Growth, Allergy and Neurodevelopment in Infants on Hydrolysed Formula

Study Overview
=================
Brief Summary
-----------------
Breastfeeding is the recommended diet for all infants during the first half of infancy and is associated with numerous health benefits. However, when breastfeeding is not possible, an infant formula is the only nutritive alternative. Formula-fed infants have a different growth pattern compared to breastfed infants. Studies have shown that the higher protein content in infant formula compared to breastmilk results in a more rapid weight gain and an increased risk of overweight and obesity in childhood. For this reason, both quantity and quality of protein in infant formulae have been optimized during the last decade, to better meet the needs of infants and to support growth close to that of breastfed infants. Protein hydrolysis, a common modification of infant formulae, has originally been developed for treatment of cow's milk protein allergy. Certain hydrolysed formulae have been suggested to prevent atopic eczema when given to infants with a family history of allergic disease but as of yet, the allergy preventive effect in infants without increased risk of allergic disease has been little studied. Partially hydrolysed infant formulae have also been suggested to reduce common functional gastrointestinal symptoms in infants. New protein hydrolysates are continually developed for use in infant formulae, with the aim of reducing allergenicity, while ensuring optimal growth and development of infants. It is important to study the effects on growth and health outcomes in infants who are fed formulae based on these newly developed hydrolysates as compared to those fed standard intact protein formulae or breastmilk. The overall aims of the current study are to evaluate the effects of two new hydrolysates on growth, immunological biomarkers, neurodevelopment, protein metabolism and gut microbiota in a randomized, controlled clinical trial of healthy infants. In compliance with European Food Safety Authority (EFSA) regulations for novel infant formulas based on hydrolysed protein, the primary outcome is change in weight standard deviation score (SDS) from baseline until 5 months of age.

Official Title
-----------------
GRANDIOSA - Growth, Allergy and Neurodevelopment in Infants on Hydrolysed Formula

Conditions
-----------------
Infant Formula

Intervention / Treatment
-----------------
* Dietary Supplement: Partially hydrolysed formula


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy infants born at term Birth weight 2500 to 4500 gram Either exclusive breast-feeding (reference group) or exclusive formula-feeding (intervention and control group) Exclusion Criteria: Suspected or verified food allergy Suspected or verified infant colic

Ages Eligible for Study
-----------------
Minimum Age: 4 Weeks
Maximum Age: 8 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised to either standard formula or one of two partially hydrolysed study formulae. Included in the study will also be a group of breast-fed infants acting as reference group.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study formula 1<br>Formula-fed intervention group randomised to one of two study formulae | Dietary Supplement: Partially hydrolysed formula<br>* Partially hydrolysed formula<br>|
| Experimental: Study formula 2<br>Formula-fed intervention group randomised to one of two study formulae | Dietary Supplement: Partially hydrolysed formula<br>* Partially hydrolysed formula<br>|
| No Intervention: Standard formula<br>Formula-fed control group randomised to standard formula | |
| No Intervention: Breast feeding<br>Reference group with exclusively breast-fed infants | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Primary outcome is weight Standard Deviation Score (SDS) at the end of the intervention. | At 5 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length. | Growth pattern during the course of the intervention measured by length in centimeters and SDS. | At enrollment at 2 months of age and monthly during the intervention up to 5 months of age. | 
| Head circumference. | Growth pattern during the course of the intervention measured by head circumference in centimeters and SDS. | At enrollment at 2 months of age and monthly during the intervention up to 5 months of age. | 
| Body composition | Assessing differences in body composition between study groups using fat percentage as measured by PeaPod (Pletysmography). | At 4 months of age | 
| Gastrointestinal tolerance. | Gastrointestinal tolerance using diary for information about stool frequency and consistency (in four grades from diarrhea to hard stools) in combination with questionnaire filled in by the parents based on Rome IV criteria for functional gastrointestinal disorders. | At enrollment at 2 months of age and during the intervention up to 5 months of age. | 
| Gastrointestinal immunology. | Markers of gastrointestinal immune activation using analysis of calprotectin, eosinophilic derived neurotoxin and secretory Immunoglobulin A (IgA) in fecal samples. | At enrollment at 2 months of age and during the intervention up to 5 months of age. | 
| Eczema severity, parent report. | Parents will fill in the Patient-Oriented Eczema Measure (POEM) score monthly during the intervention. | At enrollment at 2 months of age and during the intervention up to 5 months of age. | 
| Eczema severity, clinical assessment. | Excema severity is assessed at every study visit using the Eczema Area and Severity Index (EASI). | At enrollment at 2 months of age and during the intervention up to 5 months of age. | 
| Allergy. | Sensitization to cow's milk protein is assessed by Immunoglobulin E (IgE) in serum using ImmunoCap. | At enrollment at 2 months of age and at the end of the intervention at 5 months of age. | 
| Immunologic activity. | Blood cytokine patterns using Luminex: Interleukin 2 (IL-2) as a marker of general T cell activity. Interferon gamma (IFN-γ) as a marker of Helper T cells type 1 (Th1) activity. Interleukin 4 (IL-4) as a marker of helper T cells type 2 (Th2) activity. Tumor growth factor beta type 1 (TGF-β1) as a marker of T cell regulatory activity. Interleukin 17 A (IL17-A) as a marker of helper T cell type 17 (Th17) activity. C reactive protein (CRP) in plasma as a marker of general inflammatory response. | At enrollment at 2 months of age and at the end of the intervention at 5 months of age. | 
| Metabolic biomarkers in blood. | Insulin-like growth factor-1 (IGF-1). Insulin. C-peptide. Leptin. Leptin-receptor. | At enrollment at 2 months of age and at the end of the intervention at 5 months of age. | 
| Markers of protein metabolism. | Plasma amino acids. Blood urea nitrogen. | At enrollment at 2 months of age and at the end of the intervention at 5 months of age. | 
| Microbiota | Composition and diversity of the gut microbiota analysed in fecal samples. Bacterial DNA will be extracted and the V3-V4 region of the 16S rRNA gene will be amplified. Sequencing of all samples takes place on the Illumina MiSeq platform. Based on the results, we will also use metagenomic or Nanopore sequencing for deeper characterization of microbial composition and functions. | At enrollment at 2 months of age and during the intervention up to 5 months of age. | 
| Neurodevelopment at 6 months of age. | Response in cerebral blood flow to visual and auditory stimuli as measured by functional near-infrared spectroscopy (fNIRS). | At 6 months of age. | 
| Neurodevelopment at 12 months of age. | Bayely scales of infant development (BSID) 3rd edition. Higher score is interpreted as better outcome. | At 12 months of age. | 
| Neurodevelopment at 3 years of age. | Wechsler Preschool and Primary Scale of Intelligence (WIPPSI) 4th edition. Higher score is interpreted as better outcome. | At 3 years of age | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infant nutrition, Food hypersensitivity, Dermatitis, Atopic, Protein hydrolysates, Spectroscopy, Near-Infrared