Gut and Azithromycin Mechanisms in Infants and Children II
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 4

Summary: 
      Childhood mortality is decreasing worldwide. However, many sub-Saharan countries still have
      high children under 5 mortality rates. The MORDOR trial in Niger, Tanzania, and Malawi
      demonstrated a near 14% decrease in all-cause child mortality following biannual azithromycin
      in children 1-59 months. Current trials in Burkina aim to replicate these results from the
      MORDOR study with mass azithromycin treatment.

      The investigators conducted an individually randomized placebo-controlled trial in Burkina
      Faso called the Gut and Azithromycin Mechanisms in Infants and Neonates Trial (GAMIN:
      NCT03676751) 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 and to evaluate changes in the
      gut microbiome longitudinally (results pending). Here, the investigators propose to conduct
      an expansion of the original GAMIN trial. In GAMIN II, the investigators will evaluate 450
      additional 1-59 month old children longitudinally for 6 months with a focus on stool
      collection and malaria status.

      Objectives:

      1. To determine the effect of a single dose of azithromycin for children aged 8 days-59
      months on malaria. The investigators hypothesize that a single dose of azithromycin will
      result in a reduced malaria status within the treatment group compared to the placebo group
      after a 14 day period within children ages 8 days-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 burden. 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 the gut microflora is unclear. Longitudinal studies have been
      recommended to further investigate the role of antibiotics on the microbiome. 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, the investigators
      propose to follow 450 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. Additionally, this study will provide valuable data on the
      effect of azithromycin for malaria status within 2 weeks of treatment.
    

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.; Placebo
Other intervention name(s): Zithromax
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Individually randomized placebo-controlled trial of azithromycin vs. placebo to establish the efficacy and safety of azithromycin.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment