Feeding Tolerance and Gut Maturation of Infants Consuming a Formula Rich in Glycoprotein

Study Overview
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Brief Summary
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This is a non-randomized, single-arm, open-label, prospective interventional study using a commercially available starter infant formula in healthy term formula-fed infants with a parallel group of healthy term breast-fed infants as reference group. Approximately 120 male and female infants (60 per group) who are 3-28 days old and are exclusively or predominately formula-feeding or breastfeeding will be enrolled.

Detailed Description
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Breastmilk contains an abundance of structurally diverse compounds having important physiologic roles. These include glycoproteins which are biologically active and involved in infant gut, immune and brain development (Jiang and Lönnerdal 2016). The overall purpose of this study is to study the effectiveness of a term infant formula rich in glycoprotein (formula-fed group) on gastrointestinal tolerance, and gastrointestinal health in healthy term infants compared to a breast-fed reference group. We hypothesize that there will be comparable gastrointestinal tolerance in formula-fed and breast-fed and that fecal bifidobacteria changes in early infancy in the formula-fed group are similar to that of breast-fed infants.

Official Title
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Feeding Tolerance and Gut Maturation of Infants Consuming a Formula Rich in Glycoprotein: A Single-arm, Open-label, Prospective Interventional Study Including a Breastfed Reference Group

Conditions
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Digestion, Gut Microbiota

Intervention / Treatment
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* Dietary Supplement: Commercially Available Starter Infant Formula


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of personally signed and dated informed consent document indicating that the infant's parent(s)/ legally accepted representatives LAR have been informed of all pertinent aspects of the study. Infants whose parent(s)/LAR have reached the legal age of majority in the countries where the study is conducted. Infants whose parent(s)/LAR are willing and able to comply with scheduled visits, and the requirements of the study protocol. Infants whose parent(s)/LAR can be contacted directly by telephone throughout the study. Infants whose parent(s)/LAR have a working freezer. Infants must meet all the following inclusion criteria to be eligible for enrolment into the study: Healthy term infant (37-42 weeks of gestation). At enrolment visit, post-natal age 3-28 days (date of birth = day 0) Birth weight ≥ 2500g and ≤ 4500g. Formula-fed infants only: Infants must predominantly consume and tolerate a standard cow's milk infant formula prior to enrolment and their parent(s)/LAR must have independently elected, before enrolment, not to exclusively breastfeed. Predominantly formula feeding means that the infant's predominant source of nourishment has been formula. Specifically, infants are fed with formula for at least 75% of total milk feeds per day. Breastfed infants only: Infants must have been predominantly breastfed since birth, and their parent(s)/LAR must have made the decision to continue predominant breastfeeding for the duration of the study. Predominant breastfeeding allows infants to be mix fed with breastmilk and other milks. It means that the infant's predominant source of nourishment has been breastmilk. Specifically, infants are fed with breast milk for at least 75% of total milk feeds per day. Exclusion Criteria: Infants with conditions requiring infant feedings other than those specified in the protocol. Infants receiving complementary foods or liquids defined as 4 or more teaspoons per day or approximately 20 g per day of complementary foods or liquids at or prior to enrollment. Infants who have a medical condition or history that could increase the risk associated with study participation or interfere with the interpretation of study results, including: Evidence of major congenital malformations (e.g., cleft palate, extremity malformation). Documented systemic or congenital infections (e.g., human immunodeficiency virus, cytomegalovirus, syphilis). Previous or ongoing severe medical or laboratory abnormality (acute or chronic) which, in the judgment of the investigator, would make the infant inappropriate for entry into the study. Infants who are presently receiving or have received prior to enrollment probiotic supplements or any of the following: medication(s) or supplement(s) which are known or suspected to affect the following: fat digestion, absorption, and/or metabolism (e.g., pancreatic enzymes); stool characteristics and microbiota (e.g., oral and systemic antibiotics, glycerin suppositories, bismuth-containing medications, docusate, Maltsupex, or lactulose); growth (e.g. insulin or growth hormone); gastric acid secretion. Currently participating or having participated in another clinical trial since birth. Subjects or subjects' parent(s) or legal representative who are not willing and not able to comply with scheduled visits and the requirements of the study protocol.

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 28 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Formula-Fed (FF) Group<br>Subjects will be fed commercial bovine milk-based, whey-predominant, α-lactalbumin-enriched term formula with high sn-2 palmitate fat blend, supplemented with oligofructose for 6 weeks. | Dietary Supplement: Commercially Available Starter Infant Formula<br>* Study formula is provided in powder form and will be administered orally, ad libitum, via an infant feeding bottle and the volume of formula offered to the infant will be guided by the recommended feeding table for the age group or by physician recommendation. The amount consumed by the infant will vary by each infant's weight and appetite.<br>|
| No Intervention: Breast-Fed (BF) Group<br>Subjects will continue exclusive/ predominant breastfeeding for 6 weeks. Breastmilk may be consumed directly from the breast or breast milk may be expressed and fed through infant feeding bottle. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall gastrointestinal (GI) tolerance | Compare the overall gastrointestinal (GI) tolerance between the formula-fed and the breast-fed infants from enrolment to 6 weeks of intervention. Assessed through the IGSQ-13 (Infant Gastrointestinal Symptoms Questionnaire). The IGSQ-13, consisting of 13 questions, is a retrospective, standardized, validated, questionnaire of GI symptoms and related behaviors that the infant experienced over the past week from a parent's perspective. Overall GI tolerance is assessed from the IGSQ index score, computed from the 13 questions. Possible scores range from 13 - 65, with lower scores representing lower overall GI burden. | Day 39-45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bifidobacteria abundance | Change in Bifidobacteria abundance from baseline to be measured in the stool samples collected. | Day 1, Day 36-44 | 
| Fecal microbiota | Overall fecal microbiota composition and diversity and community type. Diversity will include relative abundance of beneficial and pathogenic bacteria species (such as beneficial bifidobacteria diversity). To be measured in stool samples collected. | Day 1, Day 36-44 | 
| Fecal metabolism | To be measured in stool samples collected. The metabolic profile consist of pH and organic acids (such as but not restricted to acetate, lactate, butyrate, and propionate), analyzed using HPLC. | Day 1, Day 36-44 | 
| GI immunity assessed from fecal markers | To be measured in stool samples collected. Fecal markers include fecal secretory IgA measured by ELISA. Cytokine profile (such as, but not restricted to: IL-1ra, IL1-alpha, IL-1beta, IL-6, IFN-gamma, and TNF-alpha) measured by multiplex assays. OPV-specific IgA measured by ELISA. | Day 1, Day 36-44 | 
| GI maturation assessed from fecal markers | To be measured in stool samples collected. Includes fecal markers of GI health and maturation assessed by ELISA, such as but not restricted to α-1-antitrypsin and lipocalin. | Day 1, Day 36-44 | 
| Stool characteristics: Stool frequency | Stool frequency using the 1-day and 3-day Stooling and Milk Intake Diary. | Day 0, Day 36-44 | 
| Stool characteristics: Difficulty in passing stool | Difficulty in passing stool using the 1-day and 3-day Stooling and Milk Intake Diary. | Day 0, Day 36-44 | 
| Stool characteristics: Stool consistency | Stool consistency using a 5-point scale in the 1-day and 3-day Stooling and Milk Intake Diary. | Day 0, Day 36-44 | 
| GI-related behaviors: Stooling | Baby bowel movements using the individual IGSQ (Infant Gastrointestinal Symptoms Questionnaire) questions. | Day 0, Day 39-45 | 
| GI-related behaviors: Incidence of spitting-up | Incidence of spitting-up using the individual IGSQ (Infant Gastrointestinal Symptoms Questionnaire) questions. | Day 0, Day 39-45 | 
| GI-related behaviors: Crying time | Baby crying time using the individual IGSQ (Infant Gastrointestinal Symptoms Questionnaire) questions. | Day 0, Day 39-45 | 
| GI-related behaviors: Fussiness | Baby fussiness using the individual IGSQ (Infant Gastrointestinal Symptoms Questionnaire) questions. | Day 0, Day 39-45 | 
| GI-related behaviors: Incidence of flatulence | Flatulence using the individual IGSQ (Infant Gastrointestinal Symptoms Questionnaire) questions. | Day 0, Day 39-45 | 
| Milk intake (Breast-Fed infants) | Total number of feedings using the 1-day and 3-day Stooling and Milk Intake Diary. | Day 0, Day 36-44 | 
| Milk intake (Formula-Fed infants) | Total number of feedings and total quantity of milk consumed for every formula-feeding using the 1-day and 3-day Stooling and Milk Intake Diary. | Day 0, Day 36-44 | 
| Infant quality of life | Assessed from the Infant Quality of Life Questionnaire (IQI). The IQI is a short, age-appropriate, and relevant tool that assesses 8 health-related domains in infants up to 1 year. The domains are sleeping, feeding, breathing, stooling, mood, skin, interaction and other health problems. | Day 0, Day 39-45 | 
| Growth: Weight of the infant | Weight in grams and corresponding weight-for-age Z-score according to the WHO growth standards. | Day 0, Day 39-45 | 
| Growth: Length of the infant | Length in centimeters and corresponding length-for-age Z-score according to the WHO growth standards. | Day 0, Day 39-45 | 
| Growth: Weight-for-length of the infant | Corresponding weight-for-length Z-score according to the WHO growth standards. | Day 0, Day 39-45 | 
| Growth: Head circumference of the infant | Head circumference in centimeters and corresponding head-circumference-for-age Z-score according to the WHO growth standards. | Day 0, Day 39-45 | 
| Growth: Body mass index (BMI) of the infant | Weight and height will be combined to report the BMI (kg/m2) and corresponding BMI-for-age Z-score according to the WHO growth standards. | Day 0, Day 39-45 | 
| Safety assessment: Infant illness | As part of the standard adverse events (AEs) reporting for safety assessment. | Day 0 through 14 days after Day 39-45 | 
| Safety assessment: Infection outcomes | As part of the standard adverse events (AEs) reporting for safety assessment. | Day 0 through 14 days after Day 39-45 | 
| Safety assessment: Medication use | As part of the standard adverse events (AEs) reporting for safety assessment. | Day 0 through 14 days after Day 39-45 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gut tolerance, gut microbiota, gut immunity