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Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial)
  1. Patricia B Pavlinac1,
  2. Benson O Singa2,3,
  3. Grace C John-Stewart1,4,5,6,
  4. Barbra A Richardson1,7,
  5. Rebecca L Brander4,
  6. Christine J McGrath1,
  7. Kirkby D Tickell1,3,
  8. Mary Amondi2,
  9. Doreen Rwigi2,
  10. Joseph B Babigumira1,8,
  11. Sam Kariuki9,
  12. Ruth Nduati10,
  13. Judd L Walson1,3,4,5,6
  1. 1 Department of Global Health, University of Washington, Seattle, Washington, USA
  2. 2 Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya
  3. 3 Childhood Acute Illness and Nutrition Network, Nairobi, Kenya
  4. 4 Department of Epidemiology, University of Washington, Seattle, Washington, USA
  5. 5 Department of Pediatrics, University of Washington, Seattle, Washington, USA
  6. 6 Department of Allergy and Infectious Disease, University of Washington, Seattle, Washington, USA
  7. 7 Department of Biostatistics, University of Washington, Seattle, Washington, USA
  8. 8 Department of Pharmacy, University of Washington, Seattle, Washington, USA
  9. 9 Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya
  10. 10 Department of Pediatrics, School of Medicine, University of Nairobi, Nairobi, Kenya
  1. Correspondence to Dr Patricia B Pavlinac; ppav{at}


Introduction Child mortality due to infectious diseases remains unacceptably high in much of sub-Saharan Africa. Children who are hospitalised represent an accessible population at particularly high risk of death, both during and following hospitalisation. Hospital discharge may be a critical time point at which targeted use of antibiotics could reduce morbidity and mortality in high-risk children.

Methods and analysis In this randomised, double-blind, placebo-controlled trial (Toto Bora Trial), 1400 children aged 1–59 months discharged from hospitals in Western Kenya, in Kisii and Homa Bay, will be randomised to either a 5-day course of azithromycin or placebo to determine whether a short course of azithromycin reduces rates of rehospitalisation and/or death in the subsequent 6-month period. The primary analysis will be modified intention-to-treat and will compare the rates of rehospitalisation or death in children treated with azithromycin or placebo using Cox proportional hazard regression. The trial will also evaluate the effect of a short course of azithromycin on enteric and nasopharyngeal infections and cause-specific morbidities. We will also identify risk factors for postdischarge morbidity and mortality and subpopulations most likely to benefit from postdischarge antibiotic use. Antibiotic resistance in Escherichia coli and Streptococcus pneumoniae among enrolled children and their primary caregivers will also be assessed, and cost-effectiveness analyses will be performed to inform policy decisions.

Ethics and dissemination Study procedures were reviewed and approved by the institutional review boards of the Kenya Medical Research Institute, the University of Washington and the Kenyan Pharmacy and Poisons Board. The study is being externally monitored, and a data safety and monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this trial will be published in peer-reviewed scientific journals and presented at relevant academic conferences and to key stakeholders.

Trial registration number NCT02414399.

  • child mortality
  • post-discharge interventions
  • toto bora trial
  • targeted empiric antibiotic therapy

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  • Contributors JW, PBP, GJ-S, BAR, BOS and RN conceived of this trial and developed the study protocol. JW and BOS are study coprincipal investigators, and PBP is the project director; BAR oversaw the statistical analyses plans; JBB developed the CEA plan; KDT developed procedures for ascertaining and reporting SAEs; CJM developed procedures related to blood specimen procedures and drug adherence measurement. GJ-S, CJM, RN and PBP provided scientific expertise. RLB and MA are involved in collection and management of the data. MA and PBP coordinated and oversaw implementation of all clinical study procedures, and SK, with assistance from DR, oversees all laboratory procedures. All authors contributed to the development of this manuscript and/or study procedures and to reading and approving the final version for publication.

  • Funding This work was funded by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health & Human Development, grant number R01 HD079695.

  • Competing interests None declared.

  • Ethics approval This study has received IRB approval by the University of Washington Human Subjects Division, KEMRI Scientific and Ethics Review Unit and the Kenya Pharmacy and Poisons Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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