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)
et al., BMJ, doi:10.1136/bmj-2022-071230, CORONAVIT, NCT04579640, Mar 2022 (preprint)
RCT 5,979 low risk patients (zero COVID-19 deaths) in the UK,
showing no significant differences with vitamin D prophylaxis.
51% of confirmed COVID-19 cases were hospitalized in the control arm which
is 7 times the median rate in other studies reporting both cases and hospitalization as of
Sep 2022 (7.2%). Only a fraction of cases may have been identified, significant
differential testing propensity is possible, and hospitalizations may be with COVID rather
than for COVID. Villasis-Keever et al. present an RCT showing conflicting results, 78%
lower cases with vitamin D prophylaxis.
This trial has multiple critical issues:
Vitamin D for COVID-19
8th treatment shown to reduce risk in
October 2020, now with p < 0.0000000001 from 138 studies, recognized in 18 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
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CRITICALHospitalization-case ratio implausible.
Hospitalizations per confirmed case were 51.3% for no offer, 43.6% for lower dose, 64.4% for higher dose, compared to a UK Alpha-wave benchmark of ~7%. This suggests that many cases may not have been identified.
CRITICALHospitalization severity profile inconsistent with contemporaneous cohorts.
The trial reports 93 COVID hospitalizations, but only 3 ventilated patients and no COVID deaths. This is an unusually low severity profile for a cohort hospitalized for COVID during the Alpha-wave period, and is unlikely for a case mix severe enough to hospitalize half of all cases. Authors' explanation that older age and cardiovascular disease increased hospitalization risk does not explain the absence of more severe outcomes. As below, hospitalization may include non-COVID-19 patients and/or patients admitted with rather than for COVID-19.
CRITICALConfirmed-case denominator requires a positive test; hospitalization does not.
A positive test was required for confirmed COVID-19, however there appears to be no such requirement for hospitalization. Table S2 lists U07.2 (COVID-19, virus not identified) alongside U07.1 among the linkage codes, Table S1 Q3.3 includes 'suspected or proven COVID-19' as a hospital diagnosis, the admission outcome is among the full ITT rather than within confirmed cases, and there is no note for swab confirmation as there is for confirmed cases. Hospitalization may include non-COVID-19 patients, and may include patients admitted with COVID-19 rather than for COVID-19.
CRITICALDifferential testing propensity likely; not discussed.
The no-offer arm was never contacted about the trial at all, whereas intervention participants received a posted blood spot kit and a personal 25(OH)D result, 86% of them were told their status was suboptimal and supplied six months of capsules, and they were sent an extra adherence questionnaire (some no offer patients received a blood spot kit but only after outcome accrual had closed). This suggests that the intervention arms could be significantly more likely to seek a SARS-CoV-2 test. The hospitalization to case ratio suggests only a fraction of cases were confirmed, and an unknown degree of differential testing propensity makes the result uninterpretable. Table S1 Q1.1 asks patients monthly if they had a swab however the data is not reported. Every ITT odds ratio in the COVID-19 outcome chain is greater than 1.0 (primary, confirmed COVID, hospitalization, symptoms at study end). This is more consistent with differential detection than with harm: harm is implausible at these doses, and a biological effect is not expected to move these heterogeneous endpoints similarly, whereas a detection differential acts on a shared step.
CRITICAL800 IU cumulative hazard plots consistent with differential ascertainment.
The 800 IU cumulative hazard plots show consistently higher risk throughout the trial period. 800 IU may have limited effect, however based on previous research it is not expected to produce consistently higher risk - for example the meta-analysis informing this trial's design found protective effects at around this dose. These results are consistent with differential ascertainment where intervention arm patients are more likely to seek a SARS-CoV-2 test.
CRITICALLower risk for 3,200 IU vs. 800 IU, which removes differential ascertainment.
Authors do not report any comparison between the 3,200 IU and 800 IU arms, however this is a useful analysis because it removes the effect of differential ascertainment between the intervention arms and the no offer arm (differences between treatment arms are still possible). The results show a trend of lower risk for the higher dose. Comparing the HRs in the pre-vaccination phase (Fig. S2) we get HR 0.68 [approx. 0.40-1.28]. Comparing the ORs for the full 6-month COVID counts we get OR 0.81 [0.55-1.21]. Results also show a trend of increased benefit earlier in the trial - at week 5 (Fig. S2) we get RR ~0.50.
CRITICALMost events occurred before supplementation could raise 25(OH)D.
Figure S2A indicates that roughly two-thirds of COVID-19 events in vaccine-naive control participants had accrued within about four weeks of randomization, consistent with the UK Alpha peak falling in early January 2021, weeks 2-4 of follow-up. Daily cholecalciferol requires 8-12 weeks to approach steady state, and capsules were dispatched after a postal kit was returned and assayed, possibly two to four weeks after randomization. The 25(OH)D separation prevailing when most events occurred was therefore likely a fraction of the end-of-study values of 12.7 and 36.3 nmol/L - on the order of 4-6 and 12-18 nmol/L - and some events occurred in participants who had taken no capsules at all. This biases results towards the null.
CRITICAL'Admitted to hospital for ARI of any cause' appears to exclude COVID-19 admissions.
Table 2 reports 12/7/11 for all-cause ARI admission - identical to Table S7's 'Non-COVID-19 acute respiratory infection' rows, while COVID admissions (40/24/29) are reported separately. An 'any cause' count of 12 should not be one-third of the COVID-only count, and Table 3 states that all-cause ARI outcomes include COVID-19.
CRITICALMajor control-arm vitamin D contamination.
1547/3100 controls (50%) reported taking supplemental vitamin D at least once during follow-up, substantially reducing the biological contrast between randomized groups.
CRITICALNo-offer baseline percentages computed on n=3200 instead of 3100.
Counts in the no-offer column sum correctly to 3100 but the printed percentages sum to 96.9% = 3100/3200.
CRITICALSensitivity-analysis no-offer denominator cannot be reconciled with flow diagram.
ITT no offer is 2949 and Fig 1 shows 1547 took an off-trial vitamin D supplement at least once, giving 1402 eligible for the sensitivity analysis, but Table 3 uses 1331 - a gap of 71 (5.1%).
CRITICALBaseline 25(OH)D missingness reported three incompatible ways.
For the 800 IU arm, 'not determined' is 179 in the Table 1 body, 198 in the Table 1 footnote, and 172 from Fig. 1 (69 declined + 103 unavailable). For the 3200 IU arm the three values are 176, 189, and 166. Table 1 also reports 43 participants at 25(OH)D ≥75 in the lower-dose arm versus 44 from Fig 1, and 28 versus 26 in the higher-dose arm.
SERIOUSCumulative hazard plot shows early benefit that declines over time.
The cumulative hazard plot for 3,200 IU vaccine-naïve patients shows a trend of increased benefit earlier in the trial. Fig. S2 C shows RR ~0.67, 0.89, and 1.26 at weeks 5, 10, and 15.
SERIOUSTable 3 confidence interval '0.95 (0.55 to 16.29)' has an impossible lower bound.
For in-hospital ventilatory support and the higher dose versus no offer, the sensitivity analysis confidence interval is highly asymmetric on the log scale; recomputation gives a lower bound of 0.055.
SERIOUSTable S5 vaccination strata omit cases; implausible residual in the higher-dose arm.
Covid cases by stratum sum to 68 of 78 (no offer), 48 of 55 (lower dose) and 32 of 45 (higher dose). The denominators imply 85, 26 and 17 ITT participants of unknown vaccination status, so the residual cases fall on 11.8%, 26.9% and 76.5% of participants respectively. The 76% rate in one cell appears implausible.
SERIOUSAbstract omits contamination, non-receipt, and the effectiveness/efficacy distinction.
Neither the 50% of controls who took off-trial vitamin D nor the 14% of intervention participants who never received capsules appears in the abstract, nor does the abstract (unlike the discussion) indicate that the trial tested a pragmatic delivery strategy rather than biological efficacy.
SERIOUSPrespecified baseline-status subgroup analysis abandoned without substitute.
The random-forest imputation of baseline 25(OH)D for the no-offer arm failed its own validity check and the subgroup analysis was dropped. This was transparently reported, however measured baseline values exist for both intervention arms, so effect modification was directly testable for the 800 versus 3200 IU comparison, and restriction to profound deficiency was possible. No direct 800 versus 3200 IU contrast is reported anywhere, despite the three-arm design being built to support a dose-response comparison.
SERIOUSHypertension 3.7% versus heart disease 19.5% potentially reversed.
In a cohort with median age 60, UK prevalence would be roughly 26-30% for hypertension and 3-4% for diagnosed heart disease, suggesting a potential reversal. The paper notes the 19.5% figure is about five times the population rate and uses it to argue that high-risk groups were over-represented.
MAJORSubstantial fraction of patients not treated.
14% of participants randomized to a vitamin D offer did not receive study supplementation - the primary intention-to-treat analysis estimates the effect of an offer of test-and-treat rather than the effect of actually taking vitamin D.
MAJORPrimary event rate far below power assumptions.
The trial assumed a 20% primary-event rate in controls for its power calculation, but the observed rate was only 4.6%.
MAJORAdherence sensitivity analysis breaks randomization.
The sensitivity analysis excluded intervention participants with poor adherence and controls who used any off-trial vitamin D, including nearly half of randomized controls. Because adherence and supplement uptake are post-randomization behaviors associated with health behavior and other prognostic factors, this analysis is vulnerable to selection and healthy-user bias and should not be treated as an unbiased efficacy estimate.
MAJORBaseline 25(OH)D standard deviations differ between Table 1 and text.
The results report SD 17.8 (lower dose) and 16.2 (higher dose); Table 1 reports 18.0 and 16.4. Ranges are identical (10.3-179.6 and 10.3-122.0), suggesting that these are the same data on undefined different subsets.
MAJORThe 94.4% adherence figure cannot be derived from Table S4.
Table S4 yields 2496 participants reporting intake four or more times per week out of 2653 respondents (94.1%). Neither the numerator (2523) nor the denominator (2674, the number supplied) follows from that table, which itself uses denominators of 1314 and 1339 against the 1328 and 1346 actually supplied.
MAJORTable 2 COPD denominators exceed baseline COPD counts.
The exacerbation analysis uses 63/28/27 COPD patients while Table 1 baseline counts show 61/27/26, despite ITT being a subset of those randomized.
MAJORPrincipal investigator is also trial statistician and data manager in an unblinded trial.
DAJ is listed as Principal Investigator, a Statistician, Data Management lead, and co-guarantor. There was no independent allocation-blinded statistical analysis, the trial is open label with no placebo, and the DMC reviewed serious adverse events once.
MAJOR'High prevalence of suboptimal vitamin D status' uses 75 nmol/L threshold.
The 97.4% suboptimal figure uses a cut-off of 75 nmol/L, above the IOM sufficiency threshold of 50 nmol/L though consistent with Endocrine Society guidance. Of the 2745 participants with baseline results, 73.0% were below 50 nmol/L and 16.3% (448) below 25 nmol/L. The profoundly deficient subgroup that dose-response analyses identify as most likely to benefit was only about a sixth of those tested.
MAJOROverall median age below the medians of three-quarters of the sample.
Overall 60.2 years against arm medians of 60.8 (no offer, 50% of sample), 59.8 (lower dose) and 60.7 (higher dose). A density-weighted calculation gives roughly 60.5. The overall result is feasible only under an unusual concentration of ages near the median.
MINORUndisclosed left-censoring of 25(OH)D at 10.3 nmol/L.
Both intervention arms (n about 1370 each) report an identical minimum of exactly 10.3 nmol/L, which equals the sum of the two stated limits of quantitation. Sub-LOQ values appear to have been set to LOQ and summed, a legitimate convention but unstated.
MINORTable 3 reports p=0.31 for an odds ratio of 1.10 (0.59 to 2.04).
For hospital admission for COVID-19 and the higher dose versus no offer, the sensitivity analysis confidence interval reproduces, but the correct Wald p-value is 0.76 (z = 0.311). The printed 0.31 is the z-statistic, not the p-value.
MINORDiscontinuation events: 25 in Table S6 versus 24 in Table S8 and the text.
Table S6 reports 25 non-serious adverse events leading to discontinuation in the higher-dose arm. The results state '23 v 24' totalling 47, and Table S8's list sums to 24.
MINORNominal baseline asthma imbalance between the two intervention arms.
265/1550 (17.1%) versus 215/1550 (13.9%), p = 0.014. Possible by chance but noted because asthma exacerbation is a secondary outcome.
This is the 14th of 41 COVID-19 RCTs for vitamin D, which collectively show efficacy with p=0.00000049.
This is the 75th of 138 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001.
Standard of Care (SOC) for COVID-19 in the study country,
the United Kingdom, is very poor with very low average efficacy for approved treatments5.
The United Kingdom focused on expensive high-profit treatments, approving only one low-cost early treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of early treatment due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.
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risk of mechanical ventilation, 94.7% higher, RR 1.95, p = 1.00, treatment 1 of 1,515 (0.1%), control 1 of 2,949 (0.0%), 3200IU/day.
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risk of mechanical ventilation, 94.7% higher, RR 1.95, p = 1.00, treatment 1 of 1,515 (0.1%), control 1 of 2,949 (0.0%), 800IU/day.
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risk of hospitalization, 41.1% higher, RR 1.41, p = 0.16, treatment 29 of 1,515 (1.9%), control 40 of 2,949 (1.4%), 3200IU/day.
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risk of hospitalization, 16.8% higher, RR 1.17, p = 0.60, treatment 24 of 1,515 (1.6%), control 40 of 2,949 (1.4%), 800IU/day.
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risk of case, 8.8% higher, RR 1.09, p = 0.55, treatment 76 of 1,515 (5.0%), control 136 of 2,949 (4.6%), 3200IU/day.
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risk of case, 24.5% higher, RR 1.25, p = 0.11, treatment 87 of 1,515 (5.7%), control 136 of 2,949 (4.6%), 800IU/day.
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risk of case, 12.3% higher, RR 1.12, p = 0.56, treatment 45 of 1,515 (3.0%), control 78 of 2,949 (2.6%), confirmed, 3200IU/day.
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risk of case, 37.3% higher, RR 1.37, p = 0.08, treatment 55 of 1,515 (3.6%), control 78 of 2,949 (2.6%), confirmed, 800IU/day.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
Villasis-Keever et al., Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial, Archives of Medical Research, doi:10.1016/j.arcmed.2022.04.003.
Jolliffe et al., 23 Mar 2022, Randomized Controlled Trial, United Kingdom, peer-reviewed, median age 60.2, 25 authors, study period December 2020 - June 2021, dosage 3,200IU daily, daily, trial NCT04579640 (history) (CORONAVIT).
Contact: d.a.jolliffe@qmul.ac.uk, a.martineau@qmul.ac.uk.
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)
BMJ, doi:10.1136/bmj-2022-071230
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.
Contributors: ARM, DAJ, and CR designed the study, with input from PP, JS, DF, RAL, GAD, FK, CJG, JN, AS, SEF, AGR, and SOS. DAJ, HH, NP, SM, MT, and ARM managed the trial. AN, NLB, and RG performed the laboratory assays. DAJ, MG, MT, GV, and CO managed and analysed the data. DAJ and ARM contributed equally and are the guarantors. All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. ARM wrote the first draft of the paper. All authors contributed to the interpretation of the results, review and approval of the manuscript, and the decision to submit it for publication. There were no agreements concerning confidentiality of the data between the sponsor and the authors or the institutions named in the credit lines. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funding:
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Objective</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Design</jats:title>\n <jats:p>Phase 3 open label randomised controlled trial.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Setting</jats:title>\n <jats:p>United Kingdom.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Participants</jats:title>\n <jats:p>6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Interventions</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Main outcome measures</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>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).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Trial registration</jats:title>\n <jats:p>\n ClinicalTrials.gov\n <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"NCT04579640\" ext-link-type=\"clintrialgov\">NCT04579640</jats:ext-link>\n .\n </jats:p>\n </jats:sec>",
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