Growth and Safety of Two Partially-hydrolyzed Feeding Systems for Preterm Infants

Study Overview
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Brief Summary
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This is an open-label trial consisting of two sub-studies to be conducted sequentially with the purpose of evaluating the safety and suitability of a two feeding systems in pre-term infants (one containing HMOs and one without HMOs).

Detailed Description
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This is a multi-center, open-label trial to be conducted in up to 70 pre-term infants in order to evaluate the safety and suitability of two feeding systems as they would typically be used in the neonatal care unit. Growth (in comparison to recommended growth goals), feeding tolerance, biochemical parameters, and adverse event reporting will be evaluated. The two feeding systems will be tested in two sub-studies to be conducted sequentially: sub-study 1 will evaluate a two-staged feeding system with HMOs in up to 35 pre-term infants; sub-study 2 will evaluate a two-staged feeding system without HMOs in up to 35 pre-term infants. A follow up period from 12 to 24 months have been added to the study protocol, to assess the neurocognitive development of the subjects during this period.

Official Title
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Growth and Safety of Two Partially-hydrolyzed Feeding Systems for Preterm Infants: a Multi-centered, Open-label Clinical Trial

Conditions
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Pre-term Infant

Intervention / Treatment
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* Other: Preterm formulas with HMO
* Other: Preterm formulas without HMO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent has been obtained from one or both parent(s) /legally acceptable representative (LAR) in accordance with local regulation. Infants' birth weight ≤1500 g and AGA. Infant's gestational age < 37 weeks. Infant is clinically stable and does not have deteriorating respiratory function after birth. Infant is eligible to start experimental formula after 24 hours of trophic feeding, but still within the first 10 days (≤240 hours) of life. Exclusion Criteria: Parent(s) not willing / not able to comply with the requirements of study protocol. Infant is experiencing early onset sepsis. Major congenital or chromosomal abnormality known to affect growth. Liver failure. Peri-/intra-ventricular haemorrhage (grade 3-4 in Papille classification). Infant who has siblings with diagnosed allergies or intolerances to lactose or cow's milk. Infant's participation in another interventional clinical trial. Infant has already achieved FEF prior to enrolment, using the definition accepted by Neonatal Unit as per standard practice (150 mL/kg/day).

Ages Eligible for Study
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Maximum Age: 10 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Two sequential sub-studies
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sub-study 1<br>Pre-term formulas with HMO | Other: Preterm formulas with HMO<br>* Preterm infants will receive Stage 1 formula as soon as possible after birth until when 1.8 kg of body weight is achieved. Preterm infants will receive Stage 2 preterm formula from when 1.8 kg of body weight is achieved until 2 months after hospital discharge.<br>|
| Experimental: Sub-study 2<br>Pre-term formulas without HMO | Other: Preterm formulas without HMO<br>* Preterm infants will receive Stage 1 formula as soon as possible after birth until when 1.8 kg of body weight is achieved. Preterm infants will receive Stage 2 preterm formula from when 1.8 kg of body weight is achieved until 2 months after hospital discharge.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth | Weight-adjusted weight gain (g/kg/day) | From FEF Day 1 to when infant reaches 1800 g (on average between 4 to 6 weeks after birth) or hospital discharge (on average 7 weeks after birth), whichever comes earlier | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight at other time points | Changes in weight gain (g/day and g/kg/day) | From Pre-FEF Day 1 to FEF Day 1, and then weekly from FEF Day 1 until hospital discharge (on average 7 weeks after birth), at 30- and 60-days PD, and at 12, 18, and 24 months | 
| Other growth parameter (length) | Change in length (cm/week) | From Pre-FEF Day 1 to hospital discharge (on average 7 weeks after birth), at 30- and 60-days PD, and at 12, 18, and 24 months | 
| Other growth parameter (head circumference) | Change in head circumference (cm/week) | From Pre-FEF Day 1 to hospital discharge (on average 7 weeks after birth), at 30- and 60-days PD, and at 12, 18, and 24 months | 
| Anthropometric z-scores for weight, length and head circumference | Corresponding z-scores and changes in z-scores expressed using Fenton growth chart will be analyzed | From Pre-FEF Day 1 to hospital discharge (on average 7 weeks after birth), at 30- and 60-days PD, and at 12, 18, and 24 months | 
| Feeding intake at neonatal unit | Neonatal unit feeding questionnaire capturing timing, type, rate and amount of feeding (parenteral & enteral), gastric residual volumes, number of missed feedings | Baseline + weekly over 3 consecutive days starting on pre-FEF Day1 + weekly over 3 consecutive days starting on FEF Day1 until Neonatal Unit Discharge (on average 7 weeks after birth) | 
| Stool frequency at neonatal unit | Stool frequency (range from 0-20 times a day) collected via neonatal unit questionnaire | Weekly between FEF Day 1 and hospital discharge (on average 7 weeks after birth) | 
| Stool consistency at neonatal unit | Stool consistency (watery, mushy soft, runny, formed, hard) collected via neonatal unit questionnaire | Weekly between FEF Day 1 and hospital discharge (on average 7 weeks after birth) | 
| Bloody stools at neonatal unit | Bloody stools (yes or no) collected via neonatal unit questionnaire | Weekly between FEF Day 1 and hospital discharge (on average 7 weeks after birth) | 
| GI symptoms at neonatal unit | GI symptoms (incidence of abdominal distention, regurgitation, spitting and vomiting) collected via neonatal unit questionnaire | Weekly between FEF Day 1 and hospital discharge (on average 7 weeks after birth) | 
| Feeding intake after discharge | Parent-reported 3-Day Intake Diary capturing the total number of bottles of formula and approximate volumes consumed per day | 3 consecutive days just prior to the 30-day PD and 60-day PD visits | 
| Stool frequency after discharge | Stool frequency captured via parent-reported 3-Day Intake Diary | 3 consecutive days just prior to the 30-day PD and 60-day PD visits | 
| Stool consistency after discharge | Stool frequency captured via parent-reported 3-Day Intake Diary | 3 consecutive days just prior to the 30-day PD and 60-day PD visits | 
| GI symptoms after discharge | GI symptoms (such as presence of stomach ballooning, bloody stools, regurgitation, spitting-up and vomiting) captured via parent-reported 3-Day Intake Diary | 3 consecutive days just prior to the 30-day PD and 60-day PD visits | 
| GI-related behaviors after discharge | GI-related behaviors (such as crying and sleep quality) captured via parent-reported 3-Day Intake Diary | 3 consecutive days just prior to the 30-day PD and 60-day PD visits | 
| Serum biomarkers for protein status | Serum albumin and blood urea nitrogen (BUN) | At Baseline (if possible), pre-FEF Day 1, then weekly pre-FEF Days 7, 14, etc. and FEF Day 1, then weekly on FEF Days 7, 14, 21, until Neonatal Unit Discharge, and at 60 days PD | 
| Serum biomarkers for bone health | Serum P, alkaline phosphatase, calcium and creatinine | At Baseline (if possible), pre-FEF Day 1, then weekly pre-FEF Days 7, 14, etc. and FEF Day 1, then weekly on FEF Days 7, 14, 21, until Neonatal Unit Discharge, and at 60 days PD | 
| Urine biomarkers for bone health | Urinary Ca, P and creatinine | At Baseline (if possible), pre-FEF Day 1, then weekly pre-FEF Days 7, 14, etc. and FEF Day 1, then weekly on FEF Days 7, 14, 21, until Neonatal Unit Discharge, and at 60 days PD | 
| Vitamin D | Vitamin D | FEF Day 1, Neonatal Unit Discharge and at 60 days PD | 
| Fecal microbiota | Fecal microbiota composition, diversity and metabolism markers (SCFAs) | Baseline, FEF Day 1, then weekly on FEF Days 7, 14, 21, until Neonatal Unit Discharge, at 30 day-PD and 60 days PD | 
| Fecal markers for gut health / maturation and immune status | Fecal levels of calprotectin, alpha 1 antitrypsin, pancreatic elastase (i.e. chymotrypsin-like elastase family, member 3B (CELA3B)), Human beta-defensin 2 (HBD2) and secretory IgA | Baseline (if feasible), FEF Day 1, Day 21, Neonatal Unit Discharge, 30 day-PD and 60 day-PD | 
| Urine markers for gut health / maturation and immune status | Urinary level (spot urine sample) of intestinal fatty acid binding protein (iFABP) | Baseline (if feasible), FEF Day 1, Day 21, Neonatal Unit Discharge, 30 day-PD and 60 day-PD | 
| AE reporting | Number of AEs through investigator-confirmed AE reporting | From the time the mother has consented to the infant's participation in the study until the 60 days PD visit | 
| Bayley-III scores | Bayley scales of Infants and Toddler development - 3rd edition | At 12, 18, and 24 months | 
| Developmental Milestone scores | Parent-reported achievements of specific-age appropriate milestones (yes/no reponses to child performing specific milestones or not) | At 12, 18, and 24 months | 
| Child temperament scores | Parent-reported child temperament questionnaire | At 12, 18, and 24 months | 
| Number of healthcare usage | Retrospective paret-reported recall of the number of healthcare usage and hospitalizations | At 12, 18, and 24 months | 
| Feeding patterns | Feeding practice outcomes collected retrospectively at each visit via a parent-reported questionnaire related to breastfeeding duration, prevalence of formula feeding, and age at initiation of complementary feeding | At 12, 18, and 24 months |