Human Milk Oligosaccharide (HMO) Supplementation in Colic Management

Study Overview
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Brief Summary
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Efficacy and tolerability of a composition comprising of HMO in a supplement format on colic management: a double-blind, randomized, placebo-controlled trial

Detailed Description
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This is a double-blinded, randomized, placebo-controlled trial. The purpose of this trial is to investigate the efficacy and tolerability of a composition comprising of HMO in a supplement format in the management of colicky infants aged 2-12 weeks.

Official Title
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Efficacy and Tolerability of a Composition Comprising of HMO in a Supplement Format on Colic Management: a Double-blind, Randomized, Placebo-controlled Trial

Conditions
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Colic

Intervention / Treatment
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* Dietary Supplement: HMO
* Dietary Supplement: Placebo
* Behavioral: Parental reassurance and support


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Infants 2 weeks - 12 weeks of age at enrolment Infants diagnosed with colic according to Rome IV criteria: Diagnostic criteria for research purposes (infant must meet all Rome IV criteria): An infant who is less than 5 months of age (in the current clinical trial, only infants 2 weeks to 8 weeks of age will be enrolled) when the symptoms start and stop Recurrent and prolonged periods of infant crying, fussing, or irritability reported by caregivers that occur without obvious cause and cannot be prevented or resolved by caregivers No evidence of infant failure to thrive, fever, or illness Excessive crying/fussiness for 3 or more hours per day during 3 or more days in the past 7 days as reported by parents to the clinician Total 24-hour crying plus fussing is 3 hours or more when measured by at least one prospectively kept 24-hour behavior diary. (The Structured Infant Crying and Fussing Diary will be dispensed at the screening visit (V0), completed for two 24-hour periods at H0 (days -3 to -1), and returned at V1 to be used as part of the diagnostic criteria for infantile colic.) Term infants (≥ 37 weeks) generally healthy with normal birth weight (≥2.5kg) and singleton born Predominantly formula fed* (formula fed ≥ 80% of the time) for at least 7 days before randomization and the choice of formula feeding has been made by the parents before the beginning of the trial. Infants who have been on the same formula for the past 5 days Signed informed consent obtained for infant's and parents'/Legally Acceptable Representative (LAR) participation in the study Parent/LAR of infant agrees not to enroll infant in another interventional clinical research study while participating in this study Parent of the infant/LAR is willing and able to fulfill the requirements of the study protocol Parent of infant can be contacted throughout the study Predominantly formula feeding defined in the study means that the infant's predominant source of nourishment is formula. Specifically, infants are fed with formula for at least 80% of total milk feeds per day. Exclusion criteria: Presence of any congenital condition and/or previous or current illness/infection and (or) medication use that could interfere with the main study outcomes. Clinical evidence of chronic illness or gastrointestinal disorders, major medical problems (e.g. ill, immunocompromised, major developmental or genetic abnormality). Known cow's milk protein allergy, lactose intolerance, or galactosaemia; including presence of any allergic manifestations. Received any special formula (e.g. lactose-free, hydrolyzed protein) within 5 days before randomization or switched formulas within 5 days before randomization. Received any of the following products/medication within 5 days before randomization: Antibiotics Alginate Prokinetics Proton pump inhibitors Simethicone L. reuteri probiotic Formula containing Human milk Oligosaccharides Other infant(s) <6months of age living in the same household. Current participation in another interventional clinical trial.

Ages Eligible for Study
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Minimum Age: 2 Weeks
Maximum Age: 12 Weeks

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blinded, placebo-controlled, parallel-arm, intervention study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liquid oral supplement comprising HMO<br>2 ampules/day for 21 days | Dietary Supplement: HMO<br>* Composition comprising of HMO<br>Behavioral: Parental reassurance and support<br>* Both groups will receive standardized written materials to provide parental reassurance and support, in alignment with local clinical practice<br>|
| Placebo Comparator: Placebo<br>2 ampules/day for 21 days | Dietary Supplement: Placebo<br>* Placebo supplementation having the same appearance and dosing regimen as the intervention<br>Behavioral: Parental reassurance and support<br>* Both groups will receive standardized written materials to provide parental reassurance and support, in alignment with local clinical practice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in average infant daily crying and fussing duration | Difference in average infant daily crying and fussing duration at the end of the intervention in the Intervention Group (IG) versus the Control Group (CG). The crying and fussing duration is measured using a structured infant crying and fussing diary. | At the end of the intervention period (day 21) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modulation of infant gut microbiota (communities of microbes, their taxonomy, strain composition, diversity, ecology, functionalities, and the metabolites produced) | Modulation of infant gut microbiota in the intervention group versus the control group assessed using metagenomics | V1 (day 0), V2 (day 7), and V4 (day 21) | 
| Difference in average infant daily crying duration | Difference in average infant daily crying duration at the end of the intervention in the IG versus the CG assessed using a structured infant crying and fussing diary. | Change from baseline (V1) to intervention end (V4) | 
| Difference in average infant daily fussing duration | Difference in average infant daily fussing duration at the end of the intervention in the IG versus the CG assessed using a structured infant crying and fussing diary. | Change from baseline (V1) to intervention end (V4) | 
| Difference in average infant daily crying and fussing duration in the IG | Difference in average infant daily crying duration and fussing duration combined from baseline (V1) to intervention end (V4) in the IG assessed using a structured infant crying and fussing diary. | Change from baseline (V1) to intervention end (V4) | 
| Difference in average infant daily crying duration in the Intervention group | Difference in average infant daily crying duration from baseline (V1) to intervention end (V4) in the Intervention group assessed using a structured infant crying and fussing diary. | Change from baseline (V1) to intervention end (V4) | 
| Difference in average infant daily fussing duration in the Intervention group | Difference in average infant daily fussing duration from baseline (V1) to intervention end (V4) in the interventional group assessed using a structured infant crying and fussing diary. | Change from baseline (V1) to intervention end (V4) | 
| Infant daily crying and fussing duration assessed longitudinally | Infant daily crying and fussing duration combined assessed longitudinally across the intervention assessed using a structured infant crying and fussing diary. | Longitudinal changes across specific visits V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Infant crying/fussing per 24 hours | Episodes of infant crying/fussing per 24 hours assessed using a structured infant crying and fussing diary. | At specific visits V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Percentage of children achieving a reduction in daily crying and fussing | Percentage of children achieving a reduction in daily crying, fussing, crying and fussing time combined of ≤ 25 % and ≤ 50 % assessed using a structured infant crying and fussing diary. | At specific visits V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Incidence of infantile colic | Incidence of infantile colic assessed using a structured infant crying and fussing diary. | At specific visits V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Parental perception of colic severity | Parental perception of colic severity assessed using a 10-cm visual analog scale (VAS) | At specific visits V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Overall GI tolerance and individual GI symptoms | Overall infant GI tolerance and individual GI and GI-related symptoms (stooling, spitup/ vomiting, gassiness, crying, fussiness) assessed using IGSQ-13 | V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Overall GI tolerance and individual GI symptoms | Change in IGSQ-13 scores assessed using IGSQ-13 | Baseline to intervention end (day 21) | 
| Overall GI tolerance and individual GI symptoms | Functional GI symptoms (regurgitation, consistency of stools), crying, allergic symptoms (atopic eczema) and respiratory symptoms assessed using CoMiSS | At V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Overall GI tolerance and individual GI symptoms | Change in CoMiSS scores assessed using CoMiSS | From baseline to intervention end (day 21) | 
| Overall GI tolerance and individual GI symptoms | Stool consistency, spitting up/vomiting and flatulence assessed using 1-day retrospective GI diary at V1 (day 0) and prospective 3-Day GI symptom diary diaries at home (H2, H3 and H4) just prior to V2 (day 7), V3 (day 14) and V4 (day 21) | 1-day retrospective GI diary at V1 (day 0) and prospective 3-Day GI symptom diary diaries at home (H2, H3 and H4) just prior to V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Infant sleep | Infant sleep duration and nighttime wakings per 24 hours assessed using Brief infant sleep questionnaire (BISQ) | V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Infant Quality of life | Infant quality of life assessed using an Infant Quality of Life instrument. The tool includes IQI includes questions on 7 health items such as sleeping, crying, feeding , skin, breathing, playfulness and Interaction, and stooling. Each item consists of 4 levels, most of which are ranked by severity. | V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Parental and family quality of life | Parental/family quality of life will be assessed using a Quality of Life Visual Analog Scale that rates the parent / family's quality of life based on a 10-point Likert scale. | V1 (day 0), V2 (day 7), V3 (day 14) and V4 (day 21) | 
| Infant fecal gut microbiota | Microbiome of fecal samples to investigate the communities of microbes, their taxonomy, strain composition, diversity, ecology, functionalities, and the metabolites produced assessed using metagenomics. | V1 (day 0), V2 (day 7), and V4 (day 21) | 
| Fecal metabolism | Fecal metabolism (pH, organic acids) | V1 (day 0), V2 (day 7), and V4 (day 21) | 
| Fecal markers of inflammation calprotectin | Inflammation biomarkers calprotectin assessed using ELISA. | V1 (day 0) and V4 (day 21) | 
| Fecal markers of inflammation lipocalin | Inflammation biomarkers lipocalin assessed using ELISA. | V1 (day 0) and V4 (day 21) | 
| Infant anthropometry weight | Weight in grams | V1 (day 0), V2 (day 7), V3 (day 14) (optional if V3 is a phone call) and V4 (day 21) | 
| Infant anthropometry length | Length in cm | V1 (day 0), V2 (day 7), V3 (day 14) (optional if V3 is a phone call) and V4 (day 21) | 
| Infant anthropometry head circumference | Head circumference in cm | V1 (day 0), V2 (day 7), V3 (day 14) (optional if V3 is a phone call) and V4 (day 21) | 
| Infant anthropometry weight gain | Weight gain in g/d | V1 (day 0), V2 (day 7), V3 (day 14) (optional if V3 is a phone call) and V4 (day 21) | 
| Infant anthropometry length gain | Length gain in cm/d | V1 (day 0), V2 (day 7), V3 (day 14) (optional if V3 is a phone call) and V4 (day 21) | 
| Infant illness and infection and medication usage | Data collected using a calendar-based electronic Infant Illness Diary (IID) | V1 (day 0) until V4 (day 21) |