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All Studies   Meta Analysis   Recent:  
0 0.5 1 1.5 2+ ER visit 48% Improvement Relative Risk Mean cumulative sympt.. 14% EQ-VAS average score <80 29% EQ5D improvement, Wk 1 29% EQ5D improvement, Wk 2 14% EQ5D improvement, Wk 3 50% EQ5D improvement, Wk 4 -12% Recovery time -4% PASC, 12 weeks 12% PASC, 8 weeks 36% PASC, 4 weeks 1% Vitamin D  Seely et al.  LATE TREATMENT  DB RCT Is late treatment with vitamin D + combined treatments beneficial for COVID-19? Double-blind RCT 90 patients in Canada (September 2021 - April 2022) Patients likely mostly recovered before treatment received c19early.org Seely et al., BMJ Open, September 2023 Favors vitamin D Favors control

Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: a double-blind randomised controlled trial

Sep 2023  
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Early terminated low-risk population (no hospitalization) very late treatment (mean 8 days) RCT with 44 patients treated with vitamin C, D, K, and zinc, and 46 control patients, showing no significant differences.
Authors acknowledge that the very late treatment is a major limitation, noting that in an ideal setting, "patients would begin taking therapeutic interventions immediately after noticing symptoms". Authors note that patients already had a low symptom burden at baseline and that "it is likely that the majority of the participants had almost fully recovered before starting treatment."
Authors note that most participants were young, had few comorbidities and had excellent self-rated health at baseline, leaving less room for improvement.
There was low compliance with completing surveys. Data from only 64% of patients was in the main analysis.
Authors claim "high internal validity", but the loss of data was statistically significantly different between arms, without analysis or mention. Since the study involves widely available treatments, one possibility is that patients in the control arm who feel sick may be more likely to independently take the treatments (via supplementation or food/sun exposure), believing that they are in the control arm or that additional dosing is safe, and they may then feel it's inappropriate to continue submitting the surveys.
Discussion is biased, stating that "evidence for the use of these products in people with COVID-19 is limited", however there were 219 controlled studies at the time, including 8, 27, and 16 RCTs for vitamin C, D, and zinc. Authors claim high similarity between arms however there was 60% vs. 41% male patients, and 88% vs. 68% of patients that received a third dose.
Authors claim that treatment "showed no beneficial effects for overall health or symptom burden". However 48% lower ER visits is beneficial, and most outcomes show a benefit. The only statistically significant effect was the loss of data, however significant clinical effects are not expected based on the small sample, very late treatment, event rates, and outcomes.
Cholecalciferol was used in this study. Meta analysis shows that late stage treatment with calcitriol / calcifediol (or paricalcitol, alfacalcidol, etc.) is more effective than cholecalciferol: 65% [41‑79%] lower risk vs. 39% [26‑49%] lower risk. Cholecalciferol requires two hydroxylation steps to become activated - first in the liver to calcifediol, then in the kidney to calcitriol. Calcitriol, paricalcitol, and alfacalcidol are active vitamin D analogs that do not require conversion. This allows them to have more rapid onset of action compared to cholecalciferol. The time delay for cholecalciferol to increase serum calcifediol levels can be 2-3 days, and the delay for converting calcifediol to active calcitriol can be up to 7 days.
This is the 29th COVID-19 RCT for vitamin D, which collectively show efficacy with p=0.0000035.
This is the 117th of 118 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 30 sextillion).
This study includes vitamin C, zinc, and vitamin D.
ER visit, 47.6% lower, RR 0.52, p = 0.68, treatment 2 of 42 (4.8%), control 4 of 44 (9.1%), NNT 23.
relative mean cumulative symptom score, 13.8% better, RR 0.86, p = 0.41, treatment mean 166.3 (±92.3) n=34, control mean 192.9 (±153.6) n=24.
EQ-VAS average score <80, 29.4% lower, RR 0.71, p = 0.54, treatment 7 of 34 (20.6%), control 7 of 24 (29.2%), NNT 12, average daily EQ-VAS score <80.
relative EQ5D improvement, 28.6% better, RR 0.71, p = 0.44, treatment 32, control 31, relative improvement in EQ5D, week 1.
relative EQ5D improvement, 14.3% better, RR 0.86, p = 0.73, treatment 33, control 30, relative improvement in EQ5D, week 2.
relative EQ5D improvement, 50.0% better, RR 0.50, p = 0.17, treatment 32, control 33, relative improvement in EQ5D, week 3.
relative EQ5D improvement, 12.5% worse, RR 1.12, p = 0.47, treatment 30, control 25, relative improvement in EQ5D, week 4.
recovery time, 4.0% higher, relative time 1.04, p = 0.81, treatment 34, control 24.
risk of PASC, 12.1% lower, RR 0.88, p = 1.00, treatment 3 of 33 (9.1%), control 3 of 29 (10.3%), NNT 80, 12 weeks.
risk of PASC, 35.7% lower, RR 0.64, p = 0.69, treatment 3 of 35 (8.6%), control 4 of 30 (13.3%), NNT 21, 8 weeks.
risk of PASC, 0.6% lower, RR 0.99, p = 1.00, treatment 6 of 35 (17.1%), control 5 of 29 (17.2%), NNT 1015, 4 weeks.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Seely et al., 22 Sep 2023, Double Blind Randomized Controlled Trial, placebo-controlled, Canada, peer-reviewed, mean age 39.9, 10 authors, study period September 2021 - April 2022, dosage 51,000IU day 1, 1,000IU days 2-21, this trial uses multiple treatments in the treatment arm (combined with vitamin C, D, K2, and zinc) - results of individual treatments may vary, trial NCT04780061 (history).
Contact: dseely@thechi.c, mlegacy@thechi.ca.
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Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: a double-blind randomised controlled trial
Dugald Seely, Mark Legacy, Ellen Conte, Caitlyn Keates, Athanasios Psihogios, Tim Ramsay, Dean A Fergusson, Salmaan Kanji, John-Graydon Simmons, Kumanan Wilson
BMJ Open, doi:10.1136/bmjopen-2023-073761
Background COVID-19 has caused morbidity, hospitalisation and mortality worldwide. Despite effective vaccines, there is still a need for effective treatments, especially for people in the community. Dietary supplements have long been used to treat respiratory infections, and preliminary evidence indicates some may be effective in people with COVID-19. We sought to evaluate whether a combination of vitamin C, vitamin D 3 , vitamin K 2 and zinc could improve overall health and decrease symptom burden in outpatients diagnosed with COVID-19. Methods Participants were randomised to receive either vitamin C (6 g), vitamin D 3 (1000 units), vitamin K 2 (240 μg) and zinc acetate (75 mg) or placebo daily for 21 days and were followed for 12 weeks. An additional loading dose of 50 000 units vitamin D 3 (or placebo) was given on day one. The primary outcome was participant-reported overall health using the EuroQol Visual Assessment Scale summed over 21 days. Secondary outcomes included health status, symptom severity, symptom duration, delayed return to usual health, frequency of hospitalisation and mortality. Results 90 patients (46 control, 44 treatment) were randomised. The study was stopped prematurely due to insufficient capacity for recruitment. The mean difference (control-treatment) in cumulative overall health was -37.4 (95% CI -157.2 to 82.3), p=0.53 on a scale of 0-2100. No clinically or statistically significant differences were seen in any secondary outcomes. Interpretation In this double-blind, placebo-controlled, randomised trial of outpatients diagnosed with COVID-19, the dietary supplements vitamin C, vitamin D 3 , vitamin K 2 and zinc acetate showed no clinically or statistically significant effects on the documented measures of health compared with a placebo when given for 21 days. Termination due to feasibility limited our ability to demonstrate the efficacy of these supplements for COVID-19. Further research is needed to determine clinical utility. Trial registration number NCT04780061.
Competing interests None declared. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Not applicable. Ethics approval This study involves human participants and this study was approved by the Research Ethics Boards of the Ottawa Health Sciences Network (20210072-01H) and Canadian College of Naturopathic Medicine (CCNMREB036. Seely.Wilson). No study activities took place before approval by both organisations. Each participant signed an informed consent form approved by both organisations prior to participation in the study. Participants gave informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available on reasonable request. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages),..
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Late treatment
is less effective
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