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Filling a Gaping Hole

ME/CFS orgs have been working recently to fill a gaping hole in the ME/CFS field - clinical trials.

ME/CFS orgs have been working recently to fill a gaping hole in the ME/CFS field – clinical trials.

ME/CFS organizations have been doing something different lately. Long focused purely on research, they’ve been putting more resources into treatment trials lately – suggesting they feel more confident about moving forward in that arena – a good sign.  They’re doing their best to fill a gaping hole in the ME/CFS field – the lack of treatment trials – and they’re being quite innovative about it as they explore emerging treatment options that organizations like the NIH would never touch. (We learned that in spades when the RECOVER Initiative failed to fund an LDN trial).

Solve M.E. recently funded small trials on Enhanced External Counterpulsation (EECP), stellate ganglion block, repetitive transcranial magnetic stimulation, and inspiratory muscle training. One nice thing about these trials is that they tend to look a bit deeper than symptom improvement and get at the physiological changes that may have occurred.

Complex Diseases Deserve Complex Clinical Trials

“These two drugs have shown a lot of promise in the clinic” David Systrom

With its new “Life Improvement”, or LIFT trial, the Open Medicine Foundation (OMF) has created the first two-fer” – a clinical trial that combines two drugs – that I can remember – a very welcome development.

ME/CFS and its cousins are, after all, complex, chronic diseases that – at least for the time being – are going to do best when hit with complex treatment protocols.

Complex diseases will likely require complex solutions

Complex diseases will likely require complex solutions

Nobody is hiding the fact that these diseases are complex and are a bear to study and treat. Just look at the names of some of the major clinics: “The Center for Complex Diseases “(Kaufman/Chedda); the Complex Chronic Diseases Clinic at the BC Women’s Hospital in British Columbia; the Institute for Neuro-Immune Medicine (Klimas) helps people with “complex neuro-inflammatory illnesses“; and the Bateman Horne Center helps doctors care for patients with “multi-symptom Chronic, Complex Diseases“. We even have an acronym, msCCD (multi-symptom Chronic, Complex Diseases) that emphasizes just how complex these diseases are!

Given that, it’s not surprising that ME/CFS experts employ a very wide variety of supplements, drugs, and techniques to treat these diseases. Dr. Arseneau, for instance, has handouts on almost 50 treatments for ME/CFS on his website.

Until a magic bullet shows up – if it ever does – good treatment protocols for ME/CFS are going to involve a variety of treatments that hopefully work together to make things better. Dan Neuffer is a patient, not a doctor, but he’s interacted with hundreds of people who have recovered and his conclusion is that recovery usually requires a multi-faceted approach.

The OMF's trial will determine if two drugs work better than one in ME/CFS

The OMF’s trial will determine if two drugs work better than one in ME/CFS

The First “Two-fer” ME/CFS Clinical Trial

So why not duplicate what works best in the real world and assess more than one treatment at once? That idea probably sends shudders down the spine of many researchers, but if you want to really move the treatment arena forward – which is what this disease really needs – it’s best to study things in tandem.

The Open Medicine Foundation’s LIFT trial is going to do that. In fact, it’s going to do both. It’s going to assess the two top medications from its treatment survey (to be released soon): low-dose naltrexone (LDN) and Mestinon (pyridostigmine bromide) – both separately and in combination.

Long Reach

You may have tried these drugs and you may have tried them together and, if so, good for you to have access to them – but this trial goes far beyond you and I. It’s designed to alert doctors, many of whom probably know little or nothing about ME/CFS, about new treatments for ME/CFS patients who are probably currently getting little or no help.

Since neither LDN nor Mestinon has been subjected to an ME/CFS treatment trial – let alone a good treatment trial – most primary care doctors won’t consider prescribing them. A successful trial should change that and finally give doctors good treatment options for their patients.

THE GIST

  • With its new “Life Improvement”, or LIFT trial, the Open Medicine Foundation (OMF) has created the first two-fer” – a clinical trial that combines two drugs – a very welcome development.
  • Most clinical trials involve one treatment but ME/CFS is a complex disease that is usually treated  – when it’s treated successfully – in multiple ways. The LIFT trial is one of the first to assess treatments the way they are done in the doctors’ office – in tandem.
  • It will assess the effects of two drugs (low-dose naltrexone (LDN) and Mestinon) separately and in combination. David Systrom and Jonas Bergquist will lead the trial which involves 160 participants and will begin shortly and last as long as two years. Neither of these drugs has been adequately tested in ME/CFS.
  • If successful the trial should begin to open the door to widespread use of these drugs by primary care doctors.
  • The trial will also, by digging deep into the patient’s physiology with proteomics, metabolomics, and other assessments, attempt to find biomarkers that can pluck out those who respond, and will help us learn more about ME/CFS. Researchers in other diseases commonly use treatments to perturb patient’s systems and learn what factors play a role in them. This is the first ME/CFS trial I remember that is actively trying to do this.
  • These drugs may be able to work together better than used separately because both fight inflammation and enhance the production of feel-good chemicals like dopamine and endorphins.
  • This trial is planned to begin soon and will take place in the Boston area. David Systrom will recruit patients from his practice and use patients who have signed up for the StudyME research project.
  • Kudos to the Open Medicine Foundation for funding such an intriguing project.

For those people who have tried LDN and/or Mestinon, this trial still offers possibilities. If you’ve taken both and neither worked, the trial could indicate that they work better together – and you might want to try them together. Or if you’ve taken one, you might want to add the other. Of course, if you’ve tried neither – the sky is open – if you can get your doctor to prescribe them.

Digging Deep to Learn More

Note that the trial is going to go way beyond the normal “did it help?” symptom assessment and dig deep into the participants’ physiology as well. Along with the symptom assessments, a new functional capacity survey (FUNCAP), and functional capacity test (a 3-minute step test that will assess aerobic capacity), the LIFT study will also assess metabolomics, proteomics, and immune assays.

This could do three things – provide validation, uncover biomarkers, help us understand ME/CFS better.

If the treatments work, having a physiological signature of success will provide validation for them – something this disease could always use more of (lol). The researchers will also attempt to uncover biomarkers that can be used – aka precision medicine – to identify which patients are likely to benefit from these treatments.

They will also attempt to learn more about ME/CFS. We haven’t, to my recollection, seen this in ME/CFS, but researchers often perturb a system with a treatment and then do deep physiological dives in order to better understand their diseases. If the treatment results in levels of certain metabolites or cytokines moving in one direction or the other, those factors are likely playing a role in the disease.

These more complete trials, then, are both treatment validating and learning experiences, and that’s why it was good to hear that the Open Medicine Foundation is planning to use this first study as a template for later studies.

Synergism?

We all want synergism! Synergism means doing better with less. When asked how these treatments might synergistically work together to prevent post-exertional malaise, Dr. Systrom had one answer – inflammation.

Studies have shown us that exertion produces an inflammatory state in ME/CFS. The latest example of that came from the Alaedini study which suggested that a hole in the immune system is allowing gut bacteria to persist in the blood longer – thus producing more inflammation – in people with ME/CFS following exercise.

Mestinon enhances the functioning of the vagus nerve and the parasympathetic nervous system. By stimulating vagus nerve activity, it may be able to do a nice two-fer itself; i.e. reduce the fight or flight response and increase the anti-inflammatory response at the same time. It also, interestingly enough, appears to enhance the production of dopamine –  a feel-good neurotransmitter in the brain.

Low-dose naltrexone’s (LDN) anti-inflammatory properties appear to enable it to quiet agitated microglial cells in the brain and tamp down neuroinflammation. Plus, it also increases endorphin levels which themselves have an anti-inflammatory effect.

Note that both dopamine and endorphins are considered “happiness chemicals”; dopamine enhances the “reward center” of the brain, while endorphins provide relief from pain and can produce euphoria. Both the reward center and endorphin levels may be lacking in these diseases.

Low Dose Naltrexone (LDN) Fibromyalgia and Chronic Fatigue Syndrome Resource Center

 

With their ability to impact both inflammation and endorphins, the two drugs seem ripe for a duo treatment trial.

The First Precision Medicine Breakthrough for ME/CFS?

Systrom and Bergstrom will also be on the hunt for biomarkers. If they can show that patients with biomarker “x” respond well to Mestinon and/or LDN, a simple lab test could identify who is likely to benefit.

LDN Pops Up Again

LDN is also interesting because it also popped up in a two-fer drug combination that a Biovista study produced about 20 years ago. In an innovative effort in the early 2000s, Suzanne Vernon and the Solve ME/CFS Initiative contracted with Biovista to do a kind of AI analysis where Biovista fed all the ME/CFS data it could find into a computer and asked it to come up with a drug combo that could help.

Biovista returned with a low-dose naltrexone-trazodone combination. Trazodone, which is used largely as a sleep aid in ME/CFS, has some fascinating properties. Not only is it able to able to reduce the activity of the alpha waves known to hamper sleep in fibromyalgia, but it also appears able to reduce neuroinflammation, and enhance lactate release (increase energy).

Low Dose Naltrexone Drug Combination Proposed for Chronic Fatigue Syndrome (ME/CFS)

Biovista never was able to get a trial funded and the effort died, but one wonders, given what Biovista found then and what Efthymios Kalatafis’s personal efforts produced recently, what gems might pop up in an AI-enhanced effort now.

AI to the Rescue? AI-Driven ME/CFS Project Unearths Clues Ahead of its Time

The Trial

This trial will begin soon and will take place in the Boston area. David Systrom will be recruiting from his patients and from patients who have signed up for the StudyME research project.

Time will tell how long the trial will last, but it may last as long as two years. Kudos to the Open Medicine Foundation for producing such an innovative and potentially far-reaching trial.

Next up – the SImmaron Research Foundation’s Rapamycin Trial

Is Learning About New Clinical Trials Helpful?

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