Q&A from July 14, 2026 R3 Seminar

RECOVER Admin: RECOVER researchers conducted a study, published in 2025, that found 4.5% of people in the study who had COVID-19 later developed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), whereas only 0.6% of people who didn’t have COVID-19 developed ME/CFS.

A National Academies of Sciences, Engineering, and Medicine report shares that the percentage of patients with Long COVID that meets criteria for ME/CFS varies across research. The report states, “An overview of the literature [citing from 5 studies] shows that on average, 40-70 percent of Long COVID patients meet the criteria for ME/CFS. In contrast, [a study] found that only 13 percent of Long COVID patients met the criteria for ME/CFS, and [another study] found an overlap of 8.1 percent. These differences could be due to the varied case definitions for both Long COVID and ME/CFS.” 

RECOVER Admin: RECOVER funds have been obligated and will be allocated over Fiscal Years 2025–2029 to support the following:

• RECOVER-Treating Long COVID (RECOVER-TLC).
• Completion of RECOVER observational studies (adults and children).
• Additional RECOVER pathobiology studies.
• Preservation and broader access to RECOVER data and biospecimens.
• Maintenance of RECOVER-supported research infrastructure.

RECOVER Admin: If you have any questions about your participation, including if you were in the intervention or control group for the RECOVER-SLEEP Complex Sleep Disturbances (Melatonin + Light Therapy) study, please reach out to the main point of contact at your RECOVER Clinical Trial site. All participants in the RECOVER-SLEEP Complex Sleep study will receive instructions about how to ensure they have the active lightbulbs and how to place the light in their space to receive the benefits of the study treatment.

Dr. Reist: The protocols for these trials were developed in early 2023 with enrollment beginning in the fall of 2023, so we used the best available information from that time.

Dr. Taub: Ivabradine is a heart-rate-lowering drug that also lowers serum norepinephrine levels in patients with POTS, so I do think it has an impact on the disease. 

Dr. Taub: It’s possible. With drug trials, it could also be due to choice of drug dosing.

RECOVER Admin: Read the full publication of RECOVER-NEURO results and the survey results of Protocol Working Groups.

Dr. Taub: There is a trial studying people with Long COVID and POTS taking ivabradine that looked at norepinephrine levels. Those results will be reported out soon. 

Dr. Taub: It was based on heart rate. They were started at 5 mg bid (taken twice each day), and if resting heart rate was less than 60, they were titrated down to 2.5 mg bid (taken twice each day).

Dr. Taub: We were very conservative with the dosing. There is another trial funded by the U.S. Department of Defense [also referred to as the Department of War] that will be presented soon that used higher doses. It will be interesting to see the differences in trials based on dosing.

Dr. Taub: No, but you may be able to get it through an online pharmacy for about $30 per month.

Dr. Taub: I agree we need to look at different phenotypes of POTS patients, and we plan to do this in secondary analyses.

RECOVER Admin: If you have any questions about your participation, including if you were in an intervention or comparator group for the RECOVER-NEURO study, please reach out to the main point of contact at your RECOVER clinical trial site.

RECOVER Admin: Yes, RECOVER posted a news story on recoverCOVID.org about REVERSE-LC in March 2026.

Note: REVERSE-LC is a clinical trial that is part of the RECOVER-TLC program, the next phase of RECOVER clinical trials.

RECOVER Admin: RECOVER Pathobiology Studies are ongoing. They use various research methods to better understand physiological processes that can cause Long COVID symptoms. The pathobiology studies are technically ancillary studies. You can learn more on the RECOVER Pathobiology Studies webpage, including about pathobiology awards.

Dr. Reist: The RECOVER-ENERGIZE (Structured Pacing) clinical trial specifically focused on PEM. Those results should be available later this fall.

Ms. Cerda: I had a positive experience because I was both in the Clinical Trial (CT) Steering Committee and in the RECOVER-VITAL Protocol Working Group. I was directly asked for my patient impact, voice, and thoughts on protocol design repeatedly throughout the process. I did experience one time when a researcher was hesitating about slowing down a trial to include patient feedback, and I weighed in, as others weighed in, to highlight the value of patient input.

I do feel like my feedback was heard. I also felt I had a reciprocal benefit from participating in the CT Steering Committee because I learned more about my own Long COVID, including dysautonomia, dizziness, falling, and POTS. I felt there was a highly invaluable part to my patient engagement in the clinical trial protocol working groups that is not often talked about.

Ms. Leverty: The recommendations and advice that came through the paper are really helpful guides to how engagement can be improved. Having at least one individual with Long COVID be part of the engagement team, or part of study leadership, is critical. 

Although there was structure set in place for inclusive engagement, experiences were different. And they weren’t perceived as different; they were different. How do we create structures of accountability so that lived-experience knowledge is honored and embedded? That is what we are hoping to create through this paper, this talk, and the knowledge of the NCEG (RECOVER’s National Community Engagement Group) and Representatives who have been informing RECOVER on an ongoing basis.

Dr. Reist: For this initial wave of RECOVER clinical trials, enrollment targets have been achieved. Most are going through follow-up, final data collection, and analysis. There is a new wave of clinical trials through the RECOVER-TLC initiative, led by NIH’s NIAID [National Institute of Allergy and Infectious Diseases]. That will be the next wave of clinical trials and will soon be recruiting participants for a variety of focused interventions. I would encourage people to check out RECOVER-TLC for more information.

Dr. Taub: The other resource I always tell patients to look at is ClinicalTrials.gov, because it has NIH trials, industry trials, and academic trials. It is a good resource to check out.

Dr. Knopman: It is difficult to look for benefits in a condition that may be experiencing spontaneous improvement over time, but the key point is that the interventions had to be superior to what was seen in the active comparator group (or control group).

Dr. Taub: Seeing patients with Long COVID clinically, it is a very heterogeneous disease. Some people improve after a few months, and some people have very severe impairment and are bed-bound. We do not understand yet what predisposes someone to more severe disease. More basic science research may help us understand whether people with more severe disease have more of an immune substrate or immunologic dysfunction. In terms of natural history, we are still trying to understand why some people get more severe disease than others.

Dr. Knopman: In RECOVER-NEURO, severity really did not seem to make a difference in terms of response. It may have been that the people recruited overall still had too mild symptoms and that more impaired people chose not to participate, but it was not obvious in the RECOVER-NEURO data that initial severity had any impact on outcome.

Dr. Taub: In RECOVER-AUTONOMIC with ivabradine, the patient characteristics of both the placebo and treatment groups showed moderate to severe symptoms based on COMPASS-31 (Composite Autonomic Symptom Score 31) results, Malmö POTS score, and related measures, so the study recruited patients with more moderate to severe disease.

Dr. Taub: That is a very good point, and we are looking to do secondary analyses. One of the things to look at is when participants enrolled in RECOVER-AUTONOMIC (Ivabradine), the duration of their symptoms, and what variant of COVID they had, such as Omicron or one of the original variants.

Dr. Knopman: In RECOVER-NEURO, we did not see anything in relation to the COVID illness experience that was predictive of outcomes.

Dr. Knopman: In RECOVER-NEURO, we have one paper looking at objective cognitive testing that has been submitted to a journal, but we have no funding to do further studies.

Dr. Taub: With the RECOVER-AUTONOMIC (Ivabradine) results, we are in the process of publishing the primary manuscript. We are awaiting results of the IVIG (intravenous immunoglobulin) arm, which we should have shortly. The goal is first to publish the primary manuscripts and then work on secondary analyses.

Dr. Knopman: In RECOVER-NEURO, we were looking at cognition, so non-cognitive measures like walking speed were not used. We used objective, standardized neuropsychological instruments as secondary outcomes and looked at differences and correlations between patient-reported outcomes or symptoms and objective cognitive performance. We did not require objective impairment for enrollment because that would have excluded about 40%–50% of people, and we wanted to be as inclusive as possible for patients who had symptoms of cognitive dysfunction related to Long COVID.

Dr. Taub: For RECOVER-AUTONOMIC (Ivabradine), one key thing is looking at the impact of coordinated care, meaning more attention and engagement with the patient on lifestyle interventions versus standard of care. As a clinician, I think you have to synergize pharmacotherapy and lifestyle; it is not one or the other. Whenever I see a patient with POTS, I prescribe medication to optimize heart rate and blood pressure, but I also tell them to do these lifestyle strategies, such as compression and exercises that do not cause too much fatigue, often not standing exercises. In terms of other implications, we need to better understand natural history and identify better objective endpoints. In this population, I don’t think we’ve really discovered what the best objective metric is to evaluate improvement.

Dr. Knopman: I agree. It would be interesting to have funding to go back 2 years later and poll RECOVER-NEURO participants to see where they are now: whether they continued to improve, worsened, or what their status is. Cognitive symptoms in chronic fatigue syndrome are very similar to cognitive Long COVID, and research in that area preceded COVID but has been challenging. It remains challenging to understand the mechanisms.

Ms. Leverty: When results are null, it is disheartening. People are suffering and seeking answers. In clinical trials, you set up the best trial structure you can with the knowledge you have at that time. Then the results speak for themselves, and you work to glean what can move forward to inform future work. These findings were shared with Patient, Caregiver, and Community Representatives associated with each project before they became public, and their responses included disappointment and hope that future treatments will be statistically significant and more broadly used.

Ms. Cerda: From a patient perspective, it is disappointing, especially if you were involved in the design process. We are looking for hope and indications of something we could do differently to improve our health. For those several years out, we are hungry for results. I do see hope on the horizon with RECOVER Cycle 2, RECOVER-TLC, and the additional work that the current team is doing.

Ms. Leverty: De-identified quantitative survey data are available from the corresponding author, Renee Leverty (renee.leverty@duke.edu) upon reasonable request. However, open-ended responses are not publicly available because they may contain potentially identifiable information provided by survey respondents.

Dr. Taub: As a clinician who treats many Long COVID patients, I was disappointed as well. But in clinical trials generally, there is a lot of learning, and sometimes it takes multiple trials to get the design right. Just because a trial is null does not mean the therapy does not work; it could mean the design was not optimal. With the ivabradine study, one lesson learned is whether the OHQ (Orthostatic Hypotension Questionnaire) was the best way to assess impact, and I think we need a better objective metric. 

Another lesson was dosing. We were conservative because of safety concerns in a vulnerable population, but the dosing was lower than in another trial and a U.S. Department of Defense–funded trial [this Department is also referred to as the Department of War] where dosing is higher. A null trial still contributes to the field. The next trial can have a different design, different metrics, and hopefully more objective metrics.

Dr. Knopman: One challenge in Long COVID, and cognitive Long COVID specifically, is that the biologic mechanisms remain unclear. Without a clear understanding of the underlying biology, therapy involves many arbitrary decisions about what the mechanism of disease might be. That has been a real challenge with cognitive Long COVID and brain fog in chronic fatigue syndrome. 

In many fields, including degenerative dementias, there has been a long track record of failure, and it took a long time to understand dosing and disease targets. We were starting from scratch in 2022 with limited information, and mechanisms of COVID and the brain remain uncertain. Until the biology is better understood, it will be a challenge to move ahead.

Dr. Reist: Yes. There was a plan, and NIH considered it extremely important to leverage a big data repository like BioData Catalyst so that the data will be available to other researchers who may want to access it, do data mining, and use it to design future trials and studies.

Note: NHLBI BioData Catalyst® (BDC) is a secure, cloud-based ecosystem managed by the National Heart, Lung, and Blood Institute that offers data, analytical tools, applications, and workflows. This ecosystem currently hosts datasets from 3 RECOVER cohorts (groups of participants) in the initiative’s observational studies. Soon, BDC will also host data from the RECOVER Clinical Trials (RECOVER-CT) program.

RECOVER Admin: A RECOVER-TLC webinar was held Thursday, July 16, from 1:00 to 2:00 pm ET. It covered TLC’s planned clinical trials and selected treatments, reviewed the trial process, explained steps being taken to help ensure participant safety, and discussed anticipated outcomes to help patients and providers make decisions.

For more information about RECOVER-TLC, visit the Foundation for the National Institutes of Health (FNIH) website.

RECOVER Admin: Funding details are available on the RECOVER website on the Funding page.

Dr. Knopman: Yes, of course, improvement in daily life would be the most meaningful outcome. Our data show that some people (58% somewhat better, 8% much better) reported being substantially improved, but on a group-wise basis, there was much variability. See table 3 in our published article.

Dr. Knopman: Since the trial was designed to detect an improvement in one of the active treatments, we did not specify ahead of time what an absolute improvement meant. We can use the global question that was asked of each participant to judge what was a meaningful improvement for them. 

Because we had no prior experience with any quantitative measure, we were not able to calculate an MCID for our outcome measures. That is why the global measure was important. See response above. Also, on the global measure across all participants, 74% said they benefited (see table 3 in our published article).

Dr. Knopman: Yes, cognitive fatigue on BrainHQ could have influenced outcomes, but our measures of post-exertional malaise (PEM) did not find that to be the case. The number of participants reporting PEM dropped from 76% at the baseline visit to 56% at the end of the study.

Dr. Knopman: Please await the publication of the RECOVER-VITAL trial for information about viral persistence of COVID.

Dr. Taub: It is proposed as one mechanism, but we need more studies.

Dr. Knopman: If you recall, in 2022, there was a great sense of urgency to do a trial. In fact, in the RECOVER-NEURO trial, the tDCS [transcranial direct-current stimulation] and our counseling intervention had shown promising results in pilot studies.

Dr. Knopman: No.

Dr. Knopman: Yes, but they were in other RECOVER trials that will be published in the future.

Dr. Taub: Blood samples have been stored, and we are currently deciding on what secondary analysis to do.

Dr. Taub: Beta blockers also lower heart rate so it would not be a good control. There is a study led by Dr. Satish Raj that compared ivabradine to propranolol (a beta blocker medication).

Dr. Taub: This analysis is forthcoming. 

Dr. Taub: We will be analyzing data from wearable trackers that patients wore.

Dr. Taub: The lifestyle activities in the coordinated care arm [of the RECOVER-AUTONOMIC (Ivabradine) trial] included compression, increased salt intake, and POTS-specific non-upright exercise.

RECOVER Admin: RECOVER has not tested the safety and effectiveness of the drug metformin in a clinical trial. RECOVER electronic health record (EHR) researchers conducted a study using previously collected health data (a retrospective study) and found that adults who use metformin to treat type 2 diabetes have a lower risk of developing Long COVID. At a previously held R3 Seminar (June 2, 2025), RECOVER researchers presented this research. Read the recap or watch the seminar video.