R3 Seminar Recap: RECOVER clinical trial results and the pursuit of Long COVID treatments
RECOVER researchers share results from clinical trials targeting cognitive and autonomic symptoms of Long COVID, offering lessons that will shape future studies and treatments tested.
During the July 14 RECOVER Research Review (R3) Seminar, panelists Craig Reist, PhD; David S. Knopman, MD; and Pam R. Taub, MD, shared findings from the RECOVER Clinical Trials (RECOVER-CT) program, the initiative's first wave of clinical trials. The trials focused on Long COVID symptoms related to thinking and memory, as well as the autonomic nervous system, which controls body functions like heart rate and blood pressure. RECOVER-CT Engagement Lead, Renee Leverty, MA, BSN, and Patient Representative Marta Cerda, JD, also explained how patient, caregiver, and community input shaped the trial design process.
Watch the R3 recording below or on YouTube
RECOVER-CT designed clinical trials around symptom clusters
Dr. Reist (RTI International) provided an overview of the RECOVER-CT program. He explained that trial study plans (platform protocols) were organized around symptom clusters or biological mechanisms (processes that take place inside the body and its cells) to test different possible treatments.
A committee at the National Institutes of Health (NIH) reviewed over 200 possible treatments submitted by clinicians and researchers and prioritized RECOVER-CT interventions (potential therapies). He noted that the trial designs reflected the knowledge available when they were chosen in 2022 and 2023, a time when Long COVID was still a new disease.
Based on findings from RECOVER observational studies and input from clinicians, experts, and Patient, Caregiver, and Community Representatives, RECOVER-CT identified 5 focus areas (symptom clusters) for the trials:
- Cognitive dysfunction (RECOVER-NEURO): Brain fog, trouble thinking clearly, memory changes, slowed attention, and other symptoms related to brain function.
- Autonomic dysfunction (RECOVER-AUTONOMIC): Dizziness, fast heart rate, shortness of breath, upset stomach, or other changes in body functions that happen automatically.
- Viral persistence (RECOVER-VITAL): Damage to organs or dysfunction of the immune system caused when the virus that causes COVID-19 stays in the body.
- Sleep disturbances (RECOVER-SLEEP): Changes in sleep patterns or ability to sleep.
- Exercise intolerance and fatigue (RECOVER-ENERGIZE): Exhaustion or low energy that interferes with daily activities.
Studying 3 non-drug interventions for improving cognitive symptoms
Dr. Knopman (Mayo Clinic) presented results from RECOVER-NEURO, a trial which studied the effect of non-drug treatments on the cognitive symptoms of Long COVID. The trial, published in JAMA Neurology in November 2025, recruited 328 adults across 22 study sites in the United States. Participants had SARS-CoV-2 infections at least 12 weeks prior to enrollment and self-reported cognitive symptoms.
The study team tested 3 interventions delivered remotely over 10 weeks:
- An interactive online brain-training program (BrainHQ).
- A mild electric current delivered to the scalp to stimulate the brain while participants use BrainHQ (transcranial direct current stimulation, or tDCS).
- A cognitive rehabilitation program with trainings, discussions, and focus groups (PASC-CoRE).
Dr. Knopman shared that the findings from the trial showed that the 3 interventions were not effective in improving cognitive symptoms of Long COVID when compared to people who did not receive the interventions (comparator groups). However, all comparator and intervention groups showed improvement over the course of the trial, including improvement with post-exertional malaise (PEM)—and continued to improve slightly even 3 months later. Dr. Knopman added that detecting a benefit from the interventions was challenging because participants in all 5 groups improved.
Testing effectiveness of ivabradine for post-COVID POTS
Dr. Taub (University of California San Diego Health System) shared results from the RECOVER-AUTONOMIC (Ivabradine) trial, which tested whether ivabradine—a drug that lowers heart rate without lowering blood pressure—could help manage postural orthostatic tachycardia syndrome (POTS), an autonomic nervous system disorder marked by fast heart rate and orthostatic intolerance (dizziness and fatigue when standing up). She noted that roughly 31% of people with Long COVID develop POTS, but there have been very few randomized trials to treat POTS, and even fewer to treat Long COVID-related POTS.
The study, first presented at the 2026 American College of Cardiology conference, is the largest study to date in patients with POTS. It randomized 181 adults with Long COVID-related POTS to either ivabradine or placebo, with a second randomization to receive coordinated non-drug care (regular check-ins with a care coordinator plus lifestyle and equipment support) or usual care. Dr. Taub noted that study participants who received ivabradine received a lower dose of the drug compared with a pilot study. Researchers anticipated older adults participating in the study and were concerned about ivabradine lowering participants’ heart rate too much.
Although RECOVER-AUTONOMIC results showed that ivabradine significantly lowered heart rate, it did not significantly improve patient-reported orthostatic intolerance. Notably, participants who received ivabradine combined with coordinated care reported greater improvement than those who received ivabradine with usual care. Dr. Taub noted future opportunities to study ivabradine’s impact on people with Long COVID-related POTS, including studying higher doses of the drug and whether different groups of people may benefit more.
Null results moving science toward possible Long COVID treatments
The panelists emphasized that even when possible treatments do not show a benefit, clinical trial results still deliver valuable knowledge. Null results provide “equally important” information, Dr. Reist said, “letting us know where the path does not lead but also allowing us to sharpen the questions that we’ll ask for the next possible treatments tested.”
Dr. Taub compared the effort to the study of other medical conditions. Heart failure with preserved ejection fraction, a condition where the heart squeezes normally but does not fill properly, required decades of null trials before leading to an FDA-approved therapy.
“When you look at clinical trials in general, it’s a lot of learning and sometimes it takes multiple trials to really get the design down,” she noted. “We had a great comment from the audience that just because a trial is null, it doesn’t mean that the therapy doesn’t work. It could be that the design wasn’t optimal.” Dr. Knopman added that a central challenge in cognitive Long COVID is that the underlying biology remains unclear, which makes designing effective treatments difficult. “Until the biology is better understood, I think it’s going to be a challenge to move ahead,” he said.
Dr. Reist confirmed that data from these trials will be made available to other researchers through NHLBI BioData Catalyst®, a secure, cloud-based ecosystem managed by the National Heart, Lung, and Blood Institute (NHLBI), so future analyses will expand beyond the original trial teams.
Learning from Patient Representatives’ past engagement to inform future research
Ms. Leverty (Duke Clinical Research Institute) and Ms. Cerda (RECOVER Patient Representative) shared findings from a study published in the Journal of Clinical and Translational Science on how RECOVER researchers and Representatives worked together to develop study plans for clinical trials.
RECOVER Representatives were included as core members of RECOVER-CT Protocol Working Groups (PWGs) along with scientific research experts. Ms. Leverty highlighted the importance of having Long COVID patients be a part of study leadership or engagement teams. The PWGs reviewed and provided feedback on the program’s study plans and weighed in on eligibility criteria, endpoints (what the trials are measuring), visit schedules, participant burden, compensation, and informed consent to participate in the study.
An anonymous survey distributed to PWG members found that 82% of Representatives felt their contributions were meaningful and valued by RECOVER. However, experiences of inclusion varied, with 21% reporting low inclusion and 46% reporting high inclusion. Representatives’ advice to researchers and funders included incorporating patient voices early, communicating roles clearly and often, ensuring representation reflects the broader patient population, training study teams on valuing patient input, and creating clear pathways for incorporating feedback.
Ms. Cerda, who served on the Clinical Trials Steering Committee and the RECOVER-VITAL PWG, shared her positive experience. She said she not only learned more about her own dysautonomia and POTS through her participation but also felt her patient perspective was valued by researchers when providing inputs. “Meaningful Representative engagement in rapid trial protocol development is both feasible and valuable,” she said, emphasizing that clarity in roles, transparent decision-making, and intentional communication are essential.
Uncovering more answers about Long COVID
Both Ms. Cerda and Ms. Leverty acknowledged the disappointment that comes with null trial results when patients are urgently seeking answers—but also expressed hope for what is ahead. “We are so looking for any hope...and I do see hope [for clinical trial treatments] in the horizon,” said Ms. Cerda, who is 6 years into her Long COVID journey.
Dr. Reist pointed to the next wave of RECOVER clinical trials through the RECOVER-Treating Long COVID (RECOVER-TLC) program. RECOVER-TLC will begin recruiting participants for 3 clinical trials this year, with enrollment for the REVERSE-LC study already open. Dr. Taub also encouraged patients to explore opportunities on ClinicalTrials.gov, which lists NIH, industry, and academic trials.
To find recordings and transcripts from previous R3 Seminars, visit the R3 Seminar Series webpage or the RECOVER YouTube channel.