Small Study Finds Remdesivir Benefit in COVID-19 But Questions Remain

Remdesivir: RemdesivirClinical activity has been reported for the unlicensed novel antiviral drug remdesivir given on a compassionate-use basis in a small uncontrolled study to patients who were severely ill with COVID-19 and had exhausted other therapeutic options (N Engl J Med 2020; doi: 10.1056/NEJMoa2007016). “It's critical that the medical community finds a safe and effective treatment for COVID-19 that's supported by solid data,” said Jonathan Grein, MD, Director of Hospital Epidemiology and leader of the Special Pathogens Response Team at Cedars-Sinai Medical Center, Los Angeles, who co-authored the investigation that analyzed findings from 53 patients treated with at least one dose of remdesivir in the U.S., Europe, Canada, and Japan for their COVID-19 infection. “Currently, there is no proven treatment for COVID-19. We cannot draw definitive conclusions from these data, but the observations from this group of hospitalized patients are hopeful,” he said. While remdesivir (originally developed as an antiviral agent with activity against the Ebola pathogen) had in vitro activity against COVID-19 (and was one of a number of agents being investigated for potential use in patients with the infection), the study authors acknowledged that the preliminary indications of activity were lacking validation. Grein said they were looking forward to the results of controlled clinical trials (such as the large NIH-sponsored randomized, controlled clinical trial) to evaluate the safety and efficacy of remdesivir in hospitalized adults diagnosed with COVID-19 recently begun at the University of Nebraska Medical Center in Omaha—the first clinical trial in the United States to evaluate an experimental treatment for COVID-19. Study Details In the small study, Grein and co-authors recruited 61 patients hospitalized with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, also known as COVID-19) infection who had oxygen saturation of 94 percent or less while they were breathing ambient air or who had been receiving oxygen support. Patients had a 10-day course of remdesivir (200 mg intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment) during the period from January 25, 2020, through March 7, 2020. The authors reported successful analysis of their data from 53 of the patients—22 in the United States, 22 in Europe or Canada, and nine in Japan. At baseline, 30 patients had been receiving mechanical ventilation and four had extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class. Seventeen of the 30 patients on mechanical ventilation were extubated. A total of 25 patients were discharged, and seven patients died (13%). Mortality was 18 percent among patients receiving invasive ventilation (six of 34) and 5 percent among those not receiving invasive ventilation (one of 19). The researchers noted that these positive findings supported validation of drug in ongoing randomized, placebo-controlled trials. But the authors tempered premature optimism over the study findings by listing caveats. A total of 32 patients (60%) had reported adverse events, including increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. In general, adverse events had been more common in patients receiving invasive ventilation. Twelve of the patients (23%) on invasive ventilation at baseline had serious adverse events including multiple organ dysfunction, septic shock, acute kidney injury, and hypotension. On the plus side, the pilot study data appeared to suggest that therapy with remdesivir had brought clearly superior outcomes in comparison to historical cohort studies using other approaches (largely from China) in which mortality rates of between 17 and 78 percent had been reported in severe cases of the infection (as defined by the need for admission to an intensive care unit, invasive ventilation, or both). “However, the patients enrolled in this compassionate treatment program are not directly comparable to those studied in these other reports,” the study authors warned. The pilot study had not investigated viral load following remdesivir intervention. So, the investigators were not able to check for any association of viral load dynamics with outcomes. Neither could they estimate any influence of the duration of remdesivir therapy on clinical parameters. The researchers also admitted that, despite the lack of “new safety signals” in the light of remdesivir's acceptable safety profile (assessed in a historical trial with 500 healthy volunteers taking the drug for research on the Ebola outbreak), the drug's hepatotoxicity in the COVID-19 study had been “challenging.” Comments have also been raised by a number of independent experts dampening any potential crescendo of support for continued “compassionate use” of this unproven antiviral agent in patients without randomization or a control group. “I would say it's impossible to discern whether there is a treatment effect or not,” said Duncan Richards, MA, DM, FRCP, Clinical Pharmacologist and Professor of Clinical Therapeutics at the University of Oxford. “This is in part due to the mixed patient population, ranging from those needing low-dose oxygen, who are more likely to survive anyway, to much more severe cases...[who] show a much more mixed picture.” Richards told the London-based Science Media Centre he was waiting for the results of ongoing large international randomized controlled trials with remdesivir. “We really need to see those data,” he said. “Safe and effective treatments for COVID-19 are critically needed and should be expedited wherever possible. But it's important not to compromise on the quality of the research.” Stephen Griffin, PhD, Associate Professor at the University of Leeds School of Medicine in the United Kingdom, also approved of waiting for the randomized clinical testing now in progress to determine the “true effectiveness” of the drug. “It is impossible to know the outcome for this relatively small group of patients had they not received remdesivir,” he said. Stephen Evans, MSc, FRCP, Professor of Pharmacoepidemiology at London School of Hygiene & Tropical Medicine, described the data from pilot study paper as “almost uninterpretable.” He agreed with the study authors that the multiple caveats they had described (including the small sample size, short follow-up, missing data, no follow-up on eight patients, and lack of a randomized control group) limited any interpretation of the results. “The drug was being used in patients who were severely ill, but reporting on 61 out of several hundred makes it clear that generalizations about the efficacy and safety must be treated with great caution,” said Evans. “There is some evidence suggesting efficacy, but we simply do not know what would have happened to these patients had they not been given the drug,” he said. The independent blogger Josh Farkas, MD, Assistant Professor of Pulmonary and Critical Care Medicine at the University of Vermont in Burlington, (who harnesses social media to garner opinion and reaction to clinical developments) raised a number of reasons for using caution in interpreting the pilot study data. One was about patient selection—which he described as “cherry picking” in his PulmCrit blog post entitled, “Eleven reasons the NEJM paper on remdesivir reveals nothing.” Remdesivir was aggressively sought-after by thousands of patients with COVID-19. Of these patients, 61 ended up receiving the drug. Why did these patients receive medication, out of scores of patients applying to receive it?” he asked. Farkas was also concerned about the outcomes of eight of the 61 patients recruited who received an initial dose of the drug but for whom there had been no follow-up data. What happened to these patients? Did they die from anaphylaxis? Did they get well? This is unknown. But I'm worried that these patients actually didn't fare so well,” he wrote. There appeared to be unanimity from the study authors and the expert commentators that, although the data might have been hypothesis-generating so far, definitive conclusions about the value of remdesivir therapy in severe COVID-19 infection needed to await findings through randomized investigation. This could be available soon, given the aggressive nature of COVID-19 infection in some patients. Peter M. Goodwin is a contributing writer.

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