Scolaris Content Display Scolaris Content Display

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.
Figures and Tables -
Analysis 1.1

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.
Figures and Tables -
Analysis 1.2

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.
Figures and Tables -
Analysis 1.3

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).
Figures and Tables -
Analysis 1.4

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).
Figures and Tables -
Analysis 1.5

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 6 Adverse events.
Figures and Tables -
Analysis 1.6

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 6 Adverse events.

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.
Figures and Tables -
Analysis 2.1

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.
Figures and Tables -
Analysis 2.2

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.
Figures and Tables -
Analysis 2.3

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).
Figures and Tables -
Analysis 2.4

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).
Figures and Tables -
Analysis 2.5

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Parasitaemia.
Figures and Tables -
Analysis 3.1

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Parasitaemia.

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Fever.
Figures and Tables -
Analysis 3.2

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Fever.

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Adverse event.
Figures and Tables -
Analysis 3.3

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Adverse event.

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Treatment failure.
Figures and Tables -
Analysis 4.1

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Treatment failure.

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Parasitaemia.
Figures and Tables -
Analysis 4.2

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Parasitaemia.

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Fever.
Figures and Tables -
Analysis 4.3

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Fever.

Table 1. Detailed search strategies

Search set

CIDG SRa

CENTRAL

MEDLINEb

EMBASEb

LILACSb

BIOSIS

1

artesunate

artesunate

ARTESUNATE

ARTESUNATE

artesunate

artesunate

2

mefloquine

mefloquine

artesunate

artesunate

mefloquine

mefloquine

3

Lariam

Lariam

arsumax

arsumax

malaria

Lariam

4

2 or 3

1 or 2 or 3

1 or 2 or 3

1 and 2 and 3

5

1 and 4

MEFLOQUINE

mefloquine

6

mefloquine

MEFLOQUINE

7

Lariam

mephaquim

8

5 or 6 or 7

Lariam

9

4 and 8

5 or 6 or 7 or 8

10

exp MALARIA

4 and 9

11

malaria

malaria

12

exp PLASMODIUM

MALARIA

13

plasmodium

PLASMODIUM‐FALCIPARUM

14

10 or 11 or 12 or 13

11 or 12 or 13

15

9 and 14

10 and 14

aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration Higgins 2005; upper case: MeSH or EMTREE heading; lower case: free text term.

Figures and Tables -
Table 1. Detailed search strategies
Table 2. Methods for future updates

Method

Details

Recrudesced and new infections

In areas of intense malaria transmission, blood smears positive for malaria parasites after day 14 may be a result of new infections or a recrudescence of the original infection. Polymerase chain reaction (PCR) is a method that can be used to differentiate between new and old infections. We will use the results of PCR analyses, if they become available, to differentiate between recrudesced and new infections

Continuous data reported with geometric means

We will extract the standard deviations on the log scale, and extract minimum and maximum values for medians. We will combine the findings on a log scale and report on the original scale; we will report medians and ranges in tables

Exploring potential sources of heterogeneity using subgroup analyses

1. Intervention: simultaneous versus sequential regimens; mefloquine dose; and artesunate dose
2. Trial setting: level of background mefloquine resistance; high malaria transmission (an area of hyperendemicity or holoendemicity) versus low transmission (an area of hypoendemicity or mesoendemicity)
3. Pre‐treatment malaria parasite density: < 250,000/µL or 5% of total red blood cells and at least 250,000/µL or 5% of total red blood cells
4. Age: ≤ 5 years and > 5 years

Sensitivity analyses

We will conduct sensitivity analyses for each of the components of methodological quality

Funnel plots

We will examine funnel plots for asymmetry, keeping in mind that the asymmetry could be caused by publication bias, differences in methodological quality, or heterogeneity

Figures and Tables -
Table 2. Methods for future updates
Table 3. Total dose and regimens: artesunate and mefloquine

Trial

Artesunate

Mefloquine

Total dose (mg/kg)

Regimen

Total dose (mg/kg)

Regimen

Karbwang 1994

3.33a

1 dose

21b

2 doses over 1 day

Looareesuwan 1992a

10

11 doses over 5 days

21b

2 doses over 1 day

Marquino 2003

12

3 doses over 3 days

15

1 dose

Nosten 1994a

4

1 dose

25

1 dose

Nosten 1994b

10

4 doses over 3 days

25

1 dose

Price 1995

12

3 doses over 3 days

25

1 dose

Smithius 2004

4

1 dose

15

1 dose

Thimasarn 1997

10a

2 doses over 2 days

21b

2 doses over 3 days

aAssuming 60 kg person (actual dose 200 mg).
bAssuming 60 kg person (actual dose 1250 mg).

Figures and Tables -
Table 3. Total dose and regimens: artesunate and mefloquine
Table 4. Risk of bias assessment

Trial

Generation of allocation sequencec

Allocation concealmentd

Blindinge

Inclusion of all randomized participants in final analysisb

Karbwang 1994

Unclear

Unclear

Unclear

Adequate

Looareesuwan 1992a

Unclear

Unclear

Unclear

Inadequate

Marquino 2003

Adequate

Unclear

Unclear

Inadequate

Nosten 1994a

Unclear

Unclear

Unclear

Inadequate

Nosten 1994b

Unclear

Unclear

Unclear

Inadequate

Smithius 2004

Unclear

Unclear

Unclear

Inadequate

Thimasarn 1997

Unclear

Unclear

Unclear

Adequate

Price 1998

Unclear

Unclear

Unclear

Inadequate

aSee the 'Assessment of risk of bias in included studies' for the assessment methods, and the Characteristics of included studies' for the methods used in each trial.
bFor primary outcomes.
cUnclear: reported as random but method not revealed.
dUnclear: not mentioned.
eUnclear: unlikely to be blinded.

Figures and Tables -
Table 4. Risk of bias assessment
Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Day 28

4

824

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.06, 0.47]

1.2 Day 42

1

298

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.14, 0.39]

1.3 Day 63

2

501

Risk Ratio (M‐H, Random, 95% CI)

0.26 [0.09, 0.77]

2 Parasitaemia Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Day 3

2

716

Risk Ratio (M‐H, Fixed, 95% CI)

0.04 [0.02, 0.11]

2.2 Day 7

2

700

Risk Ratio (M‐H, Fixed, 95% CI)

0.02 [0.00, 0.11]

2.3 Day 14

1

339

Risk Ratio (M‐H, Fixed, 95% CI)

0.09 [0.03, 0.28]

3 Fever Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Day 2

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Mean fever clearance time (h) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

5 Mean parasite clearance time (h) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

6 Adverse events Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Serious adverse events

1

368

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 8.04]

6.2 Adverse events requiring discontinuation of treatment

2

444

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.04, 3.23]

6.3 Abdominal pain

2

196

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.31, 1.20]

6.4 Cardiovascular abnormalities

1

120

Risk Ratio (M‐H, Random, 95% CI)

1.95 [0.08, 46.79]

6.5 Central nervous system abnormalities

1

120

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.53, 1.36]

6.6 Diarrhoea

2

196

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.48, 2.77]

6.7 Dizziness

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.10, 1.24]

6.8 Headache

2

196

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.38, 0.69]

6.9 Itching and rash

1

76

Risk Ratio (M‐H, Random, 95% CI)

2.85 [0.12, 67.83]

6.10 Nausea

2

196

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.33, 1.16]

6.11 Palpitations/anxiety

1

368

Risk Ratio (M‐H, Random, 95% CI)

2.97 [0.12, 72.38]

6.12 Psychosis

1

654

Risk Ratio (M‐H, Random, 95% CI)

0.32 [0.01, 7.91]

6.13 Vomiting

4

1218

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.39, 1.62]

6.14 Other adverse events

1

120

Risk Ratio (M‐H, Random, 95% CI)

8.43 [0.49, 146.28]

Figures and Tables -
Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)
Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Day 28

2

259

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.50, 1.38]

1.2 Day 42

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

2.67 [0.36, 19.71]

2 Parasitaemia Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Day 7

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Day 14

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Fever Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Day 2

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Mean fever clearance time (h) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

5 Mean parasite clearance time (h) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)
Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Parasitaemia Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Fever Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Adverse event Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Insomnia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)
Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment failure Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Day 14

1

149

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.35, 4.53]

1.2 Day 28

1

142

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.16, 1.21]

1.3 Day 42

1

147

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.48, 1.65]

2 Parasitaemia Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Day 3

1

156

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.14, 1.29]

3 Fever Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Day 3

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)