The kind of project that the RECOVER Long COVID Initiative is, with its massive funding, is beginning to emerge. It appears to be a slow-moving, highly conservative effort that is putting a premium on delivering reproducible results but which thus far lacks creativity and above all, abjures risk.
Despite the initiative’s enormous mass – it’s got oodles more money than any other long-COVID initiative – RECOVER feels restrained and cautious. One would think that a $1.15 billion budget would leave room for the initiative to take some high-risk, high-potential shots, but not so – not yet. Instead of lighting the long-COVID world on fire, thus far, RECOVER is putting it to sleep. It hasn’t produced a single finding of note.
Still, we’re still very early on with RECOVER. Creating RECOVER is more like building the Titanic than anything. It’s going to take longer than we want to launch but when it does it should be something else indeed. With its $1.15 billion budget, RECOVER has to deliver the goods on long COVID: anything else would be a huge fail.
The Clinical Trials Conundrum
RECOVER is in a bit of a tough spot with clinical trials. How do you mount clinical trials in a disease you’re still in the dark about? Do you take some educated guesses and start pouring money into clinical trials, most of which are probably not going to pan out – or do you wait until you know more about the disease and use your resources then?
RECOVER has clearly chosen the second path and that’s not going please the long-COVID community which has been clamoring for over a year for RECOVER to bring them a nice, meaty plate of clinical trials. Slate – which recently published a hit piece on long COVID – reversed gears, and highlighted the frustrations of one long-COVID patient:
“Long COVID is a vile disease that affects every bodily system. It affects your ability to live, eat, sleep, and work,” he said. “Many people have been struggling for two to three years, with no end in sight. Finding treatments makes humanitarian and economic sense. The lack of urgency is profoundly unethical and irrational.”
Eric Topol said he expected the NIH would have launched many large-scale trials by now. It hasn’t launched any and won’t launch its first until late summer – that is, if it finally meets its target. Even conservative scientists like Akiko Iwasaki have, in the face of all the suffering people, thrown out the standard playbook.
“I’m a basic scientist. I’d like to figure out the disease before treating anything. But at this point, I don’t think we have that kind of time or luxury. I think we have to start doing clinical trials and learning who benefits and how to improve these therapies,”
RECOVER’s slow but steady approach is not going to excite many, but it does appear to fit within its mandate – to provide definitive results by employing sizeable studies/trials that use a standard methodology. The downside of that approach is that is so resource-heavy that in the end, it may not explore as many corners of an issue as one might like.
The Five Clinical Trials
The long COVID community wants dozens of clinical trials – RECOVER gave it five. It was ironic hearing Dr. Hernandez acknowledge the community’s needs during RECOVER’s recent webinar, as it rolled out its minny package of clinical trials.
“Hey, we need answers now. We need interventions so we’ll improve someone’s health, their function, their quality of life,” how to do things in parallel? So having all this available to develop some of those answers is really critical because I don’t think anyone in this community is really excited about serial answers that take decades.”
The five trials are:
- Viral persistence – Paxlovid – 900 participants – late summer – It was good to see Paxlovid, but it was an obvious choice. Still it has potential. Grade- A
- Brain fog (cognitive dysfunction) – 315 participants – cognitive retraining – late summer – they didn’t say what kind of cognitive retraining but RECOVER is clearly thinking neuroplasticity which we all know can help some people and doesn’t help others. One website reported: a “2013 review suggests that CRT may be effective for mild cognitive impairment” but that “it can be an exhausting and time-consuming process.”…Ouch… Grade- C
- Sleep disturbance – hypersomnia (too much sleep) – 474 participants – drugs and behavioral training – fall – this was a surprise. While hypersomnia, of course, does happen in ME/CFS, unrefreshing sleep is much more common. (Is this a difference between long COVID and ME/CFS?). One study found hypersomnia in only 3% of long COVID participants (!). Behavioral techniques will surely play a large part and they should be helpful. We really need RECOVER’s data on hypersomnia. Grade- C-
- Autonomic dysfunction – 360 participants – immunotherapies and behavioral training – later this year. The fact that immunotherapies are involved was different and rather exciting. Other aspects of treating autonomic dysfunction will be involved. This trial should actually be quite helpful, as dysautonomia is not well-known or well-treated in the medical field, and positive results should be helpful in spreading the word. That said, dysautonomia is a large field with many potential treatments. Grade- potential A
- Exercise intolerance – 360 participants – exercise therapy – controversial, not needed, not particularly helpful even if it were to provide benefits. Grade- F (see below)
It’s not that these trials are all bad; it’s just that RECOVER stopped there. That it didn’t include low-dose naltrexone which is used widely across ME/CFS, FM, and long COVID and could really use a well-done trial was shocking.
RECOVER could have launched a series of small pilot trials. LDN, Guanifacine, gut enhancement therapies, many different kinds of immunotherapies, metformin, Abilify, anticoagulation/antiplatelet therapy, apheresis, stellate ganglion block, antihistamines for MCAS, herpes virus antivirals – the list of potential treatments goes on and on.
Michael Peluso and his colleagues at the Long Term Impact Infection with Novel Coronavirus (LIINC) hope to produce a series of small but intense clinical trials of immunotherapies to: a) see what works and b) to learn about what’s happening in long COVID.
The idea is that as you perturb the patient with a treatment, then study them intensely, and learn about the disease that way. That worked great in HIV and that’s the kind of work one might have expected the money-rich RECOVER Initiative to employ.
The Exercise Intolerance Trial
RECOVER’s mostly rather dull stabs at treatment were hardly exciting, but they made some sense. It’s with the exercise trial that one really starts to wonder. If RECOVER had to go back to the drawing board 6 months or so into the planning stages of its exercise trial because it realized – whoops – that exercise might produce some negative effects in some participants – it clearly hadn’t done its homework.
The way RECOVER clapped itself on its back for contacting post-viral disease researchers suggested it wasn’t too fond of the homework idea.
“We’ve had input from clinicians, those who are taking care of patients with long COVID every single day, as well as researchers who know things about design of clinical trials, for example, and who have had prior experiences with taking care of people with postviral syndromes and even researching postviral syndromes themselves..”
That was not a given? As we’ll see, apparently, it wasn’t. Dr. Hernandez started off with what will turn out to be a theme: we don’t know that long COVID is exactly like ME/CFS – so we’ll proceed as if it’s not.
“So I think these are examples where people are trying to translate what’s been the prior research scenario, but also noting that we may or may not know fully what the exact overlap is with long COVID, PASC, and MECFS.”
When exercise, gut, small fiber neuropathy, herpesvirus, cortisol, autonomic nervous system, blood vessel, coagulation, brainstem, results are similar – don’t we really know enough to conclude that the ME/CFS-like group of long-COVID patients is very, very similar to ME/CFS?
Dr. Eldrin Lewis – a Stanford cardiologist who specializes in heart failure – continued the theme, stating that the PEM in that the PEM in long COVID was “in many ways” different from that in ME/CFS.
That’s news. One study which directly compared PEM in both conditions found similar rates of the core symptoms of ME/CFS (fatigue, muscle and joint pain, infection and immune reaction, neurologic and gastrointestinal symptoms, and orthostatic intolerance) in both. Long-COVID patients did report more sleepiness, respiratory issues, depression and anxiety, irregular body temperature, and excessive thirst, but the core symptoms were the same as in ME/CFS. The study concluded that “People with Long COVID experience PEM that is the hallmark of ME/CFS”.
Lewis clearly isn’t so sure about this PEM stuff. As he backed away from having people with severe exercise intolerance participate in this exercise trial, his wording suggested that he clearly believed they would show up in later trials: “what we don’t want would be to have people who have severe PEM as an initial component of this trial”.
Lewis noted how the cardiology field started off low and slow with heart failure patients and exercise and worked their way up. In doing so, he negated the recommendations of the CDC, and in particular, the consensus of UK, and Dutch research establishments which poured millions of dollars and decades of effort into graded exercise therapy in ME/CFS – before abandoning it altogether.
- The RECOVER initiative for long COVID is on the clock! Patients have been clamoring for clinical trials – many clinical trials – for over a year. Eric Topol thought RECOVER would have launched many clinical trials by now. In a recent webinar RECOVER gave the long COVID community….five.
- RECOVER is a bit stuck. it doesn’t know what’s causing long COVID and appears to be wary of moving forward on the clinical trials front until it does. This isn’t necessarily a bad strategy. RECOVER may simply be hoarding its resources until it feels it has a better grasp on long COVID.
- it will not please long COVID patients, though, some of whom have been suffering for years, and who see plenty of possible, if unproven treatment options.
- RECOVER’s five clinical trials – which it expects to launch starting in the end of summer include Paxlovid, neurocognitive retraining, drugs and behavioral treatments or hypersomnolence, drugs and other therapies for dysautonomia and graded exercise for exercise intolerance.
- Paxlovid was an easy and good choice. So was attempting to treat dysautonomia – which few doctors know how to treat. Hypsomnolence seemed like a strange choice as it hasn’t been identified as a major problem in long COVID yet. Neurocognitive retraining (employing neuroplasticity) will probably not wow people who want their brain fog solved but it may help around the edges. The exercise study was the one big boner – it was a huge fail.
- RECOVER’s choices were conservative indeed and tended to focus on behavioral adjustments to long COVID. The exclusion of low-dose naltrexone, which is widely used by many doctors to treat ME/CFS and FM, was disappointing. Many other potential treatments – anticoagulants/antiplatelets, Guanifacine, immunotherapies of all types, metformin, herpesvirus antivirals, apheresis, stellate ganglion blocks were discarded.
- RECOVER’s extreme conservatism is highlighted by the small but intense trials of immunotherapies Michael Peluso and his colleagues at UCSF hope to get underway. Their goal is to use these trials to a) find treatments that help and b) to understand what’s going on in long COVID. The idea is to perturb that patient with a treatment and then study them intensely to see what happens. That’s a creative approach to long COVID – the kind of approach one hopes we’ll see at some point from RECOVER.
- A central theme that ran through the webinar was that long COVID is in important ways not like ME/CFS, and that RECOVER shouldn’t rely on ME/CFS studies – particularly regarding exercise – to inform the RECOVER initiatives approach.
- This contradicts everything we know about long COVID and ME/CFS thus far – including the results of the exercise studies. Ignoring the decades of work that have explored the exercise issue in ME/CFS and which culminated in the field abandoning the idea of graduated exercise, one RECOVER representative likened the exercise issue in long COVID to that of beta-blockers or exercise in heart failure. Both were believed to be harmful but studies later found them to be helpful.
- We just don’t know, he said, that ME/CFS is exactly like long COVID – so we have to give exercise a try. All indications including cardiopulmonary tests – indicate that it is, of course,very much like long COVID but never mind that – RECOVER is going to spend its time and money reinventing the wheel.
- The decision to exclude those with severe exercise intolerance from the exercise studies means RECOVER is not going to address deconditioning – a primary reason for exercise trials. So what is RECOVER going to address? One of the few factors left are anxiety and depression – suggesting that RECOVER believes the exercise intolerance is a result of anxiety and depression.
- RECOVER’s go-slow approach is not going to sit well with many but it has its advantages. Theoretically RECOVER’s enormous purse means it has the resources to explore long COVID thoroughly. Once it settles on some core findings it can then bring more resources to bear on them with potential treatments. At some point, though, it needs more creativity to bear on this condition.
- RECOVER’s slow as mud approach is generating some flack leading a powerful Congresswoman to ask RECOVER for answers.
- It’s getting tiresome repeating this but we’re still early in the game and this huge initiative is still getting its feet off the ground. We should know much more about it over the next year.
The difference, of course, is that we’re not relying on educated guesses with ME/CFS. The exercise studies have been done – some of them much bigger than what RECOVER is planning – in ME/CFS and exercise therapy was an active feature of ME/CFS research for decades. Unless long COVID is fundamentally different than ME/CFS, the results – which were mediocre at best – are going to be the same.
Hernandez echoed Lewis’s skepticism that the ME/CFS-like cohort of long COVID is going to react to exercise therapy like ME/CFS patients did. “Should we” he asked, “just assume something on this way that it won’t work or it will work or this and that?”
It depends. If you have unlimited amounts of time and money. the answer might be yes, you make sure everything is tightly wrapped up and has a little bow on top before you take a step forward. If resources are limited – and we know they are – and people are suffering – maybe it’s time to make some educated guesses rather than reinvent the wheel.
Does RECOVER Believe Long COVID is Depression?
The exercise issue brings up a disturbing question: Do Hernandez and Lewis believe the exercise intolerance found in long COVID is actually depression? Exercise, after all, is helpful with depression. Is that what they’re actually trying to treat?
A logical fallacy is present. If RECOVER is trying to reverse deconditioning – the only physiological reason for an exercise study that I can think of – it would logically focus on the deconditioned segment of long COVID i.e.; people with severe PEM. That is the very group of people, though, who are being excluded from the study.
If RECOVER is going to focus on people with mild PEM, who are likely not deconditioned, how do they expect them to benefit? It’s true that exercise can benefit many diseases (diabetes, asthma, arthritis, back pain, anxiety, depression, osteoporosis, heart disease), but the only diseases in that list which regularly occur in long COVID are depression and anxiety. In none of those diseases have multiple studies found evidence of a metabolic dysregulation that interferes with energy production.
Is RECOVER hoping that exercise will produce some sort of psychological boost? Is that why they’re doing this study?
It wouldn’t be that surprising. Despite the fact that there’s no hint of cardiac problems in ME/CFS-like group of long-COVID patients and lots of evidence of autonomic nervous system problems, RECOVER is top-heavy with cardiologists and very light on autonomic nervous system specialists.
That doesn’t make sense in a disease where the biggest subset of long-COVID patients have dysautonomia but it does make sense if you look at the RECOVER Initiative as a kind of big boy network where people already in the network get first preference, whether they fit the bill or not.
Take Lewis. He’s well-published in the cardiology field – hasn’t published anything on the autonomic nervous system, apparently doesn’t know or care about the exercise trials in ME/CFS – and thinks the two diseases are radically different anyway. Lewis noted how helpful exercise is in heart failure as a justification for using it in long COVID. Could it be as simple as Lewis thinks – well it works in heart failure, why not long COVID? Let’s hope not.
Time will tell. If the PEM in long COVID is fundamentally different from that of ME/CFS, RECOVER may be right. Nothing thus far suggests that, though.
RECOVER is getting pushback from Congress over its go-slow approach. STAT News reported yesterday that Rep. Anna Eshoo – an ME/CFS supporter – who sits on the committees that oversees the NIH (House Energy and Commerce Committee) sent a letter to NIH acting Director Lawrence Tabak asking what the heck is going on with clinical trials, among other things.
A case can be made for the RECOVER Initiative’s go-slow approach to clinical trials. In this scenario RECOVER investigates a few things that might modestly help long-COVID patients now and saves its resources for when it has more insights into the pathophysiology of the disease.
That’s an understandable strategy. People in the ME/CFS community know no magic bullets exist right now. Yes, some people are helped mightily by some things, but they tend to be in the minority. The really effective treatments probably lie in the future.
Theoretically, RECOVER should bring us more closely to that future than any other effort, but doing so will require more creativity and a greater tolerance for risk than it’s shown to date.
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