Trial on feeding for Low birth and premature babies

Phase 4

Recruiting

Conditions: Other low birth weight newborn, (2) ICD-10 Condition: P073||Preterm [premature] newborn [other],

Registration Number: CTRI/2023/12/060768

Lead Sponsor: Bill and Melinda Gates Foundation

Brief Summary: **Background**

Low birth weight: 20 Million per year globally & nearly 15 million are born preterm (<37 weeks). At higher risk of *Morbidity, Mortality,*growth deficits, feeding difficulties & neurodevelopmental delays. It accounts for more than 80% of neonatal deaths. *â€œWorld Health Assembly set out to reduce LBW by 30% by 2025â€.*Crucial for promoting LBW or preterm infantsâ€™ access to Motherâ€™s Own Milk (MOM). LBW or preterm infants experience unique feeding challenges compared to healthy full-term infants, including but not limited to

a. immature gastrointestinal tract resulting in feeding intolerance,

b. inability to coordinate swallow-breath interface which is important for safe feeding,

c. rapid fatigue during feeds before adequate volume is consumed,

d. inability to feed directly at the breast effectively and efficiently

Lactation support during the first two weeks postpartum is crucial to establish an adequate breast milk supply by helping the mother frequently, effectively, and efficiently remove breast milk from her breasts. Mothers and families of LBW or preterm infants in the NICU face unique psychosocial challenges, including psychological distress, guilt, shame, stress, anxiety, depression, and posttraumatic stress disorder which can impact family care of the LBW or preterm infant. KMC is a high-impact intervention, which can serve to help a mother-infant dyad to start and maintain breastfeeding. It has been proven to reduce the risk of neonatal mortality by 40%. Additionally, expressed breast milk should be safely and hygienically handled, labeled, stored, and fed to the infant in clean, dry, food-grade/BPA-free hard plastic container with a secure lid. Currently, a comprehensive specialized lactation support and management curriculum with attention to the provision of KMC and WASH measures (including trainerâ€™s guide, traineeâ€™s guide, and implementation guidance) targeted specifically to LBW or preterm infants and designed for low-resource settings does not exist.

Human milk (MOM or DHM) does not contain sufficient micro and macronutrients for preterm infants to sustain a growth pattern that matches the final weeks of in utero development. Preterm formula contains additional energy proteins, and other macro- and micronutrients that the very low birthweight/ very preterm infant needs. Therefore, fortification of human milk may be necessary to encourage increased growth rates in preterm infants. It is important to note that in-hospital fortification has not been conclusively demonstrated to improve clinical or neurodevelopmental outcomes. Probiotic supplementation, which may aid in digestion and in illness prevention/management, could be beneficial to LBW or preterm infants as they are already at increased risk of morbidity and mortality. The new WHO Recommendations for care of the preterm or low-birth-weight infant include a conditional recommendation that probiotics may be considered for human milk fed very preterm infants (<32 weeks)

This study directly addresses recommendations and call for research outlined by the WHO:

a. Fortification of human milk may be considered for very LBW (<1500g) or very preterm (<32 week) infants who are fed MOM or DHM (conditional recommendation).

b. Probiotics may be considered for human milk fed very preterm (<32 weeks) infants to reduce NEC, sepsis, and mortality (conditional recommendation).

**Study aims, objectives, and hypotheses**

**a. RCT**

**Aim:** To improve feeding and growth outcomes among very low birthweight (LBW; â‰¤1.5kg) or very preterm (<32 weeks gestational age) infants admitted to neonatal intensive care units (NICU) in India, Malawi, and Tanzania through fortification of human milk.

**Objective:** To evaluate (via individually randomized controlled study) the effectiveness of a feasible, advanced feeding and fortification clinical protocol for very LBW or very preterm infants in the NICU consuming human milk (motherâ€™s own milk [MOM] or pasteurized donor human milk [PDHM]) around the time of birth on their clinical outcomes compared to a comparison arm receiving unfortified human milk.

**Hypothesis:** Very LBW or very preterm infants in the NICU who are fed fortified human milk using a standardized protocol will have better growth outcomes by facility discharge and at 3 months of age, less illness by discharge and decreased mortality by discharge and at one month compared to those who receive unfortified human milk

**b. Exploratory Qualitative Research**

**Aim:** To improve feeding and growth outcomes among low birthweight (LBW; <2.5kg) or preterm (<37 weeks gestational age) infants in the neonatal intensive care unit (NICU) in India, Malawi, and Tanzania by exploring stakeholder perspectives regarding the provision of probiotics for very preterm (<32 weeks gestational age) infants in health facilities.

**Objective:** To determine acceptability and feasibility (via qualitative research) of probiotic use for hospitalized very preterm infants among key stakeholders.

**Hypothesis:** Key stakeholders believe that introducing probiotics for very preterm infants in the hospital setting in low- and middle-income countries (LMICs) is acceptable and feasible.

**Study design**

**a. RCT:** This is a multi-site, multi-country RCT. Quantitative data will be collected in order to comprehensively address the study objective. In order to facilitate and inform the conduct of study activities, a facility needs assessment will be conducted in each study facility.

**Intervention:** In-facility fortification of human milk with powdered HMF using a feasible, advanced feeding and fortification clinical protocol + Standardized volume targets and trajectories protocol + Provision of guideline-driven standard of care (facility-based lactation support/feeding counseling + KMC + WASH package and breast pumps)

**Control:** No fortification of human milk + Standardized volume targets and trajectories protocol + Provision of guideline-driven standard of care (facility-based lactation support/feeding counseling + KMC + WASH package and breast pumps)

**b. Exploratory Qualitative Research**

This is a multi-site, multi-country exploratory qualitative research study. The purpose of the qualitative component is to examine the feasibility and acceptability of probiotic use in hospitalized very preterm infants via IDIs with key stakeholders. The research will be conducted in India, Malawi, and Tanzania, but is not affiliated with specific facilities

**Study population**: Facility needs assessment (for India study facilities) - All study facilities (not individual-specific)

**a. RCT:** Very LBW or very preterm infants admitted to the NICU in study facilities who consume human milk, meet eligibility criteria (and their mothers) and were randomized to the intervention / comparison group

**b.****Exploratory Qualitative Research:** Key stakeholders who can provide insight on the feasibility and acceptability of probiotic use in hospitalized very preterm infants. Key stakeholders will include:

i. clinical providers,

ii. hospital leadership,

iii. supply chain experts,

iv. policymakers, Ministry of Health (MoH) officials, etc. with knowledge and expertise in probiotic use for very preterm infants.

**Sample size**

**a. RCT**

Of the total sample, 581 will be randomized to the intervention (fortified human milk) and 581 to the control (unfortified human milk). For the mother-infant dyad surveys, we plan to enroll 50% of participants in the India sites and 50% in the African sites (Malawi and Tanzania combined).

**b.****Exploratory Qualitative Research**

The maximum number of key stakeholders who will be interviewed is up to 60 key stakeholders (until saturation is reached). Each country partner will conduct a similar number of IDIs (up to 20).

**Study procedures**

**a. RCT:** Randomization

The trial has two study arms:

**Intervention:** fortification of human milk;

**Comparison:** no fortification of human milk.

Infants will be randomized individually in a 1:1 fashion to the intervention or comparison arm. Multiple births will be randomized together (i.e., all siblings will be in the same arm) and this will be accounted for in the analysis. Randomization sequences will be generated by study epidemiologists/statisticians using a computer program. Each site will have a set of randomization sequences for their study population to ensure balance of study arms at the site level.

**Blinding and bias reduction:** During the implementation of the study, data collectors and the analysis team will be blinded to study arm assignments to reduce bias in data collection and analysis. For data analysis, groups will be labeled with a letter (A vs B) to conceal allocation assignment.

**b.****Exploratory Qualitative Research**

Translations and local adaptation of the study tools

All data collection materials used in the study (e.g., consent forms, interview guides) which need translation will be translated into the local language according to established practices (Hindi and Kannada)

**IDIs with key stakeholders**

IDIs with key stakeholders (N=up to 60) will be conducted by study staff. The goal of the IDIs is to collect essential information about acceptability and feasibility probiotic use for very preterm infants among key stakeholders. Interviews will be held in a safe, private, and quiet location as determined by the study team.

Locations of interviews will meet the following criteria:

â€¢ Comfortable for participants where they can speak freely without judgment (i.e. a private location inside the personâ€™s home or their place of work).

â€¢ An open - yet private - space of the mutual agreement between the interviewer and participant

**Data analysis plan**

**a. RCT:** The analysis will include a combination of descriptive statistics as well as models to look at predictors and relationships. For each infant in the RCT, we will have data on maternal characteristics, prenatal care utilization, delivery variables, infant traits, and health outcomes. Importantly, we will also have observational and self-reported data on the feeding strategies used

**b. Exploratory Qualitative Research:** A comprehensive, thematic analysis will be conducted by two coders using an in-depth coding approach in Dedoose/NVIVO software to identify key themes related to commensality as well as similarities and differences between the two respondent groups. The two coders will double code at least 10% of the interviews before proceeding to single coding

**Data Safety Monitoring Plan**

**a. RCT:** Ariadne Labs team will regularly assess enrollment, outcomes and adverse events to monitor adherence to the protocol and data collection procedures. The team will review data through REDCap application and send queries to the sites using the REDCap system, whereupon site staff will make the necessary corrections to the database. An independent DSMB will be established and convened to assess participant safety and advise on study continuation.

**b.****Exploratory Qualitative Research:** All data collectors will be trained to make respondents comfortable and not share personal data or introduce any bias. Audio files of interviews will be uploaded to a secure data storage system as soon as possible. After the audio file is uploaded to the secure data storage system, it will be permanently deleted from the audio recorder.

Detailed Description: Not available

Recruitment & Eligibility

Status: Open to Recruitment

Sex: All

Target Recruitment: 1222

Inclusion Criteria

Very LBW (<1.5 kg) or very preterm (<32 weeks) admitted to NICU at study facility <24 hours after birth for in-born infants and up to 48 hours for out-born (timing of admission may be extended to meet sample size goals) 2.
Mother and infant alive during screening 3.
Mother age 18+ years (India and Tanzania) or 16-18 and married (Malawi only) 4.
Lives within catchment areas of the facility (50km) 5.
Infant receiving at least 60 mL/kg/day of human milk For Qualitative Research 1.
Stakeholders with some familiarity with or expertise regarding the use of probiotics for very preterm infants within the study country 2.
Key stakeholder consents for him/herself.

Exclusion Criteria

Lives outside the defined catchment area 2.
Congenital abnormalities or acquired conditions that interfere with feeding or placement of NG/OG tube [cleft lip/palate, Toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes (TORCH), Trisomy 21, Congenital cardiac defect, neural tube defect, gastrointestinal (GI) tract anomalies, hydrocephalus, NEC] 3.
Severe birth asphyxia 4.
Critically ill (i.e. not on enteral feeds) 5.
Unknown date of birth and unknown gestational age For Qualitative Research N/A.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
For RCT	At 3 months of chronological age
Mean (Standard Deviation [SD]) Length-for-age Z score (LAZ) at 3 months	At 3 months of chronological age
For Qualitative Research	At 3 months of chronological age
1. Perceived acceptability & utility of probiotic interventions	At 3 months of chronological age
2. Feasibility of implementation of probiotics	At 3 months of chronological age

Secondary Outcome Measures

Name	Time	Method
For RCT	Mean (SD) weight-for-age Z score (WAZ) at 3 months
For Qualitative Research	Facilitators/benefits & barriers/risk of introducing probiotics

Trial Locations

Locations (4): Ballari Medical College and Research Centre, Ballari
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Bellary, KARNATAKA, India
Bapuji Child Health Institute and Research Center affiliated to JJM College, Davangere
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Davanagere, KARNATAKA, India
Gadag Institute of Medical Sciences, Gadag
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Gadag, KARNATAKA, India
KLES Dr Prabhakar Kore Hospital and Medical Research Centre Belgaum
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Belgaum, KARNATAKA, India
Ballari Medical College and Research Centre, Ballari
🇮🇳Bellary, KARNATAKA, India
Dr Durugappa H
Principal investigator
9740090169
drdurgappaudbal1012@gmail.com