Chemoprophylaxis and intermittent treatment for preventing malaria in children

 

Characteristics of included studies [ordered by study ID]

Alonso 1993

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 year
Participants	Number enrolled: 1898 children Inclusion criteria: children aged 6 months to 5 years
Interventions	Prophylaxis: weekly dose for 5 months (during rainy season) 1. Pyrimethamine-dapsone (Maloprim): 12.5 mg pyrimethamine and 50 mg dapsone; 952 children 2. Placebo; 946 children All used insecticide-treated nets
Outcomes	1. Clinical malaria episodes 2. Death 3. Parasitaemia 4. Enlarged spleen
Notes	Location: The Gambia (17 rural villages) Malaria transmission: seasonal/holoendemic

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Chandramohan 2005

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Methods	Cluster-randomized controlled trial (see  Table 1) Average cluster size = 26; intra-cluster correlation coefficients (ICCs) and additional data provided by trial author Length of follow up: 24 months
Participants	Number enrolled: 96 clusters (unit of randomization = households) comprising a total of 2485 infants attending routine immunization clinics for second (DPT-2) and third doses of diphtheria-pertussis-tetanus (DPT) vaccine (DPT-3), measles vaccine (usually at age 9 months) and at age 12 months (2386 actually received treatment or placebo) Inclusion criteria: infants living in selected clusters attending routine immunization clinics Exclusion criteria: allergy to sulfadoxine-pyrimethamine
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine first dose given at 2 months, second dose at 3 months, third at 9 months, and fourth dose at 12 months 1. Sulfadoxine-pyrimethamine (500 mg sulfadoxine and 25 mg pyrimethamine): 1/2 tablet at time of DPT-2 and DPT3 vaccines; 1 tablet at time of measles vaccine and at 12 months; 1183 children 2. Placebo; 1203 children All participants concurrently received routine immunization with DPT and measles vaccines
Outcomes	1. Clinical malaria episodes 2. Anaemia 3. Hospital admissions 4. Death 5. Adverse events
Notes	Location: Kassena-Nankana District, Upper East Region, Ghana (96 out of 244 clusters) Malaria transmission: high/seasonal; entomological inoculation rate = 418 infective bites per person per year (almost all between June and November)

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Cissé 2006

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 12 months
Participants	Number enrolled: 1088 children aged 2 to 59 months Inclusion criteria: age 2 to 59 months; residence in study area Exclusion criteria: severe illness including severe anaemia
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine plus artesunate given once monthly 1. Sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine) plus artesunate (4 mg/kg give once monthly for 3 consecutive months); 542 children 2. Placebo; 546 children All participants concurrently received routine immunization with diphtheria-pertussis-tetanus (DPT) and measles vaccines
Outcomes	1. Clinical malaria episodes 2. Anaemia 3. Hospital admissions 4. Death 5. Adverse events 6. Sulfadoxine- pyrimethamine resistance markers
Notes	Location: Niakkhar, Senegal Malaria transmission: high/seasonal Registration number: NCT00132561

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David 1997

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 year
Participants	Number enrolled: 2000 children Inclusion criteria: children living in the area aged 3 months to 6 years
Interventions	Prophylaxis: twice weekly for 1 year 1. Pyrimethamine-dapsone (Maloprim): 1.6 mg pyrimethamine for age 3 to 11 months, 3.1 mg for 1 to 4 years, and 9.4 mg for > 5 years; 12.5 mg dapsone for age 3 to 11 months, 50 mg for 1 to 4 years, and 75 mg for > 5 years old; 436 children 2. Placebo; 450 children Following 2 arms not included in review: 3. Pyrimethamine-dapsone (Maloprim) and insecticide-treated nets; 467 children 4. Insecticide-treated nets; 470 children
Outcomes	1. Adverse events
Notes	Location: Bo, Sierra Leone Malaria transmission: perennial

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Desai 2003

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 to 2 years
Participants	Number enrolled: 546 children Inclusion criteria: children aged 2 to 36 months; consent; mild anaemia (haemoglobin concentration 7.0 to 10.9 g/dL); parasitaemia or parasite count < 20,000/mm^3 Exclusion criteria: intake of iron supplement; sulfadoxine-pyrimethamine treatment or blood transfusion within the last 2 weeks
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine given every 4 weeks for 3 doses; iron given daily for 12 weeks 1. Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine per tablet with 1/2 tablet for children < 10 kg or 1 tablet for children ≥ 10 kg; 271 children 2. Iron (ferrous sulphate): 3 to 6 mg/kg/day; 139 children 3. Iron and sulfadoxine-pyrimethamine; 135 children 4. Placebo; 275 children
Outcomes	1. Clinical episodes of malaria 2. Severe anaemia 3. Death 4. Parasitaemia 5. Adverse events
Notes	Location: Asemo, Bondo district, Western Kenya Malaria transmission: perennial/holoendemic

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Greenwood 1988

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Methods	Cluster-randomized controlled trial (households)^a; no estimates of average cluster size or intra-cluster correlation coefficient (ICC) given Length of follow up: 1 year
Participants	Number enrolled: 1488 children Inclusion criteria: age 3 to 59 months; resident in the area
Interventions	Prophylaxis: every 2 weeks for 1 year 1. Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 783 children 2. Placebo; 705 children
Outcomes	1. Clinical malaria episodes 2. Severe anaemia 3. Death 4. Parasitaemia 5. Enlarged spleen 6. Mean packed-cell volume (haematocrit) Outcomes assessed after stopping intervention: clinical episodes of malaria and death
Notes	Location: Farafeni, The Gambia Malaria transmission: seasonal Completion rates: 96% (1982) and 94% (1984) The Gambian trials were conducted in the same population at different time points: this is the main study and provided results from children in 38 villages (13 intervention and 25 placebo) between 9 and 21 months of the trial

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Greenwood 1989

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Methods	Cluster-randomized controlled trial (households)^a; no estimates of average cluster size or intra-cluster correlation coefficient (ICC) given Length of follow up: 3 years
Participants	Number analysed: 560 children Inclusion criteria: age 3 to 59 months; resident in the area
Interventions	Prophylaxis: every 2 weeks for 3 years 1. Pyrimethamine-dapsone (Maloprim) and folic acid: 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old 2. Pyrimethamine-dapsone (Maloprim) and placebo: 76 children (all Maloprim) 3. Chlorproguanil and folic acid: 20 mg 4. Chlorproguanil and placebo; 192 children (all chlorproguanil) 5. Placebo and folic acid 6. Placebo and placebo; 192 children (all placebo)
Outcomes	1. Clinical malaria episodes 2. Death Same outcomes assessed after stopping intervention
Notes	Location: Sarakund, The Gambia Malaria transmission: seasonal The Gambian trials were conducted in the same population at different time points: this is a subsidiary investigation to Greenwood 1988 (main study) comparing an additional antimalarial

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Greenwood 1995

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Methods	Cluster-randomized controlled trial (households)^a; average cluster size and intra-cluster correlation coefficient (ICC) not given Length of follow up: 1 year
Participants	Number analysed: 408 children Inclusion criteria: age 3 to 59 months; resident in the area
Interventions	Prophylaxis: every 2 weeks for 1 year 1. Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 208 children 2. Placebo; 200 children
Outcomes	1. Clinical malaria episodes 2. Death 3. Parasitaemia 4. Enlarged spleen 5. Mean packed-cell volume (haematocrit)
Notes	Location: Farafeni, The Gambia Malaria transmission: seasonal Completion rates 96% (1982) and 94% (1984) The Gambian trials were conducted in the same population at different time points: this trial was conducted one year after the end of prophylaxis described in Greenwood 1988 (main study)

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Hogh 1993

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 year
Participants	Number enrolled: 262 children Inclusion criteria: children aged 6 months to 6 years; resident in the area; consent
Interventions	Prophylaxis: every 3 weeks for 1 year 1. Chloroquine: 5 mg/kg; 158 children 2. Placebo; 104 children
Outcomes	1. Clinical malaria episodes 2. Parasitaemia 3. Splenomegaly (enlarged spleen) 4. Packed-cell volume (haematocrit) Not included in review: 5. Inoculation rate 6. Haemoglobinopathies
Notes	Location: Mount Nimba region, north-western Liberia Malaria transmission: perennial

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Kobbe 2007

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 21 months
Participants	Number enrolled: 1070 children Inclusion criteria: age 3 months (4-weeks tolerance accepted); permanent residence in study area Exclusion criteria: severe illness
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine given at age 3 months, 9 months, and 15 months 1. Sulfadoxine-pyrimethamine: 1 tablet (250 mg sulfadoxine and 12.5 mg pyrimethamine) per dose; 1 dose given at age 3 months, 9 months, and 15 months; 535 children 2. Placebo; 535 children All participants concurrently received routine immunization with diphtheria-pertussis-tetanus (DPT) and measles vaccines
Outcomes	1. Clinical malaria episodes 2. Anaemia/severe anaemia 3. Hospital admissions 4. Death 5. Adverse events 6. Sulfadoxine-pyrimethamine resistance markers
Notes	Location: Afigya Sekyere district, Ghana Malaria transmission: holoendemic, intense perennial (with seasonal peaks)

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Lemnge 1997

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 year
Participants	Number enrolled: 249 children; we included only the 117 children in the subgroup of those aged 1 to 4 years Inclusion criteria: age 1 to 9 years at admission and permanent residence in village Exclusion criteria: gross malnutrition; severe illness; severe anaemia (packed-cell volume < 20%); severe glucose-6-phosphate dehydrogenase deficiency
Interventions	Prophylaxis: once weekly for 1 year 1. Pyrimethamine-dapsone (Maloprim): 3.125 mg pyrimethamine and 25 mg dapsone with 1 tablet for age 1 to 4 years or 2 tablets for age 5 to 9 years; 58 children 2. Placebo; 59 children
Outcomes	1. Clinical malaria episodes 2. Death 3. Parasitaemia 4. Splenomegaly (enlarged spleen) 5. Packed-cell volume (haematocrit) 6. Adverse effects Not included in review: 7. Compliance
Notes	Location: Magoda village, north-eastern Tanzania Malaria endemicity: holoendemic

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Macete 2006

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 9 months
Participants	Number enrolled: 1503 children Inclusion criteria: infants (age 3 at first dose); permanent residence in study area Exclusion criteria: allergy to sulfa drugs; illness that required admission to hospital
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine given at age 3 months, 9 months, and 15 months 1. Sulfadoxine-pyrimethamine (administered according to weight): < 5 kg, 1/4 tablet; 5 to 10 kg, 1/2 tablet; > 10 kg, 1 tablet; 748 children 2. Placebo; 755 children All participants received routine immunization with diphtheria-pertussis-tetanus (DPT) and measles vaccines
Outcomes	1. Clinical malaria episodes 2. Severe anaemia 3. Hospital admissions 4. Death 5. Parasitaemia 6. Adverse events
Notes	Location: Manhica District (Maputo Province) Mozambique Malaria endemicity: perennial

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Massaga 2003

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 10 months Intention-to-treat analysis
Participants	Number enrolled: 291 infants Inclusion criteria: infants aged 12 to 16 weeks attending Maternal and Child Health (MCH) clinics for growth monitoring or to receive their third diphtheria-pertussis-tetanus (DPT) and oral poliovirus vaccine Exclusion criteria: congenital malformation; severe conditions that needed treatment in hospital; fever within past 2 days; packed-cell volume < 24; taking chemoprophylaxis
Interventions	Intermittent treatment: amodiaquine every 2 months and daily iron for 6 months 1. Amodiaquine and iron: 25 mg/kg over 3 days, with 10 mg/kg on first 2 days and 5 mg/kg on third day; 72 children 2. Amodiaquine and placebo; 74 children 3. Iron and placebo: 7.5 mg elemental iron; 73 children 4. Placebo and placebo; 72 children
Outcomes	1. Clinical malaria episodes 2. Hospital admissions 3. Death 4. Adverse events Not included in review: 5. Anaemia
Notes	Location: Muheza district, north-eastern Tanzania Malaria transmission/endemicity: perennial/holoendemic

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Menendez 1997

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 1 year
Participants	Number enrolled: 832 infants Inclusion criteria: infant aged 8 to 52 weeks; born at district hospital; permanent resident in Ifakara Exclusion criteria: birth weight > 1.5 kg; congenital malformation; cerebral asphyxia; congenital/neonatal infection; packed-cell volume < 25
Interventions	Prophylaxis: weekly pyrimethamine-dapsone (Deltaprim) and daily iron for 40 weeks 1. Pyrimethamine-dapsone (Deltaprim) and placebo: 2.5 mL of syrup containing 3.125 mg pyrimethamine and 25 mg dapsone/5 mL syrup; 208 children 2. Pyrimethamine-dapsone (Deltaprim) and iron; 213 children 3. Iron and placebo: 2 mg/kg iron syrup; 204 children 4. Placebo and placebo; 207 children
Outcomes	1. Hospital admissions 2. Death 3. Severe anaemia 4. Adverse events
Notes	Location: Ifakara, south-eastern Tanzania. Malaria transmission: perennial/holoendemic

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Menon 1990

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Methods	Cluster-randomized controlled trial (households)^a; no estimate of the average cluster size or intra-cluster correlation coefficients (ICCs) Length of follow up: 1 year
Participants	Number enrolled: 1792 children Inclusion criteria: age 3 to 59 months; resident in study area
Interventions	Prophylaxis: every 2 weeks for up to 1 year 1. Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 888 children 2. Placebo; 904 children
Outcomes	1. Clinical episodes of malaria 2. Death 3. Parasitaemia 4. Enlarged spleen 5. Mean packed-cell volume (haematocrit)
Notes	Location: Farafeni, The Gambia Malaria transmission: seasonal The Gambian trials were conducted in the same population at different time points: this trial was conducted 3 to 4 years after the start of the prophylaxis in the main study (Greenwood 1988) and reported on 41 villages (15 intervention and 26 placebo; 3 villages that initially declined to participate later joined the trial)

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Otoo 1988a

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Methods	Cluster-randomized controlled trial (households)^a; average cluster size and intra-cluster correlation coefficient (ICC) not given Length of follow up: 1 year
Participants	Number analysed: 95 children Inclusion criteria: aged 5 years; stopped chemoprophylaxis with Maloprim during the preceding 6 months and had achieved at least 50% compliance during the preceding 2 years Exclusion criteria: none stated
Interventions	Prophylaxis: every 2 weeks for 2 years 1. Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 48 children 2. Placebo; 47 children
Outcomes	1. Clinical episodes of malaria 2. Death 3. Parasitaemia 4. Enlarged spleen Not included in review: 5. Malaria antibody levels Also assessed 6 months after stopping intervention
Notes	Location: Farafenni, The Gambia Malaria transmission: seasonal Same population as Greenwood 1988 and Otoo 1989 (see Otoo 1988a) but 2.5 years after stopping chemoprophylaxis

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Schellenberg 2001

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 18 months
Participants	Number enrolled: 701 children aged 2, 3, and 9 months attending routine immunization clinics for second dose of diphtheria-pertussis-tetanus (DPT) vaccine Inclusion criteria: children have just received second dose of DPT and oral poliovirus vaccine Exclusion criteria: illness requiring hospital admission
Interventions	Intermittent treatment: first dose at 2 months, second dose at 3 months, and third at 9 months 1. Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, with 1/4 tablet for children < 5 kg, 1/2 tablet for children 5 to 10 kg, or 1 tablet for children > 10 kg; 350 children 2. Placebo; 351 children
Outcomes	1. Clinical episodes of malaria 2. Severe anaemia 3. Hospital admissions 4. Death 5. Adverse events
Notes	Location: Ifakara, Tanzania Malaria transmission: perennial/holoendemic

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Schellenberg 2005

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 18 months
Participants	Number analysed: 555 children aged up to 2 years at time of assessment; and 2, 3, and 9 months at time of treatment during routine immunization for diphtheria-pertussis-tetanus (DPT) and measles Inclusion and exclusion criteria: as applied to the initial enrolment (Schellenberg 2001)
Interventions	Intermittent treatment with full dose of sulfadoxine-pyrimethamine: first dose at 2 months, second dose at 3 months, and third at 9 months 1. Sulfadoxine-pyrimethamine: 1/4 tablet (< 5 kg); 1/2 tablet (5 to 10 kg); 1 tablet (> 10 kg); 277 children 2. Placebo; 278 children
Outcomes	1. Clinical episodes of malaria 2. Severe anaemia Assessed 18 months following treatment
Notes	Location: Ifakara, Tanzania Malaria transmission: perennial/ holoendemic This trial used the same population as Schellenberg 2001

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Tomashek 2001

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 12 weeks
Participants	Number enrolled: 238 children Inclusion criteria: age 6 to 59 months; haemoglobin 5.0 to 8.0 g/dL; parental consent Exclusion criteria: signs or symptoms of heart failure; severe malaria infection; splenomegaly; or sickle cell disease or trait
Interventions	Intermittent treatment: iron and folic acid given 3 times weekly for 12 weeks; sulfadoxine-pyrimethamine given at weeks 4, 8, and 12 follow-up visits; vitamins A and C both given 3 times weekly 1. Sulfadoxine-pyrimethamine, iron, folic acid, and vitamins A and C; 75 children 2. Sulfadoxine-pyrimethamine, iron, and folic acid; 81 children 3. Placebo, iron, and folic acid; 82 children Iron: ferrous sulphate (60 mg elemental iron for children 18 months or 30 mg for children < 18 months) and folic acid (250 g for children 18 months or 125 g for children < 18 months) Sulfadoxine-pyrimethamine: 500 mg sulfadoxine and 25 mg pyrimethamine per tablet with 1 tablet for children > 48 months, 1/2 tablet for children 12 to 47 months, or 1/4 tablet for children 6 to 12 months Vitamin A: 400 g all age groups Vitamin C: 75 mg for children 18 months, 30 mg for children < 18 months
Outcomes	1. Malaria blood smear (parasitaemia) 2. Mean haemoglobin (haematocrit) 3. Death Not included in review: 4. Anaemia prevalence 5. Iron-deficiency anaemia
Notes	Location: Nduta refugee camp, Kigoma Region, western Tanzania Malaria transmission: intense (perennial)

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Verhoef 2002

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 12 weeks
Participants	Number enrolled: 328 children Inclusion criteria: age 2 to 36 months; haemoglobin 60 to 110 g/L; axillary temperature < 37.5 °C; resident in area; parental consent Exclusion criteria: symptom suggestive of malaria or anaemia; systemic illness occurring in combination with a blood dipstick test result indicating current or recent malarial infection
Interventions	Intermittent treatment: sulfadoxine-pyrimethamine given every 4 weeks for 3 doses; iron given twice weekly for 12 weeks; supervised by clinical officer 1. Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine; 82 children 2. Iron (ferrous fumarate 6.25 g/L): 6 mg elemental iron/kg; 82 children 3. Sulfadoxine-pyrimethamine and iron; 82 children 4. Placebo; 82 children
Outcomes	1. Clinical episodes of malaria Not included in review: 2. Haemoglobin 3. Iron-deficiency anaemia
Notes	Location: Mtito Andei, eastern Kenya Malaria transmission: seasonal

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Wolde 1994

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Methods	Randomized controlled trial (see  Table 1) Length of follow up: 10 weeks
Participants	Number enrolled: 1005 children (age group 1 to 5 years only) Inclusion criteria: aged 1 to 14 years, stratified as 1 to 5 and 6 to 14 years
Interventions	Prophylaxis: weekly for 10 weeks 1. Chloroquine: 5 mg/kg base; 504 children 2. Placebo (multivitamin tablets); 501 children
Outcomes	1. Clinical episodes of malaria
Notes	Location: Awash Rift Valley, Ethiopia Malaria transmission: seasonal

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Akenzua 1985	Includes participants aged more than 6 years
Allen 1990	Cross-sectional survey to determine sensitivity of Plasmodium falciparum after chemoprophylaxis
Archibald 1956	Non-randomized intervention trial
Bjorkman 1985a	Non-randomized prospective study to investigate susceptibility of Plasmodium falciparum following a period of chemosuppression
Bjorkman 1985b	Surveys
Bjorkman 1986	Non-randomized study
Bradley-Moore 1985	Quasi-randomized controlled trial
Charles 1961	Randomized controlled trial with participants aged 5 to 14 years
Colbourne 1955	Non-randomized intervention study
Coosemans 1987	Randomized controlled trial with participants aged 6 to 14 years and no group given placebo only
Coulibaly 2002	Randomized controlled trial; adults and older children included as participants
Delmont 1981	Mass drug administration with participants > 5 years
Escudie 1961	Not a randomized controlled trial
Fasan 1970	Randomized controlled trial with participants aged 6 to 12 years
Fasan 1971	Randomized controlled trial with participants aged 5 to 12 years
Fernando 2006	Randomized controlled trial of school children aged 6 to 12 years
Harland 1975	Longitudinal observational study
Hogh 1994	Randomized controlled trial with participants aged 7 to 12 years
Karunakaran 1980	Small sample size: randomized controlled trial, but only 8 out of 230 participants were below 5 years old
Karwacki 1990	Two randomized controlled trials with participants aged 6 to 15 years
Kollaritsch 1988	Randomized controlled trial with participants > 5 years
Laing ABG 1970	Non-randomized controlled trial
Lell 1998	Randomized controlled trial with participants aged 4 to 16 years
Lell 2000	Randomized controlled trial with participants aged 12 to 20 years
Lewis 1975	Not randomized controlled trial
Limsomwong 1988	Randomized controlled trial with participants aged 5 to 16 years
Lucas 1969	Randomized controlled trial with participants aged 8 to 17 years
Lwin 1997	Possible randomized controlled trial with participants of all ages
MacCormack 1983	Malaria suppression project with chloroquine (not a randomized controlled trial)
McGregor 1966	Randomized controlled trial with both children and adult participants
Miller 1954	Not randomized controlled trial
Murphy 1993	Chemoprophylaxis for Plasmodium vivax malaria (not a randomized controlled trial)
Nevill 1988	Randomized controlled trial with participants aged 6 to 18 years
Nevill 1994	Randomized controlled trial with participants aged 8 to 9 years
Nwokolo 2001	Randomized controlled trial with both children and adult participants
Onori 1982	Seroepidemiological survey to determine whether chloroquinized salt affected immunity to malaria.
Oyediran 1993	Quasi-randomized (alternate allocation) of preschool children
Pang 1989	Randomized controlled trial with participants aged 6 to 15 years
Panton 1985	Drug sensitivity survey
Pividal 1992	Randomized controlled trial with participants aged 7 to 12 years
Pribadi 1986	Chemoprophylaxis given to all villagers (including adults)
Pringle 1966	Observational study following chemoprophylaxis to document early course of untreated falciparum malaria in semi-immune children
Ringwald 1989	Randomized controlled trial with adult participants
Robert 1989	Prospective non-randomized study
Rooth 1991	Randomized controlled trial with participants aged 6 to 14 years
Rosen 2005	Not randomized controlled trial
Saarinen 1988	Not randomized controlled trial
Schapira 1988	Randomized controlled trial with participants aged 7 to 14 years
Schellenberg 2004	Open-label randomized controlled trial of participants aged 2 months to 4 years in which sulfadoxine-pyrimethamine was given to both the control group (1 dose) and intervention group (3 doses at monthly intervals)
Schneider 1962	Randomized trial in which the control group received a different antimalarial and not placebo
Stace 1981	Not randomized controlled trial
Sukwa 1999	Randomized controlled trial with adult participants
Thera 2005	Randomized controlled trial with participants aged 5 to 15 years
von Seidlein 2003	Adults and children > 6 years included as participants
Vrbova 1992	Randomized controlled trial with participants aged 7 to 14 years
Watkins 1987	Randomized controlled trial with participants aged 6 to 10 years
Weiss 1995	Randomized controlled trial with participants aged 9 to 14 years
Win 1985	Randomized controlled trial with adult participants aged 18 to 40 years

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Characteristics of ongoing studies [ordered by study ID]

Kremsner ongoing

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Trial name or title	"Intermittent sulfadoxine/pyrimethamine administration to infants to reduce malaria morbidity in Gabon: assessment of efficacy, safety, and potential for malaria rebound"
Methods	Randomized, double blind, placebo-controlled trial
Participants	531 children in each group
Interventions	Sulfadoxine-pyrimethamine or placebo given during Expanded Programme of Immunization (EPI) at 3, 9, and 15 months of age
Outcomes	1. Episodes of anaemia 2. Efficacy 3. Safety 4. Rebound effects
Starting date	December 2002
Contact information	Prof Peter Kremsner ([e-mail]), Institute of Tropical Medecine, Eberhard Karls University, Tuebingen, Germany Prof Martin Grobusch ([e-mail]), Infectious Diseases Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Notes	Location: Gabon Source of funding: Intermittent Preventive Treatment in Infants Consortium; Project 1

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Lemnge ongoing

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Trial name or title	"Drug options for intermittent presumptive treatment for malaria in infants in an area with high resistance to sulfadoxine/pyrimethamine: an evaluation of short and long-acting antimalarial drugs"
Methods	Randomized, double-blind, placebo-controlled trial
Participants	1280 infants in western Usambara and 2440 infants in south Pare
Interventions	Following drugs, or placebo, given during Expanded Programme of Immunization (EPI) at 2, 3, and 9 months of age: 1. Mefloquine for 1 day 2. LapDap (chlorproguanil-dapsone) for 3 days 3. Sulfadoxine-pyrimethamine for 1 day
Outcomes	Primary outcome measure: incidence of malaria in infancy Secondary outcome measures include: 1. Mean haemoglobin level at 10 to 12 months of age 2. Incidence of severe anaemia during infancy 3. Prevalence of malaria parasitaemia at 10 to 12 months of age 4. Incidence of malaria in the second year of life
Starting date	September 2004
Contact information	Dr Martha Lemnge ([e-mail]), National Institute for Medical Research (NIMR), Amani Medical Research Centre, Tanzania Prof Brian Greenwood ([e-mail]), London School of Hygiene and Tropical Medicine, London, UK Prof Thor G Theander ([e-mail]), Centre for Medical Parasitology, Institute for Medical Microbiology and Immunology, University of Copenhagen Panum Institute, Denmark
Notes	Location: Tanzania Source of funding: Intermittent Preventive Treatment in Infants Consortium; Project 4

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Menendez ongoing

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Trial name or title	"Intermittent preventive treatment in infants delivered through the EPI scheme in Mozambique: community response and cost effectiveness, and impact on morbidity and development of malaria immunity"
Methods	Randomized, double blind, placebo-controlled trial
Participants	750 children in each group
Interventions	Sulfadoxine-pyrimethamine or placebo is given during Expanded Programme of Immunization (EPI) at 3, 4, and 9 months of age
Outcomes	1. Clinical malaria 2. Anaemia 3. Frequency and type of potential side effects 4. Development of resistance and the spread of molecular markers associated with SP resistance 5. Immune response to routine EPI immunizations 6. Development of specific and non-specific immune responses to P. falciparum infection 7. Cost effectiveness of intervention under close to programme conditions 8. Community perception and response to the introduction of intervention within the EPI scheme
Starting date	September 2002
Contact information	Dr Clara Menendez ([e-mail]), Centre de Salut, Internacional Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
Notes	Location: Mozambique Source of funding: Intermittent Preventive Treatment in Infants Consortium; Project 2

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NCT00111163

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Trial name or title	"Efficacy and safety of pediatric immunization-linked preventive intermittent treatment with antimalarials in decreasing anemia and malaria morbidity in rural western Kenya"
Methods	Prevention, randomized, double blind, placebo control, single group assignment, safety/efficacy study
Participants	Age 5 to 16 weeks Expected total enrolment: 1516 Inclusion criteria: presenting for Pentavalent 1 immunization; age 5 weeks to 16 weeks; parent or guardian currently resident in study catchment area; parent or guardian has given permission for their child to participate Exclusion criteria: known allergy to any of the study drugs; current cotrimoxazole prophylaxis; concomitant disease requiring hospitalization or transfusion; plans to be away from the study area for > 6 months during the next year
Interventions	Given at routine Expanded Programme of Immunization (EPI) visits: 1. Iron supplementation and intermittent preventive treatment with sulfadoxine-pyrimethamine plus 3 doses of artesunate 2. Iron supplementation and intermittent preventive treatment with chlorproguanil-dapsone (Lapdap) 3. Iron supplementation and intermittent preventive treatment with amodiaquine plus 3 doses of artesunate 4. Iron supplementation alone plus placebo
Outcomes	Primary outcome: clinical malaria in the first year of life Secondary outcomes: 1. Moderate and severe anemia in the first year of life 2. Serologic responses to EPI vaccines (polio, diphtheria, tetanus, pertussis, hepatitis B, Haemophilus Influenzae type B, and measles) 3. Nasal carriage rates of Haemophilus influenza type b 4. All-cause hospitalization in the first year of life
Starting date	March 2004
Contact information	Robert D Newman MD, MPH ([e-mail]), Principal Investigator, U.S. Centers for Disease Control and Prevention, USA Laurence Slutsker MD, MPH, Principal Investigator, U.S. Centers for Disease Control and Prevention, USA
Notes	Location: Kenya Registration number: NCT00111163 Source of funding: Centers for Disease Control and Prevention; Kenya Medical Research Institute; Bill and Melinda Gates Foundation

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NCT00119132

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Trial name or title	"A study of impact of intermittent preventive treatment In children with amodiaquine plus artesunate versus sulphadoxine-pyrimethamine on hemoglobin levels and malaria morbidity in Hohoe District of Ghana"
Methods	Randomized, double blind, placebo control, parallel assignment, safety/efficacy study
Participants	2240 children aged 3 to 59 months will be randomly allocated to 4 groups (560 per arm) Inclusion criteria: children between the ages of 3 and 59 months resident in the selected communities; children likely to be available for follow up for 18 months; consent by parent/guardian of child Exclusion criteria: chronic illness; history of hypersensitivity to any of the study drugs
Interventions	1. Artesunate-amodiaquine given at 2 different intervals (monthly or bimonthly) 2. Sulfadoxine-pyrimethamine 3. Placebo
Outcomes	Primary outcome: Mean haemoglobin at end of high transmission season Secondary outcomes: 1. Incidence of moderate (haemoglobin < 8.0 g/dL > 5.0 g/dL) and severe anaemia (haemoglobin < 5.0 g/dL) during the period of the intervention 2. Incidence of severe and clinical malaria during the period of the intervention 3. Prevalence of anaemia at the post intervention survey 4. Prevalence of parasitaemia and gametocytemia at the post intervention survey 5. Prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine among children who have malaria at the post-intervention survey
Starting date	Study start: June 2005 Expected completion: June 2007
Contact information	Margaret Kweku MBChB, MPH ([e-mail]), Principal Investigator, London School of Hygiene and Tropical Medicine, London, UK Daniel Chandramohan MBBS, PhD Principal Investigator London School of Hygiene and Tropical Medicine Brian Greenwood FRCP, FRS Principal Investigator London School of Hygiene and Tropical Medicine
Notes	Location: Ghana Registration number: NCT00119132 Source of funding: Gates Malaria Partnership; Ghana:INDEPTH Network

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Schellenberg ongoing

---

Trial name or title	"Community effectiveness of intermittent preventive treatment delivered through the Expanded Programme of Immunisation for malaria and anaemia control in Tanzanian infants"
Methods	Implementation study
Participants	12,000 infants per year
Interventions	Sulfadoxine-pyrimethamine will be given during Expanded Programme of Immunization (EPI) at 2, 3, and 9 months of age Evaluation will be based on comparisons between areas with and without intervention
Outcomes	1. All-cause mortality 2. Anaemia 3. Parasitaemia 4. Probable malaria episodes 5. Cost effectiveness 6. Effect of the intervention on community perceptions of, and compliance with, the EPI programme 7. Impact of intervention on rate of development of drug resistance 8. Consolidate the safety profile of sulfadoxine-pyrimethamine in infants
Starting date	January 2005
Contact information	Dr David Schellenberg ([e-mail]), Ifakara Health Research & Development Centre, Dar es Salaam, Tanzania Prof Marcel Tanner ([e-mail]), Swiss Tropical Institute, Basel, Switzerland
Notes	Location: Tanzania Source of funding: Intermittent Preventive Treatment in Infants Consortium; Project 5

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Slutsker ongoing

---

Trial name or title	"Efficacy and safety of paediatric, immunization-linked, intermittent preventive treatment with antimalarials in decreasing anaemia and malaria morbidity in rural western Kenya"
Methods	Randomized, double-blind, placebo-controlled trial
Participants	379 children recruited in each group Enrolled children followed through active and passive surveillance until 18 months of age
Interventions	Following drugs, or placebo, given during Expanded Programme of Immunization (EPI) at 2, 3, and 9 months of age: 1. Sulfadoxine-pyrimethamine for 1 day and artesunate for 3 days 2. LapDap (chlorproguanil/dapsone) for 3 day 3. Amodiaquine for 3 days and artesunate for 3 days 4. Iron supplementation alone Infants will receive iron supplementation from 2 to 6 months of age and 1 of 4 treatments at EPI visits
Outcomes	1. Clinical malaria 2. Moderate and severe anaemia 3. Serological responses to EPI vaccines
Starting date	March 2004
Contact information	Dr Larry Slutsker ([e-mail]), CDC/KEMRI Research Station, Kisumu, Kenya Dr Robert Newman ([e-mail]), Malaria Branch, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, USA
Notes	Location: Kenya Source of funding: Intermittent Preventive Treatment in Infants Consortium; Project 3

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Comparison 1. Antimalarial vs placebo: individually randomized trials [main analysis]

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Clinical malaria

10

7037

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

0.53 [0.38, 0.74]

---

1.1 Prophylaxis

3

2144

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

0.64 [0.35, 1.17]

---

1.2 Intermittent treatment

7

4893

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

0.50 [0.31, 0.80]

---

 2 Severe anaemia

9

5445

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

0.70 [0.52, 0.94]

---

2.1 Prophylaxis

1

415

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

0.48 [0.34, 0.67]

---

2.2 Intermittent treatment

8

5030

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

0.76 [0.57, 1.02]

---

 3 Death from any cause

10

7369

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

0.90 [0.65, 1.23]

---

3.1 Prophylaxis

2

2313

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

0.99 [0.53, 1.86]

---

3.2 Intermittent treatment

8

5056

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

0.87 [0.60, 1.25]

---

 4 Hospital admission for any cause

5

3722

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

0.64 [0.49, 0.82]

---

4.1 Prophylaxis

1

303

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

0.49 [0.40, 0.60]

---

4.2 Intermittent treatment

4

3419

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

0.72 [0.60, 0.88]

---

 5 Parasitaemia

5

2080

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

0.44 [0.23, 0.86]

---

5.1 Prophylaxis

2

835

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

0.26 [0.06, 1.21]

---

5.2 Intermittent treatment

3

1245

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

0.61 [0.32, 1.18]

---

 6 Enlarged spleen

2

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

Subtotals only

---

6.1 Prophylaxis

2

995

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

0.39 [0.15, 0.99]

---

 7 Impact on routine immunization: adequate protective antibodies

2

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

Subtotals only

---

7.1 Measles

2

695

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

0.97 [0.93, 1.01]

---

7.2 Diphtheria

2

795

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

0.99 [0.97, 1.01]

---

7.3 Tetanus

2

645

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

1.00 [0.99, 1.02]

---

7.4 Hepatitis B

1

495

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

1.00 [0.97, 1.04]

---

7.5 Polio 1

1

499

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

0.99 [0.94, 1.05]

---

7.6 Polio 3

1

499

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

0.97 [0.91, 1.03]

---

 

Comparison 2. Antimalarial vs placebo: cluster-randomized trials

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical malaria	1		Incidence rate ratio (Fixed, 95% CI)	Totals not selected
2 Severe anaemia	1		Incidence rate ratio (Fixed, 95% CI)	Totals not selected
3 Death from any cause	1		Incidence rate ratio (Fixed, 95% CI)	Subtotals only
4 Hospital admission for any cause	1		Incidence rate ratio (Fixed, 95% CI)	Subtotals only

---

 

Comparison 3. Antimalarial vs placebo: by drug group

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Clinical malaria

10

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

Subtotals only

---

1.1 Pyrimethamine-dapsone

2

1139

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

0.47 [0.25, 0.88]

---

1.2 Chloroquine

1

1005

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

0.94 [0.82, 1.08]

---

1.3 Sulfadoxine-pyrimethamine (intermittent treatment)

5

3673

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

0.72 [0.57, 0.91]

---

1.4 Artesunate plus sulfadoxine-pyrimethamine

1

1075

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

0.18 [0.13, 0.24]

---

1.5 Amodiaquine (intermittent treatment)

1

145

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

0.29 [0.19, 0.45]

---

 2 Severe anaemia

8

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

Subtotals only

---

2.1 Pyrimethamine-dapsone

1

415

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

0.48 [0.34, 0.67]

---

2.2 Sulfadoxine-pyrimethamine (intermittent treatment)

5

3646

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

0.86 [0.65, 1.14]

---

2.3 Artesunate plus sulfadoxine-pyrimethamine

1

1075

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

0.80 [0.57, 1.14]

---

2.4 Amodiaquine (intermittent treatment)

1

145

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

0.34 [0.17, 0.68]

---

 

Comparison 4. Antimalarial vs placebo: by seasonality

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Clinical malaria

10

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

Subtotals only

---

1.1 Seasonal: intermittent treatment

2

1239

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

0.32 [0.09, 1.08]

---

1.2 Seasonal: prophylaxis

2

1729

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

0.54 [0.11, 2.72]

---

1.3 Perennial: intermittent treatment

5

3654

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

0.61 [0.44, 0.85]

---

1.4 Perennial: prophylaxis

1

415

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

0.52 [0.38, 0.71]

---

 2 Severe anaemia

8

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

Subtotals only

---

2.1 Seasonal: intermittent treatment

1

1075

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

0.80 [0.57, 1.14]

---

2.2 Perennial: intermittent treatment

7

4206

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

0.68 [0.48, 0.98]

---

2.3 Perennial: prophylaxis

1

415

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

0.48 [0.34, 0.67]

---

 

Comparison 5. Intermittent treatment vs placebo: by presence of anaemia

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Severe anaemia

8

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

Subtotals only

---

1.1 All participants

5

4494

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

0.70 [0.51, 0.97]

---

1.2 Only anaemic children

3

536

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

1.31 [0.63, 2.72]

---

 

Comparison 6. Antimalarial vs placebo: adverse events

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Prophylaxis

2

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

Totals not selected

---

1.1 Vomiting

1

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

Not estimable

---

1.2 Hyperpigmented macules

1

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

Not estimable

---

 2 Intermittent treatment

2

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

Totals not selected

---

2.1 Minor skin rash

1

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

Not estimable

---

2.2 Pruritus

1

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

Not estimable

---

2.3 Severe skin reaction (Stevens-Johnson syndrome)

1

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

Not estimable

---

2.4 Vomiting

1

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

Not estimable

---

2.5 Diarrhoea

1

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

Not estimable

---

2.6 Nervousness

1

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

Not estimable

---

2.7 Dizziness

1

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

Not estimable

---

 

Comparison 7. Antimalarial vs placebo: adequately concealed trials

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Clinical malaria

8

5308

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

0.50 [0.33, 0.76]

---

1.1 Prophylaxis

1

415

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

0.52 [0.38, 0.71]

---

1.2 Intermittent treatment

7

4893

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

0.50 [0.31, 0.80]

---

 2 Severe anaemia

8

5282

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

0.67 [0.50, 0.91]

---

2.1 Prophylaxis

1

415

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

0.48 [0.34, 0.67]

---

2.2 Intermittent treatment

7

4867

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

0.74 [0.55, 0.99]

---

 3 Death from any cause

8

5308

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

0.87 [0.62, 1.24]

---

3.1 Prophylaxis

1

415

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

0.90 [0.37, 2.16]

---

3.2 Intermittent treatment

7

4893

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

0.87 [0.60, 1.27]

---

 

Comparison 8. Antimalarial vs placebo: impact after stopping intervention

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Clinical malaria (relative risk)

2

1625

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

0.87 [0.59, 1.26]

---

 2 Clinical malaria (incidence rate ratio)

2

Incidence rate ratio (Random, 95% CI)

Totals not selected

---

2.1 Cluster randomized

1

Incidence rate ratio (Random, 95% CI)

Not estimable

---

2.2 Individually randomized

1

Incidence rate ratio (Random, 95% CI)

Not estimable

---

 3 Severe anaemia (relative risk)

2

1625

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

1.13 [0.71, 1.79]

---

 4 Severe anaemia (incidence rate ratio)

1

Incidence rate ratio (Fixed, 95% CI)

Totals not selected

---

 5 Death from any cause (relative risk)

2

1482

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

0.80 [0.32, 2.03]

---

 6 Death from any cause (incidence rate ratio)

1

Incidence rate ratio (Random, 95% CI)

Totals not selected

---

 7 Impact on routine immunization: adequate protective antibody

1

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

Totals not selected

---

7.1 Measles

1

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

Not estimable

---

 

Table 1. Risk of bias of each included trial

---

Trial	Sequence^a	Concealment^a	Blinding	Primary outcome (n)	Number at follow up	Percentage loss
Alonso 1993	Unclear	Unclear	Participants and care providers were blinded	Clinical malaria (1898 participants)	Unclear	Unclear
Chandramohan 2005	Adequate (computer-generated random numbers)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Incidence of anaemia (2191 participants)	2191	11.8% (per protocol - inadequate)
Cissé 2006	Adequate (computer-generated random numbers)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (985 participants)	985	9.5% (adequate)
David 1997	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Desai 2003	Adequate (block randomization)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (428 participants)	468	14% (inadequate)
Greenwood 1988	Unclear	Unclear	Participants and care providers were blinded	Clinical malaria, severe anaemia (2718 participants)	Unclear	Unclear
Greenwood 1989	Unclear	Unclear	Participants and care providers were blinded	Clinical malaria (560 participants)	Unclear	Unclear
Greenwood 1995^b	Unclear	Unclear	Participants and care providers were blinded	Unclear	Unclear	19% to 22% (inadequate)
Hogh 1993	Unclear	Unclear	Participants and care providers were blinded	Unclear	Unclear	Unclear
Kobbe 2007	Adequate (computer-generated random numbers)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (1080 participants; intention to treat)	827	18.5% (per protocol)
Lemnge 1997	Unclear	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Unclear	234	6% (adequate)
Macete 2006	Adequate (computer-generated random numbers)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (1375 participants)	1375	8.5% (adequate)
Massaga 2003	Adequate (computer-generated random numbers)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (291 participants)	231	21% (inadequate)
Menendez 1997	Adequate (block randomization)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Severe anaemia (832 participants)	NA	7% (adequate)
Menon 1990	Unclear	Unclear	Participants and care providers were blinded	Unclear	Unclear	Unclear
Otoo 1988a^b	Unclear	Unclear	Participants and care providers were blinded	Clinical malaria (95 participants)	Unclear	16% (inadequate)
Schellenberg 2001	Adequate (computer-generated)	Adequate (sealed, opaque envelopes and identical, centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria, severe anaemia (701 participants)	677	3% (adequate)
Schellenberg 2005	Adequate (computer-generated)	Adequate (sealed, opaque envelopes and identical, centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria, severe anaemia, protective antibody titres against measles (555 participants)	555	Unclear
Tomashek 2001	Adequate (computer-generated)	Unclear	Only participants and assessor were blinded; care provider was not	Anaemia prevalence (238 participants)	215	9.7% (adequate)
Verhoef 2002	Adequate (block randomization)	Adequate (identical and centrally coded drugs and placebo)	Participants, care providers, and assessor were blinded	Clinical malaria (328 participants)	309	6% (adequate)
Wolde 1994	Unclear	Unclear	Unclear	Clinical malaria (1005 participants)	997	9% (adequate)

---

 NA: not available.
^aGeneration of allocation sequence; concealment of allocation.
^bLate impact trials.