But letters to NEJM question study methodology

A study published in early April on the compassionate use of remdesivir for Covid-19 has resulted in a bevy of letters to the editor in the New England Journal of Medicine questioning the study’s findings and methodology.

In this case series study of 53 patients treated with remdesivir, 36 achieved clinical improvement, according to Jonathan Grein, MD, from Cedars-Sinai Medical Center, Los Angeles, and colleagues.

“Although data from several ongoing randomized, controlled trials will soon provide more informative evidence regarding the safety and efficacy of remdesivir for Covid-19, the outcomes observed in this compassionate-use program are the best currently available data,” Grein and colleagues wrote in NEJM. “Specifically, improvement in oxygen-support status was observed in 68% of patients, and overall mortality was 13% over a median follow-up of 18 days.”

Remdesivir was provided for compassionate use for hospitalized patients in the United States (22), Japan (9), Italy (12), Austria (1), France (4), Germany (2), and Netherlands, Spain, and Canada with one patient each.

The patients were entered into the study if they had confirmed SARS-CoV-2 infections with an oxygen saturation of 94% or less while breathing ambient air, or who were on oxygen support.

“Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment,” Grein and colleagues explained.

The study authors noted that at baseline, 57% (n=30) of the patients were on mechanical ventilation and 8% (n=4) were receiving extracorporeal membrane oxygenation.

The patients were followed for a median time of 18 days (interquartile range, 13 to 23) after the initial remdesivir dose. Most of the patients in the study (75%) were men, and the age of participants was 23-82, with a median age of 64 (interquartile range, 48 to 71).

They found an improvement of oxygen class in 36 (68%) of the patients. However, 8 of the 53 patients (15%) saw their condition worsen. All 12 patients who were breathing ambient air or who were on low-flow supplemental oxygen showed improvement.

“It is notable that 17 of 30 patients (57%) who were receiving invasive mechanical ventilation were extubated, and 3 of 4 patients (75%) receiving ECMO stopped receiving it; all were alive at last follow-up,” Grein and colleagues wrote.

“By 28 days of follow-up, the cumulative incidence of clinical improvement, as defined by either a decrease of 2 points or more on the six-point ordinal scale or live discharge, was 84% (95% confidence interval [CI], 70 to 99) by Kaplan–Meier analysis,” the study authors wrote.

This improvement was not as pronounced in those who were on invasive ventilation compared with those on noninvasive ventilation (hazard ratio for improvement, 0.33; 95% CI, 0.16 to 0.68). And, improvement was also less for those who were age 70 or older compared with patients younger than age 50 (0.29; 95% CI, 0.11 to 0.74).

The study authors noted that 7 of the 53 patients in the study (13%) died after they completed treatment with remdesivir, which included 6 of the 34 patients on invasive ventilation (18%) and 1 of 19 (5% on noninvasive oxygen support.

The median time from the initiation of remdesivir therapy to death was 15 days.

While Grein and colleagues noted that the findings of their compassionate use study would need to be confirmed by randomized, placebo controlled trials, several experts voiced concern about this particular study.

Stefanos Bonovos, MD, PhD and Daniele Piovani, PhD, from the Himanitas University, Milan, Italy, quibbled with the methodology.

“Grein and colleagues reported that Kaplan–Meier analysis showed a cumulative incidence of clinical improvement of 84% (95% confidence interval [CI], 70 to 99),” they wrote. “We have found that this result is not correct. A reanalysis of the patient-level data reported in Figure 2 of the article revealed a much lower estimate (approximately 70%). Apparently, the authors erroneously censored data on the deceased patients at the time of death.”

Bonovos and Piovani noted that these deaths should not have been censored and their status noted as “not improved” through the 28-day follow-up. They called for Grein and colleagues to make the appropriate revisions to their study.

Gerd Fätkenheurer, MD, from the University Hospital of Cologne, German and Jens Lundgren, MD, from Rigshospitalet, Copenhagen, Denmark called the use of “severe Covid-19” in the study’s title “misleading.”

They wrote: “Because of the small sample size, the high variability of disease severity, and the lack of a control group, we doubt the generalizability of the results. Death was reported in 7 of 53 patients (13%), and another 10 patients did not have clinical improvement at the end of the observation period, but no definition of treatment failure was provided.”

And, like the Italian letter writers, they too noted that “death was considered a censoring event…” and “the estimated proportion of patients with clinical improvement was falsely high.”

Replying to the letter writers, Grein along with Robert P. Myers, MD, and Diana Brainard, MD, from Gilead Science, wrote: “As recommended by Bonovas and Piovani, and by Fätkenheuer and Lundgren, we have reanalyzed clinical improvement using a competing-risk approach, wherein death is rightly considered to be a treatment failure. On the basis of this analysis, the cumulative incidence of clinical improvement at 28 days after the initiation of remdesivir was 74% (95% CI, 55 to 86). We do not think this reanalysis substantially changes our assessment that remdesivir may provide clinical benefit in patients with severe Covid-19, although as we stated in our article, these findings require validation from ongoing clinical trials.”

Limitations of Grein and colleagues’ study, pointed out by other letter writers and by the authors themselves, include the study’s small size, clinical data such as levels of lymphocytes, and lactate dehydrogenase, and incomplete follow-up information. “these limitations… stem from the nature and urgency of this compassionate-use program…[and] we urged caution in the interpretation of the data…”

Remdesivir is being fast-tracked by the FDA, which gave it emergency use authorization in late April following a release by Gilead Sciences of top line results showing the drug’s efficacy in patients hospitalized with Covid-19.

  1. Sixty-eight percent of Covid-19 patients given remdesivir showed improvement in oxygen-support status, a compassionate use study shows, and overall mortality was 13% over a median follow-up of 18 days.

  2. Be aware that experts questioned the methodology of this study and the authors recalculated their findings about a month later.

Candace Hoffmann, Managing Editor, BreakingMED™

The study was supported by Gilead Sciences.

Grein disclosed no relevant relationships.

Bonovas and Piovani disclosed no relevant relationships.

Fätkenheuer reports receiving advisory board fees from Gilead Sciences, Janssen, Merck Sharp and Dohme, and ViiV Healthcare, lecture fees from Janssen, travel support from Gilead Sciences and Janssen, and research support from Gilead Sciences, Janssen, ViiV Healthcare, and Merck Sharp and Dohme.

Cat ID: 125

Topic ID: 79,125,254,930,287,570,730,933,125,190,520,926,192,927,151,928,925,934