Trial of CT38 for ME/CFS by Cortene Inc.: big claims being made...

Most patients don't have low cortisol, if you review the literature...

Some patients have flatter daily cortisol profile compared to healthy controls and an altered sleep-wake cycle and activity patterns can entirely explain this.

 

Oh, that isn't the point. The goal is similar to startups - pay yourself a whole lot of investors money as an 'innovator', regardless of long term success in the marketplace.

I apoligise for being skeptical, and I certainly want to see more clinical trials, but their model of understanding is highly speculative and not exactly consistent with empirical findings so far...

 

I think you will find that ME/CFS patients do have low cortisol, if you review the studies:

Studies finding lower cortisol in ME/CFS throughout the 24 hour cycle: one, two, three, four, five, six.

Studies finding higher cortisol in ME/CFS throughout the 24 hour cycle: one.

Studies finding lower cortisol morning awakening response in ME/CFS: one, two (this study found only women had a lowered levels), three (this study found lowered levels in the morning, but increased levels in the evening).

Studies finding blunted cortisol and ACTH responses to corticotropin-releasing hormone stimulation in ME/CFS: one.

 

@Hip are you hopeful about the cortene venture?

 

It is a bit leftfield, so I think it's hard to make any judgements about its chances of success. But we can certainly keep our fingers crossed.



What I did find interesting is Gerard Pereira's thinking about the nature of ME/CFS, as explained in Cort's part I blog:

Pereira is basically saying that because ME/CFS can often appear as a very rapid onset condition — ie, a perfectly healthy person catches an infection and 2 days later has full-blown ME/CFS — when searching for the cause of ME/CFS you have to look for immune pathways that can react on that same rapid timescale.

I think that's a very valid and important observation about the nature of ME/CFS pathophysiology.

 

All but one of those studies only tested urine or saliva... One of those studies tested blood in the morning and found that while patients had lower levels than controls, the average level was still well within normal levels.

Apart from that, the other studies showed average group differences, but histograms (if provided) show much over lap between many patients and controls. I didn't notice any sensitivity/specificity testing either, suggesting these are not potential biomarker tests.

 

I currently regard cortisol as probably tending to low, but more importantly with a shifted timing of the cortisol response as a likely issue. Its far from big or certain enough to be a major issue though, at least in most of us. Now if the elevated beta cortisol receptor research will ever get published then that is an entirely different picture ... its cortisol resistance. Given the time that has passed (over a year?) I wonder if there was a problem with the study and it wont be published. Maybe I will wake up one day and find that they did find such a result, I keep hoping so.

This switch idea, that something triggers a biochemical switch, is really old in ME discussions. We have discussed similar things on this or at least the other forum before. The fact that some of us go into full remission for a few hours, very suddenly and on rare occasions, lends to the same conclusion as very rapid onset. Something can change in a matter of hours, then can change back just as fast.

I think much of what we know about ME is about secondary markers, and this is one of the reasons they are not diagnostic. The problem is we have to research every possibility until we have a means to narrow the possibilities down. To paraphrase Holmes (actually Sir Arthur Conan Doyle), after we have eliminated all the wrong answers as to causes, then hopefully what remains will include the right answers. The only worry is if it becomes a null set.

I think we need more studies like what Ron Davis, the NIH and Stanford are doing, where patients have lots and lots of tests done, not just a few. We need to find out which abnormalities are associated with each other, and how strongly. We need longtitudinal studies too, so we can figure out how things change over time.

When these kinds of findings start being published starting with the next two years I am hoping there will be some very surprising results, the kind that makes us rethink the picture entirely.

 

There seem to be 3 steps in the model, CRF 2 overexpression, 5HT1A autoreceptor desensitization and UNC1 failure. There are 2 drugs that are full agonists, cross the bbb and impact the limbic system, or at least the raphe nucleus. One is the antidepressant Vortioxetine and one is the arousal stimulant Flibanserin. However, as I mentioned earlier in the thread, in mice, over a week of agonism of the autoreceptor lead to desensitization of it. Therefore, the agonist may only work for a week, or may not stimulate already desnsititzed receptors. I could find no comments of those drugs improving ME/CFS online, although even if I did, I wouldn't put much stock in that kind of analysis.

More problematic for me is this model. Childhood trauma primes CRF-2 expression, leading to stressful life event and viscious cycle. We even have a handbreak metaphor. As it stands, there is admittedly evidence for an underpowered, but not pathologically, HPA axis. In terms of direct evidence, there is none. The mouse models/and the mouse drug experience being similar is quite ambiguous. To quote Alan Light, "we had to stop studying mice in CFS, because you couldn't ask them if they were not moving because they were fatigued or they were not moving because they were scared" or bored or depressed.

If the peptide is CRF-2 agonist, it would increase anxiety in the mice, and as Van Elkzzor tweeted, that anxiety can superficially be observed as CFS. But, all this might be true (I will read some of the Vernon paper another day). The bigger question I have is with the biology. I am a layman. But is it not unremarkable for the 5HTA1 receptor to become desensitized? It occurs in at least some types of PTSD, anxiety, depression and scizophrenia. In fact, it must happen quite a bit naturally, and it seems to be the mechanism of action of the most commonly presribed class of drugs in human history. And while, again you can superficially list the side effects of anti-depressants and say they are similar, anyone with half a brain can tell you ME/CFS is not that.

Correct me if I'm wrong, but the second part of their model for CFS is the mechanism of action of SSRIs. The hand-break metaphor.

When you take an SSRI you wait 2 weeks to feel better, the reason being, as far as I understand it, your brain is being overloaded with serotonin, and as a result your 5HT1A receptors are trying to block it, but eventually the drug wins and your 5HT1A receptor becomes desensitized. This is not limited to SSRIs.

And the first part is equally problematic with this information.

Because SSRIs are given, frequently, during situations of intense stress coinciding with depression. Intense stress is not rare. They haven't desribed a pathology to CFS, they've described what is probably a not uncommon neuro-pathology resulting in feeling bad I'm sure, an anxiety type if I had to bet, but I'm doubtful it's feeling like ME/CFS. And, of course, we have to everyone with CFS had such intense trauma to break the CRF 2 expression, and then again to break the 5HTA1 receptors in excess of what happens to the rest of the human race during intense stress.

Kind of annyoning for people like me who were not traumatized or distressed in childhood and had an unremarkable flu resulting in the illness. I suppose there is the possibility of a genetic element somewhere in there. But I also wonder if there aren't more elements that decouple this cycle, such as increasing gaba directly in the raphe nucleus.

All that being said, the drug may help because the HPA axis is probably involved in some capacity. So I do expect positive results from the smaller studies, trending to less impressive ones over time. If the drug can actually cause a reset.

 

An update was published on June 13 with new information on the trial design.

This is a pilot study and will not have a control group by the looks of it. The CPET data should still be interesting.

https://cortene.wordpress.com/2018/06/

It is possible to leave comments on their blog.

 

I like this:

Endpoints: The study will compare pre- and post-treatment differences, in exercise performance and function during recovery, using a combination of objective and subjective endpoints. Objectively, we will measure exercise performance (via blood gases, work, time to ventilatory threshold, etc), and function during recovery (via continuous Fitbit monitoring providing data on activity, sleep, heart rate, etc, and daily online cognitive tests). Subjectively, we will measure daily symptom scores (and narratives on unusual activity and effects).

Presumably, if the open-label trial is successful, they will. I’ve on to a blinded study. But in any case, other trials could learn from using a combination of objective and subjective measures like this.

 

The choice of 2-Day CPET as an outcome measure is certainly very interesting. The downside is that it will create a bias towards who will participate in the first place. I think the primary concern is want to see whether the (exercise testing) protocol is acceptable for patients.

It is unclear whether they are attempting to measure maximal exercise, or just exercising towards ventilatory threshold. Prior research suggests that the differences in performance at ventilatory threshold on the second day only consistently occur if the participant attempts to exercise to VO2Max on the first day.

 

Have these daily online cognitive tests consistently been abnormal in the past in ME/CFS patients?

 

Some studies are using this to try to get data on cognitive issues with PEM. It depends on the testing.

 

New article by Cort about the pilot study

https://www.healthrising.org/blog/2...ic-fatigue-syndrome-me-cfs-drug-trial-begins/

 

Just skimmed it - they seem to be well behind schedule.

 

I take it they are looking for overall decline or improvement in the tests as the treatment goes on. I know my test results would be significantly better if I was given something to improve my health compared to today.

 

Finally caught up with this (had a crash yesterday after three months of pretty excellent health, boo!) and I think I'd still put it in the 'worth a shot' category, even if I think the chances of success are low. Seems they're trying to do a dose-response test which does at least try and counteract the pretty strong placebo effect we've seen in ME/CFS studies*. The flip-side is that it is single-blinded at best: the researchers will understandably start with the low does group and only do the medium and then high dose groups later. It is not clear whether patients will be informed if which group they are in (but the researchers certainly will). However (the flip-side of the flip-side ) they are using objective measures and a decent clinical team.




*My hypothesis remains that if one is diagnosed with an illness with no known cure, might be socially isolated and is often disbelieved by medical professionals, then any attention one receives on a trial is likely to lead to a strong placebo effect.


(ETA: Am I going blind? I couldn't find an entry on Clinicaltrials.gov...)

 

This is a pilot study, it is designed to inform future studies, not demonstrate efficacy.

 

"Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Bateman Horne Center

Summary
This study seeks to examine the effect of a subcutaneous infusion of CT38, an experimental peptide, on cardio-pulmonary exercise test (CPET) performance and CPET-induced changes in functional capacity and symptom levels (assessed by, Fitbit monitoring, DANA cognitive testing and patient-reported outcome measures) in ME/CFS."

https://www.bioportfolio.com/resour...ent-of-Myalgic-Encephalomyelitis-Chronic.html

https://clinicaltrials.gov/ct2/show/NCT03613129