By David Tuller, DrPH
I’ve been writing for a while about the rush to treat long Covid patients with the outdated and debunked approach long applied to ME/CFS. A major effort to demonstrate that an exercise program can lead to “recovery” from long Covid, sponsored by the University of Warwick and funded with £1.200,000 from the UK’s National Institute for Health Research, is currently recruiting. It goes without saying that the REGAIN study is seriously flawed–as we have come to expect from this type of research.
The study seeks to enroll more than 500 people who were hospitalized for Covid-19. Participants will receive either an eight-week online rehabilitation exercise and recovery support group, or a single online session of “exercise advice and support.” Here is the stated rationale: “People recovering from COVID-19 can feel weak, breathless and tired. Some people are also worried and frightened. For most people, these problems will get better on their own, but for some people, they may continue for a long time after leaving hospital.”
Fair enough. But there’s a huge problem: The study protocol and the participant information sheet include no mention of the symptom of post-exertional malaise (PEM), also known these days as post-exertional symptom exacerbation (PESE). Whatever it is called, this tendency toward serious relapses is a core symptom in case definitions of ME and ME/CFS. Given that PEM has also emerged in surveys and reports as a core symptom for many long Covid patients, this omission is troubling.
To be fair, the protocol does include this passage: “Exercise carries a very small risk of complications. All participants will be assessed for any underlying health conditions or severe complications related to COVID-19. Participants will be excluded from the study at the eligibility stage where exercise is clearly contraindicated, as assessed by a clinical member of the research team.” But is this a reference to PEM as a result of long Covid, or just to the fact that some long Covid patients might be too sick to engage in exercise because of “underlying health conditions” or “severe complications” from Covid-19 unrelated to PEM? Hard to tell. I assume that if the investigators meant to refer to PEM here, they would have referred to PEM. And on what grounds are they asserting that exercise involves only “a very small risk”?
Interestingly, the FAQ sheet for the study does include an explicit statement about PEM: “A small set of people experiencing the long-term effects of COVID-19 may suffer with general symptoms of extreme and debilitating fatigue which are thought to be similar to chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME). Post-exertional malaise (PEM) is the hallmark feature of this condition. PEM is described by patients as all-encompassing symptoms affecting every part of the body after physical or mental exertion. As part of our screening and eligibility process we diligently assess patients for PEM. Components of the REGAIN intervention are carefully selected and monitored for participants with suspected PEM.”
But why is PEM mentioned only in the FAQ, which many participants will never read? And, as with the protocol statement, what is the evidence for the claim that PEM afflicts only a “small set” of long Covid patients? I assume, perhaps correctly but perhaps not, that the addition of PEM to the FAQ was an afterthought based on objections someone likely raised following publication of trial documents already approved by the study’s research ethics committee.
That the investigators omitted mentioning PEM from two key trial documents and asserted in the FAQ that those experiencing this symptom constitute only a “small set” of the long Covid cohort indicate to me that the investigators are relatively unfamiliar with the phenomenon. If that’s the case, how can we be assured they will reliably and accurately assess whether PEM is a factor for any given participant? Answer: We can’t.
The consent form does not include any information about risk, but it requires participants to confirm that they have read the participant information sheet. It does not require them to have read the FAQ. In other words, there is no guarantee that participants entering the study are aware or have been informed about the risk of PEM and the possibility of serious relapses. This is unsettling. Study subjects are supposed to be fully informed about potential risks. This study fails completely on that count.
This cluelessness is apparent from statements in the participant information sheet. For example, here’s the description of the single online session for the non-intervention group, for example: “You will be invited to have a video or telephone call with a REGAIN exercise specialist. During the call you will be given information on how to safely increase the amount of activity and exercise you do at home.”
The statement clearly presumes that it is possible for all participants to “safely increase the amount of activity and exercise” in which they engage. How do the investigators know that all participants can, in fact, increase their activity “safely”? They do not, of course. Under the circumstances, the claim is unwarranted and unjustified.
And then there’s this very modest advisory about the possible dangers of exercise: “We do not anticipate any serious risk to you. There is always a very small chance that exercise can make you feel unwell. You will be advised and monitored by specialist staff. Exercise may cause tiredness, breathlessness and sore muscles, but this should get a bit easier each time you exercise.”
This parallels the inadequate information provided to participants in the piece of nonsense known as the PACE trial. In that disastrous enterprise, the investigators assured ME/CFS patients that any post-activity resurgence of symptoms was part of the process of recovering from the deconditioning purportedly driving the condition—not part of the disease itself. Similarly, in assuring patients that exercise “should get a bit easier each time you exercise,” the Warwick investigators appear to be assuming that deconditioning is implicated in the symptoms. Let’s be clear: This position is not supported by the available evidence. Just because the research team does not “anticipate any serious risk” does not mean there is no serious risk. Given that the Warwick investigators appear to be confused about the extent and nature of PEM, their statement about the “very small” possible risk lacks all credibility.
Beyond the fact that the investigators appear not to fully understand the condition they’re dealing with, the study also unfortunately suffers from some of the same issues afflicting most studies of the discredited CBT/GET treatment paradigm for ME/CFS.
First, the study is unblinded with largely subjective outcomes, including the primary outcome—health-related quality of life at three months. This combination is a great recipe for generating an unknown amount of bias in the responses. The investigators have included a couple of objective measures, like work status and use of health care and social services. But if the history of this type of research is any guide, positive reports on subjective outcomes will be touted to declare the intervention a success whatever the more objective outcomes show.
Second, it is self-evident that patients offered something they are told is a method for “recovery” will be more likely to say they feel better than people getting what is presented as standard care—that is, the single online support session. In other words, this is not a controlled trial, since the investigators have made no effort to “control” for the possible impact of the time and attention lavished on the intervention group. Well-designed trials try to compensate for those factors by offering the non-intervention group similar time and attention but without the elements believed to be therapeutic.
In other words, these investigators and the NIHR, which is funding this muddle, seem to have learned nothing—zero, zilch, rien, nada, nichts–from the decades-long ME/CFS debacle.
18 thoughts on “Trial By Error: Can Someone Please Slap a Warning Label on this Exercise-and-Rehab Long Covid Study?”
“You will be advised and monitored by specialist staff. Exercise may cause tiredness, breathlessness and sore muscles, but this should get a bit easier each time you exercise.”
This captures the bias involved, in trying to be too reassuring they are open to making misleading claims that are entirely aspirational. Anyone working from a position of good health and trying to be fit is familiar with how frustrating fitness conditioning can be, with ups and downs and plenty of plateaus. Highly trained people understand even deeper how much discipline it takes to keep working up that slow incline of fitness. It DOES not get easier each time. Nothing that takes discipline does.
This study mixes up the concepts of fitness and health. The participants are not starting from a position of good health and into fitness conditioning. They start from a condition of illness, in some cases resolved, in some cases not, and onto fitness, skipping over the returning to a baseline of good health. But that initial condition of illness is very different and will respond very differently to gentle return to function, which is not the same as fitness conditioning.
The researchers are monitoring for signs of known illnesses and health issues. When those signs are missing, they assume no illness, and thus relative good health that is simply not fit anymore. In research trying to assess the health/illness status of people recovering from Covid, this is circular logic that is precisely used with the usual BPS slant of “all tests are normal”. Either not knowing or not having a diagnosis that explains a patient’s illness is not the same thing as a status of good health. It is the presence of disabling symptoms that is the real determinant of illness, not the blessing of a licensed practitioner.
Except as we know there is plenty of abnormal pathology, in both Long Covid and ME. It is simply by the absence of diagnoses that good health is declared, not on a status of actual health. Here the diagnosis essentially plays the role of benediction. Medicine is not theocratic, its ignorance does not invalidate the existence of something.
Even not accounting for PEM, it’s simply not true that symptoms will get easier each time people exercise. This is only true of those 3 symptoms, which are not listed as symptoms of Long Covid, but rather conceived as the normal post-exercise fatigue after vigorous activity in unfit people. They are deliberately using an overlap in the outcome of starting an exercise regimen that are simply not the same as those reported in Long Covid. There is either a deliberate or ignorant conflation of post-exercise fatigue and PEM in the BPS community, this has long been an issue where they have shown their misunderstanding of what the patients are experiencing and it is corrupting research all over again.
There may be similarity between going on a run at high speed and being out of breath and being always out of breath at the slightest level of exertion, but only one is clearly not normal and healthy. Further there are many who after Covid have constant shortness of breath, even without exertion. This is not at all the same as hyperventilating for a few minutes after a set of activities then returning to normal breathing. This makes as much sense as equating vomiting after overconsumption of food with severe nausea. They may roughly be the same phenomenon but it takes either bad faith or ignorance to try to argue they are the same thing.
And obviously the myalgia reported in both ME (so many people forget it’s literally in the name) and LC is not the same as post-exercise muscle soreness. They feel different enough to be easy to differentiate, but only someone experiencing it can know. But here it is clearly assumed to be post-exercise soreness, not the constant irritating all-encompassing myalgia people experience with the flu, or common in ME, LC and fibromyalgia.
I think the researchers need to clarify this, and participants in this study need to be able to address this confusion and maybe save this study from being yet another useless piece in the BPS mountain of BS.
Gee, that’s some omission. I can’t help thinking it’s a risky game to play. And if this trial doesn’t go to plan, should we worry that for take 2 they might consider military training to try to jolt Long-Covid sufferers back into good health?
Oh good grief. Yet more fannying around with the acronyms. Why has ‘PESE’ come into being when we already had a perfectly described experience of ‘PENE’ ( Post-Exertion Neuroimmune Exhaustion) in the International Consensus Criteria? Why this continued re-inventing of the wheel?
The ICC Primer describes PENE thus (see below). Should Long Covid, or even post-acute Covid (because this trial seems lacking in differentiation between the two), in any way reflect ME (and until that can proven with reproducible data it’s far better to assume they are *not* one and the same for the time being), it would nevertheless be sensible for these patients to consider ME as the ‘Canary in the Coalmine’ wrt how people suffering Long Covid etc might need to be mindful of sequelae from interventions such as REGAIN.
This is PENE (emphasis should be attached to the ‘N’ which stands for ‘neuroimmune’ and is not simply a manifestation of being more exhausted, although that might present as part of its array):
“Post- Exertional Neuroimmune Exhaustion (PENE pen׳-e)
Normal fatigue is proportional to the intensity and duration of activity, followed by a quick restoration of energy. PENE is characterized by a pathological low threshold of physical and mental fatigability, exhaustion, pain, and an abnormal exacerbation of symptoms in response to exertion. It is followed by a prolonged recovery period. Fatigue and pain are part of the body’s global protection response and are
indispensable bioalarms that alert patients to modify their activities in order to prevent further damage.
The underlying pathophysiology of PENE involves a profound dysfunction of the regulatory control network within and between the nervous systems. This interacts with the immune and endocrine systems affecting virtually all body systems, cellular metabolism and ion transport. The dysfunctional activity/rest control system and loss of homeostasis result in impaired aerobic energy production and an inability to
produce sufficient energy on demand. A test-retest cardiopulmonary exercise study revealed a drop of 22% in peak VO2 and 27% in VO2 at AT on the second day evaluation. Both submaximal and self-paced exercise resulted in PENE. These impairments and the loss of invigorating effects distinguish ME from depression.”
Maybe if the ME community agreed that ‘PENE’ is the much better definition for what happens to people with ME if they overstep their own mark, even by the littlest degree, then spurious ‘research’ such as REGAIN would be less able to make ‘PEM’ into anything they want it to be. Will their subjects be assessed for PENE per se? Clearly not. Could this omission be dangerous? I’d say so. If Long Covid and ME do turn out to be closely related to each other, then using diluted versions of what the authors of REGAIN choose to define ‘PEM’ or PESE’ could lead to patients being iatrogenically harmed. Language matters. The less it can be abused the better, particularly in a context like this.
I will apologise in advance for any typos. LadyShambles is cognitively very challenged atm.
Sad read. Can you send your write up to the ethics committee overseeing this trial and to the lead researcher(s). No excuse for this in 2022
Will the patients be able to sue the researchers if they get worse? That’s the only question that matters, because that’s the only thing that will stop this.
I’ve written a brief email to the REGAIN team, cc complaints and the South Cambridgeshire research ethics Committee. Best I could do between clinics. Signposting them to publications and expert evidence from recent NICE guidelines.
I see on Twitter that Physios for ME have raised issues with them too.
I’ll let you know if I get a response
Looks like, as with their other studies, they are cherry picking people who are least affected and most likely to recover on their own, as representatives of a whole heterogeneous patient community. The results will have little relevence to the real world disease they are claiming to treat, and will be forced upon the mild and seriously disabled sufferers alike, by the medical community for decades after.
With regard to risk, it is important to note that risk is the combination of: a) The probability of an adverse event occurring, together with b) The severity of the consequences of such an event if it occurs.
So when something is referred to as a “a very small risk”, is the word “risk” being misused here? If, for example, it is a low probability that someone could end up bedridden for the rest of their life, is “very small risk” a reasonable assertion to make?
And no, relegating PEM to the FAQs is not acceptable.
Here is another program but offered in the UK
“our virtual rehabilitation classes focusing on low-level exercises – these are guided by ongoing monitoring of your symptoms including breathlessness and fatigue levels, as well as specific outcome measures identified by you and your Rehabilitation Specialist.”
“How do the investigators know that all participants can, in fact, increase their activity “safely”?”
That’s easy. Dame Clare Gerada said so on BBC:
“There is nothing that isn’t made better through exercise. OK? Nothing. No matter what age, what condition, exercise will always improve it, but in moderation.”
How dare any of us peons challenge the wisdom of our betters! Everyone in a hierarchical system understands that The Boss Is Always Right, even when the Boss is wrong. Authority and “clinical experience” trumps peons and reality every time.
Anyone who refuses to accept official pronouncements is obviously mentally ill and a danger to society. Fortunately there are special hospitals to keep decent folk safe from disbelievers.
It’s ok to conduct research trials in this way and yet the medical powers-that-be don’t seem to comprehend why people have trust issues with medical ‘advancements’ (such as vaccines) that emerge from research trials?
Trust – that small, rather insignificant thing (it would appear) but so easy to lose and so hard to regain. Inconvenient truths surely must be disclosed or trust (like paradise) might be lost and never regained?
‘Exercise may cause tiredness, breathlessness and sore muscles but this should get a bit easier each time you exercise’
Those words were also told to me by a gym instructor that l went to 45 years ago when l first went to doctors with my M.E symptoms. l was told to ‘go home and get on with my life’. So l booked a l hr gym session. And the instructor quoted those same above words.
l didn’t go back to the Gym.
l couldn’t go back.
l tried to go back to work. l couldn’t.
l became too ill .
6 months later l became severe M.E after the ‘get on with my life’ advice.
The gym instructor had told me ‘ it wont get easier if you give up’
So l have a question,
is the above taken from the REGAIN study, to be interpreted as ‘keep going’ because the quote says..
‘it SHOULD get a bit easier each time you exercise’
Is that not a powerful INCENTIVE to not give up , no matter what ?
Wording is everything in a consent form and it has consequences if everything is not fully and clearly disclosed.
I’v read the participant information sheet . Is the possibility of un-reversible PEM mentioned in ‘plain sight’ ?
I’v so many questions l would want to ask.
I’m re-living a ‘recurring nightmare’ about what happen to me after reading about the REGAIN Study 🙁
Has anyone made a petition to get this study discontinued?
‘The study seeks to enroll more than 500 people who were hospitalized for Covid-19. Participants will receive either an eight-week online rehabilitation exercise and recovery support group, or a single online session of “exercise advice and support.” ‘
Turning to the “support” element, is that really “support” or do they really want to change participants’ behaviour? I strongly suspect it’s the latter.
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Such a brilliant scientist with easy to follow protocols.
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