Pfizer 74841

Methods	Trial design: Multi‐centre, randomized, controlled trial with three treatment regimens, blinded for the azithromycin dose. Follow‐up: Subjects were hospitalised for a minimum of three days with eight‐hourly blood smears until three consecutive blood smears were negative for asexual parasitaemia and the investigator deemed discharge from hospital inappropriate. Post‐therapy evaluations and blood smears at day 3, 14, 21, 28, 35 and 42. Adverse event monitoring: "Safety evaluations included adverse events throughout the study, hematology and serum chemistry laboratory evaluations at baseline and day 3, and a complete (day 0) and focused (day 1 to 3, 7, 28) physical exam." Use of COSTART (Coding Symbol Thesaurus of Adverse Reaction Terms) terms for description of adverse events. Adverse events reported for all treated subjects who received at least one dose of study medication.
Participants	Number enrolled:  230 Number available for analysis:  204 Inclusion criteria:  Females and males ≥18 years of age with uncomplicated, symptomatic malaria as indicated by the presence of both of the following: a) blood smear positive for Plasmodium falciparum asexual parasitaemia between 1000 and100,000 parasites/µL; b.) fever or history of fever (38.5 ºC/101.2F rectal or tympanic; ≥37.5 ºC/99.5 F axillary or ≥38 ºC/100.4F oral) within the prior 24 hours; serum glucose ≥ 60 mg/dL (by fingerstick or peripheral blood collection); positive rapid diagnostic test (Binax NOW ICT) positive for P. falciparum; women of childbearing potential had a negative urine gonadotropin prior to entry into the study and agreed to use adequate contraception during the entire study. Exclusion criteria: Severe or complicated malaria, including subjects with any of the following: a) impaired consciousness (eg obtundation, unarousable coma), seizures or abnormal neurologic exam suggestive of severe or complicated malaria; b) haemoglobinuria; c) jaundice; d) respiratory distress (respiratory rate >= 30/min); 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, sulphonamides, pyrimethamine, or chloroquine; known or suspected folate deficiency; known history of blood dyscrasias (eg, megaloblastic anaemia, agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia, neutropenia, haemolytic anaemia); known G‐6PD deficiency; history of epilepsy or psoriasis; history of treatment with any antimalarial drug (chloroquine, quinine, mefloquine, Malarone, 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 were specific exclusions: a) serum creatinine > 2.0 x ULN; b) ALT and/or AST > 3 x ULN; inability to swallow oral medication in tablet form; treatment with other investigational drugs within 30 days prior to enrolment into 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 75 years, mean age (SD) 31.7 (12.9) years in arm 1; 29.5 (9.6) years in arm 2; 31.7 (11.1) years in arm 3 Proportion male:  199/230 (86.5%) Pregnant women:  Excluded
Interventions	arm 1) Azithromycin 1 gram plus chloroquine 600 mg once a day for three days arm 2) Azithromycin 500 mg plus azithromycin placebo plus chloroquine 600 mg once a day for three days arm 3) Sulfadoxine‐pyrimethamine (500 mg/25mg), three tablets at start plus chloroquine 600 mg once a day for two days and 300 mg for one day. Arm 2 removed based on second interim analysis when 190 subjects were enrolled (156 in database) on request of DSMB. Supervision of intake: Yes Other (symptomatic) medication: not reported
Outcomes	Outcomes used in this review:  Total failure by day 28 (primary endpoint) Adverse events
Notes	Location:  India: Indore, Dispur Guwahati (Assam), Bambolim (Gao), Parel Mumbai (Maharashtra), Nagpur (Maharashtra), Rourkela (Orissa), Vellore (Tamil Nadu). Date:  01 September 2003 to 31 January 2005 Malaria endemicity:  Not reported Drug resistance in area:  Not reported Method of determining parasite density:  Not reported Baseline data: Age, duration of infection by treatment arm. Look similar Drug source:  Azithromycin: Zithromax, Pfizer Inc. Not reported for chloroquine or sulfadoxine‐pyrimethamine Source of funding: Pfizer Inc.  Other notes: None
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Not described
Allocation concealment?	Unclear risk	None described
Blinding? All outcomes	High risk	Blinded for azithromycin dose in arm 1 and 2, until arm 2 was removed. Then open label. Not clear if microscopists were blinded
Incomplete outcome data addressed? All outcomes	Low risk	Losses to follow‐up similar in all groups: 83, 67 and 80 randomized in respective arms; 73 (88.0%), 59 (88.1%) and 72 (90.0%) results at day 28; 17 subjects lost to follow up (7, 7, and 3 respectively) and reasons for loss of other nine not clear.
Free of selective reporting?	High risk	Two interim analyses conducted: one planned and one at the request of the DSMB. One arm discontinued.
Free of other bias?	Unclear risk	Not clear if and how the sponsor was involved in analysis and writing of report