Rituximab and placebo response

I think on this one it's safe to say that it simply shows the problems with self-reports from arbitrary questionnaires, particularly that they are detached from objective reality. Maybe a competent bespoke questionnaire would have more accurate results but the typical ones used have little relevance.

In fact, it even shows that it's completely unnecessary to go through the trouble of making up an elaborate system to convince people, since questionnaires don't even capture much that has to do with the illness itself, they rarely ask the right questions and often have misleading options. So the millions wasted on PACE were even more wasted than initially thought as it could have been done for 1/10th the price and still gotten the same illusionary benefits. But then it would only have been 1/10th as convincing, sunk cost and all.

Asking the wrong questions generally leads to useless answers. That probably explains 90%+ of the usual "placebo" response in ME research, which isn't even placebo so much as an uncertainty baked into the questionnaires themselves. Like asking people to guesstimate their weight after not weighing themselves for a period of time. Some will get it pretty close. Others not. But asking the same a bit later will have the same general variations but some who were close would be less so and vice versa. It's just noise.

 

I don't think it is as simple as that. What I am referring to is the fact that in the unblinded study raw data you see major swings in self-reported measures, considerably greater than I have seen in the PACE data, and these swings repeatedly go up and down in exact synchrony with the supposed time scale of improvement and relapse expected in a response to rituximab. The weird thing is that these people relapse when their B cells returned, just as would have been predicted from a real response and then they improve again with another dose. Whereas in the initial blinded study there was no pattern to any of the data, once it was thought that there might genuinely be an effect and the time frame from autoimmune disease was understood, the data followed expectations with great regularity. And the synchronised ups and downs went on for up to three years.

If the proportion of people showing this sort of pattern had had a genuine response to drug then it is very hard to see why it did not show up in the blinded phase 3 trial as a difference between treatment and control.

I have no vested interest in thinking that there is placebo response in ME and it is certainly not 'convenient' for me as an explanation. But it seems to be the reality and I have not yet seen any argument as to why it should not be the reality. Maybe this is bias based on both patient and investigator expectation and therefore not pure classic placebo response but if you look at the graphs it is very hard to see how it can be anything other than expectation bias.

 

I don't remember how much was published with the trials. There was a paper on autoantibodies with Carmen Scheibenbogen but I found it hard to interpret. I have probably forgotten anything that was published simply because I am pretty sure they found nothing much, other than of course that B cells went away and came back.

 

So @Jonathan Edwards , it would be fair to say you believe ME/CFS is not a disease and ME/CFS sufferers can have remissions/improvements that last for years due simply to the placebo effect?

 

The certainty is all yours Duncan.

 

Well, in your capacity as a medical doctor, do you know of any diseases that have a history of a swathe of patients with remissions/improvements that last for years attributed to the placebo effect? Is there reasonable precedent here?

 

I am not sure that comparison with other diseases has proved terribly helpful in working out what is going on in ME on any front. I think there may be more uncertainties here than we understand. But if the evidence points to a placebo response I think that has to be taken reasonably at face value.

 

We couldn't agree more here.

Again agreed.

No. That is inference, and it belongs imo more in the psych community than a discussion of ME/CFS as an organic disease. This theory, this line of thinking, leads over a cliff. You couple that with your stated inclination that ME/CFS is NOT a disease, and where does that leave us?

 

It leaves me giving up trying to respond to a string of non sequiturs, Duncan.

 

It's a non sequitur to suggest that a belief that ME/CFS is not a disease, coupled with a belief that ME/CFS patients can enjoy improvements after medication that last for years, but due solely to the placebo effect, might present potential problems?

If so, I'm guilty. But you've managed to not address my observations and concerns. You also have not provided any sort of relevant precedent for the years-lasting placebo theory.

 

They did this one on pyruvate dehydrogenase function https://insight.jci.org/articles/view/89376

 

What self-reported outcome measures are you speaking of here? Given we are talking about placebo responses and self reported outcomes, is it possible that in the unblinded study the trial design (or things outside of the design) inadvertently boosted expectations, without the investigators realising they were doing so? I imagine that in an unblinded study it can very difficult spot all the signals that participants might pick up on?

 

I have just been informed, by somebody who knows more about the trial than me, that Fluge and Mella changed the dosing approach between Phase 2 and Phase 3 of the trial. That's worth consideration as a reason why the phases got different results.

 

It's probably worth remembering that, between the trial and placebo groups combined, 70% of the patients did not respond (105 out of 151).

26% of those who received rituximab (20 of 77), and 35% of those who received placebo (26 of 74) responded, making the combined response rate 30%.

I wonder if the response rate was lower in the rituxumab group simply because the side effects of the drug itself impeded the manifestation of any kind of placebo effect. On the other hand, you might think that an "illusory" rituximab response rate might be higher, as the drug's side effects would signify to the patients that that they were indeed getting the drug.

I guess one interpretation might be that 30% of ME patients are experiencing placebo triggered effects to the point of self-reporting improvement during a double-blinded study. I'm not sure how surprising this is. How does this compare to the placebo response rate in other diseases, where the nature of the disease mechanism is better understood?


[ ETA: Looking for information on "typical" placebo response rates, the figure of 30% does seem to come up going back to the 1950's.

A 2015 article on Placebo-Associated Blood Pressure Response found:

From an article from Harvard Medical School on The Power of the Placebo Effect:

]

 

I'm sure this will have been covered somewhere : ie the use of saline-infusion as the placebo given that this is provided as treatment for ME and CFS in some places?

Also;
can anyone shed any light on this Julia Newton research (funded by AfME) from 2016/2017

• Full title
  The effect of intravenous bolus's of fluid upon cardiac and brain function in chronic fatigue syndrome (CFS): a proof of concept study

https://www.hra.nhs.uk/planning-and...ies/research-summaries/action-for-me-cardiac/

I have been unable to find any details.

 

I would like to see the results of this too.

 

even though i think saline produces really intense changes in ME/CFS symptoms, I also thinik the effect is somewhat short lasting, so idk if I'd think it was responsible for the improvements

on the other hand there is such a thing as an active placebo. as in, something does something but we also fill in the blanks with our hopes and optimism or current state of mind to the extent that the original signal is obscured somewhat. with saline this might look like: the psychological benefit of returning to a physiological state of "normal" even for a short time, periodically, thus raising ones overall morale

throw in some antihistamines and steroids and i could see why at the very least self reported fatigue would change a lot

however, the thread was started with what i believe was an inappropriate analogy to cci surgery as placebo... and nobody answered why that would be an appropriate analogy if the rituximab study didn't track step counts or any objective measures, as some of the ppl who have recovered from ME due to cci surgery have.

 

The problem is that for CCI we do not even have controls, so it makes no difference whether measures are objective or subjective. Moreover, in this context step counts are subjective measures. Placebos are very likely to be able to improve step counts. What they do not improve are things like blood tests.

 

In a PWME, a placebo is not going to produce a persistent improvement in step count. Unless the PWME was currently doing less exercise than they actually could. Which is unusual - most of us are doing the max thay we can without making ourselves more ill. If someone increased their activity because a placebo made them think they were better, then PEM would come to bite them on the ass after a while, and they'd go back to how they were before or even worse. If placebos could improve our ability to do physical activity, then GET/CBT wouldn't be dangerous for us.

Didn't we criticise the PACE trial for not using measures of physical activity.