Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Aged 2 to 59 Months: A Double-blind, Randomized Clinical Noninferiority Trial

JAMA Pediatr. 2019 Jan 1;173(1):21-28. doi: 10.1001/jamapediatrics.2018.3407.

Abstract

Importance: Pneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African settings is lacking.

Objective: To assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin.

Design, setting, and participants: This double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017.

Interventions: Placebo or amoxicillin dispersible tablets administered twice daily for 3 days.

Main outcomes and measures: The primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14.

Results: In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, -2.1% to 5.4%). There were no deaths.

Conclusions and relevance: In HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33.

Trial registration: ClinicalTrials.gov Identifier: NCT02760420.

Publication types

  • Equivalence Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amoxicillin / therapeutic use*
  • Anti-Bacterial Agents / therapeutic use*
  • Child, Preschool
  • Developing Countries
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Intention to Treat Analysis
  • Linear Models
  • Malawi
  • Male
  • Pneumonia / drug therapy*
  • Prospective Studies
  • Recurrence
  • Severity of Illness Index
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Amoxicillin

Associated data

  • ClinicalTrials.gov/NCT02760420