Clinical trial NCT03676751: MORDOR II Burkina Faso: Longitudinal Trial
Official title: Gut and Azithromycin Mechanisms in Infants and Neonates
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Child Growth
Diversity of Microbiome
Child Mortality
Resistance Bacterial
Keywords: azithromycin
mass drug administration
childhood mortality
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Centre de Recherche en Sante de Nouna, Burkina Faso
name: Bill and Melinda Gates Foundation
First posted: 2018-09-19
Enrollment: 500
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 trail of azithromycin vs. placebo to establish the efficacy and safety of azithromycin.
Primary purpose: PREVENTION

Brief 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.

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: Intestinal Microbial Diversity
timeFrame: 6 months
measure: Macrolide Resistance
timeFrame: 2 weeks
Secondary outcomes:
measure: Change in Weight Over Time
timeFrame: 180 days post-treatment
measure: Change in Height Over Time
timeFrame: 180 days post-treatment
measure: Number of Participants With Infantile Hypertrophic Pyloric Stenosis
timeFrame: 6 months
measure: Mortality
timeFrame: 180 days post-treatment
measure: Malaria Status
timeFrame: 180 days post-treatment
measure: Adverse Events
timeFrame: 14 days post-treatment
measure: Genotypic Resistance
timeFrame: 180 days post-treatment
measure: Inflammatory Marker Changes
timeFrame: 6 months
measure: IgA-bound Bacteria From Small Intestine Changes
timeFrame: 180 days post-treatment
measure: Nutritional Status
timeFrame: 180 days post-treatment
measure: Acute Modulation of the Gut Microbiome
timeFrame: 2 weeks post-treatment
measure: L-1 Norm Distance on Bacterial Reads (Intestinal)
timeFrame: 2 weeks post-treatment
measure: L-2 Norm Distance on Bacterial Reads (Intestinal)
timeFrame: 2 weeks post-treatment
measure: Changes in Normalized Reads for Campylobacter Species
timeFrame: 2 weeks post-treatment
measure: Resistome
timeFrame: 2 weeks post-treatment
Other outcomes:
Locations:
city: Nouna
country: Burkina Faso
facility: Centre de Recherche en Sante de Nouna
Study officials:
affiliation: University of California, San Francisco
name: Catherine Oldenburg, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre de Recherce en Sante de Nouna
name: Ali Sie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Tom Lietman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Coulibaly B, Kiemde D, Zonou G, Sie A, Dah C, Bountogo M, Brogdon J, Hu H, Lebas E, Porco TC, Doan T, Lietman TM, Oldenburg CE. Effect of Single-dose Azithromycin on Pneumococcal Carriage and Resistance: A Randomized Controlled Trial. Pediatr Infect Dis J. 2022 Sep 1;41(9):728-730. doi: 10.1097/INF.0000000000003585. Epub 2022 May 23.
citation: Coulibaly B, Sie A, Dah C, Bountogo M, Ouattara M, Compaore A, Nikiema M, Tiansi JN, Sibiri ND, Brogdon JM, Lebas E, Doan T, Porco TC, Lietman TM, Oldenburg CE. Effect of a single dose of oral azithromycin on malaria parasitaemia in children: a randomized controlled trial. Malar J. 2021 Aug 31;20(1):360. doi: 10.1186/s12936-021-03895-9.
citation: Sie A, Coulibaly B, Dah C, Bountogo M, Ouattara M, Compaore G, Brogdon JM, Godwin WW, Lebas E, Doan T, Arnold BF, Porco TC, Lietman TM, Oldenburg CE. Single-dose azithromycin for child growth in Burkina Faso: a randomized controlled trial. BMC Pediatr. 2021 Mar 17;21(1):130. doi: 10.1186/s12887-021-02601-7.