Skip to main content

ACTIV

ACTIV Update: Making Major Strides in COVID-19 Therapeutic Development

Posted on by

NIH ACTIV
Credit: NIH

Right now, many U.S. hospitals are stretched to the limit trying to help people battling serious cases of COVID-19. But as traumatic as this experience still is for patients and their loved ones, the chances of surviving COVID-19 have in fact significantly improved in the year since the start of the pandemic.

This improvement stems from several factors, including the FDA’s emergency use authorization (EUA) of a number of therapies found to be safe and effective for COVID-19. These include drugs that you may have heard about on the news: remdesivir (an antiviral), dexamethasone (a steroid), and monoclonal antibodies from the companies Eli Lilly and Regeneron.

Yet the quest to save more lives from COVID-19 isn’t even close to being finished, and researchers continue to work intensively to develop new and better treatments. A leader in this critical effort is NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies.

ACTIV was founded last April to accelerate drug research that typically requires more than a decade of clinical ups and downs to develop a safe, effective therapy. And ACTIV has indeed moved at unprecedented speed since its launch. Cutting through the usual red tape and working with an intense sense of purpose, the partnership took a mere matter of weeks to set up its first four clinical trials. Beyond the agents mentioned above that have already been granted an EUA, ACTIV is testing 15 additional potential agents, with several of these already demonstrating promising results.

Here’s how ACTIV works. The program relies on four expert “working groups” with specific charges:

Preclinical Working Group: Shares standardized preclinical evaluation resources and accelerate testing of candidate therapies and vaccines for clinical trials.

Therapeutics Clinical Working Group: Prioritizes therapeutic agents for testing within an adaptive master protocol strategy for clinical research.

Clinical Trial Capacity Working Group: Has developed and organized an inventory of clinical trial capacity that can serve as potential settings in which to implement effective COVID-19 clinical trials.

Vaccines Working Group: Accelerates the evaluation of vaccine candidates.

To give you just one example of how much these expert bodies have accomplished in record time, the Therapeutics Clinical Working Group got to work immediately evaluating some 400 candidate therapeutics using multiple publicly available information sources. These candidates included antivirals, host-targeted immune modulators, monoclonal antibodies (mAb), and symptomatic/supportive agents including anticoagulants. To follow up on even more new leads, the working group launched a COVID-19 Clinical & Preclinical Candidate Compound Portal, which remains open for submissions of therapeutic ideas and data.

All the candidate agents have been prioritized using rigorous scoring and assessment criteria. What’s more, the working group simultaneously developed master protocols appropriate for each of the drug classes selected and patient populations: outpatient, inpatient, or convalescent.

Through the coordinated efforts of all the working groups, here’s where we stand with the ACTIV trials:

ACTIV-1: A large-scale Phase 3 trial is enrolling hospitalized adults to test the safety and effectiveness of three medicines (cenicriviroc, abatacept, and infliximab). They are called immune modulators because they help to minimize the effects of an overactive immune response in some COVID-19 patients. This response, called a “cytokine storm,” can lead to acute respiratory distress syndrome, multiple organ failure, and other life-threatening complications.

ACTIV-2: A Phase 2/3 trial is enrolling adults with COVID-19 who are not hospitalized to evaluate the safety of multiple monoclonal antibodies (Lilly’s LY-CoV555, Brii Biosciences’s BRII-196 and BRII-198, and AstraZeneca’s AZD7442) used to block or neutralize the SARS-CoV-2 virus. The Lilly monoclonal antibody LY-CoV555 received an EUA for high risk non-hospitalized patients on November 9, 2020 and ACTIV-2 continued to test the agent in an open label study to further determine safety and efficacy in outpatients. Another arm of this trial has just started, testing inhaled, easy-to-administer interferon beta-1a treatment in adults with mild-to-moderate COVID-19 who are not hospitalized. An additional arm will test the drug camostat mesilate, a protease inhibitor that can block the TMPRSS2 host protein that is necessary for viral entry into human cells.

ACTIV-3: This Phase 3 trial is enrolling hospitalized adults with COVID-19. This study primarily aims to evaluate safety and to understand if monoclonal antibodies (AstraZeneca’s AZD7442, BRII-196 and BRII-198, and the VIR-7831 from GSK/Vir Biotechnology) and potentially other types of therapeutics can reduce time to recovery. It also aims to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Lilly’s monoclonal antibody LY-CoV555 was one of the first agents to be tested in this clinical trial and it was determined to not show the same benefits seen in outpatients. [Update: NIH-Sponsored ACTIV-3 Clinical Trial Closes Enrollment into Two Sub-Studies, March 4, 2021]

ACTIV-4: This trial aims to determine if various types of blood thinners, including apixaban, aspirin, and both unfractionated (UF) and low molecular weight (LMW) heparin, can treat adults diagnosed with COVID-19 and prevent life-threatening blood clots from forming. There are actually three Phase 3 trials included in ACTIV-4. One is enrolling people diagnosed with COVID-19 but who are not hospitalized; a second is enrolling patients who are hospitalized; and a third is enrolling people who are recovering from COVID-19. ACTIV-4 has already shown that full doses of heparin blood thinners are safe and effective for moderately ill hospitalized patients.

ACTIV-5: This is a Phase 2 trial testing newly identified agents that might have a major benefit to hospitalized patients with COVID-19, but that need further “proof of concept” testing before they move into a registrational Phase 3 trial. (In fact, another name for this trial is the “Big Effect Trial”.) It is testing medicines previously developed for other conditions that might be beneficial in treatment of COVID-19. The first two agents being tested are risankizumab (the result of a collaboration between Boehringer-Ingelheim), which is already FDA-approved to treat plaque psoriasis, and lenzilumab, which is under development by Humanigen to treat patients experiencing cytokine storm as part of cancer therapy.

In addition to trials conducted under the ACTIV partnership, NIH has prioritized and tested additional therapeutics in “ACTIV-associated trials.” These are NIH-funded, randomized, placebo-controlled clinical trials with one or more industry partners. Here’s a table with a comprehensive list.

Looking a bit further down the road, we also seek to develop orally administered drugs that would potentially block the replication ability of SARS-CoV-2, the coronavirus that causes COVID-19, in the earliest stages of infection. One goal would be to develop an antiviral medication for SARS-CoV-2 that acts similarly to oseltamivir phosphate (Tamiflu®), a drug used to shorten the course of the flu in people who’ve had symptoms for less than two days and to prevent the flu in asymptomatic people who may have been exposed to the influenza virus. Yet another major long-term effort of NIH and its partners will be to develop safe and effective antiviral medications that work against all coronaviruses, even those with variant genomes. (And, yes, such drugs might even cure the common cold!)

So, while our ACTIV partners and many other researchers around the globe continue to harness the power of science to end the devastating COVID-19 pandemic as soon as possible, we must also consider the lessons learned this past year, in order to prepare ourselves to respond more swiftly to future outbreaks of coronaviruses and other infectious disease threats. Our work is clearly a marathon, not a sprint.

Links:

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

COVID-19 Research (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Pull Up a Chair with Dr. Freire: The COVID Conversations (Foundation for the National Institutes of Health, Bethesda, MD)

SARS-COV-2 Antiviral Therapeutics Summit Report, November 2020 (NIH)


Can Blood Thinners Keep Moderately Ill COVID-19 Patients Out of the ICU?

Posted on by

Blood Clot
Credit: iStock

One of many troubling complications of infection with SARS-CoV-2, the coronavirus that causes COVID-19, is its ability to trigger the formation of multiple blood clots, most often in older people but sometimes in younger ones, too. It raises the question of whether and when more aggressive blood thinning treatments might improve outcomes for people hospitalized for COVID-19.

The answer to this question is desperately needed to help guide clinical practice. So, I’m happy to report interim results of three large clinical trials spanning four continents and more than 300 hospitals that are beginning to provide critical evidence on this very question [1]. While it will take time to reach a solid consensus, the findings based on more than 1,000 moderately ill patients suggest that full doses of blood thinners are safe and can help to keep folks hospitalized with COVID-19 from becoming more severely ill and requiring some form of organ support.

The results that are in so far suggest that individuals hospitalized, but not severely ill, with COVID-19 who received a full intravenous dose of the common blood thinner heparin were less likely to need vital organ support, including mechanical ventilation, compared to those who received the lower “prophylactic” subcutaneous dose. It’s important to note that these findings are in contrast to results announced last month indicating that routine use of a full dose of blood thinner for patients already critically ill and in the ICU wasn’t beneficial and may even have been harmful in some cases [2]. This is a compelling example of how critical it is to stratify patients with different severity in clinical trials—what might help one subgroup might be of no benefit, or even harmful, in another.

More study is clearly needed to sort out all the details about when more aggressive blood thinning treatment is warranted. Trial investigators are now working to make the full results available to help inform a doctor’s decisions about how to best to treat their patients hospitalized with COVID-19. It’s worth noting that these trials are overseen by independent review boards, which routinely evaluate the data and are composed of experts in ethics, biostatistics, clinical trials, and blood clotting disorders.

These clinical trials were made possible in part by the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership and its ACTIV-4 Antithrombotics trials—along with similar initiatives in Canada, Australia, and the European Union. The ACTIV-4 trials are overseen by the NIH’s National Heart, Lung, and Blood institute and funded by Operation Warp Speed.

This ACTIV-4 trial is one of three Phase 3 clinical trials evaluating the safety and effectiveness of blood thinners for patients with COVID-19 [3]. Another ongoing trial is investigating whether blood thinners are beneficial for newly diagnosed COVID-19 patients who do not require hospitalization. There are also plans to explore the use of blood thinners for patients after they’ve been discharged from the hospital following a diagnosis of moderate to severe COVID-19 and to establish more precise methods for identifying which patients with COVID-19 are most at risk for developing life-threatening blood clots.

Meanwhile, research teams are exploring other potentially promising ways to repurpose existing therapeutics and improve COVID-19 outcomes. In fact, the very day that these latest findings on blood thinners were announced, another group at The Montreal Heart Institute, Canada, announced preliminary results of the international COLCORONA trial, testing the use of colchicine—an anti-inflammatory drug widely used to treat gout and other conditions—for patients diagnosed with COVID-19 [4].

Their early findings in treating patients just after a confirmed diagnosis of COVID-19 suggest that colchicine might reduce the risk of death or hospitalization compared to patients given a placebo. In the more than 4,100 individuals with a proven diagnosis of COVID-19, colchicine significantly reduced hospitalizations by 25 percent, the need for mechanical ventilation by 50 percent, and deaths by 44 percent. Still, the actual numbers of individuals represented by these percentages was small.

Time will tell whether and for which patients colchicine and blood thinners prove most useful in treating COVID-19. For those answers, we’ll have to await the analysis of more data. But the early findings on both treatment strategies come as a welcome reminder that we continue to make progress each day on such critical questions about which existing treatments can be put to work to improve outcomes for people with COVID-19. Together with our efforts to slow the spread of SARS-CoV-2, finding better ways to treat those who do get sick and prevent some of the worst outcomes will help us finally put this terrible pandemic behind us.

References:

[1] Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Heart, Lung, and Blood Institute. January 22, 2021.

[2] NIH ACTIV trial of blood thinners pauses enrollment of critically ill COVID-19 patients. National Heart, Lung, and Blood Institute. December 22, 2020.

[3] NIH ACTIV initiative launches adaptive clinical trials of blood-clotting treatments for COVID-19. National Heart, Lung, and Blood Institute. September 10, 2020.

[4] Colchicine reduces the risk of COVID-19-related complications. The Montreal Heart Institute. January 22, 2021.

Links:

COVID-19 Research (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

NIH Support: National Heart, Lung, and Blood Institute


New Online Resource Shows How You Can Help to Fight COVID-19

Posted on by

Combat COVID

There are lots of useful online resources to learn about COVID-19 and some of the clinical studies taking place across the country. What’s been missing is a one-stop online information portal that pulls together the most current information for people of all groups, races, ethnicities, and backgrounds who want to get involved in fighting the pandemic. So, I’m happy to share that the U.S. Department of Health and Human Services, in coordination with NIH and Operation Warp Speed, has just launched a website called Combat COVID.

This easy-to-navigate portal makes it even easier for you and your loved ones to reach informed decisions about your health and to find out how to help in the fight against COVID-19. Indeed, it shows that no matter your current experience with COVID-19, there are opportunities to get involved to develop vaccines and medicines that will help everyone. Hundreds of thousands of volunteers have already taken this step—but we still need more, so we are seeking your help.

The Combat COVID website, which can also be viewed in Spanish, is organized to guide you to the most relevant information based on your own COVID-19 status:

• If you’ve never had COVID-19, you’ll be directed to information about joining the COVID-19 Prevention Network’s Volunteer Screening Registry. This registry is creating a list of potential volunteers willing to take part in ongoing or future NIH clinical trials focused on preventing COVID-19—like vaccines. Why get involved in a clinical trial now if vaccines will be widely distributed in the future? Well, there’s still a long way to go to get the pandemic under control, and several promising vaccines are still undergoing definitive testing. Your best route to getting access to a vaccine right now might be a clinical trial. And the more vaccines that are found to be safe and effective, the sooner we will be able to immunize all Americans and many others around the world.

• If you have an active COVID-19 infection, you’ll be directed to information about ongoing clinical trials that are studying better ways to treat the infection with promising drugs and other treatments. There are currently at least nine ongoing clinical trials for adults at every stage of COVID-19 illness. That includes five NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership trials. All of these are promising treatments, but need to be rigorously tested to be sure they are safe and effective.

• If you’ve recovered from a confirmed case of COVID-19, you may be able to give the gift of life to someone else. Check out Combat COVID, where you’ll be directed to information about how to donate blood plasma. Once donated, this plasma may be infused into another person to help treat COVID-19 or it may be used to make a potential medicine.

• For doctors treating people with COVID-19, the website also provides a collection of useful information, including details on how to connect patients to ongoing clinical trials and other opportunities to combat COVID-19.

While I’m discussing online resources, NIH’s National Cancer Institute (NCI) also recently launched an interesting website for a critical initiative called the Serological Sciences Network for COVID-19 (SeroNet). A collaboration between several NIH components and 25 of the nation’s top biomedical research institutions, SeroNet will increase the national capacity for antibody testing, while also investigating all aspects of the immune response to SARS-CoV-2, the coronavirus that causes COVID-19. That includes studying variations in the severity of COVID-19 symptoms, the influence of pre-existing conditions for developing severe disease, and the chances of reinfection.

In our efforts to combat COVID-19, we’ve come a long way in a short period of time. But there is still plenty of work to do to get the pandemic under control to protect ourselves, our loved ones, and our communities. Be a hero. Follow the three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often. And, if you’d like to find what else you can do to help, follow your way to Combat COVID.

Links:

Coronavirus (COVID-19) (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Explaining Operation Warp Speed (HHS)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)


Can Autoimmune Antibodies Explain Blood Clots in COVID-19?

Posted on by

Blood Clots
Caption: Illustration showing a blood vessel with a platelet clot (yellow). Red blood cells (red), neutrophils (purple), and Y-shaped antibodies called aPL (white) circulate through the vessel. Credit: Stephanie King/Michigan Medicine

For people with severe COVID-19, one of the most troubling complications is abnormal blood clotting that puts them at risk of having a debilitating stroke or heart attack. A new study suggests that SARS-CoV-2, the coronavirus that causes COVID-19, doesn’t act alone in causing blood clots. The virus seems to unleash mysterious antibodies that mistakenly attack the body’s own cells to cause clots.

The NIH-supported study, published in Science Translational Medicine, uncovered at least one of these autoimmune antiphospholipid (aPL) antibodies in about half of blood samples taken from 172 patients hospitalized with COVID-19. Those with higher levels of the destructive autoantibodies also had other signs of trouble. They included greater numbers of sticky, clot-promoting platelets and NETs, webs of DNA and protein that immune cells called neutrophils spew to ensnare viruses during uncontrolled infections, but which can lead to inflammation and clotting. These observations, coupled with the results of lab and mouse studies, suggest that treatments to control those autoantibodies may hold promise for preventing the cascade of events that produce clots in people with COVID-19.

Our blood vessels normally strike a balance between producing clotting and anti-clotting factors. This balance keeps us ready to seal up vessels after injury, but otherwise to keep our blood flowing at just the right consistency so that neutrophils and platelets don’t stick and form clots at the wrong time. But previous studies have suggested that SARS-CoV-2 can tip the balance toward promoting clot formation, raising questions about which factors also get activated to further drive this dangerous imbalance.

To learn more, a team of physician-scientists, led by Yogendra Kanthi, a newly recruited Lasker Scholar at NIH’s National Heart, Lung, and Blood Institute and his University of Michigan colleague Jason S. Knight, looked to various types of aPL autoantibodies. These autoantibodies are a major focus in the Knight Lab’s studies of an acquired autoimmune clotting condition called antiphospholipid syndrome. In people with this syndrome, aPL autoantibodies attack phospholipids on the surface of cells including those that line blood vessels, leading to increased clotting. This syndrome is more common in people with other autoimmune or rheumatic conditions, such as lupus.

It’s also known that viral infections, including COVID-19, produce a transient increase in aPL antibodies. The researchers wondered whether those usually short-lived aPL antibodies in COVID-19 could trigger a condition similar to antiphospholipid syndrome.

The researchers showed that’s exactly the case. In lab studies, neutrophils from healthy people released twice as many NETs when cultured with autoantibodies from patients with COVID-19. That’s remarkably similar to what had been seen previously in such studies of the autoantibodies from patients with established antiphospholipid syndrome. Importantly, their studies in the lab further suggest that the drug dipyridamole, used for decades to prevent blood clots, may help to block that antibody-triggered release of NETs in COVID-19.

The researchers also used mouse models to confirm that autoantibodies from patients with COVID-19 actually led to blood clots. Again, those findings closely mirror what happens in mouse studies testing the effects of antibodies from patients with the most severe forms of antiphospholipid syndrome.

While more study is needed, the findings suggest that treatments directed at autoantibodies to limit the formation of NETs might improve outcomes for people severely ill with COVID-19. The researchers note that further study is needed to determine what triggers autoantibodies in the first place and how long they last in those who’ve recovered from COVID-19.

The researchers have already begun enrolling patients into a modest scale clinical trial to test the anti-clotting drug dipyridamole in patients who are hospitalized with COVID-19, to find out if it can protect against dangerous blood clots. These observations may also influence the design of the ACTIV-4 trial, which is testing various antithrombotic agents in outpatients, inpatients, and convalescent patients. Kanthi and Knight suggest it may also prove useful to test infected patients for aPL antibodies to help identify and improve treatment for those who may be at especially high risk for developing clots. The hope is this line of inquiry ultimately will lead to new approaches for avoiding this very troubling complication in patients with severe COVID-19.

Reference:

[1] Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, Sule G, Gockman K, Madison JA, Zuo M, Yadav V, Wang J, Woodard W, Lezak SP, Lugogo NL, Smith SA, Morrissey JH, Kanthi Y, Knight JS. Sci Transl Med. 2020 Nov 2:eabd3876.

Links:

Coronavirus (COVID-19) (NIH)

Antiphospholipid Antibody Syndrome (National Heart Lung and Blood Institute/NIH)

Kanthi Lab (National Heart, Lung, and Blood Institute, Bethesda, MD)

Knight Lab (University of Michigan)

ACTIV (NIH)

NIH Support: National Heart, Lung, and Blood Institute


Months After Recovery, COVID-19 Survivors Often Have Persistent Lung Trouble

Posted on by

Lung function test
Caption: Testing breathing capacity with a spirometer. Credit: iStock/Koldunov

The pandemic has already claimed far too many lives in the United States and around the world. Fortunately, as doctors have gained more experience in treating coronavirus disease 2019 (COVID-19), more people who’ve been hospitalized eventually will recover. This raises an important question: what does recovery look like for them?

Because COVID-19 is still a new condition, there aren’t a lot of data out there yet to answer that question. But a recent study of 55 people recovering from COVID-19 in China offers some early insight into the recovery of lung function [1]. The results make clear that—even in those with a mild-to-moderate infection—the effects of COVID-19 can persist in the lungs for months. In fact, three months after leaving the hospital about 70 percent of those in the study continued to have abnormal lung scans, an indication that the lungs are still damaged and trying to heal.

The findings in EClinicalMedicine come from a team in Henan Province, China, led by Aiguo Xu, The First Affiliated Hospital of Zhengzhou University; Yanfeng Gao, Zhengzhou University; and Hong Luo, Guangshan People’s Hospital. They’d heard about reports of lung abnormalities in patients discharged from the hospital. But it wasn’t clear how long those problems stuck around.

To find out, the researchers enrolled 55 men and women who’d been admitted to the hospital with COVID-19 three months earlier. Some of the participants, whose average age was 48, had other health conditions, such as diabetes or heart disease. But none had any pre-existing lung problems.

Most of the patients had mild or moderate respiratory illness while hospitalized. Only four of the 55 had been classified as severely ill. Fourteen patients required supplemental oxygen while in the hospital, but none needed mechanical ventilation.

Three months after discharge from the hospital, all of the patients were able to return to work. But they continued to have lingering symptoms of COVID-19, including shortness of breath, cough, gastrointestinal problems, headache, or fatigue.

Evidence of this continued trouble also showed up in their lungs. Thirty-nine of the study’s participants had an abnormal result in their computed tomography (CT) lung scan, which creates cross-sectional images of the lungs. Fourteen individuals (1 in 4) also showed reduced lung function in breathing tests.

Interestingly, the researchers found that those who went on to have more lasting lung problems also had elevated levels of D-dimer, a protein fragment that arises when a blood clot dissolves. They suggest that a D-dimer test might help to identify those with COVID-19 who would benefit from pulmonary rehabilitation to rebuild their lung function, even in the absence of severe respiratory symptoms.

This finding also points to the way in which the SARS-CoV-2 virus seems to enhance a tendency toward blood clotting—a problem addressed in our Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The partnership recently initiated a trial of blood thinners. That trial will start out by focusing on newly diagnosed outpatients and hospitalized patients, but will go on to include a component related to convalescence.

Moving forward, it will be important to conduct larger and longer-term studies of COVID-19 recovery in people of diverse backgrounds to continue to learn more about what it means to survive COVID-19. The new findings certainly indicate that for many people who’ve been hospitalized with COVID-19, regaining normal lung function may take a while. As we learn even more about the underlying causes and long-term consequences of this new infectious disease, let’s hope it will soon lead to insights that will help many more COVID-19 long-haulers and their concerned loved ones breathe easier.

Reference:

[1] Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG. EClinicalMedicine.2020 Aug 25:100463

Links:

Coronavirus (COVID-19) (NIH)

How the Lungs Work (National Heart, Lung, and Blood Institute/NIH)

Computed Tomography (CT) (National Institute of Biomedical Imaging and Bioengineering/NIH)

Zhengzhou University (Zhengzhou City, Henan Province, China)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


Next Page