Rituximab and placebo response

This section of a post has been copied from this thread: Jen Brea: My ME is in remission
And subsequent posts discussing it moved from that thread.

I have chosen a slide of the results from the open label extension rituximab study for my PACE presentation to my old academic unit on Wednesday. The more I look at it the more I realise that if you want a placebo effect (which Knoop and White said is how CBT works) then rituximab is a darn sight better than CBT. And the phase 3 study shows that plain water is pretty good. What is remarkable is that for a period of three years without let up a good proportion of patients go to zero score on fatigue (the score is actually maximum on the scale but presumably means 'no fatigue').

This is actually pretty surprising and thought provoking. It seems that if you sell your treatment right you can get a substantial proportion of PWME to get well and stay well for three years with no active ingredient.

 

. I’m not so familiar with the rituximab trial, so forgive me. This is a stupid question or answered elsewhere, but was there any kind of tracking of activity beyond self reported? Like actometers or whatnot. I’m not surprised by the idea that a placebo effect could improve activity short term, or improve long term self reported fatigue, but if there was significantly increased activity, I would be forced to reconsider my ideas on ME totally. It seems that actually increasing activity long term is difficult even with placebo, or id expect the PACE trial to have had impressive data around activity or other functioning.

 

This may be a little on the side, but since Rituximab and placebo are touched in the discussion here, I might bring it up as well.
Have not read the rituxme study in detail,
later when considerably improved. Maybe complicating things unnecessary, but what I would kindly ask, is if someone who know the facts and details of the study, could say something of how to interpret the results, especially interested in figuring out what the placebo group, if anything, might tell us? We know of the null-result, that rituximab had no significant effect. That’s fine.

But can anyone who actually have knowledge in detail elaborate a little in regard of the placebo results?

This is my concern: the dynamics of the disease is the same. At the same time there will be quite a considerable difference between a “new” patient able to influence PEM and the “old” patients living in or close to constant PEM. So one has to take into consideration that patients are affected differently, depending on how long they been ill, how quick they managed to stabilize and minimize harm and so on. That’s why it is important to be aware of both short and long duration.

But the important thing I would bring up here, is the dynamics of the disease, then thinking of the multi-system nature, the heavy symptom-burden, such. To simplify: it is an harsh disease. It is not “fatigue/tiredness”, not unspecific and unclear.

When the above - if that is a valid argument -
I just don’t understand how ME-patients in general can have significant lasting placebo-responses? Is that the case? Do we know anything about that? I guess I can imagine short spans of placebo but lasting over a longer period of time? I just don’t get it. Just as an opposite theoretical example, I could more easily understand that you could have better possibility of placebo if you had a patient population with only one symptom. That said, I guess one could argue that if you have many symptoms and you experience improvement in one - you could actually call that a placebo effect. On the other hand when it comes to the latter, the important thing is the multi system dynamics. So if you really experience improvement you should theoretically experience improvement overall on all symptoms.

Based on this, my simple assumption is that if you have a large number of placebo in a patient population and/or very significant improvement, you probably don’t have ME-patients at all or maybe only “new” patients. Is that a valid argument? We know of the chaos, all inclusion problems, things like these that influence every study on ME, probably also the multicenter Rituxme-study, but probably less than other studies. But as long as no biomarker there will be bias even in the most well selected patient population.

But that ME-patients, correctly diagnosed CCC should have long lasting placebo-effect with considerable improvement just seems wrong.

What I really would like, if possible, is that someone shortly summarize the data, - what does the data of placebo group actually tell us.

 

Yep

 

There are researchers who think responding subgroups are present and are working on ways to identifying them

 

Shall not make a mess of this CCI thread, just a final word.

When studying a population of ME (correctly diagnosed) I would, due to the strong systemic component, imagine this to a greater extent:

either the drug work or it doesn’t. And with the important thing in addition. You will probably have the chance of few placebo responses.

I can’t make any sense out of this, if there actually are patients who have significantly improved for years? If fatigue, guess so, but ME is not fatigue.

I will dig firsthand into rituxme next.

 

I am not sure what you are meaning by multi-system nature of the illness. This is often quoted but I don't think we have any evidence for it. There are lot of symptoms but the mechanism is unknown.
That being the case I am not sure why recovery should seem 'wrong'. The 'placebo' effect covers a whole lot of processes. I agree that it is perplexing that long lasting improvement follows inactive treatment in a number of cases but that seems to be the reality.

I cannot transfer the graph I have to the thread now for some reason. But basically the primary outcome measure of fatigue score seems to go to no fatigue for about a third of cases in the open trial and stay there for three years.

I don't think there is any good reason to think there are any true drug responders in these studies. That should have at least tipped the result in the final trial to favour the drug and in fact more people in the placebo group reported improvement.

 

I agree that ME is not fatigue but I think patients who still felt significantly ill would not rate fatigue as nil. 'Fatigue' is accepted as the index of feeling ill in the absence of a better term.

 

Didn't ALL participants get cortisone and antihistamines, too? I may misremember.

As indicated here (I don't have access to the phase 3 trial paper itself so can't check there):
https://www.s4me.info/threads/b-lym...rial-2019-fluge-et-al.8874/page-3#post-158489

In my case, cortisone helps a lot (but I only took it short-term, and the improvement is lost after stopping cortisone).

 

I think it was @Hip who had said 20mg of Prednisone seemed to prevent PEM episodes. Scary drug long term but interesting.

 

Wrong is imprecise and I would change it with “unlikely”.

Multi system nature of the illness or systemic, my meaning: many/heavy symptom burden from different systems, immunological, OI, sleep and so on.

At the bottom line, I just fear that there could be quite a considerable amount of misdiagnosis here if the, frankly speaking, quite meaningless “fatigue” is the keyword.

That placebo solves ME with long lasting effect, well that seems unbelievable knowing the dynamics of the disease. Guess I can’t argue against it, but I don’t buy it, and I think we need to look very close at possible bias.

But guess I should start reading the study first..

 

Yes but the effects would only have lasted six hours. And we know that these agents do not routinely have a lasting effect onPWME. When I said plain water I was being more or less metaphorical.

 

I found it in the paper:

"One hour before infusions, all patients received premedication with 1 g of oral acetaminophen, 10 mg of cetirizine, and 8 mg of dexamethasone (Supplement 1)."

Wow, 8mg dexamethasone is A LOT. I had severe adverse reactions with 2mg, but besides that I felt much better indeed.
That may explain some things re. "placebo effect" or adverse events...

Edit: 2mg dexamethasone helped, in my case, ca. 1 day. Everybody is different pharmacometabolically, so in some it will last longer or shorter.

Edit2: But the Placebo group didn't just get plain water.

 

I suspect too that objective parameters would not be indicative of "no fatigue" in the group with placebo. I dont think patients with long term illness are suited to judge their own functioning level after being sick so long, unless they directly compare their activity level to that of pre-illness. The over willingness to look for improvements makes subjective questionnaires kinda useless without other activity tracking in my opinion. That being said, although i cant quite get my head around people having recovery placebos in ME/CFS, it might very well be possible

 

Me too. And I doubt it was placebo because no other drug did anything whatsoever and this one made me able to walk around the hospital ward some having been bedbound for many months previously. Wore off after 24 hours or so.

 

https://www.s4me.info/threads/stanford-community-symposium-2018-fluge.6037/#post-113118

 

An odd thing I recall about the Rituximab trials was that, of the patients who improved, many did not start to get better until months later. Fluge and Mella had a hypothesis for why this might be, but, since the trial ultimately turned out null, it remains an odd delay for a placebo effect.

I suppose in the final trial some (maybe all) patients may have been aware of the "delayed effect" from the earlier trials, but it would still be curious that this delayed response showed up in the earlier pilot trials.

 

It's quite possible that they actually did feel a bit better. Just not significantly enough to make a difference. Which is the fatal flaw in all psychosocial research. Making "feeling a bit better" as the end-point answers one question, it just doesn't solve any part of the actual problem.

Beer makes me feel better. For 1-2h. Not always, but generally. By PACE-style research beer is a cure because on some questionnaires sometimes I will feel a bit better. If you fudge up the population statistics you absolutely could do PACE and switch their BS with beer, chocolate, massages, whatever, and have the exact same questionnaire effect.

Questionnaire-based research is junk, that's why it has to be secondary to an objective measurement. Real scientists understand the difference. Charlatans simply don't care, they are motivated by self-interest and nothing else.

 

I wonder why the anecdots of privat patients were nearly all negativ, only small improvements or even worsening. I think in these settings the expectation to improve must be as high as in the studies and it was very expensive for them, so you would think they would exaggerate small improvents even more than trial participants?