Renoir: A Randomised, Double-blind, Controlled Trial to Evaluate the Effects of a New Human Milk Fortifier on Growth and Tolerance in Preterm Infants. (Renoir)

Preterm birth (birth before start of the 37th week of gestation) is a major determinant of neonatal morbidity and mortality and has long-term adverse consequences for health and neurodevelopment.

Preterm infants have much higher nutrient requirements than term infants. The preferred nutrition for all infants including preterm infants is human milk from the infant's own mother, or alternatively donor human milk, provided it is fortified with several nutrients as human milk alone does not sufficiently meet the nutritional needs of preterm infants.

Human milk fortifiers (HMFs) are multicomponent enrichments that can be added to human milk (own mother´s milk or donor milk) to meet the increased nutritional needs of preterm infants. The current Nutricia HMF (control product) has been available in its current composition since 2010. It is a multicomponent HMF providing protein, energy, minerals, and vitamins in accordance with the ESPGHAN recommendations.

Recent investigation suggests positive effects on growth and development of preterm infants when lipids are added to their nutrition. Therefore, Nutricia has added lipids to their HMF (test product) for a nutritionally more complete fortification of human milk aiming for optimal growth and optimal cognitive and brain development.

The Renoir study will investigate the difference between both HMFs with regards to the growth velocity as well as the safety and tolerance of the new HMF.

Study Overview

• Status: Active, not recruiting
• Conditions: Growth; Tolerance; Safety; Subjects in Need of a Human Milk Fortifier (HMF)
• Intervention / Treatment: Other: Test product; Other: Control product

• Study Type: Interventional
• Enrollment (Anticipated): 182
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hopital de La Croix Rousse
  • Nancy, France
    • CHRU Nancy - Maternité regionale Universitaire A. Pinard
• Germany
  • Magdeburg, Germany
    • Universitätskinderklinik der Otto-v.-Guericke Universität
  • Nürnberg, Germany
    • Klinikum Nürnberg Süd
• Netherlands
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Almelo, Netherlands
    • Ziekenhuisgroep Twente
  • Almere, Netherlands
    • Flevoziekenhuis
  • Amsterdam, Netherlands
    • Amsterdam UMC (VUMC)
  • Amsterdam, Netherlands
    • OLVG Onze Lieve Vrouwe Gasthuis
  • Hoofddorp, Netherlands
    • Spaarne Ziekenhuis
  • Maastricht, Netherlands
    • Maastricht UMC
  • Venlo, Netherlands
    • VieCuri Medisch Centrum
  • Zwolle, Netherlands
    • Isala Ziekenhuis
• United Kingdom
  • Chertsey, United Kingdom
    • Saint-Peter's Hospital NHS Foundation Trust
  • Norwich, United Kingdom
    • Norfolk and Norwich NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Preterm infants fed own mother's milk (or donor human milk) in need of a HMF (as decided by the investigator)
2. Gestational age <32 weeks and birth weight <1500 g
3. Receiving enteral feeding
4. Expected to need a HMF for minimally 21 days
5. Written informed consent from custodial parent(s)

Exclusion Criteria:

1. Any relevant proven or suspected chromosomal anomaly, metabolic disorder, genetic syndrome or congenital central nervous system malformation;
2. Presence or history of any gastrointestinal malformation, including Necrotising enterocolitis (NEC) (defined as Bell's stage two or higher);
3. No realistic prospect of survival at the discretion of the attending physician;
4. Participation in any other studies involving investigational or marketed products concomitantly or within two weeks prior to entry into the study;
5. Expected or foreseen inability of the subject and/or their families to adhere to protocol instructions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test product; Human Milk Fortifier (HMF) with added lipids.	Other: Test product; HMF with added lipids - Intervention group
Active Comparator: Control product; Commercially available HMF (without lipids).	Other: Control product; Commercially available HMF (without lipids) - control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight growth velocity	Weight growth velocity (in g/kg/day) from baseline to study day 21	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length	Length gain (cm/week)	up to 16 weeks, depending on gestational age at birth
Head circumference	Head circumference gain (cm/week)	up to 16 weeks, depending on gestational age at birth
Weight for Length	Weight for Length	up to 16 weeks, depending on gestational age at birth
Z-scores	Z-scores (no unit) of anthropometric measures (weight for age, length for age, head circumference for age)	up to 16 weeks, depending on gestational age at birth
Stool consistency	Stool consistency (4-point scale Amsterdam stool scale: watery, soft, formed, hard)	up to 16 weeks, depending on gestational age at birth
Stool frequency	Stool frequency (number of stools per day)	up to 16 weeks, depending on gestational age at birth
Enteral intake	Total enteral intake (mL/kg/day)	up to 16 weeks, depending on gestational age at birth
vomiting	Incidence of vomiting (number/day)	up to 16 weeks, depending on gestational age at birth
Regurgitation	Incidence of regurgitation (number/day)	up to 16 weeks, depending on gestational age at birth
Enteral feed	Number of days that an infant is not fed enterally	up to 16 weeks, depending on gestational age at birth.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory - Age	Age at discharge from the neonatal intensive care unit (NICU, level III)	2-16 weeks, depending on gestational age at birth
Exploratory - Age	Age at discharge home	4-16 weeks depending on gestational age at birth
Exploratory - Mortality	Mortality (yes/no) during stay in NICU/hospital	up to 16 weeks depending on gestational age at birth
Exploratory - Enteral feeding volume	Time in days to achieve an enteral feeding volume of at least 150 mL/kg/day +/- 10 mL for 3 consecutive days	around 1-4 weeks, depending on gestational age at birth
Exploratory - Gastric residuals	Frequency of clinically significant gastric residuals, defined as gastric residuals leading to a change in feeding according to the investigator's assessment (if assessed per local standard practice)	up to 16 weeks, depending on gestational age at birth
Exploratory - Diarrhoea	Occurrence of diarrhoea	up to 16 weeks, depending on gestational age at birth)
Exploratory - Constipation	Occurrence of constipation	up to 16 weeks, depending on gestational age at birth)
Exploratory - Weight	Weight (g)	at 6, 12 and 24 months corrected age (CA)
Exploratory - Length	Length (cm)	at 6, 12 and 24 months corrected age (CA)
Exploratory - Head circumference	Head circumference (cm)	at 6, 12 and 24 months corrected age (CA)
Exploratory - Neurodevelopmental outcome	Neurodevelopmental outcome assessed by Bayley Scales of Infant and Toddler Development, Third Edition, on three subscales (cognitive, fine and gross motor)	at 24 months CA
Safety - Incidence (S)AE's	Incidence of (Serious) Adverse Events that are assessed by the Investigator to be possibly, probably or definitely related to the study product	up to 24 months CA
Safety - Frequency (S)AE's	Frequency of (Serious) Adverse Events that are assessed by the Investigator to be possibly, probably or definitely related to the study product	up to 24 months CA
Safety - Severity (S)AE's	Severity of (Serious) Adverse Events (mild/moderate/severe) that are assessed by the Investigator to be possibly, probably or definitely related to the study product	up to 24 months CA
Safety - Relatedness (S)AE's	Relatedness of Serious Adverse Events	up to 24 months CA
Safety - Incidence Blood in stool	Incidence blood in stool	up to 16 weeks, depending on gestational age at birth)
Safety - Frequency Blood in stool	Frequency of blood in stool	up to 16 weeks, depending on gestational age at birth)
Safety - Severity Blood in stool	Severity of blood in stool (mild, moderate, severe)	up to 16 weeks, depending on gestational age at birth)
Safety - NEC	NEC (defined as Bell's stage two or higher) (as part of the assessment of neonatal morbidity)	up to 16 weeks, depending on gestational age at birth)
Safety - Bronchopulmonary dysplasia	Bronchopulmonary dysplasia (as part of the assessment of neonatal morbidity), categorized into mild/moderate/severe based on Sahni et al	up to 16 weeks, depending on gestational age at birth)
Safety - Serious neonatal infections	Serious neonatal infections (as part of the assessment of neonatal morbidity), i.e. confirmed sepsis, pneumonia, or meningitis	up to 16 weeks, depending on gestational age at birth
Safety - Retinopathy of Prematurity	Retinopathy of Prematurity, based on International Committee for the Classification of Retinopathy of Prematurity (as part of the assessment of neonatal morbidity)	up to 16 weeks, depending on gestational age at birth
Safety - Metabolic acidosis	Metabolic acidosis (as part of the assessment of neonatal morbidity) leading to correction and/or change in clinical management of the subject (according to the investigator's assessment)	up to 16 weeks, depending on gestational age at birth

Collaborators and Investigators

• Sponsor: Nutricia Research

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2018
• Primary Completion (Actual): June 26, 2020
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: October 16, 2017
• First Submitted That Met QC Criteria: October 16, 2017
• First Posted (Actual): October 20, 2017

Study Record Updates

• Last Update Posted (Actual): December 8, 2021
• Last Update Submitted That Met QC Criteria: December 7, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: EBB16GL06402

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No