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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02414399
Recruitment Status : Completed
First Posted : April 10, 2015
Last Update Posted : June 2, 2020
Sponsor:
Collaborators:
Kenya Medical Research Institute
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Judd Walson, University of Washington

Tracking Information
First Submitted Date  ICMJE March 31, 2015
First Posted Date  ICMJE April 10, 2015
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE June 28, 2016
Actual Primary Completion Date May 4, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2015)
Composite outcome of mortality and hospital readmission [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2020)
  • Mean change in length for age z-score (LAZ) between baseline and outcome assessment [ Time Frame: 6 months ]
  • The number of children with diarrhea re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with acute respiratory illness re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with malnutrition re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with malaria re-hospitalizations following randomization [ Time Frame: 6 months ]
  • Prevalence of enteric pathogen carriage [ Time Frame: 6 months ]
  • Prevalence of Streptococcus pneumoniae carriage [ Time Frame: 6 months ]
  • Mean Enteric Inflammation Composite Score (Myeloperoxidase, Neopterin, Alpha-anti-trypsin) [ Time Frame: 6 months ]
  • Proportion of beta-lactam or macrolide resistance in Ecoli in children and caregivers [ Time Frame: 6 months ]
  • Mean fecal calprotectin levels [ Time Frame: 6 months ]
  • Proportion of beta-lactam or macrolide resistance in Strep pneumo in children and caregivers [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2015)
  • Mean change in length (cm) between baseline and outcome assessment [ Time Frame: 6 months ]
  • The number of children with diarrhea re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with acute respiratory illness re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with malnutrition re-hospitalizations following randomization [ Time Frame: 6 months ]
  • The number of children with malaria re-hospitalizations following randomization [ Time Frame: 6 months ]
  • Prevalence of pathogen carriage [ Time Frame: 6 months ]
  • Mean Enteric Inflammation Composite Score (Myeloperoxidase, Neopterin, Alpha-anti-trypsin) [ Time Frame: 6 months ]
  • Proportion of beta-lactam or macrolide resistance or both [ Time Frame: 6 months ]
  • Proportion of beta-lactam or macrolide resistance or both [ Time Frame: 90 days ]
  • Mean fecal calprotectin levels [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children
Official Title  ICMJE Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pneumonia
  • Diarrhea
  • Malaria
  • Co-infection
  • Death
  • Malnutrition
Intervention  ICMJE
  • Drug: Azithromycin
    oral administration of Azithromycin
    Other Names:
    • Zithromax
    • Zmax
  • Drug: Placebo
    5 days of taste/appearance/bottle-matched inactive substance
Study Arms  ICMJE
  • Experimental: Azithromycin
    Azithromycin 10mg/kg for one day, then 5mg/kg for four days, a total of five days of experimental treatment.
    Intervention: Drug: Azithromycin
  • Placebo Comparator: Placebo
    5 days of taste/appearance/bottle-matched placebo
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 7, 2015)
1400
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 4, 2020
Actual Primary Completion Date May 4, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 59 Months   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Kenya
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02414399
Other Study ID Numbers  ICMJE STUDY00002592
R01HD079695 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Judd Walson, University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE
  • Kenya Medical Research Institute
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
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
PRS Account University of Washington
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP