Overbosch 2001.

Methods	Design: RCT Duration of study: April to October 1999 Malaria transmission pattern and local drug resistance: not mentioned Adverse event monitoring: "evaluated 7, 28 and 60 days after return to obtain information about a targeted list of adverse events"
Participants	Number enrolled: 1013 Inclusion criteria: "travellers aged ≥ 3 years and weighing ≥ 11 kg with planned travel of ≤ 28 days to a malaria‐endemic area" Exclusion criteria: "poor general health; drug hypersensitivity (to atovaquone, chloroquine or proguanil); history of alcoholism, seizures or psychiatric or severe neurological disorders; generalized psoriasis; severe blood disorders; pregnancy/lactation; renal, hepatic or cardiac dysfunction; clinical malaria within previous 12 months; travel to malaria endemic area within previous 60 days" Countries of recruitment: Canada, Germany, Netherlands, South Africa, UK Regions of malaria exposure: various malaria‐endemic destinations (79% Africa, 6% South America) Mean duration of exposure to malaria: 2.5 weeks Type of participants: travellers, non‐immune
Interventions	1. Mefloquine (1 x 250 mg tablet; or alternatively ¼, ½ or ¾ of a tablet, according to body weight) once weekly, starting 1 to 3 weeks before travel and continuing for 4 weeks after travel* 2. Atovaquone‐proguanil (1 combined tablet containing 250 mg atovaquone and 100 mg proguanil hydrochloride; or alternatively 1 to 3 combined tablets for children according to body weight, each tablet containing 62.5 mg atovaquone and 25 mg proguanil hydrochloride) once daily, starting 1 to 2 days before travel and continuing for 1 week after leaving the malaria‐endemic area* *matched placebo for each treatment arm
Outcomes	Included in the review: 1. Clinical cases of malaria (antibody to blood‐stage malaria parasites) 2. Adverse events; any 3. Serious adverse events 4. Adverse effects; any (moderate or severe), visual impairment, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams, insomnia, anxiety, depression, pruritis 5. Adverse effects; other (mouth ulcers) 6. Discontinuation of study drug due to adverse effects 7. Measures of adherence to the drug regimen Outcomes assessed not included in the review: 8. Laboratory tests; haematology (haemoglobin level, white blood cell count and platelet count) and chemistry (creatinine and alanine aminotransferase)
Notes	Funding source: GlaxoSmithKline "Subjects were enrolled in study MAL30010"‐ Enrollment criteria and study conduct were described in a separate publication (Høgh 2000) which refers to a different study population (atovaquone‐proguanil versus chloroquine‐proguanil).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A computer‐generated code was used to randomly assign a treatment number" (Høgh 2000)
Allocation concealment (selection bias)	Low risk	"Treatment codes were provided to investigators in opaque sealed envelopes, to be opened only if knowledge of study drug assignment was required for management of a medical emergency" (Høgh 2000)
Blinding of participants and personnel (performance bias) Adverse effects/events	Low risk	"For each active drug, capsules or film‐coated tablets were identical in appearance to the matching placebo"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All subjects and study personnel remained blinded to treatment assignment with 5 exceptions. Two subjects in the atovaquone‐proguanil group and 3 in the mefloquine group lost their study drug during their return trip from a malaria‐endemic area, and the investigator broke the blind to enable completion of postexposure prophylaxis with active drug"
Incomplete outcome data (attrition bias); efficacy	Low risk	"A total of 963 subjects completed the 60‐day follow‐up period and had efficacy information recorded. A total of 915 subjects had paired serum samples available for serological testing" Comment: 963/976 (randomized and received first dose of study drug) = 98.7%. 915/976 = 93.75%. Reasons for leaving the study early were reported and numbers were balanced across groups
Incomplete outcome data (attrition bias); safety	Unclear risk	Comment: 96.35% of randomized participants were included in adverse event reporting. Reasons for leaving the study early were reported and numbers were balanced across groups
Selective reporting (reporting bias); efficacy	Low risk	Comment: Full clinical details were provided for every episode in which an episode of malaria was considered (4 cases)
Selective reporting (reporting bias); safety	High risk	Comment: Data on adverse symptoms were not reported for the placebo group due to a shorter duration of follow‐up. Data were collected 7, 28 and 60 days after travel. However, data were only presented for 7 days after return
Other bias	High risk	Funding: GlaxoSmithKline It was not made clear whether the interpretation of the study findings was independent of the study sponsor