Nutrition Therapy in the Immature Infant (ImNuT) (ImNuT)

Effects of Nutrition Therapy on Growth, Inflammation and Metabolism in Immature Infants; a Double-blind Randomized, Controlled Trial

The primary objective of this double-blind randomized study is to assess the effects of an early, enhanced supply of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA) on brain maturation, clinical outcomes and quality of growth in immature infants (gestational age <29 weeks) as compared to standard nutrient supply.

Study Overview

• Status: Active, not recruiting
• Conditions: Immature Infant; Essential Fatty Acid Deficiency
• Intervention / Treatment: Dietary supplement: Formulaid; Dietary supplement: MCT-oil

Detailed Description

This is a double-blind randomized study. 172 preterm infants with gestational age < 29 weeks will be enrolled. The intervention group will receive enteral supplementation with essential fatty acids, arachidonic acid (ARA) and docosahexaenoic acid (DHA). The control group will receive standard supplementation with medium-chain triglycerides (MCT-oil). The main hypothesis is that early, enhanced supply of ARA and DHA will improve brain growth and maturation, as compared to standard nutrient supply. Secondary hypotheses are that early, enhanced supply of ARA and DHA will improve quality of growth and cognitive development as well as reduce the frequency of inflammation-related neonatal comorbidities and long-term cardiovascular disease risk. Primary endpoint will be assessed by magnetic resonance imaging (MRI) of the brain at term equivalent age.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway
    • Oslo University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Extremely preterm infants born at Oslo University Hospital (OUH)
• Gestational age (GA) < 29 weeks
• Less than 48 hours of age at inclusion
• Signed informed consent and expected Cooperation of the patients for the treatment and follow up must be obtained and documented according to good clinical practice (GCP) and national/local regulations

Exclusion Criteria:

• Major congenital malformations which will affect growth and development
• Chromosomal abnormalities and other genetic diseases
• Critical illness with short life expectancy as defined by the study physician

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Formulaid; The intervention group will receive enteral supplementation with Formulaid containing ARA and DHA at a ratio of 2:1, from birth until 36 weeks PMA	Dietary supplement: Formulaid; Supplementation with ARA and DHA
Active Comparator: MCT-oil; The control group will receive enteral supplementation with MCT oil containing coconut and/or palm kern oil, from birth until 36 weeks PMA	Dietary supplement: MCT-oil; Supplementation with medium chain fatty acids

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain maturation assessed by magnetic resonance imaging (MRI)	MRI with spectroscopy (MRS) and diffusion tensor imaging (DTI) will be used to examine myelinisation and quantification of anatomical structures as well as neuronal integrity and inflammation	40 weeks postmenstrual age (PMA)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight gain	Weight measurements, including weight nadir.	Weight will be recorded until 36 weeks PMA and at 3, 6, 12 and 24 months and 8 years corrected age.
Growth	Length and head circumference (HC).	Length and HC will be recorded until 36 weeks PMA and at 3, 6, 12 and 24 months and 8 years corrected age.
Body composition	Body composition will be assessed using PEA POD, an air displacement plethysmography system and Dexa Scan.	At 36 weeks PMA, 3 months and 2 years corrected age
Neonatal morbidities associated with inflammation	Bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), white matter injury (WMI) of the brain, and late onset septicemia	From birth til 36 weeks PMA
Cerebral Background Activity evaluated by Electroencephalogram (EEG)	EEG maturational changes will be examined as a function of time and as a function of gestational age	First week of life, 36 weeks PMA and 2 years corrected age (CA)
Neurodevelopment assessed by standardized motor and cognitive tests	Evaluation of psychomotor development by performing Bayley III and a standardized neurological examination	2 years corrected age (CA)
Lung function evaluated by tidal breathing measurements	Tidal breathing measurements include tidal volume, respiratory rate, minute ventilation and fraction of expiratory time to peak tidal expiratory flow to total expiratory time	36 weeks PMA, 3 months and 2 years CA
Cardiovascular Health assessed by echocardiography	Echocardiography will be used to follow the transition from fetal to completed neonatal circulation, to measure superior vena cava flow, and to study mycardial function by the use of conventional two-dimensional echocardiography and tissue Doppler imaging.	First week of life, 2nd week of life, at 36 weeks PMA and 2 years CA
Blood pressure	Measurements of systolic, diastolic and mean pressure	First week of life and at 36 weeks PMA and 2 years CA
Fatty acid (FA) profiles in blood	Repeated dried blood spots (DBS) samples with approximately 10 µL blood will be collected for FA analyses. These analyses are important for assessing efficacy and protocol compliance. We will also collect 10 µL of fullblood for assessment of total lipid profile (Lipidomics).	From birth until 36 weeks PMA
Markers of inflammation	Inflammation panels will be used to assess markers of inflammation in fullblood and sputum	From birth until 36 weeks PMA
Markers of metabolic status	Metabolic pathway analyses (http://omictools.com/metabolic-pathways-category) will be performed to analyse and describe the metabolic conditions of the infants during hospitalization. Metabolites outside the standard clinical chemistry parameters will also be investigated ("untargeted metabolomics). Metabolomics will be performed by the use of dried blood spot samples	From birth until 36 weeks PMA
Markers of nutritional status in blood	The concentrations of electrolytes, minerals, albumin, alkaline phosphatase, vitamin A and D will be assessed regularly during hospitalization	From birth until 36 weeks PMA
Micronutrient content in urine	Spot urine will be obtained regularly to study the changes in electrolyte- and mineral homeostasis during the first week of life as well as during the phase of steady growth	From birth until 36 weeks PMA
Evaluation of nutrient composition of expressed breast milk	Repeated samples of breast milk will be collected for FA analyses, macronutrient content and vitamin A	From birth until 36 weeks PMA
Gut microbiota	Repeated samples of feces will be used to study the early fecal microbiota	From birth until 36 weeks PMA
Inflammatory markers in sputum	We will analyze the Expression of a standardized panel of inflammatory markers in collected laryngeal or tracheal secretion	From birth until 36 weeks PMA

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University of Oslo; Umeå University; University of Geneva, Switzerland
• Investigators: Study Director: Tom Stiris, MD, ass prof, Departement of Neonatal Intensive care, Oslo University Hospital

Publications and helpful links

General Publications

• Hortensius LM, Hellstrom W, Savman K, Heckemann RA, Bjorkman-Burtscher IM, Groenendaal F, Andersson MX, Nilsson AK, Tataranno ML, van Elburg RM, Hellstrom A, Benders MJNL. Serum docosahexaenoic acid levels are associated with brain volumes in extremely preterm born infants. Pediatr Res. 2021 Dec;90(6):1177-1185. doi: 10.1038/s41390-021-01645-w. Epub 2021 Aug 14.
• Wendel K, Pfeiffer HCV, Fugelseth DM, Nestaas E, Domellof M, Skalhegg BS, Elgstoen KBP, Rootwelt H, Pettersen RD, Pripp AH, Stiris T, Moltu SJ; ImNuT Collaboration Group. Effects of nutrition therapy on growth, inflammation and metabolism in immature infants: a study protocol of a double-blind randomized controlled trial (ImNuT). BMC Pediatr. 2021 Jan 7;21(1):19. doi: 10.1186/s12887-020-02425-x.

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2018
• Primary Completion (Actual): May 28, 2021
• Study Completion (Anticipated): May 30, 2029

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: June 12, 2018
• First Posted (Actual): June 13, 2018

Study Record Updates

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

More Information

Terms related to this study

• Keywords: Postnatal growth; Brain maturation
• Other Study ID Numbers: 2016-003700-31

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: Data will be available within 6 months of study completion
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

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