Dondorp 2010.

Methods	Study design: An open label, multi‐centre randomized controlled trial Study dates: Oct 2005 to July 2010
Participants	Number: enrolled Inclusion criteria: Age < 15 years (age criteria varied slightly between sites at the request of the respective ethics review boards), a positive rapid diagnostic test for P. falciparum, severe malaria (physicians opinion), written consent Exclusions: Prior full treatment with parenteral quinine, or an artemisinin derivative for more than 24 h.
Interventions	Each study site used either the intravenous or intramuscular route for both treatment arms 1. Artesunate (Guilin, China): 2·4 mg/kg on admission, at 12 h, at 24 h, and then once daily until starting oral therapy. 2. Quinine dihydrochloride (Indus Pharma, Pakistan): 20 mg salt per kg loading dose infused over 4 h (in 5–10 mL/kg of 5% dextrose), followed by a 10 mg salt per kg infusion over 2–8 h three times daily until starting oral therapy. (For intramuscular treatment the doses were the same as for intravenous treatment; quinine was diluted in normal saline to a concentration of 60 mg/mL, and injected into the anterior thigh. The loading dose was given as a split dose into each thigh). Once able to tolerate oral medication (but after a minimum of 24 h of parenteral treatment), all participants received oral artemether‐lumefantrine (Novartis, Switzerland) for 3 days with milk or fat)
Outcomes	1. Death 2. Death or sequelae at 28 days 3. Malaria attributable mortality 4. Case fatality in HIV +ve children 5. Time to discharge 3. Neurological sequelae 4. Adverse events Not included in the review: 1. Development of coma 2. Convulsions developing after 6 hours 3. Severe anaemia after admission 4. Blackwater fever 5. Time to speak (median, intra quartile range) 6. Time to eat (median, intra quartile range) 7. Time to sit unsupported (median, intra quartile range) 8. Time to localise pain (median, intra quartile range)
Notes	Location: 11 centres in nine African countries (Mozambique, The Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda, and Democratic Republic of the Congo). Transmission: variable Funding: The Wellcome Trust
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: 'Randomisation was done by people unrelated to the study and provided to the study sites in blocks of 20'.
Allocation concealment (selection bias)	Low risk	Quote: 'Study numbers were kept inside opaque sealed paper envelopes. After full informed written consent was obtained, the next envelope, which contained a unique study box number, was opened by the study physician or nurse. Then the corresponding numbered sealed box was opened. This box contained the study drug, case record form (labelled with the unique study number), and all disposables needed for drug administration and blood sampling'.
Blinding (performance bias and detection bias) Objective outcomes: Death	Low risk	Comment: An open‐label trial is unlikely to bias an objective outcome like death
Blinding (performance bias and detection bias) Subjective outcomes: Others	High risk	Quote: 'Although the trial was open label at each site, none of the investigators or triallists, apart from for the trial statistician (TEP), had access to the summaries of treatment allocations. When notes or case record forms were reviewed, all study drug details were removed to preserve masking'
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants are included in the primary analysis. A secondary per‐protocol analysis including only those with proven malaria who received the full course of treatment excluded 149 (5.5%) from the artesunate arm and 161 (5.9%) from the quinine arm
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting.
Other bias	Low risk	One study site did study adults as well as children but these participants are not reported in the paper, or analysis.