Protocol Pursuing Reduction in Fatigue After COVID-19 via Exercise and Rehabilitation PREFACER: a protocol for a randomised feasibility trial, 2025, Billias+

SNT Gatchaman

SNT Gatchaman

Senior Member (Voting Rights)
Staff member
Pursuing Reduction in Fatigue After COVID-19 via Exercise and Rehabilitation PREFACER: a protocol for a randomised feasibility trial
Nicole Billias; Dimitra V Pouliopoulou; Arden Lawson; Victoria D’Alessandro; Dianne M Bryant; Sue Peters; Alison B Rushton; Erin Miller; Laura Brunton; Shannon McGuire; Michael Nicholson; Trevor B Birmingham; Joy C MacDermid; Kieran L Quinn; Fahad Razak; Susie Goulding; Panagis Galiatsatos; Emily Saunders; Jacquelyn Marsh; Tiago V Pereira; Pavlos Bobos

INTRODUCTION
Over 777 million COVID-19 infections have occurred globally, with data suggesting that 10%–20% of those infected develop Long COVID. Fatigue is one of the most common and disabling symptoms of Long COVID. We aim to assess the feasibility and safety of a new, remotely delivered, multimodal rehabilitation intervention, paced to prevent post-exertional malaise (PEM), to support the conduct of a future, definitive randomised trial.

METHODS AND ANALYSIS
We will conduct a randomised, two-arm feasibility trial (COVIDEx intervention vs usual care). Sixty participants with Long COVID will be recruited and randomised prior to giving informed consent under a modified Zelen design using 1:1 allocation with random permuted blocks via central randomisation to receive either the COVIDEx intervention or usual care. The 50-minute, remotely delivered, COVIDEx intervention will occur twice weekly for 8 weeks. All participants will wear a non-invasive device throughout their entire study participation, to track heart rate, blood oxygen saturation, steps, sleep and monitor PEM. The primary feasibility objectives will be recruitment rates, intervention fidelity, adherence, acceptability (intervention and design), retention, blinding success and outcome completeness. Secondary objectives will include refined estimates for the standard deviation and correlation between baseline and follow-up measurements of fatigue. Feasibility and clinical outcomes will be collected at baseline, 4, 8, 12 and 24 weeks. Qualitative interviews with participants and physiotherapists will explore intervention acceptability and barriers/facilitators.

ETHICS AND DISSEMINATION
Ethical approval for this study was obtained by the Western University Health Sciences Research Ethics Board (REB# 123902). Dissemination plans include sharing of trial findings at conferences and through open access publications and patient/community channels.

TRIAL REGISTRATION NUMBER
NCT06156176

Web | PDF | BMJ Open | Open Access
 
A subgroup of patients with Long COVID may indicate that they experience PEM on the pre-screening and demographic questionnaires. PEM is defined as new or worsening symptoms (such as difficulty thinking, problems sleeping, sore throat, headaches, feeling dizzy or severe tiredness) up to 48 hours after a physical or mental activity that would not have caused a problem before COVID-19 infection and subsequent post-COVID-19 fatigue. Symptoms of PEM can last for days, weeks or months. We will address PEM in the trial by the following:
Click to expand...

a. Pacing the COVIDEx session to reduce over-exertion. A pacing strategy and protocol may reduce exacerbation of PEM for those with Long COVID. Pacing will entail frequently gathering subjective measurements of intensity from participants, as well as ensuring that all components of the session (ie., cardiovascular, strength training) have adequate rest and recovery in between periods of more intense activity. Participants will inform the physiotherapist or exercise instructor of their resting heart rate and blood oxygen levels before each session and after each component of the session, which will help determine the rehabilitation intensity and pacing.
Click to expand...

b. Monitoring correlated measures for blood lactate levels in participants. People with Long COVID may experience skeletal muscle abnormalities, such as mitochondrial and endothelial dysfunction, and a change to primarily anaerobic metabolism and glycolytic muscle fibres. These changes can reduce movement capacity and potentially trigger PEM. Potential causes for these skeletal muscle abnormalities include deconditioning, local tissue hypoxia, autoimmunity, electrophysiological changes and central fatigue (neurological alterations). Monitoring correlated measures for blood lactate enables examination of these metabolic responses (ie, mitochondrial dysfunction, reduced tissue oxygenation) in people with Long COVID, which could help prevent the onset of PEM by ensuring participants do not exceed a threshold that could induce PEM.
Click to expand...

Specifically, our objective of monitoring correlated measures for blood lactate is for safety purposes to prevent overreaching in participants with Long COVID. All COVIDEx participants, throughout the COVIDEx sessions, will use a smart watch to monitor correlated measures for their blood lactate levels, specifically heart rate and blood oxygen. Steps activity and sleep will also be monitored to track physical activity and sleep disturbances. […] If oxygen saturation falls below 92%, participants will be advised not to take part in (or discontinue) the session, and this will be recorded promptly.
Click to expand...
 
I struggle to see how this will add any value.

All of the proposed outcome measures are subjective, except for the sit stand test and step count.

The rationale behind certain blood lactate thresholds (through proxies) being «safe» is not sound.

There is no run-in prior to the intervention to get a long term baseline for the participants.

The participants will know if they are in a group where it’s expected to observe improvements, so the blinding measures won’t improve the risk of bias for the subjective outcomes, even though they have eliminated the nocebo argument for the CAU group.
 
PaEM do not need clinical trials on pseudo "PEM cautious"/paced physical rehabilitation (doomed to failure) ; we need clinical trials on treatments to cure the disease, or at least alleviate the most debilitating symptoms.

I my opinion, this is yet another waste of money.
 
The bullshit wheel needs to be constantly spun or it stops spinning. It has been determined that the wheel must keep spinning, as otherwise things would be embarrassing, and so the value of this research is to simply keep spinning the wheel.

Every old program is old and new again. Always new. There are always more new programs in the banana stand.
 
The paper said:
The primary feasibility objectives will be recruitment rates, intervention fidelity, adherence, acceptability (intervention and design), retention, blinding success and outcome completeness.
Click to expand...
This is a trial of the idea of conducting a trial. Not a single one of those have anything to do with anything patients need. It's all about checking boxes.

Can a trial of exercise be performed? Can the proper boxes be checked? Gee, I don't know. Judging from the LITERALLY HUNDREDS, it's kind of hard to tell. But I'm sure one more will not do anything but spin the wheel of bullshit, which is needed for the wheel's ability to keep on spinning. Perpetual motion, if one ignores the motion needed to keep it perpetually spnning.

Spiiiiin the wheeeeeeeel.

Looking back from hundreds of such trials performed over several decades: what has actually been learned? What is a single thing that anyone involved in this can assert they didn't know before? Not a single thing has been learned. Literally not a single bit of information. None of this has anything to do with research, with what patients need or has any chance of alleviating anyone's suffering.

Spiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiin the wheeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeel!
 
  • Published on: 9 December 2025
    In the Long Run, Misleading Participants Will Harm More Than Help in Long COVID Research
    • Todd E. Davenport, Professor & Chair University of the Pacific, Workwell Foundation
    • Other Contributors:
      • Staci R. Stevens, Exercise Physiologist
      • Mark A. Faghy, Professor
      • Jessica DeMars, Respiratory Physiotherapist
      • J. Mark Van Ness, Professor & Chair
    Respect for persons, beneficence, and justice are bedrock ethical principles in science. They are especially important when studying vulnerable populations. Billias et al. argue that deception is necessary to assure the internal validity of their exercise study involving people living with long COVID.[1] Here, we assert the use of deception is ethically indefensible and scientifically unnecessary in this population. It undermines informed consent, increases risks for harms, exploits the vulnerability of participants, and erodes trust in science and health care, all while exploring a question that already has been asked and answered satisfactorily enough to inform clinical recommendations.

    Physical activity is a common trigger for post-exertional malaise (PEM),[2 3] which is common in people living with long COVID.[4] PEM involves an impaired recovery response from exertion that is distinct from deconditioning.[5 6] The hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is PEM. Exercise is no longer recommended in contemporary clinical guidance for ME/CFS, because an accumulation of evidence from research and lived experience suggests it is likely to cause avoidable harms.[7] Exercise prescription without adequate safeguards for PEM even may be considered negligent practice. The protocol acknowledges people living with PEM often worsen with exercise dosages that may be appropriate for other conditions.[1] Several of the authors of this protocol also previously published a systematic review acknowledging risks of exercise in people with long COVID related to PEM.[8] However, the authors did not adequately justify using deception in this study even while clearly acknowledging the risks of the intervention they proposed.

    People with long COVID are frequently disbelieved. They face isolation, uncertainty, financial distress, and desperation for effective treatments.[9] They must engage in complex health decisions and resist bias from health care practitioners. People with long COVID deserve adequate transparency to make choices aligned with their own priorities and preferences. Withholding information reinforces an institutional bias against people with long COVID as being incompetent to choose for themselves. The lack of sensitivity to the clear power dynamic between vulnerable participant and researcher also shows a disregard for justice. People with long COVID should be afforded extra research protections, not fewer of them.

    If participants are deprived of specific education regarding the risks of exercise at the beginning of the study, they may push beyond safe limits causing increased disability and psychological harms. Symptom titration is a flawed approach for determining appropriate exercise volume in PEM, because there is a delay between acute over-exertion and PEM.[10 11] The delay between over-exertion and symptoms means it is too late to adjust exercise workloads by the time PEM becomes apparent. In addition, the compounding effects of different exertions on PEM severity raises the likelihood that exercise may occur at the expense of desired daily activities. Experiencing these harms and finding out after the fact may further amplify feelings of betrayal and mistrust from being misled. Using deception in this study runs the risk of damaging the reputation of research and researchers in long COVID simply by association.

    A key learning of the novel coronavirus-2019 pandemic has been the fragility of public confidence in health care and science. Widespread mistrust in science and medicine has allowed the rapid spread of inaccurate health information,[12] which now has become the basis for a whole host of policies and practices that range from unhelpful to harmful. Transparency and honesty are essential for building and sustaining trust. These assets are far more valuable than any short-term methodological advantage that may gained through using deception in long COVID research. In our ongoing pursuit of effective treatments to restore quality of life in people with long COVID, honesty must remain a guiding principle.

    References

    1. Billias N, Pouliopoulou DV, Lawson A, et al. Pursuing Reduction in Fatigue After COVID-19 via Exercise and Rehabilitation (PREFACER): a protocol for a randomised feasibility trial. BMJ Open 2025;15(11):e102112. doi: 10.1136/bmjopen-2025-102112
    2. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of Chronic Fatigue Syndrome 2003;11(2):7-115. doi: doi:10.1300/J092v11n01_02
    3. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med 2011;270(4):327-38. doi: 10.1111/j.1365-2796.2011.02428.x
    4. Vernon SD, Zheng T, Do H, et al. Incidence and prevalence of Post-COVID-19 myalgic encephalomyelitis: a report from the observational RECOVER-Adult Study. J Gen Intern Med 2025;40(5):1085-94. doi: 10.1007/s11606-024-09290-9
    5. Lim EJ, Kang EB, Jang ES, et al. The prospects of the two-day cardiopulmonary exercise test (CPET) in ME/CFS patients: a meta-analysis. J Clin Med 2020;9(12) doi: 10.3390/jcm9124040
    6. Thomas C, Kudiersky N, Ansdell P, et al. Submaximal 2-day cardiopulmonary exercise testing to assess exercise capacity and post-exertional symptom exacerbation in people with long COVID. Exp Physiol 2025 doi: 10.1113/EP092576
    7. National Institute for Health and Care Excellence. NICE guideline [NG206]: myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. London, United Kingdom: NICE, 2021.
    8. Pouliopoulou DV, Hawthorne M, MacDermid JC, et al. Prevalence and impact of postexertional malaise on recovery in adults with Post-COVID-19 Condition: a systematic review with meta-analysis. Arch Phys Med Rehabil 2025;106(8):1267-78. doi: 10.1016/j.apmr.2025.01.471
    9. Sawano M, Wu Y, Shah RM, et al. Long COVID characteristics and experience: a descriptive study from the Yale LISTEN research cohort. Am J Med 2025;138(4):712-20 e13. doi: 10.1016/j.amjmed.2024.04.015
    10. Moore GE, Keller BA, Stevens J, et al. Recovery from exercise in persons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Medicina (Kaunas) 2023;59(3) doi: 10.3390/medicina59030571
    11. Mateo LJ, Chu L, Stevens S, et al. Post-exertional symptoms distinguish myalgic encephalomyelitis/chronic fatigue syndrome subjects from healthy controls. Work 2020;66(2):265-75. doi: 10.3233/WOR-203168
    12. Kearney A, Sparks G, Hamel L, et al. KFF Tracking Poll on Health Information and Trust: January 2025: Kaiser Family Foundation; 2025 [cited 2025 January 28]. Available from: https://www.kff.org/health-information-trust/kff-tracking-poll-on-health... accessed November 20 2025.

    Show Less
    AI use:
    None declared.
    Conflict of Interest:
    None declared.
Click to expand...
 
Last edited:
"Participants in both groups will be blinded to the intervention via the modified Zelen design (ie, will be informed that they are participating in an observational study followingthe natural progression of Long COVID and costs associated with standard treatments, then later debriefed)."

This from the section on "blinding" confuses me. I thought they informed the intervention group that they were getting the intervention after they were randomized to get it. But this says both groups are told they're in an observational trial. Can someone explain?

I get that there are issues that might be solved by deceiving patients, but it seems you just create problems on the other side--different kinds of bias, or bias on the intervention side but not on the standard care side. But also, I'd just be really pissed off if I found out and would likely or possibly refuse to consent to being included. I'm curious what the past history is of acceptance of this design among control groups.

ADDED: I see my confusion. What I was thinking--that they consented the intervention group after randomization--is apparently a Zelin design. (I think.) What they're doing is a "modified Zelin design", in which they're deceiving both groups till the end by telling them it's an observational study of standard treatments. But in that case, they're pretending the "novel" exercise intervention is a "standard" treatment and not an experimental one? Do I understand that correctly? How is blatant lying considered ethical?

In the actual Zelin design, at least those who get an intervention are consented before they take the intervention--they're not told it's "standard" treatment. (As I understand it.)
 
Last edited:
The reference given re the "modified Zelen" design is to Campbell et al (link):
Campbell et al said:
Eligible patients were first consented to a one-year observational study of their arthritis. They were subsequently randomized into intervention and control arms. Those in the intervention arm were then asked if they were willing to participate in a further study involving regular sessions with a physiotherapist. Those in the control arm were not told about this, but were followed up as agreed.
Click to expand...
and:
In particular, the control group was not informed of their allocation, nor of the existence of the further trial.
Click to expand...
I can't immediately find any exploration of the acceptability of this design. The original Zelen was widely regarded as unethical and was found to be unacceptable to patients in a survey in Snowdon et al (link), where half of the patients in a neonatal trial disapproved.

Personally, I think the modified Zelen design is also unethical.
 
I don’t think it’s able to eliminate most bias regardless. You get rid of the so-called nocebo from the CAU controls by not having them think they missed out on the effective treatment, but that’s about it. The intervention group will be told they are doing something that is expected to have an effect, so all of the usual biases apply for them.

So I lean towards considering this trial design as proof that the researchers don’t really understand the pitfalls when conducting a trial.
 
Utsikt said:
The intervention group will be told they are doing something that is expected to have an effect, so all of the usual biases apply for them.
Click to expand...

But in this case it seems they're being told it's "standard" therapy when it's an experimental intervention, as far as I understand it. At least in the original design, if I've gotten this correctly, the people in the experimental arm are told they're undergoing an intervention that's being trialed, so at least they're not being deceived. In this modified approach, no one is being told they're in a trial, so I don't see how they explain the experimental intervention.
 
dave30th said:
But in this case it seems they're being told it's "standard" therapy when it's an experimental intervention, as far as I understand it. At least in the original design, if I've gotten this correctly, the people in the experimental arm are told they're undergoing an intervention that's being trialed, so at least they're not being deceived. In this modified approach, no one is being told they're in a trial, so I don't see how they explain the experimental intervention.
Click to expand...
I’m not sure what they are doing about that.

I was mostly thinking about if they know that they are doing something that is supposed to cause an effect or not. I assume that’s the most important source of bias, not if you think you’re in an RCT or not. For all I know, thinking it’s standard instead of experimental might increase the expectation of an effect, adding even more bias.
 
You must log in or register to reply here.
Back
Top Bottom