Friday 24 April 2020

Compassionate use of Remdesivir for Patients with Severe Covid-19

It is a sign of the times when an article of such low-quality evidence is published in the New England Journal of Medicine. We are obviously desperate to get some information regarding therapy for Covid-19.

Compassionate use, or properly termed “expanded use,” is when patients can request a not yet FDA approved drug outside of a clinical trial.

This industry funded and written study reports on 53 patients with severe Covid-19 that got expanded use remdesivir in the USA, Europe and Japan.

Short answer… they got it and they got better.

Of course, we have no idea if remdesivir did anything. This was not a trial. There was no control group, no randomization, no blinding, nothing, zip, nada.

But fear not. Gilead Sciences, the manufacturer of remdesivir, is currently conducting a large phase 3 randomized clinical trial. They plan to enroll 6000 patients at 179 sites and have it finished by a “holy shit fast” May 2020!

Fortunately, most of their recruiting sites are based in the USA where there is plenty of patients to study. (Thanks Donald). Studies out of China have now been suspended or terminated due to low patient numbers.

A search of indicates the primary outcome of the phase 3 trial is an odds ratio of improvement on a 7-point ordinal scale. This type of analysis has incredible statistical efficiency. Along with 6000 patients, this study will have the power to demonstrate miniscule differences in patient outcomes.

Do you know what else Gilead Sciences developed?


Gilead licensed the drug to Roche in 1996 on return for royalties. Despite hardly any evidence of efficacy, it was a blockbuster that saw the world stockpile billions worth during H1N1.

Now if there was just some other global scare that might sell remdesivir? Hmmmm….

Ok, I am being paranoid. But I do think we need to be careful when this study is soon published and not let emotions & politics trump science. (Pun intended.)

Nevertheless, I genuinely hope this drug works. We have antivirals that have cured hepatitis C. We’ve put the brakes on HIV. In theory, remdesivir looks quite promising. It is an RNA polymerase inhibitor specifically designed to treat coronaviruses. Perhaps there is some hope.

So, watch this space.

But be skeptical.


Grein J, Ohmagari N, Shin D, et al. Compassionate use of Remdesivir for Patients with Severe Covid-19. N Engl J Med 2020 [E pub ahead of print] [link to full text]

Hydroxychloroquine in patients with COVID-19: an open-label un-peer reviewed RCT

We want to rapidly know as much as we can about COVID-19. In the current pandemic, researchers are rushing to complete studies and often prematurely release the results on MedRxiv (pronounced “med-archive”) before they have even undergone a process of peer review.

Of course, this can be good news for rapid dissemination of information, but it can also be rather harmful if bad studies get pushed without proper scrutiny.

This multicenter RCT from china included 150 patients with COVID-19. They got hydroxychloroquine (open label) vs. standard care. The primary outcome was clearance of the virus at 28 days.

They concluded, “…adding hydroxychloroquine to the current standard-of-care in patient with COVID-19 does not increase virus response but accelerate the alleviation of clinical symptoms.” (Yes, you read that correctly).

They go on to say that the alleviation of symptoms may due to the anti-inflammatory properties of hydroxychloroquine and less lymphopenia. The authors suggest clinicians might consider it in symptomatic patients with elevated CRP and or lymphopenia because it might prevent disease progression in high risk patients.

Unfortunately, this conclusion is wrong.

Their primary outcome was negative, but at with such small numbers was at risk of a Type I error. Hidden in the manuscript, the authors mention that they wanted to enroll close to 400 patients but had to give up when recruitment fell short.

The median time from symptom onset to getting hydroxychloroquine was 16 days. For most antivirals to work, they need to be given early.

But what about the claim that the medication reduces clinical symptoms?

This comes from one of fourteen post-hoc subgroup analysis in 28 patients that was “statistically significant” with hazard ratio 95%CI of 1.09 to 71.3.

Peer reviewers will easily spot this inappropriate claim that came about through a process known as data dredging or P-hacking. 

What should we conclude?

Unfortunately, nothing.  

This was an underpowered biased study that made some silly claims based on an unadjusted post-hoc subgroup analysis.

We still don't know if hydroxychloroquine helps or harms.


Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. MedRxiv [link to un-peer reviewed manuscript]