Have any peer reviewed studies for other CFS/ME treatments matched the effectiveness of Rituximab?

[Jonathan Edwards]

I don't really understand the significance of this b/c according to my doctor, you do not truly know if RTX has worked in any given patient until about six months after B-Cell depletion. So a patient could not have any improvement at 3-mos but then have an improvement at 6-mos and this is considered successful. Why would the Fluge & Mella Study not follow this same pattern and assume that improvements at 6-mos were due to chance?

What I think your doctor means is that in other conditions where rituximab is known to work it may take 6 months before you can be sure whether or not there is improvement. I am not sure I would agree with that (as the person who probably has more experience with the drug in autoimmunity than anyone). In most autoimmune conditions some improvement is evident at 3 months. It may be that your doctor is simply quoting the results of the Norwegian study - which did seem to show that nothing much happened until 6 months. But the whole problem is that we do not know whether ornate that was a fluke.

The real problem is that Fluge and Mella used a scoring system that worked over a six week period so that the score at 3 months was actually for 6 to 12 weeks - which in retrospect one would predict was too early. But when they set up the rules for the trial they were not familiar with treating autoimmune disease.

So it is all very complicated but the bottom line is nobody can be sure the results of that trial mean anything.

Would this be the same for patients in the study (or who try RTX in general) who have had symptoms that did not fluctuate (or did every single patient who was selected have a relapsing/remitting type of illness)? I can only speak for myself in that when I had an improvement to a specific symptom, it was striking and noticeable both to myself and to all who know me (vs. other symptoms which have not yet improved). I have not been able to try RTX yet (so for me it was the combination of MCAS meds & IVIG) but none of my doctors would ever attribute what they are seeing to chance or coincidence. I have no guarantee that RTX will work for me but if it does, we will know it has worked vs. it being chance.

I am afraid it does not work like that. Any properly trained doctor will accept that improvement following a treatment may be due to chance or coincidence. That is the whole basis for the complex rules of trial design. If you get rituximab and get better nobody can tell if it is due to the rituximab. Doctors can never know that. They just work on the basis that if they use a reliably tested treatment that the chances are it was the drug that was responsible.

I don't understood how this could possibly be the case? Many physicians assume or wish the patient can get better with "wishful thinking" or CBT/GET or mindfulness/yoga or all kinds of things but when someone actually uses a specific treatment and then gets better and remains better, wouldn't it be from that treatment (especially if the person has been progressively getting worse for several years and did not have a fluctuating form of their illness)? Thanks in advance.

Again, I am afraid that getting better from wishful thinking occurs with all treatments. It is called the placebo effect and for the rituximab trial from Norway there was a 19% placebo response if I remember rightly.

 

[Gingergrrl]

What I think your doctor means is that in other conditions where rituximab is known to work it may take 6 months before you can be sure whether or not there is improvement. I am not sure I would agree with that (as the person who probably has more experience with the drug in autoimmunity than anyone).

Thank you for your detailed reply @Jonathan Edwards. How long would you say is the earliest that a person with an autoimmune condition could potentially start to feel even the smallest benefit from RTX? And on the flip side, if they feel no improvement in six months, would you be fairly confident that it did not work?

In most autoimmune conditions some improvement is evident at 3 months.

Thank you and that is good to know for the future in case I really get the opportunity to try RTX.

It may be that your doctor is simply quoting the results of the Norwegian study - which did seem to show that nothing much happened until 6 months. But the whole problem is that we do not know whether ornate that was a fluke.

I don't think he was quoting the Norwegian Study vs. just speaking of his general experience w/RTX.

The real problem is that Fluge and Mella used a scoring system that worked over a six week period so that the score at 3 months was actually for 6 to 12 weeks - which in retrospect one would predict was too early. But when they set up the rules for the trial they were not familiar with treating autoimmune disease.

I did not realize that and that makes sense.

If you get rituximab and get better nobody can tell if it is due to the rituximab. Doctors can never know that. They just work on the basis that if they use a reliably tested treatment that the chances are it was the drug that was responsible.

Thanks and I understand what you mean now. The doctor would assume it is from the RTX but no way to truly "prove" it.

Again, I am afraid that getting better from wishful thinking occurs with all treatments. It is called the placebo effect and for the rituximab trial from Norway there was a 19% placebo response if I remember rightly.

How would they determine (from the group who got better) that 19% was placebo vs. a different percent actually "truly" got better (not placebo)? I can understand with a symptom like "fatigue" that is self-reported in which there is no way to measure.

But aren't there some symptoms in which results are truly measurable (and I don't just mean re: RTX)? I'll give some examples: If someone was having anaphylaxis to all food and after treatment they can eat all food without ANA or any allergic reaction, wouldn't that be concrete and measurable? Or if someone failed every breathing/spirometry test for 4-5 years but after treatment they could pass the test, or if someone could not walk without wheelchair for several years but after treatment they could walk, or (last example, I promise!) if someone had daily BP of 80/50 but after treatment their BP was 100/70, etc, aren't some symptoms truly measurable and not placebo?

I just want to understand better and very much appreciate the info/dialogue!

 

[BurnA]

How would they determine (from the group who got better) that 19% was placebo vs. a different percent actually "truly" got better (not placebo)? I can understand with a symptom like "fatigue" that is self-reported in which there is no way to measure.

But aren't there some symptoms in which results are truly measurable (and I don't just mean re: RTX)?

I'll give this a go, but will stand corrected by anyone with more knowledge on this subject. I hope I understood your question.

Half the patients got RTX, the other half didn't. Anyone who didn't get RTX but reported improvement, falls into the placebo category. How they got better is not relevant really, the point is, this patient group is compared to the patients who got better on RTX. If there is significantly more people getting better in the RTX group then this demonstrates RTX is effective.

There may be symptoms which are measurable but if they weren't measured as part of the trial then they can't be used to demonstrate anything.

In the phase 3 trial there are measurable factors.

 

[Hutan]

Again, I am afraid that getting better from wishful thinking occurs with all treatments. It is called the placebo effect and for the rituximab trial from Norway there was a 19% placebo response if I remember rightly.

I don't think there is much evidence for getting better as a result of wishful thinking.

Reported improvement in a control group can be a result of many things - including patients thinking they are getting better as a result of wishful thinking and recording that in a subjective questionnaire. (edited for clarity)

With a disease with a variable course, fluctuations in illness severity are going to be a pretty major component of the recorded improvement in the control group.

 

[Gingergrrl]

Half the patients got RTX, the other half didn't. Anyone who didn't get RTX but reported improvement, falls into the placebo category.

Thank you for explaining that @BurnA and that completely makes sense now. I thought Dr. Edwards was saying that 19% of the actual RTX group that reported improvement were really placebo. But you are saying 19% of the control group (non-RTX) group reported improvement so are therefore placebo. Unless they may have done some other treatment at the same time (although I assume this is accounted for and not allowed)?

In my case, if RTX overlaps with IVIG, I will never really know if continued improvements were from the IVIG alone vs. the addition of the RTX. But if I am done with IVIG and start RTX, it is more likely that it is from the RTX. In my case, I am certain there is no wishful thinking involved but I do believe in prayer/miracles that can occur which are greater than anything under my own power.

In the phase 3 trial there are measurable factors.

Do you happen to know what the measurable factors in the phase 3 trial will be? The things I mentioned (like heart rate, blood pressure, breathing/spirometry tests, allergic reactions/anaphylaxis, or even CPET tests seem truly measurable to me (vs. something like "fatigue" or "PEM" which I am not sure how is measured outside of someone's self report)? I also think functional issues or ADL's & IADLS's could be measured plus something like the "six-minute walk test" or someone requiring a wheelchair and then no longer needing it, etc.

 

[BruceInOz]

then you cannot be sure that the results are not just the result of wishful thinking on the part of physician or patient.

I don't understood how this could possibly be the case?

@Gingergrrl, Jonathan's comment is about good science vs bad science. Anything that is measured in a trial is going to have some probability for being just a chance occurrence. Typically results are reported as having a 95% confidence level meaning there is still a 5% or 1 in 20 chance of it being a fluke. So if you measure a whole heap of stuff and end up with 20 different observations, there is now a very strong chance that one or more of them are just a fluke. If you search through all these results, find the one you like best and just report that, that would be very bad science (it's called p-hacking).

To do good science you pre-specify before you start collecting data what the measurement that you are going to report will be and report that as your primary outcome. This means there is a greater chance that your result is real compared with a p-hacked result. Any other patterns you may find in the data that were not pre-specified may still be interesting and should be followed up in a new study with newly collected data with the observed pattern as the pre-specified outcome. Until that is done, you just have something interesting that may or may not be significant.

Jonathan is saying (I think!) that the pre-specified result of the Fluge & Mella study was the 3-month result. The 6-month result is interesting but we don't really know it's significance until a new study is performed with that as the pre-specified outcome. To overstate it's significance would be committing the sin of p-hacking.

 

[Gingergrrl]

Jonathan is saying (I think!) that the pre-specified result of the Fluge & Mella study was the 3-month result. The 6-month result is interesting but we don't really know it's significance until a new study is performed with that as the pre-specified outcome. To overstate it's significance would be committing the sin of p-hacking.

Thank you and that makes sense. Believe it or not I studied statistics when I did my masters thesis (in the late 90's) but sadly did not retain a lot of the info. But I get it that if F&M chose 3-months as their result then they cannot, after the fact, go back and change it to 6-months as their result. But for those doctors who know that RTX usually shows results at six months, couldn't we be fairly confident that a certain percentage had a legitimate improvement at the 6-month point even if the study cannot claim it b/c it was not the original p-value that they defined?

 

[Jesse2233]

Good question @Gingergrrl

Phase 3 is in effect the follow up to "an interesting finding" you mentioned? @BruceInOz

 

[Jesse2233]

@Jonathan Edwards very interested to hear your thoughts on the science behind Ampligen and its clinical trials

 

[deleder2k]

Half the patients got RTX, the other half didn't. Anyone who didn't get RTX but reported improvement, falls into the placebo category.

Just as likely as it is due to placebo, it could be attributed to the fact that symptoms fluctuate.


@Gingergrrl, you raise several interesting questions. You'll find answer to them by reading the two latest Rituximab studies published in PLOSOne. In the last study you can see when every single patient included in the study reported improvement in graph they provide. It is available here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129898

Information about the phase 3 study is available here. It says how often and how much RTX they get, and what kind of primary and secondary endpoints they use. Look here: https://clinicaltrials.gov/ct2/show/NCT02229942

I'll also recommend watching presentations from the study coordinator + two of the doctors:

 

[Gingergrrl]

@deleder2k Thank you for these links and I just bookmarked your post so I can read/watch them when I have a chance. I really appreciate it!

 

[Gingergrrl]

@deleder2k I finally had a chance today to read many of the articles that I had bookmarked and watch some of the videos.

For some reason, I cannot get the sound/audio to work in the above video on my computer (iMac). The video itself works but not the sound. Does the sound work when you watch it? I have sound on other videos so I know my computer itself is okay!

 

[AndyPR]

@deleder2k I finally had a chance today to read many of the articles that I had bookmarked and watch some of the videos.

For some reason, I cannot get the sound/audio to work in the above video on my computer (iMac). The video itself works but not the sound. Does the sound work when you watch it? I have sound on other videos so I know my computer itself is okay!

Sounds works OK for me on that video - also on an iMac.

 

[deleder2k]

I don't know. You could try another browser than Safari and see if it works.

 

[Gingergrrl]

I don't know. You could try another browser than Safari and see if it works.

I actually use Chrome but that is a good idea to try a different browser. Thanks!