“History is merely a list of surprises that should prepare us for future surprises.” – Kurt Vonnegut
At this point in the pandemic, Cassie and I think it’s time to hit the reset button. This column is clearly not designed to be a comprehensive summary of what is going on in the COVID-19 world but rather, we have decided, some reflections on what, in our view, is meritorious to puzzle over at this stage of a true crisis. We have both been highly engaged in all facets of the disease, culminating this past Friday in three different panels that one or both of us participated in including the Interdisciplinary Autoimmunity Summit, GRAPPA annual meeting and a task force of the National Psoriasis Foundation and that is just one day and our heads are still swimming.
Given that, as of this moment, there are over 35,000 COVID-19 articles that have been put into the public domain we clearly recognize that we are seeing only the surface of a stormy sea and our eyes are merely catching an occasional white cap to focus on. So here are some things to think about this week:
- COVID-19 studies – We have been doing this exercise of scanning the COVID-19 trials registered on www.clinincaltrials.gov on a regular basis for the past few months and it’s becoming more difficult by the day. As of 10:00 AM on Saturday, July 11 there are 2,531 registered trials, the vast majority of which are therapeutic. To scan them all by title now takes easily over an hour and will make you queasy because about every 20th trial you don’t recognize the name of the investigational agent and you have to hit Wikipedia (Len just gave them another donation). Aside from the over 200 studies on hydroxychloroquine (see below) studies on kinase inhibitors, cytokine inhibitors, glucocorticoids and antivirals lead the pack.
- Hits, Balls, and Strikes – As we reflect on the news of the day of this astral baseball game we need to call them as we see them. Hydroxychloroquine, the most studies drug, was down to its last strike having fouled off about 10 pitches. As we all know virtually every well-done trial of the drug has been futile and most observers have sent it to the locker room but then comes along the Henry Ford retrospective study last week (https://www.medicalnewstoday.com/articles/does-hydroxycholorquine-cut-covid-19-mortality-expert-urges-caution). We have read the study and we are unimpressed as there are numerous confounders leading us to conclude that we should rely on the RCTs and not prescribe this agent outside of a formal trial. Having said that there is no compelling evidence to discontinue the drug in our patients following COVID-19 exposure or infection. Colchicine scored a hit in the past few weeks with a positive RCT from Greece but showed a rather marginal clinical effect size (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767593 ). Several large trials are underway including a 6000 person RCT (COLCORONA NCT04322682) designed to determine whether a short-term treatment with the medication reduces the risk of death and lung complications related to COVID-19. Stay tuned! Finally, IL-6i took a whiff this week as the Sanofi-Regeneron RCT of sarilumab was stopped for futility, failing to meet its primary and several key secondary endpoints. We are all disappointed and now await the results from the many other (over 20) trials with other agents including tocilizumab as we search to determine whether the pathway, the drug, the design, or all of the above were at fault.
- Random effects – As Cassie and my personal hero, Kurt Vonnegut said history “is merely a list of surprises that should prepare us for future surprises.” Accordingly, we are serious when we say stay tuned and open-minded about what lies ahead. Never has such an onslaught of clinical trials been launched in such short a time. Our friend Xavier Marriette said that in Paris they had set up a framework for study in which they had everything in place to plug in an experimental treatment called CORIMUNO-19. Severe counties in Europe have similar systems for rapid clinical trial design with multiple agents, more bare-boned and cost-effective than U.S. giant and expensive trials (surprised?) such as the RECOVERY trial in the UK which recently hit an extra base hit with dexamethasone. In the French trial, tocilizumab was proposed as an experimental agent on Day 0, and since IRB approval was done and systems in place, they merely had to get buy-in and drug from the sponsor. By day 10 they were recruiting and by day 20 they were fully enrolled! Unbelievable and we eagerly await the data.
Also among the trials on the website is a dizzying list of complementary and integrative therapies and some therapies we have a hard time classifying. Think ozone, hyperbaric oxygen, Ayurvedic medicine, Traditional Chinese medicine, many many vitamins and minerals and supplements, and beyond. There are also many trials we just don’t understand such as trials that target GM-CSF and protocols which give recombinant GM-CSF. Studies that give interferon Type 1 and 3 and trials that target interferon producing cells. There is also one study using a PD-1 checkpoint inhibitor, nivolumab, which from our vantage point we would NOT have equipoise to even enroll patients in. But perhaps history per Kurt Vonnegut should be kept in mind.
These are our thoughts for today. Lastly, we saw that there is a trial of resveratrol for treatment COVID-19. We are going to do our own trial tonight. Cheers!
Please give us a shout out with any questions!
Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO
Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO