Drugs for preventing malaria in travellers

 

Characteristics of included studies [ordered by study ID]

Arthur 1990a

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Methods	Design: randomized controlled trial Duration: June to August 1988 Duration of exposure to malaria: 5 weeks
Participants	Non-immune US Army soldiers (age 18 to 40, average 24), all male Number enrolled: 310  Inclusion criteria: soldiers awaiting deployment to Thailand Exclusion criteria: previous history of gastrointestinal illness
Interventions	1. Doxycycline (1 capsule containing doxycycline hyclate 100 mg) once daily, starting 1 week before travel and continuing throughout the period of deployment 2. Mefloquine (1 x 250 mg tablet) once weekly, starting 1 week before travel and continuing throughout the period of deployment For each drug regimen, a matched placebo
Outcomes	1. Clinical cases of malaria (not defined) 2. Gastrointestinal side effect* (diarrhoea, nausea, vomiting) 3. Neuropsychiatric side effect (dizziness) 4. Serious side effect *Gastrointestinal adverse events were reported separately. The most frequent adverse event (diarrhoea) is considered in the review. The true number of events might be underestimated. Not assessed in the review: 5. Incidence of diarrhoea 6. Infection with enterotoxigenic Escherichia coli (ETEC) 7. Infection with Campylobacter spp. 8. Withdrawal due to study drug related adverse event
Notes	Location: Korat, Thailand Setting: military overseas training exercise Funding sources: Pfizer Inc supplied active and placebo doxycycline; Hoffman-La Roche Inc supplied active and placebo mefloquine
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Computer-generated random numbers list"
Allocation concealment?	Unclear	Comment: information not provided
Blinding? Any adverse event	Yes	"Soldiers receiving mefloquine also received identical appearing doxycycline placebo capsules daily, and those receiving doxycycline received weekly mefloquine placebo tablets..." Participants and providers were blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Unclear	310 enrolled, 253 analysed (119 in the doxycycline arm and 134 in the mefloquine arm) Comment: insufficient reporting of reasons for attrition and exclusion and how missing data were addressed in the analysis to permit judgement of 'Yes' or 'No'
Free of selective reporting (adverse outcomes)? Adverse outcomes	Unclear	Comment: assessment of side effects and clinical case of malaria not described in the Methods section. Results for side effects not presented by drug and retrieved from another article from the same investigator.

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Camus 2004

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Methods	Randomized open-label trial Multicentre study: Canada, Denmark, France, Germany, The Netherlands, United Kingdom Duration of study: May 1999 to November 2000 Mean duration of exposure to malaria: 15 days
Participants	Non-immune paediatric travellers, 43% female Number enrolled: 232  Inclusion criteria: non-immune children (age 3 to 16, weight 11 to 50kg) with planned travel of ≤ 28 days to areas with a substantial risk of P. falciparum infection Exclusion criteria: pregnancy/lactation; cardiac, renal, hepatic, neurological disorders/impairment; travel to area when prophylaxis with chloroquine-proguanil would be inappropriate; clinical malaria within previous 12 months; travel to malaria endemic area within previous 60 days
Interventions	1. Atovaquone-proguanil (1 combined tablet containing 250 mg atovaquone and 100 mg proguanil hydrochloride, or alternatively 1 combined paediatric tablet containing 62.5 mg atovaquone and 25 mg proguanil hydrochloride) once daily, starting 1 to 2 days before travel and continuing for 7 days after travel 2. Chloroquine (one 250 mg tablet, containing the equivalent of 155 mg chloroquine base) once weekly, starting ≥ 1 week before travel and continuing for 4 weeks after travel; and proguanil (one 100 mg tablet) once daily, starting 1 to 2 days before travel and continuing for 4 weeks after travel For each drug regimen, a matched placebo
Outcomes	1. Clinical cases of malaria (malaria smears, parasite DNA analysis) 2. Any adverse event^$ 3. Gastrointestinal adverse event *^$ (diarrhoea, abdominal pain, vomiting, nausea, oral ulceration) 4. Neuropsychiatric adverse event*^$ (dreams, visual impairment, dizziness) 5. Serious adverse event^$ 6. Any adverse event attributed to study drug^$ 7. Gastrointestinal adverse event attributed to study drug*^$ (diarrhoea, abdominal pain, vomiting, nausea, oral ulceration) 8. Neuropsychiatric adverse event attributed to study drug*^$ (dreams, lethargy) 9. Discontinuation of study drug for any reason *Gastrointestinal and neuropsychiatric adverse events/effects were reported separately. For each category, the most frequent adverse events/effects (diarrhoea, dreams) are considered in the review. The number of events might be underestimated. ^$ Exposure period: start of travel through seventh day after travel Not assessed in the review: 10. Compliance with study drug (pre-travel, during travel and post-travel) 11. Withdrawal due to study drug related adverse event 12. Exposure to malaria (circumsporozoite antibody testing)
Notes	Location: various malaria endemic destinations (85% in Africa) Setting: travel clinics Funding source: GlaxoSmithKline (manufacturer of atovaquone-proguanil) gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Participants were randomized (ratio, 1:1)" Comment: information not provided. Probably done, since report of similar intervention in adults from same authors and the Malarone International Study Team describe use of a computer generated random numbers.
Allocation concealment?	Yes	Comment: information not provided. Probably done, since report of similar intervention in adults from same authors and the Malarone International Study Team describe use of "opaque sealed envelopes".
Blinding? Any adverse event	No	Open label
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Yes	232 randomized, 221 received study drugs and were analysed (110 in the atovaquone-proguanil arm and 111 in the chloroquine-proguanil arm) Comment: reasons for attrition or exclusion were reported, balanced between groups and unlikely to be related to true outcome. Thus, the risk of bias is defined as low.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Yes	—

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Croft 1997

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Methods	Randomized controlled trial Duration of study: December 1994 to March 1995 Duration of exposure to malaria: 6 weeks
Participants	Non-immune British Army soldiers, all male Number enrolled: 624  Inclusion criteria: soldiers awaiting deployment to Kenya Exclusion criteria: aviators, neuropsychiatric history, use of ß-adrenergic blocking drugs
Interventions	1. Chloroquine (one 300 mg tablet) once weekly, starting 2 weeks before travel and continuing throughout the period of deployment; and proguanil (two 100 mg tablets) once daily, starting 1 to 2 days before travel and continuing for 28 days after travel 2. Mefloquine (one 250 mg tablet) once weekly, starting 1 week before travel and continuing throughout the period of deployment For each drug regimen, a matched placebo
Outcomes	1. Clinical cases of malaria (not defined) 2. Any side effect 3. Dermatological side effect (skin rash, pruritus) - severe and very severe 4. Gastrointestinal side effect (anorexia, nausea, vomiting, abdominal pain, diarrhoea, buccal ulceration) - severe and very severe 5. Neuropsychiatric side effect (sleep disturbance, memory disturbance, blurred vision, dizziness, motor disturbance, hallucination, alteration of mood, abnormal feeling, abnormal tiredness) - severe and very severe 6. Discontinuation of study drug for any reason Not assessed in the review: 8. Self-reported compliance with study drug 9. Withdrawal due to study drug related adverse event
Notes	Location: Kenya Setting: military overseas training exercise Funding source: British Army Medical Services Research Executive gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Assigned randomly on the basis of computer-generated random numbers"
Allocation concealment?	Yes	"Opaque, sealed, individually-numbered packet"
Blinding? Any adverse event	Yes	"All took 3 tablets weekly and 2 tablet daily without knowing which prophylactic regimen each was receiving" Participants and providers blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	No	624 randomized, 287 analysed at 8 weeks (145 in the mefloquine arm and 142 in the chloroquine-proguanil arm) Comment: reasons for attrition and exclusion were not reported. The number of missing data is large. Thus, the risk of bias is defined as high.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Unclear	Comment: mild and moderate side effects were measured but not reported in the results

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Høgh 2000

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Methods	Randomized controlled trial Multicentre study: Canada, Denmark, France, Germany, The Netherlands, South Africa, United Kingdom Duration of study: April to November 1999 Mean duration of exposure to malaria: 2.5 weeks
Participants	Non-immune tourists and general travellers, 48% female Number enrolled: 1083  Inclusion criteria: travellers aged ≥ 14 years and weighing > 50 kg with planned travel of ≤ 28 days to P. falciparum endemic areas 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
Interventions	1. Atovaquone-proguanil (1 combined tablet containing 250 mg atovaquone and 100 mg proguanil hydrochloride) once daily, starting 1 to 2 days before travel and continuing for 7 days after travel 2. Chloroquine (one 250 mg tablet, containing the equivalent of 155 mg chloroquine base) once weekly, starting 7 days before travel and continuing for 4 weeks after travel; and proguanil (one 100 mg tablet) once daily, starting 1 to 2 days before travel and continuing for 28 days after travel For each drug regimen, a matched placebo
Outcomes	1. Clinical cases of malaria (malaria smear, parasite DNA analysis) 2. Any adverse event 3. Serious adverse event 4. Any adverse event attributed to study drug 5. Dermatological adverse event attributed to study drug (itching) 6. Gastrointestinal adverse event attributed to study drug (diarrhoea, nausea, abdominal pain, mouth ulcers, vomiting) 7. Neuropsychiatric adverse event attributed to study drug (dizziness, strange or vivid dreams, insomnia, visual difficulties, anxiety, depression) 8. Discontinuation of study drug for any reason Not assessed in the review: 9. Non-compliance 10. Withdrawal due to study drug related adverse event 11. Exposure to malaria (circumsporozoite antibody testing)
Notes	Location: various malaria endemic destinations (63% in Africa) Setting: travel clinics Funding source: GlaxoSmithKline (manufacturer of atovaquone-proguanil) gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Computer-generated code"
Allocation concealment?	Yes	"Treatment codes were provided to investigators in opaque sealed envelopes"
Blinding? Any adverse event	Yes	"For each active drug, capsules or film-coated tablets were identical in appearance to the matching placebo" Participants and providers were blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Yes	1083 randomized, 1022 received study drugs and were analysed (511 in the atovaquone-proguanil arm and 511 in the chloroquine-proguanil arm),1008 completed the trial (501 in the atovaquone-proguanil arm and 507 in the chloroquine-proguanil arm). Comment: reasons for attrition and exclusion were reported. It is unclear how missing data for participants included in the analysis were addressed. However the total number of missing data is low and we judge the risk of bias to be low.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Unclear	Comment: it is unclear if dermatological, gastrointestinal, and neuropsychiatric adverse events were measured, but not reported

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Ohrt 1997

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Methods	Randomized controlled trial Duration of study: May to July 1994 Duration of exposure to malaria: approximately 13 weeks
Participants	Non-immune Indonesian Army soldiers, all male Number enrolled: 204  Inclusion criteria: soldiers in military posts with a high malaria attack rate Exclusion criteria: history of frequent travel, allergy to one of the study drugs, glucose-6-phosphate dehydrogenase deficiency, history of underlying illness
Interventions	1. Doxycycline hyclate (one 100 mg capsule) once daily 2. Mefloquine (one 250 mg tablet, containing the equivalent of 228 mg mefloquine base) once weekly (after a loading dose of 250 mg per day for 3 days). 3. Placebo Matched placebo for all 3 arms
Outcomes	1. Clinical cases of malaria (malaria smear) 2. Any adverse event 3. Dermatological adverse event (skin related) 4. Gastrointestinal adverse event (nausea, vomiting, abdominal pain, diarrhoea, constipation, anorexia) 5. Neuropsychiatric adverse event (insomnia, somnolence, dreams, dizziness, palpitations, sexual dysfunction, headache) 6. Serious adverse event 7. Discontinuation of study drug for any reason
Notes	Location: North-Eastern Irian Jaya, Indonesia Setting: military posts Funding source: Pfizer Indonesia supplied active and placebo doxycycline; F. Hoffman-La Roche supplied active and placebo mefloquine, and gave financial support; US Army Medical Research and Materiel Command gave financial support; US Naval Medical Research and Development Command gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Block randomization was used (block size, 15)"
Allocation concealment?	Yes	"The randomization code was stored in individual envelopes in a locked box at the study site"
Blinding? Any adverse event	Yes	"Double dummy technique," "placebo capsules were identical in appearance" Participants and providers were blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Yes	204 randomized and analysed. "Twelve of the 204 participants did not complete the study". Comment: reasons for attrition were reported. It is unclear how missing data were addressed in the analysis. However, the percent of missing data is low and we judge the risk of bias to be low.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Yes	—

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Overbosch 2001

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Methods	Randomized controlled trial Multicentre study: Canada, Germany, The Netherlands, South Africa, United Kingdom Duration of study: April to October 1999 Mean duration of exposure to malaria: 2.5 weeks
Participants	Non-immune tourists and general travellers, 45% female 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
Interventions	1. Atovaquone-proguanil (1 combined tablet containing 250 mg atovaquone and 100 mg proguanil hydrochloride; or alternatively 1 to 3 combined paediatric tablets 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 2. Mefloquine (one 250 mg tablet; or alternatively one-fourth, one half or three-fourths of a tablet, according to body weight) once weekly, starting 7 days before travel and continuing for 4 weeks after travel For each drug regimen, a matched placebo
Outcomes	1. Clinical cases of malaria (antibody to blood-stage malaria parasites) 2. Any adverse event 3. Serious adverse event 4. Adverse event attributed to study drug 5. Dermatological adverse event attributed to study drug (itching) 6. Gastrointestinal adverse event attributed to study drug (diarrhoea, nausea, abdominal pain, mouth ulcers, vomiting) 7. Neuropsychiatric adverse event attributed to study drug (strange or vivid dreams, insomnia, dizziness or vertigo, visual difficulties, anxiety, depression) 8. Discontinuation of study drug for any reason Not assessed in the review: 9. Compliance with study drug (pre-travel, during travel and post-travel) 10. Withdrawal due to study drug related adverse event 11. Exposure to malaria (circumsporozoite antibody testing)
Notes	Location: various malaria endemic destinations worldwide (63% in Africa) Setting: travel clinics Funding source: GlaxoSmithKline (manufacturer of atovaquone-proguanil) gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Study conduct described elsewhere [Høgh 2000]" Comment: computer-generated random numbers
Allocation concealment?	Yes	"Study conduct described elsewhere [Høgh 2000]" Comment: opaque sealed envelopes
Blinding? Any adverse event	Yes	"Atovaquone-proguanil or matching placebo... Mefloquine or matching placebo..." Participants and providers were blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Yes	1083 randomized, 976 received study drug and were analysed (493 in the atovaquone-proguanil arm and 483 in the mefloquine arm), 966 completed the trial (489 in the atovaquone-proguanil arm and 477 in the mefloquine arm) Comment: reasons for attrition and exclusion were reported. It is unclear how missing data for participants included in the analysis were addressed. However, the total number of missing data is low and we judge the risk of bias to be low.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Unclear	Comment: it is unclear if dermatological, gastrointestinal, and neuropsychiatric adverse events were measured, but not reported

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Schlagenhauf 2003a

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Methods	Randomized controlled trial Multicentre study: Germany, Israel, Switzerland Duration of study: 1998 to 2001 Mean duration of exposure to malaria: unclear
Participants	Non-immune tourists and general travellers, 49% female Number enrolled: 674  Inclusion criteria: adult travellers aged 18 to 70 years, with planned travel of 1 to 3 weeks to a malaria-endemic area, and consulting at a travel clinic ≥ 17 days before departure Exclusion criteria: glucose-6-phosphate dehydrogenase deficiency; contraindication to or severe adverse events from any of the 4 study regimens; pregnancy or risk of pregnancy; severe renal or hepatic dysfunction; history of seizures, psychiatric disorders or photosensitivity; concurrent or recent vaginal infections or bacterial enteric disorder
Interventions	1. Atovaquone-proguanil (1 combined capsule containing 250 mg atovaquone and 100 mg proguanil hydrochloride) once daily, starting 17 days before travel and continuing for 1 week after travel 2. Chloroquine-proguanil (1 combined capsule containing chloroquine diphosphatase 161.21 mg, equivalent to chloroquine 100 mg base; and 200 mg proguanil hydrochloride) once daily, starting 17 days before travel and continuing for 4 weeks after travel 3. Doxycycline (1 capsule containing doxycycline monohydrate 100 mg) once daily, starting 17 days before travel and continuing for 4 weeks after travel 4. Mefloquine (1 capsule containing mefloquine hydrochloride 274.09 mg, equivalent to mefloquine 250 mg base) once weekly, starting 7 days before travel and continuing for 4 weeks after travel For each drug regimen, either a matched placebo (atovaquone-proguanil, mefloquine) or identical capsules
Outcomes	1. Any adverse event 2. Dermatological adverse event (itching, abnormal reddening of skin) 3. Gastrointestinal adverse event (nausea, diarrhoea, mouth ulcers) 4. Neuropsychiatric adverse event (strange or vivid dreams, headache, dizziness, anxiety, depression, visual disturbances, fits or seizures) 5. Serious adverse event 6. Discontinuation of study drug for any reason 7. Profile of Mood States (POMS) score Not assessed in the review: 8. Quality of life score
Notes	Location: sub-Saharan Africa (mainly Kenya and South Africa) Setting: travel clinics Funding sources: GlaxoSmithKline supplied atovaquone-proguanil and gave financial support; Zeneca supplied chloroquine-proguanil; Pfizer supplied doxycycline; Roche supplied mefloquine and gave financial support.
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Randomization was from a computer generated table to numbers in permuted blocks of five"
Allocation concealment?	Yes	"Allocation concealment was by sealed envelope"
Blinding? Any adverse event	Yes	"Drugs were provided as identical capsules... by the company that packed the study drugs" Participants and providers blinded
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	Yes	674 randomized, 634 received study drug, 623 were analysed (164 in the atovaquone-proguanil arm, 153 in the chloroquine-proguanil arm, 153 in the doxycycline arm, and 153 in the mefloquine arm), 569 completed all evaluations (154 in the atovaquone-proguanil arm, 135 in the chloroquine-proguanil arm, 142 in the doxycycline arm, and 138 in the mefloquine arm) Comment: reasons for attrition and exclusion were reported
Free of selective reporting (adverse outcomes)? Adverse outcomes	Yes	—

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van Riemsdijk 2002

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Methods	Randomized controlled trial Duration of study: unclear Mean duration of exposure to malaria: 19 days
Participants	Non-immune tourists and general travellers, 38% female Number enrolled: 140  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, psychiatric disorders, severe neurological disorders, severe blood disorders; renal, hepatic or cardiac dysfunction; clinical malaria within previous 12 months; travel to malaria-endemic area within previous 60 days; risk factors for concentration impairment (e.g. use of opioids, hypnotics, or tranquillizers; or use of alcohol 4 hours before testing)
Interventions	1. Atovaquone-proguanil (1 combined tablet containing 250 mg atovaquone and 100 mg proguanil hydrochloride; or alternatively 1 to 3 combined paediatric tablets 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 2. Mefloquine (1 250 mg tablet; or else one-fourth, one half or three-fourths of a tablet, according to body weight) once weekly, starting 7 days before travel and continuing for 4 weeks after travel For each drug regimen, a matched placebo
Outcomes	1. Profile of mood states (POMS) score Not assessed in the review: 2. Neurobehavioural evaluation system score
Notes	Location: various malaria endemic destinations (66% in Africa, 13% South America, 24% other) Setting: Rotterdam Travel Clinic, the Netherlands Funding source: Netherlands Inspectorate for Healthcare gave financial support
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"This study was independently performed in a sample of patients from one center that participated in the MAL30010 multicenter clinical trial, the methods of which have been described in detail elsewhere." (Høgh 2000; Overbosch 2001) Comment: computer-generated random numbers
Allocation concealment?	Yes	"This study was independently performed in a sample of patients from one center that participated in the MAL30010 multicenter clinical trial, the methods of which have been described in detail elsewhere" (Høgh 2000; Overbosch 2001) Comment: opaque sealed envelopes
Blinding? Any adverse event	Yes	"All placebo treatment regimens were identical to the aforementioned scheme for the active ingredient of mefloquine and atovaquone plus chloroguanide"
Incomplete outcome data addressed?(adverse outcomes)? Adverse outcomes	No	140 randomized, 119 analysed (61 in the atovaquone-proguanil arm and 58 in the mefloquine arm) Comment: reasons for attrition and exclusion were balanced between groups. However, some reasons were likely to be related to true outcome (adverse outcomes). Thus, the risk of bias was defined as high.
Free of selective reporting (adverse outcomes)? Adverse outcomes	Yes	—

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Baudon 1999	Randomization of 4 companies of soldiers stratified by country, but with results reported at individual level - inappropriate number of clusters
Carme 1997	Allocation of participants to mefloquine versus chloroquine-proguanil was not random
Pages 2002	Randomization of 4 companies of soldiers stratified by country, but with results reported at individual level - inappropriate number of clusters
Rieckmann 1993	Allocation of participants to either mefloquine, doxycycline, doxycycline plus primaquine, or doxycycline plus chloroquine was not random
van Genderen 2007	Allocation of participants to atovaquone-proguanil or mefloquine was not random

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Comparison 1. Atovaquone-proguanil vs doxycycline

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Any adverse outcome

1

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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1.1 Any adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.98 [0.88, 1.08]

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 2 Dermatological adverse outcome

1

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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2.1 Dermatological adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.88 [0.58, 1.33]

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 3 Gastrointestinal adverse outcome

1

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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3.1 Gastrointestinal adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.82, 1.25]

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 4 Neuropsychiatric adverse outcome

1

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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4.1 Neuropsychiatric adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.97 [0.83, 1.13]

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 5 Discontinuation of study drug for any reason

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.75 [0.20, 2.73]

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Comparison 2. Atovaquone-proguanil vs mefloquine

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Any adverse outcome

2

Risk Ratio (M-H, Random, 95% CI)

Subtotals only

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1.1 Any adverse event

2

1293

Risk Ratio (M-H, Random, 95% CI)

0.99 [0.86, 1.14]

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1.2 Any adverse effect

1

976

Risk Ratio (M-H, Random, 95% CI)

0.72 [0.60, 0.85]

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 2 Dermatological adverse outcome

2

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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2.1 Dermatological adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.88 [0.58, 1.33]

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2.2 Dermatological adverse effect

1

976

Risk Ratio (M-H, Fixed, 95% CI)

0.78 [0.37, 1.66]

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 3 Gastrointestinal adverse outcome

2

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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3.1 Gastrointestinal adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.92 [0.76, 1.12]

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3.2 Gastrointestinal adverse effect

1

976

Risk Ratio (M-H, Fixed, 95% CI)

0.54 [0.42, 0.70]

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 4 Neuropsychiatric adverse outcome

2

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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4.1 Neuropsychiatric adverse event

1

317

Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.75, 0.99]

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4.2 Neuropsychiatric adverse effect

1

976

Risk Ratio (M-H, Fixed, 95% CI)

0.49 [0.38, 0.63]

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 5 Serious adverse event

2

1293

Risk Ratio (M-H, Fixed, 95% CI)

0.39 [0.12, 1.24]

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 6 Discontinuation of study drug for any reason

2

1293

Risk Ratio (M-H, Fixed, 95% CI)

0.79 [0.59, 1.06]

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 7 Total Mood Disturbance (TMD) scores

1

119

Mean Difference (IV, Fixed, 95% CI)

-7.20 [-10.79, -3.61]

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Comparison 3. Doxycycline vs mefloquine

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Clinical cases of malaria

2

388

Risk Ratio (M-H, Fixed, 95% CI)

3.04 [0.13, 73.42]

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 2 Any adverse outcome

2

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

2.1 Any adverse event

2

441

Risk Ratio (M-H, Fixed, 95% CI)

0.97 [0.90, 1.04]

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 3 Dermatological adverse outcome

2

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

3.1 Dermatological adverse event

2

441

Risk Ratio (M-H, Fixed, 95% CI)

0.96 [0.72, 1.28]

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 4 Gastrointestinal adverse outcome

3

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

4.1 Gastrointestinal adverse event

2

441

Risk Ratio (M-H, Fixed, 95% CI)

0.82 [0.68, 1.00]

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4.2 Gastrointestinal adverse effect

1

253

Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.79, 1.32]

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 5 Neuropsychiatric adverse outcome

3

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

5.1 Neuropsychiatric adverse event

2

441

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.73, 0.96]

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5.2 Neuropsychiatric adverse effect

1

253

Risk Ratio (M-H, Fixed, 95% CI)

0.68 [0.25, 1.80]

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 6 Discontinuation of study drug for any reason

2

441

Risk Ratio (M-H, Random, 95% CI)

0.67 [0.31, 1.46]

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Comparison 4. Any standard drugs vs chloroquine-proguanil

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Clinical cases of malaria

3

1853

Risk Ratio (M-H, Fixed, 95% CI)

0.14 [0.01, 2.79]

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 2 Any adverse outcome

4

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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2.1 Any adverse event

3

1866

Risk Ratio (M-H, Fixed, 95% CI)

0.96 [0.90, 1.03]

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2.2 Any adverse effect

3

1530

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.73, 0.96]

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 3 Dermatological adverse outcome

3

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

3.1 Dermatological adverse event

1

623

Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.63, 1.18]

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3.2 Dermatological adverse effect

2

1309

Risk Ratio (M-H, Fixed, 95% CI)

1.19 [0.67, 2.13]

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 4 Gastrointestinal adverse outcome

4

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

---

4.1 Gastrointestinal adverse event

2

844

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.77, 1.03]

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4.2 Gastrointestinal adverse effect

3

1530

Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.60, 0.85]

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 5 Neuropsychiatric adverse outcome

4

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

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5.1 Neuropsychiatric adverse event

2

844

Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.89, 1.13]

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5.2 Neuropsychiatric adverse effect

3

1530

Risk Ratio (M-H, Fixed, 95% CI)

1.02 [0.81, 1.27]

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 6 Serious adverse event

3

1866

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.32, 3.08]

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 7 Discontinuation of study drug for any reason

4

2490

Risk Ratio (M-H, Fixed, 95% CI)

1.05 [0.75, 1.47]

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Summary of findings for the main comparison. Atovaquone-proguanil compared to Mefloquine for Non immune child and adult travellers

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Atovaquone-proguanil compared to Mefloquine for Non immune child and adult travellers
Patient or population: Non immune child and adult travellers Settings: International travel Intervention: Atovaquone-proguanil Comparison: Mefloquine
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mefloquine	Atovaquone-proguanil
Any adverse effect	422 per 1000	304 per 1000 (253 to 359)	RR 0.72 (0.6 to 0.85)	976 (1 study)	⊕⊕⊝⊝ low^1,2
Gastrointestinal adverse effect	288 per 1000	156 per 1000 (121 to 202)	RR 0.54 (0.42 to 0.7)	976 (1 study)	⊕⊕⊝⊝ low^1,3
Neuropsychiatric adverse event	771 per 1000	663 per 1000 (578 to 763)	RR 0.86 (0.75 to 0.99)	317 (1 study)	⊕⊕⊕⊝ moderate^4
Neuropsychiatric adverse effect	288 per 1000	141 per 1000 (109 to 181)	RR 0.49 (0.38 to 0.63)	976 (1 study)	⊕⊕⊝⊝ low^1,3
Total Mood Disturbance (TMD) scores Scale from: -20 to 108.		The mean Total Mood Disturbance (TMD) scores in the intervention groups was 7.2 lower (10.79 to 3.61 lower)		119 (1 study)	⊕⊕⊝⊝ low^4,5
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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 ^1 Serious indirectness. The trial enrolled both adults and children (>= 3 years), but it was unclear how many participants were children as data were not reported separately.
^2 Serious imprecision.The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non-appreciable benefit (>= 0.75 and <=1.00) with atovaquone-proguanil
^3 Serious limitation in design (selective reporting bias). It is unclear if both adverse events and adverse effects for dermatological, gastrointestinal, and neuropsychiatric were measured, but only the adverse effects reported.
^4 Serious indirectness. The trial enrolled only adults.
^5 Serious limitation in design. High risk of bias due to incomplete outcome data (>10%). Some reasons for attrition and exclusion were likely to be related to true outcome (adverse events).

 

Summary of findings 2. Doxycycline compared to Mefloquine for Non Immune Child and Adult Travellers

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Doxycycline compared to Mefloquine for Non Immune Child and Adult Travellers
Patient or population: Non Immune Child and Adult Travellers Settings: International travel Intervention: Doxycycline Comparison: Mefloquine
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mefloquine	Doxycycline
Neuropsychiatric adverse event	688 per 1000	578 per 1000 (502 to 660)	RR 0.84 (0.73 to 0.96)	441 (2 studies)	⊕⊕⊝⊝ low^1,2
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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 ^1 Serious indirectness. Both trials enrolled only adults.
^2 Serious imprecision. The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non-appreciable benefit (>=0.75 and <=1.00) with doxycycline.

 

Summary of findings 3. Any standard drugs compared to Chloroquine-proguanil for Non Immune Child and Adult Travellers

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Any standard drugs compared to Chloroquine-proguanil for Non Immune Child and Adult Travellers
Patient or population: Non Immune Child and Adult Travellers Settings: International travel Intervention: Any standard drugs Comparison: Chloroquine-proguanil
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Chloroquine-proguanil	Any standard drugs
Any adverse effect	338 per 1000	284 per 1000 (247 to 324)	RR 0.84 (0.73 to 0.96)	1530 (3 studies)	⊕⊝⊝⊝ very low^1,2,3
Gastrointestinal adverse effect	253 per 1000	180 per 1000 (152 to 215)	RR 0.71 (0.6 to 0.85)	1530 (3 studies)	⊕⊝⊝⊝ very low^2,3,4
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

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 ^1 Serious limitation in design. One trial is open label. In one trial, incomplete outcome data is largely >10% and it is unclear if mild and moderate side effects were measured but not reported in the results.
^2 Serious indirectness. One trial included children only, one trial adult soldiers, and one trial adults and children (>= 14 years).
^3 Serious imprecision. The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non-appreciable benefit (>=0.75 and <=1.00) with any standard drugs (atovaquone-proguanil, doxycycline, mefloquine).
^4 Serious limitation in design. One trial is open label. In one trial, incomplete outcome data is largely >10% and it is unclear if mild and moderate side effects were measured but not reported in the results. For the third trial, it is unclear if both adverse events and adverse effects for dermatological, gastrointestinal, and neuropsychiatric were measured, but only adverse effects reported.