Suitability of an Infant Formula With L-5-Methyltetrahydrofolate for the Particular Nutritional Use in Infants (MEFOLIN)

The study is designed to show equivalence of an infant formula containing L-5- Methyltetrahydrofolate (MTHF) compared to a standard infant formula containing folic acid in respect to weight gain of healthy term infants receiving these infant formulae exclusively during the first 4 months of life. Healthy non breast fed infants will be randomized to receive either a standard infant formula with folic acid or a corresponding formula with MTHF instead of folic acid. Besides weight and length further anthropometric measures will be taken monthly from the age of 4 weeks to the age of 16 weeks and at the age 4 and 16 weeks blood samples will be taken for the determination of folate status and genotyping. As a reference the same measures will be taken in a group of breast fed infants, whose mothers' folate status will be determined as well.

Study Overview

• Status: Completed
• Conditions: Growth and Development
• Intervention / Treatment: Other: infant formula containing folic acid; Other: infant formula containing MTHF

• Study Type: Interventional
• Enrollment (Actual): 360
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Serbia
  • Belgrade, Serbia, 11000
    • KBC Dr Dragiša Mišović-Dedinje
  • Belgrade, Serbia
    • HiPP Clinical Study Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent (by parents, caregiver)
• Healthy male or female infants <28 days of life
• Gestational age at delivery ≥37 and ≤42 weeks
• Birth weight between 2500 - 4500g
• Parents / Caregivers are able to speak Serbian language

Exclusion Criteria:

• Serious acquired or congenital diseases that is expected to interfere with normal feeding or growth
• Feeding of more than 10% of energy (1 bottle/day) from sources other than the formula (or breast milk in the reference group) at inclusion
• Participation in another clinical study
• Mothers with diabetes mellitus (including gestational diabetes)
• Reason to presume that the parents are unable to meet the study plan requirements
• Diseases of the mother which have an effect on the child's gastro-intestinal tract/ability to be fed
• Major abnormalities in hematological parameters
• Major abnormalities in hepatic, renal or metabolic functions
• Use of medication and vitamin supplements except vitamin K or D supplementation or vaccination
• Mother follows a vegan diet

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
Active Comparator: infant formula containing folic acid; Infant formula including folic acid within the range stipulated by European legislation on infant formula	Other: infant formula containing folic acid; Other Names: folic acid
Experimental: infant formula containing MTHF; Infant formula including MTHF instead of folic acid	Other: infant formula containing MTHF; Other Names: L-5-Methyltetrahydrofolate
No Intervention: Breast milk; non randomized reference group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
weight gain (gram/day)	age of 4 weeks until age of 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
body length gain (cm/day)		age of 4 weeks until age of 16 weeks
fronto-occipital head circumference gain (in cm/day)		at age of 4 weeks and at the age of 16 weeks
dietary intake of study formula, non-study formula, additional liquids and solids	dietary intake will be determined as kcal per day and as kcal per kg body weight per day	during the period age 4 weeks to age 16 weeks
feeding related behavior questionnaire		during the period age 4 weeks to age 16 weeks
stool characteristics (color and consistency)	stool characteristics are assessed by the Bristol scale criteria	during the period age 4 weeks to age 16 weeks

Other Outcome Measures

Outcome Measure	Time Frame
plasma levels of 5-MTHF in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of folic acid in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of 5-Formyl-tetrahydrofolate (fTHF) in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of 4-Alfa-hydroxy-5-methyl-THF (hmTHF) in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of Para-aminobenzoylglutamate (pABG) in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of Acetamidobenzoylglutamate (apABG) in infants	at age of 4 weeks and at the age of 16 weeks
red cell total folate in infants	at age of 4 weeks and at the age of 16 weeks
plasma levels of 5-MTHF in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of 5-MTHF in breast feeding mothers	at the infantile age of 8 weeks
plasma levels of folic acid in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of folic acid in breast feeding mothers	at the infantile age of 8 weeks
plasma levels of fTHF in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of fTHF in breast feeding mothers	at the infantile age of 8 weeks
plasma levels of hmTHF in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of hmTHF in breast feeding mothers	at the infantile age of 8 weeks
plasma levels of pABG in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of pABG in breast feeding mothers	at the infantile age of 8 weeks
plasma levels of apABG in breast feeding mothers	at the infantile age of 8 weeks
breast milk levels of apABG in breast feeding mothers	at the infantile age of 8 weeks
hemoglobin value of the breast feeding mothers	at the infantile age of 8 weeks
hematocrit value of the breast feeding mothers	at the infantile age of 8 weeks
mean corpuscular volume (MCV) of the breast feeding mothers	at the infantile age of 8 weeks
weight of infants	at infantile age 1 year
length of infants	at infantile age 1 year
head circumference of infants	at infantile age 1 year
hemoglobin value of infants	between Day 1 and Day 27 of life, at infantile age of 16 weeks and of 12 months
hematocrit value of infants	between Day 1 and Day 27 of life, at infantile age of 16 weeks and of 12 months
mean corpuscular volume (MCV) of infants	between Day 1 and Day 27 of life, at infantile age of 16 weeks and of 12 months
infantile genotype of methylenetetrahydrofolate-reductase	at infantile age 4 weeks
intake of folic acid in breast feeding mothers	at the infantile age of 8 weeks
intake of MTHF in breast feeding mothers	at the infantile age of 8 weeks

Collaborators and Investigators

• Sponsor: DSM Nutritional Products, Inc.
• Collaborators: Charite University, Berlin, Germany; Ludwig-Maximilians - University of Munich; HiPP GmbH & Co. Vertrieb KG; University Clinic Dr Dragisa Misovic-Dedinje; Institute for Laboratory Diagnostics Konzilijum; Bevital AS; Sermon CRO
• Investigators: Principal Investigator: Berthold Koletzko, Prof., Ludwig-Maximilians - University of Munich

Publications and helpful links

General Publications

• Troesch B, Demmelmair J, Gimpfl M, Hecht C, Lakovic G, Roehle R, Sipka L, Trisic B, Vusurovic M, Schoop R, Zdjelar S, Koletzko B; MEFOLIN Study Group. Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial. PLoS One. 2019 Aug 19;14(8):e0216790. doi: 10.1371/journal.pone.0216790. eCollection 2019.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: March 30, 2015
• First Submitted That Met QC Criteria: May 5, 2015
• First Posted (Estimate): May 8, 2015

Study Record Updates

• Last Update Posted (Actual): August 10, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Hematinics; Folic Acid; Vitamin B Complex
• Other Study ID Numbers: 2014-05-06-MTHF