Remdesivir is being promoted as an anti-viral agent for the treatment of COVID-19. The first randomized, blinded, placebo-controlled trial of remdesivir was just released (Wang et al.). But before we dig into this trial, a little background…
Background: Animal studies on Remdesivir
Remdesivir is an anti-viral agent with strong efficacy against COVID-19 both in vitro and in multiple animal models. The basic science evidence on remdesivir is very impressive. Perhaps most notable is the ability of remdesivir to decrease viral load and clinical symptoms across four animal studies:1–4
Of all the anti-viral treatments being investigated for COVID-19, this has perhaps the most persuasive body of supporting evidence.
Wang et al: Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial
This is a prospective, placebo-controlled, double-blind RCT of remdesivir performed among ten hospitals in China. 5
Key inclusion criteria were:
- Adults admitted to the hospital with COVID-19
- Some degree of hypoxemia (e.g. saturation <94% on room air)
- Illness duration under 12 days
- Radiographic evidence of pneumonia
- Absence of cirrhosis, pregnancy, or severe renal dysfunction (GFR < 30 ml/min)
Patients were randomized in a 2:1 fashion, with twice as many patients receiving remdesivir as placebo. The study was stopped early when the COVID-19 surge passed, due to slow recruitment.
Baseline characteristics were similar between patient groups (Table below). The median duration of illness prior to receiving remdesivir was 10 days. Most patients required only low-flow oxygen:
The primary endpoint was time to clinical improvement (defined as discharge from hospital or as improvement by 2 points on a six-point ordinal scale of disease severity). There was no difference in this endpoint:
Every secondary endpoint was also neutral, except for time to clinical improvement (which was two days shorter in the remdesivir group). Given the presence of about twenty secondary endpoints, this finding is of dubious statistical merit (using a p<0.05 cutoff, one of these secondary endpoints would be expected to be different purely due to chance).
Furthermore, remdesivir had no impact on viral load:
Remdesivir did appear to be safe, with a similar distribution of adverse events seen between the placebo and the remdesivir group:
This is a well-executed and well-designed trial. Premature termination may have reduced the statistical power to detect subtle clinical differences. However, if remdesivir is truly a miracle cure for COVID-19, then a signal should be discernable among 236 patients.
The most notable finding here might be the lack of any impact on viral load. Remdesivir’s mechanism of action is supposedly to reduce viral replication. If remdesivir is having any biological impact, this should be most easily detectable in terms of reduced viral titers (figure below). Lack of a signal here suggests that remdesivir has no biologically meaningful impact in these patients.
Reconciling Wang et al. with prior animal model data on remdesivir
So why did this study fail, whereas prior animal studies worked so well? The answer might relate to the timing of administration of remdesivir.
In prior animal studies of remdesivir, investigators felt that early administration of remdesivir would be critical to the drug’s efficacy. Thus, remdesivir was used either prophylactically or within 12-24 hours of virus inoculation.
Of course, in real-world clinical practice, remdesivir was given at a far later timepoint:
- There is a time delay between infection and the development of symptoms (the incubation period).
- There is a subsequent delay between the development of symptoms and presentation to the hospital (a median of ten days in this study).
This leaves open the possibility that earlier administration of remdesivir could be more effective. In the subgroup of patients treated within <10 days of symptoms, there was a non-significant trend towards faster clinical improvement in patients treated with remdesivir. However, subgroup analysis still found no differences in viral load.
Shifting of the goal posts
With this negative trial, it’s time for a subtle shifting of the goal posts!
Let’s step back a moment and consider what was initially suggested about remdesivir:
- Remdesivir would be a potent anti-viral agent that would decrease viral load.
- Remdesivir would have a dramatic impact on major clinical endpoints (e.g. mortality) – such a huge impact that remdesivir mandated administration on a “compassionate” basis.
These goals are looking increasingly unrealistic. Thus, the future will likely bring a subtle shift towards less ambitious goals (e.g. reduced hospital length of stay). Thus, remdesivir may begin to resemble oseltamivir – an aggressively promoted agent with dubious clinical benefit.
- Wang et al. is the first placebo-controlled, double-blinded, multi-center RCT of remdesivir. The study was stopped early due to poor recruitment after including 237 patients, but otherwise appears well designed.
- Remdesivir had no effect on any clinical or biological endpoint (including viral load), with the exception of possibly causing a very small reduction in the time to clinical improvement (21 vs. 23 days). As an isolated positive finding among about twenty secondary endpoints, this is of dubious statistical merit.
- Lack of an observable effect could theoretically relate to delayed administration of remdesivir or underpowering of the study. However, this is a thoroughly neutral study that shouldn’t be mischaracterized as showing promise.
- Further RCTs will clarify what role remdesivir has in COVID-19, if any. This study suggests that remdesivir probably doesn’t confer major clinical benefits.
- 1.Sheahan T, Sims A, Graham R, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396). doi:10.1126/scitranslmed.aal3653
- 2.Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. April 2020. doi:10.1101/2020.04.15.043166
- 3.Sheahan T, Sims A, Leist S, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. doi:10.1038/s41467-019-13940-6
- 4.de W, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771-6776. doi:10.1073/pnas.1922083117
- 5.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. April 2020. doi:10.1016/s0140-6736(20)31022-9
- IBCC chapter & cast –Gastrointestinal hypomotility in critical care - September 14, 2020
- IBCC chapter & cast – Cerebral Venous Thrombosis - September 7, 2020
- IBCC chapter & cast – Hypertriglyceridemic Pancreatitis - August 31, 2020