Angelique de Rouen

Researchers at the School of Public Health are aiming to provide some hope and clarity for those suffering with long COVID through a new study looking at Paxlovid, an antiviral pill that has been used to reduce COVID-19 symptoms. 

The study is being led by Harlan Krumholz, a professor at the School of Medicine, and Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology. The Yale Paxlovid for Long COVID trial aims to research whether consistent use of the antiviral medication can help improve the lives and symptoms of long COVID patients. 

Krumholz, who primarily researches cardiovascular diseases, said that he was drawn to the project not only because of its potential impact on many patients, but also for its innovative methods in conducting clinical research. 

“It was becoming clear to me that it was an opportunity both to try to make a contribution to those who were suffering, but also to innovate around how we pursued research … in a way that was digital, decentralized, democratized and was breaking new grounds in the ways that we were participating with people in our studies” Krumholz said. “[W]e could set an example to others how we could re-engineer the way we are doing studies.”

Iwasaki emphasized that because the study is decentralized, it is easier for people from across the country to participate. 

“Participants do not have to travel anywhere to get their biospecimen collected or obtain the medicine,” Iwasaki wrote to the News. “Everything is delivered to them. People living in Alabama to Wyoming can participate in the trial … this is particularly important for people with long COVID, who may be too ill to drive to a study site.”

Long COVID is defined in the study as a condition in which participants with prior COVID-19 infection developed symptoms of within four weeks of their initial infection. Those symptoms, according to the study’s definition, have persisted for at least three months. The study aims to test whether long COVID is caused by the persistence of the COVID-19 virus in patients. 

“[D]ifferent mechanisms may be going on in different people,” Erica Spatz, an associate professor of cardiology and one of the early organizers of the study, wrote. “One of these mechanisms is the persistence of coronavirus in the system. In fact, I have had some patients become reinfected with COVID and suddenly their Long COVID symptoms go away, potentially because their body was able to mount an effective immune response to residual virus. This study of Paxlovid is tapping into some of these theories, namely that there is persistent virus leading to symptoms of Long COVID.”

Paxlovid is an antiviral medication typically given to patients for five days during their infectious period. It works to inhibit a key enzyme that the COVID-19 virus uses to replicate itself. The researchers hypothesized that taking this medication for a longer period of time can help clear the remaining virus and alleviate patients of their long COVID symptoms. 

Interested participants take a pre-screening survey online to determine their eligibility. If they meet the qualifications, the patients compile their medical records in a secure cloud-based account and send them to the researchers, who then determine whether the patient should qualify for the study. 

Participants are randomly sorted, either receiving ritonavir-boosted nirmatrelvir — the generic name for Paxlovid — or a placebo to be taken orally for 15 days. The participants will complete a daily diary cataloging their symptoms alongside other surveys that the researchers will use to create an overall “summary score.” According to Krumholz, the summary score standardizes differences in symptoms between patients, since long COVID patients tend to have a large variety of symptoms. The overall score helps the researchers gauge whether the patients’ quality of life was generally improved by taking the medication despite the differences between patients. 

Beyond the questionnaires and summary score, blood and saliva samples will be taken from participants before and after treatment. These samples will go through an immunophenotyping analysis in the Iwasaki lab.

“They are measuring thousands of components of the immune system trying to characterize what is active, what is not, what levels are high and what levels are low, what immune antibodies may exist within the course of treatment and how it correlates with people’s response,” Krumholz said. “Even if the results are negative, it may be that we can identify the signatures of people who are responders and help us understand whether there are subsets of people that might benefit.”

Participants will continue to be followed after the 15 days of treatment to see whether the improvement of symptoms is sustained long term. 

Rohan Khera, assistant professor of medicine and biostatistics, is leading the analytic side of the project. In particular, Khera is working on decentralized data analysis in the trial. While this study is a good start, Khera said that there is still more research to be done regarding long COVID.

“There is a lot being done, and I think the biggest value will come from research that helps better characterize what symptom constellation defines Long COVID and whether there are disease subtypes representing different pathophysiologies,” Khera wrote to the News. “The treatment could then be targeted to the mechanisms causing the symptoms and challenges to patients.”

There are currently patients enrolled from 43 states, and Krumholz said they are aiming to include participants from the 48 contiguous states. As of September, roughly one third of the study is full. The researchers are still screening participants for eligibility. Krumholz hopes to be done enrolling participants by the end of this year and to get results sometime during the spring of 2024, although it would take additional time for the FDA to approve the use of Paxlovid for long COVID.

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