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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Pneumonia, Diarrhea, Malaria, Co-infection, Death, Malnutrition

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Re-hospitalization or Death | 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 | 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 | 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 |  | 6 months | 
| The Number of Children With Malnutrition Re-hospitalizations Following Randomization |  | 6 months | 
| The Number of Children With Malaria Re-hospitalizations Following Randomization |  | 6 months | 
| Prevalence of Enteric Pathogen Carriage | Prevalence of enteric bacteria, viruses, and protozoa identified by qPCR at 3 months of follow-up | 3 months | 
| Prevalence of Streptococcus Pneumoniae Carriage | 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 | 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 |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post-discharge mortality, morbidity and mortality prevention, azithromycin, linear growth