Vanderbilt University Medical Center researchers, supported by the National Institutes of Health (NIH), are leading a nationwide clinical trial to explore the safety and effectiveness of a group of novel drugs designed to protect patients hospitalized with COVID-19 at high risk of poor outcomes.
The new trial has enrolled its first patient.
Part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, the ACTIV-4 Host Tissue trial will first explore the efficacy of drugs that target the Renin Angiotensin Aldosterone System (RAAS) and the immune system, both of which become dysregulated during COVID-19 and cause widespread damage in patients infected with the SARS-CoV-2 virus.
The virus that causes COVID-19 is known to target and disrupt the RAAS and immune system, resulting in a biological imbalance triggering a cascade of potentially life-threatening complications, including blood vessel damage, lung damage, blood clots, and heart injury.
Three arms of the trial will test investigational agents that aim to intervene in the RAAS to prevent host tissue damage. TRV027, provided by Trevena, and TXA127, provided by Constant Therapeutics, are agonists that are hypothesized to restore RAAS balance. APN01, provided by APEIRON Biologics, is a recombinant, soluble receptor that is hypothesized to bind viral particles to prevent viral entry and allow the RAAS to return to more balanced levels.
A fourth arm was recently added to the trial to test the effects of inhibiting immune activation. Fostamatinib, provided by Rigel Pharmaceuticals, is a spleen tyrosine kinase (SYK) inhibitor currently FDA-approved for chronic immune thrombocytopenia (ITP). By inhibiting SYK, fostamatinib is hypothesized to decrease immune activation to prevent tissue damage and blood clotting.
VUMC’s Sean Collins, MD, MSc, Professor of Emergency Medicine at VUMC, is leading the trial to test whether drugs targeting these host tissue responses can prevent the vascular, fibrotic and inflammatory consequences of severe COVID-19 disease.
“Significant strides have been made to prevent infection, but it has become clear that SARS-CoV-2 infections will persist. There is still much to learn about the host tissue responses to COVID-19,” Collins said. “The ACTIV-4 Host Tissue trial has tremendous potential to clarify the impact of RAAS and immune dysfunction in patients hospitalized with COVID-19, and could identify life-saving therapies for patients hospitalized by the disease.”
The ACTIV-4 Host Tissue trial is enrolling approximately 1,600 patients at more than 50 sites in the United States, including members of the NHLBI-supported Prevention and Early Treatment of Acute Lung Injury (PETAL) Network.
Vanderbilt University Medical Center will play a key role in the ACTIV-4 Host Tissue trial as the clinical and data coordinating center.
ACTIV-4 Host Tissue represents the largest study to date specifically evaluating the effectiveness of drugs aimed at protecting the host tissues against COVID-19. The design of the protocol allows different agents to be started, stopped, or combined during the study in response to emerging trial data. This approach improves efficiency of testing different agents without compromising safety.
“We are very hopeful that NHLBI’s trials will help advance the understanding of COVID-19 and will lead to treatment options for severely ill patients with the disease,” said Wesley Self, MD, MPH, who leads the ACTIV-4d RAAS Clinical Coordinating Center at VUMC.
The trial is funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the NIH.
“While the availability of COVID-19 vaccines is wonderful, we still need effective treatments for COVID-19,” said David Goff, MD, PhD, director of the Division of Cardiovascular Sciences at the NHLBI. “The drugs undergoing testing in the ACTIV-4 Host Tissue trial represent a new and intriguing approach to fighting the effects of COVID-19 and could complement existing drugs, such as antivirals and anticoagulants, now in use or under study.”
For more information about this and other ACTIV therapeutic trials, visit the ACTIV website: https://www.nih.gov/research-training/medical-research-initiatives/activ.
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