Pfizer 84227

Methods	Trial design: Multi‐centre, randomized, placebo‐controlled trial with three treatment regimens. Follow‐up: Hospitalized with eight‐hourly blood smears until three consecutive blood smears were negative for asexual parasitaemia and the investigator deemed discharge from the hospital appropriate. Insecticide treated net at discharge. Post‐therapy evaluation visits and blood smears at day 7, 14, 21, 28, 35 and 42. Adverse event monitoring: Safety evaluations included adverse event and vital sign monitoring throughout the study, haematology and serum chemistry evaluations (baseline and day 3), and a complete (day 0) and focused (day 1 to 3, 7, 28) physical exam. Use of COSTART terms for the presentation of adverse events. Evaluated for adverse events all subjects who received at least one dose of study medication.
Participants	Number enrolled:  244 Number available for analysis:  225 (group 1 and 3) Inclusion criteria:  Written informed consent; male and female subjects ≥18 years with symptomatic, uncomplicated mono‐infection with P. falciparum as indicated by the following: a) blood smear with asexual parasitaemia between 1000 and 40,000 parasites/µl; b) fever or a history of fever (≥38.5 °C rectal or tympanic; ≥37.5 °C axillary or ≥38 °C oral) within the prior 24 hours; serum glucose ≥60 mg/dl or 3.3 mmol/l; rapid diagnostic test (Binax NOW ICT) positive forP. falciparum; willing to be treated in inpatient setting for a minimum of three days or more until parasitaemia has cleared and the investigator deems the subject fit for discharge; negative urine gonadotropin urine test among women of child‐bearing potential; willingness in the last group to use adequate contraception during the study and one month after the last visit.   Exclusion criteria: Severe or complicated malaria including subjects with any of the following: a) impaired consciousness (eg obtundation, unarousable coma, delirium, stupor), seizures (any seizure within a 24 hour prior to enrolment) or abnormal neurologic exam suggestive of severe or complicated malaria; b) haemoglobinuria; c) jaundice; d) respiratory distress (respiratory rate of 30 breaths/minute or more); e) persistent vomiting; f) haematuria, as reported by the patient; pregnant or breast‐feeding women; history of allergy to or hypersensitivity to azithromycin or any macrolide, atovaquone, proguanil or chloroquine; concomitant administration of rifampin or rifabutin and metoclopramide; history of epilepsy or psoriasis; history of treatment with any antimalarial drug (chloroquine, quinine, mefloquine, atovaquone/proguanil, sulphadoxine‐pyrimethamine, artemisinin compounds) or antibacterial with known antimalarial activity (macrolides, doxycycline, clindamycin) within two weeks prior to enrolment into the study; known or suspected cardiovascular, hepatic or renal abnormality that in the opinion of the investigator would place the subject at increased risk if they participated in the study. The following findings are specific exclusions: a) known or suspected creatinine clearance < 30 mL/min; b) ALT and/or AST > 3 x upper limit of normal; inability to swallow oral medication in tablet or capsule form; treatment with other investigational drugs within 30 days prior to enrolment in the study; alcohol and/or any other drug abuse; requirement to use medication during the study that might interfere with the evaluation of the study drug; specific systemic diseases or other medical conditions that would interfere with the evaluation of the therapeutic response or safety of the study drug; inability to comprehend and/or unwillingness to follow the study protocol; prior participation in this study. Age range: 18 to 86 years, mean age not provided Proportion male: 139/244 (57.0%) Pregnant women: Excluded
Interventions	arm1) Azithromycin 1 g plus chloroquine 600 mg once a day for three days plus matching placebo for atovaquone‐proguanil arm 2) Azithromycin 500 mg plus azithromycin placebo and chloroquine 600 mg once a day for three days plus matching placebo for atovaquone‐proguanil arm 3) Four capsules of atovaquone 250 mg‐proguanil 100 mg once a day for three days plus matching placebos for azithromycin and chloroquine once daily for three days. After four months, arm 2 was removed based on interim review of the entire programme including studies in India and additional treatment failures in South America by the DSMB in November 2004.  In May 2005, recruitment in Surinam halted because of poor blinded efficacy. Supervision of intake: Yes, intake of interventions with food or milky drink Other (symptomatic) medication: not reported
Outcomes	Outcomes used in this review:  Total failure by day 28 (primary endpoint), PCR‐adjusted treatment failure by day 28 Gametocyte on day 28 Adverse events
Notes	Location:  Three centres in Colombia and one in Suriname Date:  05 July 2004 to 05 July 2005 Malaria endemicity:  Not reported Drug resistance in area:  Not reported Method of determining parasite density:  Not reported Baseline: No information on characteristics by treatment arm Drug source:  Azithromycin: Zithromax, Pfizer Inc. Not reported for chloroquine or atovaquone‐proguanil. Source of funding: Pfizer Inc.  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	Low risk	Placebo controlled
Incomplete outcome data addressed? All outcomes	Low risk	Loss of participants low and similar among arms: 114, 14 and 116 randomised in respective arms; 112 (98.2%) and 113 (97.4%) results at day 28 in arms 1 and 3 respectively. Five participants defaulted.  Results for arm 2 not presented.
Free of selective reporting?	High risk	No clear definition of treatment failure at day 28. One treatment arm prematurely terminated; results not reported. Another study arm in one site prematurely terminated because of poor efficacy of blinded arm. No baseline information by treatment arm. Fever clearance time and parasite clearance time not reported by treatment arm.
Free of other bias?	Unclear risk	Not clear if and how the sponsor was involved in analysis and writing of report