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.

First10EM Remdesivir: The first real trial

REBEL EM: Two More Trials Just Published on Remdesivir 

PulmCrit: First placebo-controlled RCT on remdesivir for COVID-19


Largest international observational study on clinical features of COVID-19 to date

  • Mean number of days from (first) symptom onset to hospital admission was 11.7
  • Mean duration for the number of days from hospital admission to outcome (death or discharge) was 8.7
  • Mean and median durations for non-invasive ventilation were 2 days and 0.5 days respectively
  • Duration of stay in ICU/HDU had a mean of 7.4 days and a median of 5.5
  • Mean and median for the duration of mechanical ventilation were 9.6 days, 9 days
  • 72.4% received an antibiotic and 8.8% received antivirals

International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) global federation of clinical research networks COVID-19 Report: 27 April 2020.


Updated airway management guidelines for patients with known or suspected COVID-19 infection (care of George Kovacs)

COVID oxygenation AIME

This document nicely outlines indications for early intubation:

  • Significant hypoxemia refractory to non-rebreathing mask at flows < 15 lpm in conjunction with one or more of the following:
    • Clinical signs of the patient tiring:
      • Dyspnea;
      • Tachypnea with RR > 30-35 (adult);
      • Tachycardia;
      • Agitation;
      • Accessory muscle use; paradoxical chest/abdomen movement
    • Worsening PaO2/FiO2; Increasing PaCO2;
    • Rapidly progressive disease trajectory or other clinical judgement.
  • Other standard indications for tracheal indication, e.g., failure to protect the airway or obstructing airway pathology, hemodynamic instability, sepsis, multi-organ failure.

Airway Management Guidelines for Patients with Known or Suspected COVID-19 Infection Version 3.7


Review of COVID-19 POCUS diagnosis and disinfection

http://www.emdocs.net/lung-ultrasound-in-covid-19/


Roche’s COVID-19 antibody test receives FDA emergency use authorization, but many questions still remain

https://www.roche.com/media/releases/med-cor-2020-05-03.htm

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.