By David Tuller, DrPH
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I wrote recently about the problematic REGAIN study from the University of Warwick, which is testing an exercise-and-psychological-rehab program as a treatment for long Covid patients. Unfortunately, neither the protocol nor the participant information sheet, to which participants are referred during the consenting process, mentions the core ME/CFS symptom of post-exertional malaise (PEM), which has also been reported in long Covid.
The FAQ does mention PEM. However, since patients are not required to read the FAQ, there is no guarantee that those currently enrolling in this study will know or have heard anything about this potential risk. Moreover, the FAQ suggests that PEM likely impacts only a “small set” of long Covid patients but provides no evidence to back up this claim. In fact, surveys have indicated that many long Covid patients experience PEM—not just a “small set” of them.
This issue has a bit of a back story. The UK’s National Institute for Health Research announced that it was funding the study to the tune of £1.200,000 study late in 2020, and recruitment of the more than 500 expected participants began shortly thereafter. To enter the trial, participants must have been hospitalized for treatment of Covid-19 and still be experiencing health problems at least three months later.
After the trial announcement and launch, experts and patient representatives understandably expressed concern about the lack of any mention of PEM. In January, 2021, the group Physios for ME noted on its website that it had met with the research team the previous month to highlight concerns about REGAIN. The statement on the website included the following:
“We note that the [REGAIN] website currently says: ‘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.’…It is unfortunate that this continues to leave out any mention of the potential for post exertional malaise and the risk of continued exercise in this instance.”
Although Physios for ME was drawing attention to the potential harms of the intervention, the statement noted that this should not be taken as opposition to physical activity and psychotherapy for these patients: “As physiotherapists, we are knowledgeable and enthusiastic about promoting physical activity and recognise and support the benefits of exercise and psychological support particularly after admission to ITU. We therefore wholly support research to help develop understanding of the management of long covid in this cohort.”
Similarly, last June #MEAction posted an article about its own interactions with the investigators. The article noted that two #MEAction UK members and #MEAction’s director of scientific and medical outreach, Jamie Seltzer, held an online meeting with the REGAIN team. Here’s part of the account:
“#MEAction explained our concerns that the publicity about the trial had made no mention of any need for caution in taking part in an exercise programme. We detailed why exercise is inappropriate and potentially dangerous for people with post-exertional malaise, and the need for such people to be screened out of any exercise programme that might encourage people to do more than they could safely within their “energy envelope”. We discussed how post-exertional malaise can be identified.
The team explained that the trial had been developed with oversight from a patient group and anyone taking part in the trial had an initial one hour one-to-one session with a practitioner. They explained that once someone had been accepted onto the trial, the team could not exclude them as that would be altering the protocol which the trial was following. (They made the point that that is one of the criticisms of the PACE trial.) However, they agreed it was important to identify anyone with post-exertional malaise, explain fully to them the risks and that participants are able to withdraw from any part of the trial without any impact on health care options. A participant could, for instance, choose to continue in the support group sessions only.”
The #MEAction article noted that the REGAIN team was “willing to listen to the advice and experience we were giving,” and that information about PEM was subsequently added to the training manuals and other trial documents.
Beyond these concerns, the REGAIN trial also suffers from a methodological flaw, as I noted in my previous post–it is an unblinded trial and relies largely on subjective outcomes. This combination is a recipe for bias, especially because the comparison group receives almost nothing at all. But that’s another matter.
BMJ weighs in on the issue
Also last June, BMJ ran a news story addressing the issue called “Chronic fatigue syndrome and long covid: moving beyond the controversy.” The article rehashed the PACE scandal from Professor Michael Sharpe’s self-aggrandizing point of view and provided yet another forum for Professor Paul Garner’s tiresome account of conquering long Covid with his powerful thoughts. In the process, the article adopted the standard dismissive perspective on patients who have dared to counter the claims of these distinguished professorial oracles.
The story was published before the UK’s National Institute for Health and Care Excellence (NICE) issued its final ME/CFS guidelines last October. But it was published after a draft released in November, 2020, which reversed NICE’s former recommendations for graded exercise therapy (GET) and cognitive behavior therapy (CBT).
The BMJ article only noted that the NICE draft found the “the evidence is mixed or unclear”–a bit of a misrepresentation. In a research review published at the same time, NICE assessed the quality of the evidence for the treatments not as “mixed or unclear” but as “very low” or merely “low.” This frank assessment vindicated the arguments advanced by patients, advocates and many academic experts but left GET/CBT ideologues like Professors Sharpe and Garner braying with frustration.
The BMJ article mentioned the REGAIN study and the input the investigators received from concerned advocates. But the article’s tone implied that the critics were generally a whiny and misguided lot–even though the REGAIN team acknowledged making changes in response to the appeals. Here’s BMJ’s account:
Meanwhile, long covid researchers are also learning to live with the increased level of scrutiny and complaints that teams working on CFS/ME have come to expect.
“Gordon McGregor, a clinical exercise physiologist, is leading the University of Warwick’s Regain trial, a National Institute for Health Research funded study on whether physical activity with psychological support benefits long covid patients who were admitted to hospital. He told The BMJ that he had engaged with a number of CFS/ME patient and advocacy groups. ‘We had constructive conversations and made a number of amendments to the trial protocol as a result,’ he says. ‘We will be screening participants regularly for PEM [post-exertional malaise].’
However, some individuals, who believe that physical activity should be avoided at all costs, remain deeply unhappy and have emailed McGregor, colleagues, and funders with their views. “The impact has been tangible,” he says, “but the research is continuing.”
Hm. It is well and good that the researchers listened to these groups. And certainly if they are actually doing such PEM screening, it’s better than not doing it. But Professor McGregor’s response leaves serious questions unanswered. Presumably those questions were unasked.
If the research team was familiar with the shenanigans around the PACE trial, as the #MEAction write-up clearly suggests, then why were they apparently unaware of the controversy over GET as a treatment strategy? And why are they still claiming in the FAQ that PEM impacts only a “small set” of long Covid patients, when some of the available research does not support this statement?
Moreover, earlier in 2020, months before the study approval was announced, NICE had issued an advisory that warned against the assumption that a graded exercise program was appropriate for long Covid even thought it was recommended in the then-extant “CFS/ME” guidance from 2007. To anyone involved in this domain, this was a clear sign that NICE was likely to do away with the GET recommendation in its upcoming revision. Why was this advisory apparently disregarded by the REGAIN team, given its potential relevance?
The protocol has been amended many times since the study began—but the term post-exertional malaise has not been added. And the following phrase remains in the most recent protocol version, amended in February: “Due to the limited knowledge of the long-term health problems in COVID-19 survivors, there are no Serious Adverse Events that would be expected in exercise intervention for the population included in this study.”
This is a peculiar statement. If you don’t know much about long-term health problems, why would you automatically assume that “no Serious Adverse Events” would be expected in “exercise intervention”? Surely the cautious approach in the event of “limited knowledge” would call for extra vigilance about potentially harmful outcomes—especially after having been warned about PEM and agreed to screen for it and include mention of it in the FAQ. The investigators seem to be simultaneously acknowledging the risk but downplaying or dismissing it. Their approach comes across as somewhat confused and incoherent.
After all the changes, are newly recruited participants being informed about the potential for PEM during the consent process, or not? If not, why not? And are those already consented being re-consented to alert them to this potential risk? It all seems like a bit of a muddle.
And where was the NIHR in all of this? You’d think someone at this major funding agency would have been familiar enough with this thorny debate to raise questions during the trial approval process. How about the research ethics committee? Is no one to be asked to account for a process in which an expensive and presumably well-scrutinized proposal was funded with no one noticing the failure to mention a potentially significant risk to participants?