Jessai Flores

Since the COVID-19 pandemic’s peak, a quieter, longer battle has taken root: long COVID. With symptoms ranging from brain fog to chronic fatigue and organ dysfunction, the condition continues to affect millions — yet its causes and effective treatments remain elusive. 

One major hypothesis suggested that lingering viral fragments may drive these symptoms, prompting researchers to ask: Can antiviral drugs help?

That was the central question of the PAX LC trial, a clinical study led by Yale researchers. Their goal was to test whether Paxlovid, a five-day oral antiviral already proven to reduce severe outcomes in acute COVID-19, could reduce long COVID symptoms. The hope was that if residual virus prolonging symptoms, early antiviral intervention might help clear it and offer relief. 

Despite high hopes, the trial found no statistically significant improvement across the cohort. But the study used a new decentralized model that focused on reducing barriers for comprehensive long COVID research.

“A failed clinical trial is far from being a setback. These failures help identify what does not work,” Dr. Bornali Bhattacharjee, one of two lead authors and associate director of the Yale School of Medicine Center for Infection & Immunity, emphasized in an interview. 

Long COVID remains a medical enigma as its symptoms span physical, neurological and psychological domains, with uncertain mechanisms. A growing consensus suggests that no single explanation fits all cases.

“Long COVID is an umbrella term that likely covers multiple disease endotypes,” explained Dr. Akiko Iwasaki, the principal investigator of the study and Sterling professor of immunobiology, referring to different forms of a disease.

That complexity is central to why finding a cure remains so difficult. Long COVID encompasses a range of conditions that manifest differently depending on genetics, infection severity, pre-existing conditions and immune response. The condition typically emerges weeks or months after an initial SARS-CoV-2 infection, even in cases that were initially mild or asymptomatic. It can affect anyone — young or old, vaccinated or not. Treating it, therefore, requires precision medicine.

Just as significant as the scientific outcome was the method used to get there. The PAX LC trial was one of the first decentralized trials of its kind. Investigators enrolled more than 150 participants, all of whom had lingering symptoms for more than three months after a confirmed COVID-19 infection. In the decentralized trial, participants could complete most of the process remotely, shipping in biosamples and completing surveys online.

Unlike traditional models, which require patients to travel to sites, decentralized trials collect data from people where they are.

This shift allowed researchers to reach participants across the United States without the cost or hassle of centralized sites. Participants could provide blood and saliva samples via mobile phlebotomy services or mail-in kits, and the research team maintained contact through telemedicine. According to Iwasaki, the trial design was “a game changer.”

The success of the study’s design signals a turning point in how trials are imagined — not just for long COVID, but for clinical research at large. In a decentralized model, more diverse and representative populations can be reached, participation becomes more equitable, and the process is faster and cheaper.

From the perspective of patients, the burden is lifted. Many participants in traditional studies are constrained by job schedules, caregiving responsibilities and geography.

“We made it so that it was convenient for when they were free, we saved so much money by not having traditional sites and we were able to pay people for their time,” said Harlan Krumholz, co-principal investigator and Harold H. Hines, Jr. professor of medicine in Cardiology.

It also provides a more accurate picture of how people actually live with long COVID. Unlike hospital-centric studies, decentralized models account for the day-to-day reality of chronic illness: the ups, the downs, the unpredictability.

“We were able to show that you could do [clinical trials] this way. We didn’t have to make it so that people had to conform to our needs as investigators and our constraints,” Krumholz added.

Long COVID research primarily centers the patient experience. The philosophy drives much of the field, where the initial identification of the illness came not from clinical authorities, but from patient advocacy. People suffering from prolonged symptoms had to push for recognition and research attention.

The outcome of the Paxlovid trial — that it offers no broad benefit — was disappointing to those seeking answers.

But looking ahead, the team is expanding its focus beyond antivirals to explore a broad range of biological mechanisms that may underlie long COVID. Current efforts include examining how even short-term infections may cause lasting effects on the brain, and studying connections between COVID and the onset or worsening of autoimmune and neurodegenerative diseases. 

On the clinical trial front, teams are collaborating with researchers to test treatments such as Truvada, Maraviroc and low-dose Rapamycin — drugs that weren’t originally designed for long COVID but may hold promise when repurposed. These studies reflect a growing consensus that understanding long COVID will take time and progress depends on exploring many avenues at once.

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