The Vanderbilt Institute for Clinical and Translational Research (VICTR) has been awarded a major federal grant to lead a national trial of treatments targeting the Renin Angiotensin Aldosterone System (RAAS) in patients hospitalized with COVID-19.
Comprised of the hormones renin, angiotensin and aldosterone, RAAS is essential for the regulation of blood pressure and fluid balance. SARS-CoV-2, the virus that causes COVID-19, can disrupt this system, resulting in life-threatening complications, including pulmonary edema, thromboembolic complications and severe cardiac injury.
Sean Collins, MD, MSc, professor of Emergency Medicine at Vanderbilt University Medical Center, who has deep expertise in emergency care and RAAS, will lead the trial, which will test whether drugs targeting RAAS can prevent the vascular, fibrotic and inflammatory consequences of severe COVID-19 disease.
The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), will provide up to $60 million through the grant, which will be distributed through administrative partners at RTI International, an independent nonprofit research institute based in Research Triangle, North Carolina.
The national trial, called ACTIV-4d, is part of Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership coordinated by the Foundation for the National Institutes of Health. ACTIV unites partners from government, industry, academic and nonprofit organizations to prioritize and speed development of the most promising COVID-19 treatments.
The ACTIV-4d RAAS trial will enroll approximately 1,600 patients at more than 50 sites, including members of the NHLBI-supported Prevention and Early Treatment of Acute Lung Injury (PETAL) Network.
VICTR and the Vanderbilt Coordinating Center (VCC), which Collins co-directs and which provides support for clinical trials at VUMC, will jointly oversee the ACTIV-4d RAAS trial in the role of clinical and data coordinating center.
“While RAAS is central to both the mechanism of viral entry and the multiple organ dysfunctions associated with COVID-19, RAAS-targeted therapies remain understudied,” Collins said. “The ACTIV-4d RAAS platform has tremendous potential to clarify the impact of restoring RAAS balance in patients hospitalized with COVID-19 and to identify a therapy for patients affected by the disease.”
The SARS-CoV-2 spike protein binds the receptor for angiotensin-converting enzyme 2 (ACE2) on cell surfaces in the body, enabling the virus to enter cells and hijack their genetic machinery to replicate itself. Binding ACE2 also prevents the processing of angiotensin II (Ang II), thus creating RAAS imbalance.
ACTIV-4d will test multiple agents acting through separate mechanisms to determine if restoring RAAS balance in patients with COVID-19 improves clinical outcomes. The platform is expected to include at least three investigational drugs:
- TXA127, an investigational agent from Constant Therapeutics LLC, is a pharmaceutical formulation of the natural human peptide Ang 1-7, which binds the Mas receptor. It triggers physiological functions that oppose the vascular, immune and fibrotic effects of Ang II through the Ang II-type 1 receptor (AT1R).
- TRV027, an investigational drug from Trevena Inc., is a small molecule selective agonist for AT1R, which induces beneficial signaling through the beta-arrestin signaling pathway in a way that improves vascular, immune and fibrotic responses.
- APN01, an investigational drug from APEIRON Biologics, is a circulating recombinant version of the human ACE2 receptor. APN01 binds the SARS-CoV-2 spike protein, thereby preventing the virus from attaching to ACE2 on cell surfaces. This diversion prevents viral entry and allows cellular ACE2 to convert circulating Ang II to Ang 1-7.
“We are very hopeful that NHLBI’s platform of trials will help advance the understanding of COVID-19 and 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.
Self, who has extensive COVID-19 and other clinical trial experience at VUMC and in PETAL, is associate professor and vice chair for Research in the Department of Emergency Medicine and VICTR’s vice president for Clinical Research Networks & Strategy.
Matt Shotwell, PhD, associate professor of Biostatistics, will lead the VUMC Data Coordinating Center for ACTIV-4d RAAS. Experienced in data management, statistical methodology and adaptive clinical trial design, Shotwell is a member of the VICTR Research Methods Program.
Headed by Gordon Bernard, MD, the Melinda Bass Owen Professor of Medicine and Executive Vice President for Research at VUMC, VICTR is supported by a Clinical and Translational Science Award (CTSA) as well as other federal funding.
Since June 2020 VICTR has served as the Science Unit for CONNECTS, the Collaborative Network of Networks for Evaluating COVID-19 Therapeutic Strategies of the National Heart, Lung and Blood Institute.
The CONNECTS Science Unit organized an Agent Prioritization Committee of national experts to evaluate more than 80 promising therapeutics — prioritizing RAAS-targeting agents — for patients hospitalized with COVID-19.
The Unit also organized a Master Protocol Committee of more than 50 experts, including VUMC clinicians and scientists, who have developed an innovative trial design that optimizes efficiency for testing multiple agents simultaneously.
For more information about this and other ACTIV therapeutic trials, visit the ACTIV website: https://www.nih.gov/research-training/medical-research-initiatives/activ.
