Combining monthly dihydroartemisinin-piperaquine and azithromycin for the post-discharge management of children with severe anaemia in Malawi, Kenya and Uganda; a randomised, double-blind trial

Severe anaemia is associated with significant post-discharge morbidity and mortality in children in malaria-endemic Africa. A recent trial in areas with moderate to intense malaria transmission in Kenya and Uganda showed that three months of post-discharge malaria chemoprevention (PMC) with monthly dihydroartemisinin-piperaquine (DP) in recently transfused children with severe anaemia prevented 35% of deaths or all-cause readmissions by six months post-discharge. The protective effect was restricted to the 3-month PMC intervention period. PMC-DP did not affect non-malarial causes of readmissions; 45% and 80% of the remaining readmissions and sick-child clinic visits (SCCV) were due to other causes. We hypothesise that the beneficial effect of PMC can be boosted further by combining DP with azithromycin (AZ), a potent broad-spectrum antibiotic known to reduce all-cause mortality in African children.  The study is designed to inform a WHO and national policy for the post-discharge management of children admitted with severe anaemia living in moderate to intense malaria transmission areas.  

Trial Design: Multi-centre, 2-arm, individually randomized, placebo-controlled, superiority trial in Malawi, Kenya and Uganda. PMC courses will be given at discharge, and 1, 2, and 3 months post-discharge to provide four months of protection with 3-day DP-alone (dispersible tablets) or combined with 1-day AZ (20mg/kg syrup PO). Children in the DP-alone arm will receive AZ placebo. 

Sample Size: 952 participants (476 per arm) to allow the detection of ≥20% reduction in the incidence of all-cause SCCV from 112 to 89 per 100 child years, allowing for 10% loss to follow-up (power 90%, α=0.05). There will be one interim analysis half-way the study.

Sub-studies: a) Nested cardiac monitoring in the first 110 participants; b) Acceptability and feasibility studies; b) Cost-effectiveness studies; c) Assessment of piperaquine and macrolide resistance. 

Timeline: 51 months(m): 9m preparation, 30+6m for the trial and analysis, 6+2m for the subsequent feasibility study and analysis.  Impact: 

Trial number: PACTR202303630742194

Project details

Drug-based Strategies
Vulnerable Populations

Oct 2021 — Dec 2025

$4.01M

Kenya
Malawi
Uganda