Community Health Azithromycin Trial in Burkina Faso
Condition: Childhood Mortality
Study type: Interventional
Phase: Phase 4

Summary: 
      An estimated 7.7 million pre-school aged children die each year, the majority from infectious
      diseases. Mass azithromycin distributions for trachoma may have the unintended benefit of
      reducing childhood mortality. We recently demonstrated the biannual mass azithromycin
      distribution significantly reduces all-cause child mortality in a cluster randomized trial
      (MORDOR I) conducted in three diverse regions of Sub-Saharan Africa.

      Our long-term goal is to more precisely define the role of mass azithromycin treatments as an
      intervention for reducing childhood morbidity and mortality. We propose a cluster randomized
      trial designed to repeat the original study to confirm the original results in a different
      geographic study with similarly high child mortality, and to better understand the mechanism
      behind any effect of azithromycin on child mortality. We hypothesize that biannual mass
      azithromycin distribution will reduce child mortality compared to placebo, and that this
      effect will be primarily driven by a reduction in infectious burden.

      Objectives:

        1. Determine the efficacy of biannual mass azithromycin distribution versus placebo in
           children aged 1-59 months for reduction in all-cause mortality.

        2. Determine the efficacy of targeted azithromycin distribution to infants during an early
           infant healthcare visit (approximately 5th through 12th week of life) on infant
           mortality.

        3. Determine the mechanism behind the effect of biannual mass azithromycin distribution for
           reduction in child mortality.

      The study will be conducted in the Nouna District in northwestern Burkina Faso.
    

Detailed description: 
      Although child health and mortality are improving worldwide, children in the Sahel and
      sub-Sahel regions of West Africa have the greatest risks of mortality.Burkina Faso's current
      under-5 mortality rate is estimated 110 per 1,000 live births. Similar to other countries in
      the region, the major causes of child mortality in Burkina Faso are malaria, respiratory
      tract infection, and diarrhea. Malnutrition acts as a major underlying contributor to
      mortality. Interventions that address these underlying causes may be particularly efficacious
      for reducing mortality.

      Younger children at are at a higher risk of mortality. Approximately 2/3rd of under-5 deaths
      occur during the first year of life. In general, the child mortality rate decreases as age
      increases. While some improvement has been observed, neonatal mortality is declining at a
      slower rate than post-neonatal childhood mortality. Many child health interventions are
      designed specifically for children over 6 months of age, such as vitamin A supplementation,
      seasonal malaria chemoprevention, and lipid-based nutritional supplementation. Identification
      of strategies that are safe and effective for the youngest children will be required to
      address persistently high rates of neonatal and infant mortality.

      The MORDOR I study demonstrated a significant reduction in all-cause child mortality
      following biannual mass azithromycin distribution. Across three diverse geographic locations
      in sub-Saharan Africa (Malawi, Niger, and Tanzania), biannual mass azithromycin distribution
      over a two-year period led to a 14% decrease in all-cause child mortality. In Niger, 1 in 5-6
      deaths were averted. These results are qualitatively similar to those of a previous study of
      mass azithromycin distribution for trachoma control in Ethiopia, which found reduced odds of
      all-cause mortality in children in communities receiving mass azithromycin compared to
      control communities.

      In MORDOR I, the strongest effect of azithromycin was in the youngest cohort of children.
      Across all three countries, the strongest effect of azithromycin was consistently in children
      1-5 months of age, with an approximately 25% reduction in all-cause mortality. However,
      MORDOR I was not optimized to target the youngest age groups. Although children as young as 1
      month were eligible, biannual distributions might not reach some children until 7 months of
      age. On average, children were first treated at 4 months. Given that there may be a
      substantial benefit to treating children at younger ages, azithromycin strategies that are
      designed to target younger age groups may be even more beneficial for reducing child
      mortality.

      Here, we propose a randomized controlled trial designed to evaluate the efficacy of mass and
      targeted azithromycin strategies for child mortality. In the rural northwestern district of
      Nouna in Burkina Faso, we propose to randomize villages to biannual mass azithromycin
      distribution or placebo. This study was designed by CRSN and UCSF partners to confirm the
      results of MORDOR I, evaluate an alternative health systems distribution point (the vaccine
      visit) for delivery of azithromycin to young children, and to provide a platform for
      evaluation of potential mechanisms behind the effect of azithromycin by collecting and
      processing additional specimens and tests.

      Objectives:

        1. Determine the efficacy of biannual mass azithromycin distribution versus placebo in
           children aged 1-59 months for reduction in all-cause mortality.

        2. Determine the efficacy of targeted azithromycin distribution to infants during an early
           infant healthcare visit (approximately 5th through 12th week of life) on infant
           mortality.

        3. Determine the mechanism behind the effect of biannual mass azithromycin distribution for
           reduction in child mortality.

      Study Design:

      CRSN and UCSF (hereafter, "we") will assess childhood mortality over three years, comparing
      communities where children aged 1-59 months receive biannual oral azithromycin and/or
      targeted azithromycin during the 5th-12th week of life in conjunction with the first Expanded
      Programme on Immunization (EPI) vaccine visit or biannual placebo and targeted placebo. All
      eligible communities in Nouna District will be randomized (278 communities). A random sample
      of 48 (12/arm) communities from within the HDSS will be selected to participate in the
      "Mortality Plus" study, which will entail an annual morbidity exam among 15 randomly selected
      children per community to monitor infectious disease morbidity, nutritional status, and
      macrolide resistance. All communities will contribute to the mortality outcome.
    

Intervention name(s): Azithromycin; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): biannual azithromycin in eligible communities to children 1 to 59 months old Targeted azithromycin to children aged 5 to 8 weeks old at the vaccine visit; biannual placebo in eligible communities to children 1 to 59 months old Targeted placebo to children aged 5 to 8 weeks old at the vaccine visit
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: All eligible communities in Nouna District will be randomized in a 1:1 fashion to biannual azithromycin or placebo. Targeted treatment (vaccine visit) will be randomized 1:1 individually to azithromycin or placebo. Randomization will be conducted by T. Porco. Procedural and algorithmic details are provided in an appendix to the Statistical Analysis Plan.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Childhood mortality; Azithromycin; Mass treatment; Vaccine Visit targeted treatment