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

• ClinicalTrials.gov Identifier: NCT02414399
• Recruitment Status: Completed
• First Posted: April 10, 2015
• Last Update Posted: June 2, 2020
• Sponsor: University of Washington
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pneumonia; Diarrhea; Malaria; Co-infection; Death; Malnutrition	Drug: Azithromycin; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Azithromycin to Prevent Post-discharge Morbidity and Mortality in Kenyan Children
• Actual Study Start Date: June 28, 2016
• Actual Primary Completion Date: May 4, 2020
• Actual Study Completion Date: May 4, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Azithromycin; Azithromycin 10mg/kg for one day, then 5mg/kg for four days, a total of five days of experimental treatment.	Drug: Azithromycin; oral administration of Azithromycin; Other Names: Zithromax; Zmax
Placebo Comparator: Placebo; 5 days of taste/appearance/bottle-matched placebo	Drug: Placebo; 5 days of taste/appearance/bottle-matched inactive substance

Outcome Measures

Primary Outcome Measures :

1. Composite outcome of mortality and hospital readmission [ Time Frame: 6 months ]

Secondary Outcome Measures :

1. Mean change in length for age z-score (LAZ) between baseline and outcome assessment [ Time Frame: 6 months ]
2. The number of children with diarrhea re-hospitalizations following randomization [ Time Frame: 6 months ]
3. The number of children with acute respiratory illness re-hospitalizations following randomization [ Time Frame: 6 months ]
4. The number of children with malnutrition re-hospitalizations following randomization [ Time Frame: 6 months ]
5. The number of children with malaria re-hospitalizations following randomization [ Time Frame: 6 months ]
6. Prevalence of enteric pathogen carriage [ Time Frame: 6 months ]
7. Prevalence of Streptococcus pneumoniae carriage [ Time Frame: 6 months ]
8. Mean Enteric Inflammation Composite Score (Myeloperoxidase, Neopterin, Alpha-anti-trypsin) [ Time Frame: 6 months ]
9. Proportion of beta-lactam or macrolide resistance in Ecoli in children and caregivers [ Time Frame: 6 months ]
10. Mean fecal calprotectin levels [ Time Frame: 6 months ]
11. Proportion of beta-lactam or macrolide resistance in Strep pneumo in children and caregivers [ Time Frame: 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 59 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

Kenya

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

Kisii And Homa Bay Counties, Kenya

Sponsors and Collaborators

University of Washington

Kenya Medical Research Institute

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

Investigators

• 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

  Study Documents (Full-Text)

Documents provided by Judd Walson, University of Washington:

Study Protocol  [PDF] December 12, 2017

Statistical Analysis Plan  [PDF] May 29, 2020

More Information

Publications:

Porco TC, Gebre T, Ayele B, House J, Keenan J, Zhou Z, Hong KC, Stoller N, Ray KJ, Emerson P, Gaynor BD, Lietman TM. Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA. 2009 Sep 2;302(9):962-8. doi: 10.1001/jama.2009.1266.

Moisi JC, Gatakaa H, Berkley JA, Maitland K, Mturi N, Newton CR, Njuguna P, Nokes J, Ojal J, Bauni E, Tsofa B, Peshu N, Marsh K, Williams TN, Scott JA. Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. Bull World Health Organ. 2011 Oct 1;89(10):725-32, 732A. doi: 10.2471/BLT.11.089235. Epub 2011 Jul 13.

Lozano R, Wang H, Foreman KJ, Rajaratnam JK, Naghavi M, Marcus JR, Dwyer-Lindgren L, Lofgren KT, Phillips D, Atkinson C, Lopez AD, Murray CJ. Progress towards Millennium Development Goals 4 and 5 on maternal and child mortality: an updated systematic analysis. Lancet. 2011 Sep 24;378(9797):1139-65. doi: 10.1016/S0140-6736(11)61337-8. Epub 2011 Sep 19.

Veirum JE, Sodeman M, Biai S, Hedegard K, Aaby P. Increased mortality in the year following discharge from a paediatric ward in Bissau, Guinea-Bissau. Acta Paediatr. 2007 Dec;96(12):1832-8. doi: 10.1111/j.1651-2227.2007.00562.x.

Snow RW, Howard SC, Mung'Ala-Odera V, English M, Molyneux CS, Waruiru C, Mwangi I, Roberts DJ, Donnelly CA, Marsh K. Paediatric survival and re-admission risks following hospitalization on the Kenyan coast. Trop Med Int Health. 2000 May;5(5):377-83. doi: 10.1046/j.1365-3156.2000.00568.x.

Keenan JD, Ayele B, Gebre T, Zerihun M, Zhou Z, House JI, Gaynor BD, Porco TC, Emerson PM, Lietman TM. Childhood mortality in a cohort treated with mass azithromycin for trachoma. Clin Infect Dis. 2011 Apr 1;52(7):883-8. doi: 10.1093/cid/cir069.

Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, Manary MJ. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013 Jan 31;368(5):425-35. doi: 10.1056/NEJMoa1202851.

Walker AS, Mulenga V, Ford D, Kabamba D, Sinyinza F, Kankasa C, Chintu C, Gibb DM; CHAP Team. The impact of daily cotrimoxazole prophylaxis and antiretroviral therapy on mortality and hospital admissions in HIV-infected Zambian children. Clin Infect Dis. 2007 May 15;44(10):1361-7. doi: 10.1086/515396. Epub 2007 Apr 12.

Roy SK, Chowdhury AK, Rahaman MM. Excess mortality among children discharged from hospital after treatment for diarrhoea in rural Bangladesh. Br Med J (Clin Res Ed). 1983 Oct 15;287(6399):1097-9. doi: 10.1136/bmj.287.6399.1097.

Wiens MO, Pawluk S, Kissoon N, Kumbakumba E, Ansermino JM, Singer J, Ndamira A, Larson C. Pediatric post-discharge mortality in resource poor countries: a systematic review. PLoS One. 2013 Jun 25;8(6):e66698. doi: 10.1371/journal.pone.0066698. Print 2013.

Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, Williams TN, Mohammed S, Osier F, Kinyanjui S, Fegan G, Lowe BS, English M, Peshu N, Marsh K, Newton CR. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis. 2009 Aug 1;49(3):336-43. doi: 10.1086/600299.

Bernstein DS. Medical student indebtedness and choice of specialty. JAMA. 1992 Apr 8;267(14):1921. No abstract available.

Pavlinac PB, Singa BO, John-Stewart GC, Richardson BA, Brander RL, McGrath CJ, Tickell KD, Amondi M, Rwigi D, Babigumira JB, Kariuki S, Nduati R, Walson JL. 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). BMJ Open. 2017 Dec 29;7(12):e019170. doi: 10.1136/bmjopen-2017-019170.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pavlinac PB, Singa B, Huang ML, Shrestha L, Li V, Atlas HE, Diakhate MM, Brander R, Meshak L, Bogonko G, Tickell KD, McGrath CJ, Machuara IM, Ounga DO, Berkley JA, Richardson BA, John-Stewart G, Walson JL, Slyker J. Cytomegalovirus Viremia Predicts Postdischarge Mortality in Kenyan HIV-Exposed Uninfected Children. J Infect Dis. 2022 Nov 1;226(9):1519-1527. doi: 10.1093/infdis/jiac047.

Pavlinac PB, Singa BO, Tickell KD, Brander RL, McGrath CJ, Amondi M, Otieno J, Akinyi E, Rwigi D, Carreon JD, Tornberg-Belanger SN, Nduati R, Babigumira JB, Meshak L, Bogonko G, Kariuki S, Richardson BA, John-Stewart GC, Walson JL. Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial. Lancet Glob Health. 2021 Nov;9(11):e1569-e1578. doi: 10.1016/S2214-109X(21)00347-8. Epub 2021 Sep 21.

• Responsible Party: Judd Walson, Associate Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT02414399
• Other Study ID Numbers: STUDY00002592; R01HD079695 ( U.S. NIH Grant/Contract )
• First Posted: April 10, 2015
• Last Update Posted: June 2, 2020
• Last Verified: May 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Judd Walson, University of Washington:

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

Additional relevant MeSH terms:

Coinfection; Malnutrition; Diarrhea; Infections; Signs and Symptoms, Digestive; Nutrition Disorders; Azithromycin; Anti-Bacterial Agents; Anti-Infective Agents