Severe Malaria A Research and Trials consortium - Multisite Adaptive Platform trial: SMAART-MAP trial
Severe malaria
In each domain (i.e. renal, cerebral, or severe anaemia complications of malaria) participants will be randomised 1:1 using an online tool to either: 1. High dose paracetamol (20mg/kg every 6 hours for 66 hours (last dose), given rectally, orally or via a nasogastric tube) compared to no or minimal paracetamol for fever reduction only (10mg/kg no more frequently than every 8 hours) (control) for those with impaired renal function (renal domain) 2. Parenteral levetiracetam (40 mg/kg loading dose and then 30mg/kg at 12 hours and 24 hours for all children, with doses at 36 hours and 48 hours only if the child has a temperature of >37.5°C or had a temperature of >37.5°C within the preceding 12 hours, or has a Blantyre Coma Score of ≤4) as prophylaxis to prevent further seizures compared to standard of care following national guidelines at each site (no prophylaxis) for children in the cerebral malaria domain 3. Blood transfusion with whole blood (20mls/kg if temperature at screening is >37.5⁰C, 30mls/kg if temperature is ≤37.5⁰C) compared to red cell concentrate (10mls/kg if axillary temperature is >37.5⁰C; 15mls/kg if axillary temperature is ≤37.5⁰C) for those with severe anaemia (severe anaemia domain)
For all domains: 1. Aged >3 months and <12 years 2. Admitted to the paediatric ward in the last 24 hours 3. Current or recent evidence of malaria (slide or rapid diagnostic test (RDT) positive in this admission) 4. Guardian willing to provide consent Additional domain-specific inclusion criteria: Renal domain: 1. Creatinine >1.5xULN on point-of-care assay or laboratory test at screening 2. Meet one of the current WHO severity criteria (clinical or laboratory (where these tests are done routinely)) (Group 1 and 2 from the recent WHO reclassification of severe malaria)) Cerebral malaria domain: EITHER 1. One or more reported seizures in the current episode of illness and altered consciousness (BCS≤4) at screening OR 2. Presence of coma (BCS ≤2) at screening regardless of history Severe anaemia domain: 1. Hb <6g/dl 2. One or more or the following severity signs: Hb<4g/dl, prostration, impaired consciousness, respiratory distress, history of passing red or coca-coloured urine in this illness
Renal domain: 1. Received paracetamol within 6 hours of screening or between screening and randomisation 2. Known allergy to paracetamol 3. Severe malnutrition (middle upper arm circumference MUAC<11.5cm) Cerebral malaria domain: 1. Received an anticonvulsant within 6 hours of screening or between screening and randomisation. 2. Known cerebral palsy or significant neuro-development delay Severe anaemia domain: 1. Known congenital or valvular heart disease (not surgically corrected)