Tshefu 2010.

Methods	RCT Duration: 1 year, 3 months. January 2007 to April 2008
Participants	Adults and children with P falciparum malaria Number: 1272 Inclusion criteria: age 3‐60 years; bodyweight 20 kg ‐ 90 kg; fever or history of fever within 24 hours Exclusion criteria: severe/complicated malaria; mixed Plasmodium infection; malnutrition; anaemia (Hb < 8 g/dL); severe vomiting; severe diarrhoea; other clinically significant disorder; hepatic impairment (limit not stated); renal impairment; other febrile conditions; viral hepatitis/HIV; electrolyte imbalance; allergy to study drugs; antimalarial therapy in previous 2 weeks, investigational drug in previous 4 weeks; taking any drug metabolized by cytochrome enzyme CYP2D6; previous participation in pyronaridine‐artesunate studies; pregnancy/lactation Diagnosis: microscopy (asexual parasite density 1000 µL to 100,000/µL blood)
Interventions	Randomized in a 2:1 ratio to: pyronaridine‐artesunate tablets (180 mg:60 mg) once‐daily for 3 days. Dose according to bodyweight: 20 kg ‐ 25 kg one tablet, 26 kg ‐ 45 kg 2 tablets, 45 kg ‐ 65 kg 3 tablets, ≥ 65kg 4 tablets (N = 849) Artemether‐lumefantrine tablets (20 mg/120 mg) twice daily for 3 days at recommended intervals. Dose according to bodyweight: 20 kg ‐ 25 kg 2 tablets, 25 kg ‐ 35 kg 3 tablets, ≥ 35 kg 4 tablets
Outcomes	ACPR* day 28 PCR‐adjusted ACPR day 28 unadjusted ACPR day 42 PCR‐adjusted ACPR day 42 unadjusted Parasite clearance time (from first dose to aparasitaemia)†, ‡ Fever clearance time (from first dose to apyrexia)†, ‡ Proportion of patients with parasite clearance on days 1, 2, and 3, ‡ Proportion of patients with fever clearance on days 1, 2, and 3, ‡ Gametocyte density, ‡ Adverse events (including laboratory and ECG abnormalities) *Adequate clinical and parasitological response rate †Two consecutive normal readings taken between 7 and 25 hours apart ‡Not assessed in quantitative synthesis in this review
Notes	Location: Africa (n = 1080, 85%) and Asia (n = 192, 15%). Africa: DRC, The Gambia, Ghana, Kenya, Mali, Mozambique, Senegal. Asia: Indonesia, the Phillipines Setting: local hospitals and clinics Malaria endemicity: high Resistance profile: not described Funding: Medicines for Malaria Venture, Shin Poong Pharmaceutical Company Ltd, Seoul, Republic of Korea Follow‐up: 42 days
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomization schedule. Block randomization of 9 by study centre
Allocation concealment (selection bias)	Low risk	Individually numbered treatment packs Randomization communicated by investigator to a third party who administered the correct amount of tablets, and who was not involved in clinical assessment
Blinding (performance bias and detection bias) All outcomes	Low risk	Patients blinded: artemether‐lumefantrine placebo dosed twice daily to maintain blinding. Food not required for artemether‐lumefantrine dosing to retain blinding Outcome assessors blinded to group assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	Report lists reasons for attrition and exclusions
Selective reporting (reporting bias)	Low risk	Prospectively registered. Report includes prestated outcomes of interest. Day 42 efficacy outcomes and gametocyte counts not listed in trial registration document; listed in the report as exploratory
Other bias	Unclear risk	Sponsors designed the trial, were responsible for data collection and analysis, and developed the report; all authors had access to trial data Participants on artemether‐lumefantrine were not expected to take medication after food; unclear if this reduced bioavailability of lumefantrine
Adverse event monitoring (detection bias) Adverse Events	Low risk	Report that adverse events recorded during treatment and at all follow‐up visits
Incomplete adverse event reporting (reporting bias) Adverse events	Unclear risk	Authors report all‐cause adverse events as percentages. Report table only includes adverse events occurring in ≥ 5% (or ≥ 1% if judged to be drug related). Authors explain method for determining relation to study drug

Abbreviations: ACPR: adequate clinical and parasitological response; ALT: alanine aminotransferase; AST: aspartate transaminase; ECG: electrocardiogram; Hb: haemoglobin; MMV: Medicines for Malaria Venture; PCR: polymerase chain reaction; QT: QT interval on electrocardiogram; QTc: corrected QT interval on electrocardiogram; RCT: randomized controlled trial; ULN: upper limit of normal.