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The challenges of a Vitamin D RCT – too many already taking it, etc. – Martineau Sept 2022


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 2022

The 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
  1. 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
  2. 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
  3. 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

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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
  • VitaminDWiki - 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
  • VitaminDWiki – Is 50 ng the level needed?
  • VitaminDWiki – COVID-19 treated by Vitamin D - studies, reports, videos
  • VitaminDWiki – Loading (not daily) doses quickly raise Vitamin D levels and fight Viruses

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