Trial to Compare Two Strains of BCG
Condition: Death, Infant; Morbidity;Infant
MeSH terms: Infant Death
Study type: Interventional
Phase: Phase 4

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:

        1. Compared with BCG-Russia, receiving BCG-Japan is associated with

             1. a 16% reduction in all-cause deaths and

             2. a 10% lower case-fatality rate for hospitalized infants.

        2. 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:

        1. 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.

        2. 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).

        3. 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.
    

Intervention name(s): BCG-Japan; BCG-Russia
Intervention type(s): Biological; Biological
Intervention description(s): 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).; Infant (<1 year) 0.05 ml dose of resuspended BCG-Russia (Serum Institute of India)
Other intervention name(s): Tokyo strain 172
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Outcome assessor-blinded RCT
Masking: Double (Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: BCG vaccination; Non-specific effects of BCG; Heterologous effects; Maternal immune priming