Methods

Design: retrospective cohort study.

Study dates: November 1997 to January 2000

Malaria transmission pattern and local antimalarial drug resistance: various destinations, not specified.

Adverse event monitoring: one off telephone interview with parents whose children had previously been prescribed antimalarial prophylaxis.

Participants

Number enrolled: 177 fit inclusion criteria and interviewed, 190 contacted

Inclusion criteria: children aged ≤ 13 years who visited the travel clinic at the Children’s Memorial Hospital in Chicago within the study dates. Subjects who were not on other medications.

Exclusion criteria: "...data were only included if the child was living with the interviewed parent while taking the antimalarial". "Unwillingness to participate in the study and language barriers".

Factors influencing drug allocation: "children... instructed to take mefloquine or chloroquine for malaria prophylaxis".

Country of recruitment: USA.

Country of malaria exposure: various; Africa 58%, Central or South America 21%, India 12% or Eastern Asia 9%.

Duration of exposure to malaria: various, not specified.

Type of participants: travellers

Interventions

1. Mefloquine*

2. Chloroquine*

*dosing regimen not specified

Outcomes

1. Adverse effects; any, nausea, vomiting, diarrhoea, headache, insomnia, abnormal dreams

2. Serious adverse effects

3. Discontinuations of study drug due to adverse effects

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Age, sex and destination of travel were recorded, but were not reported across prophylactic regimens

2. Selection of participants into the study: low

Non‐response rate 1.6%

3. Measurement of interventions: moderate

The prescription was provided by a travel clinic, but participants were asked to recall if they discontinued their medication 2.8 to 28 months after visiting

4. Departures from intended interventions: serious

Information was collected up to 2 years after taking the drug. No information was captured on switches.

5. Missing data: low

All information was collected at one time point, there were no losses to follow‐up.

6. Measurement of outcomes: serious

The outcome measure was subjective, participants and personnel were not blinded.

7. Selection of the reported results: low

All outcomes included in the introduction were reported in the results

8. Other: low

"The authors had no financial or other conflicts of interest to disclose"

Methods

Design: prospective cohort study

Study dates: March 2004 to November 2006

Malaria transmission pattern and local antimalarial drug resistance: malaria attack rate of 44% with P falciparum in another similar study at the time

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 690 soldiers sent questionnaire, 609 respondents

Inclusion criteria: all Swedish soldiers deployed to Liberia within the study dates

Exclusion criteria: none stated.

Factors influencing drug allocation: "...mefloquine was prescribed to almost all soldiers in the first two contingents and to about two‐thirds in the last three contingents. The remaining soldiers were recommended atovaquone/ proguanil. The latter group consisted mainly of those with body weight < 70 kg and those who had already experienced adverse events with mefloquine. No other drug regimes were used".

Country of recruitment: Sweden

Country of malaria exposure: Liberia

Duration of exposure to malaria: 6 months

Type of participants: military

Interventions

1. Mefloquine*

2. Atovaquone‐proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse events; any, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams nightmares, insomnia sleep disturbance, depression

2. Serious adverse events; serious

3. Adverse events; other (concentration difficulties, mouth ulcers, fever, muscle pain)

4. Discontinuations of study drug due to adverse effects

Outcomes assessed not included in the review:

5. Clinical cases of malaria

6. Overall satisfaction with the drug

7. Whether they would take the drug again

8. Measures of adherence to the drug regimen (data provided on aggregate)

Notes

Funding sources: Not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Information on potential confounders is not provided across prophylactic groups

2. Selection of participants into the study: moderate

609/690 (88%) response rate

3. Measurement of interventions: low

All participants were issued with the study drug.

4. Departures from intended interventions: low

Switches were recorded and reported

5. Missing data: serious

Outcomes were reported from 3 of 5 cohorts. No information was provided for 2 remaining cohorts.

6. Measurement of outcomes: serious

The outcome measure was subjective, participants and personnel were not blinded.

7. Selection of the reported results: low

All outcomes prespecified in the introduction were reported.

8. Other: moderate

Study sponsor not mentioned, but 2 study authors worked for GlaxoSmithKline

Methods

Design: RCT

Study dates: June to August 1988

Malaria transmission pattern and local drug resistance: local chloroquine resistance

Adverse event monitoring: blood taken at induction and at days 57 and 70 of treatment. Interviews regarding side effects when sera taken. Stool sample at induction, at end of exercise and at any time participants sought medical care.

Participants

Number enrolled: 270

Inclusion criteria: soldiers (aged 18 to 40 years), awaiting deployment to Thailand

Exclusion criteria: previous history of gastrointestinal illness

Country of recruitment: USA

Country of malaria exposure: Thailand

Duration of exposure to malaria: 5 weeks

Type of participants: soldiers, non‐immune

Interventions

1. Mefloquine (1 x 250 mg tablet) once weekly, starting 1 week before travel and continuing throughout the period of deployment.*

2. Doxycycline (1 capsule containing doxycycline hyclate 100 mg) once daily, starting 1 week before travel and continuing throughout the period of deployment*

Co‐interventions: Both groups given doxycycline 100mg daily for suppression of P falciparum and primaquine 45 mg weekly for elimination of liver hypnozoites for 6 weeks on return to the USA.

*matched placebo for each treatment arm

Outcomes

Included in the review:

1. Clinical cases of malaria

2. Serious adverse event

3. Adverse events; diarrhoea

4. Discontinuation of study drug due to adverse effects

5. Measures of adherence to the drug regimen

Outcomes assessed not included in the review:

6. Laboratory tests; enteric pathogens

7. Adverse events; nausea, vomiting, headache, dizziness (data provided on aggregate)

Notes

Funding sources: Pfizer Inc supplied active and placebo doxycycline; Hoffman‐La Roche Inc supplied active and placebo mefloquine

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Volunteers were assigned from a computer generated random number list to receive daily doxycycline or weekly mefloquine"

Allocation concealment (selection bias)

Unclear risk

Comment: Unclear how the tablets were labelled and whether allocation concealment occurred

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"Soldiers receiving mefloquine also received identical appearing doxycycline placebo capsules daily, and those receiving daily doxycycline received weekly mefloquine placebo tablets"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: described as double blind but no explanation of how this was achieved for researchers and outcome assessors

Incomplete outcome data (attrition bias); efficacy

High risk

"Of the 270 volunteers who were deployed, 253 were correctly taking the assigned study malaria prophylaxis on arrival in Korat"

Comment: Reasons for not taking medication were not reported. Method of detection for malaria, frequency and duration of follow‐up were not reported

Incomplete outcome data (attrition bias); safety

Low risk

Comment: 17 participants (6%) were not "correctly taking the prophylaxis on arrival to Korat" and were excluded from the analysis. Data were not stratified by time point

Selective reporting (reporting bias); efficacy

Low risk

"None of the soldiers developed malaria"

Selective reporting (reporting bias); safety

Unclear risk

Comment: data for general side effects (e.g. headaches) were presented for the study population but not for each group

Other bias

Unclear risk

Comment: study sponsor not mentioned

Methods

Design: prospective cohort study

Study dates: October 2006 to October 2007

Malaria transmission pattern and local antimalarial drug resistance: various destinations, not specified

Adverse event monitoring: not performed

Participants

Number enrolled: 945

Inclusion criteria: People aged ≥ 18 years were eligible if they were planning to travel for 1 to 13 weeks to one or more malaria‐endemic countries.

Exclusion criteria: None stated

Factors influencing drug allocation: "Dutch national guidelines for travelers’ health advice"

Country of recruitment: Netherlands

Regions of malaria exposure: various; Asia 48%, Africa 30% and Latin America 22%

Duration of exposure to malaria: various; 49% ≤ 13 days, 35% 14 to 28 days and 9% ≥ 29 days

Type of participants: travellers

Interventions

1. Mefloquine: taken 3 weeks prior to arrival, during trip and for 4 weeks after return, dose and frequency of dose not specified

2. Atovaquone‐proguanil: 1 day prior to arrival, during trip and for 7 days after return, dose and frequency of dose not specified

3. Proguanil: On day of arrival, during trip and for 4 weeks after return, dose and frequency of dose not specified

Outcomes

Included in the review:

1. Measures of adherence to the drug regime

Outcomes assessed not included in the review:

2. Clinical cases of malaria

3. Predictors of adherence to malaria prophylaxis

4. Use of antimosquito preventive measures

Notes

Funding sources: The Amsterdam Academic Collaborative Center on Public Health is financially supported by the Netherlands Organization for Health Research and Development (ZonMw; grant number 7115 0001, http://www.zonmw.nl/nl/)

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Length of stay, travel destination, age and sex were not reported across groups

2. Selection of participants into the study: moderate

Non‐response rates were not reported

3. Measurement of interventions: low

Participants made daily diary entries during travel

4. Departures from intended interventions: low

Participants made daily diary entries during travel

5. Missing data: low

Information was collected at one time point

6. Measurement of outcomes: moderate

Outcome assessors were not blinded, methods were comparable across groups

7. Selection of the reported results: low

Outcomes were reported for 610/620 participants

8. Other: low

Government funding

Methods

Design: RCT

Study dates: July 1983 to March 1984

Malaria transmission pattern and local antimalarial drug resistance: "in this area we believe the efficacy of chloroquine prophylaxis at the time of the study was negligible"

Adverse event monitoring: "at each 2 week visit… history of symptoms over the previous fortnight was obtained. Patients were asked about fever, chills, headache, nausea, vomiting, diarrhoea, anorexia, rash, myalgia and dysuria or abnormally coloured urine". Laboratory studies were performed at baseline and at 6 weeks in participants who had not developed malaria

Participants

Number enrolled: 501

Inclusion criteria: "Only males 21 years of age or over were accepted"

Exclusion criteria: "All participants were required to have a negative malaria smear (after examination of 200 fields on thick smear) on entry into the study". "...the use of other antimalarials or antibiotics"

Country of recruitment: Cambodia

Country of malaria exposure: Cambodia

Duration of exposure to malaria: ongoing in semi immune population, 14 week study period

Type of participants: Thai gem miners with a degree of immunity

Interventions

Included in review comparisons:

1. Mefloquine (2 x 250 mg tablet) fortnightly for 14 weeks*

2. Chloroquine (1 x 300 mg tablet) weekly*

Not included in review comparisons:

3. Fansidar (2 x 500 mg sufadoxine and 25 mg pyrimethamine) fortnightly and chloroquine (1 x 300 mg tablet) weekly*

*matched placebo for each treatment arm

Outcomes

Included in the review:

1. Clinical cases of malaria

2. Adverse events; other (myalgias, rash)

Outcomes assessed not included in the review:

3. Laboratory tests; haematocrit, complete blood count, transaminase levels, total and direct bilirubin, alkaline phosphatase, blood urea nitrogen

4. Adverse events; headache, anorexia, fever, chills, nausea, diarrhoea or vomiting (data provided on aggregate)

Notes

Funding sources: Support for this study was from the USA Army Medical Research and Development Command

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Assignment… is a 4:3:2 ratio"

Comment: method of sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

Comment: no details of allocation concealment were reported

Blinding of participants and personnel (performance bias)
Adverse effects/events

Unclear risk

"Every two weeks in a double blind fashion one of the investigators administered five tablets to each subject"

Comment: not mentioned whether placebo tablets had an identical appearance

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: described as double blind but no mention of how this was achieved for researchers and outcome assessors

Incomplete outcome data (attrition bias); efficacy

Unclear risk

"Only 194 patients completed the study until positivity or end of the 14 weeks observation period". "Therefore of the original 501 enrollees, 63 were discarded due to positivity at week 0 and 104 were discarded since they never returned beyond week 0".

Comment: Losses to follow‐up during the study was not reported across groups

Incomplete outcome data (attrition bias); safety

Unclear risk

"Only 194 patients completed the study until positivity or end of the 14 weeks observation period...Any subject missing one appointment was excluded from the study though each subject's records up to the time of exclusion were entered into the survival analysis...After 3 weeks post treatment and a negative malaria smear some patients wishing to continue were reentered under a new study number and were assigned a double blind randomized treatment"

Selective reporting (reporting bias); efficacy

Unclear risk

Comment: number of people contracting malaria in each group and person‐weeks in the study were reported

Selective reporting (reporting bias); safety

Unclear risk

"There were no significant differences in frequency of complaints among the study groups for headache, anorexia, fever, chills, nausea, diarrhoea, or vomiting".

Comment: Data for specific adverse events not reported. Methods section states participants were asked about dysuria and abnormally coloured urine, but this was not reported in the results

Other bias

Low risk

Support for this study was from the USA Army Medical Research and Development Command

Methods

Design: RCT

Study dates: not mentioned

Malaria transmission pattern and local antimalarial drug resistance: not applicable

Adverse event monitoring: "At each visit, the subject answered two computerised questionnaires (the Environmental Symptoms Questionnaire and the Profile of Mood States) [and] a physician interview was performed"

Participants

Number enrolled: 359

Inclusion criteria: "males at least 18 years old, met military weight standards, were available for weekly administration of medications and monitoring during the 13 week study period, and were willing to give informed consent"

Exclusion criteria: "treatment with beta‐blocking agents or other cardiotropic drugs, underlying chronic disease, history of cardiac arrhythmia, medical history of psychiatric or neurological problems within the last 5 years, anaemia or impaired hepatic or renal function. Women were excluded from participation in the study due to the risk of teratogenicity involved when the drug is used in early pregnancy"

Country of recruitment: USA

Country of malaria exposure: not applicable

Duration of exposure to malaria: not applicable

Type of participants: military, non‐travellers

Interventions

1. Mefloquine (1 x 250 mg tablet), larium 228 mg base (F Hoffman La Roche) weekly for 11 weeks

2. Mefloquine (1 x 250 mg tablet), larium 228 mg base (F Hoffman La Roche) weekly for 11 weeks, with loading dose of 1 x 250 mg tablet daily for 3 days during the first week

3. Chloroquine (1 x 300 mg tablet), 300 mg base (F Hoffman La Roche) weekly for 11 weeks

Outcomes

Included in the review:

1. Adverse events; nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams, insomnia

2. Adverse events; other (irritability, poor concentration, anger, moodiness, abdominal distension, anorexia, environmental symptoms questionnaire (ESQ), sleep assessment, Profile of Mood States questionnaire)

Outcomes assessed not included in the review:

3. Laboratory tests: haemoglobin, haematocrit, platelets, white blood cell count, alanine aminotransferase, blood urea nitrogen and creatinine

4. Analysis of the dizziness index on the ESQ

5. Spontaneous comments on the ESQ (data provided on aggregate)

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...military personnel were assigned to drug groups in a ratio of approximately 3:3:1…stratification was performed by major subordinate command so that equal proportions of each study group would be represented in each MSC"

Comment: not mentioned how the randomisation code was generated

Allocation concealment (selection bias)

Unclear risk

Comment: method allocation concealment not mentioned

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"...the ‘double dummy’ method of blinding was employed with either chloroquine or mefloquine placebos administered with active drug… In addition, during the first week of the study, on days two and three, a single mefloquine tablet or placebo was administered. Both drugs and placebos had an extremely bitter taste... identical placebo tablets"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: described as double blind but no description provided of how this was achieved for researchers and outcome assessors

Incomplete outcome data (attrition bias); efficacy

Unclear risk

N/A

Incomplete outcome data (attrition bias); safety

Unclear risk

Comment: 15 medical withdrawals are reported within the study. It is unclear whether these are the only losses to follow up which occurred, or whether they occurred in the mefloquine loading dose group or weekly administration group.

Selective reporting (reporting bias); efficacy

Unclear risk

N/A

Selective reporting (reporting bias); safety

High risk

‘table 5 outlines the percent of the group with symptoms only when significance was demonstrated’ ‘selected haematology and biochemistry tests were performed… no significant differences were noted among the three drugs when comparing the mean values’

Comment: data is not fully reported for ‘other symptoms’; only significant results are reported for the ESQ, and data for spontaneous comments on the ESQ are not reported; data is not fully reported for the POMS.

Other bias

Unclear risk

Comment: study sponsor not mentioned, but the lead author is attributed to ‘Pharmaceutical Systems Incorporated’

Methods

Design: RCT

Study dates: July 1987 to January 1988

Malaria transmission pattern and local antimalarial drug resistance: "a malaria endemic area". Reports chloroquine, sulfadoxine‐pyrimethamine and quinine resistance within Thailand at the time of the study.

Adverse event monitoring: "volunteers asked about adverse events at each visit (weeks 4, 9, 14, 19, 24, 28)...starting week 14, volunteers reporting adverse events were interviewed by members of the hospital team; most of them were also seen by principal investigators"

Participants

Number enrolled: 605 randomized, 3 excluded because of baseline parasitaemia

Inclusion criteria: "...healthy male volunteers, aged between 16 and 60, living in this area, were recruited"

Exclusion criteria: "persons with a known history of allergy against sulphonamides, with an evidence illness of fever, or which a positive blood film (with or without symptomatic malaria) were excluded"

Country of recruitment: Thailand

Country of malaria exposure: Thailand

Duration of exposure to malaria: trial duration 24 weeks

Type of participants: Thai residents in a malaria‐endemic area (presumed semi‐immune)

Interventions

Included in the review:

1. Mefloquine (1 tablet containing 125 mg mefloquine) once weekly, double dose during first 4 weeks*

2. Chloroquine (1 tablet containing 300 mg chloroquine) once weekly*

3. Placebo

Not included in the review:

4. Fansifem (1 tablet containing 125 mg mefloquine, 250 mg sulfadoxine, 12.5 mg pyrimethamine) once weekly, double dose during first 2 weeks*

5. Fansidar (1 tablet containing 500 mg sulfadoxine, 25 mg pyrimethamine) once weekly*

*matched placebo for each treatment arm

Outcomes

Included in the review:

1. Clinical cases of malaria

2. Adverse events; any

3. Discontinuations of study drug due to adverse effects

Outcomes assessed not included in the review:

4. Laboratory tests; haematocrit, white blood cell count and neutrophil count

Notes

Funding sources: "The project was jointly organized and conducted by the Malaria Division, Department of Communicable Disease, Ministry of Public Health; the Hoffman‐La Roche company, Basel, Switzerland; and The Faculty of Tropical Medicines, Mahidol University, Bangkok"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Eligible volunteers were randomly assigned to treatment groups"

Comment: method of random sequence generation not reported

Allocation concealment (selection bias)

Unclear risk

"The tablets were identical in appearance; they were packed in numbered blister packs and were in addition labelled weeks 1‐24... the coded test drugs for weeks 1‐4 were given to every subject"

Comment: no mention of concealed opaque envelopes or central allocation

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"A randomised double blind trial…the tablets were identical in appearance; they were packed in numbered blister packs"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: described as double blind but no explanation provided of how this was achieved for researchers and outcome assessors

Incomplete outcome data (attrition bias); efficacy

Unclear risk

"Of the 605 subjects originally randomised, 3 were excluded because of baseline parasitaemia... Although some of the volunteers left the study for personal reasons (moving away from the area)"

Comment: numbers lost to follow up have not been reported

Incomplete outcome data (attrition bias); safety

Unclear risk

"94% (116/123) in the mefloquine group and 98% (119/121) in the placebo group were included for adverse event reporting"

"Although some of the volunteers left the study for personal reasons (moving away from the area)"

Comment: numbers lost to follow‐up were not reported

Selective reporting (reporting bias); efficacy

Low risk

Comment: Malaria cases were fully reported

Selective reporting (reporting bias); safety

High risk

Comment: Data were collected but not reported for adherence to drug regimen. Data were provided on aggregate across all time points. The number of adverse events were reported but not types or severity

Other bias

High risk

"The project was jointly organized and conducted by the Malaria Division, Department of Communicable Disease, Ministry of Public Health; the Hoffman‐La Roche company, Basel, Switzerland; and The Faculty of Tropical Medicines, Mahidol University, Bangkok"

Methods

Design: retrospective cohort study

Study dates: June 1992 to July 1994

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 1511 questionnaires distributed, 1054 respondents

Inclusion criteria: travellers who visited areas with a risk of malaria infection who were travelling on short trips < 6 weeks duration

Exclusion criteria: none mentioned

Factors influencing drug allocation: The fact of participating in this study did not change at all the typical prophylaxis when performing, which followed the usual criteria (Google Translate = "El hecho de participar en este estudio no cambio en absoluto el tipico de profilaxis al realizar, que siguio los criterios habituales"

Country of recruitment: Spain

Country of malaria exposure: various, not specified

Duration of exposure to malaria: various, not specified

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine (1 x 250 mg tablet) weekly, starting 1 week prior to travel, during the trip and 4 weeks following return from the malaria‐endemic area

2. Chloroquine (5 mg/kg) weekly, starting 1 week prior to travel, during the trip and 4 weeks following return from the malaria‐endemic area

Outcomes assessed not included in the review:

3. Chloroquine and proguanil (chloroquine base 5 mg/kg, once weekly plus proguanil 100 mg daily, if weight < 55 kg and 200 mg daily if weight > 55 kg) starting 1 week prior to travel, during the trip and 4 weeks following return from the malaria‐endemic area

Outcomes

Included in the review:

1. Adverse effects; any, vertigo, visual impairment, nausea, vomiting, abdominal pain, diarrhoea, insomnia, anxiety, depression, pruritis

2. Adverse effects; other (irritability)

3. Discontinuations of study drugs due to adverse effects

Outcomes assessed not included in the review:

4. Mean number of symptoms reported per traveller

5. Adverse effects; other, incidence < 1% (amnesia, tremor, paraesthesia, seizures, hyper‐reflexia, drowsiness, asthenia, nervousness, difficulty concentrating, mouth ulcers, acne, cardiac rhythm disturbance)

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Sex was reported across groups. No other confounders were reported

2. Selection of participants into the study: serious

1054/1511 (70%) response rate

3. Measurement of interventions: low

The antimalarial prescription was provided by a travel clinic which also performed the study

4. Departures from intended interventions: moderate

Discontinuations were reported across groups. It is unclear if information regarding switches was obtained

5. Missing data: low

All participants were included in the analysis. All information was included at one time point

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective, participants and personnel were not blinded

7. Selection of the reported results: moderate

The analysis of the relationship of symptoms by weight was reported only for mefloquine

8. Other: no information

No information was provided regarding the study sponsor

Methods

Design: cross‐sectional cohort study

Study dates: questionnaire emailed July 2012, reminder emails were circulated at 8 and 12 weeks

Malaria transmission pattern and local antimalarial drug resistance: various destinations, not specified

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 579 questionnaires emailed, 327 responses

Inclusion criteria: all Foreign and Commonwealth Office staff posted to a malaria‐endemic area

Exclusion criteria: none stated

Factors influencing drug allocation: "prophylaxis based on the Advisory Committee on Malaria Prevention in UK Travellers (ACMP) guidelines"

Country of recruitment: various, not specified

Country of malaria exposure: various, not specified

Duration of exposure to malaria: 0 to 3 months N = 16 (4.9%), 4 to 6 months N = 26 (8.0%), 7 to 12 months N = 46 (14.1%), 13 to 36 months N = 75 (22.9%), > 36 months N = 167 (51.1%)

Type of participants: UK Foreign and Commonwealth Office staff

Interventions

1. Mefloquine*

2. Atovaquone‐proguanil*

3. Doxycycline*

4. Chloroquine*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse effects; psychiatric disorders (abnormal dreams)

2. Adverse effects; other (skin sensitivity, indigestion, other psychological)

Outcomes assessed not included in the review:

3. Clinical cases of malaria

4. Background knowledge of malaria

5. Attitudes regarding malaria prophylaxis

6. Use of personal protective measures

7. Impact of pregnancy on malaria prevention

8. Measures of adherence to drug regimen (data provided on aggregate)

Notes

Funding sources: not mentioned

Communications with study authors: the study authors provided us with access to the full original data set. Thedata set differed from findings in the published version of the paper, and we were unable to determine the cause for differences. The included figures were from the full data set

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

No information on confounders was provided across prophylaxis groups

2. Selection of participants into the study: serious

Response rate for the survey was 56.5%

3. Measurement of interventions: moderate

Participants were asked to self‐report which medications they were prescribed. Compliance rate was 25%

4. Departures from intended interventions: serious

No questions were included in the questionnaire regarding switches between chemoprophylactic regimens

5. Missing data: low

All participants were included in the analysis

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

The entire questionnaire was provided in full, all outcomes included were reported

8. Other: no information

Study sponsor not mentioned

Methods

Design: RCT

Study dates: not mentioned

Malaria transmission pattern and local antimalarial drug resistance: not applicable

Adverse event monitoring: daily self‐reported diary. Three medical check ups for laboratory and other tests

Participants

Number enrolled: 106 randomized, 95 completed all study procedures

Inclusion criteria: "healthy adult staff and students at teaching hospitals in Perth, Western Australia"

Exclusion criteria: "Those with a past history of psychiatric conditions, or neurological, cardiac, hepatic or renal disease were excluded, as were pregnant or breastfeeding females and those with a known allergy to, or taking medication known to interact with quinolone drugs. None of the subjects had taken mefloquine in the 3 months before the study"

Country of recruitment: Australia

Country of malaria exposure: not applicable

Duration of follow up: 7 weeks

Type of participants: non‐immune non‐travellers

Interventions

1. Mefloquine (1 x 250 mg tablet), with placebo dose followed 1 week later by 250 mg mefloquine weekly, active treatment duration 4 weeks

2. Placebo, 1 tablet weekly, duration 5 weeks

Outcomes

Included in the review:

1. Measure of adherence to the drug regimen

2. Adverse events: other outcome measures (symbol digit modalities test, digit span forwards and backwards test, ECG, hearing loss at 6kHz)

Outcomes assessed not included in the review:

3. Laboratory tests: serum glucose, insulin, ionized calcium, phosphate, magnesium and albumin concentrations

4. Adverse events: headache, lethargy, abdominal pain, diarrhoea, cough, nausea; study reports events occurring in the first week (after both groups had received placebo) and the relative risk of symptoms worsening over time

Notes

Funding sources: "We thank… F. Hoffman La Roche & Co. for financial support"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"...allocation… was by a random number code generated by independent Fremantle Hospital Pharmacy staff"

Allocation concealment (selection bias)

Low risk

"...who kept the code strictly confidential until the last volunteer had completed the protocol"

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"Tablets were prepared in individually numbered but otherwise unlabelled containers... identical placebo tablets…"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Allocation of active or placebo formulation was by a random number code generated by independent Freemantle hospital staff who kept the code strictly confidential"

Comment: not mentioned whether outcomes assessors were blinded

Incomplete outcome data (attrition bias); efficacy

Unclear risk

N/A

Incomplete outcome data (attrition bias); safety

Low risk

"Of 106 randomised volunteers, 95 (90%) completed all study procedures... eight subjects withdrew after initial assessment and three after the second. Follow‐up of these individuals revealed no toxicity in those allocated mefloquine"

Selective reporting (reporting bias); efficacy

Unclear risk

N/A

Selective reporting (reporting bias); safety

High risk

Comment: not all symptoms were reported, only those occurring in > 10% of participants in both groups. Absolute numbers of participants experiencing each symptom after mefloquine/placebo commenced not provided, only relative risk of symptoms worsening over time

Other bias

High risk

"We thank… F. Hoffman La Roche & Co. for financial support"

Methods

Design: Retrospective cohort study

Study dates: 1 January 2008 to 30 June 2013

Malaria transmission pattern and local antimalarial drug resistance: Various, not specified

Adverse event monitoring: Data collected retrospectively from the Defense Medical Surveillance System, the Pharmacy Data Transaction Service and the Theater Medical Data Store

Participants

Number enrolled: 367,840

Inclusion criteria: Active component service members who filled a prescription for mefloquine, doxycycline or atovaquone‐proguanil

Exclusion criteria: Doxycycline and atovaquone‐proguanil prescriptions were excluded if the service member previously or concurrently received mefloquine. Doxycycline prescriptions were restricted to 100 mg, once daily, tabular form, minimum 30 day prescription

Factors influencing drug allocation: Not specified

Country of recruitment: USA

Country of malaria exposure: Various, not specified

Duration of exposure to malaria: Various, not specified

Type of participants: Military

Interventions

1. Mefloquine (250 mg weekly)

2. Atovaquone‐ proguanil*

3. Doxycycline (100 mg, tabular form, daily dose, 30 day minimum prescription)

*dosing regimen not specified

Outcomes

1. Adverse events (anxiety disorders, depressive disorders, psychoses, insomnia, vertigo)

2. Adverse events; other (adjustment disorders, post‐traumatic stress disorder, tinnitus, suicidal ideation, convulsions, hallucinations, paranoia, confusion)

Notes

Funding source: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Identified confounders were measured and not balanced across groups

2. Selection of participants into the study: low

Start of intervention and start of follow‐up coincided for most participants. Retrospective medical records were used, therefore there were no non‐responders

3. Measurement of interventions: moderate

Information regarding drug prescriptions were obtained from a medical database, without any verification that users took the prescription

4. Departures from intended interventions: serious

Discontinuations and switches between prophylactic regimes were not recorded in the database

5. Missing data: low

All records in the research database were included in the analysis

6. Measurement of outcomes: moderate

Participants and outcome assessors (physicians) were not blinded. However, information was collected anonymously and on aggregate. Participants were unaware of their participation at the time of seeking healthcare

7. Selection of the reported results: low

Outcome data were reported for all outcomes prespecified for analysis

8. Other: no information

No information was available regarding the study sponsor.

Methods

Design: prospective cohort study

Study dates: December 2004 to April 2006

Malaria transmission pattern and local antimalarial drug resistance: various destinations, not specified

Adverse event monitoring: "a post travel questionnaire… approximately 1 week after they were due to complete their course of medication"

Participants

Number enrolled: 252 recruited, 185 completed pre‐ and post‐travel questionnaires

Inclusion criteria: "...to be eligible, travelers had to be at least 18 years of age and to have been prescribed or supplied... an antimalarial medication as a result of planned travel for a duration of 28 days or less."

Exclusion criteria: "travelers participating in other prospective clinical research or observational studies, pregnant travelers or travelers planning to get pregnant during the study were excluded"

Factors influencing drug allocation: "Treatment choice was solely at the discretion of the traveler and practitioner"

Country of recruitment: UK

Country of malaria exposure: various, not reported

Duration of exposure to malaria: various, median 14 days (interquartile range 9 to 20)

Type of participants: travellers

Interventions

1. Mefloquine*

2. Atovaquone‐proguanil*

3. Doxycycline*

*dosing regimen not specified

Outcomes

Included in the review:

1. Any adverse effects

2. Measures of adherence to the drug regimen

Outcomes assessed not included in the review:

3. Relative importance of factors in choice of antimalarial drugs, for both healthcare professionals and travellers

Notes

Funding sources: "The study was commissioned and paid for by GlaxoSmithKline"

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

"There were statistically significant differences in mean age"

Several other confounders were not reported across groups

2. Selection of participants into the study: moderate

No information is provided regarding people who did not wish to participate

3. Measurement of interventions: low

The antimalarial prescription was provided by a travel clinic which also performed the study

4. Departures from intended interventions: moderate

No information was captured regarding switches between interventions of interest

5. Missing data: serious

185/252 participants completed the pre‐ and post‐travel questionnaire. Interim loss to follow up 27%

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: moderate

The number of reported side effects was reported, but not the types or severity

8. Other: serious

Funded by GlaxoSmithKline; the role of the study sponsor was not made clear

Methods

Design: RCT

Study dates: not mentioned

Malaria transmission pattern and local antimalarial drug resistance: "the 20‐week cumulative incidence of reinfection by P. falciparum to be nearly 100%". No mention of local drug resistance patterns

Adverse event monitoring: "...during the prophylaxis and follow‐up phases, health workers visited the subjects 3 times weekly. Subjects with physical complaints were examined by a study physician the next day or on an emergent basis, as needed. Hematologic analysis was done on days 4 and 10 after starting the loading dose phase and during weeks 4, 8, 12, and 15. Biochemical analysis was done during weeks 4, 8, 12, and 15"

Participants

Number enrolled: 530 enrolled and completed radical cure regimen. 509 participants took at least 1 dose of the weekly study drug or placebo and comprised the full intention‐to‐treat data set

Inclusion criteria: "Inclusion criteria included the following: age of 18–60 years (men) or 50–60 years (women); lack of significant systemic illness as determined by history, physical examination, and clinical laboratory test results (including negative results of a urine pregnancy test for women); and absence of seizures or other neuropsychiatric illness (past or present)"

Exclusion criteria: "The high rate of pregnancy and breast‐feeding in women aged 18–49 years precluded their enrollment... G6PD deficiency accounted for 179 of 338 exclusions"

Country of recruitment: Ghana

Country of malaria exposure: Ghana

Duration of exposure to malaria: trial duration 12 weeks

Type of participants: Ghanain residents, semi‐immune

Interventions

Included in the review:

1. Mefloquine (1 x 250 mg tablet, salt), weekly, with supervised 3 day loading dose*

2. Placebo, with supervised 3 day loading dose*

Not included in the review:

3. Tafenoquine (1 x 25 mg tablet, base), weekly, with supervised 3 day loading dose*

4. Tafenoquine (1 x 50 mg tablet, base), weekly, with supervised 3 day loading dose*

5. Tafenoquine (1 x 100 mg tablet, base), weekly, with supervised 3 day loading dose*

6. Tafenoquine (1 x 200 mg tablet, base), weekly, with supervised 3 day loading dose*

*matched placebo for each treatment arm

Outcomes

Included in the review:

1.Clinical cases of malaria

2. Adverse events; any, abdominal pain, diarrhoea, headache

3. Adverse events; other (gastritis, back pain, myalgia, polyarthralgia/arthralgia, respiratory tract infection, sore throat, rash)

4. Discontinuation of study drug due to adverse effects

Outcomes assessed not included in the review:

5. Laboratory tests; haematological and biochemical analyses

Notes

Funding sources: USA Army Medical Materiel Development

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"The randomization code was generated in blocks of 11 numbers"

Comment: not mentioned how randomization code was produced

Allocation concealment (selection bias)

Unclear risk

"Code numbers were assigned according to the chronological order of appearance of the subjects at screening. Study drugs were prepackaged and prelabeled with a unique study number according to the randomization code"

Comment: no mention of opaque sealed envelopes

Blinding of participants and personnel (performance bias)
Adverse effects/events

Unclear risk

"A ‘double‐dummy’ design allowed double‐blind administration of tafenoquine and mefloquine active drugs and their corresponding placebos"

"A placebo (tafenoquine placebo, GlaxoSmith‐Kline; mefloquine placebo, Hoffmann‐La Roche) served as the negative comparator"

Comment: does not report that the tablets were identical

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"All slides positive for the presence of malaria causing parasites, and an equal number of randomly selected slides with negative results were reevaluated by a second (blinded) microscopist."

Comment: no other mention of outcome assessors being blinded and does not report that the researchers were blinded

Incomplete outcome data (attrition bias); efficacy

Low risk

"Data analysis for efficacy used 2 data sets: the 'full, intent‐to‐treat' data set (n=509), comprising all subjects who took at least 1 dose of the weekly study drug or placebo, and the 'per‐protocol' data set (n=428), comprising those subjects who strictly fulfilled the protocol criteria"

Incomplete outcome data (attrition bias); safety

Low risk

Comment: The safety and tolerability analyses included data for all participants who received at least 1 dose of the study drug or placebo (N = 513)

Selective reporting (reporting bias); efficacy

Low risk

Comment: total number of participants with positive blood smear result at any time during prophylaxis was reported. Clinical cases of malaria were reported

Selective reporting (reporting bias); safety

High risk

"There were 9 serious adverse events in the study... No serious adverse events were considered by study physicians to be related to the study drug, and no deaths occurred"

Comment: Data for serious adverse events were not attributed to the drug regimen. No information was provided on how causality was assessed

Other bias

High risk

Acknowledgement of "Philip Pickford and Rachel Moate (GlaxoSmithKline), for statistical and editorial advisement"

Methods

Design: retrospective cohort study

Study dates: June 1989 to May 1991

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: patient self‐reported questionnaire. "Any reported illness was followed up by telephone interview about the nature of the illness, during which time more complete information was obtained using standardized questions"

Participants

Number enrolled: 869 participants enrolled, 822 completed follow‐up

Inclusion criteria: all individuals attending the International Traveler’s Medical Service at the University of Connecticut Health Center and traveling for ≤ 90 days

Exclusion criteria: none mentioned

Factors influencing drug allocation: "prior to travel each person was given extensive counseling and written material on the prevention of malaria and traveler’s diarrhea. They were given prescriptions for prophylactic antimalarials"

Country of recruitment: USA

Country of malaria exposure: Various: Indian subcontinent 21%, central and east Africa 20%, South America 16%, Southeast Asia 14%, West Africa 10%, Central America and Mexico 10%, North Africa 65, East Asia 6%, Carribean 5%, Southern Africa 5%, Middle East 3%

Duration of exposure to malaria: median 19 days (up to 90 days)

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine*

2. Chloroquine*

Not included in the review:

2. Chloroquine‐proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Any adverse effects

2. Discontinuations of study drug due to adverse effects

3. Measures of adherence to the drug regime

Outcomes assessed not included in the review:

4. Clinical cases of malaria

5. Adverse events (provided for entire cohort, not by type of malaria prophylaxis)

6. Adverse effects; other (all gastrointestinal disorders, all nervous system disorders ‐ no comparative data provided)

7. Illness during and following travel

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Age, sex, destination and duration of travel were measured but not reported across groups

2. Selection of participants into the study: moderate

Non‐response rate was not reported.

3. Measurement of interventions: low

The antimalarial prescription was provided by a travel clinic which also performed the study

4. Departures from intended interventions: moderate

Information was provided on discontinuations, but no information was captured on switches between interventions

5. Missing data: low

Information on adverse effects was available for all participants who ever filled the prescription for the study drug (571/612, 93%)

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: moderate

It is unclear which questions were included in the questionnaire. Information was provided on aggregate

8. Other: no information

No information provided on study sponsor

Methods

Design: retrospective cohort study

Study dates: January to June 1995

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: one‐off telephone interview between 4 and 20 weeks post‐travell

Participants

Number enrolled: 454 eligible travellers, 300 successfully contacted and agreed to participate

Inclusion criteria: subjects who visited the travel vaccination service of the regional public health institute in Maastricht if they had returned from their journey to tropical countries between 4 and 20 weeks previously. The group of non‐users was formed by people who travelled either to tropical countries without malaria risk or to cities in malarious areas, and by travellers who were prescribed an antimalarial drug but did not commence use

Exclusion criteria: participants who had a serious adverse reaction to mefloquine in the first week

Country of recruitment: Netherlands

Region of malaria exposure: various; Asia, Africa, South America

Duration of exposure to malaria: mean ˜3 weeks (range 1 to 9 weeks)

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine (1 x 250 mg tablet) weekly, taken 1 week prior to leaving, during travel and 4 weeks after departure

2. Non‐users of antimalarials

Not included in the review:

3. Proguanil (1 x 100 mg tablet) twice daily, taken during travel and 4 weeks after departure

Outcomes

1. Adverse events; any, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams, insomnia, anxiety, depression, pruritis

2. Adverse events; other (palpitations, severity of symptoms, time point of symptoms in relation to drug taking)

3. Discontinuations of study drug due to adverse effects

4. Measure of adherence to the drug regimen

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Travel destination varies significantly between users of mefloquine and non‐users of prophylaxis (6.7% America mefloquine versus 29.0% non‐users)

2. Selection of participants into the study: low

13/454 (2.8%) of travellers successfully contacted refused to participate

3. Measurement of interventions: low

Prescription was provided by a travel clinic which also performed the study, and discontinuations were reported

4. Departures from intended interventions: moderate

No information regarding switches been interventions of interest was reported

5. Missing data: moderate

"If somebody discontinued drug use within a certain period, symptoms that occurred in the following period were not counted"

Comment: Mefloquine has a half life of 17 to 21 days

6. Measurement of outcomes: moderate

"The participants were specifically asked about symptoms instead of adverse effects...To hide our focus on symptoms as adverse effects of the drugs, participants were informed that the aim of the study was to investigate symptoms during travelling. We structured the questionnaire so that the interviewers asked about symptoms first and drug use last, in order to blind them to the drug used when addressing symptoms"

7. Selection of the reported results: low

All prespecified outcomes were reported.

8. Other: no information

Funding source was not mentioned

Methods

Design: cross‐sectional cohort study

Study dates: 2003

Malaria transmission pattern and local antimalarial drug resistance: during the dry season (considered a low risk malaria season). Local chloroquine/proguanil resistance

Adverse event monitoring: Patient self‐reported questionnaire

Participants

Number enrolled: 90 questionnaires distributed, 68 responses

Inclusion criteria: "all expatriate employees at the mine"

Exclusion criteria: non mentioned

Country of recruitment: Mali

Country of malaria exposure: Mali

Duration of exposure to malaria: various, not specified

Type of participants: long‐term expatriates

Interventions

Included in the review:

1. Mefloquine

2. Doxycycline

3. Atovaquone‐proguanil

Not included in the review:

4. Chloroquine‐proguanil

Outcomes

1. Adverse effects; any

Notes

Study sponsor not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Sex was recorded but not reported across chemoprophylaxis groups. Duration of travel was not reported. Destination of travel was set by the study design.

2. Selection of participants into the study: serious

68/90 response rate (76%)

3. Measurement of interventions: no information

It was unclear whether information on participants chemoprophylaxis was taken from medical records or patient self‐reporting

4. Departures from intended interventions: moderate

No information regarding switches between interventions of interest were reported. Discontinuations were reported

5. Missing data: low

All information was collected at one time point

6. Measurement of outcomes: serious

The outcome measure was subjective. There was no mention of participants or outcome assessors being blinded.

7. Selection of the reported results: no information

No information was provided regarding which topics were included within the questionnaire

8. Other: no information

Funding source was not mentioned

Methods

Design: cross‐sectional cohort study

Study dates: June 2009 to June 2011

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 1119 eligible travellers, 316 enrolled

Inclusion criteria: "travelers who visited Hibiya Clinic, and requested antimalarial drugs for malaria chemoprophylaxis from June 2009 to June 2011"

Exclusion criteria: none mentioned

Factors influencing drug allocation: "The choice of anti‐malarial drug was supported by sufficient explanation about the advantages and disadvantages (efficacy, method, duration, side effect, cost and approval) of each drug"

Country of recruitment: Japan

Region of malaria exposure: various (n): East Africa 76, West Africa 63, South Africa 50, Southeast Asia 36, Central Africa 36, South Pacific 21, South America 16, India 8, North Africa 5, Central America 1

Duration of exposure to malaria: mean 20.0 ± 9.6 days in the atovaquone‐proguanil group and 59.0 ± 15.9 days in the mefloquine group

Type of participants: travellers

Interventions

1. Mefloquine (1 x 250 mg tablet, Mephaquin; Mepha) weekly, starting 1 week prior to arrival, during the stay, and continuing for 4 weeks after leaving the endemic area

2. Atovaquone‐proguanil (1 tablet containing 250 mg atovaquone and 100 mg proguanil, Malarone; GlaxoSmithKline) daily, starting 2 days prior to arrival, during the stay, and for 1 week after leaving the endemic area

Outcomes

1. Adverse effects (any vertigo/dizziness, nausea, abdominal pain, diarrhoea, headache, insomnia, depression, any cardiovascular, any gastrointestinal, any psychoneurotic, allergic reaction)

2. Discontinuations of study drug due to adverse effects

Notes

Funding sources: not mentioned

Communications with the study authors: the study authors provided us with disaggregated study data for the following outcomes: vertigo/dizziness, nausea, abdominal pain, diarrhoea, headache, insomnia, depression. Because we did not get receive the full disaggregated data set, we also retained this study in the analysis of groups of symptoms

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

PTravellers in the mefloquine group were significantly younger than travellers in the A/P group (p=0.01)"

2. Selection of participants into the study: serious

"316 of 1119 travelers (28.2 %) were enrolled"

3. Measurement of interventions: low

The prescription has been provided by travel clinic which also performed the study and discontinuations have been reported

4. Departures from intended interventions: moderate

No information was available regarding switches between interventions of interest

5. Missing data: low

One participant in the mefloquine group appears to be missing from the adverse events analysis. No reason was given

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

Study authors provided us with disaggregated study data for individual outcomes

8. Other: serious

"The authors wish to acknowledge that Makoto Ono and Tomoko Kawamura of GlaxoSmithKline are highly appreciated for conducting Data Management and Statistics Analysis of this study"

Methods

Design: prospective cohort study

Study dates: 1 August 2005 to 31 July 2006.

Malaria transmission pattern and local antimalarial drug resistance: various, chloroquine resistance specified by country of destination

Adverse event monitoring: "Peace Corps medical staff in these countries were provided surveys for distribution during mandatory in‐country volunteer training sessions"

Participants

Number enrolled: 2701 (6216 Peace Corps volunteers during the time period)

Inclusion criteria: "all Peace Corps countries with malaria risk"

Exclusion criteria: none mentioned

Factors influencing drug allocation: "Volunteers are provided chemoprophylaxis (either chloroquine, mefloquine, doxycycline, or atovaquone/proguanil)... medical officers can provide alternative chemoprophylaxis regimens for volunteers when adverse events or other factors require the cessation of any medication"

Country of recruitment: various

Country of malaria exposure: various

Duration of exposure to malaria: "6 months or longer"

Type of participants: Peace Corps volunteers

Interventions

Included in the review:

1. Mefloquine*

2. Chloroquine*

3. Doxycycline*

4. Atovaquone‐proguanil*

*dosing regimen not specified

Outcomes

1. Adverse effects; any (mild, moderate, severe, sought medical advice), nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams, insomnia, depression, anxiety, visual disturbance

2. Adverse effects; other (unsteadiness, hair loss, weakness, itchy skin, photosensitivity, yeast infection)

3. Serious adverse effects

4. Discontinuations of study drug due to adverse effects

Notes

Funding sources: "CK and PJ are employed by the Peace Corps, which has a significant number of volunteers taking anti‐malarial medications. There were no other financial disclosures"

Communications with study authors:

The study authors provided us with access to the disaggregated study data for the specific symptoms mentioned above. The questionnaire in the paper allowed participants to describe side effects from the antimalarial they were currently taking, and any regimen they had previously used. For non‐serious side effects, in line with the original paper, we only included side effects for the subject's original regimen. Where subjects had previously taken more than one regimen, we only include side effects for whichever regimen to which the participant attributed the greater number of side effects; this affected 70/2701 participants. This analysis resulted in a decrease in the effect size for side effects attributed to mefloquine. For serious side effects (hospitalizations) and discontinuations we included all participants entries for all regimens. In addition, our denominator differed from the original paper because we did not exclude participants who had been in post for fewer than six months

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

"The questionnaire did not collect demographic information because of privacy concerns"

Comment: destination has been reported, but not by type of antimalarial chemoprophylaxis. Duration was set by the study design

2. Selection of participants into the study: serious

"A total of 2701 surveys were received yielding a response rate of 43%"

3. Measurement of interventions: moderate

Participants were asked to self‐report which prophylaxis they were currently taking and had previously taken

4. Departures from intended interventions: moderate

Switches between interventions of interest were reported. Approximately 1/3 of study participants had switched prophylactic regimens

5. Missing data: low

We were able to include all participants in the study analysis because we had access to the original data set

6. Measurement of outcomes: serious

"If respondents identified any adverse event, the survey instructed them to self‐report which drug they believed caused the adverse event"

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

We were able to include all results in the analysis because we had access to the original data set

8. Other: low

No evidence of pharmaceutical company funding

Methods

Design: prospective cohort study

Study dates: 2000 to 2003

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: retrospective patient self‐reporting questionnaire

Participants

Number enrolled: 495 enrolled, 284 response rate

Inclusion criteria: unclear. Users of the travel medicine department of the lower Saxony regional health office in Hanover, Germany

Exclusion criteria: None mentioned

Factors influencing drug allocation: "the prescriptions of medications followed individual consultation"

Country of recruitment: Germany

Country of malaria exposure: various, not specified

Duration of exposure to drug: atovaquone‐proguanil mean 2.6 weeks, mefloquine mean 7 weeks

Type of participants: short‐term travellers

Interventions

Included in the review:

1. Mefloquine*

2. Atovaquone‐proguanil*

Not included in the review:

3. Chloroquine‐proguanil*

4. Chloroquine (not included in the study analysis)

*dosing regimen not specified

Outcomes

1. Adverse effects; any, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams, insomnia, pruritis

2. Adverse effects; other (concentration difficulties, palpitations, circulation disorders, rash)

3. Discontinuations of study drug due to adverse effects

Notes

Funding sources: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Sex, age and duration of travel were reported but not balanced across groups

2. Selection of participants into the study: serious

284/495 (59.8%) response rate

3. Measurement of interventions: low

The prescription was provided by a travel clinic which also performed the study; switches and discontinuations were recorded and reported.

4. Departures from intended interventions: moderate

No information was provided regarding switches between prophylactic regimens

5. Missing data: low

All information was collected at one time point

6. Measurement of outcomes: serious

The outcome measure was subjective. There was no mention of outcome assessors being blinded

7. Selection of the reported results: moderate

Insufficient information was provided regarding the questionnaire to know whether all outcomes were reported

8. Other: no information

Study sponsor not mentioned

Methods

Design: prospective cohort study

Study dates: 19 August to 30 September 2013

Malaria transmission pattern and local antimalarial drug resistance: various

Adverse event monitoring: participant self‐reported questionnaire

Participants

Number enrolled: 3207 emails sent, 1184 unique, valid responses received

Inclusion criteria: "(volunteers in) Peace Corps offices of all 23 countries with active posts in the Africa region to all active Volunteers in‐country"

Exclusion criteria: Volunteers serving in Ethiopia, Kenya, Tanzania, Namibia, Botswana, South Africa

Region of recruitment: African region except Ethiopia, Kenya, Tanzania, Namibia, Botswana, South Africa

Factors influencing drug allocation: "all prophylaxis options (mefloquine, doxycycline, atovaquone‐proguanil) [are] equally available... They are instructed to individualize their choice of agent based on area‐specific recommendations, drug contraindications and precautions, drug tolerance, and dosing schedule"

Country of malaria exposure: various: Togo (3.7%), Sierra Leone (6.3%), Uganda (7.8%), Liberia (5.6%), Malawi (2.0%), Cameroon (11.4%), Benin (10.2%), Burkina Faso (1.9%), Zambia (6.0%), Mozambique (4.5%), Ghana (10.8%), Rwanda (5.4%), Gambia (4.4%), Madagascar (11.1%), Swaziland (2.3%)

Duration of exposure to malaria: various, not specified

Type of participants: Peace Corps volunteers

Interventions

1. Mefloquine*

2. Atovaquone‐proguanil*

3. Doxycycline*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse effects; any, vertigo, headache, abnormal dreams, insomnia, anxiety, depression, psychosis

2. Adverse effects; other (any neuropsychiatric disorder, any gastrointestinal disorder, any skin or subcutaneous disorder, limb numbness, tinnitus, 'constitutional', genitourinary)

3. Measures of adherence to the drug regimen

Outcomes assessed not included in the review:

4. Reasons for non‐adherence (not ascribed to prophylactic regimen, provided on aggregate),

5. Malaria knowledge

6. Health behaviours

Notes

Funding sources: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

The age, sex and BMI of included participants was not recorded. The destination and duration of travel was not reported by prophylactic regimen

2. Selection of participants into the study: serious

1184/3248 (36%) response rate

3. Measurement of interventions: moderate

Travellers were asked to self‐report which prophylaxis they were taking at various time points during treatment

4. Departures from intended interventions: serious

"Two hundred seventy‐six (35%) respondents reported having changed prophylaxis at some point during their service"

Comment: this was not provided by prophylactic regimen

5. Missing data: low

703/781 (90%) participants reported data for adherence; 733/781 (94%) participants reported data for adverse events. Data were only included from the 2015 version of the publication

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

All outcomes prespecified in the methods section were reported

8. Other: no information

Study sponsor not mentioned

Methods

Design: cross‐sectional cohort study

Study dates: February 2000

Malaria transmission pattern and local antimalarial drug resistance: "during February 2000, which was a peak period of malaria transmission in Zimbabwe"

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 660

Inclusion criteria: Passengers in Harare and Victoria Falls international airport during February 2000

Exclusion criteria: "Children under the age of 18 were excluded on the assumption that parents probably influence their health seeking behavior... Excluded, were travelers from the African continent and VIP travelers who exited through special departure lounges"

Factors influencing drug allocation: no infromation provided

Country of recruitment: Zimbabwe

Country of malaria exposure: Zimbabwe

Duration of exposure to malaria: various: 1 week or less, N = 317; 8 days to 2 weeks, N = 144; 15 days to 4 weeks, N = 90; > 4 weeks, N = 41

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine*

2. Doxycycline*

3. Chloroquine*

Not included in the review:

4. Proguanil*

5. Dapsone and pyrimethamine*

6. Chloroquine and proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Measure of adherence to the drug regimen

Outcomes assessed not included in the review:

2. Sources of pre‐travel health advice

3. Knowledge about malaria transmission

4. Knowledge about malaria prevention

5. Threat and risk perception

Notes

Funding sources: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Sex (P < 0.008), education (P < 0.022), previous episodes of malaria (P < 0.001) and access to pre‐travel advice (P < 0.001) were all significantly associated with reduced compliance at the significance value set by the study. None of these factors were adjusted for in the analysis

2. Selection of participants into the study: moderate

"The nonresponse rate was about 10% (n = 65), with the main reason being the short transit time"

3. Measurement of interventions: low

Participants were asked to self‐report which prophylactic regimen they were taking while they were still taking it

4. Departures from intended interventions: moderate

No information was provided regarding switches between prophylactic regimens

5. Missing data: low

Adherence information was not available for 4/595 participants

6. Measurement of outcomes: serious

The outcome measure was based on participant self‐reporting; participants and personnel were not blinded.

7. Selection of the reported results: moderate

There was insufficient information provided to know what questions were asked regarding adherence

8. Other: low

"The authors had no financial or other conflicts of interest to disclose"

Methods

Design: retrospective cohort study

Study dates: 1 January 2003 to 31 December 2004

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: "An anonymous survey in a post‐travel situation"

Participants

Number enrolled: 1176 agreed to participate, 1237 approached

Inclusion criteria: "travellers who had already completed their journey for which they had undergone immunization prophylaxis and who had returned to complete their vaccination schedule"

Exclusion criteria: none mentioned

Factors influencing drug allocation: "offered health advice following the World Health Organization guidelines for international travel"

Country of recruitment: Italy

Regions of malaria exposure: 97 countries: 39 states in Africa, 25 in Asia, 16 in North and Central America, 8 in South America, 6 in Europe and 3 in Oceania

Duration of exposure to malaria: 1 to 7 days, 8.9%; 8 to 14 days, 30.1%; 15 to 21 days, 34.6%; 22 to 30 days, 16.8%; > 30 days, 8.9%; not available 0.7%

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine*

2. Atovaquone‐proguanil*

3. Chloroquine*

Not included in the review:

4.Chloroquine‐proguanil*

5. Proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse effects; any, visual impairment (blurred vision), nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, abnormal dreams (nightmares), insomnia, anxiety (anxiety disorder), depression, psychosis (hallucinations)

2. Adverse effects; other (slight illness, tiredness, restlessness, drowsiness, palpitations, weakness, photosensitization, mental confusion, rash)

Outcomes assessed not included in the review:

3. Adverse effects; other, incidence < 1% (liver pain, aerophagy, rise in transaminase levels, gastrointestinal disturbance, epistaxis, fever)

4. Compliance with vaccinations

5. Side effects from vaccinations

6. Occurrence of health problems and unforeseen events during travel in the countries visited

7. Attention to avoiding potentially risky food and drink

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Demographic information was collected, but provided on aggregate for the entire cohort

2. Selection of participants into the study: low

1176 of 1237 (95.1%) response rate

3. Measurement of interventions: serious

Participants were asked to self‐report which prophylactic regimen they had used, up to over 12 months since travelling

4. Departures from intended interventions: serious

No switches were reported, and this information was not sought in the questionnaire

5. Missing data: low

642/646 (99%) participants were included in the analysis

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

The questionnaire was provided in full, and all outcomes were reported

8. Other: no information

No information was provided regarding the study sponsor

Methods

Design: cross‐sectional cohort study

Study dates: 13 July to 9 August 1997

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: patient self‐reported questionnaire

Participants

Number enrolled: 6633 respondents, 5626 met inclusion criteria

Inclusion criteria: "travelers departing Nairobi, or Mombasa, Kenya, from July 13 to August 9, 1997, on flights to Europe, including London, Paris, Frankfurt, Amsterdam, and Rome"

Exclusion criteria: residents of African countries, individuals who had remained in Africa for more than 1 year, individuals who visited only non malarious areas, including Nairobi and Lesotho

Factors influencing drug allocation: no information available

Region of recruitment: Nairobi or Mombasa, Kenya

Region of malaria exposure: Nairobi or Mombasa, Kenya

Duration of exposure to malaria: < 5 weeks

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine*

2. Doxycycline*

3. Chloroquine*

Not included in the review:

4. Chloroquine‐proguanil*

5. Proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse effects; any,

2. Serious adverse outcomes

3. Adverse effects; other (neuropsychologic, gastrointestinal, respiratory)

4. Measure of adherence to the drug regimen

Outcomes assessed not included in the review:

5. Pre‐travel medical advice

6. Compliance with antimosquito measures

7. Self‐treatment of presumed malaria

Notes

Funding sources: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

The number of travellers and country of origin was reported, but was not adjusted for in the analysis. Sex, age and duration of stay were reported on aggregate.

2. Selection of participants into the study: serious

Response rate 6633/15,487 (43%)

3. Measurement of interventions: low

Participants were asked to provide information regarding their prophylactic regimen during their flight home, while they should have still been using it

4. Departures from intended interventions: moderate

No information was available regarding switches between alternative prophylactic regimens

5. Missing data: low

4934/4982 (99%) participants included in adverse event reporting

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: moderate

There was insufficient information provided regarding the questions included in the questionnaire. Symptoms were grouped together to report outcomes

8. Other: low

"The authors had no financial or other conflicts of interest to disclose"

Methods

Design: retrospective cohort study

Study dates: October to December 2005, with a 2 year follow‐up

Malaria transmission pattern and local antimalarial drug resistance: "Malaria endemic area. Local chloroquine/proguanil resistance"

Adverse event monitoring: Not clear

Participants

Number enrolled: 33

Inclusion criteria: not explicitly stated. Participants were travellers who took part in a scientific survey and rafting expedition in Ethiopia between October and December 2005

Exclusion criteria: none stated

Country of recruitment: various, participants were from "a non‐malarious area, mainly the UK"

Country of malaria exposure: Ethiopia

Duration of exposure to malaria: 3 months

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine, dose not specified, during travel and 4 weeks after return

2. Atovaquone‐proguanil, dose not specified, during travel and for 1 week after return

3. Doxycycline, dose not specified, during travel and 4 weeks after return

Not included in the review:

4. Chloroquine‐proguanil, dose not specified, during travel and 4 weeks after return

Outcomes

Included in the review:

1. Measures of adherence to the drug regimen

Outcomes assessed not included in the review:

2. Clinical cases of malaria

3. Adverse effects (information not provided by drug class)

4. Factors influencing choice of prophylaxis

Notes

Funding sources: Work was supported by the Biomedical Research Centre (Grant RG561620 to AMLL)

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Demographic information is provided for the entire cohort

2. Selection of participants into the study: low

No participants refused to participate in the study. Start of follow‐up began at the start of travel and not at the start of treatment, but this was judged to have a low impact on monitoring self‐reported adherence

3. Measurement of interventions: low

Intervention status was determined by one of the participants on the expedition

4. Departures from intended interventions: low

There are no documented switches between interventions of interest

5. Missing data: low

Two people (6%) were lost to follow‐up in respect to data on efficacy. No participants were lost to follow‐up when monitoring adherence

6. Measurement of outcomes: serious

Adherence was monitored by the medical officer on the trip, and reporting may have been influenced by social desirability bias

7. Selection of the reported results: low

All prespecified outcomes have been reported

8. Other: low

Government funding

Methods

Design: retrospective cohort study

Study dates: 1 January 1990 and 31 December 1999

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: incident cases of depression, psychoses and panic attacks severe enough to require hospitalisation, referral to a specialist or specific pharmacological treatment within the UK general practice research database

Participants

Number enrolled: 35,370

Inclusion criteria: "men and women aged 17‐79 years who received between one and four prescriptions for mefloquine, proguanil and/or chloroquine, or subjects who received one prescription only for doxycycline... we included only those subjects who medical record contained a code indicating that the person received the drug for malaria prophylaxis within 1 week of the prescription date e.g. ‘travel advice’ or ‘prophylactic drug use’"

Exclusion criteria: "participants who received the study drugs on a longer‐term basis...subjects had to be enrolled in the database for at least 12 months before the date of the first prescription for a study drug and had to have had some recorded activity (diagnoses or drug prescriptions) after the prescription(s) for an antimalarial drug... subjects with a history of alcoholism"

Country of recruitment: UK

Country of malaria exposure: various, not specified

Duration of exposure to malaria: various, not specified

Type of participants: travellers

Interventions

Included in the review:

1. Mefloquine*

2. Doxycycline*

Not included in the review:

3. Chloroquine‐proguanil*

4. Proguanil*

5. Chloroquine* (data reported combined with proguanil and chloroquine‐proguanil)

*dosing regimen not specified

Outcomes

1. Serious adverse events

2. Adverse events; psychiatric disorders (depression, psychosis)

3. Adverse events; other (panic attacks, suicide)

Notes

Funding sources: "This study was funded by an unconditional grant by F. Hoffmann‐La Roche Ltd, Basel, Switzerland"

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Women and those aged 40 to 49 years were at higher risk of depression but this was not adjusted for in the analysis. Risk ratio estimates for psychoses and panic attacks could not be adjusted for because numbers were too small for the multivariate model. Data on destination and duration of travel were not available

2. Selection of participants into the study: low

Recruitment onto the General Practice Research Database was unlikely to be related to exposure or outcome

3. Measurement of interventions: moderate

"Antimalarial drugs can be used for malaria prophylaxis, for treatment of an acute malaria infection, or as a reserve drug… In order to distinguish these options, we included only those subjects whose medical records contained a code indicating ‘travel advice’ or ‘prophylactic drug use’"

4. Departures from intended interventions: serious

Discontinuations and switches between prophylactic regimens were not recorded in this database

5. Missing data: low

All participants in the research database were included in the analysis

6. Measurement of outcomes: moderate

"...we reviewed all computer records of potential cases and included or excluded cases on the available clinical information, blinded to exposure status"

Comment: general practitioners diagnosing patients would have been aware of their exposure status

7. Selection of the reported results: low

Information on all outcomes prespecified in the methods section were reported for all participants.

8. Other: serious

Funded by Roche pharmaceuticals

Methods

Design: retrospective cohort study

Study dates: 1 October 2005 to 30 June 2006

Malaria transmission pattern and local antimalarial drug resistance: various, not specified

Adverse event monitoring: telephone questionnaire to all travellers to tropical countries for whom antimalarial chemoprophylaxis was prescribed

Participants

Number enrolled: 1906 questionnaires returned

Inclusion criteria: participants staying in high risk malarial areas, aged between 18 and 65 years, with no severe underlying disease (e.g. heart disease, diabetes) with an available phone number

Exclusion criteria: immigrants (due to potential difficulty in linguistic communication)

Country of recruitment: Italy

Country of malaria exposure: various: Kenya, Tanzania/Zanzibar, India, Madagascar, Brazil, other countries of South America, South Africa, Senegal, Mali, Myanmar, Ghana, Congo, and others

Duration of exposure to malaria: mean stay 2 weeks

Type of participants: Travellers

Interventions

Included in the review:

1. Mefloquine*

2. Chloroquine*

3. Atovaquone + proguanil*

4. Doxycycline*

Not included in the review:

5. Chloroquine + proguanil*

*dosing regimen not specified

Outcomes

Included in the review:

1. Adverse effects; any

2. Serious adverse effects

3. Adverse effects; other (any gastrointestinal, any neuropsychiatric)

4. Discontinuations of study drug due to adverse effects

Outcomes assessed not included in the review:

5. Clinical cases of malaria

6. Eating habits during travel

Notes

Funding sources: Not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Other bias

Unclear risk

1. Confounding: moderate

Demographic information was provided on aggregate for the entire cohort

2. Selection of participants into the study: moderate

Non‐response rates to the questionnaire were not reported

3. Measurement of interventions: moderate

The prescription was provided by several travel clinics which also performed the study. However, it was unclear whether this information was used to determine intervention status or relied on participant self‐reporting

4. Departures from intended interventions: low

Discontinuations were reported, with detailed reasons for discontinuations. No switches to alternative regimens were reported

5. Missing data: low

All participants were included in the analysis

6. Measurement of outcomes: serious

Comment: the outcome measure was subjective; participants and personnel were not blinded

7. Selection of the reported results: low

The methods section makes clear which outcomes were being assessed; all outcomes were reported

8. Other: no information

No information was provided regarding the study sponsor

Methods

Design: RCT

Study dates: January 1987 to November 1990

Malaria transmission pattern and local antimalarial drug resistance: "in an area of seasonal malaria transmission... mefloquine and quinine resistance is increasing in this area, and the proportion of recrudescent infections is rising"

Adverse event monitoring: trial occurred over two phases. Phase 1: Weekly basic observations and simple symptom questionnaire. ECG, haematological and biochemical tests were done fortnightly. Children born to women in the trial were assessed at birth and at 3, 6, 12, and 24 months. Phase 2: weekly basic observations and expanded simple symptom questionnaire. ECG and blood tests were performed at baseline, at midstudy and at term. Each delivery was supervised. Additional assessments at 1 week and 2 and 9 months for children born to women in the trial

Participants

Number enrolled: 339

Inclusion criteria: "Women attending the weekly clinic were admitted to the study if they were at > 20 weeks of estimated gestation"

Exclusion criteria: Not mentioned

Region of recruitment: Thai‐Burmese border

Region of malaria exposure: Thai‐Burmese border

Duration of exposure to malaria: ongoing exposure in a semi‐immune population, monitored until delivery

Type of participants: Pregnant Thai residents in malaria‐endemic area (presumed semi‐immune)

Interventions

1. Mefloquine (1 x 250 mg tablet, Lariam; Hoffmann‐La Roche) weekly for 4 weeks, then 125 mg weekly until delivery, with 500 mg base loading dose in phase 1 but not phase 2

2. Placebo (1 tablet) weekly until delivery

Outcomes

Included in the review:

1. Clinical cases of malaria

2. Episodes of parasitaemia

3. Serious adverse events (including childhood deaths)

4. Adverse events; vertigo, visual impairment (visual abnormalities), nausea, vomiting, abdominal pain, headache, dizziness, pruritis

5. Adverse events; other (weakness, anorexia, cough, falls, constipation, unsteadiness)

6. Discontinuation of study drug due to adverse effects

7. Adverse pregnancy outcomes (spontaneous abortions, still births, congenital malformations)

Outcomes assessed not included in the review:

8. Laboratory tests; haematologic (full blood count, haematocrit) and biochemical (creatinine, blood urea, transaminases, alkaline phosphatase, albumin, globulin)

9. Outcomes related to pregnancy; weight gain during follow‐up, complications of labour, mean duration of labour, maternal anaemia

10. Fetal outcomes; mean birth weight, percent premature, fetal distress

11. Infant follow up; mean age at which children could crawl, sit, walk or talk, Romberg test

Notes

Funding sources: United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases; Wellcome Trust of Great Britain; Praevention Foundation. The Hague (to FLK)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...women were randomized to receive either mefloquine…or placebo"

Comment: unclear what method of randomization was used

Allocation concealment (selection bias)

Unclear risk

"...the investigators were unaware of the randomisation"

Comment: no mention of method used to conceal allocation

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"...double blind...women were randomised to receive either mefloquine…or identical placebo"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"...the investigators were unaware of the randomisation"

Incomplete outcome data (attrition bias); efficacy

Low risk

Comment: total number of participants with positive blood smear result at any time during prophylaxis was reported. Clinical cases of malaria were reported"

Incomplete outcome data (attrition bias); safety

High risk

"Ten women (8%) in phase I (3 mefloquine, 7 placebo) and 18 (8%) in phase II (9 in each group) dropped out of the study. The main reason was the discomfort of blood sampling (26 cases) and, in 1 case, pruritus attributed to mefloquine"

Comment: 28 women dropped out but reasons were provided for only 27 women; numbers were not provided across groups

Selective reporting (reporting bias); efficacy

Low risk

Comment: all episodes of parasitaemia and clinical cases of malaria were reported

Selective reporting (reporting bias); safety

High risk

Comment: Data on adverse effects were reported for only participants from phase 2 of the trial (220/339 women). Fifteen symptoms were listed in the comparative table, but the narrative states "twenty questions were asked". Romberg test results were not reported. Biochemical, haematological and ECG parameters were not reported other than "there were no differences"

Other bias

Low risk

Funding: United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases; Wellcome Trust of Great Britain; Praevention Foundation. The Hague (to FLK)

Methods

Design: RCT

Duration of study: May to July 1994

Malaria transmission pattern and local drug resistance: "P. falciparum resistant to sulfadoxine‐pyrimethamine and both P falciparum and P vivax resistant to chloroquine"

Adverse event monitoring: symptoms reported in the first week of the study, daily questioning about symptoms, exit questionnaire

Participants

Number enrolled: 204

Inclusion criteria: "All soldiers from military posts that were considered to have high malaria attack rates"

Exclusion criteria: history of frequent travel, allergy to one of the study drugs, glucose‐6‐phosphate dehydrogenase deficiency, history of underlying illness

Country of recruitment: Indonesia

Country of malaria exposure: Indonesia

Duration of exposure to malaria: Study duration was approximately 13 weeks

Type of participants: military, semi‐immune (60% of participants had prior exposure to malaria)

Interventions

1. Mefloquine (1 x 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).*

2. Doxycycline hyclate (1 x 100 mg capsule) once daily*

3. Placebo*

Co‐interventions: All soldiers were given doxycycline tablets for 4 to 6 weeks to enable clearance of sulfadoxine‐pyrimethamine from the blood before study prophylaxis began. All participants received radical treatment for pre‐existing malaria parasites in the blood and liver prior to beginning study prophylaxis.

*matched placebo for each treatment arm

Outcomes

Included in the review:

1. Clinical cases of malaria

2. Adverse events; any, nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness, insomnia, abnormal dreams

3. Serious adverse events

4. Adverse events; other (all gastrointestinal, all neurologic, constipation, anorexia, fever, malaise, skin related, cough, somnolence, palpitations, sexual dysfunction)

5. Discontinuation of study drug due to adverse effect

Outcomes assessed not included in the review:

6. Exit questionnaire (incomplete data reported)

Notes

Funding source: Pfizer Indonesia supplied active and placebo doxycycline; F. Hoffman‐La Roche supplied active and placebo mefloquine, and gave financial support; USA Army Medical Research and Materiel Command gave financial support; USA Naval Medical Research and Development Command gave financial support

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Block randomization was used (block size, 15)"

Comment: Used a randomization code, but it was not stated how it was generated

Allocation concealment (selection bias)

Unclear risk

"The randomization code was stored in individual envelopes in a locked box at the study site...Drugs were packaged into weekly ziplock plastic bags"

Comment: Unclear whether the investigators or participants would foresee assignment. There was no mention of central allocation, sequentially numbered drug containers or sequentially numbers opaque sealed envelopes

Blinding of participants and personnel (performance bias)
Adverse effects/events

Low risk

"Drugs were packaged into weekly zipper‐lock plastic bags: each bag contained a mefloquine or mefloquine placebo tablet and a blister pack of seven doxycycline or doxycycline placebo capsules (double‐dummy technique)"

The placebo medication had an "identical appearance"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The randomisation code was stored in individual envelopes in a locked box at the study site. All investigators and study personnel did not have access to or know the randomisation code throughout the study"

Incomplete outcome data (attrition bias); efficacy

Unclear risk

"Sixteen of the 204 participants did not complete the study"

Comment: It was unclear whether the duration of follow up included the post‐prophylaxis period to monitor for relapses

Incomplete outcome data (attrition bias); safety

High risk

Exit questionnaire: "Only data from persons who were still receiving the study drug at the time of the questionnaire were included"

Comment: numbers not reported

Selective reporting (reporting bias); efficacy

Low risk

"The primary end point for efficacy was the first occurrence of malaria, as documented by a positive malaria smear"

Comment: all cases of malaria were reported.

Selective reporting (reporting bias); safety

High risk

Comment: Not all data were reported from the exit questionnaire; the study reports "...the only statistically significant finding". Data on adverse symptoms were not reported for the placebo group

Other bias

Low risk

"Neither of the pharmaceutical companies that provided support played any role in the gathering, analysing or interpreting the data"

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