COVID-19: Two new remdesivir studies offer competing results

According to a senior official in the Trump administration, the FDA is planning to announce an emergency use authorization for the investigational antiviral remdesivir for the treatment of COVID-19. However, two studies evaluating the drug have offered competing conclusions as to its effectiveness against the disease.

Gilead Sciences recently announced positive results from the SIMPLE study, their first phase 3 trial involving hospitalized patients with severe symptoms of COVID-19. While the full data have not yet been submitted for publication, the company announced topline results Wednesday in a press release.

The first SIMPLE study was conducted in countries with high prevalence of COVID-19, and it evaluated the safety and efficacy of two dosing regimens. A total of 397 patients were randomized to receive standard of care in addition to intravenous remdesivir 200 mg once, followed by remdesivir 100 mg once daily for either 5 or 10 days.  

According to Gilead, time to improvement of COVID-19 symptoms for 50% of patients receiving the 5-day dose was 10 days, compared with 11 days for those who received the 10-day dose. More than half of patients in both groups were discharged from the hospital by day 14. 

Across both treatment groups, the overall mortality rate for all locations (excluding Italy) at 14 days was 7%. Results from Italy were not included in the company’s release.

Referring to the study, Anthony Fauci, MD, director of the National Institutes of Allergy and Infectious Diseases, said it “doesn’t look like a knockout,” but he acknowledged the results indicate an important proof of concept for the drug, according to a White House pool report.

An expanded phase of the first SIMPLE study that will enroll 5,600 patients—including those receiving mechanical ventilation—is set to begin shortly. Patients will be enrolled at 180 sites worldwide, including the United States, China, France, and Italy.  Additionally, results from a second SIMPLE trial are expected by the end of May. This trial is evaluating the same dosing regimens vs standard of care in patients with moderate COVID-19 symptoms.

Seemingly contradictory results on remdesivir’s efficacy were detailed in a study published in The Lancet. The randomized, double-blind, placebo-controlled trial was conducted across 10 hospitals in Hubei, China, between February 6, 2020, and March 12, 2020. Patients received either intravenous remdesivir 200 mg on day one, followed by remdesivir 100 mg for 10 days, or the same volume of placebo for 10 days.

The study authors concluded that remdesivir resulted in a non-significant time to clinical improvement when compared with placebo. Adverse effects occurred in 66% of those in the remdesivir group vs 64% of those receiving placebo. Remdesivir was stopped early in 12% of patients due to adverse events.

In a commentary accompanying the Lancet study, John David Norrie, PhD, Edinburgh Clinical Trials Unit, User Institute, University of Edinburgh, Edinburgh, United Kingdom, noted that while the study was well designed and well conducted, it was underpowered due to the lack of patients meeting eligibility criteria by March 12. Importantly, although the main findings were not statistically significant, data on safety, viral load, and secondary outcomes are not altogether promising.

“[Twenty-two] (14%) of 158 patients on remdesivir died versus [10] (13%) of 78 on placebo, and there was no signal that viral load decreased differentially over time between remdesivir and placebo groups. Furthermore, there were no differential signals on safety,” wrote Dr. Norrie.

He also underscored that little is known for certain in the studies conducted during the early phases of a pandemic.

“The particular challenges of delivering pandemic trials underline the importance of data sharing, allowing rapid curation of relevant datasets for individual patient data meta-analyses,” he wrote. “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works.”