Clinical trial NCT05576207: BEP Supplementation Research in Bangladesh (JiVitA-BEP-IR)
Official title: Balanced Energy and Protein (BEP) Supplementation Research in Bangladesh (JiVitA-BEP IR)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Fetal Growth Retardation
Low Birth Weight
Preterm Birth
Gestational Weight Gain
Anemia of Pregnancy
Stunting
Pregnancy Complications
Keywords: Pregnancy
Birth weight
Energy and protein
Micronutrients
Antenatal care
Nutrition
Birth outcomes
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: BRAC James P Grant School of Public Health, BRAC University
First posted: 2022-10-12
Enrollment: 2120
Sex: FEMALE
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary aim of the study is to evaluate the effect of fortified balanced energy and protein (BEP) supplementation vs. control (multiple micronutrient supplement, MMS) without targeting and with targeting (either by low prepregnancy BMI or low prepregnancy BMI and inadequate gestational weight gain) on birth weight and adverse birth outcomes of low birth weight (LBW \< 2500 g) and small-for-gestational age (SGA). To do this we are proposing a cluster-randomized, open labeled effectiveness trial with four arms The main question\[s\] it aims to answer are:

• Does mean birth weight and rate of LBW and SGA differ among mothers randomized to four arms that include targeted or untargeted BEP supplementation vs. MMS differ.

Participants will be recruited in early pregnancy and be enrolled in the trial and randomly receive:

1. A daily BEP supplement from enrollment until birth
2. A daily BEP supplement from enrollment until birth, if they have low pre-pregnancy BMI with the rest receiving a MMS supplement
3. A daily BEP supplement from enrollment until birth, if they have low pre-pregnancy BMI with the rest receiving a MMS supplement or get switched to a BEP supplement based on inadequate gestational weight gain.

Researchers will compare the above groups to women receiving a MMS daily to see if birth weight is higher in the intervention arms. Other adverse outcomes such as low birth weight, small-for-gestational age and preterm birth will also be compared between groups and relative to the control.

Detailed description: The primary aim of the study is to evaluate the effect of a fortified balanced energy and protein (BEP) supplementation vs. control (multiple micronutrient supplement, MMS) without targeting and with targeting (either by low pre-pregnancy BMI or low pre-pregnancy BMI and inadequate gestational weight gain) on birth weight, low birth weight and SGA as the main outcomes. To do this we are proposing a cluster-randomized, open labeled effectiveness trial with four arms . Our main overall aim is:

1. To compare the mean birth weight and rates of LBW and SGA among mother randomized across four arms including targeted and untargeted BEP versus MMS.

   Additionally, to examine the effectiveness of untargeted and targeted BEP supplementation as follows:
2. To compare the mean birth weight, and rates of LBW and SGA among mothers who were randomized to receive BEP supplementation versus control (MMS) during pregnancy. \[arm 2 versus 1\]
3. To compare mean birth weight and rates of LBW and SGA among mothers who were randomized to receive BEP supplementation based on low pre-pregnancy BMI (w/wo inadequate gestational weight gain) versus control (MMS) during pregnancy. \[arms 3+4 versus 1\]
4. To compare mean birth weight and rates of LBW and SGA mothers who were randomized to receive BEP supplementation based on low pre-pregnancy BMI (w/wo inadequate gestational weight gain) versus BEP supplementation during pregnancy regardless of pre-pregnancy BMI. \[arms 3+4 versus 2\]

In addition to the above comparisons, between group differences and 95% confidence intervals will be estimated for both primary and secondary outcomes (shown below), with specific comparisons as described below for the primary outcome of birth weight.

Secondary Aims:

1. To compare the mean birth weight and rates of LBW and SGA among mothers who received BEP supplementation during pregnancy based on low pre-pregnancy BMI versus untargeted BEP supplementation during pregnancy \[arm 3 versus 2\]
2. To compare the mean birth weight and rates of LBW and SGA among mothers who received BEP supplementation during pregnancy versus BEP supplementation during pregnancy based on low pre-pregnancy BMI and gestational weight gain. \[arm 4 versus 2\]
3. To compare the mean birth weight and rates of LBW and SGA among mothers who received BEP supplementation during pregnancy based on pre-pregnancy BMI only versus BEP supplementation during pregnancy based on low pre-pregnancy BMI and gestational weight gain. \[arm 4 versus 3\]
4. To compare the difference in mean birth weights and rates of LBW and SGA among mothers who were randomized to receive BEP without targeting or with targeting relative to the control (MMS). \[arm 2 versus 1 versus arm 3 and 4 versus 1\]

Other objectives of the study include:

1. Assess how low mid upper arm circumference (MUAC) compares relative to low BMI in identifying women for targeting and how well MUAC change tracks with gestational weight gain change throughout pregnancy.
2. Conduct a qualitative study in the three BEP arms of the study to better understand acceptability, use, sharing and other components of adherence to BEP among women and family members and understand women's perceptions related to the screening and targeting employed in the trial.
3. Conduct a mixed methods implementation feasibility study to assess how feasible the most effective delivery approach of BEP (according to the trial findings) would be according to national and subnational stakeholders in Bangladesh.
4. Conduct a costing and cost-effectiveness analysis to compare cost of screening and cost-effectiveness of targeted vs. an untargeted supplementation approach to inform future programs.

The study design will be conducted as a cluster-randomized, unblinded trial with 4 arms among newly pregnant women. A total of 240 sectors (unit of randomization, comprising 150-200 households with women of reproductive age) will be randomized to one of the four supplementation arms, with control arm being provided a daily multiple micronutrient supplement (MMS).

Arm 1: Control - Daily MMS Arm 2: All women receive BEP Arm 3: Low BMI women receive BEP, others receive MMS Arm 4: Low BMI women receive BEP, women with inadequate gestational weight gain get switched to BEP, other receive MMS

Study Site and Participants:

The study will be conducted in the re-sized "JiVitA" (a well established field site) study area in a rural northwestern district of Bangladesh. The BEP effectiveness trial will be done among married pregnant women of reproductive age. A home-based initial census will identify all women of reproductive age living in the selected JiVitA area. We will use the JiVitA pregnancy surveillance system entailing monthly ascertainment of last menstrual period and urine-based testing among women who missed their period in the past 30 days to identify newly pregnant women for enrollment in the study. During the surveillance weight and height of the women will be assessed to calculate pre-pregnancy body mass index (BMI).

Randomization in the study will be done at a cluster level, with JIVitA sectors being used as the unit of randomization, as done in our previous studies. At pregnancy ascertainment, women will be consented for participation in the trial, and begin receiving their daily supplements as per their random allocation at the beginning of the second trimester.

Field Procedures and Data Collection

A cadre of JiVitA female staff (known as Community Health Research Workers (CHRWs), community health research workers) who are responsible for conducting the pregnancy surveillance will also be doing monthly anthropometry and distribution of the study interventions. Enrollment into the main trial will be conducted by experienced Field Interviewers (FIs), who will also be responsible for conducting a late pregnancy visit and birth assessment visits. Once a consenting pregnant woman has reached 12-14 weeks gestation, according to last menstrual period (LMP), her local CHRW will visit her monthly to distribute BEP and MMS supplements, collect compliance measurements for both, and to collect antenatal care (ANC) visit and provider history.

Information collected from the women includes: household socioeconomic status and food security using the Food \& Nutrition Technical Academy (FANTA) Household Food Insecurity Access Scale (HFAIS), pregnancy history, 7-day diet recall, 28-day morbidity recall, an empowerment and agency module based on the Women's Agency Scale, a depression module adapted from the Edinburgh Postnatal Depression Scale, and anthropometry, including weight, and MUAC. Hemoglobin levels will also be assessed using a finger-prick blood draw and Hemocue machine. A late pregnancy visit will also be conducted at about 32-34 week of gestation to collect diet, morbidity, anthropometry, depression and food security information as well as to repeat Hb. A birth surveillance system will be set up for birth notification and an early visit to the home for birth assessment and anthropometry. A female interviewer (FI) will conduct the visit to collect pregnancy outcome information, infant anthropometry (length, weight, head and chest circumference) and ask a brief questionnaire on labor and delivery and measure blood pressure. One month post livebirth or stillbirth a home visit will be done to assess infant vital status and to measure maternal weight to estimate BMI.

Monitoring Supplement Adherence and Use In this effectiveness trial, supplement distribution will be done monthly. Empty food packets and MMS blister packs will be collected back and counted. A calendar to mark daily consumption will be given as an aid. After 2 weeks a phone based assessment of number of BEP packets or MMS tablets will be done as well counseling provided for any issues related to daily adherence and to encourage high compliance.

Counseling:

All women in the trial will receive counseling for antenatal care and danger signs using the behavior change communications materials developed by the Ministry of Health of Bangladesh. In addition, pamphlets for supplement benefits and use will be used for counseling. Adequate weight gain counseling using pamphlets will be done over the course of the pregnancy, across all four arms.

Sample Size:

Our sample size estimates are based on the hypothesis that either untargeted or targeted low pre-pregnancy BMI based BEP supplementation (along with MMS to women with normal BMI) will increase birth weight by 83 g and result in a relative risk reduction of 20% and 24% in SGA and LBW, respectively, compared with supplementation with MMS alone. We anticipate a total sample size of upto 2400 (600 \*4 arms) live births and up to 3800 pregnant women identified through a pregnancy surveillance over 1.5 year of enrollment for the study. This is assuming a pregnancy loss of 30% and loss to follow-up of 6% and recruitment from 240 (or 60 per arm) sectors (units created in JiVitA and used for cluster randomization) across 6-8 Unions (sub-district administrative unit) of northwestern Bangladesh.

Data Analysis Our primary treatment effects analysis will be done on singleton livebirths. The analysis will be an intention-to-treat approach, i.e. all study outcomes will be analyzed as randomized. We will present crude estimates of all primary and secondary outcomes with their 95% confidence intervals adjusted for clustering at the sector level using Huber-White sandwich estimators.

Eligibility criteria: Inclusion Criteria:

* Married women of reproductive age (15-35 y)
* living in the selected study area who are pregnant and consent to participate in the study.

Exclusion Criteria:

* Currently pregnant or lactating women (through 12 months postpartum),
* Married women who are sterilized or widowed/divorced will not be included in the pregnancy surveillance being used to identify newly pregnant women.
* Women with gestational age of \>=28 weeks of gestation using reported last menstrual period.

Primary outcomes:
measure: Birth weight
timeFrame: Weight taken within 0-72 hours of birth
measure: Low birth weight (weight < 2500 g) at birth
timeFrame: Weight taken within 0-72 hours of birth
measure: Small-for-gestational age
timeFrame: Measured within 0-72 hours of birth
Secondary outcomes:
measure: Birth length
timeFrame: Measured within 0-72 hours of birth
measure: Gestational weight change
timeFrame: weight from pre-pregnancy to weight measured at birth
measure: Proportion of inadequate gestational weight gain
timeFrame: From pre-pregnancy to birth
measure: Head circumference at birth
timeFrame: at birth
measure: Chest circumference at birth
timeFrame: at birth
measure: Large for gestational age at birth
timeFrame: at birth
Other outcomes:
measure: Length-for-age Z score at birth
timeFrame: At Birth
measure: weight-for-length Z score at birth
timeFrame: At Birth
measure: Stunting at birth
timeFrame: At birth
measure: Wasting at birth
timeFrame: At birth
measure: Short length for gestational age
timeFrame: At birth
measure: Postpartum BMI
timeFrame: 1 month postpartum
measure: Maternal Hemoglobin
timeFrame: At the third trimester (27-40 weeks)
measure: Maternal Anemia
timeFrame: At the third trimester (27-40 weeks)
Locations:
city: Rangpur
country: Bangladesh
facility: JiVitA Project
Study officials:
affiliation: Johns Hopkins University
name: Parul Christian, DrPH
role: PRINCIPAL_INVESTIGATOR
References: