Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT)
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Abstract
Objective
To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19.
Design
Phase 3 open label randomised controlled trial.
Setting
United Kingdom.
Participants
6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.
Interventions
Offer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.
Main outcome measures
The primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.
Results
Of 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).
Conclusions
Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.
Trial registration
ClinicalTrials.gov NCT04579640 .
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SciScore for 10.1101/2022.03.22.22271707: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization RANDOMIZATION AND INTERVENTION: A randomly-selected subset of 6200 cohort participants who were assessed as eligible on the basis of data from their enrolment questionnaire, and who reported no supplemental vitamin D intake at baseline, were individually randomized by the trial statistician using a computer program (Stata v14.2) to receive an offer of a postal vitamin D test with supply of 3200 IU vitamin D/day if their blood 25(OH)D concentration was found to be less than 75 nmol/L (‘higher-dose offer group’) vs. the same testing offer with supply of 800 IU vitamin D/day if 25(OH)D was less than 75 nmol/L (‘lower-dose … SciScore for 10.1101/2022.03.22.22271707: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization RANDOMIZATION AND INTERVENTION: A randomly-selected subset of 6200 cohort participants who were assessed as eligible on the basis of data from their enrolment questionnaire, and who reported no supplemental vitamin D intake at baseline, were individually randomized by the trial statistician using a computer program (Stata v14.2) to receive an offer of a postal vitamin D test with supply of 3200 IU vitamin D/day if their blood 25(OH)D concentration was found to be less than 75 nmol/L (‘higher-dose offer group’) vs. the same testing offer with supply of 800 IU vitamin D/day if 25(OH)D was less than 75 nmol/L (‘lower-dose offer group’) vs. no offer of vitamin D testing or supplementation (‘no offer group’), with a 1:1:2 allocation ratio. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study also has limitations. Provision of supplements to participants randomized to intervention was contingent on demonstrating inadequate vitamin D status: thus, a subset (13.7%) of participants randomized to intervention did not receive study supplements. On the other hand, another subset (49.9%) of participants randomized to no offer took a vitamin D supplement on one or more occasions during follow-up. This may have led to increases in 25(OH)D concentrations in the no offer arm over the course of the study, although seasonal effects (sampling in June vs. December) will also have contributed. Together, these factors could have diluted any effect of vitamin D in the primary intention-to-treat analysis. We sought to overcome this by conducting a sensitivity analysis, which included only those randomized to offer vs. no offer who did vs. did not take supplemental vitamin D, respectively. The fact that this analysis showed no effect of vitamin D supplementation on all outcomes investigated, despite the larger differences in end-study 25(OH)D concentrations between intervention vs. no-offer arms seen for this analysis vs. the intention-to-treat analysis (Fig. 2), provides some reassurance that the null result yielded by the intention-to-treat analysis is valid. Ultimately, however, this trial was designed to investigate the effectiveness of a pragmatic ‘test-and-treat’ approach to boosting population vitamin D status, rather than biologic efficacy of vitamin D to prevent AR...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04579640 Active, not recruiting Trial of Vitamin D to Reduce Risk and Severity of COVID-19 a… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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