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Artemisinin-based combination therapy for treating uncomplicated malaria

  1. David Sinclair1,*,
  2. Babalwa Zani2,
  3. Sarah Donegan1,
  4. Piero Olliaro3,
  5. Paul Garner1

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 8 JUL 2009

Assessed as up-to-date: 25 MAR 2009

DOI: 10.1002/14651858.CD007483.pub2


How to Cite

Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007483. DOI: 10.1002/14651858.CD007483.pub2.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, UK

  2. 2

    Medical Research Council, South African Cochrane Centre, Cape Town, Western Cape, South Africa

  3. 3

    World Health Organization, Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

*David Sinclair, International Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. davesinkers@yahoo.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 JUL 2009

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Characteristics of included studies [ordered by study ID]
Adjei 2006 GHA

MethodsTrial design: A single blind randomized controlled trial

Follow up: Clinical and laboratory assessment on days 0, 1, 2, 3, 7, 14, 28 and then monthly for 1 year

Adverse event monitoring: Assessed at each visit up to 1 year using open questions about side effects, behavioural and developmental concerns. Neurological examination at each visit. Audiometry assessment on days 0, 3, 7, 28, and 1 year. WBC, aminotransferase and total bilirubin at days 0, 3, 7, 14, and 28.


ParticipantsNumber: 227 randomized

Inclusion criteria: Age 6 months to 14 yrs, axillary temp > 37.5 ºC, signs and symptoms of uncomplicated malaria, P. falciparum mono-infection 2000 to 200,000/µl, willingness to comply with the follow up, informed consent

Exclusion criteria: Signs or symptoms of severe malaria, chronic malnutrition or other severe disease, known intolerance or allergy to study meds, reported treatment with any of the study drugs during preceding month


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Plasmotrim: Mepha, Camoquine: Pfizer)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


Only the first dose each day was supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and PCR unadjusted
  2. Adverse events including neurological, biochemical, and audiological events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance
  3. Further episodes of symptomatic malaria in 1 year


NotesCountry: Ghana

Setting: Urban primary health facilities

Transmission: Not described

Resistance: AQ

Dates: Oct 2004 to Dec 2006

Funding: Danish Council for Development Research, Global Fund for AIDS, TB and Malaria through the National Malaria Control Programme


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A computer generated randomisation scheme was prepared in advance'

Allocation concealment?Yes'Allocated treatments were kept in sealed opaque envelopes'

Blinding?
All outcomes
Yes'All study personnel (except project nurses) were unaware of the assigned treatments'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (7.2% AL6 vs 7.8% AS+AQ)

Free of selective reporting?YesAll WHO outcomes reported. The WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6.

Free of other bias?YesNo other sources of bias identified

Ashley 2003a THA

MethodsTrial design: A 3-arm randomized controlled trial

Follow up: All patients admitted to hospital for 28 days, oral temperature taken every 6 hours, parasite counts 12-hourly until negative then daily for 28 days

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. All patients had full blood counts, urea, electrolytes, creatinine, and liver function tests at days 0 and 7.


ParticipantsNumber: 134 randomized into included treatment arms

Inclusion criteria: Age > 14 yrs, weight > 40 kg, symptoms of malaria, P. falciparum parasitaemia, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, contraindication to mefloquine, treatment with mefloquine in the previous 60 days, sulphonamides or 4-aminoquinolones present in urine on admission


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses at 0, 8, 24 and 48 hours


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Cure rate at day 28, all reappearances of parasites presumed to be recrudescences as patients hospitalized for duration
  2. Adverse events


Not included in this review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low transmission

Resistance: Multiple-drug resistance

Dates: Jul 2002 to Apr 2003

Funding: Mahidol University, Tak Malaria Initiative Project, supported by Bill and Melinda Gates Foundation, Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'The randomisation was computer generated (STATA; version 7; Statacorp)'. Randomized in blocks of 6

Allocation concealment?Yes'The treatment allocation was concealed in sealed envelopes labelled with the study code'

Blinding?
All outcomes
No'Laboratory staff reading the blood smears had no knowledge of the treatment received'. No other blinding described

Incomplete outcome data addressed?
All outcomes
YesSimilar loss to follow up in all groups (10.6% DHA-P vs 11.9% AS+MQ)

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 28 outcomes are likely to underestimate treatment failure with AS+MQ and DHA-P.

Free of other bias?YesNo other sources of bias identified

Ashley 2003b THA

MethodsTrial design: A randomized controlled trial

Follow up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. A subset of 55 patients in the DHA-P group had full blood counts, urea, electrolyte, creatinine and liver function tests at days 0 and 7. 32 patients from the DHA-P group also had ECG monitoring before and after treatment.


ParticipantsNumber: 355 randomized into included treatment arms

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum parasitaemia, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, contraindication to mefloquine, treatment with mefloquine in the previous 60 days


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hours


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Cure rate at day 63, PCR adjusted and unadjusted
  2. P. vivax during follow up, and mean time to reappearance
  3. Gametocyte development during follow up
  4. Mean haematocrit at days 0 and 7
  5. Adverse events


Not included in this review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Thailand

Setting: 4 clinics on the Thai-Myanmar border

Transmission: Unstable low and seasonal transmission

Resistance: Multiple-drug resistance

Dates: Jul 2002 to Apr 2003

Funding: Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'The randomisation was computer generated (STATA; version 7; Statacorp)'. Randomized in blocks of 9.

Allocation concealment?Yes'The treatment allocation was concealed in sealed envelopes labelled with the study code'

Blinding?
All outcomes
No'Laboratory staff reading the blood smears had no knowledge of the treatment received'. No other blinding described.

Incomplete outcome data addressed?
All outcomes
YesSimilar losses to follow up in all groups (12.8% DHA-P vs 13.6% AS+MQ)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Ashley 2004 THA

MethodsTrial design: A 3-arm randomized controlled trial

Follow up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance for examination, symptom enquiry, malaria smear and haematocrit until day 63

Adverse event monitoring: Adverse events defined as signs or symptoms that occurred or became more severe after treatment started. Symptoms were screened at each visit


ParticipantsNumber: 499 randomized

Inclusion criteria: Age 1 to 65 yrs, symptomatic P. falciparum mono-infection or mixed infections, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, treatment with mefloquine in the previous 60 days


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 4 divided doses at 0, 8, 24, and 48 hours


2. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.4 mg/kg DHA and 51.2 mg/kg P in 3 divided doses at 0, 24, and 48 hours


3. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mequin: Atlantic)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Cure rate at days 63, 42, and 28, PCR adjusted and unadjusted
  2. P. vivax during follow up, and median time to reappearance
  3. Gametocyte development during follow up
  4. Mean haematocrit during follow up
  5. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Thailand

Setting: 4 clinics on the Thai-Myanmar border

Transmission: Unstable low and seasonal transmission

Resistance: Multiple-drug resistance

Dates: Apr 2003 to Apr 2004

Funding: Medicines for Malaria Venture, Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'The randomisation list was generated using STATA; version 7 (Stata)'. Randomized in blocks of 9.

Allocation concealment?Yes'The treatment allocation was concealed in sealed envelopes labelled with the study code'

Blinding?
All outcomes
No'Laboratory staff reading the blood smears had no knowledge of the treatment received'. No other blinding described.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low in all groups (4.2% DHA-P vs 4.8% AS+MQ)

Free of selective reporting?YesAll WHO outcomes reported. 2 patients were considered to be early treatment failures by the reviewers and reclassified as such. This was not clearly stated in the paper.

Free of other bias?YesNo other sources of bias identified

Ashley 2005 THA

MethodsTrial design: An open label randomized controlled trial

Follow up: Temperature and blood smears daily until clearance of fever and parasites, then weekly attendance for clinical examination, symptom enquiry, malaria smear, and haematocrit until day 63

Adverse event monitoring: Adverse events were actively screened at each visit. Adverse events were defined as signs or symptoms that occurred or became more severe after treatment started.


ParticipantsNumber: 500 randomized

Inclusion criteria: Age 6 months to 65 yrs, weight > 5 kg, symptomatic P. falciparum mono-infection or mixed infections, informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% of red blood cells parasitized, treatment with mefloquine in the previous 60 days, contraindication to mefloquine


Interventions1. Artesunate plus mefloquine, fixed-dose combination, adult tablets 100 mg/220 mg, paediatric tablets 25 mg/55 mg (Far-Manguinhos)

  • 5 to 8 kg 1 paediatric tablet per day
  • 9 to 17 kg 2 paediatric tablets per day
  • 18 to 29 kg 1 adult tablet per day
  • > 30 kg 2 adult tablets per day


2. Artesunate plus mefloquine, loose combination, (Arsumax: Sanofi-Synthelabo, Lariam: Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. Cure rate at day 63, PCR adjusted and unadjusted
  2. P. vivax during follow up, and median time to reappearance
  3. Gametocyte development during follow up
  4. Mean haematocrit during follow up
  5. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Thailand

Setting: 6 clinics on the Thai-Myanmar border

Transmission: Unstable low and seasonal transmission

Resistance: Multiple-drug resistance

Dates: Nov 2004 to Jun 2005

Funding: DNDi, European Union International Co-operation programme, Médecins sans Frontières, WHO/TDR, Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomised in blocks of 10 by a statistician using a computer-generated randomisation'

Allocation concealment?Yes'The treatment allocation was concealed in numbered, sealed envelopes...opened only after enrolment in the study'

Blinding?
All outcomes
NoAn open label study. '50% of enrolment slides, 10% of follow up slides and all slides reported as showing recrudescence were subjected to a second blind reading'

Incomplete outcome data addressed?
All outcomes
NoLosses to follow-up are moderate (15.5% FDC vs 15.3% loose). Reasons are not clearly stated and some losses may represent early treatment failures.

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Bonnet 2004 GIN

MethodsTrial design: A randomized controlled trial

Follow up: Clinical and parasitological assessment on days 0, 1, 2, 3, 7, 14, 21 and 28. Gametocyte carriage measured at day 0 and 28. PCR genotyping on all reappearances after day 9.

Adverse event monitoring: None described


ParticipantsNumber: 220 randomized

Inclusion criteria: Age 6 to 59 months, axillary temp > 37.5 ºC, P. falciparum mono-infection 2000 to 200,000/µl

Exclusion criteria: Signs of severity or severe malaria, severe anaemia (Hb < 5 g/dl), severe malnutrition, concomitant febrile condition with the potential to confound study outcome, history of allergic reaction to the study drugs


Interventions1. Artesunate plus amodiaquine, loose combination (Arsumax: Guilin, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination, (Arsumax: Guilin, Fansidar: Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg as a single dose


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage at baseline and day 28


NotesCountry: Guinea

Setting: Outpatient department

Transmission: Perennial seasonal malaria with increased transmission between June and October

Resistance: CQ, AQ and SP resistance

Dates: Jun 2004 to Sept 2004

Funding: Médecins sans Frontières


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomization list with a block size of 20 was electronically generated by the methodological center (Epicentre, Paris)'

Allocation concealment?Yes'Sealed opaque envelopes corresponding to each inclusion number, and containing the name of the allocated treatment regimen, were prepared before the study started.' (Additional information from authors)

Blinding?
All outcomes
NoNo comment on blinding. A random sample of 92 slides were cross-checked by an independent technician.

Incomplete outcome data addressed?
All outcomes
YesLow loss to follow up in both groups (2.7% AS+AQ vs 3.6% AS+SP)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Bousema 2004 KEN

MethodsTrial design: A 3-arm, single blind (outcome assessors) randomized controlled trial

Follow up: Days 0, 1, 2, 3, 7, 14, and 28 or any other day they became ill

Adverse event monitoring: None described


ParticipantsNumber: 376 randomized to included treatment arms

Inclusion criteria: Age 6 months to 10 yrs, temp > 37.5 ºC or history of fever, P. falciparum mono-infection > 500/µl. Additionally for AL group: weight > 10 kg and living < 5 km from the clinic.

Exclusion criteria: Signs of severe malaria, inability to take meds orally, evidence of chronic disease or an acute infection other than malaria, known hypersensitivity to any of the study drugs, reported treatment with antimalarials in the previous 2 weeks, resident outside of study area


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 1/2 tablet per 5 kg bodyweight twice daily for 3 days


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination (Arsumax: Sanofi-Aventis, Fansidar: Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg as a single dose


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination (Camoquine: Pfizer, Fansidar: Roche)

  • AQ 10 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg as a single dose


All doses supervized and given with a fatty meal


Outcomes
  1. Adequate clinical response at day 28, PCR adjusted and unadjusted (excluded from primary analysis)


Not included in the review:

  1. Gametocytes carriage at days 0 and 7
  2. Assessment of infectiousness of participants


NotesCountry: Kenya

Setting: Rural clinic

Transmission: High and perennial

Resistance: Not reported

Dates: Oct to Dec in 2003 and 2004

Funding: Foundation for the Advancement of Tropical Research, Netherlands Organization for Scientif Research, Ter Meulen Fund


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?NoChildren were divided in age strata and randomized to different treatment regimens using Excel generated randomization tables. Serious flaws in randomization.

Allocation concealment?NoNone described

Blinding?
All outcomes
Yes'Other than those administering the medication, all staff engaged in the trial were blinded to allocation'

Incomplete outcome data addressed?
All outcomes
NoLosses to follow up were different between groups with no losses in the AL group (0% AL6 vs 8.0% AS+SP vs 9.4% AQ+SP). This is likely to be related to the different inclusion criteria for AL6.

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may underestimate treatment failure with AL6.

Free of other bias?NoDue to differing inclusion criteria for the 3 arms children in the AL6 group were older, heavier and had higher Hb levels at baseline. This may improve outcome in this group and consequently the AL6 arm was excluded from this review.

Bukirwa 2005 UGA

MethodsTrial design: A single blind randomized controlled trial

Follow up: Days 0, 1, 2, 3, 7, 14, and 28 or any other day they became ill, for a standardized history, examination and malaria film. Haemoglobin measurement day 0, 28 or day of failure. Participants with Hb < 10 g/dl given ferrous sulphate and antihelminthic treatment.

Adverse event monitoring: Assessed at each follow-up visit, an adverse event defined as any untoward medical occurrence


ParticipantsNumber: 419 randomized

Inclusion criteria: Age 1 to 10 yrs, axillary temp > 37.5 ºC or history of fever in previous 24 hrs, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs or evidence of severe malaria, evidence of a concomitant febrile illness, repeated vomiting of first dose of medication, history of serious side effects to study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 10 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Aventis, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg on days 0 & 1 and 5 mg/kg on day 2
  • Plus placebos in the evening for 3 days


All doses supervized


Outcomes
  1. Risk of recurrent parasitaemia and recurrent symptomatic malaria at day 28, PCR adjusted and unadjusted
  2. Gametocytes during follow up
  3. Mean change in haemoglobin from baseline to last day of follow up
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Uganda

Setting: Rural health centre

Transmission: High transmission, holoendemic with peaks following 2 rainy seasons

Resistance: CQ and SP resistance

Dates: Dec 2004 to July 2005.

Funding: Centers for Disease Control and Prevention, Association of Schools of Public Health, DfID


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'An off-site investigator prepared computer-generated age-stratified randomisation codes'

Allocation concealment?Yes'The randomisation list was secured in a locked cabinet accessible only by the study nurse. Participants were enrolled by study physicians and treatments were assigned by the study nurse'

Blinding?
All outcomes
Yes'Only the study nurse was aware of treatment assignments. All other study personnel including study physicians and laboratory personnel involved in assessing outcomes were blinded'

Incomplete outcome data addressed?
All outcomes
YesParticipants were excluded before enrolment only by predefined criteria. Losses to follow up after enrolment were low (1% AL6 vs 1.5% AS+AQ)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6.

Free of other bias?YesNo other sources of bias identified

Djimde 2004 MLI

MethodsTrial design: A single blind (outcome assessors) randomized controlled trial

Follow up: Days 0, 1, 2, 3, 7, 14, 21, and 28 or any other day they became ill, for a clinical assessment and malaria film

Adverse event monitoring: Haemoglobin, glucose, complete blood count, liver enzymes, and creatinine were measured on days 0, 7, 14, and 28


ParticipantsNumber: 502 randomized to included treatment arms

Inclusion criteria: Age > 6 months, weight > 5 kg, axillary temp > 37.5 ºC, uncomplicated malaria of any species 2000 to 200,000/µl, able to tolerate oral treatment, resident of study area for entire period of follow up, informed consent

Exclusion criteria: Pregnancy, symptoms of severe malaria, allergy to a study drug, documented consumption of 1 of the study drugs in the previous 7 days


Interventions1. Artesunate plus amodiaquine, fixed dose combination, 50/153 mg tablets (Arsucam: Sanofi-Aventis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination (Arsumax: Sanofi-Aventis, Fansidar: Roche)

  • AS 4 mg/kg once daily for 3 days
  • Plus half a tablet of SP (500/25mg tablets) per 10 kg as a single dose


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Treatment outcome in non-falciparum species
  3. Gametocyte carriage during follow up
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Mali

Setting: A village

Transmission: Hyperendemic with seasonal peaks

Resistance: CQ and SP resistance

Dates: Dec 2002 to Oct 2004

Funding: Access to Medicines, Sanofi-Aventis and the International Atomic Energy Agency


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Enrolled patients were randomly assigned to treatment groups'. No further details.

Allocation concealment?Unclear'The randomisation list was concealed to clinicians'. No further details.

Blinding?
All outcomes
UnclearDescribed as single blind, although details not given

Incomplete outcome data addressed?
All outcomes
NoIn the day 28 efficacy analysis 13 patients in the AS+AQ group and 9 in the AS+SP group are unaccounted for

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?No'The study sponsor was involved in the protocol development and reporting of severe adverse events'

Dorsey 2006 UGA

MethodsTrial design: A 3-arm, single blind (outcome assessors) randomized controlled trial. An unusual design where participants were randomized to a treatment and followed up through however many episodes of malaria happened to occur during the time period.

Follow up: Days 0, 1, 2, 3, 7, 14, and 28 or any other day they became ill, for a standardized history, examination and malaria film. Anthelminthics, iron sulphate, and vitamin A were prescribed as per IMCI guidelines.

Participants with P. vivax during follow up were censored on day of occurrence

Adverse event monitoring: Assessed at each follow-up visit, an adverse event defined as any untoward medical occurrence. Complete blood count and alanine aminotransferase on day 0 and 14.


ParticipantsNumber: 329 children randomized to a treatment group

Inclusion criteria: Age 1 to 10 yrs, weight >10 kg, agreement to remain in Kampala, agreement to attend the study clinic for any febrile illness, agreement to avoid medications outside of the study, informed consent

Exclusion criteria: Known adverse reactions to study meds, severe malnutrition, known serious chronic disease, life threatening lab results on screening


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, loose combination

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • Plus placebo in the evenings


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • SP 25/1.25 mg/kg on day 1
  • Plus placebo in the evenings


Only the first dose was supervized each day


Outcomes
  1. Risk of treatment failure at day 28, PCR adjusted and unadjusted
  2. Recurrent malaria caused by non-falciparum species
  3. Gametocyte carriage by day of follow up
  4. Mean change in haemoglobin from baseline to day 14
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Uganda

Setting: Urban clinic

Transmission: Mesoendemic with peaks during the 2 rainy seasons

Resistance: CQ, AQ and SP resistance

Dates: Nov 2004 to June 2006

Funding: National Institutes of Health, Doris Duke Charitable Foundation


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomisation list was computer generated with variable blocks of 3, 6, and 9 by an off-site investigator'

Allocation concealment?Yes'Sequentially numbered, sealed envelopes containing the treatment group assignments were prepared from the randomisation list'

Blinding?
All outcomes
Yes'All study personnel involved in outcome assessment were blinded to treatment allocation'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in all groups and reasons given (2.9% AL6 vs 5.4% AS+AQ vs 5.4% AQ+SP)

Free of selective reporting?YesThe WHO recommends 42 days follow-up in studies of AL6. Day 28 outcomes may underestimate the failure rate with AL6.

Free of other bias?YesNo other sources of bias identified

Falade 2005 NGA

MethodsTrial design: An open-label randomized controlled trial

Follow up: Examination and malaria film on days 0 to 7, 14, 21, and 28. Participants were admitted to hospital for the first 3 days then seen at days 7, 14, 21, and 28.

Adverse event monitoring: Assessed at each visit by examination and questioning about the progress of presenting symptoms and new symptoms. FBC, WBC, and liver enzymes on days 0, 7, and 28. An adverse event defined as not present at enrolment but occurring during follow up.


ParticipantsNumber: 132 participants randomized

Inclusion criteria: Age 6 months to 10 yrs, axillary temp > 37.5 ºC, signs and symptoms of malaria, P. falciparum mono-infection 2000 to 200,000/µl, willingness to comply with the protocol, informed consent

Exclusion criteria: Signs of severe and complicated malaria or other febrile illness, severe malnutrition, history of hypersensitivity to any of the study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 15 kg 1 tablet twice daily for 3 days
  • 15 to 25 kg 2 tablets twice daily for 3 days
  • 25 to 35 kg 3 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Synthelabo, Camoquine: Pfizer)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervized and given with food, fruit drink, or dissolved in water


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Haematocrit on days 0, 7, and 28
  3. Adverse events, including mean WBC and liver enzymes


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Nigeria

Setting: General Outpatient Department of University College Hospital

Transmission: Intense and occurs all year round

Resistance: CQ and SP

Dates: Aug 2004 to Aug 2005

Funding: Study meds were supplied by Novartis, Sanofi-Sycitilabo and Pfizer


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A pregenerated randomisation table'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of lab staff

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (7.5% AL6 vs 6.0% AS+AQ)

Free of selective reporting?YesAll WHO outcomes reported. The WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6.

Free of other bias?YesNo other sources of bias identified

Fanello 2004 RWA

MethodsTrial design: An open-label randomized controlled trial

Follow up: Participants were admitted to hospital for the first 3 days then seen at days 7, 14, 21, and 28. At each visit history, clinical signs and symptoms, temperature and malaria film. PCV and WBC were recorded on days 0 and 14.

Adverse event monitoring: All adverse events were recorded on the clinical record form and a causality assessment was made


ParticipantsNumber: 500 randomized

Inclusion criteria: Age 12 to 59 months, weight >10 kg, axillary temp > 37.5 ºC or history of fever in the previous 24 hrs, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Severe malaria, concomitant illness or underlying disease, known allergy to the study drugs, a clear history of adequate antimalarial treatment in the previous 72 hrs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets

  • < 15 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days


2. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg on day 0


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage during follow up
  3. Mean PCV at days 0 and 14
  4. Adverse events, including mean WBC at days 0 and 14


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Rwanda

Setting: Rural health clinics

Transmission: Variable

Resistance: Not described

Dates: July 2004 to Dec 2004

Funding: Belgian Development Co-operation (DGIS) and the Prince Leopold Institute of Tropical Medicine


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomly allocated in blocks of 20...according to a randomization list prepared in Belgium'

Allocation concealment?Unclear'Allocation of treatment was concealed from both the doctor and the patient, until final recruitment of the patient'. Method not described.

Blinding?
All outcomes
NoAn open-label trial. 'Laboratory technicians reading malaria slides did not know the treatment received by individual patients'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up (2% AL6 vs 0.8% AQ+SP)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may overestimate the efficacy of AL6.

Free of other bias?YesNo other sources of bias identified

Faye 2003 SEN

MethodsTrial design: A 5-arm, open-label randomized controlled trial

Follow up: Days 0, 1, 2, 7, 14, 21, and 28 for a clinical examination and malaria film

Adverse event monitoring: All side effects were monitored actively and passively during the study. 25% randomly selected for blood counts, liver, and renal function tests at days 0, 14, and 28.


ParticipantsNumber: 815 randomized into included treatment arms

Inclusion criteria: 'as per WHO 2002 protocol'

Exclusion criteria: 'as per WHO 2002 protocol'


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Twice daily dosing for 3 days
  • Exact dosing regimen not specified


2. Artesunate plus mefloquine, co-blistered (Artequine: Mepha)

  • Adults: AS 200 mg/day plus MQ 250 mg/day for 3 days
  • Children: AS 100 mg/day plus MQ 125 mg/day for 3 days


3. Artesunate plus amodiaquine, co-blistered (Arsucam: Sanofi-Aventis)

  • AS 4 mg/kg/day for 3 days
  • AQ 10 mg/kg/day for 3 days


4. Amodiaquine plus sufadoxine-pyrimethamine (Pharmacie Nationale d'Approvisionnement d Senegal)

  • AQ 10 mg/kg/day for 3 days
  • Plus half a tablet of SP per 10 kg as a single dose


All doses supervized


Outcomes
  1. Day 28 ACPR PCR adjusted and unadjusted
  2. Gametocyte carriage at days 0, 7, 14, 28
  3. Anaemia (Hb < 12) days 0, 14
  4. Adverse events


NotesCountry: Senegal

Setting: Healthcare centres

Transmission: Moderate with a peak in the rainy season

Resistance: High levels of chloroquine resistance

Dates: The transmission periods of 2002 and 2003

Funding: Study drugs supplied by Sanofi-Aventis, Mepha, and Novartis


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearNot described. Only described as 'randomized'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of lab staff

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were not reported in the original paper and figures were only given as percentages. Unpublished data reveal loss to follow up as low in all groups (3.1% AS+AQ, 0.7% AS+MQ, 1.3% AL6, 3.1% AQ+SP).

Free of selective reporting?YesThe WHO recommend 42 days follow up for studies involving AL6 and 63 days for AS+MQ. Day 28 outcomes may underestimate treatment failure with AL6 and AS+MQ.

Free of other bias?YesNo other sources of bias identified

Grande 2005 PER

MethodsTrial design: An open-label randomized controlled trial

Follow up: Days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42, 49, 56, and 63 or any other day they became ill, for a clinical assessment and malaria film. PCV measurement day 0, 7, 14 and 63. P. vivax treated with CQ.

Adverse event monitoring: Assessed at each follow-up visit, an adverse event defined as any unfavourable and unintended sign, symptom or disease temporally associated with the drug administered. Complete blood count, liver, and renal function tests at days 0 and 7.


ParticipantsNumber: 522 randomized

Inclusion criteria: Age 5 to 60 yrs, fever > 37.5 ºC or history of fever in the previous 24 hours, P. falciparum mono-infection 1000 to 200,000/µl

Exclusion criteria: Pregnancy or lactation, severe malaria, any concomitant illness or underlying disease, contraindication to any of the trial drugs, history of treatment with mefloquine in the previous 60 days or chloroquine, primaquine or quinine in previous 14 days


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holleykin)

  • Total dose: 6.3 mg/kg DHA and 50.4 mg/kg PQP in 3 divided doses, given once daily for 3 days


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Lariam: Hoffman La-Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Day 63 cure rate PCR adjusted and unadjusted
  2. P. vivax during follow up
  3. Gametocyte prevalence at day 0, 7, 14, 21 and 28
  4. Gametocyte development during follow up
  5. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Peru

Setting: 9 rural health posts

Transmission: Low malaria transmission

Resistance: High CQ and SP resistance

Dates: July 2003 to July 2005

Funding: Directorate-General for Development and Cooperation of the Belgian Government


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomized in blocks of 10'. No further details given.

Allocation concealment?Yes'Sealed opaque envelopes were opened only after the final decision to recruit the patient had been made'

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesSimilar loss to follow up in both groups (8.7% DHA-P vs 5.9% AS+MQ)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Guthmann 2003 AGO

MethodsTrial design: An open label randomized controlled trial

Follow up: Reassessed clinically and parasitologically on days 0, 3, 7, 14, 21, and 28. Gametocytes were measured at each visit. Haemoglobin was measured at days 0 and 28.

Adverse event monitoring: None described


ParticipantsNumber: 187 randomized into included treatment arms

Inclusion criteria: Age 6 to 59 months, weight > 5 kg, axillary temp > 37.5 ºC or history of fever in the previous 24 hours, P. falciparum mono-infection 2000 to 100,000/µl, living within 1 hours walk of the clinic, informed consent

Exclusion criteria: Signs of severity or severe malaria, severe anaemia (Hb < 5 g/dl), severe malnutrition, any concomitant febrile condition with the potential to confound the study outcome, history of allergic reaction to the study drug, reported intake of a full course of antimalarials in the previous 7 days


Interventions1. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Aventis, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg/day for 3 days


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination (Arsumax: Sanofi-Aventis, Fansidar: Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg as a single dose


All doses supervized


Outcomes
  1. Failure at day 28 PCR adjusted
  2. Prevalence of anaemia at days 0 and 28
  3. Gametocyte carriage at day 28


NotesCountry: Angola

Setting: Hospital outpatient dept., health centre, 3 health posts and 1 maternal and child health centre

Transmission: Mesoendemic with stable and seasonal transmission with a peak from September to April

Resistance: CQ and SP resistance

Dates: March 2003 to July 2003

Funding: Médecins sans Frontières


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomly allocated in blocks of 20'. Due to technical problems randomization only started after the first 30 patients had been enrolled.

Allocation concealment?No'Without a concealment procedure'

Blinding?
All outcomes
NoNo comment on blinding. External quality control on a random sample of malaria films was conducted.

Incomplete outcome data addressed?
All outcomes
No3 times as many withdrawals in AS+AQ group vs AS+SP (12% vs 4%). Reasons for this disparity are not given.

Free of selective reporting?YesOnly PCR adjusted results given, PCR unadjusted is unpublished data

Free of other bias?YesNo other sources of bias identified

Guthmann 2004 AGO

MethodsTrial design: A randomized controlled trial

Follow up: Days 0, 1, 2, 3, 7, 14, 21, and 28, for a clinical assessment and malaria film. Haemoglobin and gametocyte measurement on days 0 and 28.

Adverse event monitoring: Not described


ParticipantsNumber: 137 randomized

Inclusion criteria: Age 6 to 59 months, confirmed clinical P. falciparum malaria, informed consent

Exclusion criteria: As per WHO 2003 protocol


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Twice daily for 3 days as per manufacturers guidance


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Aventis, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Recurrent parasitaemia at day 28, PCR adjusted and unadjusted
  2. Prevalence of anaemia at days 0 and 28
  3. Early vomiting


Not included in the review:

  1. Gametocytes on days 0 and 28


NotesCountry: Angola

Setting: Health centre

Transmission: High transmission, mesoendemic

Resistance: CQ and SP resistance

Dates: Apr 2004 to Jul 2004

Funding: Médecins sans Frontières, The American Society of Tropical Medicine and Hygiene (ASTMH) and the American Committee on Clinical Tropical Medicine
and Travelers’ Health (ACCTMTH)


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearDescribed as 'randomized' but no other details

Allocation concealment?NoNone described

Blinding?
All outcomes
NoBlinding not mentioned. 100 malaria films were checked by an independent laboratory

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up low in both groups (6.2% AL6 vs 7.2% AS+AQ)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6.

Free of other bias?YesNo other sources of bias identified

Hamour 2003 SDN

MethodsTrial design: An open label randomized controlled trial

Follow up: Reassessed clinically and parasitologically on days 0, 1, 2, 3, 7, 14, 21, and 28

Adverse event monitoring: Not described


ParticipantsNumber: 161 randomized

Inclusion criteria: Age 6 to 59 months, weight > 5 kg, axillary temp > 37.5 ºC, P. falciparum mono-infection 2000 to 200,000/µml, informed consent

Exclusion criteria: Signs of severe malaria, concomitant febrile conditions except mild viral upper respiratory tract infections, hypersensitivity to study drugs


Interventions1. Artesunate plus sulphadoxine-pyrimethamine, loose combination (Arsumax: Sanofi-Aventis, Fansidar: Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg as a single dose


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Aventis, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage on days 0, 14, and 28
  3. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Sudan

Setting: Rural health care centre

Transmission: Markedly seasonal

Resistance: CQ resistance

Dates: Sept 2003 to Nov 2003

Funding: Médecins sans Frontières


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomized by sealed envelopes'. No further details given.

Allocation concealment?Unclear'Sealed envelopes'. No further details.

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff to allocation, but slides read independently with external quality control.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (2.5% AS+SP vs 0% AS+AQ). A large number of PCR samples were indeterminate but equally distributed across groups.

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Hasugian 2005 IDN

MethodsTrial design: An open label randomized controlled trial

Follow up: Daily until fever and parasites cleared then weekly until day 42, for a physical examination, a symptom questionnaire and malaria film. Haemoglobin measured on days 0, 7, and 28.

Adverse event monitoring: Assessed at each follow-up visit


ParticipantsNumber: 340 randomized

Inclusion criteria: Age > 1 yr, weight > 5 kg, slide confirmed malaria (P. falciparum, P. vivax or both), fever or history of fever in the preceding 48 hours

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severe malaria, > 4% red blood cells parasitized, concomitant disease that required hospital admission


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination (Artekin: Holley)

  • Total dose: 6.75 mg/kg DHA and 54 mg/kg PQP in 3 divided doses given once daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Arsumax: Guilin, Flavoquine: Aventis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Parasitological failure on days 42 and 28, PCR adjusted and unadjusted
  2. Parasitological failure with P. vivax on days 42 and 28
  3. Gametocyte carriage after treatment
  4. Anaemia at day 0, 7, 28
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Indonesia

Setting: Rural clinics

Transmission: Unstable

Resistance: Chloroquine and SP resistance

Dates: Jul 2005 to Dec 2005

Funding: Wellcome Trust - National Health and Medical Research Council


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomisation list was generated in blocks of 20 by an independent statistician'

Allocation concealment?Yes'Treatment allocation concealed in an opaque, sealed envelope that was opened once the patient had been enrolled'

Blinding?
All outcomes
NoAn open-label trial. 'All slides were read by a certified microscopist who was blinded to treatment allocation'.

Incomplete outcome data addressed?
All outcomes
NoThe primary outcome data are unpublished data including only participants with P. falciparum mono or co-infection at baseline. High losses to follow up in both groups at day 42 (21% DHA-P vs 24.5 % AL6), moderate at day 28 (16.6% DHA-P vs 18.8 % AL6).

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Hutagalung 2002 THA

MethodsTrial design: An open-label randomized controlled trial

Follow up: Examination and malaria film daily until fever and parasites cleared then weekly to day 42 or any other day they became unwell

P. vivax during follow up was treated with CQ and continued in follow up

Adverse event monitoring: At each visit a questionnaire on adverse events was completed


ParticipantsNumber: 490 randomized

Inclusion criteria: Weight > 10 kg, slide confirmed P. falciparum, informed consent

Exclusion criteria: Pregnancy, clinical or laboratory signs of severe illness and/or severe and complicated malaria severe malaria, treatment with mefloquine in previous 63 days


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • < 15 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days
  • Plus glass of chocolate milk with each dose


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilan, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. Cure rates at days 42 and 28, PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Gametocyte development
  4. Mean decrease in HCT by day 7
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance
  3. Gametocyte clearance


NotesCountry: Thailand

Setting: Malaria clinics of the Shoklo Malaria Research Unit

Transmission: Low and unstable

Resistance: Multiple-drug resistance

Dates: July 2001 to June 2002

Funding: Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computerized randomisation was in blocks of ten'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up balanced and low in both groups (8% AL6 vs 7% AS+MQ)

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes may under estimate treatment failure with AS+MQ.

Free of other bias?YesNo other sources of bias identified

Janssens 2003 KHM

MethodsTrial design: An open label randomized controlled trial

Follow up: Monitored daily until fever and parasites cleared then weekly to day 63. Temperature, symptom questionnaire, malaria film, and haematocrit at each visit.

Adverse event monitoring: An adverse event defined as any new sign or symptom appearing after treatment started. At each visit a symptom questionnaire was completed.


ParticipantsNumber: 464 randomized

Inclusion criteria: Age > 1 yr, axillary temp > 37.5 ºC or history of fever, signs and symptoms of uncomplicated malaria, P. falciparum mono or mixed infections, written informed consent

Exclusion criteria: Pregnancy or lactation, signs or symptoms of severe malaria, > 4% red blood cells parasitized, a history of convulsions or neuropsychiatric disorder, treatment with mefloquine in the past 60 days


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Adult total dose: 6 mg/kg DHA and 48 mg/kg P in 4 divided doses, given at 0, 8, 24, and 48 hours
  • Children total dose: 6.4 mg/kg DHA + 51.2 mg/kg P in 4 divided doses, given at 0, 8, 24, 48 hours


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Mefloquine: Mepha)

  • Adults: 100 mg AS plus 500 mg MQ twice daily on day 0, then 200 mg AS once daily on day 1 and day 2
  • Children: AS 4 mg/kg once daily for 3 days plus 25 mg/kg MQ split into 2 doses on day 0


All doses supervized


Outcomes
  1. Cure rate at days 63, 42, and 28, PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Mean haematocrit at day 0 and 63
  4. Adverse effects


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Cambodia

Setting: Rural health centres and outreach malaria clinics

Transmission: Low and seasonal

Resistance: Multiple-drug resistance

Dates: Oct 2002 to March 2003

Funding: Médecins sans Frontières


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computer generated randomisation (STATA version 8, Statacorp)'

Allocation concealment?Unclear'Treatment allocations were concealed in sealed envelopes'. No further details.

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up balanced and low in both groups (9.3% DHA-P vs 10% AS+MQ)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Kamya 2006 UGA

MethodsTrial design: A single blind (outcome assessors) randomized controlled trial

Follow up: Standardized history and examination and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42 and any other day they felt unwell. Haemoglobin measured at day 0 and day 42 or day of failure. Anaemia was treated with ferrous sulphate and anthelminthics according to IMCI guidelines.

Adverse event monitoring: Assessed for any new or worsening event at each visit. An adverse event defined as any untoward medical occurrence, irrespective of its suspected relationship to the study medications.


ParticipantsNumber: 509 randomized

Inclusion criteria: Age 6 m to 10 yrs, weight > 5 kg, axillary temp > 37.5 ºC or history of fever in the past 24 hours, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs or signs of severe malaria, evidence of concomitant febrile illness, history of serious side effects to study medication


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + P 51.2 mg/kg in 3 divided doses, given once daily for 3 days
  • Plus placebo tablet in the evening to simulate twice daily dosing


All doses supervized. All participants received a glass of milk after each dose


Outcomes
  1. Risk of treatment failure at day 42, PCR adjusted and unadjusted
  2. Non falciparum species during follow up
  3. Gametocyte development during follow up
  4. Mean increase in haemoglobin at last day of follow up
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Uganda

Setting: Rural health centre

Transmission: Perennial holoendemic malaria with very high transmission intensity

Resistance: Not reported

Dates: Mar 2006 to July 2006

Funding: US Centres for Disease Control, Malaria Consortium Drugman, DFID, DHA-P supplied by HolleyPharm


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomisation list was computer generated by an off-site investigator'

Allocation concealment?Yes'Sequentially numbered, sealed envelopes containing the treatment group assignments were prepared from the randomisation list'

Blinding?
All outcomes
Yes'Study physicians and laboratory personnel involved in assessing outcomes were blinded to treatment assignments'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (0.9% AL6 vs 0.9% DHA-P). A large number of participants were excluded after randomization for failing to meet the entry criteria.

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Karema 2004 RWA

MethodsTrial design: A 3-arm open label randomized controlled trial

Follow up: History, clinical signs and symptoms, and malaria film on days 0, 1, 2, 3, 7, 14, 21, and 28 and any other day they felt unwell. PCV measured at days 0 and 14.

Adverse event monitoring: An adverse event defined as any unfavourable and unintended sign associated temporally with the use of the drug administered. Differential WBC count (and liver function tests at 1 site only) assessed at days 0 and 14.


ParticipantsNumber: 762 randomized

Inclusion criteria: Age 12 to 59 months, weight > 10 kg, axillary temp > 37.5 ºC or history of fever in the preceding 24 hrs, P. falciparum mono-infection 2000 to 200,000/µl

Exclusion criteria: Severe malaria, any other concomitant illness or underlying disease, known allergy to study drugs, clear history of adequate antimalarial treatment in the previous 72 hours, PCV < 15%


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleypharm)

  • Total dose: DHA 4.8 to 9.3 mg/kg + P 38.4 to 73.8 mg/kg in 3 divided doses, given once daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination.

  • AQ 10 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte prevalence during follow up
  3. Mean PCV at baseline and day 14
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Rwanda

Setting: Peri-urban and rural health centres

Transmission: Not reported

Resistance: Not reported

Dates: Oct 2003 to Apr 2004

Funding: Belgian Development Co-operation in collaboration with the Prince Leopold Institute of Tropical Medicine. DHA-P provided by Holleypharm


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomly allocated in blocks of 15', computer generated sequence (information from author)

Allocation concealment?Unclear'Allocation of treatment was concealed until final recruitment'. No further details

Blinding?
All outcomes
NoAn open-label trial. 'Laboratory technicians reading malaria slides did not know the treatment received'

Incomplete outcome data addressed?
All outcomes
YesVery low losses to follow up in all groups (0.8% DHA-P vs 0.4% AS+AQ vs 1.2% AQ+SP)

Free of selective reporting?YesAll WHO outcomes reported. Day 28 outcomes may underestimate failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Karunajeewa 2007 PNG

MethodsTrial design: A 4-arm open label randomized controlled trial

Follow up: Standardized follow up including temperature and malaria film on days 0, 1, 2, 3, 7, 14, 28, and 42. Drug levels assayed on day 7.

Adverse event monitoring: None described


ParticipantsNumber: 372 randomized to included treatment arms

Inclusion criteria: Age 0.5 to 5 years, axillary temp > 37.5 ºC or history of fever in the preceding 24 hrs, > 1000/µl asexual P. falciparum or > 250/µl asexual P. vivax, P. ovale or P. malariae, informed consent

Exclusion criteria: Features of severe malaria, evidence of another infection or coexisting condition including malnutrition, intake of study drug in previous 14 days


Interventions1. Artesunate plus sulfadoxine-pyrimethamine, loose combination (Sanofi-Aventis, Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


2. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Beijing Holley-Cotec)

  • DHA 2.5 mg/kg once daily for 3 days
  • P 20 mg/kg once daily for 3 days


3. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Novartis), given with milk

  • A 1.7 mg/kg twice daily for 3 days
  • L 10 mg/kg twice daily for 3 day


All doses supervized except the evening dose of AL6


Outcomes
  1. ACPR (P. falciparum) at days 28 and 42, PCR adjusted and unadjusted
  2. ACPR (P. vivax) at day 42
  3. Gametocyte prevalence during follow up
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance
  3. Drug levels day 7


NotesCountry: Papua New Guinea

Setting: Health centres

Transmission: Holoendemic

Resistance: CQ and SP

Dates: Apr 2005 to Jul 2007

Funding: WHO Western Pacific Region, Rotary against Malaria in Papua New Guinea, National Health and Medical Research Council of Australia


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computer-generated randomised assignment with blocks of 24 for each site'

Allocation concealment?NoNot described

Blinding?
All outcomes
NoAn open label trial. Microscopists were unaware of treatment assignments.

Incomplete outcome data addressed?
All outcomes
YesModerate losses to follow up in all groups (11.5% AS+SP vs 13.0% DHA-P vs 14.2% AL6)

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Kayentao 2006 MLI

MethodsTrial design: An open label 3-arm randomized controlled trial

Follow up: Assessment and malaria film on days 0, 1, 2, 7, 14, and 28. Haemoglobin on days 0, 14, 28 or day of failure.

Adverse event monitoring: None described


ParticipantsNumber: 397 randomized

Inclusion criteria: Age 6 to 59 months, axillary temp > 37.5 ºC, P. falciparum mono-infection of 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs, evidence of another febrile illness, haemoglobin < 5 g/dl


Interventions1. Artesunate plus amodiaquine, loose combination

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


All doses supervized


Outcomes
  1. ACPR at days 28, PCR adjusted and unadjusted
  2. Mean haemoglobin at days 14 and 28
  3. Gametocyte carriage during follow up


Not included in this review:

  1. Proportion with fever days 0, 1, 2, 3
  2. Proportion parasitaemic days 0, 1, 2, 3


NotesCountry: Mali

Setting: Rural health centre

Transmission: Seasonal with peak in October

Resistance: CQ

Dates: Jul 2005 to Jan 2006

Funding: US Centers for Disease Control and Prevention, Malaria and Research Training Center, University of Bamako


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Block randomisation (block size of 20)'. No further details.

Allocation concealment?NoNone described

Blinding?
All outcomes
NoDescribed as 'open-label'. Patients were not informed of the drug received but no placebos were used. Microscopists were unaware of treatment allocation.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in all groups (1.5% AS+AQ vs 1.5% AS+SP vs 1.5% AQ+SP)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Kobbe 2007 GHA

MethodsTrial design: An open label randomized controlled trial

Follow up: Standardized history and examination, malaria film and haemoglobin on days 0, 3, 7, 14, and 28 and any other day they felt unwell

Adverse event monitoring: 'The comparative tolerability was assessed by the risk of occurrence of an adverse event'. For each adverse event causality was assessed as recommended by the WHO.


ParticipantsNumber: 246 randomized

Inclusion criteria: Age 6 to 59 months, axillary temp > 37.5 ºC or history of fever in the preceding 24 hrs, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs or signs of severe malaria, any other severe underlying disease, severe malnutrition, antibiotics or adequate antimalarials in the previous 7 days, a history of hypersensitivity to study drugs, unable to tolerate oral treatment


Interventions1. Artesunate plus amodiaquine, co-blister combination 50 mg AS/153 mg AQ, (Arsucam: Sanofi-Aventis)

  • 5 to 10 kg AS 1/2 tablet + AQ 1/2 tablet once daily for 3 days
  • 10 to 21 kg AS 1 tablet + AQ 1 tablet once daily for 3 days
  • 21 to 40 kg AS 2 tablets + AQ 2 tablets once daily for 3 days


2. Artemether-lumefantrine, fixed dose combination 20/120 mg (Coartem: Novartis)

  • 5 to 15 kg 1 tablet twice daily for 3 days
  • 15 to 25 kg 2 tablets twice daily for 3 days
  • 25 to 35 kg 3 tablets twice daily for 3 days


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Haematological recovery at day 28
  3. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance
  3. Parental acceptance of drug therapy


NotesCountry: Ghana

Setting: District Hospital

Transmission: Holoendemic with seasonal peaks

Resistance: CQ

Dates: Oct 2006 to Sept 2007

Funding: Vereinigung der Freunde des Tropeninstituts Hamburg E.V., German Academic Exchange Service. Drugs supplied free of charge by Novartis and Sanofi-Aventis


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computer generated list with randomisation in blocks of ten'

Allocation concealment?Yes'Children received the first dose of the individually allocated treatment (in sealed, numbered, opaque envelopes)'

Blinding?
All outcomes
NoAn open label trial. 10% of malaria slides were cross-checked by a blinded microscopist.

Incomplete outcome data addressed?
All outcomes
NoModerate losses to follow up in both groups (14% AL6 vs 16% AS+AQ)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Koram 2003 GHA

MethodsTrial design: A 4-arm, open-label randomized controlled trial

Follow up: Examination, symptoms recorded, temperature and pulse and malaria film on days 0, 1, 2, 3, 7, 14, 21 and 28 and any other day they felt unwell. Full blood count and haemoglobin measured at days 14 and 28.

Adverse event monitoring: None


ParticipantsNumber: 105 randomized into included treatment arms

Inclusion criteria: Age 6 to 59 months, signs and symptoms of uncomplicated malaria including axillary temp > 37.5 ºC, P. falciparum mono-infection of 2000 to 200,000/µl, informed consent

Exclusion criteria: Signs and symptoms of severe malaria, other diseases requiring drugs with antimalarial or antihistaminic activities, Hb < 5 g/dl


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Twice daily for 3 days based on weight


2. Artesunate plus amodiaquine, loose combination

  • AS 4 mg/kg/day for 3 days
  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted (excluded from primary analysis due to baseline differences)
  2. Gametocyte carriage on days 0, 7, and 14
  3. Mean haemoglobin on days 0, 14, and 28


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Ghana

Setting: Hohoe District Hospital and Navrongo War Memorial Hospital

Transmission: High transmission and markedly seasonal

Resistance: CQ and SP resistance

Dates: June 2003 to Aug 2003

Funding: Multilateral Initiative on Malaria, UNICEF/UNDP/World Bank/WHO Special Program for Research & Training in Tropical Diseases


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computer generated random list based on a simple random selection procedure'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff

Incomplete outcome data addressed?
All outcomes
No'Patients who showed signs/symptoms of severe malaria, had serious adverse events or required blood transfusion were withdrawn from the study'. These events after enrolment would represent treatment failure and should not be withdrawn.

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6.

Free of other bias?NoParticipants in the AL6 group were significantly older and had a higher Hb at baseline. This is due to differing inclusion criteria for the 2 groups and is likely to affect the result.

Lefevre 1999 THA

MethodsTrial design: An open-label clinical and pharmacokinetic randomized controlled trial

Follow up: Monitored 3 times daily until parasites and fever cleared. Then follow up at days 1, 2, 3, 7, 14, 21, and 28 for temp and malaria film.

P. vivax during follow up was treated with CQ and primaquine and continued in follow up

Adverse event monitoring: Assessed at each visit. ECG monitoring and laboratory tests (including FBC liver and renal function tests) at baseline and each day of follow up.


ParticipantsNumber: 219 randomized

Inclusion criteria: Age > 12 yrs, weight > 35 kg, microscopically confirmed P. falciparum, informed consent

Exclusion criteria: Signs or symptoms of severe malaria, heart disease or significant ECG abnormalities, psychiatric disorders, severe renal or hepatic impairment, history of drug hypersensitivity or allergy


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 4 tablets twice daily for 3 days


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilan, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. Cure rate at day 28 PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Gametocyte development
  4. Mean Hb at days 0 and 28
  5. Adverse events


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low transmission

Resistance: Multiple-drug resistance

Dates: Sept 1998 to Jan 1999

Funding: Novartis Pharma AG


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomized in a ratio of 3:1'. No further details given.

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low and proportional in the 2 groups (5.4% AL6 vs 3.6% AS+MQ)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6 and 63 days with AS+MQ. Day 28 outcomes may overestimate the efficacy of AL6 and AS+MQ.

Free of other bias?NoIt is stated that participants whose condition deteriorated were to be excluded from the trial. There is no flow chart so it is unclear how many participants this represented, and whether these should have been classified as early treatment failures.

Martensson 2003 TZA

MethodsTrial design: A randomized controlled trial

Follow up: Clinical assessment, malaria film, and haemoglobin measurement on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42

Adverse event monitoring: Possible adverse events recorded at each visit. Differential white cell counts at days 0, 3, 7, 14, 21, and 28. An adverse event was defined as any undesirable medical occurrence regardless of wether it was related to the treatments.


ParticipantsNumber: 408 randomized

Inclusion criteria: Age 6 to 59 months and weight > 6 kg for AS+AQ group, 9 to 59 months and > 9 kg for AL6 group, axillary temp > 37.5 ºC or history of fever in previous 24 hrs, P. falciparum parasitaemia 2000 to 200,000/µl

Exclusion criteria: Symptoms and signs of severe malaria, any danger sign, serious underlying disease, Hb < 5 g/dl, known allergy to study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 9 to 15 kg 1 tablet twice daily for 3 days
  • 15 to 25 kg 2 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, loose combination (Plasmotrim: Mepha, Flavoquin: Roussel)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Cure rate at days 28 and 42, PCR adjusted and unadjusted (excluded from primary analysis due to baseline differences)
  2. Gametocyte carriage on days 0 and 7
  3. Mean haemoglobin on days 0 and 42
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Zanzibar, Tanzania

Setting: Outpatient departments in densely populated rural areas

Transmission: Holoendemic

Resistance: Not reported

Dates: Nov 2002 to Feb 2003

Funding: UNDP/World Bank/WHO Special Program for Research & Training in Tropical Diseases, Swedish Development Co-operation Agency Department for Research Cooperation, European 5th Framework Project


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?UnclearDescribed as 'randomized' but no details given

Allocation concealment?NoNone described

Blinding?
All outcomes
NoNo blinding is described. 10% of malaria films were cross-checked by an independaent examiner in a central laboratory

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up (1.5% AL6 vs 1% AS+AQ)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?NoDue to different inclusion criteria for the 2 groups, participants in the AL6 group were, on average, older and heavier at baseline

Mayxay 2003 LAO

MethodsTrial design: A 3-arm, open label randomized controlled trial

Follow up: Temperature was measured every 6 hours and patient reviewed daily until fever and parasites cleared then weekly until day 42 or any time they felt unwell. At each visit a malaria film and haematocrit measurement was taken.

Adverse event monitoring: Potential side effects were recorded at each visit


ParticipantsNumber: 220 randomized into included treatment arms

Inclusion criteria: Age > 1 yr, axillary temp > 37.5 ºC or history of fever in previous 3 days, P. falciparum parasitaemia 5000 to 200,000/µl, likely to stay in hospital until fever cleared and complete 42 days follow up, informed consent

Exclusion criteria: Pregnancy or lactation, signs of severe malaria, history of allergy or contraindication to the study drugs, a full course of antimalarials in the previous 3 days


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • < 15 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days
  • Advised to take with fatty food


2. Artesunate plus mefloquine, loose combination (artesunate: Guilan, Lariam: Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. Cure rates at day 42, PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Gametocyte development
  4. Mean haematocrit after treatment
  5. Adverse events


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Lao People's Democratic Republic

Setting: District clinic

Transmission: Not stated

Resistance: CQ and SP resistance

Dates: June to Oct in 2002 and 2003

Funding: Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomized in blocks of 15'. No further details given.

Allocation concealment?Yes'The treatment choice was kept in a sealed opaque envelope that was opened only after the decision to recruit had been made'

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (2.7% AL6 vs 1.8% AS+MQ)

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes may underestimate treatment failure with AS+MQ.

Free of other bias?YesNo other sources of bias identified

Mayxay 2004 LAO

MethodsTrial design: An open label randomized controlled trial

Follow up: Temperature was measured every 6 hours and patient reviewed daily until fever and parasites cleared then weekly until day 42 or anytime they felt unwell. At each visit a malaria film and haematocrit measurement was taken.

Adverse event monitoring: Potential adverse events were recorded at each visit


ParticipantsNumber: 220 randomized

Inclusion criteria: Age > 1 year, axillary temp > 37.5 ºC or history of fever in the previous 3 days, P. falciparum mono-infection 1000 to 200,00/µl, were likely to stay in hospital until parasite clearance and complete 42 days follow up, informed consent

Exclusion criteria: Pregnancy or lactation, signs of severe malaria, antimalarials in the previous 3 days, contraindications to the study drugs


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days


2. Artesunate plus mefloquine, loose combination (Artesunate: Guilin, Lariam: Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg base/kg on day 1 and 10 mg base/kg on day 2


All doses supervized


Outcomes
  1. Cure rate at day 42, PCR adjusted and unadjusted
  2. P. vivax during follow up
  3. Adverse events


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time
  3. Gametocyte carriage after treatment


NotesCountry: Lao People's Democratic Republic (Laos)

Setting: District clinic

Transmission: Not reported

Resistance: Not reported

Dates: May 2004 to Sept 2004

Funding: Western Pacific Regional office of WHO, Wellcome Trust of Great Britain, Artekin provided by Holleykin Pharmaceuticals


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomized in blocks of 10'. No further details given.

Allocation concealment?Yes'The treatment choice was kept in a sealed opaque envelope, which was opened only after the decision to recruit'

Blinding?
All outcomes
NoAn open-label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (3.6% DHA-P vs 1.8% AS+MQ)

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes are likely to overestimate the efficacy of the 2 drugs.

Free of other bias?YesNo other sources of bias identified

Menard 2006 MDG

MethodsTrial design: A 5-arm single blind (outcome assessors) randomized controlled trial

Follow up: Patients returned for malaria films on days 0, 1, 2, 3, 7, 14, 21, 28, and any other day they felt ill. Haemoglobin was assessed on days 0 and 28.

Adverse event monitoring: Not described


ParticipantsNumber: 166 randomized to included treatment arms

Inclusion criteria: Age 6 months to 15 yrs, weight > 5 kg, axillary temp > 37.5 ºC, P. falciparum mono-infection 1000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs, severe or complicated malaria, febrile conditions other than malaria, severe malnutrition, severe anaemia (Hb < 5 g/dl), development of concomitant disease which could interfere with study outcome, known hypersensitivity to the study drugs, repeated vomiting of the first dose


Interventions1. Artesunate plus amodiaquine

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


2. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg once on the first day


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage at days 0, 7, 14, 21, and 28
  3. Mean increase in haemoglobin by day 28
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Madagascar

Setting: Primary health centres

Transmission: Low and predominantly seasonal

Resistance: CQ resistance

Dates: Feb 2006 to June 2006

Funding: Natixis, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the IAEA project


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomization was in blocks of 5'. Drawing numbered papers from a box (additional detail from author).

Allocation concealment?Yes'Treatment regimens were allocated by an independent individual not involved in the analysis of the study'

Blinding?
All outcomes
Yes'All other study personnel were blinded to the treatment assignments, and patients not informed of their treatment regimen'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (8.4% AS+AQ vs 4.8% AQ+SP)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Mens 2007 KEN

MethodsTrial design: An open label randomized controlled trial

Follow up: Malaria film and haemoglobin level on days 0, 1, 2, 3, 7, 14, and 28, plus QT-NASBA for detection of sub-microscopic gametocytaemia

Adverse event monitoring: Adverse events were recorded at each visit in the case record form. An adverse event defined as any unfavourable and unintended sign.


ParticipantsNumber: 146 randomized

Inclusion criteria: Age 6 months to 12 years, axillary temp > 37.5 ºC or history of fever, P. falciparum mono-infection 1000 to 200,000/µl, informed consent

Exclusion criteria: Severe malaria, any other underlying illness


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 20 mg/160 mg tablets (Sigma-Tau)

  • 4 to 7 kg 1/2 tablet once daily for 3 days
  • 7 to 13 kg 1 tablet once daily for 3 days
  • 13 to 24 kg 2 tablets once daily for 3 days
  • 24 to 35 kg 4 tablets once daily for 3 days


2. Artemether-lumefantrine, fixed dose combination, 20/120 mg tablets (Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days


All doses supervized and given with a glass of milk


Outcomes
  1. Recurrent parasitaemia at day 28, PCR adjusted and unadjusted
  2. Gametocyte prevalence during follow up
  3. Mean haemoglobin at day 28
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Kenya

Setting: Health centre

Transmission: High transmission

Resistance: Not reported

Dates: Apr 2007 to July 2007

Funding: The Knowledge and Innovation Fund, Koninklijk Instituut voor de Tropen/Royal Tropical Institute. DHA-P provided free of charge by Sigma-Tau.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A computer generated randomisation list'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoMicroscopists were blinded to treatment allocation. No other blinding described.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (8.2% DHA-P vs 8.2% AL6)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may underestimate treatment failure with AL6 and DHA-P.

Free of other bias?YesNo other sources of bias identified

Mukhtar 2005 SDN

MethodsTrial design: A randomized controlled trial

Follow up: On days 0, 1, 2, 3, 7, 14, 21, and 28. A malaria film taken at each visit

Adverse event monitoring: None described


ParticipantsNumber: 160 randomized

Inclusion criteria: All age groups, as per WHO protocol 2003

Exclusion criteria: As per WHO protocol 2003


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Dosing details not given


2. Artesunate plus sulfadoxine-pyrimethamine, loose combination

  • Dosing details not given


Only first dose of each day was supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted


NotesCountry: Sudan

Setting: 3 villages in eastern Sudan

Transmission: Low endemicity

Resistance: CQ and SP resistance

Dates: Oct to Dec in 2004 and 2005

Funding: National Centre for Research, drugs provided by Novartis, Amipharma and the national Malaria Control Programme


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'A simple random technique of a hat draw'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoNo details of blinding given. Malaria films were read by 2 independent microscopists.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (0% AL6 vs 3.8% AS+SP)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate the failure rate of AL6.

Free of other bias?NoIn general details of the trial were limited. Very few baseline data given and no detail on drug regimens.

Mutabingwa 2004 TZA

MethodsTrial design: A 4-arm, randomized controlled trial

Follow up: Participants were assessed clinically and by malaria film on days 0, 14, and 28 or any other day they were unwell

Adverse event monitoring: Parents or guardians were asked to report on side effects, tolerability, and usefulness of the treatment


ParticipantsNumber: 1541 randomized into included treatment arms

Inclusion criteria: Age 4 to 59 months, symptoms suggestive of malaria, P. falciparum > 2000/µl, able to take oral meds, able to attend clinic for follow up, informed consent

Exclusion criteria: Mixed infections, severe or complicated malaria, concomitant disease masking assessment of the response to treatment, intake of antimalarials other than CQ within the past 7 days, known hypersensitivity to any of the study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 10 to 15 kg 1 tablet twice daily for 3 days
  • 15 to 25 kg 2 tablets twice daily for 3 days
  • 25 to 35 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Artesunate plus amodiaquine, co-blistered/loose (Sanofi)

  • AS 4 mg/kg/day for 3 days
  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination (Sanofi, Roche)

  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • SP 25/1.25 mg/kg on day 0


All doses unsupervized


Outcomes
  1. Parasitological failure at day 28 PCR unadjusted
  2. Mean change in haemoglobin from baseline day 14
  3. Adverse events


Not included in the review:

  1. PCR corrected data (only conducted for 1 year of the trial and we were unable to adequately extract attrition data)
  2. Gametocytes during follow up (no baseline data)


NotesCountry: Tanzania

Setting: Maternal and child health clinic

Transmission: Very high

Resistance: High level CQ and SP resistance

Dates: Sept 2002 to Oct 2004

Funding: Gates Malaria Partnership. AS+AQ donated by Sanofi. AL6 donated by WHO


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomization was done by computer (Stata Version 6), with blocks of variable sizes'

Allocation concealment?Yes'Treatment allocations were put into opaque, sealed and countersigned, sequentially numbered envelopes'

Blinding?
All outcomes
NoMalaria films were read by 2 different laboratories unaware of treatment allocation. No other blinding is reported.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low in all groups (6.5% AL6 vs 8.3% AS+AQ vs 8.7% AQ+SP)

Free of selective reporting?NoNo baseline data is given on gametocytes. PCR data is only given for 1 year of the trial. It is not possible to calculate attrition for this period.

Free of other bias?YesNo other sources of bias identified

Owusu-Agyei 2006 GHA

MethodsTrial design: A 3-arm, randomized controlled trial

Follow up: Participants were assessed for adverse events and by malaria film on days 0, 2, 3, 7, 14, and 28 or any other day they were unwell. Haemoglobin measured on days 1, 2, 3, 7, and 28. Anaemia was treated with iron according to national guidelines

Adverse event monitoring: Field workers visited their homes to solicit adverse events on days 0, 2, 3, 7, 14, and 28


ParticipantsNumber: 355 randomized into included treatment arms

Inclusion criteria: Age 6 months to 10 yrs, weight > 5 kg, axillary temp > 37.5 ºC or history of fever, parasitaemia 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs, signs of severe malaria, concomitant febrile illness, Hb < 7 g/dl


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Details not given


2. Artesunate plus amodiaquine, co-blistered (Arsucam: Sanofi-Aventis)

  • Details not given


All doses supervized for 3 days


Outcomes
  1. Parasitological and clinical failure at day 28, PCR unadjusted and PCR adjusted
  2. Gametocytaemia at day 7
  3. Haemoglobin at day 28
  4. Adverse events


NotesCountry: Ghana

Setting: District hospital

Transmission: Perennial, high with a peak July to August

Resistance: Not stated

Dates: June 2005 to May 2006

Funding: Gates Malaria Partnership of the London School of Hygiene and Tropical Medicine


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomization was done using Microsoft Excel 2003 randomisation generator'

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of lab staff.

Incomplete outcome data addressed?
All outcomes
YesModerate losses to follow up but similar in both groups (14% AL6 vs 15% AS+AQ)

Free of selective reporting?YesAll WHO outcomes reported. Biochemical monitoring is stated although this outcome is not reported

Free of other bias?YesNo other sources of bias identified

Ratcliff 2005 IDN

MethodsTrial design: An open-label randomized controlled trial

Follow up: A symptom questionnaire, physical examination, malaria film and haemoglobin measurement daily until fever and parasites cleared then weekly to day 42

Adverse event monitoring: A symptom questionnaire at each visit


ParticipantsNumber: 774 randomized

Inclusion criteria: Weight >10 kg, fever or a history of fever in the preceding 48 hours, slide confirmed malaria (P. falciparum, P. vivax or mixed infections)

Exclusion criteria: Pregnancy or lactation, danger signs or signs of severity, parasitaemia > 4%, concomitant disease requiring hospital admission


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.75 mg/kg + P 54 mg/kg in 3 divided doses, given once daily for 3 days


2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 10 to 15 kg 1 tablet twice daily for 3 days
  • 15 to 25 kg 2 tablets twice daily for 3 days
  • 25 to 35 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


Only the first dose of each day was supervized. All participants advised to take each dose with a biscuit or milk.


Outcomes
  1. Parasitological failure at days 42 and 28, PCR adjusted and unadjusted
  2. P. vivax during follow up
  3. Gametocyte carriage after treatment
  4. Anaemia during follow up
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Indonesia

Setting: Rural outpatient clinics

Transmission: Unstable

Resistance: Multiple-drug resistance

Dates: Jul 2004 to Jun 2005

Funding: Wellcome Trust UK and National Health and Medical Research Council Australia


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomisation list was generated in blocks of 20 patients by an independent statistician'

Allocation concealment?Yes'With each treatment allocation concealed in an opaque sealed envelope'. No further details given.

Blinding?
All outcomes
NoAn open label trial. The microscopists were blinded to treatment allocation.

Incomplete outcome data addressed?
All outcomes
NoThe primary outcome data are unpublished data including only participants with P. falciparum mono or co-infection at baseline. Losses to follow up were high in both groups at day 42 (28.4 % DHA-P vs 25.6 % AL6) and moderate at day 28 (19% DHA-P vs 17.6% AL6).

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Sagara 2005b MLI

MethodsTrial design: An open label randomized controlled trial

Follow up: Examination and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, and any day they felt unwell. Haemoglobin on days 0, 14, and 28.

Adverse event monitoring: CBC, ALT, and creatinine on 20% of participants on days 0 and 14


ParticipantsNumber: 470 randomized

Inclusion criteria: Age > 1 yr, weight >10 kg, axillary temperature > 37.5 ºC, P.falciparum mono-infection 2000 to 200,000, resident at study site, able to take oral medication, informed consent

Exclusion criteria: Pregnancy, severe malaria, a serious underlying disease, an allergy to 1 or more study drugs, use of study drugs within 28 days


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Artesunate plus mefloquine, co-blistered (Artequin: Mepha)

  • 10 to 14 kg AS 4 mg/kg and MQ 5 mg/kg once daily for 3 days
  • 15 to 30 kg AS 100 mg and MQ 150 mg once daily for 3 days
  • > 31 kg AS 200 mg and MQ 250 mg once daily for 3 days


All doses supervized


Outcomes
  1. ACPR at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage
  3. Prevalence of anaemia on days 0, 28
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Mali

Setting: Peri-urban

Transmission: Hyperendemic with highly seasonal transmission

Resistance: Not stated

Dates: Aug 2004 to Feb 2005

Funding: Pharmatech Inc (also donated AS+MQ), and Mepha Ltd.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A bloc randomisation code with treatment arm was computer generated by the study statistician'

Allocation concealment?Yes'Study codes were sealed in individual opaque and sequentially numbered envelopes'

Blinding?
All outcomes
NoAn open label trial. Microscopists were blinded to the treatment arm.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low in both groups (2.1% AS+MQ vs 1.7% AL6)

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6 and 63 days with AS+MQ. Day 28 outcomes may overestimate the efficacy of AL6 and AS+MQ.

Free of other bias?YesNo other sources of bias identified

Smithuis 2004 MMR

MethodsTrial design: A 4-arm open-label randomized controlled trial

Follow up: A symptom questionnaire, malaria film, and gametocyte count on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Haemoglobin was measured on days 0 and 28.

Adverse event monitoring: A symptom questionnaire at each visit


ParticipantsNumber: 652 randomized

Inclusion criteria: Age > 1 year, axillary temperature > 37.5 ºC or history of fever in the previous 48 hrs, P. falciparum mono-infection 500 to 100,000 parasites/µl or co-infection with P. vivax, informed consent

Exclusion criteria: Pregnancy, signs of severe malaria, signs or symptoms of other diseases, history of taking mefloquine in the previous 2 months or any other antimalarial in the previous 48 hrs, history of psychiatric disease


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days
  • Supervized


2. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6.3 mg/kg + P 50.4 mg/kg in 3 divided doses, given once daily for 3 days
  • Unsupervized


3. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as a single dose on day 0
  • Supervized


4. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as a single dose on day 0
  • Unsupervized


Outcomes
  1. Failure Rate at days 42 and 28, 42 PCR unadjusted and PCR adjusted
  2. P. vivax during follow up and median time to appearance
  3. Gametocyte carriage at days 0, 7, 14, 21, and 28
  4. Mean change in haemoglobin from day 0 to day 28
  5. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance
  3. New gametocyte appearance at day 7 and day 14


NotesCountry: Myanmar

Setting: Rural village tracts

Transmission: Seasonal with peaks in the monsoon season Nov to Jan and sometimes in the early monsoon, May to June

Resistance: Very high rates of CQ and SP resistance

Dates: Nov 2003 to Feb 2004

Funding: Médecins sans Frontières (Holland)


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesUnmarked and sealed envelopes, containing the treatment allocation were drawn from a box

Allocation concealment?Unclear'Unmarked and sealed envelopes'. No further details given.

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesVery low losses to follow up in both groups

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes are likely to overestimate the efficacy of the 2 drugs.

Free of other bias?YesNo other sources of bias identified

Staedke 2003 UGA

MethodsTrial design: An open label randomized controlled trial

Follow up: A standardized history and examination and malaria film on days 1, 2, 3, 7, 14, 21, and 28 or other times if they were unwell. Haemoglobin was measured on days 0, 7, and 28.

Adverse event monitoring: Assessed at each visit. Neurological assessment on days 0, 7, 14, and 28. Complete blood count, creatinine, and alanine transferase on days 0, 7, and 28.


ParticipantsNumber: 278 randomized into included treatment arms

Inclusion criteria: Age 6 months to 10 yrs, tympanic temp > 38.0 ºC or febrile symptoms in previous 48 hrs, P. falciparum mono-infection 500 to 200,000/µl, willingness to participate in 28 day follow up, informed consent

Exclusion criteria: Danger signs, severe malaria, alternative diagnosis for febrile illness, antifolate use in the previous 4 weeks, history of serious side effects to any of the study drugs, severe anaemia (Hb < 5 g/dl)


Interventions1. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • SP 25/1.25 mg/kg once on day 0


2. Artesunate plus amodiaquine

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2


All doses supervized. Meds crushed and mixed with chocolate to mask the colour and taste.


Outcomes
  1. Risk of treatment failure at day 28, PCR unadjusted
  2. Gametocytes during follow up
  3. Anaemia during follow up
  4. Adverse events


Not included in the review:

  1. Risk of treatment failure at day 28, PCR adjusted (only late clinical failures underwent PCR testing)
  2. Fever clearance
  3. Parasite clearance


NotesCountry: Uganda

Setting: Urban hospital

Transmission: Mesoendemic with peaks in the 2 rainy seasons

Resistance: CQ and SP resistance

Dates: Aug 2002 to July 2003

Funding: NIH and the Fogarty International Centre/NIH


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'An off-site investigator generated randomization codes with a computer for two age groups using variable blocking'

Allocation concealment?Yes'Sequentially numbered sealed envelopes containing the treatment group assignments were prepared from the randomization lists'

Blinding?
All outcomes
Yes'All study personnel (excluding study nurse), including the doctors, were unaware of the treatment assignments'

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low in both groups (3% AS+AQ vs 3.7% AQ+SP)

Free of selective reporting?YesWe were unable to use PCR adjusted data as PCR was only performed on late clinical failures, not on late parasitological failures

Free of other bias?YesNo other sources of bias identified

Stohrer 2003 LAO

MethodsTrial design: An open label randomized controlled trial

Follow up: A history, axillary temperature and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, and 42 or other times if they were unwell. Haemoglobin was measured on days 0 and 28

Participants experiencing P. vivax during follow up were withdrawn

Adverse event monitoring: Treatment emergent symptoms and signs were recorded on days 0 to 3


ParticipantsNumber: 108 randomized

Inclusion criteria: Weight > 10 kg, axillary temperature > 37.5 ºC, P. falciparum mono-infection 1000 to 100,000/µl, ability to attend follow up, informed consent

Exclusion criteria: Pregnancy or lactation, signs of severe or complicated malaria, severe malnutrition, febrile diseases other than malaria, history of hypersensitivity reaction to any of the study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 10 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2, Artesunate plus mefloquine, loose combination (Plasmotrim: Mepha, Mephaquine: Mepha)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. ACPR at day 42, PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Gametocyte carriage at day 7
  4. Adverse events


Not included in the review:

  1. Parasite clearance


NotesCountry: Lao People's Democratic Republic

Setting: Hospital and community based

Transmission: Perennial with peaks during the rainy season May to Oct

Resistance: CQ and SP resistance

Dates: Oct to Dec 2003

Funding: USAID, mefloquine and artesunate donated by Mepha, Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Envelope randomisation' in blocks of various sizes, no further details given

Allocation concealment?Unclear'A sealed envelope was opened which assigned patients to one of the two treatment arms'. No further details given.

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff, quality control was conducted by rechecking malaria films by expert microscopists.

Incomplete outcome data addressed?
All outcomes
YesDisproportionate losses to follow up (11.3% AL6 vs 3.6% AS+MQ) but unlikely to have affected the overall result

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes may overestimate the efficacy of AS+MQ.

Free of other bias?YesNo other sources of bias identified

Swarthout 2004 ZAR

MethodsTrial design: An open label randomized controlled trial

Follow up: Examination and malaria film on days 0, 1, 2, 3, 7, 14, 21, and 28, or other times if they were unwell

Adverse event monitoring: Parents and guardians were asked about tolerability and potential side effects of the drugs


ParticipantsNumber: 180 randomized

Inclusion criteria: Age 6 to 59 months, symptoms suggestive of malaria, P. falciparum mono-infection 2000 to 200,000/µl, able to take the study drugs orally, able to attend follow up, informed consent

Exclusion criteria: Severe or complicated malaria, concomitant disease that could mask response to antimalarial treatment, known hypersensitivity to any of the study drugs


Interventions1. Artesunate plus amodiaquine

  • No dosing details given


2. Artesunate plus sulfadoxine-pyrimethamine

  • No dosing details given


All doses supervized


Outcomes
  1. Failure rate at day 28, PCR adjusted and unadjusted
  2. Gametocytaemia during follow up
  3. The percentage of participants with mild and moderate anaemia during follow up
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Democratic Republic of Congo

Setting: Small town health centre

Transmission: Highly endemic and seasonal with peaks in the rainy seasons; March to May and September to November

Resistance: CQ and SP resistance

Dates:April 2004 to May 2004

Funding: Médecins sans Frontières (Holland) and ECHO


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomization in blocks of 12 was performed by computer before the study started'

Allocation concealment?Unclear'A sealed envelope containing the treatment allocation...was opened only after informed consent had been obtained'

Blinding?
All outcomes
No'Neither patients nor clinicians were blinded to the treatment given, microscopists unaware of treatment allocation read all slides'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (7.8% AS+AQ vs 10% AS+SP)

Free of selective reporting?YesAll WHO outcomes reported

Free of other bias?YesNo other sources of bias identified

Tangpukdee 2005 THA

MethodsTrial design: An open label randomized controlled trial

Follow up: The patients were admitted to hospital for 28 days. Clinical evaluation and parasite counts were performed 12-hourly until parasites cleared then daily for 28 days.

Adverse event monitoring: Assessed daily using non-suggestive questioning. Side effects were defined as signs and symptoms which occurred or became more severe after treatment started. Routine haematology, biochemistry, and urinalysis were conducted and baseline and weekly during follow up.


ParticipantsNumber: 180 randomized

Inclusion criteria: Age >14 years, weight > 40 kg, P. falciparum on blood smear, ability to take oral medicines, agree to stay in hospital for 28 days, informed consent

Exclusion criteria: Pregnancy or lactation, severe malaria, severe vomiting, concomitant systemic diseases, other antimalarials in the previous 14 days or the presence of sulphonamides or 4-aminoquinolones in the urine


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Total dose: DHA 6 mg/kg + P 45 mg/kg in 3 divided doses, given once daily for 3 days


2. Artesunate plus mefloquine, loose combination

  • AS 4 mg/kg once daily for 3 days
  • MQ 8 mg/kg once daily for 3 days


All doses supervized


Outcomes
  1. Cure rate at day 28. PCR analysis not performed as all patients hospitalised for duration of follow up, so all recurrent parasitaemias presumed to be recrudescence
  2. Adverse events


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time


NotesCountry: Thailand

Setting: Bangkok Hospital for Tropical Diseases

Transmission: Low

Resistance: Multiple-drug resistance

Dates: Not given

Funding: Mahidol University Research Grant, Artekin supplied by Holleykin Pharmaceuticals


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Randomly treated at a ratio of 1:2'. No further details given.

Allocation concealment?NoNone described

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
YesLosses to follow up were low and similar between groups (10.8% DHA-P vs 10% AS+MQ)

Free of selective reporting?YesDay 28 outcomes may overestimate the efficacy of drugs with long half-lives such as AS+MQ and DHA-P

Free of other bias?YesNo other sources of bias identified

Tran 2002 VNM

MethodsTrial design: An open label randomized controlled trial

Follow up: Malaria film on days 0, 2, and 7. Participants followed up to day 56 but further details not described

Adverse event monitoring: Not described


ParticipantsNumber: 243 randomized to included treatment arms

Inclusion criteria: Age > 2 yrs, microscopically confirmed uncomplicated P. falciparum malaria

Exclusion criteria: Pregnancy, evidence of organ dysfunction, unable to tolerate oral medication, unable to return for follow up, resident in Dac O for > 2 years


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Artekin: Holleykin)

  • Adults: 2 tablets at 0, 6, 24, and 48 hrs
  • Children < 15 yrs: 1 tablet at 0, 6, 24, and 48 hrs


2. Artesunate plus mefloquine, loose combination (artesunate: Guilin, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 25 mg base/kg as 2 divided doses 6 hours apart on day 3


Outcomes
  1. Parasitological failure at days 42 and 28, PCR adjusted and unadjusted
  2. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Vietnam

Setting: Health station

Transmission: Low and seasonal

Resistance: Multiple-drug resistance

Dates: Nov 2001 to Mar 2002

Funding: Wellcome Trust of Great Britain


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Patients were randomly allocated one of three treatments in a ratio of 2:2:1'. No further details given.

Allocation concealment?Unclear'Drugs were kept in identically numbered opaque envelopes'. No further details.

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff.

Incomplete outcome data addressed?
All outcomes
Yes'There were no losses to follow-up'

Free of selective reporting?UnclearIt is unclear from the paper whether it is only clinical failure that is being reported

Free of other bias?YesNo other sources of bias identified

Van den Broek 2003a BGD

MethodsTrial design: A 3-arm, open label randomized controlled trial

Follow up: Clinical assessment and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42 and any other day when feeling ill

P. vivax or P. malariae during follow up were treated with CQ and continued in follow up

Adverse event monitoring: Possible side effects assessed at each visit


ParticipantsNumber: 242 randomized to included treatment arms

Inclusion criteria: Age > 1 yr, history of fever, P. falciparum mono-infection 1000 to 100,000/µl, informed consent

Exclusion criteria: Pregnancy, signs of severe malaria, signs of another febrile illness or severe illness requiring treatment, Hb < 6 g/dl


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 2 doses per day for 3 days according to weight (no further details).
  • Taken with 250 ml of sweetened milk


2. Artesunate plus mefloquine, loose combination

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 0 and 10 mg/kg on day 1


All doses supervized


Outcomes
  1. ACPR at day 42, PCR adjusted and unadjusted
  2. P. vivax parasitaemia during follow up
  3. Gametocyte prevalence at days 0, 3, 7, and 14
  4. Adverse events


NotesCountry: Bangladesh

Setting: Outpatient clinics

Transmission: High endemicity with a clear seasonal pattern

Resistance: Multiple-drug resistance

Dates: May 2003 to Sept 2003

Funding: Médecins sans Frontières (Holland)


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomisation was done in blocks of 30 by drawing a card from a box'

Allocation concealment?No'Treatment allocation was done by drawing a card from a box containing three types of cards coding for treatments'

Blinding?
All outcomes
NoAn open label trial. No comment on blinding of laboratory staff. 10% of slides were cross-checked.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up (1.6% AL6 vs 5.8% AS+MQ)

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ. Day 42 outcomes may underestimate treatment failure with AS+MQ.

Free of other bias?YesNo other sources of bias identified

Van den Broek 2004 ZAR

MethodsTrial design: A 3-arm, open label randomized controlled trial

Follow up: Clinical assessment and malaria film on days 0, 1, 2, 3, 7, 14, 21, and 28. Haemoglobin measured at days 0, 14, and 28

Adverse event monitoring: Possible side effects as passively reported to the examiner were recorded at each visit


ParticipantsNumber: 298 randomized

Inclusion criteria: Age 6 to 59 months, weight > 5 kg for AS+AQ and AS+SP groups and > 10 kg for AL6, fever > 37.5 ºC or history of fever in the previous 24 hrs, P. falciparum mono-infection 2000 to 200,000/µl, lives within 2 hours walking distance, informed consent

Exclusion criteria: Signs of severe or complicated malaria, any danger sign, a serious concomitant illness, malnutrition, known hypersensitivity to the study drugs


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • Twice daily for 3 days, weight based as per manufacturers guidance
  • Given with fatty food or a glass of milk


2. Artesunate plus amodiaquine, loose combination (Arsumax: Sanofi-Aventis, Camoquin: Parke-Davis)

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg once daily for 3 days


3. Artesunate plus sulphadoxine-pyrimethamine, loose combination (Arsumax: Sanofi-Aventis, Fansidar: La Roche)

  • AS 4 mg/kg once daily for 3 days
  • SP 25/1.25 mg/kg on day 1


All doses supervized


Outcomes
  1. Recurrent parasitaemia at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage at days 0 and 28
  3. Changes in haemoglobin during follow up
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Republic of Congo

Setting: Health centre

Transmission: Holoendemic with a peak in the rainy seasons

Resistance: CQ, SP, and AQ resistance

Dates: May 2004 to Oct 2004

Funding: Médecins sans Frontières (Holland)


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomized to the three treatments by a random number list' (information from author)

Allocation concealment?NoAllocation was not concealed (information from author)

Blinding?
All outcomes
NoAn open label trial. 10% of malaria films were cross-checked by external laboratories.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in all groups (5.7% AL6 vs 4% AS+AQ vs 6.6% AS+SP). A significant number of PCR samples were indeterminate or missing which may affect the result.

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may underestimate the failure rate with AL6.

Free of other bias?NoDue to differing inclusion criteria for the 3 arms children in the AL6 group were older, heavier and had higher Hb levels at baseline. This may improve outcome in this group and consequently the AL6 arm was excluded from this review.

Van Vugt 1998 THA

MethodsTrial design: An open-label randomized controlled trial

Follow up: Examination and malaria film daily until fever and parasites cleared then weekly to day 28

Adverse event monitoring: A questionnaire for adverse effects was completed at each visit. Full neurological examination on days 0, 3, 7, and 28. Complete haematology and biochemistry (at 1 centre) on days 0, 3, 7, and 28.


ParticipantsNumber: 200 randomized

Inclusion criteria: Age > 2 yrs, P. falciparum parasitaemia > 500/µl, informed consent

Exclusion criteria: Pregnancy or lactation, severe or complicated malaria


Interventions1. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • < 15 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Artesunate plus mefloquine, loose combination (artesunate: Guilan, Lariam: Hoffman-La Roche)

  • AS 4 mg/kg once daily for 3 days
  • MQ 15 mg/kg on day 1 and 10 mg/kg on day 2


All doses supervized


Outcomes
  1. Cure rate at day 28, PCR adjusted and unadjusted
  2. Anaemia (haematocrit < 30%) on days 0, 3, and 28
  3. Adverse events


Not included in the review:

  1. Fever clearance time
  2. Parasite clearance time
  3. Gametocyte clearance during first 3 days


NotesCountry: Thailand

Setting: Bangkok Hospital for Tropical Diseases and an outpatient clinic

Transmission: Not reported

Resistance: Multiple-drug resistance

Dates: Nov 1997 to Mar 1998

Funding: Wellcome Trust of Great Britain, Novartis


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear'Using a 3:1 randomization scheme'. No further details given.

Allocation concealment?Unclear'The allocation was in sealed envelopes'. No further details given.

Blinding?
All outcomes
NoAn open label trial. No other comment on blinding.

Incomplete outcome data addressed?
All outcomes
YesDifferent losses to follow up in each group (11% AL6 vs 6% AS+MQ) but unlikely to affect the overall result

Free of selective reporting?YesThe WHO recommends 63 days follow up in studies of AS+MQ, and 42 days with AL6. Day 28 outcomes may underestimate treatment failure with both drugs.

Free of other bias?YesNo other sources of bias identified

Yeka 2004 UGA

MethodsTrial design: A 3-arm single blind randomized controlled trial

Follow up: Malaria film on days 0, 1, 2, 3, 7, 14, 21, 28 and any other day they were unwell. Haemoglobin on days 0 and 28 or the day of failure.

Adverse event monitoring: Not described


ParticipantsNumber: 1537 randomized to included treatment arms

Inclusion criteria: Age > 6 months, axillary temp > 37.5 ºC or history of fever in the previous 24 hours, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Pregnancy, danger signs, signs of severe malaria, concomitant febrile illness, history of treatment with an antifolate or amodiaquine during the previous week, history of serious side effects to the study meds


Interventions1. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination

  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • SP 25/1.25 mg/kg once on day 0, plus placebo on days 1 and 2


2. Artesunate plus amodiaquine

  • AS 4 mg/kg once daily for 3 days
  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2


All doses supervized


Outcomes
  1. Risk of recurrent infection at day 28, PCR adjusted and unadjusted
  2. Gametocytes during follow up
  3. Mean increase in haemoglobin
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Uganda

Setting: District health centres

Transmission: 4 sites with medium-high to high endemicity

Resistance: CQ and SP resistance

Dates: Nov 2002 to May 2004

Funding: CDC/Association of Schools of Public Health co-operative agreement, Malaria Surveillance and Control in Uganda, DfID


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomisation codes were computer generated'

Allocation concealment?NoNot described

Blinding?
All outcomes
Yes'All other study personnel (except study nurse) were blinded to the treatment assignments and participants were not informed of their treatment regimen'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (3.4% AS+AQ vs 4.0% AQ+SP). High transmission with very high reinfection rates results in very high exclusions from primary analysis.

Free of selective reporting?YesOutcomes only presented as percentages. Additional data gained from authors.

Free of other bias?YesNo other sources of bias identified

Yeka 2007 UGA

MethodsTrial design: A single blind randomized controlled trial

Follow up: Standardized history, physical exam, and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42 and any other day they were unwell. Haemoglobin on days 0 and 42 or the day of failure. Anaemia was treated with ferrous sulphate and antihelminthics according to IMCI guidelines.

Adverse event monitoring: Assessed at each visit including neurological examination. Adverse events described as any untoward medical occurrence.


ParticipantsNumber: 461 randomized

Inclusion criteria: Age 6 months to 10 yrs, weight > 5 kg, axillary temp > 37.5 ºC or history of fever in the previous 24 hours, P. falciparum mono-infection 2000 to 200,000/µl, informed consent

Exclusion criteria: Danger signs or evidence of severe malaria, concomitant febrile illness, history of serious side effects to the study meds


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + P 51.2 mg/kg in 3 divided doses, given once daily for 3 days
  • Plus placebo in the evenings to simulate twice daily dosing


2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


All doses supervized and given with a glass of milk


Outcomes
  1. ACPR at day 42, PCR adjusted and unadjusted
  2. Gametocytes development during follow up
  3. Mean increase in haemoglobin at last day of follow up
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Uganda

Setting: Health centre

Transmission: Moderate transmission

Resistance: Not stated

Dates: Aug 2006 to Apr 2007

Funding: CDC, DfID, DHA-P supplied by Holleypharm, AL6 supplied by Uganda Ministry of Health


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'A randomisation list was computer generated by an off-site investigator'

Allocation concealment?Yes'Sealed opaque envelopes containing the study number and assigned treatment were secured in a locked cabinet'

Blinding?
All outcomes
Yes'Only the study nurse was aware of assignments. All other study personnel were blinded. Patients were not informed of their treatment regimen'.

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in both groups (1.4% DHA-P vs 1.5% AL6)

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate treatment failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

Zongo 2005 BFA

MethodsTrial design: A randomized controlled trial

Follow up: A standardized history, examination, and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, or any other day they felt unwell. Haemoglobin measured on days 0 and 28 or day of clinical failure. Children with Hb < 10 g/dl were treated with ferrous sulphate and antihelminthic treatment.

Adverse event monitoring: Assessed at each visit


ParticipantsNumber: 580 randomized

Inclusion criteria: Age > 6 months, weight > 5 kg, axillary temp > 37.5 ºC or history of fever in the last 24 hours, P. falciparum mono-infection 2000-200,000/µl, the ability to participate in 28 days follow up, informed consent

Exclusion criteria: Danger signs or signs of severe malaria, history of serious adverse effects related to study meds, evidence of concomitant febrile illness, antimalarial use other than chloroquine in previous 2 weeks, haemoglobin < 5 g/dl


Interventions1. Artemether-Lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


2. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination (Amodiaquine: Aventis, Fansidar: Roche)

  • AQ 10 mg/kg on days 0 and 1 and 5 mg/kg on day 2
  • SP 25/1.25 mg/kg on day 0


Placebos were used to simulate equal numbers of pills. All doses supervized.


Outcomes
  1. Recurrent parasitaemia at day 28, PCR adjusted and unadjusted
  2. Gametocyte carriage assessed weekly
  3. Changes in haemoglobin during follow up
  4. Adverse events


Not included in the review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Burkina Faso

Setting: Urban health centres

Transmission: Holoendemic with transmission peaks during the rainy season

Resistance: Not stated

Dates: Aug 2005 to Dec 2005

Funding: Fogarty International Centre of the National Institutes of Health, International Atomic Energy Agency, National Budget of the Institut de Recherche en Sciences de la Sante


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Computer-generated randomisation lists'

Allocation concealment?NoNone described

Blinding?
All outcomes
Yes'Investigators responsible for classification of treatment outcomes were unaware of treatment assignment'. Placebos were used and participants not informed of allocation.

Incomplete outcome data addressed?
All outcomes
YesMildly disparate losses to follow up (6.1% AL6 vs 10.4% AQ+SP), unlikely to have affected overall result

Free of selective reporting?YesThe WHO recommends 42 days follow up in studies of AL6. Day 28 outcomes may under estimate treatment failure with AL6 and DHA-P.

Free of other bias?YesNo other sources of bias identified

Zongo 2007 BFA

MethodsTrial design: A 3-arm randomized controlled trial

Follow up: A standardized history, examination, and malaria film on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Haemoglobin measured on days 0 and 42 or day of clinical failure. Children with Hb < 10 g/dl were treated with ferrous sulphate and antihelminthic treatment.

Adverse event monitoring: Assessed at each visit. Adverse events defined as untoward medical occurrences.


ParticipantsNumber: 580 randomized

Inclusion criteria: Age > 6 months, weight > 5 kg, axillary temp > 37.5 ºC or history of fever in the last 24 hours, P. falciparum mono-infection 2000 to 200,000/µl, the ability to participate in 42 days follow up, informed consent

Exclusion criteria: Danger signs or signs of severe malaria, history of serious adverse effects related to study meds, evidence of concomitant febrile illness, antimalarial use other than chloroquine in previous 2 weeks, haemoglobin < 5 g/dl


Interventions1. Dihydroartemisinin-piperaquine, fixed dose combination, 40 mg/320 mg tablets (Duocotexin: HolleyPharm)

  • Total dose: DHA 6.4 mg/kg + PQP 51.2 mg/kg in 3 divided doses, given once daily for 3 days


2. Artemether-lumefantrine, fixed dose combination, 20 mg/120 mg tablets (Coartem: Novartis)

  • 5 to 14 kg 1 tablet twice daily for 3 days
  • 15 to 24 kg 2 tablets twice daily for 3 days
  • 25 to 34 kg 3 tablets twice daily for 3 days
  • > 35 kg 4 tablets twice daily for 3 days


3. Amodiaquine plus sulfadoxine-pyrimethamine, loose combination (Flavoquine: Aventis, Fansidar: Roche)

  • AQ 10 mg/kg once daily on days 0 and 1, then 5 mg/kg once on day 2
  • SP 25/1.25 mg/kg on day 0


All doses supervized


Outcomes
  1. Risk of treatment failure at days 42 and 28, PCR adjusted and unadjusted
  2. Gametocyte development during follow up
  3. Hemoglobin (mean g/dl) on day 0 and last day of follow up
  4. Adverse events


Not included in this review:

  1. Fever clearance
  2. Parasite clearance


NotesCountry: Burkino Faso

Setting: Health dispensaries

Transmission: Holoendemic, transmission principally in the rainy season May to Oct

Resistance: Not reported

Dates: Not reported

Funding: Doris Duke Charitable Foundation, Holley Cotec Pharmaceuticals, International Atomic Energy Agency, National Budget of the Institut de Recherche en Sciences de la Sante


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes'Randomly assigned on the basis of a computer-generated code provided by an off-site investigator'

Allocation concealment?Yes'Referred for treatment allocation by a study nurse not involved in enrolment or assessment of treatment outcomes'

Blinding?
All outcomes
No'The study was not blinded'

Incomplete outcome data addressed?
All outcomes
YesLow losses to follow up in all groups (8% DHA-P vs 6.4% AL6 vs 8.2% AQ+SP)

Free of selective reporting?YesAll WHO outcomes reported. Day 42 outcomes may underestimate treatment failure with DHA-P due to its long half-life.

Free of other bias?YesNo other sources of bias identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abacassamo 2002 MOZOnly 21 days follow up

Abuaku 2005Conference presentation of Koram 2003 GHA

Adjei 2005Conference presentation of Adjei 2006 GHA

Bell 2008Comparison not relevant to this review: artesunate plus sulfadoxine-pyrimethamine vs amodiaquine plus sulfadoxine-pyrimethamine

Blair 2006Duration of follow up in the group given amodiaquine plus sulfadoxine-pyrimethamine was only 21 days. The randomization procedure is also unclear.

Denis 2006Not randomized

Dorsey 2002Comparison not relevant to this review: artesunate plus sulfadoxine-pyrimethamine vs amodiaquine plus sulfadoxine-pyrimethamine

Dorsey-G 2003A paper based on the trial reported in Dorsey 2002. Contains no new efficacy data.

Fofana 2005Conference presentation of Djimde 2004 MLI

Ibrahium 2007Quasi-randomized

Jiao 1997Comparison not relevant to this review: benflumetol vs artesunate plus benflumetol

Kabanywanyi 2007Not randomized. Participants were randomized to monotherapy or artemether-lumefantrine at 1 site and monotherapy or artesunate plus amodiaquine at a second site. This does not allow a proper randomized comparison of AL6 vs AS+AQ.

Massougbodji 2005Comparison not relevant to this review: trial of 2 different regimens of artesunate plus mefloquine

Meremikwu 2004 NGAOnly 14 days follow up

Mockenhaupt 2005Comparison not relevant to this review: artesunate plus sulfadoxine-pyrimethamine vs amodiaquine plus sulfadoxine-pyrimethamine

Mohamed 2006Not randomized. Participants at 1 centre received artemether-lumafantrine, participants at a second centre received artesunate plus sulfadoxine-pyrimethamine.

Mulenga 2006Comparison not relevant to this review: artemether-lumefantrine vs sulfadoxine-pyrimethamine

Ndayiragije 2004Follow up only 14 days. Differences between groups at baseline. Not randomized.

Ndiaye 2005Conference presentation of Faye 2003 SEN

Obonyo 2007A meta-analysis of trials included in this review

Okell 2008A meta-analysis of 6 trials. All trials relevant to this review are included.

Piola 2005Comparison not relevant to this review: artemether-lumefantrine supervized vs unsupervized

Rwagacondo 2003Comparison not relevant to this review: artesunate plus sulfadoxine-pyrimethamine vs amodiaquine plus sulfadoxine-pyrimethamine

Sagara 2006Comparison not relevant to this review: artesunate plus sulphamethoxypyrazine-pyrimethamine vs artemether lumefantrine

Sowunmi 2007aReports the same trial as Sowunmi 2007b. No new efficacy data.

Sowunmi 2007bComparison not relevant to this review: artemether-lumefantrine vs amodiaquine-sulphalene-pyrimethamine

Tall 2005A conference presentation of Tall 2007

Tall 2007Quasi-randomized

Thapa 2007Quasi-randomized. Comparison not relevant to this review: artemether-lumefantrine vs sulfadoxine-pyrimethamine.

Tranh 2009Quasi-randomized

van den Broek 2005bQuasi-randomized

van Vugt 1998Comparison not relevant to this review: artemether-lumefantrine (4 doses) vs artesunate plus mefloquine

Vugt 1999Comparison not relevant to this review: artemether-lumefantrine (4 doses) vs 2 different 6-dose regimens of artemether-lumefantrine

Wilairatana 2002Comparison not relevant to this review: Artecom (dihydroartemisinin-piperaquine -trimethoprim) vs artesunate mefloquine

Wiseman 2006A cost-effectiveness analysis based on the findings of Mutabingwa 2005. Contains no new efficacy data.

 
Comparison 1. Dihydroartemisinin-piperaquine vs Artesunate plus mefloquine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 63 PCR unadjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Asia
31182Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.54, 0.98]

    1.2 South America
1445Risk Ratio (M-H, Fixed, 95% CI)6.19 [1.40, 27.35]

 2 Total Failure (P. falciparum) Day 63 PCR adjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Asia
31062Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.19, 0.79]

    2.2 South America
1435Risk Ratio (M-H, Fixed, 95% CI)9.55 [0.52, 176.35]

 3 Total Failure (P. falciparum) Day 42 PCR unadjusted5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Asia
51969Risk Ratio (M-H, Random, 95% CI)0.88 [0.46, 1.69]

 4 Total Failure (P. falciparum) Day 42 PCR adjusted5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Asia
51898Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.30, 1.39]

 5 Total Failure (P. falciparum) Day 28 PCR unadjusted6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Asia
62034Risk Ratio (M-H, Random, 95% CI)1.20 [0.22, 6.42]

 6 Total Failure (P. falciparum) Day 28 PCR adjusted6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Asia
62020Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.31, 1.56]

 7 P. vivax parasitaemia6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Mixed P. falciparum and vivax infection at baseline
52248Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.63, 1.12]

    7.2 Total P. vivax parasitaemia by day 28
1402Risk Ratio (M-H, Fixed, 95% CI)7.43 [0.39, 142.89]

    7.3 Total P. vivax parasitaemia by day 42
31251Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.57, 1.11]

    7.4 Total P. vivax parasitaemia by day 63
41661Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.91, 1.34]

    7.5 P. vivax parasitaemia by day 63 in those negative at baseline
31172Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.95, 1.56]

    7.6 P. vivax parasitaemia by day 63 in those positive at baseline
279Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.57, 1.65]

 8 Gametocyte development (in those negative at baseline)31234Risk Ratio (M-H, Fixed, 95% CI)3.06 [1.13, 8.33]

 9 Gametocytaemia carriage2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    9.1 Gametocyte carriage day 0
21174Risk Ratio (M-H, Random, 95% CI)1.07 [0.66, 1.73]

    9.2 Gametocyte carriage day 7
21152Risk Ratio (M-H, Random, 95% CI)2.00 [1.54, 2.58]

    9.3 Gametocyte carriage day 14
21142Risk Ratio (M-H, Random, 95% CI)5.14 [3.17, 8.33]

    9.4 Gametocyte carriage day 21
21123Risk Ratio (M-H, Random, 95% CI)7.23 [0.10, 519.79]

    9.5 Gametocyte carriage day 28
21124Risk Ratio (M-H, Random, 95% CI)9.68 [1.23, 75.98]

 10 Serious adverse events (including deaths)72374Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.38, 2.15]

 11 Early vomiting72473Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.69, 1.16]

 12 Sensitivity analysis: Total Failure Day 63 PCR unadjusted4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    12.1 Total Failure (P. falciparum) Day 63 PCR unadjusted
41627Risk Ratio (M-H, Random, 95% CI)0.94 [0.52, 1.70]

    12.2 Total Failure Day 63 PCR unadjusted (losses to follow up included as failures)
41801Risk Ratio (M-H, Random, 95% CI)0.95 [0.65, 1.38]

    12.3 Total Failure Day 63 PCR unadjusted (losses to follow up included as successes)
41801Risk Ratio (M-H, Random, 95% CI)0.94 [0.52, 1.68]

 13 Sensitivity analysis: Total Failure Day 63 PCR adjusted4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 Total Failure (P. falciparum) Day 63 PCR adjusted
41497Risk Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.83]

    13.2 Total Failure Day 63 PCR adjusted (indeterminate PCR included as failures)
41508Risk Ratio (M-H, Random, 95% CI)0.67 [0.32, 1.39]

    13.3 Total Failure Day 63 PCR adjusted (new infections included as successes)
41627Risk Ratio (M-H, Random, 95% CI)0.67 [0.34, 1.35]

    13.4 Total Failure Day 63 PCR adjusted (losses to follow up included as failures)
41801Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.30]

    13.5 Total Failure Day 63 PCR adjusted (losses to follow up included as successes)
41801Risk Ratio (M-H, Random, 95% CI)0.67 [0.34, 1.33]

 
Comparison 2. Dihydroartemisinin-piperaquine vs Artemether-lumefantrine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 42 PCR unadjusted5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Africa
31136Risk Ratio (M-H, Random, 95% CI)0.44 [0.20, 0.95]

    1.2 Asia
1356Risk Ratio (M-H, Random, 95% CI)0.60 [0.35, 1.05]

    1.3 Oceania
1216Risk Ratio (M-H, Random, 95% CI)1.07 [0.76, 1.50]

 2 Total Failure (P. falciparum) Day 42 PCR adjusted5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Africa
3869Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.24, 0.64]

    2.2 Asia
1317Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.16, 3.76]

    2.3 Oceania
1151Risk Ratio (M-H, Fixed, 95% CI)2.31 [0.85, 6.23]

 3 Total Failure (P. falciparum) Day 28 PCR unadjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Africa
2484Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.05, 0.32]

    3.2 Asia
1451Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.17, 1.12]

    3.3 Oceania
1224Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.75, 2.15]

 4 Total Failure (P. falciparum) Day 28 PCR adjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Africa
2453Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.17, 1.99]

    4.2 Asia
1436Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.13, 6.36]

    4.3 Oceania
1193Risk Ratio (M-H, Fixed, 95% CI)3.63 [1.04, 12.60]

 5 P. vivax parasitaemia4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Mixed P. falciparum and vivax infection at baseline
41608Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.73, 1.42]

    5.2 P. vivax parasitaemia by D28
1473Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.01, 0.36]

    5.3 P. vivax parasitaemia by D42
41442Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.24, 0.43]

 6 Gametocyte development (in those negative at baseline)41203Risk Ratio (M-H, Random, 95% CI)0.95 [0.35, 2.59]

 7 Anaemia4Mean Difference (IV, Fixed, 95% CI)Subtotals only

    7.1 Mean haemoglobin (g/dl) at baseline
41356Mean Difference (IV, Fixed, 95% CI)-0.07 [-0.27, 0.13]

    7.2 Mean haemoglobin (g/dl) at day 28
1134Mean Difference (IV, Fixed, 95% CI)0.36 [-0.03, 0.75]

    7.3 Mean haemoglobin (g/dl) at day 42
1375Mean Difference (IV, Fixed, 95% CI)0.30 [-0.02, 0.62]

    7.4 Mean change in haemoglobin (g/dl) from baseline to Day 42
2835Mean Difference (IV, Fixed, 95% CI)0.26 [0.00, 0.51]

 8 Serious adverse events (including deaths)52110Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.66, 4.46]

 9 Early vomiting21147Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.68, 2.78]

 
Comparison 3. Dihydroartemisinin-piperaquine vs Artesunate plus amodiaquine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted2679Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.35, 0.81]

    1.1 Africa
1501Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.34, 0.85]

    1.2 Asia
1178Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.17, 1.42]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted2629Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.23, 0.94]

    2.1 Africa
1458Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.27, 1.27]

    2.2 Asia
1171Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.02, 1.22]

 3 Total Failure (P. falciparum) Day 42 PCR unadjusted1152Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.10, 0.72]

    3.1 Asia
1152Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.10, 0.72]

 4 Total Failure (P. falciparum) Day 42 PCR adjusted1141Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 0.81]

    4.1 Asia
1141Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 0.81]

 5 P. vivax parasitaemia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Mixed P. falciparum and vivax infection at baseline
1220Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.67, 2.29]

    5.2 P. vivax parasitaemia by day 28
1181Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.04, 4.90]

    5.3 P. vivax parasitaemia by day 42
1170Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.09, 0.74]

 6 Serious adverse events (including deaths)1334Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.71]

 7 Early vomiting1334Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.22, 1.30]

 
Comparison 4. Dihydroartemisinin-piperaquine vs Artesunate plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 42 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Oceania
1215Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.74, 1.45]

 2 Total Failure (P. falciparum) Day 42 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Oceania
1161Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.39, 1.51]

 3 Total Failure (P. falciparum) Day 28 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Oceania
1223Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.62, 1.64]

 4 Total Failure (P. falciparum) Day 28 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Oceania
1195Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.46, 2.22]

 5 P. vivax parasitaemia by day 421Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Participants with P. falciparum mono-infection at baseline
1194Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.32, 0.65]

    5.2 Participants with P. vivax ± P. falciparum at baseline
175Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.27, 0.79]

 
Comparison 5. Dihydroartemisinin-piperaquine vs Amodiaquine plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Africa
2848Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.25, 0.55]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Africa
2802Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.17, 0.54]

 3 Total Failure (P. falciparum) Day 42 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Africa
1341Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.33, 1.24]

 4 Total Failure (P. falciparum) Day 42 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Africa
1319Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.16, 1.83]

 5 Gametocyte development1367Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.79]

 6 Anaemia2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    6.1 Mean haemoglobin (g/dl) at baseline
1371Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.68, 0.28]

    6.2 Mean haemoglobin (g/dl) at day 42 or last day of follow up
1371Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.51, 0.11]

    6.3 Mean packed cell volume at baseline
1510Mean Difference (IV, Fixed, 95% CI)Not estimable

    6.4 Mean packed cell volume at day 14
1510Mean Difference (IV, Fixed, 95% CI)-1.10 [-1.73, -0.47]

 7 Early vomiting1383Risk Ratio (M-H, Fixed, 95% CI)3.34 [0.70, 15.87]

 
Comparison 6. Artesunate plus mefloquine vs Artemether-lumefantrine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 42 PCR unadjusted4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Asia
41000Risk Ratio (M-H, Random, 95% CI)0.53 [0.29, 0.94]

 2 Total Failure (P. falciparum) Day 42 PCR adjusted4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Asia
4904Risk Ratio (M-H, Random, 95% CI)0.38 [0.05, 2.84]

 3 Total Failure (P. falciparum) Day 28 PCR unadjusted5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Africa
2752Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.48, 0.89]

    3.2 Asia
3854Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.41, 1.58]

 4 Total Failure (P. falciparum) Day 28 PCR adjusted51479Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.63, 2.50]

    4.1 Africa
2643Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.41, 2.85]

    4.2 Asia
3836Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.53, 3.86]

 5 P. vivax parasitaemia5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Mixed P. falciparum and vivax infection at baseline
51279Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.57, 3.00]

    5.2 P. vivax parasitaemia by day 28
1208Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.01, 3.88]

    5.3 P. vivax parasitaemia by day 42
41003Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.21, 0.41]

 6 Gametocyte development (in those negative at baseline)3883Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.54, 3.28]

 7 Gametocyte carriage3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Gametocyte carriage day 0
1294Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.10]

    7.2 Gametocyte carriage day 3
2536Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.21, 1.48]

    7.3 Gametocyte carriage day 7
3636Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.14, 0.85]

    7.4 Gametocyte carriage day 14
2536Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.08, 2.10]

 8 Serious adverse events (including deaths)71773Risk Ratio (M-H, Fixed, 95% CI)2.96 [0.64, 13.76]

 9 Early vomiting61479Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.55, 2.08]

 
Comparison 7. Artesunate plus mefloquine vs Artesunate plus amodiaquine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Africa
1493Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.12, 2.46]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Africa
1482Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Gametocyte carriage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Gametocyte carriage day 0
1505Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    3.2 Gametocyte carriage day 3
1505Risk Ratio (M-H, Fixed, 95% CI)17.31 [0.90, 332.99]

    3.3 Gametocyte carriage day 7
1505Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    3.4 Gametocyte carriage day 14
1505Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 8. Artesunate plus mefloquine vs Amodiaquine plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Africa
1300Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.15, 7.59]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Africa
1296Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Gametocyte carriage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Gametocyte carriage day 0
1306Risk Ratio (M-H, Fixed, 95% CI)0.10 [0.01, 1.81]

    3.2 Gametocyte carriage day 3
1306Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.06, 0.70]

    3.3 Gametocyte carriage day 7
1306Risk Ratio (M-H, Fixed, 95% CI)0.03 [0.00, 0.47]

    3.4 Gametocyte carriage day 14
1306Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 
Comparison 9. Artemether-lumefantrine vs Artesunate plus amodiaquine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted9Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 East Africa
3Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    1.2 West Africa
5Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    1.3 South/Central Africa
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 2 Total Failure (P. falciparum) Day 28 PCR adjusted81729Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.95, 2.87]

    2.1 East Africa
2365Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.15, 4.59]

    2.2 West Africa
51245Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.00, 3.26]

    2.3 South/Central Africa
1119Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 3 Gametocyte development1305Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.15, 0.74]

 4 Gametocyte carriage3Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    4.1 Gametocyte carriage day 0
3Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.2 Gametocyte carriage day 3
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.3 Gametocyte carriage day 7
3Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    4.4 Gametocyte carriage day 14
2Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 5 Anaemia5Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 Mean haemoglobin (g/dl) at baseline
4Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.2 Mean haemoglobin (g/dl) at Day 28
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.3 Mean change in haemoglobin (g/dl) from baseline to Day 28
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.4 Mean haematocrit at baseline
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.5 Mean haematocrit at Day 28
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 6 Proportion anaemic (Haemoglobin < 11 g/dl)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    6.1 At baseline
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    6.2 At day 28
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 7 Serious adverse events (including deaths)62749Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.59, 2.08]

 8 Early vomiting51097Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.59, 1.31]

 9 Sensitivity analysis: Total Failure Day 28 PCR unadjusted12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    9.1 Total Failure (P. falciparum) Day 28 PCR unadjusted
93021Risk Ratio (M-H, Random, 95% CI)0.88 [0.60, 1.27]

    9.2 Total Failure Day 28 PCR unadjusted (trials with baseline differences included)
123719Risk Ratio (M-H, Random, 95% CI)0.69 [0.49, 0.97]

    9.3 Total Failure Day 28 PCR unadjusted (losses to follow up included as failures)
93230Risk Ratio (M-H, Random, 95% CI)0.81 [0.62, 1.06]

    9.4 Total Failure Day 28 PCR unadjusted (losses to follow up included as successes)
93230Risk Ratio (M-H, Random, 95% CI)0.89 [0.61, 1.30]

 10 Sensitivity analysis: Total Failure Day 28 PCR adjusted11Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Total Failure (P. falciparum) Day 28 PCR adjusted
81729Risk Ratio (M-H, Fixed, 95% CI)1.65 [0.95, 2.87]

    10.2 Total Failure Day 28 PCR adjusted (trials with baseline differences included)
112311Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.69, 1.67]

    10.3 Total Failure Day 28 PCR adjusted (indeterminate PCR included as failures)
81747Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.06, 2.78]

    10.4 Total Failure Day 28 PCR adjusted (new infections included as successes)
82064Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.06, 2.75]

    10.5 Total Failure Day 28 PCR adjusted (losses to follow up included as failures)
82196Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.78, 1.31]

    10.6 Total Failure Day 28 PCR adjusted (losses to follow up included as successes)
82196Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.08, 2.83]

 
Comparison 10. Artemether-lumefantrine vs Artesunate plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 42 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Oceania
1217Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.68, 1.36]

 2 Total Failure (P. falciparum) Day 42 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Oceania
1158Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.13, 0.86]

 3 Total Failure (P. falciparum) Day 28 PCR unadjusted2382Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.48, 1.16]

    3.1 Africa
1157Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.28, 1.48]

    3.2 Oceania
1225Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.47, 1.34]

 4 Total Failure (P. falciparum) Day 28 PCR adjusted2345Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.25, 1.13]

    4.1 Africa
1151Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.34, 2.47]

    4.2 Oceania
1194Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.08, 0.97]

 5 P. vivax parasitaemia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 P. vivax parasitaemia by day 42 (P. vivax ± P. falciparum at baseline)
172Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.76, 1.43]

    5.2 P. vivax parasitaemia by day 42 (P. falciparum mono-infection at baseline)
1196Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.87, 1.35]

 6 Sensitivity analysis Total Failure Day 28 PCR unadjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Total Failure (P. falciparum) Day 28 PCR unadjusted
2382Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.48, 1.16]

    6.2 Total Failure Day 28 PCR unadjusted (trials with baseline differences included)
4802Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.39, 0.79]

    6.3 Total Failure Day 28 PCR unadjusted (losses to follow up included as failures)
2409Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.57, 1.17]

    6.4 Total Failure Day 28 PCR unadjusted (losses to follow up included as successes)
2409Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.47, 1.15]

 7 Sensitivity analysis: Total Failure Day 28 PCR adjusted4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Total Failure (P. falciparum) Day 28 PCR adjusted
2345Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.25, 1.13]

    7.2 Total Failure Day 28 PCR adjusted (trials with baseline differences included)
4718Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.17, 0.66]

    7.3 Total Failure Day 28 PCR adjusted (indeterminate PCR included as failures)
2349Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.29, 1.16]

    7.4 Total Failure Day 28 PCR adjusted (new infections included as successes)
2382Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.29, 1.17]

    7.5 Total Failure Day 28 PCR adjusted (losses to follow up included as failures)
2409Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.48, 1.23]

    7.6 Total Failure Day 28 PCR adjusted (losses to follow up included as successes)
2409Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.30, 1.17]

 
Comparison 11. Artemether-lumefantrine vs Amodiaquine plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 East Africa
31646Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.30, 0.41]

    1.2 West Africa
31130Risk Ratio (M-H, Fixed, 95% CI)2.88 [1.86, 4.47]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 East Africa
2618Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.06, 0.24]

    2.2 West Africa
31051Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.55, 3.47]

 3 Total Failure (P. falciparum) Day 42 PCR unadjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 West Africa
1345Risk Ratio (M-H, Fixed, 95% CI)2.64 [1.66, 4.21]

 4 Total Failure (P. falciparum) Day 42 PCR adjusted1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 West Africa
1284Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.44, 3.38]

 5 Gametocyte carriage4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Gametocyte carriage day 0
41545Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.51, 1.39]

    5.2 Gametocyte carriage day 3
31331Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.25, 0.75]

    5.3 Gametocyte carriage day 7
41538Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.18, 0.54]

    5.4 Gametocyte carriage day 14
41536Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.21, 1.01]

 6 Gametocyte development (in those negative at baseline)1371Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.08, 1.04]

 7 Anaemia2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 Mean haemoglobin (g/dl) at baseline
2Mean Difference (IV, Fixed, 95% CI)Not estimable

    7.2 Mean change in haemoglobin (g/dl) from baseline to Day 28
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    7.3 Mean haemoglobin (g/dl) at Day 42 or last day of follow up.
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 8 Serious adverse events (including deaths)52684Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.56, 2.08]

 9 Early vomiting2893Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.54, 3.68]

 
Comparison 12. Artesunate plus amodiaquine vs Artesunate plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted7Risk Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 Africa
7Risk Ratio (M-H, Random, 95% CI)Not estimable

 2 Total Failure (P. falciparum) Day 28 PCR adjusted7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Africa
71419Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.37, 1.08]

 3 Gametocyte carriage3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Gametocyte carriage day 0
3532Risk Ratio (M-H, Random, 95% CI)0.89 [0.60, 1.32]

    3.2 Gametocyte carriage day 3
2363Risk Ratio (M-H, Random, 95% CI)0.91 [0.67, 1.25]

    3.3 Gametocyte carriage day 7
2363Risk Ratio (M-H, Random, 95% CI)1.02 [0.64, 1.61]

    3.4 Gametocyte carriage day 14
3520Risk Ratio (M-H, Random, 95% CI)1.08 [0.32, 3.73]

 4 Proportion of participants with anaemia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 At baseline
2452Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.83, 1.00]

    4.2 At Day 28
2429Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.79, 1.14]

 5 Serious adverse events (including deaths)41108Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.14, 7.02]

 
Comparison 13. Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine-pyrimethamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure (P. falciparum) Day 28 PCR unadjusted8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 East Africa
53317Risk Ratio (M-H, Random, 95% CI)0.72 [0.51, 1.01]

    1.2 West Africa
2766Risk Ratio (M-H, Random, 95% CI)6.57 [0.68, 63.26]

    1.3 Other
1155Risk Ratio (M-H, Random, 95% CI)3.12 [1.05, 9.25]

 2 Total Failure (P. falciparum) Day 28 PCR adjusted6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 East Africa
31515Risk Ratio (M-H, Random, 95% CI)0.44 [0.22, 0.89]

    2.2 West Africa
2701Risk Ratio (M-H, Random, 95% CI)9.72 [1.19, 79.26]

    2.3 Other
1148Risk Ratio (M-H, Random, 95% CI)2.23 [0.58, 8.58]

 3 Gametocyte development21354Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.54, 0.82]

 4 Gametocyte carriage3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Gametocyte carriage day 0
3909Risk Ratio (M-H, Random, 95% CI)0.69 [0.13, 3.59]

    4.2 Gametocyte carriage day 3
1521Risk Ratio (M-H, Random, 95% CI)Not estimable

    4.3 Gametocyte carriage day 7
3897Risk Ratio (M-H, Random, 95% CI)0.25 [0.02, 2.69]

    4.4 Gametocyte carriage day 14
3894Risk Ratio (M-H, Random, 95% CI)0.57 [0.16, 2.02]

 5 Anaemia4Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 Mean haemoglobin (g/dl) at baseline
4Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.2 Mean change in haemoglobin (g/dl) from baseline to day 14
1Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.3 Mean change in haemoglobin (g/dl) from baseline to Day 28
2Mean Difference (IV, Fixed, 95% CI)Not estimable

    5.4 Mean haemoglobin (g/dl) at Day 28
1Mean Difference (IV, Fixed, 95% CI)Not estimable

 6 Serious adverse events (including deaths)74200Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.36, 1.03]

 
Comparison 14. Dihydroartemisinin-piperaquine dose analysis: 3 dose vs 4 dose regimen

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure PCR unadjusted1318Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.84, 3.53]

    1.1 Day 63
1318Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.84, 3.53]

 2 Total Failure PCR adjusted1292Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.05, 6.09]

    2.1 Day 63
1292Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.05, 6.09]

 
Comparison 15. Dihydroartemisinin-piperaquine dose analysis (versus Artesunate plus mefloquine)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure Day 63 PCR unadjusted41784Risk Ratio (M-H, Random, 95% CI)0.83 [0.49, 1.38]

    1.1 DHA-P 4 doses
31019Risk Ratio (M-H, Random, 95% CI)0.81 [0.59, 1.10]

    1.2 DHA-P 3 doses
2765Risk Ratio (M-H, Random, 95% CI)1.44 [0.09, 22.81]

 2 Total Failure Day 63 PCR adjusted41634Risk Ratio (M-H, Random, 95% CI)0.48 [0.18, 1.31]

    2.1 DHA-P 4 doses
3908Risk Ratio (M-H, Random, 95% CI)0.42 [0.17, 1.04]

    2.2 DHA-P 3 doses
2726Risk Ratio (M-H, Random, 95% CI)1.27 [0.03, 48.28]

 3 Total Failure Day 42 PCR unadjusted52126Risk Ratio (M-H, Random, 95% CI)0.77 [0.43, 1.35]

    3.1 DHA-P 4 doses
3957Risk Ratio (M-H, Random, 95% CI)0.80 [0.50, 1.28]

    3.2 DHA-P 3 doses
31169Risk Ratio (M-H, Random, 95% CI)0.88 [0.20, 3.81]

 4 Total Failure Day 42 PCR adjusted52043Risk Ratio (M-H, Random, 95% CI)0.62 [0.20, 1.91]

    4.1 DHA-P 4 doses
3903Risk Ratio (M-H, Random, 95% CI)0.62 [0.14, 2.82]

    4.2 DHA-P 3 doses
31140Risk Ratio (M-H, Random, 95% CI)0.70 [0.08, 5.87]

 5 Total Failure Day 28 PCR unadjusted62191Risk Ratio (M-H, Random, 95% CI)0.74 [0.20, 2.65]

    5.1 DHA-P 4 doses
41075Risk Ratio (M-H, Random, 95% CI)0.56 [0.10, 3.14]

    5.2 DHA-P 3 doses
31116Risk Ratio (M-H, Random, 95% CI)1.29 [0.09, 18.93]

 6 Total Failure Day 28 PCR adjusted62171Risk Ratio (M-H, Random, 95% CI)0.74 [0.19, 2.86]

    6.1 DHA-P 4 doses
41067Risk Ratio (M-H, Random, 95% CI)0.79 [0.10, 6.11]

    6.2 DHA-P 3 doses
31104Risk Ratio (M-H, Random, 95% CI)0.79 [0.08, 7.82]

 
Comparison 16. Artesunate Mefloquine dose analysis: FDC versus split dose regimen

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure Day 63 PCR unadjusted1423Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.68, 1.27]

 2 Total Failure Day 63 PCR adjusted1342Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.34, 1.28]

 
Comparison 17. Artesunate plus mefloquine dose analysis (versus Dihydroartemisinin-piperaquine)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total Failure Day 63 PCR adjusted3Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Total Failure Day 28 PCR adjusted2279Risk Ratio (M-H, Fixed, 95% CI)2.16 [0.23, 19.88]

 
Comparison 18. How does Dihydroartemisinin-piperaquine perform?

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Day 63: DHA-P vs Artesunate plus mefloquine
41497Risk Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.83]

    1.2 Day 42: DHA-P vs Artemether-lumefantrine
51337Risk Ratio (M-H, Random, 95% CI)0.62 [0.29, 1.30]

    1.3 Day 28: DHA-P vs Artesunate plus amodiaquine
2629Risk Ratio (M-H, Random, 95% CI)0.42 [0.13, 1.35]

    1.4 Day 42: DHA-P vs Artesunate plus sulfadoxine-pyrimethamine
1161Risk Ratio (M-H, Random, 95% CI)0.77 [0.39, 1.51]

    1.5 Day 28: DHA-P vs Amodiaquine plus sulfadoxine-pyrimethamine
2802Risk Ratio (M-H, Random, 95% CI)0.32 [0.16, 0.64]

 
Comparison 19. How does Artesunate plus mefloquine perform?

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Day 63: AS+MQ vs Dihydroartemisinin-piperaquine
41497Risk Ratio (M-H, Random, 95% CI)1.77 [0.55, 5.72]

    1.2 Day 42: AS+MQ vs Artemether-lumefantrine
4904Risk Ratio (M-H, Random, 95% CI)0.38 [0.05, 2.84]

    1.3 Day 28: AS+MQ vs Artesunate plus amodiaquine
1482Risk Ratio (M-H, Random, 95% CI)Not estimable

   1.4 Day 28: AS+MQ vs Artesunate plus sulfadoxine-pyrimethamine
00Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.5 Day 28: AS+MQ vs Amodiaquine plus sulfadoxine-pyrimethamine
1296Risk Ratio (M-H, Random, 95% CI)Not estimable

 
Comparison 20. How does Artemether-lumefantrine perform?

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Effectiveness: Total Failure (P. falciparum) Day PCR adjusted19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Day 42: AL vs Dihydroartemisinin-piperaquine
51337Risk Ratio (M-H, Random, 95% CI)1.61 [0.77, 3.39]

    1.2 Day 42: AL vs Artesunate plus mefloquine
4904Risk Ratio (M-H, Random, 95% CI)2.66 [0.35, 20.09]

    1.3 Day 28: AL vs Artesunate plus amodiaquine
81729Risk Ratio (M-H, Random, 95% CI)1.71 [0.97, 3.02]

    1.4 Day 42: AL vs Artesunate plus sulfadoxine-pyrimethamine
1158Risk Ratio (M-H, Random, 95% CI)0.33 [0.13, 0.86]

    1.5 Day 28: AL vs Amodiaquine plus sulfadoxine-pyrimethamine
51669Risk Ratio (M-H, Random, 95% CI)0.40 [0.08, 2.11]

 
Comparison 21. How does Artesunate plus amodiaquine perform?

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted19Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Day 28: AS+AQ vs Dihydroartemisinin-piperaquine
2629Risk Ratio (M-H, Random, 95% CI)2.36 [0.74, 7.54]

    1.2 Day 28: AS+AQ vs Artesunate plus mefloquine
1482Risk Ratio (M-H, Random, 95% CI)Not estimable

    1.3 Day 28: AS+AQ vs Artemether-lumefantrine
81729Risk Ratio (M-H, Random, 95% CI)0.59 [0.33, 1.03]

    1.4 Day 28: AS+AQ vs Artesunate plus sulfadoxine-pyrimethamine
71419Risk Ratio (M-H, Random, 95% CI)0.70 [0.34, 1.45]

    1.5 Day 28: AS+AQ vs Amodiaquine plus sulfadoxine-pyrimethamine
62364Risk Ratio (M-H, Random, 95% CI)0.74 [0.33, 1.63]