Nutrition Therapy in the Immature Infant (ImNuT)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Immature Infant, Essential Fatty Acid Deficiency

Intervention / Treatment
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* Dietary Supplement: Formulaid
* Dietary Supplement: MCT-oil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 48 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomized-controlled. Parallel group, single center trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Formulaid<br>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<br>* Supplementation with ARA and DHA<br>|
| Active Comparator: MCT-oil<br>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<br>* Supplementation with medium chain fatty acids<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain maturation, Postnatal growth