The National Institutes of Health (NIH) has selected the University of Pittsburgh to lead a trio of Phase 3 clinical trials involving COVID-19 patients. Collectively known as ACTIV-4 Antithrombotics, these trials will explore the use of blood thinners in saving lives and improving care, particularly among adult COVID-19 patients who are at risk of developing life-threatening blood clots.
As the coordinating center for these trials, Pitt is occupying a leading role in the National Institutes of Health’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, funded through Operation Warp Speed. Six other universities—Harvard University, New York University, the University of Illinois at Chicago, the University of Michigan, the University of North Carolina at Chapel Hill and the University of Vermont—are also participating in the initiative, which will continue to add qualifying institutions.
“This is a massive undertaking supported by the NIH—one that is leveraging a global network to help improve patient outcomes for COVID-19,” said Anantha Shekhar, who serves as Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of the School of Medicine. “It is also a challenge that the University of Pittsburgh, a longtime leader in health care innovation, is perfectly positioned to tackle.”
Researchers and clinicians have noted that many patients who have died from COVID-19 formed blood clots throughout their bodies, including in their smallest blood vessels. This unusual clotting—one of many life-threatening effects of the disease—causes multiple health complications, from lung and other organ damage to heart attacks, pulmonary embolisms and strokes.
Antithrombotics, also known as blood thinners or anticoagulants, keep blood protein and platelets from turning into clumps or sticking to each other, but doctors have not yet figured out if—and at what point in the course of COVID-19—blood thinners might be effective at treating patients with this condition.
Stephen Wisniewski, vice provost for budget and analytics, and two physician scientists from Pitt—Matthew D. Neal, the Roberta G. Simmons Associate Professor of Surgery; and Frank Sciurba, a professor of medicine and education who directs the Pulmonary Function Exercise Physiology Laboratory—are leading this effort.
“Understanding how to treat coagulation risk in COVID-19 patients is critical to lessening the impact of this pandemic,” said Wisniewski. “Pitt’s ability to innovate and collaborate enables us to help ensure that these trials will be completed with the rigor and speed necessary to make an impact at this critical moment. In collaboration with the National Institutes of Health and our peer institutions, we will use the combined tools of biology and statistics to advance the treatments of this deadly virus.”
ACTIV-4: Improving care in and out of the hospital
ACTIV-4 consists of three platforms: an inpatient platform launching now, an outpatient platform that will focus on patients who do not need hospitalization and a post-hospitalization outpatient platform that will focus on patients who have already been discharged from care.
“There is currently no standard of care for anticoagulation in hospitalized COVID-19 patients, and there is a desperate need for clinical evidence to guide practice,” said Francis S. Collins, director of NIH. “Conducting trials using multiple existing networks of research sites provides the scale and speed that will get us answers faster.”
The first trial, ACTIV-4 Antithrombotics Inpatient, is a master platform for collaboration among several randomized clinical trial platforms, including PROTECT COVID-19 at NYU Langone Health; the international REMAP-CAP, including leadership from Pitt and UPMC; and ATTACC from Canada. It will evaluate the safety and effectiveness of varying doses of the blood thinner heparin.
The trial will assign patients to either a low or high dose of heparin and, as the trial progresses, additional anticoagulants may be tested, depending on early results. Throughout the study, all participants will receive clinical care as indicated for their condition.
“This has been an amazingly cooperative endeavor—unequivocally the most rapidly moving, complex but also highly collaborative experience of my life,” said Neal. “By harmonizing these platforms, we’ll be able to arrive at an answer as to whether antithrombotics can improve outcomes in COVID-19—and at what doses—far faster than we would otherwise.”
Neal is co-chair of the protocol development committee and a lead investigator for the ACTIV-4 Antithrombotics Inpatient platform. Sciurba, who also serves as director of UPMC’s Pulmonary Physiology Center, is co-chair of the protocol development committee and a lead investigator of the outpatient platform.
“While the greatest focus on blood clotting complications has been in the inpatient setting, earlier attention in more stable patients prior to hospitalization may have an important impact on progression to the more serious consequences of COVID-19,” said Sciurba.
Other investigators from Pitt include Maria Mori Brooks, professor of epidemiology and biostatistics and co-director of Pitt’s Epidemiology Data Center, who is leading the statistical design of the outpatient platform; Alison Morris, chief of the Division of Pulmonary, Allergy and Critical Care Medicine, who is the co-chair of the protocol development committee of the post-hospitalization outpatient platform; and Abdus S. Wahed, director of PhD Graduate Programs in Pitt’s Department of Biostatistics, who is leading the statistical design of the post-hospitalization outpatient platform.
Given the unpredictable geographic variability of COVID-19, the ACTIV-4 team is actively recruiting sites with clinical trial experience that have significant COVID-19 burden. To inquire, email ACTIV4siteenroll@pitt.edu.
Leading the fight against COVID-19
Scientists and clinicians across Pitt’s six health sciences schools, along with colleagues from other academic departments, have taken a prominent role in responding to the pandemic. In all, Pitt is home to more than 400 ongoing studies related to COVID-19 and the coronavirus.
Earlier this month, a study led by Derek Angus, distinguished professor and the Mitchell P. Fink Endowed Chair of Pitt’s Department of Critical Care Medicine, appeared in the Journal of the American Medical Association and informed the World Health Organization’s recommendation to use steroids to treat critically ill COVID-19 patients.
Additional efforts at Pitt to fight COVID-19 include work led by Paul Duprex, in Pitt’s Center for Vaccine Research to harness a measles vaccine engineered to express SARS-CoV-2 proteins on its surface to generate immunity to the virus that causes COVID-19.
Also in the Center for Vaccine Research: William Klimstra, an associate professor of immunology, is investigating an antibody therapy called SAB-185 that could be used to both treat COVID-19 and prevent it in front-line workers and military personnel. Last month, clinical staff began injecting SAB-185 into healthy volunteers for a Phase 1 safety study.
Pitt’s Clinical and Translational Science Institute has awarded nearly $1 million to 17 studies that are exploring different aspects of the pandemic, from modeling the virus to examining how the lung’s microbiome may impact infection.
Two pharmaceutical companies, Moderna and AstraZeneca, are also partnering with Pitt and UPMC on vaccine trials. The Phase 3 trials, led by Judy Martin, director of the Pittsburgh Vaccine Clinical Trials Unit and professor of pediatrics, and Sharon Riddler, director of clinical research in Pitt’s Division of Infectious Diseases, seek to determine if the vaccines can prevent COVID-19 and for how long.