Growth, Allergy and Neurodevelopment in Infants on Hydrolysed Formula (GRANDIOSA)

• ClinicalTrials.gov Identifier: NCT05578716
• Recruitment Status: Recruiting
• First Posted: October 13, 2022
• Last Update Posted: October 13, 2022
• Sponsor: Umeå University
• Collaborators: Lund University; Arla Foods
• Information provided by (Responsible Party): Magnus Domellöf, Umeå University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Infant Formula	Dietary Supplement: Partially hydrolysed formula	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 312 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Each formula in the study will have the same packaging besides from colour coding (green, blue, yellow). None of the study personnel are aware of which colour represents which formulae during the course of the intervention.
• Primary Purpose: Prevention
• Official Title: GRANDIOSA - Growth, Allergy and Neurodevelopment in Infants on Hydrolysed Formula
• Actual Study Start Date: October 3, 2022
• Estimated Primary Completion Date: June 2026
• Estimated Study Completion Date: June 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Study formula 1; Formula-fed intervention group randomised to one of two study formulae	Dietary Supplement: Partially hydrolysed formula; Partially hydrolysed formula
Experimental: Study formula 2; Formula-fed intervention group randomised to one of two study formulae	Dietary Supplement: Partially hydrolysed formula; Partially hydrolysed formula
No Intervention: Standard formula; Formula-fed control group randomised to standard formula
No Intervention: Breast feeding; Reference group with exclusively breast-fed infants

Outcome Measures

Primary Outcome Measures :

1. Weight [ Time Frame: At 5 months of age ]
   Primary outcome is weight Standard Deviation Score (SDS) at the end of the intervention.

Secondary Outcome Measures :

1. Length. [ Time Frame: At enrollment at 2 months of age and monthly during the intervention up to 5 months of age. ]
   Growth pattern during the course of the intervention measured by length in centimeters and SDS.
2. Head circumference. [ Time Frame: At enrollment at 2 months of age and monthly during the intervention up to 5 months of age. ]
   Growth pattern during the course of the intervention measured by head circumference in centimeters and SDS.
3. Body composition [ Time Frame: At 4 months of age ]
   Assessing differences in body composition between study groups using fat percentage as measured by PeaPod (Pletysmography).
4. Gastrointestinal tolerance. [ Time Frame: At enrollment at 2 months of age and during the intervention up to 5 months of age. ]
   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.
5. Gastrointestinal immunology. [ Time Frame: At enrollment at 2 months of age and during the intervention up to 5 months of age. ]
   Markers of gastrointestinal immune activation using analysis of calprotectin, eosinophilic derived neurotoxin and secretory Immunoglobulin A (IgA) in fecal samples.
6. Eczema severity, parent report. [ Time Frame: At enrollment at 2 months of age and during the intervention up to 5 months of age. ]
   Parents will fill in the Patient-Oriented Eczema Measure (POEM) score monthly during the intervention.
7. Eczema severity, clinical assessment. [ Time Frame: At enrollment at 2 months of age and during the intervention up to 5 months of age. ]
   Excema severity is assessed at every study visit using the Eczema Area and Severity Index (EASI).
8. Allergy. [ Time Frame: At enrollment at 2 months of age and at the end of the intervention at 5 months of age. ]
   Sensitization to cow's milk protein is assessed by Immunoglobulin E (IgE) in serum using ImmunoCap.
9. Immunologic activity. [ Time Frame: At enrollment at 2 months of age and at the end of the intervention at 5 months of age. ]
   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.
10. Metabolic biomarkers in blood. [ Time Frame: At enrollment at 2 months of age and at the end of the intervention at 5 months of age. ]
    Insulin-like growth factor-1 (IGF-1). Insulin. C-peptide. Leptin. Leptin-receptor.
11. Markers of protein metabolism. [ Time Frame: At enrollment at 2 months of age and at the end of the intervention at 5 months of age. ]
    Plasma amino acids. Blood urea nitrogen.
12. Microbiota [ Time Frame: At enrollment at 2 months of age and during the intervention up to 5 months of age. ]
    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.
13. Neurodevelopment at 6 months of age. [ Time Frame: At 6 months of age. ]
    Response in cerebral blood flow to visual and auditory stimuli as measured by functional near-infrared spectroscopy (fNIRS).
14. Neurodevelopment at 12 months of age. [ Time Frame: At 12 months of age. ]
    Bayely scales of infant development (BSID) 3rd edition. Higher score is interpreted as better outcome.
15. Neurodevelopment at 3 years of age. [ Time Frame: At 3 years of age ]
    Wechsler Preschool and Primary Scale of Intelligence (WIPPSI) 4th edition. Higher score is interpreted as better outcome.

Eligibility Criteria

• Ages Eligible for Study: 4 Weeks to 8 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Contacts

Contact: Magnus Domellöf, MD, PhD; +46907852128; magnus.domellof@umu.se

Locations

Sweden

Department of clinical science, Preventive Paediatrics, Lund university; Recruiting

Malmö, Sweden, 20502

Contact: Pia Karlsland-Akeson, MD, PhD pia.karlsland_akeson@med.lu.se

Principal Investigator: Pia Karlsland-Akeson, MD, PhD

Department of Clinical Sciences, Pediatrics, Umeå University Hospital; Recruiting

Umeå, Sweden, 901 85

Contact: Magnus Domellöf, MD, PhD 0046 90 7852128 magnus.domellof@umu.se

Principal Investigator: Magnus Domellöf, MD, PhD

Sponsors and Collaborators

Umeå University

Lund University

Arla Foods

Investigators

• Principal Investigator: Magnus Domellöf, MD, PhD; Department of Clinical Sciences, Pediatrics, Umeå University Hospital

More Information

• Responsible Party: Magnus Domellöf, Professor, Umeå University
• ClinicalTrials.gov Identifier: NCT05578716
• Other Study ID Numbers: 20210707401
• First Posted: October 13, 2022
• Last Update Posted: October 13, 2022
• Last Verified: October 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Magnus Domellöf, Umeå University:

Infant nutrition; Food hypersensitivity; Dermatitis, Atopic; Protein hydrolysates; Spectroscopy, Near-Infrared

Additional relevant MeSH terms:

Hypersensitivity; Immune System Diseases