Clinical trial NCT03722550: Second Generation Human Milk Oligosaccharides Blend Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy Infants
Lead sponsor: Société des Produits Nestlé (SPN)
Sponsor class: INDUSTRY
First posted: 2018-10-29
Enrollment: 789
Sex: ALL
Minimum age (years): 7
Maximum age (years): 21
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: To compare the growth of infants between the groups
timeFrame: From Study Day 1 to 4 months of age
measure: To compare recurrent incidences of illness of infants between the groups
timeFrame: From Study Day 1 to 15 months of age
Secondary outcomes:
measure: Infant illness and infection outcomes
timeFrame: at different stages of feeding 1st age Infant Formula, 2nd age Follow-up Formula, and 3rd age Growing-up Milk when applicable
measure: Medication use (specifically antimicrobials and antipyretics)
timeFrame: From enrollment until 15 months of age
measure: Absenteeism: Time away from daycare (infant) or work (parent)
timeFrame: From enrollment until 15 months of age
measure: Fecal microbiome composition, diversity, community type
timeFrame: 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)
measure: Fecal metabolic profile
timeFrame: 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)
measure: Markers of immune and gut health
timeFrame: 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)
measure: Blood Markers of immune health
timeFrame: At 6 months of age
measure: Gastrointestinal tolerance
timeFrame: 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)
measure: Cognitive and behavioral outcomes
timeFrame: At 15 months of age
measure: DNA Genotyping of fucosyltransferase 2 and 3 (secretor status)
timeFrame: At Study Day 60 +/- 5 days
measure: Breastmilk collection for Human Milk Oligosaccharides profile analysis (breastfeeding mothers only)
timeFrame: At Study Day 90 +/- 5 days
measure: Anthropometric measurements: Weight
timeFrame: From enrollment until 15 months of age
measure: Anthropometric measurements: Length
timeFrame: From enrollment until 15 months of age
measure: Anthropometric measurements: Head circumference
timeFrame: From enrollment until 15 months of age
measure: Anthropometric measurements: BMI
timeFrame: From enrollment until 15 months of age
measure: Anthropometric measurements: World Health Organization (WHO) growth standard calculated z-scores
timeFrame: From enrollment until 15 months of age
measure: Vital signs: Infant respiration
timeFrame: From enrollment until 15 months of age
measure: Vital signs: Heart rate
timeFrame: From enrollment until 15 months of age
measure: Vital signs: Body temperature
timeFrame: From enrollment until 15 months of age
measure: Standard adverse events (AEs) reporting for safety assessment
timeFrame: 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
measure: Bone index measurement
timeFrame: From enrollment until 15 months of age
measure: Dietary pattern
timeFrame: From 6 months of age until 15 months of age
Other outcomes:
Locations:
city: Blagoevgrad
country: Bulgaria
facility: Sveti Ivan Rilski - Chudotvorets
city: Burgas
country: Bulgaria
facility: University Hospital Deva Maria, Department for Naonatology
city: Kozloduy
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Sveti Ivan Rilski Kozloduy,Department of Pediatrics
city: Montana
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment City Clinic - Sveti Georgi EOOD,Department of Paediatrics
city: Plovdiv
country: Bulgaria
facility: University Multiorofile Hospital for active treatment Sveti Georgi EAD, Pediatric clinic
city: Ruse
country: Bulgaria
facility: Multiprofile Hospital for Active treatment- Ruse AD, Department of Paediatrics
city: Sevlievo
country: Bulgaria
facility: Medical Center-1-Sevlievo EOOD
city: Sofia
country: Bulgaria
facility: 1st Pediatric Consultative Clinic
city: Sofia
country: Bulgaria
facility: Medical Center Excelsior
city: Sofia
country: Bulgaria
facility: Medical Centre - Izgrev EOOD
city: Sofia
country: Bulgaria
facility: Alitera-Med-Medical Center EOOD
city: Stara Zagora
country: Bulgaria
facility: Diagnostic-consultative center Ritam TR'' OOD
city: Stara Zagora
country: Bulgaria
facility: SMA Dr Stefan Banov
city: Balassagyarmat
country: Hungary
facility: Dr. Kenessey Albert Kórház-Rendelőintézet Csecsemő és Gyermekosztály
city: Budapest
country: Hungary
facility: Clinexpert Kft.
city: Gyöngyös
country: Hungary
facility: Clinexpert Gyöngyös Egészségügyi Szolgáltató Kft.
city: Miskolc
country: Hungary
facility: Futurenest Kft.
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Kórház Csecsemő és Gyermekgyógyászati Osztály
city: Szeged
country: Hungary
facility: Házi Gyermekorvosi Rendelő / Babadoki Kft.
city: Székesfehérvár
country: Hungary
facility: Mentaház Magánorvosi Központ Kft.
city: Veszprém
country: Hungary
facility: Csolnoky Ferenc Kórház
city: Białystok
country: Poland
facility: Poliklinika Ginekolo.-Poloznicza
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2
city: Gdańsk
country: Poland
facility: Clinical Vitae Sp z o.o. Poradnia Podstawowej Opieki Zdrowotnej
city: Gdańsk
country: Poland
facility: Gdańskie Centrum Zdrowia Sp. Z o.o
city: Kraków
country: Poland
facility: Centrum Medyczne Plejady
city: Kraków
country: Poland
facility: Grażyna Jasieniak-Pinis ATOPIA Niepubliczny Zakład Opieki Zdrowotnej Poradnie Specjalistyczne
city: Kraków
country: Poland
facility: Centrum Medyczne PROMED
city: Lublin
country: Poland
facility: Uniwersytecki Szpital Dziecięcy w Lublinie
city: Ostrołęka
country: Poland
facility: Centrum Medyczne Pratia Ostrolęka
city: Piaseczno
country: Poland
facility: Centrum Innowacyjnych Terapii Sp. z o.o.
city: Rzeszów
country: Poland
facility: Korczowski Bartosz Gabinet Lekarski
city: Tarnów
country: Poland
facility: ALERGO-MED Specjalistyczna Przychodnia Lekarska Sp. Z o.o
city: Warsaw
country: Poland
facility: Centrum Medyczne Pratia Warszawa
Study officials:
affiliation: Gdańskie Centrum Zdrowia Sp. Z o.o.
name: Aleksander Krasnow, Lek. Med.
role: PRINCIPAL_INVESTIGATOR
affiliation: ALERGO-MED Specjalistyczna Przychodnia Lekarska Sp. Z o.o.
name: Wiesław Olechowski, Dr n.med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centrum Medyczne Pratia Ostrolęka
name: Sylwia Korzyńska, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Prywatna Praktyka Lekarska Gabinet Pediatryczno-Alergologiczny Anna Płoszczuk
name: Anna Płoszczuk, Dr. n.med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centrum Medyczne Pratia Warszawa
name: Magdalena Sidorowicz, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: ATOPIA Niepubliczny Zakład Opieki Zdrowotnej Poradnie Specjalistyczne
name: Grażyna Jasieniak-Pinis, Lek. Med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Korczowski Bartosz Gabinet Lekarski
name: Bartosz Korczowski, PhD MD Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Szpital Uniwersytecki nr 2 Im. Dr Jana Biziela w Bydgoszczy Oddział Kliniczny Noworodków, Wcześniaków z Intensywną Terapią Noworodka wraz z
name: Piotr Korbal, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centrum Medyczne Plejady
name: Marta Żołnowska, Lek. Med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Vitae Sp z o.o. Poradnia Podstawowej Opieki Zdrowotnej
name: Bogusław Cimoszko, Lek. Med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Uniwersytecki Szpital Dziecięcy w Lublinie
name: Wanda Furmaga-Jabłonska, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centrum Medyczne PROMED
name: Marzena Nowak, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centrum Innowacyjnych Terapii Sp. z o.o.
name: Georgios Marek Vasilopoulos, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Dr. Kenessey Albert Kórház-Rendelőintézet
name: Viktor Bauer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Futurenest Kft.
name: Robert Simkó, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kanizsai Dorottya Kórház
name: István Laki, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Házi Gyermekorvosi Rendelő / Babadoki Kft.
name: Éva Kovács, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Csolnoky Ferenc Kórház
name: Éva Szabó, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mentaház Magánorvosi Központ Kft.
name: István Tokodi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinexpert Kft.
name: Zsuzsanna Tengelyi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinexpert Gyöngyös Egészségügyi Szolgáltató Kft.
name: Katalin Fister, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MC ''Sveti Ivan Rilski - Chudotvorets''
name: Anton Bilev, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Multiorofile Hospital for active treatment Sveti Georgi EAD, Pediatric clinic
name: Miroslava Bosheva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Multiprofile Hospital for Active Treatment City Clinic - Sveti Georgi EOOD,Department of Paediatrics,
name: Toni Grigorov, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Center-1-Sevlievo
name: Rositsa Karcheva-Beloeva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Diagnostic-consultative center Ritam TR
name: Margarita Koleva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Alitera -Med-Medical Center
name: Stelyana Kraeva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Multiprofile Hospital for Active Treatment Sveti Ivan Rilski Kozloduy,Department of Pediatrics
name: Olga Nikolova, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Centre - Izgrev
name: Tatyana Stoeva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital 'Deva Maria', Department for Naonatology
name: Irina Popova, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Multiprofile Hospital for Active treatment Ruse AD, Department of Paediatrics
name: Svilen Dosev, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SMA Dr Stefan Banov
name: Stefan Banov, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Center Excelsior
name: Sirma Dimitrova, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Poliklinika Ginekolo.-Poloznicza
name: Malgorzata Arciszewska, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.