Last week, the World Health Organization (WHO) published data from its SOLIDARITY trial on a preprint server. The SOLIDARITY trial is a global, pragmatic, adaptive, master protocol trial investigating 4 therapies for hospitalized COVID-19 patients, including remdesivir. Disappointing findings for remdesivir in the SOLIDARITY trial elicited a statement from Gilead Sciences, questioning the validity of SOLIDARITY, and emphasizing its ACTT-1 trial as the “gold standard” regarding remdesivir’s value for COVID-19.
Here, we look at remdesivir in two phases.
· First, we take a close look at the raw data from the randomized clinical trials of remdesivir in COVID-19 patients
· Second, we discuss the potential impact of the SOLIDARITY trial on the clinical use of remdesivir with critical care physicians and inDemic.org advisors, Dr. Bob Dickson and Dr. Hrishikesh Kulkarni
Before looking at the raw clinical trial data, it’s important to discuss the design and methodology of the SOLIDARITY trial. Gilead Sciences criticized the SOLIDARITY trial’s:
· Open-label design
· Prioritization of broad access, with heterogeneity in trial adoption, implementation, controls, and patient populations
Gilead’s ACTT-1 trial was double-blind, although its SIMPLE-Severe trial was open-label. The strength of an open-label trial is its simplicity and lower costs, practical advantages in a global pandemic. A blinded trial may be at lower risk of bias than an open-label trial, because it minimizes impact of investigators’ opinions on post-randomization treatment decisions and on reporting of subjective outcomes [1].
Still, we believe that SOLIDARITY’s design (and hence the validity of its findings) is at least complementary to that of ACTT-1, if not superior. SOLIDARITY, despite being open-label, is nonetheless randomized and controlled. Further, SOLIDARITY’s endpoint is overall mortality, whereas ACTT-1’s endpoint is time-to-hospital-discharge. No matter what biases SOLIDARITY investigators may’ve had, overall mortality is not subjective or open to interpretation, so an open-label design does not undermine SOLIDARITY’s overall findings. In addition, the UK RECOVERY trial also uses an open-label design, and it is arguably the most influential trial of COVID-19 therapies to date. Finally, perhaps partly due to the simplicity of SOLIDARITY’s enrollment process and open-label design, SOLIDARITY enrolled several times more patients than ACTT-1 onto its remdesivir vs. placebo arms.
As for the “heterogeneity” of SOLIDARITY, we view this as a strength of the trial. It more closely reflects real-world use of remdesivir, and given that the FDA granted an Emergency Use Authorization (EUA) to remdesivir for all hospitalized COVID-19 patients, it is appropriate to evaluate remdesivir in a heterogeneous patient population.
Looking at the patient population in SOLIDARITY by level of oxygen support, it’s striking that patients on mechanical ventilation may have been harmed by remdesivir. Similarly, in the ACTT-1 trial [2], patients on mechanical ventilation also did not benefit from remdesivir (Figure 1; excerpted from [2]).
Broadly speaking, the early stages of COVID-19 disease are dominated by virus-induced pathophysiology, whereas the late stages of COVID-19 disease are dominated by host-related pathophysiology (e.g. complement overactivation, etc.). Dr. Leon Henderson-MacLennan, an internist and advisor to inDemic.org, notes that most effective antiviral therapies (e.g. for hepatitis C, HIV, etc.) are used in the ambulatory care or outpatient setting. Hence, since remdesivir is also an antiviral, perhaps it would be more effective in the early stages of COVID-19, prior to or just after hospitalization.
Unfortunately, the limited data on remdesivir suggests it is a poor antiviral against SARS-CoV-2. Neither ACTT-1 nor SOLIDARITY’s preprint study looked at immunologic correlates of remdesivir’s purported activity against SARS-CoV-2. However, an earlier study from Wuhan, China looked at the viral load after treatment with remdesivir vs. placebo [3]. Viral load in the upper and lower respiratory tract decreased at similar rates for patients treated with remdesivir vs. placebo (Figure 2; excerpted from [3]).
In contrast, another class of “antivirals”, the antibody cocktails against SARS-CoV-2, clearly reduce viral load compared to placebo. For example, Lilly’s antibody cocktail (LY-CoV555 and LY-CoV016) reduced viral load compared to placebo in an interim analysis of the BLAZE-1 trial of outpatients with COVID-19 (Figure 3).
Regeneron has released similar data for its antibody cocktail, REGN-COV2, showing that it reduces viral load compared to placebo in outpatients with COVID-19 (Figure 4).
It is difficult to claim that remdesivir acts as an “antiviral” against SARS-CoV-2 without data that it reduces viral load more effectively that placebo.
Next, we will discuss remdesivir and the SOLIDARITY trial with critical care physicians and inDemic.org advisors, Dr. Bob Dickson and Dr. Hrishikesh Kulkarni.
Previously, we discussed the SOLIDARITY trial, which showed that for hospitalized adults with COVID-19, remdesivir plus local standard of care (SOC) did not improve mortality or hospitalization compared to local SOC alone. On October 21, 2020, the FDA granted regulatory approval to remdesivir for use in adult and pediatric patients 12 years or older with COVID-19 requiring hospitalization. In its Q&A on remdesivir, the FDA said that “the SOLIDARITY results do not refute these findings of…shorter time to recovery and better odds of clinical improvement…with remdesivir.”
Not all physicians and health agencies agree with the FDA’s synthesis of Gilead’s trials and the SOLIDARITY trial. In fact, we predict that the next catalyst for remdesivir is likely to be guidelines from the WHO, NIH, and professional societies (e.g. Society for Critical Care Medicine) regarding its use in hospitalized patients. Here, as a preview, we discuss the potential impact of the SOLIDARITY trial on the clinical use of remdesivir with critical care physicians and inDemic.org advisors, Dr. Bob Dickson and Dr. Hrishikesh Kulkarni.
What do you think of the SOLIDARITY trial?
Great. Let’s move on to remdesivir. With SOLIDARITY being a negative study with overall mortality as the primary endpoint, and ACTT-1 being a positive study with time-to-recovery as the primary endpoint, how do you reconcile their findings?
As you know, the FDA used the ACTT-1 trial extensively in its review of remdesivir. This is quite a loaded question, but which is a “better” or “more trustworthy” trial, ACTT-1 or SOLIDARITY?
Will the SOLIDARITY results change your use of remdesivir for hospitalized COVID-19 patients?
Let’s turn to Dr. Kulkarni. Any thoughts on how the SOLIDARITY trial will affect remdesivir’s use in hospitals, or in a clinical research setting?
Great, thank you so much, Dr. Dickson and Dr. Kulkarni! We appreciate your clinical perspectives.
inDemic.org will be revisiting remdesivir again after SOLIDARITY results are formally published in NEJM, and after the WHO and other organizations publish guidelines on use of remdesivir in hospitalized COVID-19 patients.
[1] Beigel, John H., et al. “Remdesivir for the treatment of Covid-19.” New England Journal of Medicine (2020).
[2] Beyer‐Westendorf, J., and H. Büller. “External and internal validity of open label or double‐blind trials in oral anticoagulation: better, worse or just different?.” Journal of Thrombosis and Haemostasis 9.11 (2011): 2153-2158.
[3] Wang, Yeming, et al. “Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.” The Lancet (2020).