Artemether-lumefantrine (four-dose regimen) for treating uncomplicated falciparum malaria

 

Characteristics of included studies [ordered by study ID]

Hatz 1998

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Methods	Generation of allocation sequence: not described Allocation concealment: concealed allocation, numbered blister packs Blinding: none Inclusion of all randomized participants in the analysis of reported primary outcome: 45% (118/260) Number of blocks used in randomization: 6
Participants	Number: 260 children aged 1 to 5 years Inclusion criteria: weight > 5 kg; microscopically confirmed P. falciparum parasitaemia > 5000/mL; fever; within 5 km of trial site Exclusion criteria: severe malaria; severe malnutrition/kwashiorkor; other antimalarial previous in 48 h; sensitivity to chloroquine; chronic disease
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 1 to 2 mg/kg/dose; lumefantrine 6 to 12 mg/kg/dose 2. Chloroquine: 4 doses over 48 h; total dose 25 mg/kg All participants had paracetamol
Outcomes	1. Day 7 cure 2. Day 14 cure 3. Parasite reductions on days 1 to 3 4. Proportion of children with negative slide on days 1 to 3 5. PCR genotype 6. Gametocyte carriage on days 0, 1, 2, 3, and 7 7. Haemoglobin
Notes	Location: Ifakara, Tanzania 48 not evaluable at day 7 (14 artemether-lumefantrine, 34 chloroquine); 53 not evaluable at day 14 (20 artemether-lumefantrine, 33 chloroquine) Malaria transmission: perennial Chloroquine resistance

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Kshirsagar 2000

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Methods	Generation of allocation sequence: computer-generated Allocation concealment: concealed allocation, central randomization Blinding: double dummy parallel, blinding not specified Inclusion of all randomized participants in the analysis of reported primary outcome: 21% (38/179) Number of blocks used in randomization: 4
Participants	Number: 179 adults aged 16 to 70 years Inclusion criteria: microscopically confirmed P. falciparum or mixed infection (including P. falciparum > 1000/µL) Exclusion criteria: P. falciparum > 200,000/µL; severe malaria
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 80 mg/dose; lumefantrine 480 mg/dose 2. Chloroquine: 4 doses over 48 h; first dose 600 mg, then 300 mg per dose All had primaquine on day 8 (single dose of 45 mg)
Outcomes	1. Day 28 cure 2. Parasite clearance time 3. Reduction in parasite load at 24 h 4. Fever clearance time 5. Gametocyte carriage within first 72 h 6. Gametocyte clearance time 7. PCR genotype 8. Adverse events
Notes	Location: Mumbai, India Participants hospitalized for 8 days 38 not evaluated on day 28: 24 (artemether-lumefantrine); 14 (chloroquine) 64 treatment failures: 3 artemether-lumefantrine (RI); 61 chloroquine (49 (RI), 8 (RII), 4 (RIII)) Premature termination of trial because of 1 death (chloroquine group) and decrease in chloroquine cure rate to < 50% Malaria transmission: perennial Chloroquine resistance

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Looareesuwan 1999

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Methods	Generation of allocation sequence: computer-generated Allocation concealment: concealed allocation, central randomization Blinding: double dummy, participants and all personnel Inclusion of all randomized participants in the analysis of reported primary outcome: 8% (19/252)
Participants	Number: 252 adults and children aged 13 to 63 Inclusion criteria: microscopically confirmed P. falciparum; parasitaemia 1000 to 200,000/µL (mixed infection acceptable) Exclusion criteria: complicated malaria
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 80 mg/dose; lumefantrine 480 mg/dose 2. Mefloquine: 2 doses over 8 h; first dose 750 mg; second dose 500 mg
Outcomes	1. Day 28 cure 2. Parasite clearance time 3. Fever clearance time 4. Gametocyte clearance time 5. Gametocyte carriage within first 72 h 6. Adverse effects
Notes	Location: Bangkok, Thailand Inpatients 19 not evaluated on day 28: 12 (artemether-lumefantrine); 7 (mefloquine) 56 treatment failures: 35 artemether-lumefantrine (RI); 21 mefloquine (12 (RI), 5 (RII), 4 (RIII)) Malaria transmission: low transmission Multiple-drug resistance

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Van Agtmael 1999a

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Methods	Generation of allocation sequence: computer-generated Allocation concealment: not described Blinding: double dummy, participants and all personnel Inclusion of all randomized participants in the analysis of reported primary outcome: 17% (17/103) Number of blocks used in randomization: 4
Participants	Number: 103 participants aged 17 to 62 (73 non-immune; 3 immune; 27 possibly immune) Inclusion criteria: microscopically confirmed P. falciparum (> 1000 and < 200,000/µL) Exclusion criteria: severe malaria
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 80 mg/dose; lumefantrine 480 mg/dose 2. Halofantrine: 3 doses over 12 h; repeated after 1 week; 500 mg/dose
Outcomes	1. Day 28 cure 2. Parasite clearance time 3. Parasite reduction at 24 h 4. Fever clearance time 5. Gametocyte carriage within first 72 h 6. Adverse effects 7. QT interval
Notes	Location: residents of France and the Netherlands returning from 22 African countries and French Guyana 17 not evaluable on day 28: 6 (artemether-lumefantrine); 11 (halofantrine) 8 treatment failures: artemether-lumefantrine 8 (RI)

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Van Vugt 1998a

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Methods	Generation of allocation sequence: not described Allocation concealment: concealed allocation, numbered sealed opaque packets Blinding: none Inclusion of all randomized participants in the analysis of reported primary outcome: 23% (139/617) Number of blocks used in randomization: 4
Participants	Number: 617 participants aged 5 to 66 years Inclusion criteria: microscopically confirmed malaria Exclusion criteria: severe malaria
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 1 to 2 mg/kg/dose; lumefantrine 6 to 12 mg/kg/dose 2. Artesunate: 3 doses over 48 h (4 mg/kg/dose); mefloquine 2 doses over 48 h (15 mg/kg on day 2; 10 mg/kg on day 3)
Outcomes	1. Day 63 cure 2. Day 28 cure 3. Parasite clearance time 4. Fever clearance time 5. Gametocyte carriage 6. PCR analysis 7. Adverse effects
Notes	Location: Karen, Thailand 139 not evaluated on day 63: 61(artemether-lumefantrine); 78 (artemether plus mefloquine) Malaria transmission: low Multiple-drug resistance

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Van Vugt 1999

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Methods	Generation of allocation sequence: not described Allocation concealment: concealed allocation, numbered sealed opaque packets Blinding: none Inclusion of all randomized participants in the analysis of reported primary outcome: 15% (53/359) Number of blocks used in randomization: 6
Participants	Number: 359 adults and children age 3 to 75 Inclusion criteria: microscopically confirmed P. falciparum Exclusion criteria: severe malaria, children < 2 years
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h 2. Artemether-lumefantrine: 6 doses over 60 h 3. Artemether-lumefantrine: 6 doses over 90 h Single dose: 4 tablets for 15 kg; 8 tablets for 15 to 25 kg; 12 tablets for 25 to 35 kg; 16 tablets if > 35 kg
Outcomes	1. Day 28 cure 2. Parasite clearance time 3. PCR analysis 4. Adverse effects 5. Fever clearance time 6. Gametocyte carriage
Notes	Location: Thailand 2 trial centres: Bangkok (inpatients for 28 days); Karen (outpatients) Multiple-drug resistance

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Von Seidlein 1998

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Methods	Generation of allocation sequence: computer-generated Allocation concealment: concealed allocation, central randomization Blinding: double dummy, participants and all personnel Inclusion of all randomized participants in the analysis of reported primary outcome: 14% (40/287) Number of blocks used in randomization: 4
Participants	Number: 287 children aged 1 to 5 years Inclusion criteria: parasitaemia > 5000/µL; fever; within 10 km of trial centre Exclusion criteria: requiring parenteral treatment
Interventions	1. Artemether-lumefantrine: 4 doses over 48 h; artemether 1.3 to 2.6 mg/kg/dose; lumefantrine 8.8 to 17.5 mg/kg/dose) 2. Sulfadoxine-pyrimethamine: single dose; 8.8 to 17.5 mg/kg
Outcomes	1. Day 4 cure 2. Day 15 cure 3. Parasite clearance time 4. Proportion of children with fever on days 1 to 4 5. Gametocyte carriage on days 1, 2, 3, 4, and 15 6. PCR genotype
Notes	Location: The Gambia 2 trial centres: semi-urban and rural 40 not evaluated on day 28: 25 (artemether-lumefantrine); 15 (sulfadoxine-pyrimethamine) Local malaria transmission: seasonal Local drug resistance: chloroquine; sulfadoxine-pyrimethamine

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 ECG: electrocardiogram; P. falciparum: Plasmodium falciparum; PCR: polymerase chain reaction; QT interval: difference between the longest and shortest measurable interval on the 12 lead electrocardiogram; RI: (drug resistance) recrudescence of infection between 7 and 28 d of completing treatment following initial resolution of symptoms and parasite clearance; RII: (drug resistance) reduction of parasitaemia of > 75% at 48 h but failure to clear parasites within 7 d; RIII: (drug resistance) parasitaemia does not fall by > 75% within 48 h.

 

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Espino 2002	Data in unpublished report are not interpretable
Falade 2005	Not a randomized controlled trial
Jiao 1997	Compared artemether-lumefantrine with lumefantrine, which is not a recommended standard therapy for uncomplicated malaria
Karbwang 2002	Artemether-lumefantrine (6-dose regimen) not compared with another antimalarial
Krudsood 2003	Used 6-dose artemether-lumefantrine regimen
Lefevre 2001	Used 6-dose artemether-lumefantrine regimen
Lefevre 2002	Investigated electrocardiographic and pharmacokinetic interactions between artemether-lumefantrine and quinine
Mayxay 2004	Used 6-dose artemether-lumefantrine regimen
Mutabingwa 2005	Used 6-dose artemether-lumefantrine regimen
Ndayiragije 2004	Used 6-dose artemether-lumefantrine regimen
Piola 2005	Used 6-dose artemether-lumefantrine regimen
Popov 2002	Not a randomized controlled trial
Stohrer 2004	Used 6-dose artemether-lumefantrine regimen
Sun 2000	Compared artemether-lumefantrine with lumefantrine, which is not a recommended standard therapy for uncomplicated malaria
Sutherland 2005	Used 6-dose artemether-lumefantrine regimen
Van Agtmael 1999b	Compared artemether
Van Vugt 2000	Used 6-dose artemether-lumefantrine regimen
Von Seidlein 1997	Not randomized control trial (safety trial)
Zhiwei 1999	Compared artemether-lumefantrine with lumefantrine, which is not a recommended standard therapy for uncomplicated malaria

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Comparison 1. Artemether-lumefantrine (4 doses) versus sulfadoxine-pyrimethamine

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total failure by day 14	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
2 Total failure by day 14 (excluding new infections)	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
3 Gametocyte carriage by day 4	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
4 Gametocyte carriage by day 15	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only

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Comparison 2. Artemether-lumefantrine (4 doses) versus mefloquine

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total failure by day 28	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
2 Gametocyte carriage within the first 72 h	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only

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Comparison 3. Artemether-lumefantrine (4 doses) versus halofantrine

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total failure by day 28	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
2 Gametocyte carriage within the first 72 h	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only

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Comparison 4. Artemether-lumefantrine (4 doses) versus chloroquine

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total failure by day 28	2		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
2 Gametocyte carriage within the first 72 h	2	427	Risk Ratio (M-H, Fixed, 95% CI)	0.79 [0.63, 0.99]

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Comparison 5. Artemether-lumefantrine versus mefloquine plus artesunate

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Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total failure by day 28	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
2 Total failure by day 28 (excluding new infections)	1		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
3 Total failure by day 63	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
4 Gametocyte carriage within the first 72 h	1		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only

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Comparison 6. Artemether-lumefantrine (4 doses) versus artemether-lumefantrine (6 doses)

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 Total failure by day 28

1

306

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

7.71 [2.99, 19.88]

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1.1 6-dose regimen taken over 60 h

1

148

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

6.15 [1.77, 21.38]

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1.2 6-dose regimen taken over 96 h

1

158

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

10.19 [2.32, 44.84]

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Table 1. Detailed search strategies

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Search set	CIDG SR*	CENTRAL	MEDLINE**	EMBASE^a	LILACS^b
1	artemether	artemether	artemether	artemether	artemether
2	lumefantrine	lumefantrine	lumefantrine	lumefantrine	lumefantrine
3	benflumetol	benflumetol	benflumetol	benflumetol	benflumetol
4	co-artemether	co-artemether	co-artemether	coartemether	co-artemether
5	coartem	coartem	coartem	coartem	coartem
6	coarteme	coarteme	coarteme	coarteme	1 or 2 or 3 or 4 or 5
7	riamet	riamet	riamet	riamet	malaria
8	CGP56697	CGP56697	CGP56697	CGP56697	6 and 7
9	—	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8	—
10	—	malaria	exp MALARIA	exp MALARIA	—
11	—	9 and 10	malaria	malaria	—
12	—	—	10 or 11	10 or 11	—
13	—	—	9 and 12	9 and 12	—
14	—	—	Limit 13 to human	Limit 13 to human	—

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 ^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.

 

Table 2. Reported outcome measures

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Trial	Total failure (day)	PCT	FCT	GCT	Gametocyte carriage	PCR analysis	Adverse events
Hatz 1998	7 and 14	No	No	No	Yes	Yes	Yes
Van Vugt 1998a	28 and 63	Yes	Yes	No	Yes	Yes	Yes
Von Seidlein 1998	4 and 15	Yes	No	No	Yes	Yes	Yes
Looareesuwan 1999	28	Yes	Yes	Yes	Yes	No	Yes
Van Agtmael 1999a	28	Yes	Yes	No	Yes	No	Yes
Van Vugt 1999	28	Yes	Yes	No	Yes	Yes	Yes
Kshirsagar 2000	28	Yes	Yes	Yes	No	Yes	Yes

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 FCT: fever clearance time; GCT: gametocyte clearance time; PCR: polymerase chain reaction; PCT: parasite clearance time.

 

Table 3. Risk of bias assessment

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Trial	Generation of allocation sequence	Allocation concealment	Blinding	Inclusion of all randomized participant in the analysis^a
Hatz 1998	Not described	Adequate	No	Inadequate (45%)
Von Seidlein 1998	Adequate	Adequate	Double	Inadequate (86%)
Van Vugt 1998a	Not described	Adequate	No	Inadequate (77%)
Looareesuwan 1999	Adequate	Adequate	Double	Adequate (92%)
Van Agtmael 1999a	Adequate	Not described	Double	Inadequate (83%)
Van Vugt 1999	Not described	Adequate	No	Inadequate (85%)
Kshirsagar 2000	Adequate	Adequate	Double	Inadequate (79%)

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 ^aFor primary outcomes. see the 'Data collection and analysis' for the assessment methods, and the 'Characteristics of included studies' for each trial's methods.

 

Table 4. Total failure (excludes new infections)

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Trial	Comparator	Measure	Day 14		Day 28
			Artemether-lumefantrine	Comparator	Artemether-lumefantrine	Comparator
Hatz 1998	Chloroquine	Number participants failing treatment/number followed up	18/113	106/116	43/118	113/119
		Number with PCR tests/number total failures	7/18	52/106	23/43	44/113
		Missing sample of failed test	0	0	1	1
		Number of recrudescent infections	2	20	3	17
		Number with a new infection	4	5	12	6
		Number with new and recrudescent infections	1	27	7	20
		Corrected failure rate	14/113	101/116	31/118	107/119
Von Seidlein 1998	Sulfadoxine-pyrimethamine	Number participants failing treatment/number followed up	8/119	3/128	20/no data	1/no data
		Number with PCR tests/number total failures	6/8	0/3	16/20	1/1
		Missing sample of failed test	2	3	4	0
		Number of recrudescent infections	0	No results	4	0
		Number with a new infection	6	No results	12	1
		Corrected failure rate	2/119	3/128	8/no data	0/no data
Kshirsagar 2000	Chloroquine	Number participants failing treatment/number followed up	—	—	3/65	61/76
		Number with PCR tests/number total failures	—	—	0/3	42/61
		Missing sample of failed test	—	—	3	0
		Number of recrudescent infections	—	—	0	40
		New infections	—	—	0	2
		Corrected day 28 failure rate	—	—	3/65	59/76

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Table 5. Severe adverse events

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Comparator	Trial	Number with event
		Artemether-lumefantrine	Comparator
Sulfadoxine-pyrimethamine	Von Seidlein 1998	Anaemia (4), vomiting (1), splenomegaly (1), conjunctivitis (1)	Anaemia (1), fever (1), glomerulonephritis (1), proteinuria (1), haematuria (1)
Mefloquine	Looareesuwan 1999	Severe fatigue (1)	Pneumonia (1), AIDS-related (1)
Halofantrine	Van Agtmael 1999a	Haemolytic anaemia (1), hepatitis A (1)	Prolonged QTc interval (treatment stopped) (1), pneumonia (1)
Chloroquine	Hatz 1998	Treatment stopped (reason not stated) (8), treated for adverse events (7)	Treated for adverse events (7)
	Kshirsagar 2000	None	Died from cerebral malaria (1)

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Table 6. Parasite clearance time

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Trial	Treatment	No. participants	Median	25 to 75 percentile	95% CI	P value
Looareesuwan 1999	Artemether-lumefantrine	126	43	35 to 51	42 to 45	< 0.001^a
	Mefloquine	126	66	52 to 82	61 to 70	—
Van Agtmael 1999a	Artemether-lumefantrine	51	32	23 to 48	32 to 48	< 0.001
	Halofantrine	52	48	47 to 60	48 to 60	—
Van Vugt 1999	Artemether-lumefantrine (4 doses)	120	44	34 to 51	—	0.96
	Artemether-lumefantrine (6 doses over 60 h)	118	44	22 to 47	—	—
	Artemether-lumefantrine (6 doses over 90 h)	121	44	40 to 47	—	—
Kshirsagar 2000	Artemether-lumefantrine	89	36	24 to 48	30 to 36	< 0.001^a
	Chloroquine	90	60	48 to 91	45 to 66	—

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 CI: confidence interval.
^aWilcoxon test.

 

Table 7. Fever clearance time

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Trial	Treatment	No. participants	Median	25 to 75 percentile	95% CI	P value
Looareesuwan 1999	Artemether-lumefantrine	75	32	17 to 54	23 to 37	0.003^a
	Mefloquine	67	54	29 to 82	36 to 66	—
Van Agtmael 1999a	Artemether-lumefantrine	32	24	12 to 48	18 to 42	0.835
	Halofantrine	39	32	6 to 64	18 to 48	—
Van Vugt 1999	Artemether-lumefantrine (4 doses)	61	23	20 to 44	—	0.38
	Artemether-lumefantrine (6 doses over 60 h)	59	35	20 to 46	—	—
	Artemether-lumefantrine (6 doses over 90 h)	80	22	20 to 44	—	—
Kshirsagar 2000	Artemether-lumefantrine	40	18	6 to 30	12 to 29	0.0456^a
	Chloroquine	54	27	12 to 48	18 to 36	—

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 CI: confidence interval.
^aWilcoxon test.

 

Table 8. Gametocyte clearance time

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Trial	Treatment	No. participants	Median	25 to 75 percentile	95% CI	P value
Looareesuwan 1999	Artemether-lumefantrine	62	152	68 to 285	89 to 185	< 0.001
	Mefloquine	74	331	128 to 512	281 to 492	—
Kshirsagar 2000	Artemether-lumefantrine	51	120	60 to not reached	—	< 0.001^a
	Chloroquine	63	Not reached	—	—	—

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 CI: confidence interval.
^aWilcoxon test.

 

Table 9. Mild to moderate adverse events

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Comparator	Trial	Adverse event	Artemether-lumefantrine (%)^a	Comparator (%)^a
Chloroquine	Hatz 1998	Rashes	5/130 (3.8)	5/130 (3.8)
		Pruritis	1/130 (0.8)	8/130 (6.2)
		Sleep disorders	50/130 (39.0)	48/130 (37.0)
	Kshirsagar 2000	Pruritis	2/89 (2.2)	11/90 (12.2)
		Vomiting	1/89 (1.1)	14/90 (15.3)
		Headache	5/89 (5.6)	7/90 (7.8)
		Diarrhoea	4/89 (9.5)	7/90 (7.8)
		Sleep disorders	3/89 (3.4)	2/90 (2.2)
		Abdominal pain	10/89 (11.2)	10/90 (11.1)
Mefloquine	Looareesuwan 1999	Vomiting	1/126 (0.8)	8/126 (6.3)
		Headache	11/126 (8.7)	14/126 (11.1)
Halofantrine	Van Agtmael 1999a	Vomiting	1/51 (2.0)	7/52 (14.0)
		Headache	7/51 (14.0)	4/52 (8.0)
		Sleep disorders	4/51 (8.0)	6/52 (12.0)
		Diarrhoea	3/51 (6.0)	6/52 (12.0)

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 ^aNumber of participants with event calculated from percentage using the total number of participants originally randomized to each group.