Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children

NCT ID: NCT02414399

Last Updated: 2023-12-04

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 1400 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-28
• Study Completion Date: 2025-12-28

Brief Summary

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.

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.

Conditions

Pneumonia; Diarrhea; Malaria; Co-infection; Death; Malnutrition

Keywords

post-discharge mortality; morbidity and mortality prevention; azithromycin; linear growth

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Azithromycin

Azithromycin 10mg/kg for one day, then 5mg/kg for four days, a total of five days of experimental treatment.

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

oral administration of Azithromycin

Placebo

5 days of taste/appearance/bottle-matched placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

5 days of taste/appearance/bottle-matched inactive substance

Interventions

Azithromycin

oral administration of Azithromycin

Intervention Type: DRUG

Placebo

5 days of taste/appearance/bottle-matched inactive substance

Intervention Type: DRUG

Other Intervention Names

Zithromax; Zmax

Eligibility Criteria

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

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 59 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Kenya Medical Research Institute

OTHER

Sponsor Role: collaborator

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

NIH

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Judd Walson

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Judd L Walson, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Washington Department of Global Health

Patricia B Pavlinac, PhD, MS

Role: STUDY_DIRECTOR

University of Washington Department of Global Health

Locations

Kisii Teaching and Referral Hospital, Homa Bay District Hospital, St. Paul's Mission Hospital

Kisii and Homa Bay Counties, , Kenya

Countries

Kenya

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Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

R01HD079695

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00002592

Identifier Type: -

Identifier Source: org_study_id