Methods

Trial design: Individually randomized, controlled double‐blind trial

Multicentre trial: Yes

Trial duration: 2 years

Participants

Recruitment: Children presenting to the out‐patient clinic or ward at the Royal Teaching Hospital, Banjul; Medical Research Council Hospital, Fajara; and major health centres at Birkama, Essau and Faji Kunda during 2003 and 2004 transmission period (July to December), Sibanor was added during the 2004 period.

Inclusion criteria:

• Age: 3 months to 9 years

• Anaemia: Hb < 7 g/dL

• Sickle‐cell anaemia: not reported

• Other: signed consent from guardian

Other co‐morbidities: Not reported

Sample size: 1200 enrolled

Interventions

Total number of intervention groups: 2

Presumptive treatment for all participants:

• Malaria was treated with intramuscular quinine followed by SP (majority) or CQ plus SP

• Children stayed in hospital until all signs of respiratory distress had subsided and Hb concentration had increased over that found on admission

• Children with Hb < 5 g/dL received blood transfusion

• All children received iron (ferrous fumerate syrup: 2 mg/kg) for 28 days, starting at time of discharge

• 1st follow‐up 7 days after discharge: Hb measurement and blood films for malaria, and treatment of any medical condition

Interventions:

1. IPT with SP

2. Placebo (lactose and maize starch)

Dose and timing of intervention:

• SP dose: 1.25 mg pyrimethamine/25 mg sulphadoxine per kg

• 1st dose (SP or placebo): at 7 day follow‐up

• Monthly doses until end of transmission season

Duration of intervention period: until the end of the transmission season (July to December)

Place and person delivering intervention:

• 1st dose administered by project staff at the hospital or health centre where the child had been admitted

• Monthly doses were given at health centre closest to where the child was living by trained field workers under supervision of clinic staff

Co‐interventions:

• ITN use: was assessed at the end of the transmission period (20.7% in IPT group; 15.3% in placebo group)

• Other: none

Additional treatments:

• Children with fever ≥ 37.5°C or a history of recent fever and malaria parasitaemia were treated with SP and CQ

• Children with severe malaria were treated with IM quinine

• Children that presented with uncomplicated malaria within one week of receiving SP chemoprevention received oral quinine

• Children with Hb < 9 g/dL were treated with iron for a further 28 days if they had completed their initial iron treatment

• Children with severe anaemia were referred for admission

Co‐interventions equal in each arm? (if not, describe): Yes

Outcomes

Primary outcome:

1. Proportion of children with moderate or severe anaemia at the end of the transmission period

Secondary outcomes:

1. Mean Hb level at end of transmission period

2. Clinical episodes of malaria during the surveillance period

3. Outpatient attendance

4. Prevalence of parasitaemia and splenomegaly

5. Nutritional status at the end oft he transmission period

6. Compliance with treatment regimen

Measurement time points:

• Day 7: Hb, blood film

• Passive surveillance during intervention period

• End of malaria season

• End of dry season

How were outcomes assessed?

• Hb and blood film at day 7 and end of malaria transmission season

• Passive morbidity surveillance during intervention period

Interviews with mothers at end of dry season

Notes

Country: The Gambia

Setting: Urban and peri‐urban

Transmission area: Seasonal transmission

Source of funding: Gates Malaria partnership

Conflict of interest stated: Authors state that they have no competing interests

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"children were individually randomised into either the SP or the placebo group in a 1:1 ratio at the time of admission, using permuted blocks of 12 generated by computer using the STATA program. Blockswere not split across centres".

Allocation concealment (selection bias)

Low risk

"Tablets (enough for 6 doses) were packed into envelopes bearing the randomisation number by MRC staff not involved in the trial in any other way. The next envelope in sequence was assigned to the child at the time of their admission to hospital".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"None of the investigators, health care centre staff or laboratory staff participating in the trial had access to the code during the trial". Placebo and active tablet were identical in shape and colour.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"None of the investigators, health care centre staff or laboratory staff participating in the trial had access to the code during the trial".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up was similar in both groups (SP: 23%; placebo: 21.5%), but was over 20% in each group.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes reported and checked with protocol.

Other bias

Low risk

Discrepancy between text and flow‐chart regarding number of children seen at follow‐up.

Methods

Trial design: Population‐based RCT (proof of concept study)

Multicentre trial: No

Trial duration: 2007 to 2008

Participants

Recruitment: Eligible children identified through active and passive malaria surveillance in participating communities (West Kiang district, lower river region, The Gambia)

Inclusion criteria:

• Age: 12 to 72 months

• For enrolment: Uncomplicated malaria at day 0 (history of fever 48 hours prior to presentation or a measured temperature > 37.5°C with peripheral parasitaemia)

• For randomization: Anaemia Hb 6.9 to 11.0 g/dL on day 3 with no peripheral parasitaemia

• Sickle‐cell anaemia: not reported

Exclusion criteria:

• Unable to take oral medication

• Features of severe malaria

• Known haemoglobinopathy

• Enrolled in another project

• Had already received antimalaria drugs from outside the project

• Were prescribed other drugs with potential antimalarial or anti‐anaemic effects (for example, cotrimoxazole or haematinics)

• Severely wasted children

Other co‐morbidities: Not reported

Sample size: Enrolled into trial: 132; randomized to receive IPT/placebo: 96

Interventions

Baseline treatment for all children:

• CQ syrup (3 days) with SP on day 0 (52 children in 2007)

• AL course (80 children in 2007 and 2008)

Total number of intervention groups: 2

1. IPT (CQ)

2. Placebo

Dose and timing of intervention:

• Weekly CQ or placebo syrup: 50 mg CQ base per 5 mL at a dose of 5 mg/kg for 3 days

Duration of intervention period: 90 days (12 weeks)

Place and person delivering intervention:

• Study nurse administered syrup at home of child

Co‐interventions:

• ITN use: ITN distribution part of standard malaria but trial does not report the use of bed nets per group

• Other: none

Additional treatments:

• Comorbidities were treated accordingly avoiding cotrimoxazole and haematinics

Children with positive tests were treated with either CQ/SP (2007) or ACT (2007 and 2008)

Co‐interventions equal in each arm? (if not, describe):

Yes

Outcomes

Primary outcome:

1. Hb change from day 3 post‐treatment (randomization to IPT or no IPT)

Secondary outcomes:

1. Changes in erythropoietic response

2. Changes in urinary neopterin

3. Prevalence of submicroscopic malaria parasitaemia

4. Hb change in 2 placebo groups to investigate effects of initial malaria treatment therapy

Measurement time points:

• Baseline (day 3); days 15, 30, 45, 70, 90

How were outcomes assessed?

• Fingerprick or venous blood taken by study nurse at follow‐up visits

• Active and passive surveillance

• Twice weekly temperature monitoring of enrolled children by village assistants

• Children with fever screened for malaria with rapid test

Notes

Country: The Gambia

Setting: Rural

Transmission area: Seasonal transmission

Source of funding: UK Medical Research Council

Conflict of interest stated: Authors stated no competing interests.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The block randomisation to the post‐malaria treatment of weekly CQ or placebo in both 2007 and 2008 was double blinded and was carried out in blocks of eight. The randomisation codes were generated by a staff member independent of the study team and held by the external trial monitor".

Allocation concealment (selection bias)

Low risk

"Treatment codes were labelled A to H and placed in sequentially numbered, opaque, sealed envelopes held by the study nurses. Allocation to the treatment was by matching the code in the envelope to a bottle of the intervention labelled with the same code and then labelled with the subject ID".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Both participants and personnel were blinded, intervention and placebo syrups were in similar amber‐coloured bottles with matching caps and labels.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Double‐blinded trial, treatment codes held by external trial monitor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for, loss to follow‐up: 2% in IPT group; 7% in placebo group. All lost due to second malaria episode.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes reported on.

Other bias

Low risk

No other sources of bias identified.

Methods

Trial design: RCT with 2 X 2 factorial design

Multicentre trial: no

Trial duration: Children were screened between April to November 1999

Participants

Recruitment: All resident children in 15 villages in Asembo, Bondo district, Kenya were screened

Inclusion criteria:

• Age: 2 to 36 months

• Anaemia: mild anaemia (Hb 7.0 to 10.9 g/dL)

• Malaria: aparasitaemic or parasite counts < 20,000 parasites/mm³

• Sickle‐cell anaemia: children with HbSS phenotype excluded

• Other: no reported iron supplementation, SP treatment or blood transfusions within the last 2 weeks

Other co‐morbidities: Not reported

Sample size: 554 participants randomized; 546 enrolled; 491 followed up at 12 weeks; 468 followed up at 24 weeks.

Interventions

Total number of intervention groups: 4

Presumptive treatment for all participants: single dose of SP (500 mg sulphadoxine and 25 mg pyrimethamine per tablet). Children ≤ 10kg received half a tablet, children > 10kg received one tablet

1. IPT (SP) + iron

2. IPT (SP) + iron placebo

3. IPT placebo + daily iron

4. IPT placebo + iron placebo (double placebo)

Dose, and timing of intervention: IPT with SP (or placebo) at 4 and 8 weeks; iron (or placebo) given daily for 12 weeks (3 to 6 mg/kg/day, orally). IPT given as crushed tablets mixed with water.

Duration of intervention period: 12 weeks

Place and person delivering intervention:

• Iron delivered through daily home visits by staff

• Unclear where SP presumptive dose was administered

• Unclear where and by whom other doses of SP were given – not reported

Co‐interventions:

• ITN use: All households were issued with ITNs but the use thereof was not further assessed

• Other: none

Additional treatments: Children with symptomatic malaria (temp ≥ 37.5°C with any malaria parasitaemia or parasitaemia > 5000 parasites/mm³) received oral quinine (10 mg/kg, 3 times/day for 7 days). Children who developed severe malaria, severe anaemia (Hb < 5.0g/dL) or other severe disease requiring hospitalization were referred for further treatment.

Co‐interventions equal in each arm? (if not, describe):

Yes

Outcomes

Outcomes not specified according to primary and secondary outcomes:

1. Hb concentration ( measured in g/dL)

2. Hematological recovery (Hb ≥11 g/dL before or at week 12)

3. Severe anaemia (Hb < 7g/dL before or at week 12)

4. MCV (measured in fL)

5. sTfR concentration (measured in µg/mL)

6. Parasite density (parasites/mm³)

7. Malaria parasitaemia

8. Clinical malaria (axillary temperature 37.5°C with co‐existing malaria parasitaemia)

9. Clinic visits (Incidence, number of episodes)

Measurement time points: Every 4 weeks

How were outcomes assessed?

• Home visits every 2 weeks for completion of a morbidity questionnaire and assessment of cutaneous reactions and axillary temperature

• Fingerprick or heel‐prick blood samples were obtained every 4 weeks (just before the next dose of SP or SP placebo) for Hb levels and presence of malaria parasites

• The frequency of local clinic and hospital attendance was monitored using a passive surveillance system

Notes

Country: Western Kenya

Setting: Rural

Transmission area: Perennial transmission

Source of funding: US agency for International Development, Netherlands Foundation for the advancement of Tropical research

Conflict of interest stated: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Balanced block randomisation (8 children/block) and a random number listing generated independently before the study".

Allocation concealment (selection bias)

Unclear risk

Children were assigned to 1 of the 4 groups sequentially according to the random number listing by one author. Drugs and placebos were identical. Code to true drug and placebo assignment was revealed only after completion of analysis. Still unclear whether allocation was concealed sufficiently – did they use numbered envelopes or bottles?

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo and trial drugs were identical; participants (or their mothers) and staff administering the drugs were thus not aware of the study group. The code was only broken after data analysis.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Placebo and trial drugs were identical; staff assessing outcomes were thus not aware of the trial group. The code was only broken after data analysis.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up at 12 weeks: 4% (IPT + iron), 8.6% (iron), 6.6% (IPT) and 20.5% (double placebo). Reported reason: mostly migration (23/28 for double placebo group), loss to follow‐up at 24 weeks – data missing.

Selective reporting (reporting bias)

Unclear risk

Outcomes not listed in Methods section (protocol?).

Other bias

Low risk

No.

Methods

Trial design: Randomized double‐blind, placebo‐controlled trial

Multicentre trial: Yes

Trial duration: June 2006 to August 2009

Participants

Recruitment: Children were recruited from four hospital in southern Malawi: Queen Elizabeth Central hospital (Blantyre), Chikwawa District hospital, Thyolo District hospital, Zomba Central hospital.

Inclusion criteria:

• Age: 4 to 59 months

• Anaemia: admitted with and treated for severe malarial anaemia

• Convalescent children surviving hospital stay (received transfusion and completed the course of intravenous quinine) with Hb > 5g/dL

• Weight > 5 kg

• Able to switch to oral medication

• Sitting unaided

Exclusion criteria:

• Sickle‐cell anaemia

• Blood loss due to trauma

• Haematological malignancy

• Known bleeding disorder

• Hypersensitivity to AL

• Treatment with AL within a week of admission

• Non‐residency in trial area

• Previous participation in the trial

• Participation in another clinical trial

• Known need for medication prohibited during the intervention period

• Surgery scheduled during the trial

Other co‐morbidities: 8% of children were infected with HIV

Sample size: 1431 randomized, 1414 allocated to groups; analysed 4310

Interventions

Presumptive treatment for all participants: Six doses of AL as part of the standard 3 day course in hospital. Children < 15 kg received one tablet; children > 15 kg received 2 tablets, once every 12 hours for 3 days.

Total number of intervention groups: 2

1. AL

2. Placebo

Dose and timing of intervention:

• AL or placebo: Children < 15kg received one tablet; children > 15kg received 2 tablets, once every 12 hours for 3 days at 1 month and 2 months post discharge

Duration of intervention period: 3 months

Place and person delivering intervention:

• The first daily dose (both at 1 and 2 months pd) was given by trial team member who visited the home every morning for 3 day

• The second dose was left with the parent or guardian to give in the evening (adherence assessed the following morning)

Co‐interventions:

• ITN use: similar in both groups; 35% used treated net; 16% used untreated net; and 48% used no net (self‐reported)

• Other: none

Additional treatments:

• Rescue treatment for acute malaria

• Discharge ‐ month 3: oral quinine for 5 days

• Month 4 to 6 (extended follow‐up period): AL

• Treatment for severe malaria

• Discharge – month 3: intravenous quinine and oral quinine for 5 days

• Month 4 to 6 (extended follow‐up): intravenous quinine and AL

• Children with severe disease were admitted to hospital

• Children with recurrent severe anaemia received blood transfusions

• Bacterial and other infections treated as per physician’s discretion

Co‐interventions equal in each arm? (if not, describe): Yes

Outcomes

Primary outcome:

1. Composite outcome of all‐cause mortality and hospital readmission because of all‐cause severe anaemia (Hb < 5 g/dL or clinical indication for blood transfusion) or severe malaria (readmittance to hospital due to confirmed malaria treated with parenteral quinine) between 1 and 6 months

Secondary outcomes:

1. All‐cause mortality

2. Hospital readmission because of all‐case severe anaemia or severe malaria

3. All‐cause hospital admission

4. All‐cause sick child clinic visits

5. Clinic visits because of microscopically confirmed non‐severe malaria

Measurement time points:

• Observation time divided into 3 periods:

• Discharge ‐ month 1 pd (before IPT)

• 1 to 3 months pd (IPTpd period)

• 4 to 6 months pd (extended follow‐up period)

• All children seen at 6 months for assessment of Hb and malaria parasitaemia

• Passive case detection from discharge to month 6

How were outcomes assessed?

• 6 month follow‐up by passive case detection: mothers were asked to bring children to a study clinic if they had fever or were unwell. Standardized forms used to record information; Hb, temp and malaria smear

Notes

Country: Malawi

Setting: Urban/peri‐urban/rural

Transmission area: Perennial

Source of funding: Netherlands African Partnership for Capacity Development and Clinical Interventions against Poverty‐related Diseases; UBS Optimus foundation; Gates Malaria Partnership.

Conflict of interest stated: Authors declared no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated list of random numbers, "stratified by hospital and weight group (< 15 kg and 15 kg or more) in randomly varying block sizes of two, four, or six".

Allocation concealment (selection bias)

Low risk

Sequentially numbered envelopes containing AL or placebo.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Authors did not mention that placebo and AL were identical tablets, but described the trial as "double‐blind".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Masking was maintained and the code only broken once all data sets were closed.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for. Loss to follow‐up rates similar across groups (7% at 6 months).

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes reported on.

Other bias

Low risk

No.

Methods

Trial design: Randomized double‐blind trial

Multicentre trial: No

Trial duration: March 1998 to May 1998

Participants

Recruitment: Children living in refugee camp diagnosed with clinical anaemia

Inclusion criteria:

• Age: 6 to 59 months

• Anaemia: Hb 5.0 to 8.0 g/dL

• Malaria: severe malarial infection excluded

• Informed consent

Exclusion criteria

• Sickle‐cell anaemia

• Signs or symptoms of heart failure

• splenomegaly

Other co‐morbidities: Hookworm

Sample size: 238 randomized, 215 analysed

Interventions

Presumptive treatment for all participants:

• Treatment for malaria with SP (> 48 months: one SP tablet (500 mg sulphadoxine and 25 mg pyrimethamine); 12 to 47 months: half a tablet; 6 to 12 months: quarter of a tablet)

• Mebendazole (24 to 59 months one tablet (500 mg mebendazole); 12 to 23 months half a tablet; 6 to 12 months did not receive)

Total number of intervention groups: 3

1. Vitamin placebo 3X per week

2. Vitamin placebo + SP

3. VAC + SP

Dose, and timing of intervention:

• Vitamin (or placebo) given 3 times a week (> 18 months: chewable tablet of 400 µg vitamin A and 75 mg vitamin C; < 18 months: chewable tablet: 400 µg vitamin A and 30 mg vitamin C)

• SP week 4, 8, and 12 (> 48 months: one SP tablet (500 mg sulphadoxine and 25 mg pyrimethamine); 12 to 47 months: half a tablet; 6 to 12 months: quarter of a tablet)

Duration of intervention period: 3 months

Place and person delivering intervention:

• Home health visitor administrated one dose of iron and placebo or iron and VAC at weekly home visits

• At visits parents were given 2 additional doses oft he appropriate treatment to be given on every second day for that week

• In addition, each participant visited the clinic monthly (at week 4, 8, 12) for physical examination, weight and height measurement, Hb measurement, malaria blood smear

• Participants in group 2 and 3 were given monthly doses of SP at this visit

Co‐interventions:

• ITN use: not reported

• Other: Iron and folic acid supplement for all children (> 18 months: one tablet containing 250 µg ferrous fumerate (= 60mg of elemental iron) and 250 µg folic acid three times a week; < 18 months received half a tablet 3 times a week)

Additional treatments:

• Participants in group 1 were given CQ if they presented to the clinic with symptomatic malaria

Co‐interventions equal in each arm? (if not, describe): No

Outcomes

Outcomes not specified as primary or secondary outcomes

1. Mean Hb

2. Prevalence of anaemia (Hb < 11.0 g/dL)

3. Mean TfR level

4. Prevalence of iron deficiency (TfR < 8.5 µg/mL)

5. Proportion of positive high density parasitaemia

Measurement time points:

• Hb: enrolment, week 4, 8 and 12

• TfR: enrolment, week 12

How were outcomes assessed?

• At each monthly visit: physical examination, height and weight measurement, Hb and malaria smear

• Laboratory measurements

Notes

Country: Tanzania

Setting: Rural

Transmission area: Not reported

Source of funding: Woodruff Foundation, Atlanta, Georgia.

Conflict of interest stated: Not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomization list.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Personnel distributing medications had access to the list of group assignment; group 1 did not receive SP placebo.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The study coordinator and the study nurse, who were responsible for distributing medications, were the only team members with access to the register containing participants' names and group assignment. All other research team members were blinded to participants’ treatment group assignment". Laboratory workers were not aware of group assignment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

All participants accounted for. Loss to follow‐up rates: Group 1: 6%, Group 2: 10%; Group 3: 13% reasons for loss to follow‐up not stratified according to groups.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes reported on.

Other bias

Low risk

No.

Methods

Trial design: Double‐blind, placebo controlled trial with a 2x2 factorial design

Multicentre trial: No

Trial duration: 1998 to 2000

Participants

Recruitment: Children were recruited (randomly selected) from communities neighbouring the research clinic in the Mtito Andei Division, Eastern Province, Kenya at the start of the rainy season

Inclusion criteria:

• Age: 2 to 36 months

• Anaemia: Hb 6.0 to 11.0 g/dL

• Sickle‐cell anaemia: not reported

• Other:

• Temperature < 37.5°C

• No symptoms suggestive of malaria or anaemia

• No systemic illness in combination with a blood dipstick result showing current or recent malarial infection

• Signed consent from parents

• No allergy to sulfa drugs

• No history of using drugs containing sulfa in previous 3 weeks

• Positive dipstick result without symptoms of systemic illness were included

Other co‐morbidities: Not reported

Sample size: 328 randomized, 307 analysed

Interventions

Total number of intervention groups: 4

1. IPT (SP) + iron

2. IPT (SP) + iron placebo

3. IPT placebo + iron

4. IPT placebo + iron placebo

Dose, and timing of intervention:

• SP: 1.25 mg pyrimethamine/25 mg sulphadoxine per kg every 4 weeks

• Iron: ferrous fumerate suspension, targeted dose: 6 mg elemental iron/kg/week administered twice per week

Duration of intervention period: 12 weeks

Place and person delivering intervention:

• Iron (or placebo) administered by community health workers twice a week, mothers took children to health workers (place unknown)

• SP (or placebo) administered by clinical officer

Co‐interventions:

• ITN use: not reported

• Other: none

Additional treatments:

• Children withdrawn and treated appropriately if they had

• Hb < 5.0 g/dL

• Severe and complicated malaria

• Manifestations of other diseases

• Children with malaria attacks were treated with amodiaquine or halofantrine if unsuccessful

• Treated for other common illnesses

Co‐interventions equal in each arm? (if not, describe): Yes

Outcomes

Primary outcome:

1. Hb concentration at the end of follow‐up (12 weeks)

2. Proportion of children with at least one malaria attack (defined as presence of fever, that is temperature ≥ 37.5°C, and a positive dipstick result)

Secondary outcomes:

1. Anaemia (Hb < 11.0 g/dL)

2. Iron deficiency (serum ferritin concentration < 12 µg/L)

3. Adverse drug reactions

4. Time to first occurrence of malaria attack

Measurement time points:

• Baseline, 4 weeks, 8 weeks, 12 weeks

How were outcomes assessed?

• Capillary blood tested for malaria (dipstick) and Hb measured at each visit (4, 8, 12 weeks)

Surveillance and monitoring of illness episodes and adverse effects at twice weekly meetings with community healthworker (questionnaires)

Notes

Country: Kenya

Setting: Unclear – rural?

Transmission area: Seasonal transmission

Source of funding: Netherlands foundation for the Advancement of Tropical Research

Conflict of interest stated: Declared no conflicts. Author contacted for follow‐up Hb concentration values

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The allocation schedule was generated by one of us (HV) for each block, by means of tables with randomised permutations, and only after acceptance of all children making up a block".

Allocation concealment (selection bias)

Unclear risk

"The order of the children listed in each block was concealed from the person generating the allocation schedule" – unclear, was this not the same person?

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants were blinded, placebos and active compounds were indistinguishable in taste and appearance.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

None of the field investigators was aware of the code until after crude analysis and a plan for further analysis had been prepared.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for. Loss to follow‐up rates similar across groups.

Selective reporting (reporting bias)

High risk

Do not report on mean Hb concentrations (primary outcome), only on the difference in Hb concentration between groups.

Other bias

Low risk

No.