Title: Dihydroartemisinin-piperaquine and azithromycin for the post-discharge management of children with severe anaemia in Malawi, Kenya and Uganda; A multicentre, parallel-group, two-arm, randomised, double-blind superiority trial

Short Title: Post-discharge Malaria Chemoprevention - II (PDMC-II) study

Background and rationale: 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 (PDMC) 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 PDMC intervention period. PDMC-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 PDMC can be boosted further by combining DP with azithromycin (AZ), a potent broad-spectrum antibiotic known to reduce all-cause mortality in African children.

Primary efficacy objective: To determine if PDMC with four courses of monthly AZ treatment courses (given monthly) in combination with four months of weekly DP is superior to PDMC with weekly DP-alone in reducing non-malaria SCCV by six months post-discharge in children aged <5 years admitted with severe anaemia (Hb<5g/dl) who are ready to be discharged and are clinically stable and able to switch to oral medication.

Hypothesis: An addition of four monthly AZ courses to a four months of malaria chemoprevention with weekly treatment courses with DP provided during the post-discharge period to children recently admitted with severe anaemia is superior to reduce all-cause sick-child visits rates by 6 months compared to a placebo (AZ-placebo).

Study Type: Multi-centre, 2-arm, placebo-controlled, individually randomized, trial of 4 courses of monthly AZ added to PDMC-DP in Malawi, Uganda and Kenya, using randomisation stratified by age and study centre.

Sites: 6 hospitals, 2 in Malawi, 2 in western Kenya and 2 in Uganda, in areas with moderate to intense malaria transmission. The number of hospitals will be expanded during recruitment if so required.

Study Population: Inclusion criteria: convalescent children aged less than 5 years and weighing ≥5 kg admitted with severe anaemia (haemoglobin<5g/dL or Ht<15%); clinically stable, able to take or switch to oral medication; post-transfusion Hb >5g/dL. Exclusion criteria: blood loss due to trauma, malignancy, known bleeding disorders or sickle cell disease, known hypersensitivity to study medication, known heart conditions, non-resident in study area, previous participation in study, known need at enrolment for prohibited medication (including cotrimoxazole prophylaxis) and scheduled surgery during the 6-month course of the study.

Study Interventions: Children in both arms will receive standard in-hospital care for severe anaemia (blood transfusion, often combined with quinine or artesunate IV/IM). All children will then receive a 3-day course of DP (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication, and will be completed at home after discharge. They will further take weekly doses of DP for 16 weeks (approximately 4 months). At 1 week after enrolment surviving children will be randomized to receive either a standard 3-day courses of AZ 10mg/kg body weight (Fosun Pharmaceuticals, China) or an identical placebo regimen at 1, 5, 9 and 13 weeks after enrolment.

Outcome Measures: Primary: Non-malaria sick-clinic visits (SCCV) by 6 months from randomization. Key secondary: 1) all-cause SCCV, 2) readmissions due to non-severe anaemia or non-severe malaria, 3) readmissions due to severe anaemia (requiring a blood transfusion), 4) all-cause hospital readmission, 5) All-cause mortality.

Follow-up procedures: Children will be followed for 6 months by passive case detection in 3 phases: Pre-intervention (1 week between discharge and randomisation); Intervention (1-17 weeks post-discharge); post-intervention (extended follow-up period from 18 to 26 weeks post-discharge).

Sample size: 958 participants (479 per arm) to allow the detection of ≥25% reduction in the incidence of all-cause SCCV from 147 to 110 per 100 child years, allowing for 15% loss to follow-up (power 90%, α=0.05). There will be one interim analysis half-way the study.

Data Analysis: Primary analysis will be by intention to treat. Incidence rates will be calculated and rate ratios estimated using Poisson regression, stratified by country, with treatment (as randomised) as the only co-variate. One interim analysis is planned. A Lan-DeMets α spending function with O’Brien-Fleming type of boundaries will be used to preserve the overall type I error rate (α=0.05). To assess how long any initial beneficial effect of the intervention is sustained, the observation time will also be divided into a) PDMC period (1-16 weeks); and b) Extended follow-up period (17-26 weeks post-discharge).

Partners institutions: Training and Research Unit of Excellence; University of Bergen; Makerere University; Global Health, Uganda; KEMRI-CDC, Kenya; Indiana University; Liverpool School of Tropical Medicine; University of Amsterdam; US Centers for Disease Control and Prevention, Kenya.