Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic

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Date: Apr. 14, 2020
From: CMAJ: Canadian Medical Association Journal(Vol. 192, Issue 15)
Publisher: CMA Impact Inc.
Document Type: Viewpoint essay
Length: 1,973 words
Lexile Measure: 1770L

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While aggressive mitigation strategies are being implemented to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we must also strive to optimize clinical outcomes for those infected and prevent transmission among their close contacts. As the number of severely ill patients with coronavirus disease 2019 (COVID-19) continues to increase, we must learn as much as possible about this disease, as quickly as possible, to inform patient care. Fortunately, the Canadian clinical research community has already mobilized to ensure a coordinated effort of randomized controlled trials (RCTs) on treatment, prophylaxis and vaccines. We discuss why and how, in collaboration with global colleagues, Canadian researchers are poised to generate high-quality evidence that may improve outcomes for all Canadians and patients worldwide.

When faced with an unknown and frightening disease such as COVID-19, and given concerns over a potentially high case fatality rate, some clinicians and patients will feel strongly compelled to try unproven therapies based on theory, in vitro data, animal models, clinical anecdotes, observational studies confounded by severity, and uncontrolled or underpowered trials that may later be shown to be misleading. (1-3) For example, during the novel influenza A (H1N1) viral pandemic in 2009, countries stockpiled and used oseltamivir extensively, at great expense, based on data of suboptimal quality showing a potential benefit in patients admitted to hospital. (4) Even now, because there has been no RCT, it is not definitively known whether oseltamivir is efficacious for preventing or treating the complications of influenza in admitted patients.

In the COVID-19 pandemic, experimental medications that are not currently approved for any indication in any country have already been widely used outside of clinical trial protocols. (5) But there is a strong ethical and clinical argument for replacing such "random" care with randomized care, in which patients are routinely randomly assigned to the most promising available option(s) or to control arm(s), so that evidence regarding the safest, most effective therapies may be generated in the shortest possible time. This means that although earlier patients may receive our best-guess treatments, subsequent patients can receive evidence-based therapies and be spared from harm.

The World Health Organization (WHO) has prioritized several medications for further study in COVID-19--based on in vitro data, available safety data and biologic plausibility--and has recommended that these be evaluated in the context of a clinical trial (www.who.int/blueprint/priority-diseases/key-action/novel -coronavirus/en). These agents currently include lopinavir-ritonavir, remdesivir and (hydroxy)chloroquine; as new data emerge, others may be added. With no proven effective treatments for COVID-19, showing that any drug has a net clinical benefit is a public health priority.

More than 500 clinical trials are already registered on the WHO International Clinical Trials Registry Platform, many of which are actively recruiting (https://apps.who.int/trialsearch). This is impressive, but also concerning. With so many different trials, there are risks of wasteful duplication, competition for the same participants, and the potential for underpowered studies to lead to either the premature rejection of promising drugs (6) or premature adoption into standard...

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Gale Document Number: GALE|A621084361