Sagara 2018.

Study characteristics
Methods	RCT* Duration: 4 years, 4 months: 24 October 2011 to 1 February 2016 *Different arms at different study centres, therefore we requested disaggregated data
Participants	Adults and children with Plasmodium falciparum malaria Number: 4710 (2640 within pyronaridine‐artesunate subsection) Inclusion criteria: age > 2 years*; bodyweight ≥ 15 kg (decreased to ≥ 5 kg after review); fever or history of fever within 24 hours Exclusion criteria: severe/complicated malaria; severe vomiting; severe diarrhoea; other clinically significant disorder including QTc ≥ 450 ms, active tuberculosis, jaundice and others; anaemia (haemoglobin < 70 g/dL); other febrile conditions; allergy to study drugs; antimalarial therapy in previous 2 weeks; investigational drug in previous 4 weeks; pregnancy/lactation; alcohol abuse; viral hepatitis/HIV; hepatic impairment (ALT > 2 x ULN); renal impairment (1.5 x ULN) Diagnosis: positive microscopy for Plasmodium spp. (> 0 to < 200,000 parasites/μL blood) *For pyronaridine‐artesunate group, inclusion criteria changed during the study. (i) Beginning of the study, inclusion age of 15 years or older and bodyweight of 24 kg or over, (ii) after 20 retreatments, inclusion age of 2 years or older and bodyweight of 15 kg or over, and (iii) after 40 retreatments, inclusion age of at least 6 months with bodyweight of 5 kg or over Children under 5: 344 (PY‐AS); 129 (AL); 249 (AS‐AQ) The total number of participants receiving at least 1 study treatment in each comparison are below. Pyronaridine‐artesunate (n = 658) versus artemether‐lumefantrine (n = 665) Pyronaridine‐artesunate (n = 659) versus artesunate‐amodiaquine (n = 658) The breakdown of total participants receiving each treatment at each site is below. Bobo‐Dioulasso, Burkina Faso: PY‐AS (n = 212) versus AL (n = 220) Ouagadougou, Burkina Faso: PY‐AS (n = 215) versus AS‐AQ (n = 214) Bougoula, Mali: 1. PY‐AS (n = 214) versus AL (213); 2. PY‐AS (n = 94) versus AS‐AQ (n = 98) Djoliba, Mali: PY‐AS (n = 87) versus AS‐AQ (n = 85) Kolle, Mali: 1. PY‐AS (n = 86) versus AL (87); 2. PY‐AS (n = 11) versus AS‐AQ (n = 11) Sotuba, Mali: 1. PY‐AS (n = 146) versus AL (145); 2. PY‐AS (n = 17) versus AS‐AQ (n = 17) Mafrinyah, Guinea: PY‐AS (n = 235) versus AS‐AQ (n = 233) The total numbers of participants and numbers disaggregated by each site were obtained from the trial authors in response to a request for further information in May 2017.
Interventions	Pyronaridine‐artesunate granules (60 mg:20 mg) or tablets (180 mg:60 mg) once daily for 3 days. Dose according to bodyweight: 5 kg to 8 kg, 2 sachet; 8 kg to 15 kg, 2 sachets; 15 kg to 20 kg, 3 sachets; 20 kg to 24 kg, 1 tablet; 24 kg to 45 kg, 2 tablets; 45 kg to 65 kg, 3 tablets; ≥ 65 kg, 4 tablets Artemether‐lumefantrine tablets (20 mg/120 mg) twice daily for 3 days at recommended intervals. Dose according to bodyweight: 5 kg to 15 kg, 1 tablet; 15 kg to 25 kg, 2 tablets; 25 kg to 35 kg, 3 tablets; ≥ 35 kg, 4 tablets Amodiaquine‐artesunate tablets once daily for 3 days. Dose according to bodyweight: 5 kg to 9 kg, one 25 mg:67.5 mg tablet; 9 kg to 18 kg, one 50 mg:135 mg tablet; 18 kg to 36 kg, one 100 mg:270 mg tablet; ≥ 36 kg, two 100 mg:270 mg tablets Dihydroartemisinin‐piperaquine* *Not compared against pyronaridine‐artesunate in this trial
Outcomes	2‐year incidence rate of all repeat malaria episodes (uncomplicated and complicated) irrespective of parasite species* Crude and PCR‐corrected ACPR for Pfalciparum and crude ACPR for other Plasmodium species at days 28 and 42, irrespective of axillary temperature, without previous early treatment failure, late clinical failure, or late parasitological failure Parasite clearance time (time from first dose until parasite negative, with aparasitaemia maintained for at least 48 h)* Re‐infection and recrudescence rates over 42 days* Gametocyte density and carriage* Difference in time to the second infection between treatments* Difference in the mean interval between re‐infection* Adverse events *Not assessed in quantitative synthesis in this review
Notes	Location: West Africa (Burkina Faso, Guinea, Mali), conducted by the West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) Setting: tertiary health facilities Malaria endemicity: high Resistance profile: not described Source of funding: European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture, United Kingdom Medical Research Councils, Swedish International Development Co‐operation Agency, German Ministry for Education and Research, University Claude Bernard (France), University of Science Techniques and Technologies of Bamako, Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo‐Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea) Follow‐up: 42 days active; 2 year passive
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization list for each site within each country was used; block size of 2
Allocation concealment (selection bias)	Low risk	Sealed, opaque, sequentially numbered envelopes
Blinding (performance bias and detection bias) All outcomes	Low risk	Open‐label: participants and investigators not blinded to treatment allocation Microscopists assessing parasite outcomes masked to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons provided for all withdrawals across study arms. Withdrawal numbers small and balanced across the intervention arms with reasons for withdrawal similar between groups.
Selective reporting (reporting bias)	Low risk	All outcomes reported as listed in the trial register; however, day 63 outcomes are not reported.
Other bias	Low risk	Some authors employed by trial sponsors, but all authors assumed responsibility for reporting accuracy.
Adverse event monitoring (detection bias) Adverse events	Low risk	Authors report that physical examinations made and adverse events recorded at all assessments. Describes ECG and biochemistry monitoring schedule. Used Medical Dictionary for Regulatory Activities (MedDRA)
Incomplete adverse event reporting (reporting bias) Adverse events	Low risk	Authors enumerate adverse events clearly, and report events of interest. Supplementary tables are provided. We were unable to extract adverse events by study site.