Clinical trial NCT04315272: Gut and Azithromycin Mechanisms in Infants and Children II
Official title: Gut and Azithromycin Mechanisms in Infants and Children II
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Centre de Recherche en Sante de Nouna, Burkina Faso
First posted: 2020-03-19
Enrollment: 449
Sex: ALL
Minimum age (years): 8
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Individually randomized placebo-controlled trial of azithromycin vs. placebo to establish the efficacy and safety of azithromycin.
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Between 8 days and 59 months old
* Primary residence within catchment area of study site
* Available for full 6 month study
* No known allergy to macrolides/azalides
* Appropriate written informed consent from at least one parent or guardian
* Able to feed orally

Exclusion Criteria:

* \<8 days old or \>59 months
* Primary residence outside catchment area of study site
* Not available for full 6 month study
* Known allergy to macrolides/azalides
* No written informed consent from at least one parent or guardian
* Unable to feed orally

Primary outcomes:
measure: Malaria Status
timeFrame: 2 weeks
Secondary outcomes:
measure: Clinical Malaria
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Nouna
country: Burkina Faso
facility: Centre de Recherche en santé de nouna
state: Boucle Du Mouhoun
Study officials:
affiliation: University of California, San Francisco
name: Catie Oldenburg, ScD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brogdon J, Dah C, Sie A, Bountogo M, Coulibaly B, Kouanda I, Ouattara M, Compaore G, Nebie E, Seynou M, Lebas E, Nyatigo F, Hu H, Arnold BF, Lietman TM, Oldenburg CE. Malaria positivity following a single oral dose of azithromycin among children in Burkina Faso: a randomized controlled trial. BMC Infect Dis. 2022 Mar 25;22(1):285. doi: 10.1186/s12879-022-07296-4.