Poravuth 2011

Methods	Trial design: Randomized, multicentre, double-blind, double-dummy, parallel-group, non-inferiority trial Period of trial: March 2007 to March 2008
Participants	Number randomized: 456 Age range: Seven years to 60 years Gender: Both Inclusion criteria: Aged three years to 60 years Fever or documented fever in the previous 24 hrs Microscopically confirmed mono-infection withP. vivax (parasite density:  ≥ 250 µL with at least 50% asexual parasites/µL blood) Body weight 20 kg to 90 kg Written informed consent from participants or their guardians, with assent from children able to understand the trial Able to swallow oral medication Willingness to comply with protocol Negative urine test for pregnancy and agreement to practice contraception (women of child-bearing potential) Exclusion criteria: Complicated or severe malaria Mixed infections Anaemia (< 8 g/dL); severe vomiting Clinical severe malnutrition Hepatic or renal impairment Presence or history of clinically important disorders Hypersensitivity or allergy to trial drugs or excipients Use of antimalarials in the previous two weeks by testing; or use of any trial drug for previous four weeks Treatment with any drug metabolised by CYP2D6; pregnant and lactating women Previous inclusion in a similar trial of artesunate-pyronaridine
Interventions	Intervention: Artesunate-pyronaridine tablets (180:60 mg) once daily for three days* (N = 228) Control: Chloroquine based on body weight once daily for three days** (N = 228) *For artesunate-pyronaridine, drug dose was based on body weight: 20 kg to 25 kg, 1 tablet; 26 kg to 44 kg, two tablets; 45 kg to 64 kg, three tablets; and 65 kg to 90 kg, four tablets, (giving a artesunate-pyronaridine target dose of between 7.2:2.4 mg/kg and13.8:4.6 mg/kg). **The chloroquine dose for adults was 620 mg on Day 0 and 1, and 310 mg on Day 2. The chloroquine target dose for children was 10 mg/kg on Days 0 and 1, and 5 mg/kg on Day 2.
Outcomes	Outcomes used in this review: Adverse events affecting liver functions (Grade 3 and 4 toxicity: aspartate amino transferase, alanine amino transferase, bilirubin) Outcomes reported but not used in this review: Cure rates on days 14, 21, 35, and 42 Treatment failure Day 28 cure rate Fever clearance time Proportions afebrile and aparasitaemic on days 1, 2, and 3 Adverse events other than those affecting liver function
Notes	Countries of recruitment: Four countries in Asia (Cambodia, India, Indonesia, and Thailand) Setting: Five local hospitals in four countries in Asia Funding: Medicines for Malaria Venture, Poong Pharmaceutical Company Ltd, Seoul, Republic of Korea Endemicity: High Duration of follow-up: Until day 42 Comment: Age range of participants: 14 (6.1%) in the Py-AS arm and 13 (5.7%) in the chloroquine arm were < 12 years of age Sample size estimation: Assuming a day-14 cure rate of 95%, and a dropout rate of 10%, the sample size was estimated to provide = 99% power to demonstrate non-inferiority of artesunate-pyronaridine compared to chloroquine G6PD deficiency was detected in 16/228 (7.0%) of patients in each treatment group Primaquine was administered to 185/228 (87.3%) patients in the artesunate-pyronaridine group and 181/228 (85.4%) in the chloroquine group starting on Day 28 of the trial Definitions of Grade 3 and 4 toxicity: Grade 3 toxicity: Hb (65 to 79 g/L); ALT/AST/ALP (5.1 to 10.6 times the upper limit of normal); TBIL (2.6 to 5.6 times the upper limit of normal). Grade 4 toxicity: ALT/AST (=10.6 times the upper limit of normal). Trials registration: ClinicalTrials.gov identifier: NCT00440999
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from report: "A computer-generated randomisation scheme was provided by the sponsor. Subjects were randomised 1:1 within each study site in blocks of six."
Allocation concealment (selection bias)	Low risk	Quotes from report: "Subjects were randomised...to receive either artesunate-pyronaridine plus matching chloroquine placebo or oral chloroquine plus matching artesunate-pyronaridine placebo". "The subject was allocated an individually numbered treatment pack, which contained sufficient tablets for 3 days' therapy plus an overage bottle containing tablets in case the subject vomited the first dose. All study investigators, laboratory technicians and patients were blind to treatment assignment". "Sealed opaque envelopes containing the study medication assignment for each subject were provided to the study site investigator for use in an emergency; no code breaks were required."
Blinding (performance bias and detection bias) Objective outcomes: parasitological and biochemical	Low risk	Quotes from report: "Study drugs were administered on a double-blind, double-dummy basis. The investigator calculated the appropriate dose and study drug was administered by a different member of staff, designated by the investigator". "Active drugs and placebos were packaged similarly."
Blinding (performance bias and detection bias) Subjective outcomes: adverse events	Low risk	Comment: The double-blind, double-dummy design used minimized the risk of performance and detection bias. Pruritis that is common with chloroquine could potentially compromise blinding but was not reported in = 2% of participants.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote from report: " Most patients (83.3%) completed the study. A similar number of patients withdrew prematurely from the study in both groups." Comment: The results were assessed in per-protocol and intention-to-treat analyses.
Selective reporting (reporting bias)	Low risk	Comment: This trial was prospectively registered and reported all pre-stated outcomes adequately.
Other bias	Low risk	Quote from report: "The sponsors and study site principal investigators developed the protocol, interpreted the data and developed the report. The study sponsors were responsible for data collection and statistical analysis. All authors had access to the primary data, take responsibility for data reporting accuracy and completeness and had responsibility for the final decision to submit for publication." Comment: Some of the authors are employed by the trial sponsors but all authors had access to data and assumed responsibility for reporting accuracy.