Soofi 2013 (C).

Methods	Study design: cluster‐randomised trial Unit and method of allocation: cluster level within urban and rural strata Method of sequence generation: computer‐generated random numbers to 1 of 3 groups Masking of participants, personnel, and outcome assessors: investigators and field staff masked to composition of MNP preparations; participants not blinded
Participants	Location of the study: urban and rural sites of Sindh, Pakistan. Urban areas were in Bilal colony, an urban squatter settlement in Karachi with population of 75,000. Rural areas in Matari district, about 200 km from Karachi, with population of 500,000. Both have functional health centres and research infrastructure and are broadly representative of urban and rural Pakistan Sample size: 2746 children in 256 clusters Age: 6 to 18 months Sex: not reported Socioeconomic status: similar between randomised groups (piped drinking water, underground sewage, monthly income) but lower underground sewage in rural vs urban clusters Baseline prevalence of anaemia: 23% Baseline prevalence of soil helminths: not reported Baseline malaria prevalence: not reported Inclusion and exclusion criteria: all children younger than 5 months in the 3 groups were eligible
Interventions	Participants were randomly assigned to 1 of 3 groups Interventions Group B (n = 910, 85 clusters): same as group A plus receiving a fortnightly supply of MNP without zinc for daily use between 6 and 18 months of age Group C* (n = 889, 85 clusters): same as group A plus receiving a fortnightly supply of MNP with zinc (as zinc gluconate, 10 mg per day) for daily use between 6 and 18 months of age MNP composition for groups B and C (all amounts represent elemental content) = 12.5 mg of iron (as microencapsulated ferrous fumarate), 50 mg of vitamin C (as ascorbic acid), 300 μg of vitamin A (as retinol acetate), 5 μg of vitamin D (as vitamin D3), and 150 μg of folate (as folic acid) 100 community health workers with at least 12 years of schooling were hired and trained for 1 week to support IYCN, use of oral rehydration solution and zinc for treatment of acute diarrhoea, and continued breastfeeding and complementary feeding during episodes. Also trained to distribute 2 weeks worth of MNP for daily use for children aged 6 to 18 months mixed with normal weaning food; told to continue MNP at the same dose during common illnesses; community health workers counted empty and remaining sachets every 2 weeks and replenished supplies Comparison Group A* (n = 947, 85 clusters): non‐supplemented control. Children received basic infant and young child feeding messages based on UNICEF/WHO recommendations; exclusive breastfeeding was promoted up to 6 months and continued breastfeeding with appropriate complementary feeding with locally available foods thereafter Duration of the intervention: 6 months. *For the purposes of this review, only groups A and C were compared
Outcomes	Primary: growth, episodes of diarrhoea, acute lower respiratory tract infection, fever, incidence of admission to hospital Secondary: micronutrient status (haemoglobin, hematocrit, C‐reactive protein, ferritin, retinol, zinc) Timing of outcome assessment: information on presence or absence of diarrhoea, including presence of visible blood in the child's stools; respiratory signs; fever in the preceding week or 2 weeks obtained from families during regular household visits from recruitment to 24 months of age; monthly anthropometric assessments; blood samples collected at recruitment and at 6 and 18 months of age; routine stool samples collected at recruitment and at 6, 12, 18, and 24 months of age; diarrhoeal stool samples collected when mothers reported acute diarrhoea to visiting data collectors
Notes	Study start date: 1 November 2008 Study end date: 31 December 2011 Conflict(s) of interest: none reported Funding source(s): Bill and Melinda Gates Foundation Malaria‐endemic area: yes Comments Length or height measured, depending on child's ability to stand (not just length for < 2 years). 12 independent teams collected morbidity info from mothers of participating children starting at recruitment until 24 months of age through regular household visits. Subset of children visited weekly; routine blood and stool specimens collected and analysed Routine stool samples collected at recruitment and at 6, 12, 18, and 24 months for microbiological assessment. Diarrheal stool samples collected when mothers reported acute diarrhoea to visiting collectors and transported within 6 hours in transport medium for assessment of possible bacterial and viral pathogens Higher proportion of children in urban setting had been hospitalised with diarrhoea at baseline, presumably reflective of better access to health services Prevalence of wasting was high (approximately 25%) in enrolled children at baseline. Data were analysed on an intention‐to‐treat basis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: within urban and rural strata, computer‐generated random numbers to 1 of 3 groups
Allocation concealment (selection bias)	Low risk	Comment: MNP sachets for groups B and C were identical except for colour (colour coding known only to the manager of Genera Pharmaceuticals (Islamabad), who produced the powders under license, and the Chair of the trial's DMC)
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: field staff masked to composition of the MNP until after results of the trial were presented to the independent DMC. No placebo was used in the control group; therefore parents knew whether their child was receiving MNP but did not know whether the powder contained zinc
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: investigators and supervisory staff masked to composition of MNP until after results of the trial were presented to the independent DMC
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 108 children (11.4%) lost to follow‐up in group A and 87 children (9.8%) in group B at 24 months of age; no clusters lost to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: appears to be no selective reporting, as outcomes pre‐specified in trial registration were reported in the final publication
Other bias	Low risk	Comment: appears to be free of other sources of bias