Vitamin D Supplementation to Prevent Tuberculosis Infection in South African Schoolchildren: Multicentre Phase 3 Double-Blind Randomised Placebo-Controlled Trial (ViDiKids)

BACKGROUND: Vitamin D metabolites induce innate antimycobacterial responses in vitro. Observational studies consistently report independent associations between vitamin D deficiency and increased susceptibility to Mycobacterium tuberculosis infection.  METHODS: We conducted a double-blind individually randomised placebo-controlled trial to determine whether weekly oral supplementation with 250 μg (10,000 IU) vitamin D3 for 3 years reduced risk of sensitisation to M. tuberculosis in Cape Town schoolchildren aged 6-11 years with negative QuantiFERON-TB Gold Plus (QFT-Plus) assay results at baseline. The primary outcome was a positive end-trial QFT-Plus result, analysed using a mixed effects logistic regression model with school of attendance included as a random effect. Secondary outcomes were end-study serum 25-hydroxyvitamin D (25[OH]D) concentrations and adverse events.  RESULTS: 1682 children attending 23 schools were randomised (829 to vitamin D, 853 to placebo). Mean end-study 25(OH)D concentrations in participants randomised to vitamin D vs. placebo were 104.3 vs. 64.7 nmol/L, respectively (95% CI for difference, 37.6 to 41.9 nmol/L). 76/665 (11.4%) participants allocated to vitamin D vs. 88/684 (12.9%) participants allocated to placebo tested QFT-Plus positive at 3-year follow-up (adjusted odds ratio 0.87, 95% CI 0.62 to 1.20, P=0.39). The incidence of adverse events did not differ between study arms.  INTERPRETATION: Weekly oral supplementation with 250 μg (10,000 IU) vitamin D3 for 3 years elevated serum 25(OH)D concentrations among Cape Town schoolchildren but did not reduce their risk of QFT-Plus conversion. FUNDING: This research was funded by the UK Medical Research Council (MR/M026639/1 awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also received support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). DECLARATION OF INTERESTS: 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. ETHICS APPROVAL: The trial was sponsored by Queen Mary University of London, approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2) TRIAL REGISTRATION: South African National Clinical Trials Register (DOH-27-0916-5527) and ClinicalTrials.gov (ref NCT02880982).