Can Earlier BCG Vaccination Reduce Early Infant Mortality? A Randomised Trial (BCGR)

The purpose of this study is to determine whether BCG vaccination shortly after birth can reduce early infant mortality in a rural and an urban setting.

Study Overview

• Status: Terminated
• Conditions: Infant Mortality; BCG
• Intervention / Treatment: Biological: BCG-Denmark 1331 (Statens Serum Institute)

Detailed Description

Background: BCG and oral polio vaccines (OPV) at birth are associated with beneficial non-specific effects, reducing neonatal mortality by more than what can be explained by prevention of the target diseases. BCG is recommended at birth, but is often given much later, especially in rural areas. In two RCTs in Guinea-Bissau, BCG-at-birth reduced neonatal mortality in low birthweight (<2500g; LBW) children by 48% (95%CI: 18-67%) and in children with a birthweight >2500g (NBW), OPV+BCG vs BCG was associated with a 32% (95%CI: 0-55%) lower mortality.

WHO recommends home visits shortly after birth to reduce mortality, but vaccinations are not normally provided. If the vaccines indeed have profound effects on innate immunity and neonatal mortality in both LBW and NBW children many lives could be saved if BCG and OPV was provided earlier. Urban and rural clusters are randomised to home visits with and without vaccinations. All children participating in the study will be offered routine vaccines at village visits by the BHP team in the rural area. In the urban area, BCG and OPV will be provided at follow-up visits if the child has not yet received the vaccines. Thereby the study will provide earlier vaccination for all children.

Hypothesis: BCG+OPV at birth provided at village visits shortly after birth will reduce early infant mortality by 40%.

Methods: The study will be conducted in Biombo, Oio and Cacheu in rural Guinea-Bissau and in six suburban districts in the capital of Guinea-Bissau. In Guinea-Bissau home visits are not yet implemented as part of the routine program. Pregnant women will be offered to participate in the study at the time of pregnancy registration, which is conducted as part of the routine registration in the rural and urban health and demographic surveillance systems, respectively. Community key informants or mothers will communicate information on births to the BHP study team, and a study nurse will visit every new-born child shortly after a CKI or mother calls, if possible on the same day. Clusters will be randomised to receive immediate vaccination of their children shortly after birth or at the first visit by the BHP team in the rural area and at 2-months follow-up visits in the urban area.

Statistical analyses: The primary analysis of early infant non-accidental mortality will be assessed on a PP analysis stratifying for factors used in the randomization (Region, pre-study mortality level (high/low)) and sex, thus allowing different baseline hazards for boys and girls. To account for clustering we will employ cluster-robust variance estimates.

For the primary outcome, we will use Cox proportional hazards models, stratified for the above mentioned factors and with age as underlying time-scale. Deaths due to accidents will be censored.

The effect of early vaccination will be assessed for the following secondary outcomes:

• Non-accidental hospital admission
• Severe morbidity (composite outcome of non-accidental mortality and non-accidental hospital admissions)
• Consultations
• Growth
• Mid-upper-arm circumference
• Weight-for-age z-score
• BCG scarring
• Cost-effectiveness of providing BCG and OPV at home visits

Based on previous data from the rural HDSS in the areas where the current study will be conducted, the expected proportion of events (deaths and hospitalisation) between day 1 and the next home visit or 60 days of age, whichever comes first is 2.4% (unpublished data). The proportion of events are expected to be at least as high in the urban area. A recent trial in Ghana indicated that three home visits during the first week of life to promote essential new-born care practices and to weigh and assess children for danger signs was associated with an 8% (-12 to 25%) reduction in neonatal mortality. Based on pre-trial mortality data from the same rural clusters, the design effect is measured to be 1.43 (ratio of square of the standard errors for the cluster-adjusted/unadjusted HRs). Thus, in order to obtain 80% power to detect a reduction in early infant severe morbidity if the true reduction of BCG and OPV provided at home visits is larger than 40%, at least 6666 children need to be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 2332
• Phase: Phase 4

Contacts and Locations

Study Locations

• Guinea-Bissau
  • Bissau, Guinea-Bissau
    • Bandim Health Project

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All children registered during pregnancy will be eligible for the study provided they have not yet received BCG at the date of the home visit.

Exclusion Criteria:

• Children born outside the cluster, and returning more than 72 hours after the delivery
• Children that the nurse evaluates to die within the next 24 hours.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Intervention: BCG and OPV at home visits; Infants randomised to receive vaccines at home visits shortly after birth will receive one 0.05 ml dose of Mycobacterium bovis BCG live attenuated vaccine (BCG-Denmark 1331 (Statens Serum Institute) or BCG Japan (Japan BCG Laboratory) by intradermal injection in the left deltoid region. Dependent on national supply, infants will receive oral polio vaccine (OPV) at the time of BCG vaccination. For all children, the nurse will perform umbilical cord and skin care, encourage skin-to-skin contact to keep the new-born warm, examine and weigh the child at a home visit shortly after birth.	Biological: BCG-Denmark 1331 (Statens Serum Institute); See above; Other Names: BCG-Japan (Japan BCG Laboratory)
NO_INTERVENTION: Control: No vaccines at home visits; For all children, the nurse will perform umbilical cord and skin care, encourage skin-to-skin contact to keep the new-born warm, examine and weigh the child at a home visit shortly after birth. No vaccines will be administered at these home visits for children in the control arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-accidental mortality	Non-accidental mortality between the home visit and the next follow-up visit by BHP, when all unvaccinated children who are home will be offered BCG or the date of registering a non-trial vaccine or 60 days, whichever comes first.	60 days after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-accidental hospital admission	Non-accidental hospital admission between the home visit and the next follow-up visit by BHP, when all unvaccinated children who are home will be offered BCG or the date of registering a non-trial vaccine or 60 days, whichever comes first.	60 days after birth
Severe morbidity	Composite outcome of non-accidental mortality and non-accidental hospital admissions	60 days after birth
All-cause consultations	All-cause out-patient consultation between the home visit and the next follow-up visit by BHP, when all unvaccinated children who are home will be offered BCG or the date of registering a non-trial vaccine or 60 days, whichever comes first.	60 days after birth
Mid-upper-arm circumference	Development in mid-upper-arm circumference measured using a TALC insertion tape between enrollment and first visit by the BHP team will be assessed.	60 days after birth
Weight-for-age z-score	Development in weight between enrollment and first visit by the BHP team will be assessed using WHO's weight-for-age z-score reference.	60 days after birth
BCG scarring	Development of a BCG vaccination scar (yes/no) will be assessed.	6 months after birth
Cost-effectiveness analysis of providing BCG at home-visits	A cost effectiveness analysis seeking to measure the cost per death averted using a societal perspective, contrasting the costs of vaccine provision in the present programme and an outreach system as tested in the trial. The costs/savings associated with different rates of consultations and admissions will also be taken into account.	60 days after birth
Cause specific mortality	For every death a verbal autopsy will be made	60 days after birth

Collaborators and Investigators

• Sponsor: Bandim Health Project
• Collaborators: Research Center for Vitamins and Vaccines, Statens Serum Institute
• Investigators: Principal Investigator: Sanne M Thysen, MD, PhD, Bandim Health Project; Principal Investigator: Ane B Fisker, MD,PhD, Bandim Health Project; Principal Investigator: Amabelia Rodrigues, PhD, Bandim Health Project; Study Director: Christine S Benn, MD,PhD,DMSc, Research Center for Vitamins and Vaccines; Study Director: Peter Aaby, PhD,DMSc, Bandim Health Project

Publications and helpful links

General Publications

• Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sorensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52. doi: 10.1093/infdis/jir240.
• Biering-Sorensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J. 2012 Mar;31(3):306-8. doi: 10.1097/INF.0b013e3182458289.
• Thysen SM, Byberg S, Pedersen M, Rodrigues A, Ravn H, Martins C, Benn CS, Aaby P, Fisker AB. BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study. BMC Public Health. 2014 Oct 4;14:1037. doi: 10.1186/1471-2458-14-1037.
• Thysen SM, Jensen AKG, Rodrigues A, Borges IDS, Aaby P, Benn C, Fisker A. Can earlier BCG vaccination reduce early infant mortality? Study protocol for a cluster randomised trial in Guinea-Bissau. BMJ Open. 2019 Sep 24;9(9):e025724. doi: 10.1136/bmjopen-2018-025724.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (ACTUAL): June 1, 2021
• Study Completion (ACTUAL): June 1, 2021

Study Registration Dates

• First Submitted: July 20, 2015
• First Submitted That Met QC Criteria: July 20, 2015
• First Posted (ESTIMATE): July 21, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 4, 2022
• Last Update Submitted That Met QC Criteria: February 3, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Death; Infant Death
• Other Study ID Numbers: BCG150501