New Phase 3 trial of therapeutics begins enrolling severely ill hospitalized COVID-19 patients

A new Phase 3 trial to test the safety and efficacy of therapeutics for COVID-19 has begun enrolling patients hospitalized with life-threatening cases of COVID-19, including those with acute respiratory failure. The trial is supported by two components of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung and Blood Institute (NHLBI), and is part of the NIH Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) public-private partnership.

The randomized, blinded, placebo-controlled clinical trial is called ACTIV-3 Critical Care. It will begin by testing Zyesami, a formulation of aviptadil acetate, produced by NeuroRx, Wilmington, Delaware, and the antiviral remdesivir (Veklury), developed by Gilead, Foster City, California. Aviptadil is a synthetic version of Vasoactive Intestinal Peptide or VIP, which is made naturally in the human body and appears to have lung-protective antiviral and anti-inflammatory effects. Administered intravenously, it may provide additional protection for lung cells commonly targeted by SARS-CoV-2, the virus that causes COVID-19.

It is licensed in the United States for treating hospitalized patients with COVID-19. However, its benefit in patients with more severe COVID-19 is unclear. The trial will test Zyesami and remdesivir (alone and in combination), for their safety and efficacy in hospitalized COVID-19 patients who are experiencing Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition in which the lungs are severely inflamed and may be unable to maintain sufficient oxygen in the blood.

Finding more effective therapeutics for critically ill COVID-19 patients remains an essential need in the ongoing response to the pandemic. We need more treatment options to increase the chances of recovery for people who are extremely sick so they can leave the hospital more quickly, continue their recovery at home, and return to life as usual."

Anthony S. Fauci, M.D., NIAID Director

ACTIV-3 Critical Care allows for sub-studies of different therapeutics to run concurrently. Each sub-study will enroll approximately 620 participants. Participants will be randomly assigned to receive either the investigational agents in the sub-study or a placebo. In the current version of the study, participants will be randomly assigned to receive one of four treatment regimens in addition to standard of care: both Zyesami and remdesivir, Zyesami and a placebo, remdesivir and placebo, or only placebo. Zyesami is administered for 12 hours daily for three days, with the infusion rate increasing each day. Those randomized to receive remdesivir will receive it for up to 10 days via IV.

"There is a strong body of previous research that supports the use of these agents in ARDS, which is associated with substantial morbidity and mortality," said Gary H. Gibbons, M.D., director of NHLBI. "Not only is this an important trial, in terms of potential new treatments for COVID-19, but it could open new understanding into the repair of damaged lungs following ARDS."

The study evaluating Zyesami and remdesivir will enroll hospitalized patients with acute respiratory failure due to COVID-19 who require high-flow supplemental oxygen, delivered by nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation.

Initially, a small cohort of 40 participants will be enrolled at sites in the United States. If no safety concerns are identified, a larger group of participants will be enrolled at additional U.S. and international sites. If necessary, the treatment regimens may be adjusted before additional participants are enrolled.

For the primary analysis of the trial, participants will be assessed on a 6-category ordinal scale 90 days after enrolment, and outcomes will be compared among treatment groups. This scale ranges from recovered and living at home without supplemental oxygen within two weeks of enrolment, to death. Following the assessment at the primary endpoint, participants will receive one additional follow-up at 180 days.

During the trial, an independent Data and Safety Monitoring Board (DSMB) will review the data on an ongoing basis. ACTIV-3 Critical Care is part of the overall ACTIV-3 effort, which has been testing new therapeutics in hospitalized patients since Aug. 4, 2020.

The principal investigator of ACTIV-3 Critical Care is Samuel Brown, M.D., M.S., of Intermountain Healthcare and the University of Utah, Salt Lake City. Leaders of the participating networks include James Neaton, Ph.D., of the NIAID-sponsored International Network for Strategic Initiatives in Global HIV Trials network; Taylor Thompson, M.D., of the Prevention and Early Treatment of Acute Lung Injury network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the Cardiothoracic Trials Surgical Network, both NHLBI-sponsored networks; and Victoria Davey, Ph.D., M.P.H., of the U.S. Department of Veterans Affairs.

NIAID conducts and supports research–at NIH, throughout the United States, and worldwide–to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.