The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab -

[heapsreal]

http://simmaronresearch.com/2015/01...ronic-fatigue-syndrome-rituximab-fluge-mella/

Not sure if its been posted but theres the link.

cheers!!

 

[Sidereal]

Fascinating stuff.

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning. We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.

Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms. We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more. Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al. reported both small and large blood vessel dysfunction was present in ME/CFS.

 

[deleder2k]

How sophisticated and thorough isnt this study going to be? I am celebrating with a beer.

 

[Sidereal]

I am continually blown away by these guys.

 

[A.B.]

I was impressed by the RituxME trial protocol. They will select patients that fulfill the Canadian criteria and have been ill for several years at least. The outcome measures include measured physical activity. While it is standard in other areas of research, a large double blind placebo controlled study for ME is not. Patients will be tracked over a long period of time, so we should get a clear picture despite any symptom fluctuations. The substudies seem relevant and could yield very useful information together with the effect of Rituximab. According to this article the exercise substudy will include two day CPET.

The weakness is that it will still rely heavily on self-report measures. However, one can have much more confidence in these due to the long duration and blinding.

 

[deleder2k]

I agree, but they also use Sensewear + the cycle test. I think the cycle test will be beneficial to prove whether a patient is better or not after RTX. If I got it right there is no way of faking or "placeboing" a cycle test.

 

[Sherlock]

flow-mediated dilation

This is what is talked about by every low fat vegan guru in the diet wars, so there should be lots of studies on that in the setting of impairment by high fat ingestion.

 

[Forbin]

In 1975, there was an outbreak of cases resembling ME/cfs at Mercy San Juan Hospital in Carmichael, California, a suburb of Sacramento. These cases, however, were distinguished by severe vascular involvement, leading investigator Erich D. Ryll, M.D. to term the illness "Infectious Venulitis."

The CDC investigated and documented 45 cases. The largest percentage of cases by occupation were among ICU nurses. Four cases were non-hospital contacts of employees. One case was an ICU patient. Additional cases were reported later.

Below is a link to Dr. Ryll's 30-year-follow-up report on this outbreak:

http://www.iacfsme.org/LinkClick.aspx?fileticket=DFTt0/5WSAU=&tabid=477

INTRODUCTION
An infectious epidemic outbreak, characterized by acute onset of severe influenza like symptoms and accompanied by severe venous involvement, occurred in 1975 in a community hospital in Carmichael, a suburb of Sacramento, CA. Vascular features ranged from spontaneous bruising with numbness, tingling, and burning to painfully swollen veins. The severity of disease appeared to be associated with the extent of vascular sequelae. The hallmark symptom of painful veins appeared to be similar but more severe and extensive than the Epidemic Phlebodynia documented in three other hospital epidemics reported in 1953, 1957, and 1965 (1-3). Headaches, sore throat, fever, dizziness, runny nose, nausea and vomiting, severe exhaustion and weakness, severe generalized pain, disturbances of cognition/mentation, and nervous system abnormalities resembled Epidemic Neuromyasthenia (ENM), Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME). Today these illnesses are thought to represent the same and/or a spectrum of related disease states.

In summary, while the outbreak had many features resembling the documented diseases described in this report, the “infectious venulitis”, severity of pain and symptoms, and long-term disability suggest that it may be a more virulent form of these illnesses or that the outbreak may represent a new disease entity. Indeed, the observed vasculopathy, severe generalized pain, dementia, severe neurologic findings, and peri-articular disease may suggest that this illness is disparate from CFS. Regardless, the information gleaned from the 1975 outbreak will add to the growing body of literature to an illness that has long been trivialized despite its devastating sequelae.

[Bolding mine.]

 

[lansbergen]

Endothelium function testing is good but they should also test epithelium.

 

[Sasha]

The weakness is that it will still rely heavily on self-report measures. However, one can have much more confidence in these due to the long duration and blinding.

They're using actimeters at baseline and at the end of the trial.

 

[Sidereal]

And they're using 2-day CPET at three study sites on patients who are not severe so as to not induce a prolonged crash.

 

[Aurator]

If, when the present study is complete, similar results (i.e. fairly positive ones) to those of the first study emerge, and if the UK study now under way meets with positive results likewise, what practical changes, if any, can we expect the experience of the trials to bring to the treatment of the disease in the short or medium term?
Am I being unduly pessimistic when I envisage yet more encouraging trial results and pats on the back for all involved being greeted by a sphinx-like impassiveness on the part of the authorities whose co-operation (and money) we ultimately need if there are to be any positive changes in the treatment patients actually receive?

 

[WillowJ]

Am I being unduly pessimistic when I envisage yet more encouraging trial results and pats on the back for all involved being greeted by a sphinx-like impassiveness on the part of the authorities whose co-operation (and money) we ultimately need if there are to be any positive changes in the treatment patients actually receive?

It is the right study design, being a sizeable blinded RCT, so should get some attention. Will require replication by another group before the governments think about changing any treatment recommendations, although if they are smart, they would fund more such studies.

I do not know how many countries will expect studies to be done in-country, but we have a good start with 3 countries working on trials.

 

[Kati]

It is the right study design, being a sizeable blinded RCT, so should get some attention. Will require replication by another group before the governments think about changing any treatment recommendations, although if they are smart, they would fund more such studies.

I do not know how many countries will expect studies to be done in-country, but we have a good start with 3 countries working on trials.

3 countries? What is the third country after Norway and UK?

 

[alex3619]

Vance Spence in the UK was working on endothelial issues in ME going back to before 2000. He is also a patient though, and I suspect had funding issues.

 

[alex3619]

what practical changes, if any, can we expect the experience of the trials to bring to the treatment of the disease in the short or medium term?

None in the short term. Some in the medium term. If we want more we will have to fight. If the science shows something then its a great goal of advocacy to fight for it. Competing interests will always try to oppose advances. In the end though its psychobabble that has no biomarkers that always loses.

Psychobabble wins early because its unsubstantiated appeal to doctrine. Then there are biomarkers. Then attitudes change. Then the research funding and opportunities change. Then even more findings are made. The psychobabble is dead on this specific disease, and continues fighting to hold its ground with other diseases and disorders it has claimed.

In the long term biomedical science trumps psychobabble.

Please let me be clear that not all psych (-iatry or -ology) is psychobabble. Some are trying to put these disciplines on an even better scientific basis. Its just that the worst issues and dogma are pervasive and damaging, and need to be addressed. So I don't use "psychobabble" lightly. If I have anything disparaging to say about these professions as a whole (and not individuals) its that they have allowed this to continue without sufficient challenge. In the long run it may be psychs who are our best allies - but we are definitely not there yet.

 

[alex3619]

My best guess is that those with better resources will be able to get some cutting edge treatments, including possibly Rituximab, in three to five years. It may take another decade before this is routinely available to most patients.

This of course presumes that studies like the phase 3 Rituximab study go as expected. I have to say that I think the countdown to the release of the results may be the most tense and exciting time in ME history. Just look at how we reacted to XMRV ... and multiply that by ten. These are not just tests but treatments.

 

[Sasha]

3 countries? What is the third country after Norway and UK?

The Open Medicine Institute have a Rituximab/Valcyte RCT listed as their first research priority on a list that's been up for a couple of years now:

http://phoenixrising.me/archives/17128

It's costed at $7.65 million and there's been no update on it: presumably they haven't been successful in getting funding.

Prof. Carmen Scheibenbogen in Germany had been interested in doing a Rituximab trial but I think she ran into problems and abandoned it.

I'm not aware of any other country running a trial.

@Jonathan Edwards, do you know of a rituximab trial on ME/CFS, other than the UK and Norwegian ones?

 

[Bob]

From the Simmaron article, genetics study section:

"To further elucidate possible clues, we are also working on exom-sequencing of families with many affected individuals among first- and second-degree relatives, sequencing all coding parts of the genome (with flanking introns) both from affected and healthy family members."

"exom-sequencing" and "flanking introns"? The mind boggles! (I've never heard of these before!)

 

[Bob]

New Open Phase-II Trial
After observing a few pilot patients for one year, we have decided to begin another open-label phase-II study in Spring 2015 on another immunomodulatory drug, in three sets of ME/CFS patients: ME/CFS patients who have not treated before with rituximab, in nonresponders to rituximab treatment, and in patients with a clear response to rituximab but with evidence of gradual relapse the last year. This study has been approved by the Ethical Committee, and will occur at a single center study in Bergen (Haukeland University Hospital).

This has been discussed on another thread in the rituximab section of the forum, but thought I'd post it here as well. Looks interesting.