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I’ve been writing for a while about the rush to treat long Covid patients with the outdated and debunked approach long applied to ME/CFS.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.