We have previously shown that high-dose vitamin D3 improved weight gain and neurodevelopmental indices in children receiving standard therapy for uncomplicated severe acute malnutrition (SAM). We conducted a randomised placebo-controlled trial to determine whether two oral doses of 200,000 international units (IU) vitamin D3 would benefit children aged 6-59 months receiving standard therapy for complicated SAM in Lahore, Pakistan. The primary outcome was mean weight-for-height or -length z-score (WHZ) at 2-month follow-up. Secondary efficacy outcomes were mean WHZ at 6-month follow-up and mean lean mass index, Malawi Development Assessment Tool (MDAT) scores and serum 25-hydroxyvitamin D (25[OH]D) concentrations at 2- and 6-month follow-up. 259 children were randomised (128 to vitamin D, 131 to placebo), of whom 251 (96.9%) contributed data to analysis of the primary outcome. At 2-month follow-up, participants allocated to vitamin D had significantly higher mean serum 25(OH)D concentrations than those allocated to placebo (adjusted mean difference [aMD] 100.0 nmol/L, 95% confidence interval [CI] 72.2 to 127.8 nmol/L). This was not associated with an inter-arm difference in mean WHZ (aMD 0.02, 95% CI -0.20 to 0.23), or in any other anthropometric or neurodevelopmental outcome assessed at 2- or 6-month follow-up overall. However, sub-group analyses revealed some evidence of greater benefit from the intervention among participants with baseline serum 25(OH)D concentrations <50 nmol/L vs. ≥50 nmol/L for the outcomes of mean WHZ at 2-month follow-up (P for interaction 0.13) and mean MDAT score at 2-month follow-up (P for interaction 0.039). The intervention was safe. In conclusion, high-dose vitamin D3 elevated mean serum 25(OH)D concentrations in children receiving standard therapy for complicated SAM in Pakistan, but did not influence any anthropometric or neurodevelopmental outcome studied overall. Further trials are needed to determine whether children with lower baseline vitamin D status benefit from this intervention. The trial was registered at ClinicalTrials.gov with the identifier NCT04270643.

ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref NCT04641195); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests.

NCT04270643

The trial was funded by the Thrasher Research Fund (ref 15080).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trial was approved by the National Bioethics Committee (NBC) of Pakistan (ref. 4-87/NBC-516/20/477) and the Liverpool School of Tropical Medicine Research Ethics Committee (ref. 20-028).

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