September 11, 2020 — The National Institutes of Health (NIH) has launched two of three adaptive clinical trials evaluating the safety and effectiveness of varying types of blood thinners to treat adults diagnosed with COVID-19 (SARS-CoV-2). Coronavirus can cause venous thrombo-embolism (VTE), leading to stroke, pulmonary embolism and deep vein thrombosis.
Part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, these trials will be conducted at more than 100 sites around the world, including University of Florida Health and the OneFlorida Clinical Research Consortium. The studies will involve patients in various clinical settings — those who have not been hospitalized, those currently hospitalized and those discharged after hospitalization for moderate to severe cases of the disease.
Collectively known as ACTIV-4 Antithrombotics, the trials will provide critical insights that could help guide the care of patients with COVID-19, particularly those who suffer from life-threatening blood clots. The trial for hospitalized COVID-19 patients and the trial for patients with COVID-19 who have not been hospitalized are now underway. A third trial to start later will focus on patients discharged after hospitalization for moderate to severe COVID-19 disease. All three clinical trials will be coordinated and overseen by the National Heart, Lung, and Blood Institute (NHLBI), part of NIH, and funded through Operation Warp Speed.
Researchers have noted that many patients who have died from COVID-19 had formed blood clots throughout their bodies, including in their smallest blood vessels. This unusual clotting, one of many life-threatening effects of the disease, has caused multiple health complications, from organ damage to heart attack, stroke and pulmonary embolism.
ACTIV-4 Antithrombotics will be recruiting at sites with significant COVID-19 burden and are interested in enrolling patients in studies testing potential treatments to prevent or reduce the formation of blood clots.
Within the next four to six weeks, UF Health and OneFlorida have a goal of recruiting 1,600 of the 7,000 participants needed to determine which therapy is most effective.
“Health systems around the state are combining their efforts to be a key part of this clinical trial,” said Eileen Handberg, Ph.D., ARNP, a professor in cardiology at UF Health and site principal investigator for the ACTIV-4 Antithrombotic Outpatient trial. “Our centralized administration and OneFlorida’s extensive network of health partners in Florida and around the country make us an ideal site for handling the kind of rapid recruitment needed for COVID-19 trials like ACTIV-4.
UF Health serves as the coordinating center for the OneFlorida Clinical Research Consortium, a statewide research network and data trust that includes 12 academic centers and health systems across Florida, many of which will be participating in this clinical trial. OneFlorida’s network of 22 hospitals, 1,240 practices/clinics and 4,100 providers care for about 74% of Floridians in all 67 counties. OneFlorida is also one of nine clinical research networks nationwide participating in PCORnet, the national patient-centered clinical research network.
The adaptive design of the protocol allows different blood thinners to be started, stopped or combined during the study in response to emerging trial data. This approach accelerates the timeline for testing different agents without compromising safety.
Antithrombotics, also known as blood thinners or anticoagulants, keep blood protein and platelet cells from turning into clumps or sticking to each other, but doctors have not yet figured out if, and at what point during the course of the disease, blood thinners might be effective at treating patients with COVID-19.
“It is imperative that national treatment guidelines for COVID-19 interventions such as blood thinners are informed by clinical trials like this one,” said Lisa H. Merck M.D., M.P.H., associate professor of emergency medicine and vice chair of research in emergency medicine in the UF College of Medicine. Merck is the site physician for the ACTIV-4 Outpatient trial in Florida.
Randomized, controlled clinical trials are considered the gold standard of scientific evidence for medical interventions because participants are carefully selected and monitored throughout the study, drug dosages and the duration of treatment are controlled, and participants are randomly assigned to well-defined treatment or placebo groups. This way, Merck said, researchers can objectively evaluate the safety and effectiveness of a therapy.
“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 NIH Director Francis S. Collins, M.D., Ph.D. “Conducting trials using multiple existing networks of research sites provides the scale and speed that will get us answers faster.”
ACTIV-4 Antithrombotics Inpatient will investigate the safety and effectiveness of using varying doses of the blood thinner heparin to prevent clotting events and improve outcomes in hospitalized COVID-19 patients. Patients will be assigned to either a low or high dose of heparin, and as the trial progresses, additional antithrombotics may be tested, depending on the trial results. All participants in the study will continue to receive clinical care as indicated for their condition.
ACTIV-4-Antithrombotics Outpatient will investigate whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed COVID-19 patients who do not require hospital admission. Researchers will also collect patient data and blood samples to help identify new drug targets and biomarkers that may help identify a patient’s risk of developing complications related to COVID-19. Participants will be assigned to take either a placebo, aspirin, or a low or therapeutic dose of the blood thinner apixaban.
“We must use therapies that support the natural inhibitors of clotting in the blood,” said Keith Hoots, M.D., director of NHLBI’s Division of Blood Disorders and Resources. “Heparin has shown promise, but we really need clinical trial data to determine how much blood thinner, or even anti-platelet medication, to give.”
“By leveraging the infrastructure and expertise of our existing research networks, we can more rapidly gather the scientific evidence needed to help prevent or treat these very serious complications caused by COVID-19,” said NHLBI Director Gary H. Gibbons, M.D. “Harnessing and integrating the assets within existing networks gives us an enormous head start and will allow us to get answers much sooner.”
Trial planning and development work is being done through a collaborative effort with a number of universities, including the University of Florida, Gainesville; University of Pittsburgh; University of Michigan, Ann Arbor; New York University, New York City; Brigham and Women’s Hospital, Boston; University of Illinois at Chicago; University of North Carolina at Chapel Hill; and The University of Vermont, Burlington.
NIH announced the ACTIV public-private partnership in April 2020 to develop a coordinated national research response to speed COVID-19 treatment and vaccine options. As part of this partnership, Bristol-Myers Squibb and Pfizer have agreed to donate the treatments for the trials for patients with COVID-19 who have not been hospitalized and for patients discharged after hospitalization with moderate to severe COVID-19 disease. Managed by the Foundation for the National Institutes of Health, ACTIV brings together multiple partners from government, industry, academia and non-profit organizations. For more information about this and other ACTIV therapeutic trials, visit the ACTIV Therapeutics page.
About the OneFlorida Clinical Research Consortium
The OneFlorida Clinical Research Consortium, a statewide clinical research network and database, unites researchers, clinicians, patients and stakeholders to address some of today’s biggest health challenges. The consortium’s 12 academic institutions and health systems provide care for about 74% of Floridians in all 67 counties, creating a dynamic statewide resource to facilitate health care research and improve health, health care and health policy. For more information, visit https://onefloridaconsortium.org/.