Researchers are testing treatments for long COVID symptoms, ranging from brain fog to shortness of breath

The studies, which are part of the RECOVER initiative, target a host of symptoms that are most troubling for patients enduring long-term health effects after COVID-19.
September 12, 2023
Symptoms of long COVID include shortness of breath, brain fog, sleep disturbances and fatigue. Two new clinical trials at UCHealth University of Colorado Hospital are testing treatments for long COVID symptoms. Photo: Getty Images.
Symptoms of long COVID include shortness of breath, brain fog, sleep disturbances and fatigue. Two new clinical trials at UCHealth University of Colorado Hospital are testing whether there are treatments for long COVID symptoms. Photo: Getty Images.

Sweeping new research in Colorado aims to help patients who are suffering from varied, persistent and often debilitating symptoms of long COVID, the disorder that has saddled millions of people with a patchwork of health problems long after they supposedly recovered from COVID-19.

The long COVID clinical trials are launching at UCHeath University of Colorado Hospital on the Anschutz Medical Campus in Aurora. They’re part of the RECOVER initiative, a massive, multi-year national effort to test and study people with long COVID symptoms, those who had COVID but did not suffer long-term effects, and those who never had COVID.

Studying long COVID from multiple angles

The RECOVER clinical trials are focusing on five categories of health issues linked to long COVID. These include:

  • Viral persistence: damage caused by the SARS-CoV-2 virus staying in the body
  • Cognitive dysfunction: chronic issues that disrupt thinking, such as brain fog
  • Sleep disturbances
  • Autonomic dysfunction: symptoms like dizziness and shortness of breath caused by disruptions to systems that regulate body functions
  • Exercise intolerance and fatigue.

The Colorado RECOVER site exceeded its Phase 1 enrollment goals, said Dr. Kristine Erlandson, associate professor of Medicine – Infectious Diseases at the University of Colorado School of Medicine. Erlandson is co-principal site investigator for RECOVER.

Infectious disease specialist Dr. Kristine Erlandson is co-principal site investigator for the RECOVER initiative, which has launched the clinical trials testing treatments of long COVID. Photo by the University of Colorado.
Infectious disease specialist Dr. Kristine Erlandson is the co-principal site investigator for the RECOVER initiative, which has launched clinical trials testing treatments for long COVID. Photo by the University of Colorado.

RECOVER is an observational trial that does not provide treatments for long COVID.

Colorado researchers are now starting the next phase of clinical trials and are recruiting patients for two studies that are testing treatments for long COVID symptoms that have proved particularly troublesome. Dr. Sarah Jolley, assistant professor of Pulmonary Sciences & Critical Care Medicine at the University of Colorado School of Medicine and director of the UCHealth Post-COVID Clinic, is the site principal investigator.

Two studies test treatments for long COVID symptoms

The course of the Post-COVID clinic illustrates the need for the trials. The clinic opened in 2020 in response to the crush of COVID-19 patients at UCHealth University of Colorado Hospital. The viral assault quickly sent patients in droves to intensive care units, where many who survived endured long and debilitating stretches on ventilators and emerged physically weakened, mentally shaken and vulnerable to clusters of physical, cognitive and psychological symptoms collectively known as post-intensive care syndrome.

Since its opening, the clinic has treated some 2,000 long COVID patients with varying COVID-19 experiences and a host of enduring symptoms. Providers still handle an average of 20 long COVID referrals per week, Jolley said. Over time, the patient mix has shifted, she added, from mostly very sick ICU survivors to a greater number of outpatient referrals.

There are likely many more to come. A 2022 report from the state of Colorado estimated “the burden” of long COVID in the state at between 228,000 and 651,000 people.

The team is set to recruit patients for the viral persistence and cognitive dysfunction trials and plans to be involved in the sleep disturbances study, Jolley said.

Erlandson noted that data gleaned from the studies may overlap. For example, sleep disruptions may worsen cognitive decline, while viral reservoirs that remain in the body could drive symptoms unpredictably, damaging organs and disrupting physical and mental functioning.

“One of the nice features of the trial designs is they are assessing multiple systems,” Erlandson said.

Treating the viral persistency of long COVID

The viral persistence trial, dubbed RECOVER-VITAL, aims to learn if an extended course of Paxlovid, the anti-viral medication used to treat COVID-19, can be safely and effectively used to reduce symptoms in long COVID patients. The idea is to reduce the “viral reservoir” that appears to remain in some patients after a COVID infection, Jolley said.

Dr. Sarah Jolley, medical director of the UCHealth Post-COVID Clinic is principal site investigator for two clinical trials testing treatments for long COVID symptoms. Photo by UCHealth.
Dr. Sarah Jolley, medical director of the UCHealth Post-COVID Clinic, is the principal site investigator for two clinical trials testing treatments for long COVID symptoms. Photo by UCHealth.

“We’ve seen viral persistence in some patients for up to a year,” she said.

A normal course of Paxlovid, which prevents the SARS-CoV-2 virus from replicating, is five days; patients in one arm of the trial will receive the drug for 25 days. Their results will be compared to patients who receive a 15-day course of Paxlovid followed by Ritonavir, a component of Paxlovid, plus a placebo for 10 days. A third group will receive only Ritonavir and a placebo for 25 days.

Jolley said the CU group aims to recruit 25 study participants as part of the national enrollment goal of 900.

Working to address long COVID’s effects on the brain

Patients in the RECOVER-NEURO trial will be randomized to five groups to test combinations of online brain training programs and transcranial direct current stimulation (tDCS) – mild impulses of electricity delivered through a headset to specific areas of the brain. The overall goal: discover the most effective treatments for dispelling the brain fog, concentration issues, memory changes and other cognitive issues that plague many long COVID patients.

“The sheer burden of neurocognitive symptoms in our patients attracted us to this trial,” Erlandson said. She noted that tDCS has been used to treat patients with Parkinson’s disease and other neurologic conditions.

“It’s a safe and effective treatment” that could help ease “the incredible burden of cognitive fatigue and brain fog” in long COVID patients, Erlandson said

The Colorado researchers aim to enroll 10 to 20 patients for the RECOVER-NEURO study; the national enrollment goal is 315. Patients will participate from home in a 10-week intervention, Jolley said.

Lessons from RECOVER enrollment could help clinical trial patient recruitment

Another important goal for the clinical trials group: recruiting a diverse group of patients for the trials. That work could benefit from the groundwork laid by the RECOVER enrollment effort. As of late August, Erlandson said that University of Colorado and Denver Health researchers have combined to enroll 374 patients, more than meeting the original goal of 360. She credited that success to building a “dedicated group of research coordinators focused on the study” that now numbers a dozen people.

Patient recruitment continues, with a focus on enrolling more Hispanic patients and those who come from rural areas, Erlandson said.

“We’ve taken multiple enrollment approaches” to boosting recruitment in those and other areas, Erlandson said. For example, the RECOVER team identifies patients from the target populations who have been newly diagnosed with COVID and reaches out to them directly to see if they are interested in joining the research. Study materials are now printed in both Spanish and English, she noted. Providers in Denver Health’s community health centers have also had success in recruiting patients and diversifying the study population, Erlandson said.

In addition, Erlandson pointed to community education and partnerships spearheaded by CO-CEAL, the Colorado chapter of Community Engagement Alliance (CEAL), which NIH formed to probe and address the heavy burden of COVID-19 on some racial and ethnic groups.

Dr. Donald Nease, a Family Medicine physician with UCHealth, is co-principal investigator for CO-CEAL and a key player with community groups in boosting awareness of RECOVER in underserved communities, Erlandson said.

The Colorado Clinical and Translational Sciences Institute (CCSTI) has worked with community research liaisons toward the same goal, she added. Erlandson pointed to Javier Garcia Arellano, a liaison with 2040 Partners for Health, which serves communities in northeast Denver, northwest Aurora and Commerce City, as especially effective in linking individuals in these neighborhoods to RECOVER.

Building on the success of long COVID treatment to recruit patients for clinical trials

This established work means recruitment for the clinical trials won’t be starting from scratch – and as Jolley points out, the Post-COVID Clinic itself represents a potent resource. She noted that more than one-third of the clinic’s patients are Hispanic, while roughly one-fifth are Black.

Through more than three years of work with long COVID patients, the clinic has built valuable trust, Jolley said. She would like to repay that trust and commitment with new hope for recovery from the symptoms that have disrupted their lives.

“We want to allow patients who have been waiting for treatments to get into these trials,” Jolley said.

More than three years after she spearheaded the opening of the Post-COVID clinic, Jolley continues to lead investigations aimed at bringing the elusive long COVID out of the shadows. She co-authored a recently published JAMA Network paper that developed a “framework” for defining long COVID based on clusters of symptoms – a key to directing patients to the most effective care.

Attitudes toward long COVID have also slowly changed, Jolley said. An early lack of information about the condition sometimes spurred mistrust between patients frustrated by a lack of help for their symptoms and providers grasping for clues to address them. The reality of long COVID is now well-established, Jolley said. The task for researchers and clinicians now is to learn as much as possible about the condition and use their knowledge to devise evidence-based therapies to help patients.

“Suspicion of the diagnosis has lessened over time,” Jolley said. “There is acknowledgement that long COVID is a real entity; the problem is more that physicians have discomfort with how to approach it. That’s why we need these trials to happen.”

Find detailed information about the RECOVER-VITAL trial and the RECOVER-NEURO trial

About the author

Tyler Smith has been a health care writer, with a focus on hospitals, since 1996. He served as a writer and editor for the Marketing and Communications team at University of Colorado Hospital and UCHealth from 2007 to 2017. More recently, he has reported for and contributed stories to the University of Colorado School of Medicine, the Colorado School of Public Health and the Colorado Bioscience Association.