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Due to fewer than expected children enrolled and lower than expected overall mortality rate.
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| Name | Class |
|---|---|
| Research Center for Vitamins and Vaccines, Statens Serum Institute | UNKNOWN |
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention: BCG and OPV at home visits | Active Comparator | 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. |
|
| Control: No vaccines at home visits | No Intervention | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BCG-Denmark 1331 (Statens Serum Institute) | Biological | See above |
|
| 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 |
| 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 |
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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:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Christine S Benn, MD,PhD,DMSc | Research Center for Vitamins and Vaccines | Study Director |
| Peter Aaby, PhD,DMSc | Bandim Health Project | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bandim Health Project | Bissau | Guinea-Bissau |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38350670 | Background | Thysen SM, da Silva Borges I, Martins J, Stjernholm AD, Hansen JS, da Silva LMV, Martins JSD, Jensen A, Rodrigues A, Aaby P, Stabell Benn C, Fisker AB. Can earlier BCG-Japan and OPV vaccination reduce early infant mortality? A cluster-randomised trial in Guinea-Bissau. BMJ Glob Health. 2024 Feb 12;9(2):e014044. doi: 10.1136/bmjgh-2023-014044. | |
| 21673035 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. BCG-Denmark 1331 (Statens Serum Institute): See above |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. BCG-Denmark 1331 (Statens Serum Institute): See above |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Children entered the analysis on the date of enrolment or 24 hours of age, whichever came last, and remained in the analysis until whatever came first: the first subsequent visit by the BHP team, date of registering first non-trial vaccine after enrolment, death, migration, or 60 days of life. | Posted | Count of Participants | Participants | 60 days after birth |
|
6 months
With the exception of Lymphadenitis (Other AE) which is assessed by examining the child, the population at risk is the entire study population. Therefore numbers differ for Other AE and the other outcomes (All-cause mortality, SAE)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. BCG-Denmark 1331 (Statens Serum Institute): See above |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mortality and Hospital Admission | General disorders | Systematic Assessment | Mortality and Hospital Admission were the main outcomes of the trial |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenitis | Blood and lymphatic system disorders | Systematic Assessment |
The trial was stopped due to low enrolment rates and low mortality. Obtaining information on births within 72 hours was far from always possible, and among those who were registered and consented during pregnancy, 33% provided information on delivery more than 72 hours after birth.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Sanne Marie Thysen | Bandim Health Project | 004531127825 | s.thysen@bandim.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 30, 2017 | Mar 23, 2026 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 27, 2017 | Mar 23, 2026 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D066088 | Infant Death |
| ID | Term |
|---|---|
| D003643 | Death |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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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 enrolment and first visit by the BHP team will be assessed using the WHO Child Growth Standards. These standards were developed using data collected in the WHO Multicentre Growth Reference Study. A child with a weight-for-age Z-score of 0 has a weight-for-age corresponding to the reference mean. A negative z-score indicates that the childs weight-for-age is below the reference mean, while a child with a positive score is above the mean. | 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 |
| 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. |
| 22189537 | Background | 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. |
| 25282475 | Background | 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. |
| 31551370 | Derived | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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. |
|
|
| Secondary | 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. | Children entered the analysis on the date of enrolment or 24 hours of age, whichever came last, and remained in the analysis until whatever came first: the first subsequent visit by the BHP team, date of registering first non-trial vaccine after enrolment, death, migration, or 60 days of life. | Posted | Count of Participants | Participants | 60 days after birth |
|
|
|
| Secondary | Severe Morbidity | Composite outcome of non-accidental mortality and non-accidental hospital admissions | Children entered the analysis on the date of enrolment or 24 hours of age, whichever came last, and remained in the analysis until whatever came first: the first subsequent visit by the BHP team, date of registering first non-trial vaccine after enrolment, death, migration, or 60 days of life. | Posted | Count of Participants | Participants | 60 days after birth |
|
|
|
| Secondary | 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. | Same as for the primary outcome | Posted | Count of Participants | Participants | 60 days after birth |
|
|
|
| Secondary | 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. | Measured at first follow-up visit within 6 months of age. | Posted | Mean | Standard Deviation | mm | 60 days after birth |
|
|
|
| Secondary | Weight-for-age Z-score | Development in weight between enrolment and first visit by the BHP team will be assessed using the WHO Child Growth Standards. These standards were developed using data collected in the WHO Multicentre Growth Reference Study. A child with a weight-for-age Z-score of 0 has a weight-for-age corresponding to the reference mean. A negative z-score indicates that the childs weight-for-age is below the reference mean, while a child with a positive score is above the mean. | Measured at first follow-up visit within 6 months of age. | Posted | Mean | Standard Deviation | Z-score | 60 days after birth |
|
|
|
| Secondary | BCG Scarring | Development of a BCG vaccination scar (yes/no) will be assessed. | All children in the primary analysis, who had their scar status assessed at a follow-up visit | Posted | Count of Participants | Participants | 6 months after birth |
|
|
|
| Secondary | 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. | Reported in DOI: 10.1136/bmjgh-2023-014044: "In the analysis plan, a cost-effectiveness analysis was specified. As the trial was stopped prematurely, we did not perform a cost-effectiveness analysis." | Posted | Number | USD | 60 days after birth |
|
|
|
| Secondary | Cause Specific Mortality | For every death a verbal autopsy will be made | Posted | Number | Cause of death | 60 days after birth |
|
|
|
| 7 |
| 1,006 |
| 14 |
| 1,006 |
| 3 |
| 887 |
| EG001 | 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. | 28 | 1,206 | 36 | 1,206 | 0 | 1,046 |
|
| Suppurative lymphadenitis | Blood and lymphatic system disorders | Systematic Assessment |
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| Sepsis |
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| Gastrointestinal infection |
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| Other |
|