“I was taught that the way of progress was neither swift nor easy.”
- Marie Curie
The general public is often confused about what and whom to believe when it comes to claims about therapeutic breakthroughs with respect to any disease. This must be especially true in the rapidly evolving field of COVID-19.
This past week the news touted the anti-inflammatory drug dexamethasone as a huge breakthrough in the treatment of severe COVID-19. This news was based on the results of a single clinical trial in the UK. And at about the same time the U.S. Food and Drug Administration (FDA) revoked its March 28, 2020 emergency use authorization (EUA) for two other anti-inflammatory agents, chloroquine and hydrochloroquine, for the treatment of COVID-19 because of concerns about cardiotoxicity and lack of evidence of efficacy. (President Trump called hydrochloroquine a “game-changer” and concerns arose that his enthusiasm had pressured the FDA to issue the EUA for these drugs).
In my long career as an internist and infectious diseases specialist, I’ve seen enough breakthrough drugs come and go to become chastened in my excitement about all “new and improved” medicines or breakthroughs. In the process I’ve come to fully appreciate the FDA’s prioritization of “safety first” and its requirement of properly controlled clinical trials, aka evidence-based medicine (EBM).
What is EBM? The term “evidence-based medicine” was coined by Gordon Guyatt and first appeared in an article in the Journal of the American Medical Association in 1992. While the roots of EBM go much further back, it then became, and still is, the prevailing method for assessing the risks and benefits of all drugs.
The cornerstone of EBM is the randomized clinical trial (RCT). In RCTs patients are randomly assigned to treatment (those receiving the drug of interest) or control (those receiving a currently used drug or placebo—the so called “sugar pill”) groups thus overcoming biases that might arise by other methods of assignment of who gets the treatment or control.
Dexamethasone for COVID-19: What’s the evidence? Dexamethasone was approved in 1961. It is an old tried-and-proved medication that suppresses multiple inflammatory genes. It has a long track record of successful use in many inflammatory conditions and in certain kinds of cancer. It can be taken as a tablet or by infusion and is very cheap. But it has a number of side effects, including inhibiting the immune system’s defense against infectious agents.
On June 17, a New York Times article, “Common Drug Reduces Coronavirus Deaths, Scientists Report” announced exciting news released by researchers at Oxford University that dexamethasone had reduced deaths by one-third in COVID-19 patients on ventilators and reduced deaths overall by one-fifth. As stated in the NYT, if the finding is borne out, it would be the first treatment shown to reduce mortality in severely ill patients.
This dexamethasone study was part of a large RCT in the UK known as RECOVERY (Randomised Evaluation of COVid-19 thERapY). During the trial, 2,104 randomly selected COVID-19 patients who received dexamethasone were compared to 4,321 random patients who received conventional therapies.
So, what do I think? This was a large RCT carried out by a highly regarded research group. Nonetheless, it’s too soon to know where dexamethasone fits into the treatment of COVID-19. Of concern to me is that the results were presented by press release and have yet to be published in a peer-reviewed journal. The rapidity of the study was also amazing—going from hypothesis to evidence in only 3 months! Also concerning is whether unrecognized biases crept into the study due to the fervor of wanting an effective treatment of this devastating infection.
The study was based, however, upon the prevailing and reasonable hypothesis that much of the damage inflicted by SARS-CoV-2 is the result of inflammation caused by an overly active, dysregulated immune response to the virus. But it is important to remember that activation of the immune system is also crucial in host defense against the virus. One has to ask: Could there be consequences from interfering with ‘Mother Nature?’
Also, there are publications of smaller studies reporting negative findings with the use of corticosteroids in COVID-19. In addition, there are publications calling for discretion regarding use of dexamethasone, including, for example, a May 25 Lancet paper from China, “Caution against corticosteroid-based COVID-19 treatment.” I therefore believe additional RCTs of dexamethasone are needed, perhaps in combination with an antiviral drug, such as remdesivir, which received FDA EUA based on its shortening of the illness of patients with severe COVID-19. Most importantly, before physicians and health care professionals can properly assess the Oxford trial, we need to see more about its study design and the results. In other words, we need to assess the evidence—the safety and efficacy reported in this RCT before recommending its use for severe COVID-19.
What about chloroquine and hydrochloroquine? Given the frantic pace of the COVID-19 pandemic, concern has arisen about rushing to publish research on the coronavirus. Not only do we need to be cautious in adopting new therapies but also in dismissing potential therapies before we have adequate evidence.
The report of the successful use of dexamethasone came quickly on the heels of a series of blunders and retractions in the scientific literature regarding chloroquine and hydrocholorquine. Most notably, in early June two top medical journals, Lancet and New England Journal of Medicine, retracted papers on the use of chloroquine and hydrocholorquine for the treatment of COVID-19 based on concerns about toxicity or veracity of the primary data sources, respectively. Like dexamethasone, these drugs also target an overly active immune system, and toxicity issues aside, should theoretically work. The question is: Does the use of choloroquine and hydrochloroquine in the treatment of COVID-19 warrant further study?
In a June 16 Annals of Internal Medicine publication, “A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychlorquine for COVID-19,” Alfred Kim and his colleagues provide a convincing case that there “is enough rationale to justify the continued investigation of the efficacy and safety of hydrocholoroquine in hospitalized patients with COVID-19.” Upon reviewing the National Institutes of Health (NIH) ClinicalTrials.gov registry, in mid-June there were 381 studies listed for COVID-19, 23 of which are recruiting COVID-19 patients for hydrochloroquine trials. It therefore appears that others share Dr. Kim’s view.
Where do we go from here? As I mention above, there are numerous studies underway of “new and improved” drugs that more selectively target certain aspects of an overly active immune system, or the virus itself, or its entry into cells via its spike protein. Additionally, 25 studies are listed in the NIH registry of convalescent plasma containing antibodies that neutralize SARS-CoV-2 (and the preliminary results are promising).
Given the potential importance of the Oxford trial, I’m sure we will soon see the published results. In the meantime, we should apply the brakes. We should be cautiously optimistic that the old anti-inflammatory drug dexamethasone is beneficial in treating life-threatening COVID-19. And, if the results of the Oxford trial are as good as reported initially in the news I think we have cause to celebrate a bona fide breakthrough in the treatment of SARS-COV-2.
