Table of contents
- Behind the scenes at the Coronavit trial
- Vitamin D Life - Risk of COVID not reduced by 3,200 IU of vitamin D during 6 months (no surprise) – RCT March 2022
- Vitamin D Life -
43 studies in both categories Virus and Intervention Behind the scenes at the Coronavit trial
Adrian Martineau discusses the challenges in getting a trial of vitamin D for covid-19 prevention off the ground
BMJ 2022;378:o2203 http://dx.doi.org/10.1136/bmj.o2203 Published: 12 September 2022The striking overlap between risk factors for severe covid-19 and those for vitamin D deficiency—older age, obesity, and black or South Asian ethnic origin—rang alarm bells in the vitamin D research community from the earliest days of the pandemic in the UK. Laboratory experiments had shown that vitamin D boosted innate responses to other respiratory viruses in cell culture, while our meta-analyses of randomised controlled trials found that supplements reduced the risk of acute respiratory infections in the pre-covid era.12 It seemed possible—likely, even—that the same might apply for covid-19.
Given the potential benefits and low risk of taking vitamin D, our initial instinct was to promote, rather than to evaluate, widespread supplementation. A major international micronutrient company offered to supply all NHS staff with free vitamin D supplements. When individual NHS trusts were approached to discuss implementation of this proposal, however, enthusiasm was limited: occupational health departments raised concerns about safety (vitamin D supplements can, very rarely, precipitate hypercalcaemia in hypersensitive people) and highlighted that they were not set up or indemnified to get involved—especially in the absence of hard evidence showing a benefit of vitamin D for covid-19 specifically. It became clear that randomised controlled trials (RCTs) would be required.
The obvious population for such a study was patient facing healthcare workers, as they were among those at highest risk. However, it soon became clear that such a study would not be practical: the vast majority of interested colleagues were already taking vitamin D because of the low risk:benefit ratio and the absence of effective vaccines or treatment for covid-19. A population based trial enrolling people at lower risk was an alternative—however, this would need to be much larger than a study in healthcare workers, since the lower event rate would require many more participants to be enrolled to demonstrate a given effect size with the same power.
Enter Clare Relton, a colleague who pioneered the trials-within-cohorts study design, which allows pragmatic RCTs to be nested within an observational longitudinal study, allowing for rapid and cost efficient delivery of large population based trials. Barts Charity provided funding at short notice, and the cohort (Covidence UK) launched on 1 May 2020. Within a month, more than 7000 participants had signed up.
Meanwhile, discussions with the Medicines and Healthcare Products Regulatory Agency were in progress. They advised that the trial would be classified as a Clinical Trial of an Investigational Medicine Product (CTIMP)—a fully regulated pharmaceutical trial—if we offered participants supplements without first testing their vitamin D status. The intensive oversight required to conduct CTIMPs makes them extremely costly: a seven figure sum would be required to conduct a trial of the necessary size. Grant applications to major funding bodies were submitted—and rejected.
Reluctant to throw in the towel, we redesigned the trial to incorporate a vitamin D testing step, so that participants randomised to the intervention arm of the study would only receive supplements if their vitamin D status was found to be suboptimal. This tweak introduced complexity, but allowed us to side step the CTIMP classification, thereby achieving a fourfold reduction in costs. We then approached philanthropists and micronutrient companies with requests for funding. To their great credit, many provided generous donations without imposing any conditions on publication of our findings, even if they were null—as they turned out to be.3
Apart from the main findings, what did we learn? In the face of the pandemic, members of the public stepped up to participate in medical research in huge numbers—and print and broadcast media united to help us reach out to them. The trial-within-cohort design allowed the study to be conducted rapidly and efficiently, once we overcame funding and regulatory hurdles. However, classifying a phase 3 RCT investigating physiological doses of a vitamin that is freely available over the counter in the same bracket as a phase 2 trial of a toxic cancer chemotherapeutic does not seem appropriate. A more proportionate and risk stratified approach to regulatory classification of clinical trials of micronutrient supplements or other low risk interventions is needed.Competing interests:
ARM has completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declares: funding from Barts Charity, Pharma Nord, Fischer Family Foundation, DSM Nutritional Products, Exilarch’s Foundation, Karl R Pfleger Foundation, AIM Foundation, Synergy Biologics, Cytoplan, UK National Institute for Health and Care Research Clinical Research Network, the HDR UK BREATHE Hub, the UK Research and Innovation Industrial Strategy Challenge Fund, Thornton and Ross, Warburtons, Matthew Isaacs (a philanthropist without financial interests constituting a potential conflict), and Hyphens Pharma.
- ARM declares receiving funding in the past three years to support vitamin D research from several companies that manufacture or sell vitamin D supplements:
- Pharma Nord, DSM Nutritional Products, Thornton and Ross, and Hyphens Pharma.
ARM also declares
- support for attending meetings from companies that manufacture or sell vitamin D supplements (Pharma Nord and Abiogen Pharma);
- receipt of a consultancy fee from DSM Nutritional Products;
- receipt of a speaker fee from the Linus Pauling Institute;
- participation on data and safety monitoring boards forthe 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);
- unpaid work as a programme committee member for the Vitamin D Workshop; and
- receipt of vitamin D capsules for clinical trial use from Pharma Nord, Synergy Biologics, and Cytoplan. Provenance and peer review: commissioned, not peer reviewed.
References
- Martineau AR,Jolliffe DA,Hooper RL,etal.VitaminDsupplementationtopreventacuterespiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ2017;356:.doi:10.1136/bmj.i6583 pmid: 28202713
- Jolliffe DA, Camargo CA, JrSluyter JD, etal. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. LancetDiabetes Endocrinol 2021;9:-92. doi:10.1016/S2213-8587(21)00051-6 pmid: 33798465
- Jolliffe DA, Holt H, Greenig M, etal. 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). BMJ2022;378:e071230 doi:10.1136/bmj-2022-071230
Vitamin D Life - Risk of COVID not reduced by 3,200 IU of vitamin D during 6 months (no surprise) – RCT March 2022
Table of contents
- Vitamin D Supplements for Prevention of Covid-19 or other Acute Respiratory Infections: a Phase 3 Randomized Controlled Trial (CORONAVIT)
- Major problem - did not wait for Vitamin D levels to plateau before gettng infection data
- Vitamin D Life - 36 studies have found that 5,000 IU gets only about half to >40 ng
- Many studies are finding at >50 ng level of vitamin D is needed to fight COVID
- Vitamin D Life – Is 50 ng the level needed?
- Vitamin D Life – COVID-19 treated by Vitamin D - studies, reports, videos
- Vitamin D Life – Loading (not daily) doses quickly raise Vitamin D levels and fight Viruses
Vitamin D Life -
43 studies in both categories Virus and Intervention This list is automatically updated
- 5 X less COVID infection of health care workers who took lots of vitamin D – meta-analysis Feb 2024
- COVID deaths cut in half by a single dose of 600,000 IU of Vitamin D - RCT Jan 2024
- COVID in hospital stopped by Vitamin D Receptor activators (curcumin, quercetin) – RCT June 2023
- Vitamin D Supplements Don’t Reduce COVID-19 Risk (used only 3,200 IU daily) - Oct 2022
- High dose vitamin D fights Folate gene changes by COVID, autoimmune, CVD, ALZ – Oct 2022
- COVID in hospital fought by Vitamin D (25,000 IU daily for 4 days, then 25K weekly) - RCT – July 2022
- Small Vitamin D doses for a short time never help (not improve vaccination in this case) – RCT Sept 2022
- The challenges of a Vitamin D RCT – too many already taking it, etc. – Martineau Sept 2022
- Early COVID treatments rarely work 7 days after symptoms, this trial gave Vitamin D on 7th day – RCT May 2022
- COVID children helped by Vitamin D, trial terminated: unethical to not give Vitamin D to all: – RCT July 2022
- COVID hospital deaths reduced 2X by 8 days of UVB – pilot RCT May 2022
- 21 fewer days in hospital with ARDS (COVID) if 10,000 IU of Vitamin D daily after enter hospital – RCT April, 2022
- 4X less likely to get COVID following 4,000 IU daily for a month – RCT April 2022
- Risk of COVID not reduced by 3,200 IU of vitamin D during 6 months (no surprise) – RCT March 2022
- Group achieving 30 ng (vs 26 ng) were 2X less likely to get COVID symptoms - RCT Jan 2022
- Tested positive for COVID, taking probiotics stopped symptoms 5 days sooner - RCT Jan 2022
- Vitamin D given slowly in hospital did not fight COVID-19 much - Nov 2021
- Nursing home vaccinated against Influenza, 800 IU of vitamin D daily cut infection rate in half – small RCT Oct 2021
- COVID-19 appears reduced by Resveratrol plus 100K IU of vitamin D – Small RCT Sept 2021
- Vitamin D trial for COVID-19 – using their patented slow-release form – Aug 2021
- COVID-19 mortality reduced 4X (chart looks like 2X) by large, infrequent doses of Vitamin D in France – July 2021
- COVID-19 outpatients getting Quercetin nanoemulsion had excellent outcomes (Q increased Vitamin D in cells) – RCT – June 2021
- 5,000 U daily raised Vitamin D a bit and helped COVID-19 a bit – RCT June 2021
- COVID-19 inflammation extinguished by 60,000 IU of vitamin D nanoemulsion daily for a week – RCT May 2021
- Better response to shingles virus after 6,400 IU Vitamin D raised above 40 ng – Jan 2021
- COVID-19 ICU survival rate increased 7X by daily Omega-3 – RCT March 2021
- Kidney patients who happened to be getting high-dose Calcitriol were 9X less likely to die of COVID-19 - April 6, 2021
- Vitamin D not help 10 days after COVID-19 symptoms - RCT March 2021
- 5X less likely to enter ICU with COVID-19 if get Calcifediol (semi-activated vitamin D) - RCT Feb 19, 2021
- calcifediol rct
- COVID-19 defeated 3x faster by 420,000 IU Vitamin D nanoemulsion – RCT Nov 12, 2020
- COVID-19 defeated by calcifediol form of Vitamin D in Spain - pilot RCT Aug 29, 2020
- Swine flu not prevented by 2,000 IU of vitamin D daily (the upper limit at the time) – RCT 2014
- Influenza vaccine antibodies not change with Vitamin D – 21 ng or 44 ng – RCT Feb 2019
- Dengue virus prevented by a small amount of Vitamin D – RCT Nov 2019
- Half the risk of Influenza -A in infants taking 1200 IU of vitamin D for 4 months – RCT Jan 2018
- Chikungunya virus arthritis pain reduced by weekly 60,000 IU vitamin D – Sept 2016
- Many Infectious diseases (virus) treated and prevented by Vitamin D – review July 2009
- Influenza prevented by 40 ng levels or treated with vitamin D hammer (50,000 IU) – June 2015
- Infection fighting ability increased with 5,000 IU Vitamin D daily – April 2015
- Vitamin D prevents Hepatitis-C and helps treat it (many studies)
- Malaria in mice brains, and associated inflammation, prevented by Vitamin D intervention – July 2014
- Influenza A: 5X reduction in first month (only) with 2,000 IU of vitamin D– RCT July 2014
The challenges of a Vitamin D RCT – too many already taking it, etc. – Martineau Sept 2022739 visitors, last modified 13 Sep, 2022, This page is in the following categories (# of items in each category) - ARM declares receiving funding in the past three years to support vitamin D research from several companies that manufacture or sell vitamin D supplements: