The National Institutes of Health has launched two of three adaptive Phase 3 clinical trials evaluating the safety and effectiveness of varying types of blood thinners to treat adults diagnosed with COVID-19. 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 and 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 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 three Phase 3 clinical trials are coordinated and managed by the National Heart, Lung, and Blood Institute (NHLBI), part of NIH. Funding comes from Operation Warp Speed.
COVID-19 & Blood Clotting: Early Concerns at Weill Cornell Medicine
Researchers have noted that many patients who have died from COVID-19 — the deadly disease caused by SARS-CoV-2 — 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.
The concern for blood clotting in association with COVID-19 arose after Dr. Jeffrey Laurence, professor of medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and a hematology and oncology specialist at NewYork Presbyterian/Weill Cornell Medical Center, and his colleagues authored a paper published in Translational Research back in early April that triggered concern about abnormal blood clotting in severe COVID-19 cases. TrialSite offers a link to a question and answer article published on the Weill/Cornell website.
“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.”
Adaptive Design of Studies
This study is deemed an “adaptive design,” meaning a certain level of flexibility is offered to the study teams. 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.
ACTIV-4 Antithrombotics Site Network
Trial planning and development work is being done through a collaborative effort with a number of universities, including the 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.
Class of Drugs
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 during the course of the disease, blood thinners might be effective at treating patients with COVID-19. One drug mentioned by the NIH in their recent interview is heparin.
Discovered in 1916, this drug is on the World Health Organization’s List of Essential Medicines. Also known as “unfractionated heparin” (UFH), this medication is a naturally occuring glycosaminoglycan. Its used not only as a blood thinner but also to treat heart attacks and unstable angina. Administered via injection into a vein or under the skin, other uses include inside test tubes and kidney dialysis machines.
Side effects can include bleeding, pain at the site of injection, and low blood platelets. Serious side effects have occurred and include heparin-induced thrombocytopenia. Patients with bad kidneys require greater attention from attending physicians.
Competition or Collaboration with Existing Studies?
TrialSite recently shared a Canada-led study revealing that with about $200 billion spent on medical research annually, the problem is broken especially in the context of COVID-19. A seemingly “free for all,” where various studies potentially centered on the same topic actually end up competing for patients. One recent study argued that about 85% of research is wasted.
The creation of ACTIV in the United States, in part, helps address this challenge as this managing and coordinating body would vet all federally funded COVID-19 research—or at least a good deal of it. Aside from the potential issues associated with such consolidation introduced by TrialSite, the hope would be that the ACTIV-4 Antithrombotics COVID-19 research will leverage at least those relevant research initiatives in the United States also involving overlapping research.
For example, TrialSite ran a search of existing Antithrombotics COVID-19-based studies ongoing and found a total of 47; about a dozen of these studies are currently underway in the United States. At least one is sponsored by NHLBI, such as NCT04505774 led by Dr. Matthew Neal at University of Pittsburgh. Part of ACTIV-4 Antithrombotic, this adaptive platform trial seeks 2000 hospitalized COVID-19 patients to compare the effectiveness of antithrombotic strategies for prevention of adverse outcomes.
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.
ACTIV-4 Antithrombotic 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. 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.
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 antithrombotic drugs 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.”
More on ACTIV
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/Pfizer have agreed to donate the treatments for the trials for patients with COVID-19 who have not been hospitalized. 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.
The National Heart, Lung, and Blood Institute (NHLB)
NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives.
About the National Institutes of Health (NIH)
NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.