Results
anaemia, diarrhoea, fever, malaria, inflammation, cough, diarrhoeal disease
ANAEMIA, WASTING, ADVERSE EVENTS, INFLAMMATION, MINOR, MALARIA, SECONDARY, REGRESSION, DIARRHOEAL DISEASE
Between April 26, 2014, and Aug 7, 2015, we prescreened 783 children, of whom 407 were enrolled into five cohorts. Overall, 135 were randomly assigned to the control group, 136 to the 12·0 mg screen-and-treat group, and 136 to the 6·0 mg screen-and-treat group (Trial profileMMPs=multiple micronutrient powders.Baseline characteristics were similar between intervention groups, with only minor differences in the proportions of children with underweight or wasting, and in the EGRAC index (Baseline characteristics of the intention-to-treat populationData are mean (SD), n (%), n/N (%), or median (IQR). sTfR=soluble transferrin receptor. CRP=C-reactive protein. AGP 1=alpha-1-acid glycoprotein 1. EGRAC=erythrocyte glutathione reductase activation coefficient. REG1B=regenerating gene 1B.Defined as either ferritin <12 μg/L and ferritin index >3·2 if CRP ≤5 mg/L, or ferritin <30 μg/L and ferritin index >2 if CRP >5 mg/L, where ferritin index is sTfR/log ferritin.Defined as haemoglobin <110 g/L, ferritin <12 μg/L, and ferritin index >3·2 if CRP ≤5 mg/L; or haemoglobin <110 g/L, ferritin <30 μg/L, and ferritin index >2 if CRP >5 mg/L.Adjustments and cutoffs are provided in the The directly observed compliance with daily iron supplementation was high and similar across all intervention groups: 94·8% in the control group, 95·3% in the 12 mg screen-and-treat group, and 95·0% in the 6 mg screen-and-treat group. In the per-protocol population, the iron dose consumed over the 12-week study period ranged from 900 mg to 996 mg in the control group (mean 984 mg), from 0 mg (eight participants) to 996 mg (one participant) in the 12 mg screen-and-treat group (500 mg), and from 0 mg (seven participants) to 498 mg (three participants) in the 6 mg screen-and-treat group (246 mg; Iron intake and non-inferiority analysis(A) Total iron intake by intervention group. (B) Non-inferiority analysis. Dotted line indicates the predefined margin of –5 g/L; error bars indicate 98·3% CI.In the control group, 82 days of supervised iron supplementation increased mean haemoglobin concentration by 7·7 g/L (95% CI 3·2 to 12·2) in the per-protocol population (Primary outcomes, secondary outcomes, and continuous variables at day 84 in the per-protocol analysisData are n/N (%) unless otherwise indicated. Results are from a mixed-effects linear regression, including baseline values with study group as fixed-effect and participant as random-effect factor; log-transformed data for sTfR, ferritin index (sTfR/log ferritin), plasma iron, transferrin saturation, CRP, AGP 1, EGRAC; Tobit regression with log-transformed data for hepcidin, ferritin, ferritin adjusted for inflammation (CRP <5·0 mg/L), calprotectin, and REG1B. All log-transformed data were exponentiated for presentation of estimates as geometric means in the table. Effect sizes are unadjusted and are presented as absolute effects for non-transformed variables and as relative effects (percentage change in geometric mean relative to the control group) for log-transformed variables. EGRAC was measured in a random subsample. sTfR=soluble transferrin receptor. CRP=C-reactive protein. AGP 1=alpha-1-acid glycoprotein 1. EGRAC=erythrocyte glutathione reductase activation coefficient. REG1B= regenerating gene 1B.98·3% CI for primary outcome considering comparison of all three intervention groups, adjusting for multiple testing using a one-sided test. 95% CI for the secondary outcomes, which have not been corrected for multiple testing because they represent alternate measures of related outcomes.In combined analyses across all intervention groups, the total amount of iron administered significantly (but weakly) predicted changes between baseline and day 84 in haemoglobin (RThe prevalence of anaemia remained high in all study groups after the 12-week supplementation period (Secondary outcomes as categorical variables in the per-protocol analysisData are n/N (%) unless otherwise indicated. Results are from a mixed-effects logistic regression with study group as fixed-effect and participant as random-effect factor. CRP=C-reactive protein. sTfR=soluble transferrin receptor.Defined as either ferritin <12 μg/L and ferritin index >3·2 if CRP ≤5 mg/L, or ferritin <30 μg/L and ferritin index >2 if CRP >5 mg/L, where ferritin index is sTfR/log ferritin.Defined as haemoglobin <110 g/L, ferritin <12 μg/L, and ferritin index >3·2 if CRP ≤5 mg/L; or haemoglobin <110 g/L, ferritin <30 μg/L, and ferritin index >2 if CRP >5 mg/L.Serum ferritin (adjusted for inflammation), hepcidin, CRP, AGP1, EGRAC, faecal calprotectin, and REG1B concentrations in the two screen-and-treat groups did not differ from the control group at the end of the study period (Monitoring morbidity twice a week, asking specifically about the presence of fever, diarrhoea, vomiting, cough, or any other symptom, did not show any differences between intervention groups (Over the whole study period, we observed 580 adverse events in 316 participants, of which eight were serious adverse events requiring hospitalisation mainly due to diarrhoeal disease (one [1%] participant in the control group, three [2%] in the 12 mg screen-and-treat group, and four [3%] in the 6 mg screen-and-treat group; Compared with blood samples from control participants without anaemia used in the standardised assays, the growth of malaria parasites in fresh red blood cells from participants with anaemia was suppressed at day 0. At day 49, growth was stimulated in all groups and was significantly higher than at baseline (p=0·0012), before a subsequent reduction until day 84, although this still remained higher than at baseline (p=0·0054; Ex-vivo assays of malaria growth in erythrocytes, reticulocyte count, and sentinel bacteria growth in plasma samples at days 0, 49, and 84Growth rates of The ex-vivo growth rate of 