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Rituximab Phase III - Negative result

Marky90

Science breeds knowledge, opinion breeds ignorance
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Some good news though...
A slide showed they found p-001 decreases in flow mediated dilation in both RITUXME-baseline patients and pilot patients, and also a prolonged systemic hyperemia response after a POHR-test (http://www.perimed-instruments.com/post-occlusive-reactive-hyperemia)

They ask why? This is normally seen in patients with severe hypertension. Is the NO-production compromised? And by what? Autoantibodies? (which still is possible, there are other autoantibody-producing cells, and it might be going on in tissue too). Other negative bloodflow-regulators in bloodstream? And how does these findings relate with exercise or brain activity, e.g. reading).

Findings yet to be published..

23722272_10154881975167657_7109278639074187878_n.jpg
 

Rossy191276

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It's of interest that in both Fluge and Mella's doubled-blinded phase II trial (30 patients, 67% response rate) and their open label phase II trial (29 patients, 64% response rate), the CDC Fukuda definition was used to recruit patients.

Whereas in the phase III trial, they used the stricter Canadian consensus criteria.This returns us to the idea that ME and CFS may be different diseases, and that rituximab works for CFS but not ME. Although I don't myself tend to subscribe to this idea that ME and CFS are different.
I had actually never looked at the Fukuda definition as I was diagnosed with ICC/CCC criteria but in looking at the contrasts doesn't it seem obvious that these criteria are describing vastly different illnesses and thus going from Fukuda to CCC will bring completely different results.

Fukuda seems to be describing some sort of 'normal' flu like illness that doesn't go away whereas ICC/CCC describes a disease consistent with varying levels and areas of mitochondrial disfunction.
 

deleder2k

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It's of interest that in both Fluge and Mella's doubled-blinded phase II trial (30 patients, 67% response rate) and their open label phase II trial (29 patients, 64% response rate), the CDC Fukuda definition was used to recruit patients.

Whereas in the phase III trial, they used the stricter Canadian consensus criteria.


This returns us to the idea that ME and CFS may be different diseases, and that rituximab works for CFS but not ME.

Although I don't myself tend to subscribe to this idea that ME and CFS are different.

This is not accurate. From the open-label study:

A total of 29 patients, including two pilot patients, met the Fukuda criteria [8] and were accepted for the KTS-2-2010 study. All 29 patients also fulfilled the Canadian diagnostic criteria (2003) for ME/CFS [1].
Or do you mean that the way the recruited patients would have made a difference when everyone did fit CCC? Remember that if you have ME according to the CCC you also have it according to Fukuda 99.99% of the time (or 100%?) Edit: In a study 55% of the patients or so did match both criteria

In the double-blinded phase 2 study 28 out of 30 patients was retrospectively checked according to the CCC. 15 out of 15 in the rituximab group did fit the criteria. In the placebo group 13 og 15 did so. In the study 10/15 improved with rituximab, while 2 out of 15 responded in the placebo group.
 
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pibee

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I had actually never looked at the Fukuda definition as I was diagnosed with ICC/CCC criteria but in looking at the contrasts doesn't it seem obvious that these criteria are describing vastly different illnesses and thus going from Fukuda to CCC will bring completely different results.

Fukuda seems to be describing some sort of 'normal' flu like illness that doesn't go away whereas ICC/CCC describes a disease consistent with varying levels and areas of mitochondrial disfunction.
+1

I don't meet Fukuda (have 3 symptoms: impairment in memory, unrefreshing sleep, PEM. None: lymph, throat,..)

and meet almost perfectly CCC. Have all, except pain, including 6 a, b, c parts
 
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Diwi9

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Although I don't myself tend to subscribe to this idea that ME and CFS are different.
Why do you not think they are different? We have recently learned that GWI and ME/CFS are biologically different and clinically the same. Lipkin and Hornig have found distinctions too, with typical and atypical.

The IOM report makes cognitive dysfunction an optional criterion. To me, this is core symptom of ME/CFS. Orthostatic Intolerance is not, it is likely an autoimmune sequelae from a prior infection.

My feeling about the Phase II trials with the addition of our preliminary knowledge of the Phase III trial:

1/3 cured = autoimmune subgroup whose symptoms overlap with CFS (meet Fukuda, not CCC)
1/3 improved = ME/CFS with autoimmune complications (some Fukuda, some CCC)
1/3 unaffected = ME/CFS...remains undefined without biomarkers (only meet CCC)

I hope the papers published by Fluge & Mella will help us define a proper case definition. We are not biologically the same, but present clinically similar.
 

Gingergrrl

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Rossy, I just re-looked at the Fukuda criteria out of curiosity and I do not meet a single item with the exception of muscle pain.

Whereas with CCC or ICC criteria, I meet almost the entire section with the autonomic, cardiac & neuro dysfunction.

To me, they are describing different illnesses.

Edit: Whatever illness I have, the core problem is orthostatic intolerance and inability to regulate heart rate, BP, breathing, muscle strength, etc, when I stand. Vs. I have absolutely zero flu like symptoms, sore throat, swollen lymph nodes etc.
 
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deleder2k

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Why do you not think they are different? We have recently learned that GWI and ME/CFS are biologically different and clinically the same. Lipkin and Hornig have found distinctions too, with typical and atypical.

The IOM report makes cognitive dysfunction an optional criterion. To me, this is core symptom of ME/CFS. Orthostatic Intolerance is not, it is likely an autoimmune sequelae from a prior infection.

My feeling about the Phase II trials with the addition of our preliminary knowledge of the Phase III trial:

1/3 cured = autoimmune subgroup whose symptoms overlap with CFS (meet Fukuda, not CCC)
1/3 improved = ME/CFS with autoimmune complications (some Fukuda, some CCC)
1/3 unaffected = ME/CFS...remains undefined without biomarkers (only meet CCC)

I hope the papers published by Fluge & Mella will help us define a proper case definition. We are not biologically the same, but present clinically similar.
But all patients that responded did have ME according to the CCC in both phase 2 trials.
 

Ember

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Maria writes, “Perhaps there are subgroups within the Canadian criteria? However, the criteria are useful as a way to compare results from the different studies" (Posted on November 21, 2017 by Maria Gjerpe.)

Shown graphically here, the ICC is narrower than either the CCC or Fukuda. And the ICC authors suggest further classifying patients by subgroups in some studies, eg., criterial subgroups: neurological, immune, energy metabolism/transport or eclectic. An immune subgroup would seem to be the most relevant in studying immunomudulation.

Under their optional considerations, the ICC authors also suggest other subgroups, eg., symptom severity: mild, moderate, severe, very severe. ME patients have been found to be more severely impaired than CFS patients: “Patients that fulfill the ME-ICC have more severe functional impairment and more physical, mental, and cognitive problems than those that fulfill the Fukuda definition.”
 

Hip

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This is not accurate. From the open-label study:

Or do you mean that the way the recruited patients would have made a difference when everyone did fit CCC? Remember that if you have ME according to the CCC you also have it according to Fukuda 99.99% of the time (or 100%?)

In the double-blinded phase 2 study 28 out of 30 patients was retrospectively checked according to the CCC. 15 out of 15 in the rituximab group did fit the criteria. In the placebo group 13 og 15 did so. In the study 10/15 improved with rituximab, while 2 out of 15 responded in the placebo group.
Thanks for pointing that out that error, deleder2k. I clearly was not reading at the phase II papers carefully enough, because I missed the bits where they said that the ME/CFS patients also satisfied the Canadian consensus criteria.




I had actually never looked at the Fukuda definition as I was diagnosed with ICC/CCC criteria but in looking at the contrasts doesn't it seem obvious that these criteria are describing vastly different illnesses and thus going from Fukuda to CCC will bring completely different results.

Fukuda seems to be describing some sort of 'normal' flu like illness that doesn't go away whereas ICC/CCC describes a disease consistent with varying levels and areas of mitochondrial disfunction.
Why do you not think they are different? We have recently learned that GWI and ME/CFS are biologically different and clinically the same. Lipkin and Hornig have found distinctions too, with typical and atypical.
The reason I think it unlikely that CDC Fukuda and the CCC definitions are describing different diseases is that these two definitions are probably just picking up different levels of severity of ME/CFS.

If you look at the ME/CFS scale of mild, moderate and severe, there is a huge difference between say severe ME/CFS (mostly bedbound all day) and mild ME/CFS (usually able to work part or full time).

I suspect that people with milder ME/CFS will fall into the CDC Fukuda definition, but their symptoms may be too mild for them to satisfy the stricter CCC definition. Whereas someone with severe ME/CFS is likely going to easily satisfy the CCC, as well as of course satisfy the CDC Fukuda definition




The IOM report makes cognitive dysfunction an optional criterion. To me, this is core symptom of ME/CFS. Orthostatic Intolerance is not, it is likely an autoimmune sequelae from a prior infection.
It's interesting that there are patients on this forum such as @Valentijn whose ME/CFS is severe enough to require mobility devices to prevent PEM from physical exertion, yet have no brain fog at all normally (except during PEM).
 
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Rossy191276

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Rossy, I just re-looked at the Fukuda criteria out of curiosity and I do not meet a single item with the exception of muscle pain. Whereas with CCC or ICC criteria, I meet almost the entire section with the autonomic, cardiac & Neuro dysfunction. To me, they are describing different illnesses.
Edit: Whatever illness I have, the core problem is orthostatic intolerance and inability to regulate heart rate, BP, breathing, muscle strength etc when I stand. Vs. I have absolutely zero flu like symptoms, sore throat, swollen lymph nodes etc.
Hi Gingergrrl... Yes I actually couldn't believe the criteria when I looked at it. The only item I meet is PEM...

Yet I am very similar to you when it comes to the CCC/ICC and symptoms...But there is a lot of work to be done on those criteria as well from my experience and talking to other patients and this may just reflect that we have grouped a whole heap of different diseases into one.

For example, there seems to be a large % of ME sufferers who stop getting the normal sicknesses described in Fukuda and Section C of the ICC...

But I think a huge one is something that another patient pointed out to me which makes recruiting patients for research incredibly difficult. I will use me as an example that seems to be reasonably common. When I have used to much physical/emotional energy I am the ideal case of very severe ME as per the ICC except for the flu like symptoms.

However, when I rest aggressively enough for long enough alot of symptoms reduce of fade away and I am left with very severe symptoms in just a few categories. So whether people meet criteria depends on what stage of Post Exertional Crash they are in. This is why I think researchers focusing on Mitochondrial Disfunction and what causes it are on the right track for a big subset of sufferers of whatever illness/illnesses we have.
 

Diwi9

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It's interesting that there are patients on this forum such as @Valentijn whose ME/CFS is severe enough to require mobility devices to prevent PEM from physical exertion, yet have no brain fog at all normally (except during PEM).
I'm righteously confounded by our differences, but hopeful that this negative study that has had positive findings, helps researchers to clarify what questions to ask and where to look. I just wish I had a fast-forward button. If this study had shown a positive effect, it would have been a catalyst for further research. All I know is that my brain has been profoundly impacted by whatever disease I have and I'm desperate for answers, as I can manage PEM better than the cognitive dysfunction.
 

Hip

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All I know is that my brain has been profoundly impacted by whatever disease I have and I'm desperate for answers, as I can manage PEM better than the cognitive dysfunction.
I am the same: brain fog (as well as mental PEM due to mental exertion) is a much more of a problem for me than PEM from physical exertion.

In my case, though, my ME/CFS began not long after a viral brain infection (meningitis and/or encephalitis), possibly explaining why I suffer more with the brain symptoms of ME/CFS like brain fog, emotional flatness, etc, rather than the physical symptoms of ME/CFS like body pain (which I don't have) and exercise induced PEM (which I almost don't have).

One idea I had is that the organs that get infected by your ME/CFS-triggering virus may determine the sort of ME/CFS symptoms you get. If the virus hits your brain badly, then maybe you will get stronger brain symptoms like brain fog; it the virus infects the muscle tissues, then maybe you will get lots of PEM from physical exercise.
 

Rossy191276

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I am the same: brain fog (as well as mental PEM due to mental exertion) is a much more of a problem for me than PEM from physical exertion.

In my case, though, my ME/CFS began not long after a viral brain infection (meningitis and/or encephalitis), possibly explaining why I suffer more with the brain symptoms of ME/CFS like brain fog, emotional flatness, etc, rather than the physical symptoms of ME/CFS like body pain (which I don't have) and exercise induced PEM (which I almost don't have).

One idea I had is that the organs that get infected by your ME/CFS-triggering virus may determine the sort of ME/CFS symptoms you get. If the virus hits your brain badly, then maybe you will get stronger brain symptoms like brain fog; it the virus infects the muscle tissues, then maybe you will get lots of PEM from physical exercise.
At first I couldn't differentiate but now I have figured out I am the opposite. I get severe brain fog in crashes but my crashes are only caused by physical and emotional exertion so I can do 8hrs mental exertion on computer in one day and not be affected yet I am completely bed bound and have been to weak to talk until recently after a severe crash a few months ago...
 

Ruthie24

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Disappointing results obviously but I have a question.

I have read that the placebo effect in studies can be as high as 30% in some studies. I also heard (trying to remember the source, but think it was my ME/CFS doc who talked to the folks at Cell Trend) that about 25-30% of patients in the Fluge and Mella phase lll study were found to have autoantibodies to the various adrenergic and muscarinic receptors that they found.

Assuming that auto-antibodies play a role in these 25-30% of patients' disease, and even if every patient with the antibodies was a responder, which we seem to know was not the case, then only 25-30% of the actual study patients could have shown an improvement from Rituxan. If the placebo effect can be as high as 30%, could this be why the results didn't show a significant difference between Rituxan and placebo?

Could it be that Rituxan is effective in a percentage of people with this antibody profile but not for patients who don't have them? And since the total percentage of people who had this profile was small compared to the total number of subjects, might that be an explanation for the negative results? Might it mean that not everything about the study was negative?

Personally, I have been using IVIg for a couple years now and added in Rituxan in May. I have been very much better with the Rituxan and have had far fewer side effects from it than from IVIg.

Like @Gingergrrl , I had many of the auto-antibodies at Cell Trends come back positive, have very high GAD65, and have had several other auto-antibodies test positive. I also have POTS, NMH, MCAS, EDS, and possible Sjogren's along with my ME/CFS diagnosis. I also have had very high viral titers (EBV, CMV, etc) and chronic elevation of EBV PCRs. Since starting Rituxan my EBV PCRs have finally been zero.

Very disappointed to hear the study results were not what we were hoping for but also don't think my improvement in symptoms is just a placebo effect. I have tried so many other things in the 8 years I've been sick that I surely would have chosen one of the much cheaper placebos to be successful than these two drugs. ;)

Hoping this study can at least help to tease out one subgroup of patients under the big umbrella of ME/CFS.
 

Gingergrrl

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Remember that if you have ME according to the CCC you also have it according to Fukuda 99.99% of the time (or 100%?)
That seems very strange to me as the symptoms described are different. Fukuda seems like your immune system never got over mono or a severe cold (flu-like symptoms, sore throat, swollen lymph nodes, headaches, joint pain, etc) and I have none of these but yet I meet many of the symptoms of CCC and ICC. I don't see how they are the same.

In the study 10/15 improved with rituximab, while 2 out of 15 responded in the placebo group.
Then wouldn't this actually be a positive result?!! How could 10/15 respond to Rituximab but only 2/15 in the placebo group? Wouldn't this actually mean something significant?

Oh no, I’m sorry for the confusion. I meant it as a figure of speech. It thought @lnester, did, too. My puppy is alive and well !
I am so relieved to hear that, Dechi, and was in a rush this morning and did not read every single post carefully. I did not know that was a figure of speech but in any case, am glad your puppy is alive and well! :dog::dog::dog:
 
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Some good news though...
A slide showed they found p-001 decreases in flow mediated dilation in both RITUXME-baseline patients and pilot patients, and also a prolonged systemic hyperemia response after a POHR-test (http://www.perimed-instruments.com/post-occlusive-reactive-hyperemia)

They ask why? This is normally seen in patients with severe hypertension. Is the NO-production compromised? And by what? Autoantibodies? (which still is possible, there are other autoantibody-producing cells, and it might be going on in tissue too). Other negative bloodflow-regulators in bloodstream? And how does these findings relate with exercise or brain activity, e.g. reading).

Findings yet to be published..

View attachment 25178
Fascinating. A pet theory of mine (which I will discard like that if evidence comes in!) is an endothelial problem.

I can create super PEM by combining two or more of these ingredients: alcohol, exercise, and sushine. (Combining all three is a mistake I made one fine day during a remission and boy was it costly.) It took me a while but I realised they are linked as causes of vasodilation. (They may be linked by other things too, of course).

This excellent presentation by a blood pressure expert was influential. POTS is huge for us and he explains why very clearly.


Fluge and Mella's NO patent also focused me in on the issue.

There might even be a link with purinergic singalling problems. Red blood cells release ATP when they hit areas of turbulence in the blood vessels and that helps expand those blood vessels in the right places. I don't see exactly the link from weak flow mediated dilation to Naviaux's purinergic signalling theory but there may be one. Systemic ATP shortage? idk.
 
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Gingergrrl

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Could it be that Rituxan is effective in a percentage of people with this antibody profile but not for patients who don't have them?
This is what I have been wondering all along, too.

Personally, I have been using IVIg for a couple years now and added in Rituxan in May. I have been very much better with the Rituxan and have had far fewer side effects from it than from IVIg.
I have had IVIG for 16 months (and for one year at the point of my first Ritux infusion in July 2017). I am also much better with the Ritux and had no side effects from it vs. it takes a few days to recover from the side effects of IVIG.

Like @Gingergrrl , I had many of the auto-antibodies at Cell Trends come back positive, have very high GAD65, and have had several other auto-antibodies test positive. I also have POTS, NMH, MCAS, EDS, and possible Sjogren's along with my ME/CFS diagnosis.
Ruthie, we are very similar re: the Cell Trend Abs and the GAD65. I also have POTS and MCAS (but do not have EDS or Sjogrens). Can you remind me if you test positive for any of the calcium channelopathies?

Very disappointed to hear the study results were not what we were hoping for but also don't think my improvement in symptoms is just a placebo effect. I have tried so many other things in the 8 years I've been sick that I surely would have chosen one of the much cheaper placebos to be successful than these two drugs. ;)
My improvement is not placebo either and I have tried everything under the sun in the last 4+ years of being sick. I went into my first IVIG expecting to get anaphylaxis and die. My expectations that I would even tolerate it, let alone have this much benefit were zero. I think for placebo, at least part of you has to believe that what you are receiving will help you and I was very skeptical going in. When it put my MCAS into remission, that was something I had never dreamed of and did not think was possible. But I finally reached a plateau with IVIG that was only broken when I began Ritux. We are very similar.