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Why do the Fluge/Mella trials seem to be more successful than off/trial reports?

RustyJ

Contaminated Cell Line 'RustyJ'
Messages
1,200
Location
Mackay, Aust
I must have missed all the buzz and excitement about rituximab in the metabolomics studies.

That's probably because most of the metabolomic studies are just 'buzz and excitement'. They don't reference a treatment, and don't differentiate between cause and effect. If you have put your faith in metabolimics, you might be in for a long wait.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
I should add to this thread that Dr Chia told me that he believes the positive response to RTX in Norway is due to regional homogeneous genetics, and that he has not heard good results from his American patients who have tried RTX. Caveat being that Dr Chia is of course an enterovirus expert and so may self-select a patient cohort with chronic enterovirus infections w/o autoimmunity.

Curious if @Jonathan Edwards has anything to add to the overall thread topic regarding off-label RTX resutls vs Norway
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
I should add to this thread that Dr Chia told me that he believes the positive response to RTX in Norway is due to regional homogeneous genetics, and that he has not heard good results from his American patients who have tried RTX. Caveat being that Dr Chia is of course an enterovirus expert and so may self-select a patient cohort with chronic enterovirus infections w/o autoimmunity.

I don't buy the genetic argument at all. It is possible that there are diagnostic/participation biases involved in the Fluge/Mella Trials.

I also am not believing the hype about the cyclophosphamide (open label) trials unless there are substantial improvements on the objective measures at a reasonable follow up interval. We'll see.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
I don't buy the genetic argument at all. It is possible that there are diagnostic/participation biases involved in the Fluge/Mella Trials.

I also am not believing the hype about the cyclophosphamide (open label) trials unless there are substantial improvements on the objective measures at a reasonable follow up interval. We'll see.

Fair enough on both counts.

Looking though the Phase II study Fluge / Mella seemed to use good critia. Are you saying that there was perhaps some implicit section bias not mentioned?
 

Gingergrrl

Senior Member
Messages
16,171
and that he has not heard good results from his American patients who have tried RTX.

I suspect that many American patients are trying Ritux without solid evidence that they have autoantibodies. I wonder what the statistics would be (for those trying it outside of a trial) if we only looked at those who 100% had autoantibodies vs. those who 100% did not have them or who did not know whether they actually had them or not. I think the results might be different.
 

Hip

Senior Member
Messages
17,802
I should add to this thread that Dr Chia told me that he believes the positive response to RTX in Norway is due to regional homogeneous genetics, and that he has not heard good results from his American patients who have tried RTX.

That does not seem to tie into what Dr Kaufman said to @eljefe19, which was that in the OMI in the US, they get a similar success rate to the Norwegians.

However, I have aways found it suspicious that there are so few ME/CFS rituximab success story accounts to be found online (on forums, blogs, newspaper articles, etc), and to me that suggests that rituximab is not working as well as it touted to in Norway. So I am inclined to give credence to Dr Chia.

It is a pity that the Open Medicine Institute is not more, well, open with its data on rituximab treatment. Outside of Norway, this is the only other place with a program for treating ME/CFS patients with rituximab, so you'd think they would publish some info, even if just on their website.



I suspect that many American patients are trying Ritux without solid evidence that they have autoantibodies.

In the Fluge and Mella phase II study, they say the inclusion criteria are: "a diagnosis of ME/CFS according to the Fukuda 1994 criteria, and age 18–66 years."

They did test the patients for some autoantibodies, but there is no mention that I could see about preferentially selecting patients with autoantibodies.
 
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Jesse2233

Senior Member
Messages
1,942
Location
Southern California
That does not seem to tie into what Dr Kaufman said to @eljefe19, which was that in the OMI in the US, they get a similar success rate to the Norwegians.

However, I have aways found it suspicious that there are so few ME/CFS rituximab success story accounts to be found online (on forums, blogs, newspaper articles, etc), and to me that suggests that rituximab is not working as well as it touted to in Norway.

This is what confuses me as well. Is it possible there's a negative reporting bias, where people who have success just move on with their lives? Or perhaps people who are more severe (and thus less likely to respond) are more willing to try an experimental treatment. Maybe there's an especially strong placebo effect for those getting it from Fluge / Mella

Chia's self reported Equilibrant numbers have the same problem in terms of real world anecdotes
 

Gingergrrl

Senior Member
Messages
16,171
That does not seem to tie into what Dr Kaufman said to @eljefe19, which was that in the OMI in the US, they get a similar success rate to the Norwegians.

I have been told the same thing and have no reason to doubt that it is true.

It is a pity that the Open Medicine Institute is not more, well, open with its data on rituximab treatment. Outside of Norway, this is the only other place with a program for treating ME/CFS patients with rituximab, so you'd think they would publish some info, even if just on their website.

My sense is not that they are withholding the data vs. that they had two doctors trying to see thousands of very ill patients from worldwide plus issues going on behind the scenes (like all organizations face). Now that they are splitting into two separate clinics, I think they will have to focus even more on patient care (both for existing patients and new patients) and probably even less likely they will have the time or funding to release this data. I wish it were not the case, I just think it is the reality.

In the Fluge and Mella phase II study, they say the inclusion criteria are: "a diagnosis of ME/CFS according to the Fukuda 1994 criteria, and age 18–66 years." They did test the patients for some autoantibodies, but there is no mention that I could see about preferentially selecting patients with autoantibodies.

I did not mean that they preferentially selected patients with certain autoantibodies to the exclusion of others. I was referring to the article in which it stated that the responders had the autoantibodies and showed a decrease in autoantibodies after Rituximab. I don't have the link right now but I have the printed copy and it's called "Antibodies to B adrenergic and muscarinic cholinergic receptors in patients with chronic fatigue syndrome" by 12 authors including Fluge & Mella, Heidecke, Scheibenbogen, etc. It's the article that said that the responders also had a positive ANA titer and anti-thyroid autoantibodies. (But not that patients were pre-selected b/c they had all of those criteria).
 

deleder2k

Senior Member
Messages
1,129
I also am not believing the hype about the cyclophosphamide (open label) trials unless there are substantial improvements on the objective measures at a reasonable follow up interval. We'll see.

Fluge and Mella are known for being extremely careful with respect to stating that a drug does actually work or not. They are reserved. It took them one pilot study with rtx, two phase two studies, and years into the phase 3 study for them to state that rituximab definitely works in a subgroup of patients. Usually researchers tend to take another approach. Many state that their latest research shows that ME is this and that, and that they've found a biomarker that works. The researchers from Haukeland is nowhere like that.

To my knowledge Fluge and Mella are the ones who created a "hype" about the cyclo trial. They've said that it looks like it is beneficial for a significant group of patients (freely paraphrased by me). The study is open label. I.e, they know that everyone got the active drug. They've used objective measures like sensewear armband and cardiopulmonary exercise test on bicycle.

I don't understand how you can make a statement like you did. Could you elaborate? Do you think they would make statement about the effect of the drug if objective measures showed no or little benefit?
 

Hip

Senior Member
Messages
17,802
they had two doctors trying to see thousands of very ill patients from worldwide plus issues going on behind the scenes (like all organizations face)

It's possible to give basic info without much effort, just by comments made during interviews, presentations and conferences. You don't have to have to do a study to give a rough estimate of what percentage of your ME/CFS patients rituximab is curing / putting into full remission during an interview.

Maybe the OMI want to keep their rituximab treatment quiet, because Fluge and Mella have recommended that ME/CFS patients should not be given rituximab out of clinical trials at this stage, so perhaps they feel it is a controversial, touchy subject. There is no mention of rituximab anywhere on their website.


Anyway, the fact that Dr Chia says his patients are not getting good results from rituximab ties in with the same lackluster response to rituximab we have seen on these forums (one good response, one or two mediocre responses, out of the 14 patients who posted their results on this forum).



I did not mean that they preferentially selected patients with certain autoantibodies to the exclusion of others.

When you said that "I suspect that many American patients are trying Ritux without solid evidence that they have autoantibodies," I thought you were suggesting a theory that US patients might be getting poorer results than the Norwegians because the US patients were not ensuring they had autoantibodies before getting treated.



I was referring to the article in which it stated that the responders had the autoantibodies and showed a decrease in autoantibodies after Rituximab. I don't have the link right now but I have the printed copy and it's called "Antibodies to B adrenergic and muscarinic cholinergic receptors in patients with chronic fatigue syndrome"

The link to that paper is here, and a PR thread discussing it is here. It's not easy to understand the implications of this paper; however, as far as I can see:

Although ME/CFS patients responding to rituximab showed a reduction in certain elevated autoantibodies they may have had prior to treatment, and the non-responders showed no such decline in the same elevated autoantibodies, I don't think that translates into a requirement to have these particular autoantibodies beforehand in order for rituximab to work for ME/CFS.

In other words, even if you did not have prior elevated autoantibodies, you can still be a rituximab responder (but if you did have prior elevated autoantibodies, then the study observed that these would fall in responders, but not in non-responders).

Only 29.5% of ME/CFS patients had some autoantibodies significantly elevated compared to controls; but 60% of the patients treated with rituximab experienced either a partial or complete remission. So that shows you don't need these autoantibodies to be a responder.

Think of it like this: it could be that ME/CFS is caused by a completely different autoantibody (call it autoantibody X) to the ones measured in this study. We can hypothesize that it's when rituximab reduces the production of autoantibody X that ME/CFS is ameliorated or cured. But since we don't know that X is, we can only measure the effects of rituximab on other known autoantibodies. And we find, perhaps not surprisingly, that in the rituximab responders, these known autoantibodies are reduced; but that finding may just indicate that rituximab is working to reduce autoantibodies in general — reducing autoantibodies of all types, including autoantibody X.



As far as I could see (but I am a bit tired today), there was no indication in the study that ME/CFS patients with prior elevated autoantibodies were more likely to respond to rituximab.
 
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Kenny Banya

Senior Member
Messages
356
Location
Australia
I should add to this thread that Dr Chia told me that he believes the positive response to RTX in Norway is due to regional homogeneous genetics, and that he has not heard good results from his American patients who have tried RTX. Caveat being that Dr Chia is of course an enterovirus expert and so may self-select a patient cohort with chronic enterovirus infections w/o autoimmunity.
American patients didn't receive 4 infusions of RTX for at least 6 months.
Cheers
 

deleder2k

Senior Member
Messages
1,129
American patients didn't receive 4 infusions of RTX for at least 6 months.
Cheers

I am pretty sure that some did. When that is said the last thing I've heard is that they were experiencing roughly the same results as Haukeland.

On a another note this very weekend of Pentecost; the results from the phase 3 trial looks promising. The study is blinded so take the following info with a big grain of salt; I've learned that multiple sources around hospitals involved in the trial report that the results looks "promising".



(I don't know more than what I've said, and I can't answer any questions regarding the information. Please don't send me PMs :))
 

Gingergrrl

Senior Member
Messages
16,171
It's possible to give basic info without much effort, just by comments made during interviews, presentations and conferences. You don't have to have to do a study to give a rough estimate of what percentage of your ME/CFS patients rituximab is curing / putting into full remission during an interview.

I don't disagree but I am only their patient (and nothing more!) so I can't speculate on why they do or do not disclose any data on Rituximab.

Anyway, the fact that Dr Chia says his patients are not getting good results from rituximab ties in with the same lackluster response to rituximab we have seen on these forums (one good response, one or two mediocre responses, out of the 14 patients who posted their results on this forum).

It seems similar to what Jesse said in a post above re: Equilibriant and that if it cured a large (or even mediocre) percentage of patients, we would hear about it in here but we don't.

I belong to another group for people with my calcium autoantibody (and most have a collection of various autoantibodies like I do but we have a variety of diagnoses) and in that group, the response to Rituximab has been much better than here on PR. That is why I suspected it is the presence of autoantibodies (vs. the diagnosis or label) that is more likely to make someone a responder. But this is also anecdotal of course.

When you said that "I suspect that many American patients are trying Ritux without solid evidence that they have autoantibodies," I thought you were suggesting a theory that US patients might be getting poorer results than the Norwegians because the US patients were not ensuring they had autoantibodies before getting treated.

I sort of was trying to say that but I don't think I am expressing what I mean very well. What I meant is NOT that Fluge & Mella were hand-selecting patients with certain autoantibodies or something was going on behind the scenes with Cell Trend Labs. I believe their study is one million percent legit and the real deal from beginning to end.

What I was trying to say is that American (or other) patients who may try Rituximab out of desperation but have no evidence that they have a single autoantibody of any type are probably less likely to be a responder vs. someone like me who has eleven different autoantibodies (and probably more if we kept looking). Although until my insurance allows me to try Ritux, this is pure speculation and I could end up not being a responder. I just cannot come up with any other explanation as to why I've had such a profound improvement from high dose IVIG if not that it reduces the autoantibodies that were weakening my muscle strength and breathing.

The link to that paper is here, and a PR thread discussing it is here. It's not easy to understand the implications of this paper; however, as far as I can see:

I agree and I am the last one who can really interpret a scientific paper so take my opinions with a grain of salt!

American patients didn't receive 4 infusions of RTX for at least 6 months.

I believe that the ones at OMI did receive at least 4 infusions (if not more). If I get approved, we'll be doing the original autoimmune protocol (not the Fluge & Mella ME/CFS protocol from the study). I will be doing the dosing formula of 375 mg/BSA (body surface area) or approx 600 mg at day zero and day 14 vs. the 1000 mg that each patient got in the study. We will monitor that I maintain total B-Cell depletion and future maintenance infusions based on that. Although none of this will happen until my insurance gets on board or I win the lottery.
 

Gingergrrl

Senior Member
Messages
16,171
But since we don't know that X is, we can only measure the effects of rituximab on other known autoantibodies. And we find, perhaps not surprisingly, that in the rituximab responders, these known autoantibodies are reduced; but that finding may just indicate that rituximab is working to reduce autoantibodies in general — reducing autoantibodies of all types, including autoantibody X.

@Hip, I meant to reply to this quote in my post above but forgot so am doing an addendum post :D. I think you may be 100% correct that there is an "Autoantibody X" that no one has identified yet that could be the biomarker or the reason why Rituximab works in autoimmune disease or in subgroups of ME/CFS.

If I end up being a responder, I could assume it is b/c it reduced any of my seven beta-adrenergic or anti-muscarinic & anti-cholinergic autoantibodies or that it reduced my calcium antibody or GAD65 antibody or Hashimoto's antibodies, etc, but really it may be none of the above and it is reducing an autoantibody that I do not even know that I have.

I think this is a very good point and something we'd never be able to measure. All I would know for sure is if I have symptom improvement above and beyond what I have achieved with IVIG (which is my dream scenario). But if I do, I will never be able to tell you exactly why it occurred.
 

Kenny Banya

Senior Member
Messages
356
Location
Australia
On a another note this very weekend of Pentecost; the results from the phase 3 trial looks promising. The study is blinded so take the following info with a big grain of salt; I've learned that multiple sources around hospitals involved in the trial report that the results looks "promising".
Pentecost?
 

deleder2k

Senior Member
Messages
1,129
It is The Christian Holiday of Pentecost. It is marked this very Sunday (+ Monday) for those who care ;)
I Australia they have renamed it to Whit Monday or Pentecoast Monday. Not sure if it because someone wanted every Australian to head up to the Whitsundays in the NE in QLD or not ;)
 

Kenny Banya

Senior Member
Messages
356
Location
Australia
It is The Christian Holiday of Pentecost. It is marked this very Sunday (+ Monday) for those who care ;)
I Australia they have renamed it to Whit Monday or Pentecoast Monday. Not sure if it because someone wanted every Australian to head up to the Whitsundays in the NE in QLD or not ;)
Umm, ok. Its a good thing fairy tales have no place in (& kept far away from) science.
 

deleder2k

Senior Member
Messages
1,129
Absolutely. It is a holiday in a number of countries. It is just like saying "happy Easter". Most people including my self isnt sure what it is all about, but we still love the days off.