Pukrittayakamee 2001

Methods	Trial design: Single‐centre, open‐label, randomized, controlled trial with four treatment regimens. Follow up: Hospitalized until clearance of parasitemia. Blood smear every six hours in thin film until only detectable in thick film and then every 12 hours in thick film until clearance, then daily for 28 days. Vital signs recorded four‐hourly until resolution of fever, and thereafter six‐ to12‐hourly. Adverse event monitoring: Routine biochemical and haematological test performed on admission and repeated weekly. Only adverse event of delayed appearance of P. falciparum reported for 66 participants who completed the study.
Participants	Number enrolled: 92 Number available for analysis: 66 Inclusion criteria:  Adult male patients with acute symptomatic P. vivax malaria; informed consent. Exclusion criteria: Mixed infections; a history of drug hypersensitivity; intake of any antimalarial drug within the previous 48 hours; urine positive in screening tests for sulphonamides (lignin test) or 4‐aminoquinolones (Wilson‐Edeson test). Age range:  14 to 51 years. Mean age: 24 (SD 8) years Proportion male:  92/92 (100%) Pregnant women:  Excluded
Interventions	arm 1) Azithromycin 500 mg/day for three days arm 2) Tetracycline 250 mg four times a day for seven days arm 3) Doxycycline 200 mg/day for seven days arm 4) Clindamycin 300 mg four times a day for seven days Supervision of intake: yes Other (symptomatic) medication:  Paracetamol (0.5 to 1 g four‐hourly) was given for fever ≥38 °C. Note: Only after P. vivax treatment failure was established, participants were treated with primaquine for 14 days and chloroquine
Outcomes	Outcomes used in this review:  Total failure by day 28 Parasite and fever clearance time Adverse events
Notes	Location:  Bangkok Hospital for Tropical Diseases, Bangkok, Thailand Date: 1995 to 1998 Malaria endemicity: No transmission in Bangkok, unstable/seasonal in parts of country Drug resistance: P. vivax: pyrimethamine reported in the study area Method of determining parasite density: Giemsa or field‐stained thick and thin smears; parasite density counted per 1000 red blood cells in a thin smear or per 200 WBC in a thick smear. No definition for negative smear. Baseline data: Age, number of previous malaria attacks, haematocrit, WBC, creatinine, total bilirubin and SGOT of randomised participants. Look similar. Drug source: Azithromycin: donated by Pfizer International Corp, Thailand; tetracycline: Thai Government Pharmaceutical Organization; doxycycline: Siam Pharmaceutical Co.; clindamycin: Pharmacia & Upjohn Pharmaceuticals, donated by R.X. Company Limited, Thailand. Source of funding: Wellcome Trust, UK Other notes: None
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not reported
Allocation concealment?	Unclear risk	None described
Blinding? All outcomes	High risk	Open label, not clear if microscopist is blinded
Incomplete outcome data addressed? All outcomes	High risk	Moderate to high loss to follow‐up; not equally distributed across arms: 20, 27, 25, and 20 randomised in respective groups, 18 (90.0%), 18 (66.7%), 18 (72.0%) and 12 (60.0%) results at day 28. Not reported why no results for 26 participants.
Free of selective reporting?	High risk	All male participants. Only adverse event of P. falciparum infection during follow‐up reported by treatment arm; other adverse events not reported by treatment regimen.
Free of other bias?	Unclear risk	Insufficient information