Health limitations, distance, work schedules, family obligations, and financial constraints are all barriers that prevent patients from participating in clinical trials. For those living with Long COVID, debilitating symptoms can make traveling to a study site impossible.
Now, Harlan Krumholz, MD, Harold H. Hines, Jr. Professor of Medicine (Cardiology), is pioneering a new approach that makes participation in clinical research accessible for those whose lives have been upended by the post-acute infection syndrome. At Yale School of Medicine, working closely with Sterling Professor Akiko Iwasaki, PhD, he is the principal investigator of the Yale Paxlovid for Long COVID (PAX LC) Trial. This phase 2 investigational new drug clinical trial evaluating the use of the antiviral for people with Long COVID with a decentralized nationwide design that brings the research into participants’ homes. Operating throughout the contiguous United States, it is the first fully decentralized phase 2 trial with this complexity and scale.
Krumholz believes that this trial demonstrates that a future of clinical research that allows patients to participate at their convenience is not only possible, but more efficient and even cost-effective than standard clinical trials.
For example, April 9 marked Cindy’s* fourth anniversary of living with Long COVID.
It started with severe fatigue that made her feel as if her limbs “weighed a million pounds,” followed by shortness of breath and gastrointestinal issues after she was infected with COVID-19 in 2020. Her symptoms never went away. A single mom in Texas with a 6-year-old son, she says the disease forced her to get creative: She made up a game where he rolled a ball around her while she lay still on their trampoline.
Over the years, her symptoms have ebbed and flowed. She suffered a sharp decline in January 2022 — the height of the Omicron wave — when she was hit with her second acute COVID infection. This triggered the start of a slow decline that eventually took a toll on her cognitive abilities, hindering her ability to perform her job as an aerospace engineer and eventually forcing her to take a leave of absence in the fall of 2023. This was also when she began experiencing another common Long COVID symptom known as post-exertional malaise (PEM), in which her symptoms significantly worsened after physical or mental activity, sometimes leaving her bedbound for days at a time.
“I was known for thinking outside of the box, being able to juggle things, look to the future, and solve problems. I knew how to put big, complicated puzzles together,” she says. “Suddenly, everything seemed so complicated. Living became so hard. I was just trying to survive day-by-day, if not hour-by-hour, managing all of my symptoms.”
Desperate for answers, Cindy stayed on top of ongoing clinical trials. Last year, she applied for a stem cell therapy trial in Houston but was eliminated as a potential participant during the final screening. On the one hand, she was devastated. “I was absolutely convinced that the therapy was going to be the answer for me,” she says.
But enrolling in the trial would have presented its own challenges. She lives 45 minutes away from Houston and would have needed help getting rides. And she wondered if she had the capacity to be able to participate in all that the trial required. “From an accessibility standpoint, most clinical trials require you to be there in person for exams, bloodwork, tests, or whatever else they need,” she says. “That’s just not feasible when you have a limiting condition.”
Then, she came across that the PAX LC Trial. Typically, participating in a clinical trial with a Connecticut-based university would have been impossible. But the YSM team was prepared to bring the study to patients no matter where they lived in the U.S. Participants received the drug or placebo in their mailboxes and filled out electronic diaries. They gave blood and saliva samples at home or at a nearby lab. “The Pax LC trial is a historic contribution to the evolution of a new way of doing trials,” Krumholz says. “I’m really proud of what we’ve accomplished, and I’m hoping it will be a spark for the future.”
Slow enrollment of clinical trials hinders scientific progress
Researchers currently have several hypotheses for the underlying causes of Long COVID, including persistent virus, lingering SARS-CoV-2 viral remnants, autoimmune dysfunction, reactivated latent viruses like Epstein-Barr, and tissue damage. These hypotheses are not mutually exclusive, and it is possible that individuals with Long COVID may experience a combination of these mechanisms. Krumholz, Iwasaki, and their team designed the Pax LC Trial to test the persistent virus hypothesis.
Cindy initiated the prescreening process by filling out a survey about pre-existing conditions and syncing her medical records to an app on her phone. Several months later, she received an email inviting her to move forward. The next steps of the prescreening involved going to a local medical laboratory to give blood samples, as well as adjusting some of her medications.
Once enrolled, Cindy received her course of either Paxlovid or a placebo by mail. Each night, she answered survey questions about her symptoms from her phone. She also gave blood and saliva samples five times. Three of these times, the Pax LC team sent a technician to her home. “To be able to have somebody come to your house — that just made life so much easier,” she says. For the other two sample collection dates, she went to a nearby laboratory.
Despite the fact that our trial is sort of built as a concierge service for each individual patient, it was much less expensive than what we had been doing.
Harlan Krumholz, MD
Patients aren’t the only ones who can benefit from decentralized trials, says Krumholz. For over a decade, he has been an advocate for reforming clinical research, arguing that its current structure stymies innovation. His colleagues in the laboratory are discovering potential avenues to treating diseases at a “dizzying pace,” he says. However, because standard clinical trials struggle to recruit and keep patients, they have not been able to keep up with the pace of scientific discovery, which prevents new drugs and medical devices from reaching the market.
“We’re in the midst of a life sciences revolution,” says Krumholz. “The central chokepoint is evidence generation — cycle times are too slow, and trials are so expensive that our level of confidence has to be very high, or no one will make the investment.”
This is because for many, the ability to participate in clinical trials and conform to the schedule they demand is a luxury. Not only does this slow enrollment, but it also contributes to the stark lack of diversity in research. “The current way of doing things is often leaving us in a position where we are having to chase participants and cajole them to stay in the studies that were built for their benefit,” says Krumholz. “Imagine how off-putting clinical trials must be when people who have the most to gain are left in the position where they don’t want to continue.”
The solution, he proposes, is creating clinical trials, modeled after PAX LC, that treat participants as partners and accommodate their constraints. PAX LC not only conformed to participants’ schedules, but also strived to create a sense of community through running virtual town halls for people with ong COVID so they could ask questions and stay updated on results as researchers got them. “People don’t have any obligation to join trials, so we need to make it so they’re something they want to join,” he says.
Bringing clinical trials into patients’ homes
Ezra,* a freelance cartoonist in Minnesota, began experiencing COVID-19 symptoms in September 2022 and never recovered. At the time, he suffered PEM so severe that exertion as small as “microwaving lunch” could put him in bed for days. He saw doctor after doctor at his nearby hospital, and when that failed, he decided to try traveling to the Mayo Clinic. “I feel very fortunate that I was able to get somewhere like Mayo a few times, but it is an hour and a half drive from Minneapolis,” he says. “It cost my partner gas money and lost time at work [to take me there].”
In his search for answers, he learned of the Pax LC Trial and decided to enroll. “The effort to bring the trial into people’s houses is valiant, especially for a population that is chronically ill,” he says. “For disabled people to become a part of clinical trials already requires so much of us—even those of us who have support systems that are able to take care of us. Adding an extra thing to our plates is often just not feasible for most people with chronic illness.”
Other Pax LC Trial participants echo Ezra’s sentiments. “Early on [in my illness], there was no way I could have traveled on my own [to a clinical trial]. It would have taken everything out of me,” says Kyle*, a Vermont filmmaker who has been living with Long COVID since April 2022. While the launch of the ambitious clinical trial was not without its kinks — Kyle and others say they experienced scheduling delays, such as receiving the drug/placebo or payments late, that prolonged the process — he says that PAX LC has opened a window for him that otherwise would have been unavailable. “It was nice the trial tried to make it work for people, understanding that part of our illness is incapacity.”
The PAX LC Trial was largely made possible by the Yale Center for Clinical Investigation team, with Yashira Henriquez, the clinical investigation project manager, who is based in New York, playing a central role. Her daily activities included monitoring participants’ surveys and checking in on anyone who had reported adverse events. “Since there are no study visits, we texted or called each other all the time,” she says. The most common adverse event was dysgeusia, or a metallic taste in the mouth, which has been a common complaint among patients with acute COVID who have received the drug. “In this type of trial where you never meet someone face-to-face, you need to show even more compassion to make them feel at ease.”
In previous roles, Henriquez had worked on studies evaluating treatment for acute COVID-19 infections but wasn’t as familiar with Long COVID. Her experience working for the PAX LC Trial has opened her eyes to the dire need for more research in treatments for the chronic condition.
“I’ve worked on clinical trials in numerous positions, but this is one where patients are especially in desperate need to find answers,” she says. She recalls an hour-long phone conversation she had with a participant who was struggling with depression and becoming a stay-at-home mom after Long COVID forced her to leave her job. “It’s hard to see people who were living a healthy life end up in a state where they’re now debilitated and can’t even get out of bed.”
Most participants she worked with responded well to the design of the trial, she adds. Their cooperation allowed the study to run smoothly despite many of them being states away. “We didn’t have to bother them to do the surveys or get their study visits done,” Henriquez says, “because they all wanted to help.”
New technologies make cost-effective decentralized trials possible
The “record rate” of enrollment speaks to the success of PAX LC Trial’s design. It can take years for clinical trials to finish the enrollment period. PAX LC finished in under a year. Although it is a small trial of 100 participants, given its numerous restrictions around eligibility to participate and requirements for collecting blood and saliva specimens for Iwasaki’s lab, enrollment would have taken significantly longer without its decentralized format, Krumholz says.
Previously, a trial like this was not practical. But now, the evolution of new technologies is making the possibility of decentralized trials more accessible than ever. Recently, for example, Krumholz co-founded Hugo Health, a platform that enables people to transfer their medical records more seamlessly, with their permission, to researchers. “Because of the 21st century Cures Act [a 2016 law created to advance medical product innovation], people can get access to their medical records and share them with trusted partners,” he says. “Now we don’t have to go through a Byzantine set of obstacles through a particular health system to access a patient’s medical data – we just need to work in partnership with participants.”
Traveling to each participant’s home would seem to be a pricey endeavor. But given its greater efficiency, the design of the PAX LC Trial has actually cut down on costs, Krumholz argues. If it had been run like a standard clinical trial, his team would have had to set up study sites across the country. The associated costs would have been extremely high; also, the complexities involved in a multitude of institutional review boards (IRBs) whose approval would be needed, would have significantly slowed the study’s progress. Furthermore, many clinical trials need to extend their study periods as they struggle to retain participants, which also adds to the costs.
“Despite the fact that our trial is sort of built as a concierge service for each individual patient, it was much less expensive than what we had been doing,” Krumholz says. “What I hope will happen is that it will be a competitive advantage to do decentralized trials.”
Decentralized clinical trials can be applied to a multitude of fields
About a month into the PAX LC Trial, Ezra noticed that his symptoms had dramatically declined. He still doesn’t know if he had taken the drug or the placebo, but “the brain fog is gone, the memory issues are gone, the cognitive problems seem to have pretty much evaporated,” he says. He can take a 45-minute walk again and was able to return to work. He is not cured, however. He still has symptoms of postural orthostatic tachycardia syndrome (POTS) [a disorder in which standing up triggers symptoms such as rapid heart rate] and gets winded easily.
Unfortunately, for many people with Long COVID, there won’t be a magic pill that restores them to normal. More clinical trials aimed at other possible underlying mechanisms of Long COVID, such as autoimmune dysfunction, will be needed. And these patients, many of whom are struggling to work and provide for their families, don’t have years to wait. Decentralized trials could help bring much-needed answers more quickly.
And this type of trial doesn’t need to be confined to Long COVID. “I’m confident the way we set this up can work with almost any population,” says Krumholz. He is optimistic that PAX LC will inspire other researchers to adopt a more participant-centric format for different kinds of research.
“Our trial is like Kitty Hawk [the Wright Flyer], we just needed to show that it could fly,” he says. “The hope is that soon there will be fleets of planes that adopt this approach.”