NIH clinical trial explores use of convalescent plasma in at-risk outpatients with early COVID-19

Researchers supported by the National Institutes of Health have launched a key study to explore  the safety and effectiveness of convalescent plasma in treating patients who have recently (within the last week) developed mild to moderate symptoms of COVID-19 disease. The study, which focuses on patients not yet hospitalized, comes on the heels of an announcement by the U.S. Food & Drug Administration (FDA) authorizing emergency use of convalescent plasma to help treat hospitalized patients with COVID-19. 

The NIH study hopes to provide more in-depth information about the much-heralded treatment than is currently known. It will also provide a key element that several previous studies of the COVID-19 convalescent plasma have lacked: a randomized controlled trial design, considered the gold standard for establishing scientific proof that a treatment works.

COVID-19 convalescent plasma, also known as “survivor’s plasma,” is blood plasma derived from patients who have recovered from COVID-19 disease. It contains antibodies, or special proteins, generated by the body’s immune system to fight Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes the disease. More than 90,000 people in the United States and thousands worldwide have already been treated with COVID-19 convalescent plasma since the pandemic began, and some of them credit the “miracle” treatment for saving their lives.

But despite its growing use among hospitalized patients and several recent studies suggesting the plasma is very safe, no studies have definitively proved its effectiveness against COVID-19.

The NIH is hoping to change that. 

The new nationwide clinical trial will test COVID-19 convalescent plasma in at-risk patients who have recently (within one week) developed mild to moderate symptoms of COVID-19 but are not so ill that they need hospitalization.  The Clinical Trial of COVID-19 Convalescent Plasma of Outpatients (C3PO) will enroll 600 men and women aged 18 and older at an anticipated 50 hospital emergency rooms across the United Sates participating in the NIH funded Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN) . Each participant will have one or more risk factors associated with severe COVID-19, including for example hypertension, diabetes, heart disease, or chronic lung disease. Older adults, in this trial defined as 50 years of age or older, are also considered most at risk for severe complications.

The C3PO trial will determine whether transfusions with the COVID-19 convalescent plasma can prevent the relatively mild to moderate symptoms in this vulnerable group from developing into advanced illness that can lead to organ failure and may require life-saving mechanical ventilation. It also will assess the safety of the plasma transfusion itself.

“We think from preliminary information that COVID-19 convalescent plasma may have the best chance of being effective if used when patients are just starting to show symptoms,” said Simone Glynn, M.D., M.P.H., chief of the NHLBI’s Blood Epidemiology and Clinical Therapeutics branch, who is coordinating the trial. “What we want to find out is whether this plasma is effective enough to keep these at-risk patients from progressing to a point where they need hospitalization.” 

The study, which comes at a time when COVID-19 cases are still on the rise, is being funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the NIH, and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services (HHS). It will be conducted as part of the NHLBI’s Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) initiative, which takes advantage of existing NHLBI research networks and resources to conduct COVID-19 clinical trials more quickly and efficiently.

The trial, which was launched in August 2020, will randomize participants to receive either the COVID-19 convalescent plasma or a placebo, and both groups will receive all usual standard care. It joins just a handful of other studies evaluating the effectiveness of the plasma as a treatment for COVID-19, Glynn said.

Yet it is not the first time that convalescent plasma has been tested to fight disease. The treatment has been around for over a century, predating many modern medicines.  Significantly, it has been used in other respiratory illness epidemics, including the 1918 influenza pandemic, the 2003 SARS-CoV-1 outbreak, and the 2009 H1N1 influenza, or “swine flu,” pandemic. It has even been used to fight the Ebola virus. 

Although its efficacy against these diseases is still unclear, researchers remain optimistic about using the treatment to fight the new coronavirus and even prevent future infections. Recent studies have helped propel this optimism. For example, a large U.S. study of about 50,000 hospitalized patients with COVID-19 who received treatment with convalescent plasma found that the treatment was safe and suggested that patients for whom it was given early in the disease were most likely to improve. However, that study was not randomized, and it focused only on patients who were already severely ill and in the hospital.

Specifically, the C3PO trial will monitor patients for their disease progression—from mild stages marked by symptoms such as fever, muscle pain, fatigue, or dry cough—to severe stages marked by symptoms such as shortness of breath, need for oxygen, and organ failure. Almost 80% of COVID-19 cases are characterized as mild, while 15-20% are considered severe. Currently there is no known therapy proven to prevent the progression of mild COVID-19 to severe illness. 

“We would like to have a treatment that could reduce that 15-20% of severe cases to something much lower, and we think COVID-19 convalescent plasma would be a good option to reduce how severe the disease becomes,” said Clifton Callaway, M.D., Ph.D., the principal investigator for the C3PO trial and professor of emergency medicine at the University of Pittsburgh.

For the trial, doctors will transfuse half of the patients with nearly a cup of COVID-19 convalescent plasma and the other half with a placebo in the form of an equivalent amount of saline (salt) solution that does not contain antibodies. Investigators will closely monitor the patients for a month to determine if their condition improves, or whether it gets worse, defined primarily by whether the patients need to seek emergency or urgent care within 15 days of the treatment or get hospitalized or die. Patients who received the placebo and become severely ill during the trial can be treated with COVID-19 convalescent plasma per their physician, the researchers say.

Nahed El Kassar, M.D., Ph.D., medical officer with NHLBI’s Epidemiology and Clinical Therapeutics branch and program officer for the C3PO study, said adverse reactions likely will be “very low,” thanks to careful screening of the plasma to detect HIV and hepatitis B and C.  Mild side effects may include fever, chills, itching, rash, headache, and bruising. El Kassar is encouraged by the safety report of adverse events in the initial population of 20,000 subjects enrolled in the Expanded Access Program sponsored by the Mayo Clinic. That report has found no specific safety concerns related to COVID-19 convalescent plasma.

The widespread use of convalescent plasma may lead to other problems, however—the biggest one being a scarcity in supply, Callaway said. But that’s a problem he said can be fixed by increasing plasma donations. “People who have recovered from COVID-19 will need to step up and donate plasma if they can,” he said, noting that a single donor can give plasma multiple times. “It’s somewhat of a renewable resource.”

And while the cost of the plasma treatment could be prohibitive in some financially strapped areas, in most places it should cost roughly the same as procedures involving regular plasma transfusions, Callaway said. He also noted that the procedure is simple enough that it can be performed almost anywhere where blood transfusions are now done, including some remote areas of the world.

Currently, convalescent plasma which contains antibody against COVID is available for immediate use as a treatment. If more rigorous research studies prove it works, it could speed the development of new antibody preparations, including lab-made antibodies, that can be used for future outbreaks and preventive treatments, Callaway said. 

More than 6.2 million people have contracted COVID-19 in the United States alone, and more than 188,000 have died, according to the Centers for Disease Control and Prevention. Because of concern about a second wave of outbreaks this fall, NHLBI’s Glynn said the C3PO research team is working hard to get preliminary study results by the end of the fall. NHLBI’s Glynn remains cautiously optimistic the treatment will work in at-risk patients who have just developed mild COVID disease. “It’s always better to prevent severe illness than to fix it once it happens,” she said.