NIH initiates a clinical trial evaluating an investigational antiviral for treatment of COVID-19

The National Institutes of Health has initiated a multi-site clinical trial evaluating an investigational antiviral for the treatment of COVID-19. The therapeutic, known as S-217622 or ensitrelvir fumaric acid, was discovered by Hokkaido University, Sapporo, Japan; and Shionogi & Co., Ltd., Osaka, Japan. The trial is assessing whether S-217622 can improve clinical outcomes for patients who are hospitalized for management of COVID-19 as compared to a placebo and will enroll approximately 1,500 people at sites worldwide. S-217622 is the first agent to be evaluated in a new global, adaptive clinical research protocol known as Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE).

The National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, is funding the trial and working in partnership with NIH's National Center for Advancing Translational Sciences (NCATS). Developed under the auspices of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, STRIVE may be adapted to rapidly assess multiple therapeutic interventions during outbreaks of respiratory diseases, such as COVID-19 or influenza.

We hope results from this trial can be applied to improve the standard of care for people with COVID-19, which still causes hundreds of deaths each day in the United States, as well as to strengthen our pandemic preparedness. The STRIVE protocol and clinical research infrastructure can be adapted to evaluate additional agents for COVID-19, as well as therapeutics for other respiratory pathogens."

H. Clifford Lane, M.D., NIAID Deputy Director for Clinical Research and Special Projects

Findings from the ACTIV-3 trials, which evaluated therapeutics for adults hospitalized with COVID-19, indicated that ongoing viral replication may play a role in driving disease progression to critical illness. The research team hypothesized that a significant number of patients hospitalized with COVID-19 may still benefit from antiviral therapy.

S-217622 suppresses SARS-CoV-2 replication by inhibiting the function of a key virus protein known as 3CL protease. The antiviral reduced COVID-19 symptoms in people with mild-to-moderate COVID-19, regardless of risk factors or vaccination status, according to results shared by Shionogi from a Phase 3 clinical trial conducted mainly in Japan. S-217622 was well-tolerated, and there were no treatment-related serious adverse events or deaths in the study. In November 2022, the drug received emergency regulatory approval in Japan, where it is referred to by the brand name Xocova. The ongoing ACTIV-2 SCORPIO-HR clinical trial, also funded by NIAID, is evaluating the antiviral in the outpatient population.

Jason Baker, M.D., chief of infectious diseases at Hennepin Healthcare and associate professor of medicine at the University of Minnesota, Minneapolis, is serving as trial chair. Trial co-chairs include Marcelo Losso, M.D., principal investigator at Hospital J.M. Ramos Mejia in Buenos Aires, Argentina, and director of Latin America Coordination of Academic Clinical Research, Buenos Aires; and Shikha Vasudeva, M.D., assistant professor of medicine, Virginia Tech Carilion School of Medicine, Roanoke, and infectious disease specialist, Department of Veterans Affairs Medical Center, Salem, Virginia.

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Participants will be assigned at random to receive S-217622 or a placebo. Neither the investigators nor the participants will know who is receiving the investigational drug. S-217622 is taken by mouth once daily for five days. The first-day dose is three 125 milligram (mg) tablets totaling 375 mg, followed by one 125 mg tablet per day for the next four days. All participants will receive the local standard of care for COVID-19, which may differ based on location, and could include another antiviral, as well as immunomodulatory drugs, corticosteroids and/or anticoagulants.

Investigators will monitor and record participants' health status every day during the first week and then on prespecified days over a 60-day period. Participants also will be asked to provide blood samples and nose swabs for laboratory tests.

The study team will conduct analyses to understand any statistically significant differences—meaning those unlikely due to chance—between the treatment group and the placebo group. The key metric they will focus on is whether people receiving S-217622 recover (defined as returning home and remaining alive through day 60) more quickly than those in the placebo group.

Participant safety will be monitored closely throughout the trial. An NIAID Medical Monitor will review any potential safety issues in real time, and an independent data and safety monitoring board (DSMB) will review safety and efficacy data regularly.

The pace of enrollment and, ultimately, the amount of time it takes to complete the trial will depend on the trajectory of COVID-19 cases in various parts of the world. For more information about the trial, please visit clinicaltrials.gov and search identifier NCT05605093.

STRIVE is part of the NIH ACTIV public-private-partnership, which was initiated in April 2020 to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines for COVID-19. STRIVE builds on the efforts of prior ACTIV master protocols that evaluated various therapeutics for people hospitalized with COVID-19. The STRIVE Scientific Committee, chaired by Professor Jens Lundgren, M.D., from the University of Copenhagen, is composed of clinical trial experts from several medical specialties including infectious diseases, pulmonology, intensive care, and emergency medicine. STRIVE is also overseen by a leadership committee and a community advisory board.

The Statistical and Data Management Center at University of Minnesota, led by James Neaton, Ph.D., is managing STRIVE in collaboration with eight international coordinating centers, bringing together former sites from the ACTIV-1, ACTIV-3, and ACTIV-5 clinical trials. In all, STRIVE can enroll participants at more than 200 sites on all six inhabited continents.