Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children (Toto Bora)
The primary aim of this trial is to compare rates of re-hospitalization and mortality in the 6 months following hospital discharge among Kenyan children receiving 5-day azithromycin vs. 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.
The hypothesis is that 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.
- 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.
- To identify correlates and intermediate markers of post-discharge mortality and hospital readmission among hospitalized Kenyan children.
- 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.
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.
ClinicalTrials.gov Identifier: NCT02414399
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||1400 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|