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MORDOR II Burkina Faso: Longitudinal Trial

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ClinicalTrials.gov Identifier: NCT03676751
Recruitment Status : Not yet recruiting
First Posted : September 19, 2018
Last Update Posted : March 7, 2019
Sponsor:
Collaborators:
Centre de Recherche en Sante de Nouna, Burkina Faso
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
University of California, San Francisco

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 throughout the study. 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.

The study will be conducted in Nouna Town in northwestern Burkina Faso.


Condition or disease Intervention/treatment Phase
Child Growth Diversity of Microbiome Child Mortality Resistance Bacterial Drug: Azithromycin Drug: Placebo Phase 4

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 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. 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
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)
Masking Description: Quadruple: (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Mortality Reduction After Oral Azithromycin II Burkina Faso: Longitudinal Trial
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : March 1, 2020
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Azithromycin
A single dose of azithromycin will be administered to children between the ages of 8 days and 59 months old.
Drug: Azithromycin
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 Comparator: Placebo
A single dose of placebo will be administered to children between the ages of 8 days and 59 months old.
Drug: Placebo
Oral suspension of placebo for azithromycin




Primary Outcome Measures :
  1. Intestinal microbial diversity [ Time Frame: 6 months ]
    Simpson's diversity estimated from next generation sequencing


Secondary Outcome Measures :
  1. Change in weight over time [ Time Frame: 180 days post-treatment ]
    WAZ. Weight will be measured at all follow-ups and weight-for-age z-scores will be calculated. Weight measured in g/kg/day.

  2. Change in height over time [ Time Frame: 180 days post-treatment ]
    Height or length will be measured at all follow-ups and height-for-age z-scores will be calculated.

  3. Proportion of infants developing infantile hypertrophic pyloric stenosis [ Time Frame: 6 months ]
  4. Mortality [ Time Frame: 180 days post-treatment ]
    Vital status will be assessed at all follow-up time points. Mortality will be defined as death within the study period. Date of death will be collected.

  5. Malaria status [ Time Frame: 180 days post-treatment ]
    Blood smears (thin and thick) for malaria will be collected at all follow-ups to determine malaria infection status.

  6. Adverse Events [ Time Frame: 180 days post-treatment ]
    Caregivers will be asked if the child has been taken to the health post since the last visit and why

  7. Genotypic resistance [ Time Frame: 180 days post-treatment ]
    Measured with targeted PCR

  8. Inflammatory marker changes [ Time Frame: 6 months ]
    Measured by C-reactive protein

  9. IgA-bound bacteria from small intestine changes [ Time Frame: 180 days post-treatment ]
    Measured using BugFACS from whole blood and stool

  10. Nutritional status [ Time Frame: 180 days post-treatment ]
    To be measured using mid-upper arm circumference



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 59 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 antibiotic use within the past 7 days
  • No clinical complications requiring antibiotic treatment
  • No clinical complications requiring inpatient treatment
  • No congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc.)
  • No 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
  • Antibiotic use in the past 7 days
  • Clinical complications requiring antibiotic treatment
  • Clinical complications requiring inpatient treatment
  • Congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc.)
  • Known allergy to macrolides/azalides
  • No written informed consent from at least one parent or guardian
  • Unable to feed orally

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03676751


Contacts
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Contact: Tom Lietman, MD 4155022662 tom.lietman@ucsf.edu
Contact: Jessica Brogdon, MPH 4155141582 jessica.brogdon@ucsf.edu

Sponsors and Collaborators
University of California, San Francisco
Centre de Recherche en Sante de Nouna, Burkina Faso
Bill and Melinda Gates Foundation
Investigators
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Principal Investigator: Catherine Oldenburg, PhD University of California, San Francisco
Principal Investigator: Ali Sie, MD, PhD Centre de Recherce en Sante de Nouna
Principal Investigator: Tom Lietman, MD University of California, San Francisco

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03676751     History of Changes
Other Study ID Numbers: OPP1187628
First Posted: September 19, 2018    Key Record Dates
Last Update Posted: March 7, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of California, San Francisco:
azithromycin
mass drug administration
childhood mortality