Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children (Toto Bora)

November 30, 2023 updated by: Judd Walson, University of Washington
Children hospitalized with severe illness in sub-Saharan Africa are at high risk of morbidity and mortality following discharge from hospital. These children represent an accessible high-risk population in which targeted interventions to prevent morbidity and mortality could have dramatic impact. A large cluster randomized trial of azithromycin delivered in a mass drug administration program within trachoma endemic areas in sub-Saharan Africa demonstrated an almost 50% mortality benefit in children 1-9 years of age in treated communities. However, mass drug administration of azithromycin leads to the rapid emergence of macrolide resistance within treated communities and is expensive. The targeted delivery of azithromycin to children at hospital discharge may be a novel and practical intervention to maximize benefit while minimizing risk of antibiotic resistance. This is a randomized, double-blind, placebo-controlled trial to determine the efficacy of azithromycin provided at discharge, compared to placebo, in reducing mortality and re-hospitalization rates in children age 1-59 months in Kenya. The study will also investigate potential mechanisms by which azithromycin may reduce morbidity and mortality in this population and will assess the emergence of antibiotic resistance among treated individuals and their primary caregivers. A cost-effectiveness analysis of the intervention will also be conducted.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

An estimated 3.5 million deaths occur annually in children less than 5 years of age in sub-Saharan Africa, approximately 70% of which are due to infectious causes. One-year mortality rates as high as 15% have been documented following hospital discharge in sub-Saharan Africa, a rate that is 8-fold higher than non-hospitalized children. Children being discharged from hospital in Africa may represent an accessible high-risk population in which to target interventions to reduce mortality. A recent trial of mass drug administration of azithromycin reduced childhood mortality by half among children in Ethiopia in communities receiving the intervention. However, concerns about the potential for the emergence of antimicrobial resistance, possible toxicity, and the feasibility of delivery are all barriers to community-wide distribution of antibiotics. Targeted chemotherapeutic interventions, including the use of cotrimoxazole among HIV-infected children and the use of amoxicillin or cefdinir among malnourished children, have been shown to reduce mortality in these specific vulnerable populations. Children who have been recently hospitalized are a high-risk population in which a similar targeted approach to azithromycin distribution may optimize benefit while reducing both individual and population level risks. The mechanisms by which azithromycin may impact morbidity and mortality have not been well described. Among high-risk pediatric populations with history of recent illness, azithromycin may act by treating residual disease not eliminated during inpatient therapy, by providing prophylaxis from future infectious exposures during a time of immune suppression and vulnerability following illness, by treating underlying enteric dysfunction and associated mucosal immune/gut barrier disruption and inflammation, and/or by clearing asymptomatic carriage of potentially pathogenic organisms. This is a randomized, double-blind, placebo-controlled trial of a 5-day course of azithromycin in children age 1 to 59 months discharged from hospital in Western Kenya to reduce post-discharge re-hospitalizations and mortality, to explore possible mechanisms by which azithromycin has benefit and risk, and to identify correlates and intermediate markers of re-hospitalization and death in the post discharge period.

Primary Aims Aim 1. To compare rates of re-hospitalization and mortality in the 6 months following hospital discharge among Kenyan children receiving 5-day azithromycin vs. placebo.

Hypothesis: The provision of a 5-day course of azithromycin provided at discharge will reduce hospital readmission and death within the 6 months following discharge, as compared to placebo.

Aim 2a. To evaluate possible mechanism(s) by which azithromycin may affect morbidity and mortality, by comparing reasons for re-hospitalization, prevalence of pathogen carriage, and markers of enteric dysfunction between the randomization arms.

Hypothesis: Children treated with azithromycin will experience fewer hospitalizations due to diarrhea, acute respiratory infection, and malnutrition, will be less likely to have respiratory and gastrointestinal carriage of potentially pathogenic organisms, and will have less evidence of enteric dysfunction, as compared to children treated with placebo in the 6 months following hospital discharge.

Aim 2b. To determine whether empiric administration of azithromycin at hospital discharge increases risk of antimicrobial resistance in commensal Escherichia coli (E. coli) and Streptococcus pneumoniae (S. pneumoniae) isolates from treated children and their household contacts.

Hypothesis: Isolates of commensal E. coli and S. pneumoniae from children treated with azithromycin and their household contacts will have higher levels of macrolide and β-lactam resistance, compared to the placebo group, after 90 days of follow-up, but resistance in the 2 arms will be similar by 6 months.

Aim 3. To identify correlates and intermediate markers of post-discharge mortality and hospital readmission among hospitalized Kenyan children.

Hypothesis: Children younger in age, with enteric dysfunction, higher levels of bacterial pathogen carriage,immune dysfunction, and malnutrition will experience more frequent re-hospitalizations and deaths.

Aim 4. To determine the cost-effectiveness of post-discharge administration of a 5-day course of azithromycin in settings of varying antibiotic use, re-hospitalization rates, and mortality rates.

Hypothesis: The provision of a 5-day course of azithromycin provided at discharge is cost-effective in settings with moderate to high re-hospitalization and mortality rates.

Study Type

Interventional

Enrollment (Actual)

1400

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kenya
      • Kisii And Homa Bay Counties, Kenya
        • Kisii Teaching and Referral Hospital, Homa Bay District Hospital, St. Paul's Mission Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 4 years (Child)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Age 1-59 months,
  • Plan to remain in study area greater than 6 months
  • Discharged from hospital following non-trauma related admission

Exclusion Criteria:

  • Contraindication to azithromycin use and other prophylactic antibiotic use

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Azithromycin
Azithromycin 10mg/kg for one day, then 5mg/kg for four days, a total of five days of experimental treatment.
Drug: Azithromycin
oral administration of Azithromycin
Other Names:
  • Zithromax
  • Zmax
Placebo Comparator: Placebo
5 days of taste/appearance/bottle-matched placebo
Drug: Placebo
5 days of taste/appearance/bottle-matched inactive substance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Re-hospitalization or Death
Time Frame: 6 months
Incidence rate of a composite outcome of mortality and hospital readmission during the 6 month post-discharge (follow-up) period.
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mean Change in Length for Age Z-score (LAZ) Between Baseline and Outcome Assessment
Time Frame: 6 months
Mean change in length for age z-score (LAZ) between baseline and M3 or M6
6 months
The Number of Children With Diarrhea Re-hospitalizations Following Randomization
Time Frame: 6 months
The number of children with diarrhea re-hospitalizations following randomization through follow-up
6 months
The Number of Children With Acute Respiratory Illness Re-hospitalizations Following Randomization
Time Frame: 6 months
6 months
The Number of Children With Malnutrition Re-hospitalizations Following Randomization
Time Frame: 6 months
6 months
The Number of Children With Malaria Re-hospitalizations Following Randomization
Time Frame: 6 months
6 months
Prevalence of Enteric Pathogen Carriage
Time Frame: 3 months
Prevalence of enteric bacteria, viruses, and protozoa identified by qPCR at 3 months of follow-up
3 months
Prevalence of Streptococcus Pneumoniae Carriage
Time Frame: 6 months
Prevalence of Streptococcus pneumoniae from nasopharyngeal swabs collected at M3 and M6 follow-up timepoints.
6 months
Number of Participants With Escherichia Coli Isolates From Fecal Samples Resistant to Azithromycin
Time Frame: 6 months (E.coli isolated at baseline, month 3, and month 6)
Among participants with E.coli isolated, # of participants with aizhtromycin resistance detected in E.coli form disc diffusion.
6 months (E.coli isolated at baseline, month 3, and month 6)
Proportion of Beta-lactam or Macrolide Resistance in Strep Pneumo in Children and Caregivers
Time Frame: 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Kenya Medical Research Institute

Investigators

  • Principal Investigator: Judd L Walson, MD, MPH, University of Washington Department of Global Health
  • Study Director: Patricia B Pavlinac, PhD, MS, University of Washington Department of Global Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 28, 2016

Primary Completion (Actual)

May 4, 2020

Study Completion (Estimated)

December 28, 2025

Study Registration Dates

First Submitted

March 31, 2015

First Submitted That Met QC Criteria

April 7, 2015

First Posted (Estimated)

April 10, 2015

Study Record Updates

Last Update Posted (Actual)

December 4, 2023

Last Update Submitted That Met QC Criteria

November 30, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00002592
  • R01HD079695 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified data for the primary analysis is available

IPD Sharing Time Frame

With publication of primary manuscript (Sep 2021)

IPD Sharing Access Criteria

Open Access

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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