''Sveti Ivan Rilski - Chudotvorets''; Principal Investigator: Miroslava Bosheva, MD, University Multiorofile Hospital for active treatment Sveti Georgi EAD, Pediatric clinic; Principal Investigator: Toni Grigorov, MD, Multiprofile Hospital for Active Treatment City Clinic - Sveti Georgi EOOD,Department of Paediatrics,; Principal Investigator: Rositsa Karcheva-Beloeva, MD, Medical Center-1-Sevlievo; Principal Investigator: Margarita Koleva, MD, Diagnostic-Consultative center Ritam TR; Principal Investigator: Stelyana Kraeva, MD, Alitera -Med-Medical Center; Principal Investigator: Olga Nikolova, MD, Multiprofile Hospital for Active Treatment Sveti Ivan Rilski Kozloduy,Department of Pediatrics; Principal Investigator: Tatyana Stoeva, MD, Medical Centre - Izgrev; Principal Investigator: Irina Popova, MD, University Hospital 'Deva Maria', Department for Naonatology; Principal Investigator: Svilen Dosev, MD, Multiprofile Hospital for Active treatment Ruse AD, Department of Paediatrics; Principal Investigator: Stefan Banov, MD, SMA Dr Stefan Banov; Principal Investigator: Sirma Dimitrova, MD, Medical Center Excelsior; Principal Investigator: Malgorzata Arciszewska, MD, Poliklinika Ginekolo.-Poloznicza

Publications and helpful links

General Publications

• Bosheva M, Tokodi I, Krasnow A, Pedersen HK, Lukjancenko O, Eklund AC, Grathwohl D, Sprenger N, Berger B, Cercamondi CI; 5 HMO Study Investigator Consortium. Infant Formula With a Specific Blend of Five Human Milk Oligosaccharides Drives the Gut Microbiota Development and Improves Gut Maturation Markers: A Randomized Controlled Trial. Front Nutr. 2022 Jul 6;9:920362. doi: 10.3389/fnut.2022.920362. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 19, 2018
• Primary Completion (ACTUAL): November 5, 2021
• Study Completion (ACTUAL): January 19, 2022

Study Registration Dates

• First Submitted: September 27, 2018
• First Submitted That Met QC Criteria: October 24, 2018
• First Posted (ACTUAL): October 29, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 17, 2022
• Last Update Submitted That Met QC Criteria: February 16, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 1624INF

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