| Protocol No: | ECCT/15/12/05 | Date of Protocol: | 27-11-2014 |
| Study Title: | Malaria Chemoprevention with monthly treatment with dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: A 3-year, multi-centre, parallel-group, two-arm randomised placebo controlled superiority trial |
| Study Objectives: | Primary objective
Secondary objectives
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| Laymans Summary: | N/A |
| Abstract of Study: |
Background and rationale: Children hospitalised with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No strategy specifically addresses this post-discharge period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly 3-day treatment courses of artemether-lumefantrine (AL) in children with severe malarial anaemia prevented 31% of deaths and readmissions. The effect was in addition to the effect of insecticide-treated bednets. These promising findings now need to be confirmed in other settings before the World Health Organisation can consider PMC for the post-discharge management of severe anaemia.
Primary efficacy objective: To determine if 3 months of post-discharge malaria chemoprevention with monthly 3-day treatment courses of dihydroartemisinin-piperaquine (DP) (PMC-DP) is safe and superior to the standard single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia.
Hypothesis: An additional three months of malaria chemoprevention with monthly 3-day treatment courses with DHA-piperaquine (each providing about 4 weeks of post-treatment prophylaxis) provided during the post-discharge period to children recently admitted with severe anaemia is superior to reduce all-cause readmission and mortality rates by 6 months compared with 2 weeks of post-treatment prophylaxis provided by the single course of oral artemether-lumefantrine when given as part of the standard in-hospital care around the time of discharge.
Study Type: Multi-centre, 2-arm, placebo-controlled, individually randomized, trial of 3 courses of monthly PMC-DP in Uganda and Kenya, using randomisation stratified by age and study centre.
Sites: 7 hospitals, 4 in western Kenya and 3 in Uganda, in areas with moderate to intense malaria transmission. The number of hospitals will be expanded if 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 / 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 trait, known hypersensitivity to study drug, known heart conditions, non-resident in study area, previous participation in study, known need at enrolment for prohibited medication and scheduled surgery during the 6-month course of the study. HIV infection and cotrimoxazole prophylaxis are not exclusion criteria.
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 AL (whether they initially had malaria or not), which will be started in-hospital assoon as they are able to take oral medication, and will be completed at home after discharge. At 2 weeks after enrolment surviving children will be randomized to receive either a standard 3-day courses of DP (Duo-Cotecxin®, HolleyCotec) or an identical placebo regimen at 2, 6 and 10 weeks after enrolment.
Outcome Measures: Primary: Death or all-cause re-admission between randomisation and 6 months from enrolment (composite primary outcome). Key secondary: 1) all-cause mortality, 2) all-cause hospital readmission, 3) readmissions due to severe anaemia or severe malaria (requiring parenteral quinine or artesunate), 4) non-severe all-cause sick-child clinic visits, 5) clinic visit because of RDT or microscopy confirmed non-severe malaria.
Follow-up procedures: Children will be followed for 6 months by passive case detection in 3 phases: Pre-PMC (2 weeks between discharge and randomisation); PMC (2-14 weeks post-discharge); post-PMC (extended follow period from 15 to 26 weeks post-discharge).
Sample size: A sample size of 1106 children per arm (2212 total children) allows detection of a 30% reduction from 17.6% to 12.3% with 10% loss to follow-up (power 90%, α=0.05).
Data Analysis: Primary analysis will be by intention to treat, and include all events to capture the potential effect of PMC on reducing first and repeat events. The protective efficacy (95% CI) will be calculated as 100 multiplied by (1–hazard ratio) and covariate-adjusted for prognostic factors at baseline. Incidence rates per child-year and absolute rate reductions will also be calculated. To assess how long any initial beneficial effect of PMC is sustained, the observation time will also be divided into a) PMC period (1-3 months); and b) Extended follow-up period (4–6 months).
Partners institutions: University of Bergen; University of Malawi; Makerere University; KEMRI-CDC, Kenya; University of Minnesota; Liverpool School of Tropical Medicine; London School of Hygiene & Tropical Medicine; Imperial College London; University of Amsterdam; US Centers for Disease Control and Prevention, University of North Carolina, and University of Massachusetts.
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