Results From the REsCue Trial: A Randomized Controlled Trial with Extended-Release Calcifediol in Symptomatic Outpatients with COVID-19
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Abstract
Importance
The benefit of vitamin D treatment for coronavirus disease 2019 (COVID-19) remains unclear.
Objective
To investigate the effect of raising serum total 25-hydroxyvitamin D (25D) to 50-100 ng/mL with oral extended-release calcifediol (ERC) on time to symptom resolution in mild to moderate COVID-19.
Design, Setting, and Participants
A multicenter, randomized, double-blind, placebo-controlled study evaluated treatment of 160 outpatients with COVID-19 diagnosed between November 2020 and October 2021.
Interventions
Patients were treated for 4 weeks with ERC (30 mcg/capsule; 300 mcg on Days 1-3 and 60 mcg on Days 4-27) or placebo.
Outcome Measures
Primary endpoints were raising serum 25D to ≥50 ng/mL at Day 14 and resolution time for five aggregated symptoms. Secondary endpoints included resolution time for aggregated and individual symptoms as a function of serum 25D and changes in clinical biomarkers.
Results
171 subjects randomized, 160 treated and 134 (65 ERC and 69 placebo) retained. Average age was 43 (range: 18-71); 59% female, 92% White, 80% Hispanic, 7% African-American, 1% Other, 76% overweight, 40% obese, 26% comorbidities, mean baseline 25D of 37±1 (SE) ng/mL. ERC increased mean 25D to 82±4 ng/mL (p<0.001) by Day 7; 88% of subjects attained a level ≥50 ng/mL; the placebo group trended lower. Resolution time for five aggregated symptoms was unchanged by ERC given that two composite non-respiratory symptoms responded poorly. Prespecified analyses showed that respiratory symptoms tended to resolve earlier when serum 25D levels reached ≤50 ng/mL, but statistical significance was limited by small sample size and non-compliance: 25D increased in seven placebo subjects (unauthorized supplementation) and none occurred in five ERC subjects (failure to dose). A post-hoc composite of three respiratory symptoms (trouble breathing, chest congestion and dry or hacking cough) resolved 3.0 days faster when 25D was elevated at Days 7 and 14 (p<0.05); chest congestion resolved 4.0 days faster with 25D increases of ≥25 ng/mL (p<0.05). Safety concerns including hypercalcemia were absent with ERC treatment.
Conclusions and Relevance
ERC was effective in increasing serum 25D in outpatients with COVID-19, which may have accelerated resolution of respiratory symptoms suggesting mitigation of COVID-19 pneumonia risk, findings which warrant further study.
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SciScore for 10.1101/2022.01.31.22270036: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participants: All patients provided written informed consent before participation in the study.
IRB: Independent Oversight and Blinding: The study was approved by Advarra (Columbia, MD), a central Institutional Review Board (IRB), and overseen by an independent five-member Data Safety Monitoring Board (DSMB) comprised of an expert in viral disease pathogenesis, a nephrologist, a biostatistician, a pulmonary medicine expert and an endocrinologist experienced in clinical safety monitoring.Sex as a biological variable not detected. Randomization This multicenter trial (NCT04551911) titled “A Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Safety and Efficacy of Rayaldee … SciScore for 10.1101/2022.01.31.22270036: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Participants: All patients provided written informed consent before participation in the study.
IRB: Independent Oversight and Blinding: The study was approved by Advarra (Columbia, MD), a central Institutional Review Board (IRB), and overseen by an independent five-member Data Safety Monitoring Board (DSMB) comprised of an expert in viral disease pathogenesis, a nephrologist, a biostatistician, a pulmonary medicine expert and an endocrinologist experienced in clinical safety monitoring.Sex as a biological variable not detected. Randomization This multicenter trial (NCT04551911) titled “A Randomized, Double-Blind Placebo-Controlled Study to Evaluate the Safety and Efficacy of Rayaldee (calcifediol) Extended-release Capsules to Treat Symptomatic Patients Infected with SARS-CoV-2 (REsCue)” enrolled symptomatic COVID-19 outpatients from 10 sites across the United States and randomized them in a 1:1 ratio for 4 weeks of treatment with ERC (30 mcg/capsule) or placebo and a 2-week follow-up. Blinding Subjects, study personnel and the sponsor (and its designees, with the exception of the DSMB and three unblinded members of the data management team) were blinded until after database lock to treatment assignments and to serum vitamin D metabolite laboratory data. 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:Limitations: The inability of this study to show more significant differences in time to resolution for respiratory symptoms is likely due to inadequate power (small sample size); the modest severity of COVID-19 in the enrolled subjects; the fact that 17% of subjects assigned to placebo treatment had, unexpectedly, serum 25D levels above 50 ng/mL at baseline; dosing noncompliance (four previous but unpublished pharmacokinetic studies of a single 900 mcg ERC loading dose in healthy volunteers have shown that no subject failed to achieve an increase in serum 25D of at least 6 ng/mL); and, varying periods of time between onset of symptoms and diagnosis in of COVID-19 as well as between diagnosis and initiation of ERC treatment. The observed positive effect of 25D elevation on resolution of COVID-19 respiratory symptoms is based on a post-hoc analysis and needs to be confirmed in a larger study with an appropriate prespecified endpoint.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04551911 Completed Safety and Efficacy of Rayaldee for Treating Mild to Moderat… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
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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