Kounnavong 2011.

Methods	Design: randomised controlled trial with a 3‐arm design Unit and method of allocation: a computer‐generated random number was used to randomise households to 1 of the 3 arms Method of sequence generation: computer randomised by household to 3 arms Masking of participants, personnel, and outcome assessors: No method was in place to conceal the allocation (confirmed by study author, Kounnavong 2011). Anthropometrists and trained technicians who collected haemoglobin data were unaware of the participant arm allocation. Because of technical and financial constraints, the placebo could not be produced locally, so trialists followed the normal standard of care in Lao People's Democratic Republic (PDR) at the time of the study; the control group received 6‐monthly high‐dose vitamin A supplementation instead of placebo. Village health volunteers monitored adherence and were aware of arm allocation of participants. They visited households every week and recorded the number of sachets consumed by children in the 2 intervention groups, any side effects, and any illnesses that occurred during the study period
Participants	Location of the study: 6 communities in the Lahanam zone, Songkhone District, Savannakheth Province, 600 km south of the capital city, Vientiane, Lao PDR Selection of participants: since 2004, the entire population in the study area is registered in the Health and Demographic Surveillance System (HDSS) of the National Institute of Public Health (NIOPH). From the HDSS database, 367 eligible pre‐school‐age children were identified and invited to participate if they met all inclusion criteria. All eligible children in each household were enrolled and followed the same intervention randomly assigned to the household Sample size: 336. Of the 367 children who originally met the criteria, 17 were absent at the time of enrolment and 14 were excluded because they had infection with fever on the day of enrolment. Therefore, a total of 336 children were enrolled in the study Age: 6 to 52 months (mean = 32 months) Sex: female and male (58% female) Socioeconomic status (as defined by trialists): each household was categorised into 1 of 2 socioeconomic status groups: high (with electricity, improved water source, and latrine) or low (lacking one or all of these) Baseline prevalence of anaemia: 48.9% Baseline prevalence of soil helminths: not reported Baseline malaria prevalence: not reported Inclusion and exclusion criteria: "inclusion criteria were (i) age 6 to 53 months at the time of recruitment; (ii) willingness to participate; (iii) receiving complementary food in addition to breast milk; and (iv) apparently healthy. Exclusion criteria were: (i) having a fever or any illness on the day of enrolment; (ii) baseline level of haemoglobin less than 70 g/L; and (iii) currently receiving iron supplementation" (quote)
Interventions	Households were randomised to 1 of 3 groups Group 1 (n = 111) received a daily MNP sachet (MixMe™) containing 10 mg iron as ferrous fumarate 7 days a week (total of 168 MNP sachets) Group 2 (n = 115): twice‐weekly multiple micronutrient powder (MNP) sachets (MixMe™) per week (Monday and Friday, total of 48 MNP sachets) Group 3 (n = 110): no intervention For the purposes of this review, results from groups 1 and 2 were combined and were reported separately in the subgroup assessing the scheme All subjects received a single high dose of vitamin A every 6 months, and those aged 24 months or older received a single dose of mebendazole for deworming in the 2 months before the study. Children who had not received mebendazole received it during the baseline survey. Because of technical and financial constraints, placebo could not be produced locally, so trialists followed the normal standard of care in Lao People’s Democratic Republic (PDR) at the time of the study; the control group received 6‐monthly, high‐dose vitamin A supplementation instead of placebo Duration of the intervention: 24 weeks
Outcomes	Study authors did not distinguish between primary and secondary outcomes Outcomes and timing of outcome assessment: haemoglobin, anaemia (measured at baseline, at week 12, and at week 24), height‐for‐age z score, weight‐for‐age z score, weight‐for‐height z score (taken every 4 weeks)
Notes	Study start date: March 2009 for 24 weeks Study end date: October 2009 Conflict(s) of interest: none reported Funding source(s): this study was conducted as a part of the Eco‐Health Project of the Research Institute for Humanity and Nature, Kyoto (Japan), in collaboration with the National Institute of Public Health, Ministry of Health (MOH) of Lao PDR. MNP supplements were provided by the United Nations Children's Fund (UNICEF), Lao PDR. SK was in receipt of an Asian Health & Education Fund, Tokyo (Japan), and was in partial receipt of the Institute of Tropical Medicine, Nagasaki University (NEKKEN) Fellowship Malaria‐endemic area: yes Comments A malaria control programme was successfully executed in all villages 10 years ago Analyses in this review include estimated effective sample size only, after data adjustment to account for the clustering effect. Study authors provided the average cluster size and the intracluster correlation coefficient for anaemia All children in group 2 consumed 2 sachets of micronutrient powder per week, giving 100% compliance for this group Although it was unintended, the haemoglobin concentration was significantly different at baseline in the control group (n = 110) compared with the 2 intervention groups. Children in the control group had, on average, a higher mean haemoglobin concentration and thus a lower incidence of anaemia compared with children in the 2 supplementation groups. Baseline anaemia prevalence varied by arm: daily (53.6%); twice weekly (58.6%); and control (34.5%). Village health volunteers monitored adherence and were aware of arm allocation of participants. They visited households every week and recorded the number of sachets consumed by children in the 2 intervention groups, any side effects, and any illnesses that occurred during the study period In group 1, 72.7% of children consumed 5 or more sachets of micronutrient powders per week and 43.6% consumed all 7 sachets per week for all 24 weeks. The most common reasons for not consuming the micronutrient powder in group 1 were illness, such as diarrhoea (n = 20) and cough (n = 10), and forgetting to take supplements (n = 32). About 42% (93/221) of mothers reported that the micronutrient powders changed the colour of their children’s food, and 97/221 reported that they had an unpleasant smell or taste. Some mothers mixed the micronutrient powders in liquids such as juice or milk. Many mothers felt the micronutrient powders had increased their child’s appetite (31.7%) and playfulness (48.4%) 98.5% of participants completed the study without imbalance between groups
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: computer‐generated random number used to randomise households to 1 of the 3 arms
Allocation concealment (selection bias)	High risk	Comment: no method in place to conceal allocation
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: because of technical and financial constraints, placebo could not be produced locally, so followed the normal standard of care in Lao People's Democratic Republic at the time of the study. The control group received 6‐monthly, high‐dose vitamin A supplementation instead of placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: assessment of haemoglobin concentration by trained technicians, who were unaware of the allocation of micronutrient supplement; anthropometric measurement by 2 field workers who were unaware of which group a child belonged to
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 98.5% of participants completed the study without imbalance between groups
Selective reporting (reporting bias)	Unclear risk	Comment: information insufficient to permit judgement
Other bias	High risk	Comment: although this was unintended, the haemoglobin concentration was significantly different at baseline in the control group (n = 110) compared with the 2 intervention groups. Children in the control group had, on average, a higher mean haemoglobin concentration and thus a lower incidence of anaemia compared with children in the 2 supplementation groups. Baseline anaemia prevalence varied by arm: 53.6% (daily); 58.6% (twice weekly); and 34.5% (control). Village health volunteers monitored adherence and were aware of arm allocation of participants. They visited households every week and recorded the number of sachets consumed by children in the 2 intervention groups, any side effects, and any illnesses that occurred during the study period