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The GIST
The Blog
Thanks to John Bolecek for putting together this thought-provoking blog. A former Statewide Bicycle and Pedestrian Coordinator at the Virginia Department of Transportation, John was in great shape before he came down with long COVID and is now disabled. Check out John’s story “A life derailed by long COVID“.
This is a call for the NIH, FDA, Congress, and private donors interested in long-COVID clinical trials to come together, fund, and select a well-designed, meaningful slate of clinical trials.
The RECOVER Initiative’s low-risk, low-reward treatment trials have failed to impress. Here’s what it could be doing.
On February 13th of 2024, the National Institutes of Health (NIH) announced an additional $515 million for the RECOVER initiative to study long COVID. The NIH has largely fumbled the use of the money allocated so far, spending it mostly on observational studies that haven’t produced useful data yet, and failed to do even the most routine autonomic testing on all participants. (Only 20% of the cohort will undergo any autonomic testing.)
The slate of clinical trials the NIH has chosen is also weak and has been criticized previously. The NIH must use this new money wisely and expeditiously.
Many patients have been disabled over 4 years now. With limited time, money, and institutional capacity, trialing ineffective drugs will have a huge opportunity cost. Unfortunately, RECOVER funding is for one time use and, although desperately needed, there is no permanent program providing a yearly source of funds for long-COVID research.
The FY25 appropriations process is currently underway in Congress. Since NIH has moved so slowly and ineptly, Congress should consider naming specific drugs to trial and allocating additional funding for future trials to agencies other than the NIH, such as the Congressionally Directed Research Funds in the Department of Defense, the Advanced Research Projects Agency for Health (ARPA-H), or as Senator Marshall suggested during the Long COVID hearing in the Senate HELP Committee, the Biomedical Advanced Research and Development Authority (BARDA).
THE GIST
- With the RECOVER Initiative’s initial funding ($1.15 billion) about to run out, the Initiative was handed a $500 million lifeline from the Biden administration. Whether RECOVER deserved such a lifeline is beyond the scope of this blog, but suffice it to say, the Initiative has impressed no one and its initial slate of clinical trials received much criticism.
- With the tenuous funding state RECOVER is in, it behooves the Initiative to make the maximum use of its dollars. Thus far, it has spent the lion’s share of them on rudimentary observational studies that have failed to produce any insights, thus putting more pressure on RECOVER to deliver with its clinical trials.
- RECOVER, however, continued its conservative bent by focusing mostly on low-risk, low-reward clinical trials. RECOVER was so behind the eight ball on its proposed exercise study that it was forced to postpone the study for a year and rejigger it. In its current iteration, people with post-exertional malaise will not be in the exercise portion of the study and people with PEM will instead engage in pacing. This 1,200-person may cost as much as $50 million.
- In a similar vein, RECOVER is spending enormous amounts of money to study low-risk, low-reward treatments such as cognitive retraining, sleep hygiene, melatonin and light therapy for sleep that are well known and readily available. Its stimulant, transcranial magnetic stimulation, Ivabradine, Paxlovid and IVIG trials are more welcome, but all these treatments have been tried in ME/CFS and it is unlikely any will prove particularly helpful for more than a subset of patients.
- RECOVER’s conservative, low-risk / low-reward approach to long COVID meant that it missed the chance to provide substantial help to long-COVID patients. By putting all its eggs in the big trials basket, RECOVER missed the chance to assess a wide variety of drugs in smaller trials that could have paved the way for real success. Check out the blog for a list of them.
Long COVID is a broad term describing any sequelae from a COVID-19 infection that persists for more than three months, including symptoms like persistent cough or loss of smell. The more serious, disabling versions of long COVID limit the amount of physical and cognitive activity patients can perform. Post-exertional malaise (PEM), the worsening of symptoms and capacity following even minor physical or mental exertion, limits many patients from functioning because they crash and can potentially decline after performing even basic activities of daily life.
The ability to increase cognitive and physical exertion without PEM should be the end point of a successful trial. Devices that track heart rate, sleep, daily steps, and heart rate variability (HRV) can provide a more complete picture of a patient’s recovery than patient-reported surveys and six-minute walk tests.
Ranked from worst to best; the reported RECOVER trials are listed below:
RECOVER has grouped their interventions into various categories. The first categories include RECOVER-VITAL, RECOVER-AUTONOMIC and RECOVER-NEURO which have details on the website. RECOVER-ENERGIZE and RECOVER-SLEEP were announced on May 8th, 2024 and now have ClinicalTrials.Gov pages. The list of drugs below may not be complete as it only reflects the current public disclosures from the NIH and the reporting in the STAT News article titled, “Underwhelming’: NIH trials fail to test meaningful Long COVID treatments — after 2.5 years and $1 billion”, from July 2023.
Terrible
RECOVER announced its initial exercise trial before doing its homework, forcing it to backtrack for a year. In a turnaround, the 1,200-person trial will not trial exercise in people with post-exertional malaise. People with PEM will get pacing.
Exercise – Accessible and cheap – and recommended by most doctors – most long-COVID patients have undoubtedly already tried to exercise their way out – sometimes with the help of a physical therapist – of their illness.
Most long-COVID patients who are disabled, are so precisely because their ability to exert is limited by PEM. A recent study in the Netherlands showed that in long-COVID patients with PEM, exercise damages the muscles with increased amyloid-containing deposits and worsens their metabolism compared to controls. Graded exercise therapy has repeatedly shown to not work in those with PEM, yet RECOVER was adamant it was going to do an exercise trial.
How lost was RECOVER with regard to PEM, exercise and long COVID? RECOVER appeared to be caught off guard by the pushback from the ME/CFS and long-COVID communities when it announced the study over a year ago. STAT News reporting suggested that RECOVER, at least initially, wasn’t clear on or even interested in this strange post-exertional malaise (PEM) symptom.
The outcry caused RECOVER to retrench, and we’ve been in a holding pattern since then. RECOVER released the details of its long-awaited exercise trial a couple of days ago. Ultimately, it got the message – people with PEM will not take part in the exercise trial – but will participate in a pacing trial.
Trial funding is not available, but AI Copilot estimated that a 1,300-person clinical trial will typically cost about $50 million to try to increase activity in a group for whom exertion is not a problem and to assess a simple and well-known lifestyle change in patients for whom it is.
Brain training game software – This is akin to telling patients who can’t think clearly to play computer games to try to think better. Most importantly, it doesn’t address the most functionally limiting factor with regard to “brain fog” – the cognitive exertion problem that makes it impossible for many people with these diseases to work.
Goal management training (PASC-CoRE) – A series of virtual meetings where “trained study staff will help participants, plan and manage personal goals, learn mindfulness-based ways to work through distractions, learn skills to focus attention on goal-oriented tasks, and develop strategies to manage mental tiredness.” Goal management has nothing to do with treating an energy limiting, neuroinflammatory disease and it is hard to imagine a more insulting list of recommendations.
Weak
RECOVER will determine if sleep hygiene – a well-known approach to sleep – helps.
Facing fierce criticism for its delay to producing trials in July of 2023, RECOVER provided information on five clinical trials. The sleep trial (474 participants) was slated to begin last fall, but only in the last week has RECOVER released the final protocols. The focus was going to be hypersomnia (too much sleep) which is found in ME/CFS, possibly in the earlier stages of the illness, but does not appear to be common.
Educational coaching for sleep – Sleep hygiene information is free and accessible, a Google search away. RECOVER underestimates the number of treatments the average patient has tried to get better sleep. Trying sleep hygiene is a logical first step that any sleep doctor or PCP will suggest.
Melatonin – Accessible and cheap, many patients have already tried melatonin. While it may help some fall asleep, it often does not help patients stay asleep nor does it treat unrefreshing sleep.
Light therapy – If something so accessible and cheap worked, we would know about it. Unfortunately, some patients are so severe, they are sensitive to both light and sound.
Middling
Pacing is already a well-known approach in both the ME/CFS and long-COVID communities.
Pacing – Presumably added to RECOVER-ENERGIZE due to criticism of the exercise trial, this trial is geared towards those with PEM. They will undergo structured pacing to see if it helps their symptoms.
Patients with PEM have learned to pace in their own way, but unavoidable exertions due to work, childcare and other activities of daily living make serious pacing a privilege for most. A management strategy is not exciting for patients, who are looking to regain as much of their lives as possible, but may help further the scientific evidence around pacing.
Transcranial direct current stimulation (tDCS) – NIH claims this is a noninvasive form of brain stimulation. Participants will wear a headset that delivers a mild electrical current to specific parts of the brain to increase activity.
Modafinil and Solriamfetol – Modafinil is a central nervous system stimulant used to combat narcolepsy which results in people falling asleep in the middle of the day, and is also used in attention deficit hyperactivity disorder which may be common in ME/CFS and fibromyalgia (FM).
Modafinil’s stimulation of the sympathetic nervous system seems iffy given the sympathetic nervous system upregulation found in long COVID (and ME/CFS). Modafinil also, though, promotes dopamine production which may be low in long COVID and ME/CFS.
Some ME/CFS studies have shown that stimulants can be helpful and modafinil is on the ME/CFS Clinician Coalition’s list of potential drugs to use (with caution) in ME/CFS. Modafinil may help around the edges, and given the functional issues with long COVID, is arguably worth trying. It will not, however, get at the cause of long COVID.
OK
Paxlovid – COVID antiviral targeting viral persistence. There are already several other Paxlovid trials being run. A trial at Stanford ended early, presumably because of a lack of efficacy. Another at Yale will readout later this spring.
Good
Intravenous immunoglobulin (IVIG) – A pooled antibody used in autoimmune diseases, extremely expensive and inaccessible to patients. The trial is proposing to use a high dose for a long period and has thorough endpoints. Unfortunately, there is a forced exercise component of this trial, no open extension for placebo patients, and an intense regimen of in-person visits that will exclude more severe patients.
Ivabradine – Currently used off-label for autonomic dysfunction. This drug lowers heart rate without lowering blood pressure, an advantage over beta blockers for those with low blood pressure. This drug is still on patent and extremely expensive, with many US patients sourcing from Canadian pharmacies. Getting this drug on label would make it more easily covered by insurance. Uniformed Services University of the Health Sciences (USUHS), a federal hospital in NIH’s backyard in Bethesda, Maryland has already launched and started recruiting for an Ivabradine trial.
What NIH should trial
Instead of spending hundreds of millions of dollars on low reward treatments, RECOVER could be trialing drugs that have a chance at getting at the core of long COVID.
Various papers and groups have suggested lists of drugs to trial for long COVID. Unfortunately, few drug trials are underway. An editorial in the Lancet Infectious Diseases titled, “Where are the Long COVID trials”, published in August 2023 stated, “ClinicalTrials.gov currently lists 386 trials under the search term Long COVID.
However, only 94 of those studies are classed as interventional and are currently recruiting, and even more disturbing, only 12 trials are testing pharmacological interventions. The rest comprise follow-up of trials in acute infection, rehabilitation, food supplements, telehealth, psychological support, physiotherapy, acupuncture, light therapy, Chinese herbal medicine etc.”
Furthermore, public money is needed to target drugs without a profit motive. Additionally, without a single biomarker, patients are potentially suffering from different underlying causes. With the current slate of fiscally constrained, small trials, it is difficult to identify subsets of patients. Public funding would enable otherwise private trials to be larger, and more testing could be done to identify subsets.
NIH should also convene an international group of researchers experienced in treating dysautonomia and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and should solicit ideas from these groups. Some long-COVID patients are lucky enough to respond to similar treatment approaches. This group should include Mark Davis, Derya Unutmaz, Ian Lipkin, Amy Proal, Peter Rowe, Carmen Scheibenbogen, Øystein Fluge, Olav Mella, John Chia, Liisa Selin, Maureen Hanson, David Systrom, Lucinda Bateman, Ron Davis, and Avi Nath, among others.
In no particular order, the following is a list of drugs that should be trialed, grouped by hypothesis.
Viral persistence and reactivation:
These drugs should be trialed alone and in combination.
Ensitrelvir / Leritrelvir – A COVID antiviral, approved in Japan and China respectively, they are 3CL protease inhibitors similar to Paxlovid but with fewer drug interactions, and potentially safer to take for longer periods because they does not contain Ritonavir.
Remdesivir / VV116 – Remdesivir is an broad antiviral drug that is administered intravenously, requiring daily trips to an infusion center, making it difficult to trial. VV116, also known as “Oral Remdesivir”, would make administration of a trial much cheaper and more practical for patients.
Rintatolimod – Trademarked ‘Ampligen’, a drug that targets the TLR3 Pathway to increase innate immune function. A poorly run phase 2 trial that failed to screen patients for post-exertional malaise or use immune function as an entrance criterion did not show statistically significant results; howeve,r several long-COVID and ME/CFS patients report reductions in PEM and the ability to increase activity while they remain on the drug.
Anti-SARS-CoV-2 monoclonal antibodies (mAbs) – May help clear persistent virus. In contrast to oral antivirals, which can only stop viral replication, mAbs could bind to virus particles, replicating or not, and alert T-cells to clear the debris. A small trial testing the mAb AER002 is being conducted at the University of California San Francisco.
Immune checkpoint inhibitors – Checkpoint inhibitors like PD-1 inhibitors, combat T cell exhaustion. There is a potentially risky safety profile for those who may have autoimmunity. Recently mentioned in the NIH ME/CFS intramural study, and by Liisa Selin, and Maureen Hanson at the 2023 Invest in ME conference.
2-thiouridine – A broad-spectrum antiviral drug candidate that targets positive-strand RNA viruses like SARS-COV-2.
Immunomodulators
Anti CD-19, Anti CD-20, Mycophenolate, Tacrolimus, Jak/STAT inhibitors, IL-1 Blockers, IL-6 Antagonist, and TNF-Alpha Inhibitors – Drugs floated by Avi Nath, Clinical Director at Senior Investigator and Clinical Director at National Institute of Neurological Disorders and Stroke at NIH. He has suggested these immunomodulating drugs be tested in ME/CFS and long COVID in a platform trial.
Baricitinib (Olumiant) is a JAK1/JAK2 inhibitor with antiviral properties. Wes Ely MD is in the midst of a large baricitinib long COVID trial that does not need more funding but Ely’s trial is listed here as an example of the kind of creative approach to long COVID that the RECOVER Initiative did not pursue.
Bacille Calmette-Guerin (BCG) vaccine – Used as an immunotherapy for cancer. Case reports and a paper have outlined a hypothesis on how it might work for long COVID. One person with ME/CFS recovered using the vaccine.
Autoimmunity
BC007 – An oligonucleotide aptamer that neutralizes G protein-coupled receptor autoantibodies. Originally developed to treat heart failure in dilated cardiomyopathy by removing functional autoantibodies. A case series in Germany showed significant improvements in four long-COVID patients. A phase 2 trial is underway in Europe.
Rituximab, Cyclophosphamide, and Daratumumab – Drugs used in cancer. Øystein Fluge, a Norwegian doctor and researcher in the Department of Oncology and Medical Physics at the University of Bergen who splits his time between cancer and ME/CFS patients, has run trials and observed improvements with these drugs in subsets.
Anti-FcRn drugs and IgG degraders – Drugs that work by preventing the recycling of IgG antibodies back into the blood. Efgartigimod, a medication approved to treat myasthenia gravis, currently in a Phase 2 trial to treat post-COVID POTS, does not need another trial; however, other candidates for trial include Rozanolixizumab, Batoclimab, and Nipocalimab.
Autonomic Dysfunction:
Pyridostigmine, Midodrine, Fludrocortisone, and Desmopressin: FDA approved drugs currently used off label for POTS. The private sector has no incentive to trial these drugs, and therefore, a public effort is needed to get these drugs ‘on label’ which would increase access for patients by ensuring they are included in medical school curriculums, more easily covered by insurance, and that primary care physicians know about them. Pyridostigmine is being trialed with ME/CFS in an Open Medicine Foundation-funded trial and was able to promote energy production during an exercise test.
Various:
ASHA-091 – A drug that works as a mitochondrial fragmentation inhibitor. Asha Therapeutics may run a long-COVID trial.
Omalizumab – Trademarked ‘Xolair’, some long-COVID patients have Mast Cell Activation Syndrome (MCAS). A trial should be run to see if those patients with high urine or serum tryptase benefit from this expensive monoclonal antibody. Formerly approved for allergic asthma, this drug was recently FDA approved to also treat food allergies.
AMX0035 – A combination of sodium phenylbutyrate and taurursodiol. Targets both the endoplasmic reticulum and mitochondria. In the fall of 2023. NIH published a paper that found high levels WASF3 in those with ME vs controls. A clinical trial for ME/CFS has been floated but not started. Long-COVID patients should also be tested for this protein and included in trials if they also have elevated levels. This drug is approved for ALS, but the drug was pulled based on poor results from a phase 3 trial.
Glymphatic flow stimulation – Some studies suggest COVID can impact glymphatic flow. No one has deeply studied the role of glymphatic flow in long-COVID sleep. Can drugs or other techniques that increase gymphatic flow treat unrefreshing sleep?
Dextro Naltrexone – A stronger form of low-dose naltrexone which temporarily blocks pain receptors, encouraging the body to produce more endorphins. Some patients experience a mild or moderate amount of relief from low dose naltrexone. While low dose naltrexone is not a cure, and although not effective for some patients, a trial should be run to understand the pathway and why this drug works for some subsets. Dextro naltrexone is not an available drug and patients do not currently have access to try it. Jarred Younger believes he will be able to get a trial underway in the near future.
Low-dose Aripiprazole – An antipsychotic and putative anti-neuroinflammatory at low doses, Dr. Bonilla at Stanford published a retrospective study in 2021 of its use in 101 patients at the Stanford University ME/CFS clinical practice.
Vagus Nerve Stimulation – A recent study from the University of Oklahoma shows that vagus nerve stimulation improved autonomic function in a group with POTS. While not a cure, a large trial should be run to see if this can provide some relief to patients.
Thanks to Stephen Smith of @postviraltrials for providing input on trial suggestions
Thank you for the interesting article, John. Autonomic dysfunction is my pet subject – nice to see ot well covered. Judging by forum posts, many patients still aren’t receiving even the most basic autonomic assessments, like a NASA lean test.
I only recently learned about the glymphatic system. Research there could be so helpful. Maybe there is a connection between cerebrovascular dysregulation (found in LC, ME/CFS, and of course some types of dysautonomia) and glymphatic dysfunction.
Can we put you in charge?
We have found that thorough lymphatic drainage — especially of the head, face and neck — reduces brain fog in my daughter w/ ME/CFS. This is consistent with the argument that there is impaired glymphatic function in at least some people w/ ME that is affecting cognitive function. In my daughter, we have seen impaired lymphatic function throughout the body, particularly in the months after a relapse. It would be really helpful to see trials focused on: (a) reducing vascular permeability and (b) improving lymphatic function.
The Perrin Technique ?
We’ve found some of the techniques described in the Perrin technique to be helpful. We’ve improvised from there.
I second that, SarahTee – can we put you in charge, John?!
Third that. I hope the people in charge at NIH and Recover get their hands on this article… obviously they need help from educated and experienced mecfs patients. Well here it is! Do this.
Thanks. I don’t see why 100% of the RECOVER cohort could get tested just using a simple 10 minute stand test at the initial visit.
Personally, it doesn’t feel like my glymphatic system is working and washing my brain or repairing my muscles overnight as I wake up in pain feeling awful every morning.
Yes, it’s relatively safe, inexpensive, and doesn’t even require a doctor for the data collection.
On a personal note, I hope you’ve been able to get help with your own autonomic symptoms.
I was unwell with an autonomic condition for many years before taking matters into my own hands and getting diagnosed. Despite me repeatedly complaining of feeling faint, no-one took my blood pressure standing up for the first 15 years.
I too had postprandial symptoms, and no-one suggested checking my heart rate or blood pressure during these episodes either.
I went through rounds of useless tests and specialist appointments.
It is amazing how little doctors know about orthostatic intolerance. Some cases are complex, yes, but many can be elucidated by checking vital signs, surely from Day One of medical school.
Thanks for all the helpful suggestions! I would recommend taking fludrocortisone off the list. It made my daughter much worse, triggering long-lasting MCAS. I suspect the problem was that the increased fluid volume contributted to increased intracranial hypertension / brainstem compression. She has spinal complications, so it’s possible there is some interaction with her complex chiari.
I recognize that some benefit from Fludrocortisone. But we need to be careful with drugs that can make a signficiant portion of people worse.
Isn’t that something! Increasing blood volume made her intracranial hypertension worse. It makes sense but illustrates how complicated treating these diseases can be. I don’t know if anything is going on with assessing intracranial hypertension or spinal abnormalities in long COVID.
I agree it’s really complicated. But we need hypotheses that account for these variations in response. For what it’s worth, my working hypothesis these days is that vascular hyperpermeability plays a key role in ME and ME-type presentations of Long COVID. Inflammation and vascular damage both independently and in combination increase vascular permeability, leading to the release of protein-rich fluid (or even in extreme cases blood) into the extracellular space. Something happens to impair the lymphatic system — possibly the fibrin in the protein-rich fluid, which forms a gel that can obstruct the lymphatic and glymphatic system. Without a way to exit the body, the fluid builds up, leading to hypoxic conditions, formation of subcutaneous adipose tissue, and, in the brain, increased intracranial hypertension and irritated microlglia. The increased blood flow and velocity that comes with physical and mental exertion makes things worse by leading to increased vascular leakage. Individuals with spinal issues that impair CSF outflow may suffer the worst, as the body cannot relieve the intracranial hypertension. Surgery can help by improving CSF outflow but it’s very risky. A better solution would be to figure out how to stop the vascular leakage, heal the vascular damage and fix the lymphatic system. Just my two cents . . . I’ll talk about this a bit at Unite to Fight 2024.
Meant to say “extravascular space,” rather than “extracellular space.”
Really interesting hypothesis. Also think we should not be trialing immune checkpoint inhibitors given the complex and not fully understood immune situation in long COVID and post-infectious illnesses, could make things much worse.
This is a great list – I’d love to see everything here trialed! Thanks for putting it together. A couple of notes:
– UC San Francisco has just begun a trial of Ensitrelvir (Japanese SARS-CoV-2 antiviral). It’s a short, small study designed to quickly identify signal but I’m looking forward to seeing the results. https://clinicaltrials.gov/study/NCT06161688
– A couple months ago, I collaborated with The Sick Times to review the current state of Long Covid trials listed in ClinicalTrials.gov. It’s similar to the analysis you cited from The Lancet but a bit more up to date. The good news is that the number of trials registered has increased, but the bad news is that they are still overwhelmingly not testing appropriate interventions – and many suffer from poor design. https://thesicktimes.org/2024/03/26/want-to-enroll-in-a-long-covid-clinical-trial-this-new-project-helps-track-them/
Interesting – I had not heard of Ensitrelvir (Japanese SARS-CoV-2 antiviral) before. This is the kind of small, potentially high reward study that RECOVER for some reason is not doing. I understand the need to have large trials but why not throw some smaller more experimental trials in there?
It truly boggles the mind! The UCSF team has been doing an exceptional job with limited resources in these kinds of trials. They have been putting together funds from PolyBio, PLRC, and their existing grants to not only run these trials but also set up imaging and tissue collection programs to make these trials more impactful. I’m in the Ensitrelvir trial and, and I am doing PET imaging (to identify T-cell activation), a gut biopsy, and a lumbar puncture before and after the trial. This is exactly the kind of costly/labor intensive trial design that the NIH ought to fund. And the kind of platform that would be well-poised to include ME/CFS and other comparator cohorts.
Imaging substudy details: https://polybio.org/projects/use-of-total-body-pet-imaging-to-identify-deep-tissue-sars-cov-2-viral-reservoirs-and-t-cell-responses-in-patients-with-long-covid/
Tissue collection substudy details: https://polybio.org/projects/liinc-pasc-tissue-program-a-multimodal-assessment-of-the-tissue-based-virologic-drivers-of-long-covid/
Reading this brings up some really conflicting emotions. Excitement at what PolyBio/UCSF are doing with their limited resources mixed with dismay at what RECOVER could be doing but apparently is not. It’s a bit painful
I reported in my last blog that except for one test, RECOVER has not made any changes to their testing protocol. Surely by now they know what tests are a waste of time and money?
Where is the nimble, flexible RECOVER we were promised?
Thanks for compiling those trials Erza. I learned about an exercise trial happening in Charlottesville from your site, another patient contacted them and promptly got it canceled!
It would be so much better if the RECOVER had Ensitrelvir and VV116 arms instead of replicating the other Paxlovid studies.
I’m currently enrolled in the Hopkins arm or a RECOVER study involving Paxlovid. I’m just so relieved to see that some of the brightest minds in the world are working on this!!
I’m surprised I see no mention of rapamycin. That is the only thing that got me back up on my feet and able to tolerate light and sound again. I say every time it has saved my life! I know everything doesn’t work for everyone, I tried several things and most made me worse. Low dose Abilify seems to help lots of people and it made me horrifically worse. I am so very grateful for the opportunity to be on rapamycin. I have moved across the country for better healthcare, but my doctors are not familiar with it for anything besides kidney transplant folks and don’t want to prescribe it. I literally cannot live without it. I’ve pointed them to the trial through Simmaron Research, fingers crossed my doctor will write the script for me and continue to allow me to have life.
I’m not sure if you’ve seen the Every Cure story from Dr. David Fajgenbaum, but he uses Rapamycin (Sirolimus) to treat Complex Multisystem Castleman’s disease. It literally saved his life as well. He wrote a book about finding a drug to repurpose to put his disease into remission called Chasing My Cure.
Yes, thank you. He is doing such amazing work trying to get off label/ repurposed drugs quickly trialed and FDA approved to help folks.
So glad rapamycin has helped you – you will find a doctor to help, with persistence…
Unfortunately, a 9 month trial of low dose rapamycin suppressed my immune system and led to reactivated HHV6. Each of us is unique and what will work may be different.
I’m so very sorry to hear that. Were you taking it daily or once weekly? I take my dose all at once, once a week and in that way I avoid any and all side effects, thankfully.
Rapamycin could haved been on this list and other possibilities have already come up – which is nice.
Good to hear particularly for people who tend to react negatively to treatments that it is possible to find something that works. We have a blog on someone who had a similar experience. Rapamycin checks quite a few possible boxes.
https://www.healthrising.org/blog/2022/07/06/apamycin-resurgence-doctor-chronic-fatigue-syndrome/
Yes, I read that, thank you. I read absolutely everything that you write as soon as it is available and hang on every single word! I am so very grateful for all that you provide for our community. You are my number one go to for information!
By the time these trials complete, groups with shoe-string budgets like PolyBio and UCSF will have found effective treatments and patients around the world will be requesting them with their PCP.
RECOVER is the next big dig. A complete failure and waste of our tax dollars.
ARPA-H or even direct special public/private institution grants would have been by far more effective.
Here is the original publication where you can sense the “divide” of the participants and what would be effective and what would not be.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034329/
They continue to fail to prioritize what is important to patients and leading researchers. Where is the Long COVID therapeutics board which is comprised of actual hardcore researchers and not paper pushers?
RECOVER could fix all this by attending the two Long COVID conferences next week and establishing actual collaborative relationships with leading researchers and patient-researchers.
To see articles like this published in Nature goes to show how little faith even leading patient-advocates have in the initiative:
https://www.nature.com/articles/d41586-024-00901-3
I hope you’re right about PolyBio and UCSF. You may be. Time will tell – the RECOVER saga is not done yet – but thus far it looks like the NIH did its best with RECOVER to remind everyone why so many people are pushing efforts like ARPA-H. Let’s hope RECOVER turns it around.
We need large, never been done before initiatives like RECOVER, but they have completely missed the forest for the trees and severely lack ambition/urgency.
It saddens me to regularly hear even well-respected scientists and science journalists disheartened by RECOVER’s potential and the lack of collaboration is clear as day as a patient-researcher.
There are positive things yet to come from RECOVER such as its large omics initiative, biospecimens biobank, EHR sharing, and funding vital projects to answer the remaining questions. But many groups have been forced to create their own programs because of the lack of collaboration/openness.
Their clinical trial platform, if opened up to more collaboration could be used for rapid, iterative, and adaptive clinical trials or even target trial emulation so we don’t waste significant amounts of money and time trying the wrong things.
Hoping RECOVER turns around. I email their leadership & PIs regularly to drop the silos and collaborate with leading researchers & research-informed patients. To get more involved in the public narrative to build empathy.
For what it is worth, I did interview with ARPA-H over a Long COVID program I pitched regarding fast, iterative novel/existing therapeutics akin to many in this post & in BARDA’s NextGen pipeline. They were super interested but this was around the time ~$500M was infused into NIH and the program didn’t gain enough traction to proceed.
Big results require big ambitions.
Great comment Jon. Thanks for your advocacy around this.
RECOVER is playing out just about as I predicted, repeating what’s been going on with ME/CFS. And the exercise/pace trial appears to be no more than a repeat of PACE.
Antivirals, immunomodulators and autoimmune drugs also have been tried and failed for ME/CFS though, and I don’t see a point in repeating more of the same hoping for a different result. LDN, on the other hand, hasn’t been trialed for ME/CFS. They should do a large trial, perhaps for dextro naltrexone. If it fails, we could at least write off microglial hypothesis and move on to the next one.
The problem with many of the trials you mention is that patients with ME/CFS symptoms who may have had a variety of actual problems that were not the same from patient to patient were included in them, leading to poor results.
I know of many ME/CFS patients who have been helped by antivirals, IV immunoglobulins, Rituximab, rapamycin, LDN, and other immunomodulating interventions, when prescribed appropriately after detailed lab work identified treatable problems. As these patients were treated, ME/CFS symptoms lessened and disappeared completely. Unfortunately, there are too few doctors knowledgeable, thoughtful and gutsy enough to do this for patients, and the NIH doesn’t seem to be imaginative enough to try this approach. And, from what I’ve seen, no single intervention leads to a cure, but rather, carefully chosen interventions – drugs, supplements, other treatments – applied in a phased approach, can lead to success.
Health Rising has IVIG and antiviral recovery stories on its RECOVER/RECOVERING section. It may be that we simply need big enough studies to uncover who benefits and who doesn’t.
Nath proposed doing platform trials where you test several drugs and I guess have one placebo group. I think that’s how it goes. It sounds like a great way to cut drug trial costs.
Probably as many people have been helped by supplements or diet. We’ll never know if those are coincidence or cause-effects, though. That’s why we do RCT rather than relying on success stories aka anecdotes.
Not that I’m against anecdotes. By all means, people should try on their own if they think it’s safe and cheap enough for them, ’cause you never know. But spending more taxpayers money on failed hypotheses or peddling them as solutions is not the way to go.
This notion of subset, btw, is no more than an ex-post excuse for failed RCTs unless you can identify them ex-ante so that you can do RCT specifically on them. That they never have means that no such subsets exist.
Exactly. If RECOVER had been done smartly, it would have taken labs and other tests to direct patients into the proper trials.
For example, if they had taken a serum tryptase level for every RECOVER enrollee, they could shunt those with high levels into the Xolair trial I suggest.
If they had done a stand test for everyone they would have already prescreened the best patients to a series of POTS drugs platform trials.
Was about to say something similar. More ‘barking up the wrong tree’ with antivirals etc.
Luckily some people are barking up the right tree! ( eg. Jarred Younger)
Griffith University in Australia is embarking on a trial of LDN as we speak.
Thanks for a very interesting, hopeful, and information-dense article. A sound critique of RECOVER, with lots of alternative possibilities proposed. However I was surprised there was no mention of Stellate Ganglion Block, which a previous Health Rising article indicated as a promising procedure for Long Covid and ME/CFS because it has the potential to reset the autonomic nervous system. Any thoughts as to why we don’t see SGB mentioned here?
This peptide should definitely be trialed:
“In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting ”
https://pubmed.ncbi.nlm.nih.gov/37369668/
Abstract:
“In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.”
Layperson description:
“New drug could treat long COVID and prevent re-infection”
https://www.youtube.com/watch?v=JTYVd9daLAo
I have ordered this peptide from two different labs, they have yet to arrive. I will report when I have tried it.
Antiretrovirals have been used VERY successfully in HIV, and now are found useful in treating Alzheimer’s (!) … I personally know three people with HIV who are far more active and engaged than average with family, friends and community strictly because of these medications… meanwhile I’m bedridden with severe Myalgic Encephalomyelitis and NO HELP from FDA, CDC, etc.
THESE LONG COVID TRIALS SHOULD INCLUDE Antiretrovirals!!! https://www.fightaging.org/archives/2024/05/antiretroviral-drug-use-associated-with-lower-risk-of-alzheimers-disease/
When I read about the additional RECOVER trials recently I just went facepalm. Basically they are ignoring everything from ME/CFS and fibromyalgia that we already know and that we have painstakingly observed over decades of slow progress. The only positive for long COVID is enough people have it and there is enough Congressional interest and pharma interest in it that it likely will get private, if not continued government research funding, unlike fibromyalgia. They are doomed to repeat history by treating long COVID like a totally new unique disease.
Also, RE the BCG vaccine trial – there was a trial for this in fibromyalgia, I believe it was withdrawn but don’t know why. Another repeating of previous attempts but would have been nice to have had results, I guess funding ran out? https://classic.clinicaltrials.gov/ct2/show/NCT03582085
I wonder why studies into ME and now Long Covid are usually designed in such a way that they are doomed to failure. Are the doctors incompetent? Or do the patients know everything better?
I would like to see more research with low dose anti-epileptic drugs. So is benzodiazepine.
With an EEG you can objectively see abnormalities in ME patients.
https://pubmed.ncbi.nlm.nih.gov/21722376/
I think peptides should be in the list. Some ideas are MOTS-C and or SS-31 for mitochondrial and inflammation issues. GHK-cu for connective tissue disorders. There are lots more that can target specific issues and can be stacked for synergistic effects.
They really should be made to have someone from the patient community, Solve, or OMF involved in the decision making process to keep them connected to the reality of the situation
I am simply astonished that anticoagulants get NO mention at all, when they have been shown to work rather well. See links at http://dbkgroup.org/longcovid/.
Thank you again Cort for excellent analysis and writing, and for all the things I learn and better understand as a result.
Reading through this, the drug list is utterly beyond my skill, but I do have one observation.
What we are seeing from RECOVER is what we would see if:
(1) The RECOVER team were researching a disinformation narrative from the existentially terrified (of understanding, biomarkers, treatments) payers of disability income, and had lost touch with the actual patient experience (particularly self aware and self starting patients)
(2) Regulatory capture of RECOVER, but only partial, by those interests had occurred.
It’s very easy to test whether a disease hypothesis is pursuing PEM/PESE as patients experience it, or pursuing the disinformation narrative: at the asymptote, is the PEM/PESE patient bedbound alone in a silent dark room?
I discussed this on Twitter today
https://twitter.com/FStevenChalmers/status/1789893418681872642
belated contribution to #WorldMEDay
Lots of good suggestions in the comments for other drugs I didn’t mention in the piece. I couldn’t include everything and it sort of feels like I picked too many already.
Parallel to clinical trials used to narrow down hypotheses, we need just as much focus into the research of the basic biology of the disease and to try to validate more biomarkers.
Cort, thanks for the list of trials and therapies for Long Covid.
Here is one to add. Hope Biosciences near Houston last October published an Expanded Access trial n=10 of high-dose stem cells that had significant findings. This is a mega dose of Mesenchymal Stem Cells, 5 IVs of 2 x 10^8 (200 million) autologous HB-adMSCs each at week 0, 2, 6, 10 and 14 (1 billion total MSCs)
SF-36 Fatigue/Energy improved 275%
FAS (fatigue) 32.5 dropped to 15.0, improved 54%
VAS (pain) 37.6 dropped to 4.9, improved 87%
Has anyone seen published improvements like this?
A phase 2 RCT n=80 for Long Covid has just completed, topline results end of May.
A phase 2 RCT n=24 for MS will announce topline results this August.
This profile I wrote links to the published Long Covid study, and has a lay-person translation of the statistics.
http://bit.ly/HopeStemCells
The MS community, like others with pre-existing chronic conditions, is suffering further disability and an increase in all cause-mortality from LC. At Solving MS we track all the curative and regenerative therapies in trials for MS, and several also help LC, like MSCs, LDN, Rituximab. We use Google Sheets so no programming is required, and we score them, weighted by closest to approval. You might try this approach to keep track real time.
https://solvingms.org/research-database
You had some new drugs listed I haven’t heard of I will check. We are always looking for EBV treatments, like the antiretroviral Vemlidy, now that EBV has been proven in 2022 to be the trigger and/or driver of MS… after 50 years of publications pointing this out!
Thanks for bringing up the Stem Cell trial. The goal of the post was to point out things that RECOVER should be trialing. It was a difficult line to walk sometimes.
In general, if the private sector was underway with a well designed trial I did not include it, which is why I left the Stem Cell trial out.
John, thanks for the clarification. It’s great RESTORE is developing new therapies, but is there any focus on getting treatments already in trials that are showing significant benefit in small phase 2 trials, into large phase 3 or EAP so thousands could get treatment?
What’s your opinion on the Hope Bio Long Covid EA results? If the phase 2 RCT is as positive or better, is this something NIH should fund for phase 3 or a large EAP? But the funds would have to come from either the proposed Long Covid Moonshot from FY25 appropriation or Bernie Sanders’ proposed Moonshot bill for FY26?
As an example of a similar effort for a life-threatening disease, Act For ALS got $100 million per year for 5 years in 2021. Oct 2023 NINDS awarded a $45.1 grant for a 4 year EAP of CNM-Au8 nanocatalytic gold, so the very disabled who can’t qualify for trials can get treatment.
Here is a report on the progress of Act For ALS
https://www.ninds.nih.gov/news-events/events/act-als-als-strategic-priorities-community-update
IVIG (1 g/k), Abilify, NAD+, & LDN haven’t helped my CFS. I still have hope for Naltrexone, since I just started 2-17-24, & am up to 6 mg/day.
I will be starting Xyrem soon for Idiopathic Hypersomnia. A friend w/CFS has benefitted from Xywav (both contain sodium oxybate).
Another friend had an 8 yr. remission from high dose Valcyte, prescribed by Dr. Darren Lynch. Sadly, he’s no longer taking new CFS patients.
I’ve gone steadily downhill for 41 yrs., although I’m sure it doesn’t help that I have to take high dose stimulants (Dexedrine IR) to stay awake due to IH. I’m struggling badly to stand long enough to get something quick to eat or shower. It’s sooo frustrating that there still isn’t a single FDA-approved treatment!
As always, I enjoyed your informative article, Cort!
The author points to the fact that Long COVID manifests as a system metabolic disorder. I’m curious why mitochondrial dysfunction is not on the list of root causes and suggested targets for treatment. Several high profile papers have demonstrated that SARS-CoV-2 attacks mitochondria and the endoplasmic reticulum resulting in localized inflammatory processes (ROS) and damage to mitochondria, and mitochondrial DNA (mtDNA). Mitochondrial dysfunction can effect any system in the body.
Mitochondrial dysfunction is treatable.
Respecting PEM and following Stop-Rest-Pace, reducing inflammatory processes through education of patients through changes in lifestyle and environment are part of the process. Initiating protocols similar to education needed to self-manage/regulate for patients with diabetes would seem like a natural first step. Supplementing essential nutrients that are required for mitochondrial vitality and for biogenesis would also be prudent.
While it would be great if NIH and RECOVER were involved, I’m not holding my breath. The steps to treat mitochondrial dysfunction are low hanging fruit that can make an impact.
What additional drugs would you have included?
I included both ASHA-091 and AMX0035 which both work on mitochondria.
The only other drug I was familar with was the Astellas trial with David Systrom that failed. Also, Klaus Wirth’s company MITODICURE has a few new patents but it is unclear to me whether those are ready for trials.
Greeting John and thank you for responding.
These two drugs do look promising. In combination with changes in lifestyle, diet and appropriate supplements, they could be game changers.
My take is that the profound damage to mitochondria in chronic Long COVID patients will require sustained support. Reducing sources of inflammation, including those normally produced by the mitochondria themselves, will need to be included. The Stop-Rest-Pacing protocols should be respected by those who want to recover. Inflammatory foods, often foods well tolerated prior to COVID, need to be identified and reduced or eliminated. Stresses need to be recognized, addressed and mitigated.
I’ve written a good many posts on Substack about my four year journey to recover my health. There are details about how I’ve approached my journey back to wellness.
Thanks Mardi! Congratulations – looking forward to reading how you did it. 🙂
Thanks so much. Your feedback would be deeply appreciated!
Mardi,
Mitochondrial dysfunction is a great target, and so much has already been studied for other diseases. I mentioned CNM-Au8 nanocatalytic gold for ALS in the comment above. This is also reporting positive results in phase 2 trials for MS and is starting for Parkinson’s. How do the mitochondrial effects in this profile compare to the other therapies you mentioned?
CNM-Au8 acts as a nanocatalyst, increasing the conversion rate of NADH to NAD+. This essentially boosts the production of available ATP “fuel” for energy production within cells. NAD+/NADH increased by 10.4% after 12 + weeks in the MS trial.
The blood-brain barrier penetrant, cell-permeant gold nanocrystals both restore energetic homeostasis via mitochondrial complex I-like activity, as well as reduce oxidative stress via catalase-like activity.
This is the Solving MS research profile we did on CNM-Au8
https://bit.ly/CNM-Au8
The CNM-Au8 sounds interesting and again, a potential game changer. Similar to my comment to John Boleck, I wonder if a comprehensive and sustained approach to treating mitochondrial dysfunction will be needed to optimize outcomes.
Thanks so much for sharing this with me.
I paid $1,000 to trial a specific NAD+ supplement that my brilliant Neurologist friend recommended for my ME/CFS. Sadly, it didn’t help.
IVIG hasn’t helped it either. I’ve been getting Panzyga (1g/k body weight) since 11-22 for SFN. Currently every 3 wks.
Another thought – I don’t know whether the NIH purchases its own equipment, but a couple of blood volume measurement set-ups wouldn’t go astray. Testing is simple – two small vials of blood – and takes about 15 minutes. Samples then go to a basic pathology lab for blood gas analysis.
The new(ish) technology, carbon monoxide rebreathing, doesn’t have to be hosted by a nuclear medicine department and is economical and easy to do. All you need is a phlebotomist and a medical technician (can be the same person).