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Trial to Compare Two Strains of BCG (STRAIN III)

Primary Purpose

Death, Infant, Morbidity;Infant

Status
Recruiting
Phase
Phase 4
Locations
Guinea-Bissau
Study Type
Interventional
Intervention
BCG-Japan
BCG-Russia
Sponsored by
Bandim Health Project
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Death, Infant focused on measuring BCG vaccination, Non-specific effects of BCG, Heterologous effects, Maternal immune priming

Eligibility Criteria

0 Days - 42 Days (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy infants present at the HNSM maternity ward on the day of discharge or procuring vaccination at the ward.

Exclusion Criteria:

  • Infants older than 6 weeks (>42 days) of age
  • Infants that have already received either BCG or oral polio vaccine (OPV)
  • Infants that are moribund due to gross malformation or acute illness (about to die or be transferred to the pediatric ward according to the local health physician assessment; the latter children may be recruited when they are discharged from the pediatric ward or the neonatal intensive care unit).

Sites / Locations

  • Bandim Health ProjectRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

BCG-Japan

BCG-Russia

Arm Description

Infants randomized to receive BCG-Japan at discharge from the Maternity Ward will receive one 0.05 ml dose of Mycobacterium bovis BCG live attenuated vaccine BCG-Japan (Tokyo 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.

Infants randomized to receive BCG-Russia at discharge from the Maternity Ward will receive one 0.05 ml dose Mycobacterium bovis BCG live attenuated vaccine BCG-Russia-I (Serum Institute of India) 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.

Outcomes

Primary Outcome Measures

Rate of all-cause mortality overall and stratified by maternal BCG scar status and sex
Data on mortality is collected from all available information sources (admission at HNSM, telephone follow-up, HDSS data)

Secondary Outcome Measures

Rate of hospital admissions overall and stratified by maternal BCG scar status and sex
Data on hospital admissions is collected at HNSM's Pediatric Ward
In-hospital case-fatality risk ratio overall and stratified by maternal BCG scar status and sex
Data on hospital admission and in-hospital case-fatality among admitted infants is collected at HNSM's Pediatric Ward
Prevalence of BCG skin reactions
The effect of the BCG strains on the BCG skin reaction prevalence will be evaluated by six weeks and six months of age. The data is obtained from telephone follow-up.
Prevalence of BCG skin reactions
The effect of the BCG strains on the BCG skin reaction prevalence by two months and six months of age. The data is obtained from home visits to infants residing in the BHP HDSS.
Prevalence of different BCG skin reaction types
The effect of the BCG strains on the BCG skin reaction type. The reaction types are papules, pustules, scars and no reaction. Data is obtained from home visits to infants residing in the BHP HDSS.
Size of BCG skin reactions
The effect of the BCG strains on the BCG skin reaction size. Data is obtained from home visits to infants residing in the BHP HDSS.
Rate of adverse events
To register adverse events from BCG vaccination in the form of simple or suppurative lymphadenitis, mothers are given a detailed explanation of these conditions and they are encouraged at inclusion and at subsequent follow-up visits to bring their child to a HDSS health center for consultation if such a condition should arise. Furthermore, mothers are asked at the time of telephone follow-up whether their child has or had a swollen lymph node in the left armpit and if yes, whether there has been secretion. At HDSS study area home visits, mothers are equally asked, and the size of the axillary lymph node is examined. A size <16 mm will be considered normal.

Full Information

First Posted
May 4, 2020
Last Updated
May 22, 2022
Sponsor
Bandim Health Project
Collaborators
University of Southern Denmark
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1. Study Identification

Unique Protocol Identification Number
NCT04383925
Brief Title
Trial to Compare Two Strains of BCG
Acronym
STRAIN III
Official Title
Randomized Trial Evaluating the Non-specific Effects of Different BCG Strains in Guinea-Bissau: Effects on Early-life Mortality and Morbidity
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 4, 2020 (Actual)
Primary Completion Date
June 2022 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bandim Health Project
Collaborators
University of Southern Denmark

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The trial will be a two-year outcome assessor-blinded RCT at the maternity ward of hospital Simão Mendes (HNSM) in urban Bissau, Guinea-Bissau to compare BCG-Japan versus BCG-Russia 1:1 in 15,000 infants with respect to mortality, morbidity and case-fatality rate during hospital admission. The trial will also examine the association between BCG strains and BCG skin reaction characteristics by six weeks (data collected by telephone) and at two and six months (data collected at home-visits to a subgroup of the cohort). As a secondary aim, this large study will be used to further evaluate the role of maternal BCG immune priming for overall health, since there are indications that maternal BCG scarring enhances the non-specific effects of BCG.
Detailed Description
This two-year outcome assessor-blinded RCT will be conducted at the maternity ward of hospital Simão Mendes (HNSM) in urban Bissau, Guinea-Bissau to compare BCG-Japan versus BCG-Russia 1:1 in 15,000 infants with respect to mortality, morbidity and case-fatality rate during hospital admission. The trial will also examine the association between BCG strains and BCG skin reaction characteristics by six weeks (data collected by telephone) and at two and six months (data collected at home-visits to a subgroup of the cohort). HYPOTHESES The aim is to investigate the following hypotheses: Compared with BCG-Russia, receiving BCG-Japan is associated with a 16% reduction in all-cause deaths and a 10% lower case-fatality rate for hospitalized infants. BCG-vaccinated children have lower mortality if the mother has a BCG scar, when compared to if the mother does not have a BCG scar. METHODS Setting: The RCT will be carried out by the Bandim Health Project (BHP) in a close collaboration with the HNSM Maternity Ward. BHP maintains a Health and Demographic Surveillance System (HDSS) site in Guinea-Bissau, covering approx. 100,000 individuals in six suburbs of the capital Bissau. A dedicated BHP team registers all births and vaccinations at the Maternity Ward, where BHP has conducted a series of RCTs since 2002, with the aim of improving early-life health outcomes. Inclusion: Neonates born at the HNSM Maternity Ward and neonates referred to the ward for vaccination are eligible for participation in the study. Mothers/guardians to infants eligible for the study will receive an oral study explanation in Portuguese Creole and a written explanation in Portuguese. Provided that oral consent is obtained, the mother/guardian signs a written consent form; if the mother or guardian is illiterate, a fingerprint can be provided to confirm participation. The family can request that their child leaves the trial at any time. Infants that are not eligible for participation or whose mother/guardian declines participation will be registered and vaccinated by our team (standard practice). Information on maternal and paternal BCG scar status, scar size, mid-upper-arm circumference and socioeconomic factors will be collected during the inclusion procedure. Telephone contact information for the mother, the father and family members and/or persons living in the same house are recorded at inclusion. BCG will be provided at discharge for all infants at the ward. Randomization: Following informed consent, the mother selects, from a stack of envelopes, a closed envelope that contains a sealed randomization lot indicating allocation to either BCG-Japan or BCG-Russia. The mother, inclusion assistant and vaccinator will thus not be blinded to the intervention allocation. Vaccination: The infant is vaccinated intradermally with 0.05 ml of the allocated BCG strain in the left upper deltoid, followed by vaccination with OPV. OPV is provided via the National Vaccination Program; if OPV is in shortage, only BCG vaccination will be provided. Follow-up: All assistants assessing outcomes during the follow-up procedures outlined below will be blinded to the randomization allocation. Follow-up takes place through three mechanisms: All enrolled infants with a telephone number recorded at inclusion: Family telephone interview at 6 weeks and 6 months to register dates and outcomes of consultations, hospital admissions and whether the child died. If the child died, the mother/guardian is briefly asked about symptoms and whether the death occurred at home or at a hospital. Information on adherence to the 6-week vaccination schedule, infant BCG reaction status and adverse events is also collected. If the infant has not yet received the 6-week vaccines, the mother/guardian will be reminded that it is time for the infant to be vaccinated. Cohort of BHP HDSS infants: home visits at 2 and 6 months of age. With the proposed sample size of 15,000 infants and an estimated 15.5% residing in the HDSS study area, the trial will enroll approximately 2,300 children from the HDSS. These children will be followed by our routine surveillance system and receive two additional home visits at 2- and 6 months of age. At the visits, data is collected on mortality, morbidity, BCG scar status and size, adverse events and maternal and paternal BCG scar status (if not collected at inclusion). All enrolled infants: Registration of admissions and consultations at the HNSM pediatric ward. Admissions, diagnoses and outcomes at the pediatric ward are documented by a BHP team on all days of the year. Parental names and telephone numbers are registered for all admissions. Sample size: Primary outcome: Based on BCGSTRAIN I trial data and BCGSTRAIN II trial data (unpublished), an overall mortality rate of 1.1% by 6 weeks of age is anticipated. Given that two large-scale RCTs testing BCG-Japan vs. BCG-Russia have been conducted in Guinea-Bissau, the sample size needed to demonstrate a significant difference in all-cause mortality between BCG-Japan and BCG-Russia has been calculated based on the conditional power of a meta-analysis involving BCGSTRAIN I, II and a third RCT, as detailed by Roloff et al. In order to detect a 16% reduction in all-cause mortality associated with BCG-Japan in the meta-analysis of the three RCTs, with an expected heterogeneity of 0.002 between the trials, a conditional power of 0.80 and an alpha of 0.05, an additional 148 events in the third trial is necessary. With an expected mortality rate of 1.1%, this corresponds to a sample size of 15,000 inclusions when considering an expected loss to follow-up of approx. 10%. With an expected monthly inclusion rate of 600 infants based on previous experiences, it is expected that at least 15,000 children, i.e. 7,500 in each BCG strain group, can be included during an expected timeframe of approx. 2 years for inclusion procedures and an additional 6 months for follow-up procedures. Analyses: The mortality and morbidity data will be analyzed as intention-to-treat in Cox regression models with age as the underlying time variable. In-hospital case-fatality rates between BCG strains will be compared using Fischer's exact test (2-sided). In case an OPV or vitamin A supplementation campaign or similar campaigns with potential immune stimulatory effects occurs during the study period, the main comparison of the two strains and of the effects of maternal BCG scarring on infant outcomes will be conducted by censoring all children on the first day of the campaign, to exclude any interaction of the campaign with the BCG strains. As sensitivity analyses, an analysis where same-day deaths and admissions (events occurring on the day of BCG vaccination) are omitted will be conducted. An analysis of main outcomes excluding neonates that were admitted to intensive care before inclusion will also be conducted. All analyses will be conducted overall and stratified by maternal BCG scar status and sex. Trial vaccines: The BCG vaccines will be acquired from the Japan BCG laboratory (BCG-Japan) and the Serum Institute of India (BCG-Russia). Ethical considerations: The proposed study will randomize children to BCG strains that are distributed by UNICEF and widely used in Guinea-Bissau and the rest of the world. Our previous studies have shown that providing BCG vaccination at discharge is safe and beneficial. Oral and written informed consent will be obtained in all cases. The study protocol was approved by the Ethical Committee in Guinea-Bissau and the Central Ethical Committee in Denmark gave its consultative approval. A local clinical monitor will be appointed to oversee the study. Public health importance: Global annual infant BCG vaccinations exceed 120 million. Current BCG vaccine strains are heterogeneous due to accumulation of genetic diversity and non-standardized production techniques. Yet, there is a substantial lack of data comparing the various BCG strains both in terms of specific and non-specific effects. By providing information regarding BCG strains and data on the importance of maternal immune priming with BCG, the proposed study is likely to be an important contribution to future BCG policies. Substantial improvements in protection from TB and reductions in early-life morbidity and mortality will likely be achieved at low cost, if more information on the efficacy of the different strains of BCG and the importance of maternal immune priming is made available.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Death, Infant, Morbidity;Infant
Keywords
BCG vaccination, Non-specific effects of BCG, Heterologous effects, Maternal immune priming

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Outcome assessor-blinded RCT
Masking
Care ProviderOutcomes Assessor
Masking Description
Following informed consent, the mother selects, from a stack of envelopes, a closed envelope that contains a sealed randomization lot indicating allocation to either BCG-Japan or BCG-Russia. The mother, inclusion assistant and vaccinator will thus not be blinded to the intervention allocation. All assistants assessing outcomes during the follow-up procedures outlined and providers of care will be blinded to the randomization allocation.
Allocation
Randomized
Enrollment
15000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BCG-Japan
Arm Type
Experimental
Arm Description
Infants randomized to receive BCG-Japan at discharge from the Maternity Ward will receive one 0.05 ml dose of Mycobacterium bovis BCG live attenuated vaccine BCG-Japan (Tokyo 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.
Arm Title
BCG-Russia
Arm Type
Active Comparator
Arm Description
Infants randomized to receive BCG-Russia at discharge from the Maternity Ward will receive one 0.05 ml dose Mycobacterium bovis BCG live attenuated vaccine BCG-Russia-I (Serum Institute of India) 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.
Intervention Type
Biological
Intervention Name(s)
BCG-Japan
Other Intervention Name(s)
Tokyo strain 172
Intervention Description
Infant (<1 year) 0.05 ml dose of resuspended BCG-Japan (Tokyo strain 172, Japan BCG Laboratory, 1-5-21 Otsuka, Bunkyo-ku, Tokyo, 112-0012 Japan).
Intervention Type
Biological
Intervention Name(s)
BCG-Russia
Intervention Description
Infant (<1 year) 0.05 ml dose of resuspended BCG-Russia (Serum Institute of India)
Primary Outcome Measure Information:
Title
Rate of all-cause mortality overall and stratified by maternal BCG scar status and sex
Description
Data on mortality is collected from all available information sources (admission at HNSM, telephone follow-up, HDSS data)
Time Frame
Six weeks of age
Secondary Outcome Measure Information:
Title
Rate of hospital admissions overall and stratified by maternal BCG scar status and sex
Description
Data on hospital admissions is collected at HNSM's Pediatric Ward
Time Frame
Six weeks and six months of age
Title
In-hospital case-fatality risk ratio overall and stratified by maternal BCG scar status and sex
Description
Data on hospital admission and in-hospital case-fatality among admitted infants is collected at HNSM's Pediatric Ward
Time Frame
Six weeks and six months of age
Title
Prevalence of BCG skin reactions
Description
The effect of the BCG strains on the BCG skin reaction prevalence will be evaluated by six weeks and six months of age. The data is obtained from telephone follow-up.
Time Frame
Six weeks and six months of age
Title
Prevalence of BCG skin reactions
Description
The effect of the BCG strains on the BCG skin reaction prevalence by two months and six months of age. The data is obtained from home visits to infants residing in the BHP HDSS.
Time Frame
Six weeks and six months of age
Title
Prevalence of different BCG skin reaction types
Description
The effect of the BCG strains on the BCG skin reaction type. The reaction types are papules, pustules, scars and no reaction. Data is obtained from home visits to infants residing in the BHP HDSS.
Time Frame
Two and six months of age
Title
Size of BCG skin reactions
Description
The effect of the BCG strains on the BCG skin reaction size. Data is obtained from home visits to infants residing in the BHP HDSS.
Time Frame
Two and six months of age
Title
Rate of adverse events
Description
To register adverse events from BCG vaccination in the form of simple or suppurative lymphadenitis, mothers are given a detailed explanation of these conditions and they are encouraged at inclusion and at subsequent follow-up visits to bring their child to a HDSS health center for consultation if such a condition should arise. Furthermore, mothers are asked at the time of telephone follow-up whether their child has or had a swollen lymph node in the left armpit and if yes, whether there has been secretion. At HDSS study area home visits, mothers are equally asked, and the size of the axillary lymph node is examined. A size <16 mm will be considered normal.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Days
Maximum Age & Unit of Time
42 Days
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy infants present at the HNSM maternity ward on the day of discharge or procuring vaccination at the ward. Exclusion Criteria: Infants older than 6 weeks (>42 days) of age Infants that have already received either BCG or oral polio vaccine (OPV) Infants that are moribund due to gross malformation or acute illness (about to die or be transferred to the pediatric ward according to the local health physician assessment; the latter children may be recruited when they are discharged from the pediatric ward or the neonatal intensive care unit).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Peter Aaby, Professor
Phone
3201672
Ext
+245
Email
p.aaby@bandim.org
First Name & Middle Initial & Last Name or Official Title & Degree
Christine Stabell Benn, Professor
Phone
25883964
Ext
+45
Email
cbenn@health.sdu.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Aaby, Professor
Organizational Affiliation
Bandim Health Project
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Christine Stabell Benn, Professor
Organizational Affiliation
Bandim Health Project, University of Southern Denmark
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Frederik Schaltz-Buchholzer, MD
Organizational Affiliation
Bandim Health Project, University of Southern Denmark
Official's Role
Study Director
Facility Information:
Facility Name
Bandim Health Project
City
Bissau
Country
Guinea-Bissau
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Aaby, Professor
Email
p.aaby@bandim.org
First Name & Middle Initial & Last Name & Degree
Christine Benn, Professor
Phone
25883964
Ext
+45
Email
cbenn@health.sdu.dk
First Name & Middle Initial & Last Name & Degree
Peter Aaby
First Name & Middle Initial & Last Name & Degree
Frederik Schaltz-Buchholzer

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The trial steering committee can share individual participant data after after approval of a data sharing agreement sent to cbenn@health.sdu.dk
IPD Sharing Time Frame
One year after follow-up procedures have been completed.
IPD Sharing Access Criteria
The trial steering committee can be approached for data sharing at cbenn@health.sdu.dk
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Links:
URL
http://www.who.int/gho/child_health/mortality/neonatal_text/en/
Description
WHO data regarding child mortality.
URL
https://clinicaltrials.gov/ct2/show/NCT03400878
Description
The BCGSTRAIN II trial from which the results have not yet been published (follow-up is still pending and will be finished by october 2020).
URL
https://cdn.who.int/media/docs/default-source/mca-documents/verbal-autopsy-standards-the-2012-who-verbal-autopsy-instrument---release-candidate-1.pdf?sfvrsn=68f9b5a4_1&download=true
Description
Description of the verbal autopsy instrument which will be used for HDSS infants included in the trial.

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Trial to Compare Two Strains of BCG

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