The COVID-19 virus has taken over life as we know it, creating a novel environment for science in which collaboration is key and extraordinary speed is expected without sacrificing accuracy. Funded through Operation Warp Speed, the National Institutes of Health (NIH) launched the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership April. Since that time, the Brigham has taken a leadership role in launching a trial to determine if anticoagulant or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications from COVID-19.
ACTIV aims to coordinate a research strategy and prioritize the rapid development of treatments and vaccines. It consists of five adaptive master protocols: immune modulators (ACTIV-1), outpatient monoclonal antibodies and other therapies (ACTIV-2), inpatient monoclonal antibodies and other therapies (ACTIV-3), antithrombotics (ACTIV-4), and “big effect trial” (ACTIV-5). Under the umbrella of ACTIV-4, there are three narrower topics: ACTIV-4 Antithrombotics Inpatient anticoagulant trials, ACTIV-4 Antithrombotics Outpatient anticoagulant and antiplatelet trials, and ACTIV-4 Antithrombotics Convalescent outpatient anticoagulant trials. Brigham investigators are playing a lead role in the ACTIV-4 Antithrombotics Outpatient anticoagulant and antiplatelet trial, which is now underway.
“COVID-19 has overwhelmed the world because no one has prior immunity. This lack of immunity often results in significant inflammation and activation of coagulation,” said Jean Connors, MD, of the Brigham’s Hematology Division and ACTIV-4 Antithrombotics Outpatient trial principal investigator. “We think that patients who get diagnosed with COVID-19 — but aren’t admitted to the hospital — appear to have increased risk for developing blood clots and pulmonary microvascular thrombosis.”
The ACTIV-4 Antithrombotics COVID-19 Outpatient Thrombosis Prevention Trial is an adaptive, randomized, double-blind, placebo-controlled platform trial, wherein the efficacy of anticoagulation, antiplatelet, and placebo drugs are compared for their capacity to prevent thrombotic events in COVID-19 patients. 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 —accelerating the timeline for testing different agents without compromising safety.
“We are honored that Operation Warp Speed and the NIH came to us at the Brigham to coordinate this effort,” said Paul Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and ACTIV-4 Antithrombotics Outpatient Trial chairman. “I am particularly pleased with how our Brigham support staff creatively built a nationwide ‘low touch’ trial structure in an incredibly short period of time, reflecting the emergency we are all dealing with.”
Patients enrolled must exhibit increased inflammation but have stable symptoms not requiring hospitalization. Additionally, the study will only enroll patients between ages 40 and 80, due to their increased risk for thrombotic events. Enrolled patients will receive one of four possible treatments: prophylactic dose anticoagulation (apixaban), therapeutic dose anticoagulation (apixaban), antiplatelet therapy (aspirin), or a placebo.
Shifting the Landscape
Using a new remote approach, researchers will collect outpatient information throughout the 45-day treatment period and for 30 days following treatment termination, tracking thrombotic events such as pulmonary embolism, myocardial infarction, and ischemic stroke without the need for conventional in-person study visits. Utilizing express shipping, patients will receive their prescribed treatment and will have contact with researchers through weekly phone calls or texts — an entirely remote experience with potential to shift the landscape of clinical research in the modern era.
“Remote monitoring is a unique aspect of this trial,” said Connors. “We are shipping the medications and contacting patients electronically to capture information. There is even a unique consent process that includes videos we send to participants.”
ACTIV-4 Antithrombotics Outpatient is actively recruiting COVID-19 patients in states with surging cases, including Illinois, California, Utah, Florida, and Massachusetts. The Brigham will also be enrolling patients under the leadership of Peter Hou, MD, in the Emergency Medicine Department. As surges have resulted in tens of thousands of patients diagnosed daily, the study investigators hope they can rapidly reach their enrollment goal of 7,000 patients.
“Our goal is to determine the best treatment to prevent blood clots in patients, and to possibly prevent pulmonary microvascular thrombosis. We want to prevent patients from needing to be admitted to the hospital, and we want to prevent them from developing thrombosis as a complication,” said Connors. “Successful enrollment and corresponding research would be a huge step toward optimizing treatment for outpatient COVID-19 cases, preventing both hospital admission rates and traumatic thrombotic events.”
“We need physicians and patients to recognize that individuals infected with COVID-19 are at thrombotic risk even if they are not admitted to hospital,” said Ridker. “Once enrolled, the ACTIV-4 Outpatient Thrombosis Prevention Trial will greatly inform patient care and treatment.”