Remdesivir for treatment of COVID-19 by Andrew Morris
This week saw 3 trial results “announced”. One is the Lancet trial https://doi.org/10.1016/S0140-6736(20)31022-9 posted online on April 29. This trial is a multicenter double-blind RCT with 2:1 allocation of remdesivir: placebo with a total of 237 patients with <12 days of symptom onset admitted to hospital in Hubei, China. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. Primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done ITT. No improvement in mortality. Possibly improved median time to clinical improvement … although the data is very difficult to interpret, because they use this wacky ordinal scale, so that going from 4l/min O2 and hospitalized —> meeting discharge criteria (even if you stay in hospital) is given the same weight on improvement as going from ventilated in ICU—> supplemental O2 on ward. They aren’t the same. Most importantly, the data showed no difference in mortality. The “improvement” differences are so over the map that they are largely uninterpretable.
We then have another study, from Gilead themselves, announced with a media release on April 29: it is the open-label, Phase 3 SIMPLE trial evaluating 5-day and 10-day dosing durations in 397 patients. Bottom line: no appreciable difference in 5 vs. 10 days … except more side effects with 10 days (5% vs. 10% leading to discontinuation, p=.07). Tells us nothing otherwise.
Finally, it brings me to the Fauci-Birx-Trump press announcement—again on April 29 (boy that was a busy day for Gilead. And me!): I cannot express enough how disappointed I was in this. It was a press release announcing that the DSMB of the NIAID (one of the 27 institutes of the NIH … we have Institute of Infection and Immunity for CIHR) looked at the data—as is normal in an adaptive trial—and concluded that the median time to clinical improvement (i.e moving 2 points on an ordinal scale) was 11 vs 15 days favouring remdesivir. Dr. Fauci referred to this as highly significant, emphasized that there were over 1000 patients enrolled … we then learn that the analysis has only been done on 600 patients. He then says that the data are so compelling that remdesivir now needs to be considered the “standard of care”—meaning that all patients enrolled in COVID-19 therapeutic trials should be receiving remdesivir. At to the nuttiness of all of this, but the endpoint of the trial was switched from mortality to median time to clinical improvement literally days before the DMSB analysed the data.
Am I incensed? Absolutely. The Fauci-Birx-Trump conference—held in the Oval Office—has undermined ongoing clinical trials, rational exploration of the role of remdesivir, and has seriously compromised the credibility and independence of scientific/medical expertise in the most important country for research in the world. What do I think of remdesivir? I dunno. We don’t have the paper yet. It could really be helpful. Or not. But cherry-picking an outcome and then saying that it is a reason for calling it the standard of care and halting one of the few trials able to give us the answer makes me question the independence of all of this. Gilead on the other hand … well their stocks went up … and then went right back down. So investors are starting to question that announcement just as much as people like me.
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020.
Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.
As outlined in the latest FOAMcast, cross-reactivity can cause false positives and false negatives are common early in the disease. If prevalence is very low, then a positive test probably indicates past infection, but immunity is still questionable.
Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020.
This study suggests that reinfections with the same coronavirus are possible within one year.
Dr. Anton Helman is an Emergency Physician at North York General in Toronto. He is an Assistant Professor at the University of Toronto, Division of Emergency Medicine and the Education Innovation Lead at the Schwartz-Reisman Emergency Medicine Instititute. He is the founder, editor-in-chief and host of Emergency Medicine Cases.