MORDOR II Burkina Faso: Longitudinal Trial
Condition: Child Growth; Diversity of Microbiome; Child Mortality; Resistance Bacterial
Study type: Interventional
Phase: Phase 4

Summary: 
      Globally, childhood mortality has shown a promising downward trend in recent years, however,
      many sub-Saharan countries still have relatively high child mortality rates. In previous
      studies within Niger, Tanzania, and Malawi, mass azithromycin treatment to children aged 1-59
      months old effectively reduced all-cause childhood mortality. A similar study will be
      conducted in Burkina Faso to replicate the results of mass azithromycin treatment.

      The investigators propose an individually randomized placebo-controlled trial alongside the
      MORDOR II Burkina Faso trial to evaluate the effect of a single dose of azithromycin (20
      mg/kg) on potential mediators of the effect of azithromycin on all-cause mortality. Many
      questions surround the mechanism behind azithromycin's effect on reducing childhood
      mortality. Further questions exist regarding antibiotic resistance and how mass antibiotic
      administration can impact intestinal microflora. The goal of this study is to demonstrate the
      changes in the gut microbiome after antibiotic administration and to measure the growth of
      children after receiving a single dose of azithromycin. Additionally we will measure
      resistance markers, inflammatory markers, and IgA-bound bacteria. We hypothesize that a
      single dose of azithromycin will lead to a significant increase in child growth and that the
      gut microbiome will be significantly different in children who received azithromycin compared
      to those who received placebo.

      Objectives:

        1. . To determine the effect of a single dose of azithromycin for children aged 8 days-59
           months on longitudinal changes in the intestinal microbiome over a 6-month period. We
           hypothesize that a single dose of azithromycin will result in a significant difference
           in the intestinal microbiome within the treatment group compared to the placebo group
           after a 6-month period within children ages 8 days-59 months.

        2. . To determine the effect of a single dose of azithromycin for children aged 8 days-59
           months on child growth over a 6-month period. We hypothesize that a single dose of
           azithromycin will increase child growth over a 6-month period in children aged 8 days-59
           months.

        3. . To determine the effect of a single dose of azithromycin for children aged 8 days to
           59 months on the presence of macrolide genetic resistance determinants within the first
           two weeks post-treatment. The investigators hypothesize that a single dose of
           azithromycin will increase the presence of macrolide resistance determinants over a 2
           week period in children aged 8 days to 59 months.

      The study will be conducted in Nouna Town in northwestern Burkina Faso.
    

Detailed description: 
      The investigators' previous MORDOR I research demonstrated a significant reduction in
      all-cause child mortality after biannual mass azithromycin distribution. In three sub-Saharan
      Africa countries, (including Niger, Tanzania, and Malawi) mass azithromycin treatment over 2
      years resulted in a 14% reduction in child mortality. Moreover, 1 in 5-6 deaths were shown to
      be averted within Niger alone1. Similar findings were demonstrated in a previous study for
      trachoma control in Ethiopia with mass azithromycin distribution. This study in rural
      Ethiopia noted a nearly 50% decrease in all-cause childhood mortality5. However, neither of
      these studies evaluated the longitudinal impact azithromycin has on the gut microbiome. The
      MORDOR II trial in Burkina Faso will further evaluate the efficacy of biannual azithromycin
      treatment. The under-5 child mortality rate in Burkina Faso is approximately 110 per 1,000
      live births. Major causes of child mortality in this area are infectious mostly due to
      malaria, diarrhea, and upper respiratory tract infections. In addition, malnutrition
      contributes to a high burden of child mortality and morbidity within this region as well. By
      treating underlying conditions, the use of routine antibiotic treatment could reduce diverse
      health outcomes leading to morbidity and mortality. The investigative team proposes to
      conduct this study alongside the MORDOR II trial in the town of Nouna where a majority of
      childhood deaths are attributable to infectious causes and malnutrition.

      The World Health Organization is considering adopting the presumptive use of azithromycin and
      other antibiotics as a recommendation to reduce childhood mortality in areas with a high
      infectious disease burden2. Many questions remain unanswered surrounding the use of mass
      antibiotic treatment in areas with high child morbidity and mortality. This study will add to
      the current knowledge of mass azithromycin distribution from our previous MORDOR I research.
      The investigators propose to evaluate how azithromycin will impact childhood growth and to
      assess the changes that occur in the intestinal microbiome following a single dose of
      azithromycin treatment. The goal is to contribute more scientific literature that could
      assist future guidelines regarding antibiotic use.

      The role of antibiotics on child growth is unclear. Recent studies indicate that antibiotic
      use could impact child growth, but a previous study in Niger failed to find a statistically
      significant correlation between antibiotic treatment with azithromycin and stunting,
      underweight, or MUAC of pre-school aged children. Longitudinal studies have been recommended
      to further investigate the role of antibiotics on child growth6. Meanwhile some studies
      suggest antibiotics may create modifications in the gut microbiota impacting nutrient
      absorption and weight gain7.The investigative team proposes to measure child growth through
      anthropometric measurements longitudinally over a 6-month period to see if azithromycin
      treatment impacts child development. We hypothesize that children receiving a dose of
      azithromycin will have more growth and development in terms of height, weight, and mid-upper
      arm circumference compared to children who receive placebo.

      The investigators propose a longitudinal study designed to improve our knowledge about the
      changes in the intestinal microbiome following the course of a single dose of antibiotic in a
      setting with high childhood mortality and morbidity. More specifically, we propose to follow
      500 children for a 6-month time period that are between the ages of 8 days old and 59 months
      old. Children in this age bracket are at the highest risk for mortality from infectious
      causes, and furthermore, they are at the highest risk for malnutrition. This group of
      children would receive the greatest benefit from this intervention. The causal changes in the
      microbiome are vastly understudied in regards to changes in the gut microbiome following a
      course of antibiotics. The investigators hypothesize that children receiving a dose of
      azithromycin will have a higher prevalence of pneumococcal resistance in nasopharyngeal
      samples, decreased bacterial diversity, and a higher likelihood of identification of
      bacterial resistance genes in stool and nasopharyngeal samples.

      A small group of 50 children (25 per arm) will be followed more intensely within the first 2
      weeks of treatment to evaluate macrolide resistance. The investigators hypothesize that
      children receiving azithromycin will have a greater presence of macrolide genetic resistant
      determinants.
    

Intervention name(s): Azithromycin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Zithromax® for oral suspension is supplied in bottles containing azithromycin dehydrate powder equivalent to 1200mg per bottle and the following inactive ingredients: sucrose; tribasic anhydrous sodium phosphate; hydroxypropyl cellulose; xanthan gum; FD&C Red #40; and flavoring including spray dried artificial cherry, crème de vanilla, and banana. After constitution, a 5mL suspension contains 200mg of azithromycin.; Oral suspension of placebo for azithromycin
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Individually randomized placebo-controlled trail of azithromycin vs. placebo to establish the efficacy and safety of azithromycin.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: azithromycin; mass drug administration; childhood mortality