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

Malaria Clinical Trial

— Toto Bora  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02414399
• Other study ID #: STUDY00002592
• Secondary ID: R01HD079695
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: June 28, 2016
• Est. completion date: December 28, 2025

Study information

• Verified date: November 2023
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1400
• Est. completion date: December 28, 2025
• Est. primary completion date: May 4, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Month to 59 Months

Eligibility

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

Related Conditions & MeSH terms

• Co-infection
• Coinfection
• Death
• Diarrhea
• Malaria
• Malnutrition
• Pneumonia

Intervention

Drug:
• Azithromycin
oral administration of Azithromycin
• Placebo
5 days of taste/appearance/bottle-matched inactive substance

Locations

Country	Name	City	State
Kenya	Kisii Teaching and Referral Hospital, Homa Bay District Hospital, St. Paul's Mission Hospital	Kisii And Homa Bay Counties

Sponsors (3)

Lead Sponsor	Collaborator
University of Washington	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Kenya Medical Research Institute

Country where clinical trial is conducted

Kenya, 

References & Publications (13)

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	The Number of Children With Acute Respiratory Illness Re-hospitalizations Following Randomization		6 months
Secondary	The Number of Children With Malnutrition Re-hospitalizations Following Randomization		6 months
Secondary	The Number of Children With Malaria Re-hospitalizations Following Randomization		6 months
Secondary	Prevalence of Enteric Pathogen Carriage	Prevalence of enteric bacteria, viruses, and protozoa identified by qPCR at 3 months of follow-up	3 months
Secondary	Prevalence of Streptococcus Pneumoniae Carriage	Prevalence of Streptococcus pneumoniae from nasopharyngeal swabs collected at M3 and M6 follow-up timepoints.	6 months
Secondary	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)
Secondary	Proportion of Beta-lactam or Macrolide Resistance in Strep Pneumo in Children and Caregivers		6 months