It might be interesting to discuss what a failed trial means, not necessarily only in terms of biology but also in terms of trials. Would it mean that in the current state, without any pathological understanding of ME/CFS, that non-placebo controlled trials with positive results would be even more worthless or perhaps even useless because multiple trials have shown both subjective and certain measurements like step count improving despite no efficacy? What would that mean for drug trials in ME/CFS in general? Go straight to a blinded phase or dose-response trials? F&M's response to RTX seems to have been paying attention to fluctuations and step count. Could there be another learning? Why did PACE not show such improvements, or did it do exactly that?
Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al
V.R.T.
Senior Member (Voting Rights)
I think this should be standard. If F&M had done this with dara we'd be much further on by now.
V.R.T.
Senior Member (Voting Rights)
Can you say anything about any more targeted projects you're aware of? All I can think of is the CA10 investigations that JEs pain colleagues are setting up.
Which part would be standard? I think this may be an oversimplification. A small placebo-controlled trial might not have told us much more (just like it didn’t in RTX) and a larger trial placebo-controlled trial is not always that easy to justify and find funding for when there is no other data. Would people have as willingly donated to the current trial had there been no open label study?
V.R.T.
Senior Member (Voting Rights)
I mean that F&M should have included controls in the pilot. If none of the controls had had sustained improvements like the improvers who got the drug did, we could be a good deal more confident that the results are not placebo.
What sample sizes are we talking about? Because from RTX we know that a portion of people on placebo do report sustained improvement. Other than that it was the negative but maybe positive results at a different timepoint of the small placebo-controlled RTX study that launched the negative larger trial, so I'm a bit sceptical that just adding a few controls to the open label study would have given us much more knowledge.
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V.R.T.
Senior Member (Voting Rights)
I think we could debate this til the cows come home but I disagree.
Quite possibly.
At the same time one must also consider the opposite scenario for which there is already a known history in ME/CFS: Smaller placebo-controlled trial with negative results still sometimes need a large follow-up because of Type II errors or post-hoc analyses showing something interesting.
V.R.T.
Senior Member (Voting Rights)
The responses in the ritux pilot do not look like the dara ones - someone posted them in one of these threads the other day. They are not anything like as sustained or as large.
In phase 2 ritux failed in its primary outcomes but they went ahead because of secondary stuff iirc.
I'm not saying dara definitely works but the scenario is not identical.
If F&M had included controls, We would at least have some information on whether sustained 'responses' like in the dara pilot occur in ten pwME who recieve a placebo. And I think that would be valuble whatever it said.
That did not seem very convincing. What @Murph posted a while ago and @Evergreen discussed a while ago, does not suggest that substantial differences. The results are somewhat more consistent and slightly better (which might also be a necessary criterium for F&M to pursue things in the first place) but I don't think they are of a different kind per se. There exists large and sustained improvements in RTX samples (for example there are some with sustained improvements after 6 years, even if they are the small minority) so it's a bit a matter of sample sizes, recruitment factors etc.
Yes and here we see plenty of talk about NK cells with that being only a post-hoc analysis, which are the type of things that are bound to show up in small trials. Certain issues will always remain.
Yes, 10 controls would probably have given a quite bit more information, but of course would have taken longer and required more funding. More useful data is always better, no arguing that. If the argument is for a 20 person controlled trial, does it make more sense to do a 60 person controlled trial straight away and how easy is it to get funding for that if you have no other data?
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Utsikt
Senior Member (Voting Rights)
As a layperson wrt to trials, but with experience from project management, I thought the idea was to build more and more reliable information as you go, because there is always a tradeoff between the cost of the trial and the reliability of the data.
Most ideas will not pan out, so testing every idea with a full scale trial is simply too reaource intensive. So you do a small and possibly uncontrolled trial to see if there is at least a chance that a larger trial will be positive. In product design this is similar to the concept of MVP - minimum viable product.
Arguing after the fact that we’d have been further along if they did a more comprehensive trial from the beginning is a non-starter, because at the time they made the decision on what kind of trial to do, they didn’t have enough information to justify the use of resources a larger trial would require.
Most ideas will not pan out, so testing every idea with a full scale trial is simply too reaource intensive. So you do a small and possibly uncontrolled trial to see if there is at least a chance that a larger trial will be positive. In product design this is similar to the concept of MVP - minimum viable product.
Arguing after the fact that we’d have been further along if they did a more comprehensive trial from the beginning is a non-starter, because at the time they made the decision on what kind of trial to do, they didn’t have enough information to justify the use of resources a larger trial would require.
Agree. My inital question was more so about how to run trials and how one can build more and more reliable data if it turns out Dara is negative, which would quite strongly suggest that one currently can't get much reliable information in open label trials of ME/CFS (it would also suggest a much higher rate of natural medium term recovery or something of that sort than is typically suspected under certain recruitment conditions etc). What alterations could be made in the future to hopefully get more reliable data? It would be nice to learn something, just as something was learned after RTX. For example does one place more focus on having clinical cohorts of patients that are regularity checked, focus on improving activity tracking (some devices might be iffy) etc..
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Utsikt
Senior Member (Voting Rights)
And a lot less phase 1s because they’d require far more resources to do.
Minimising the amount of failed p2s isn’t inherently positive.
Yann04
Senior Member (Voting Rights)
Agreed. The problem is a very large chunk of people doing pilots aren’t exactly looking to find out “the rigorous truth” but to get more funding / create advertisment-hype. When a certain group has every single one of their pilots a success. The signal provided is essentially zero, unless they have some objective data they publish and people like this forum can compare between trials and flag the one that “stands out”. But in most cases it’s just a couple questionnaires.
Obviously this is not the case for F&M. But it is for much of the rest of the field.
Utsikt
Senior Member (Voting Rights)
Absolutely.
A good scientist would still start with a p1 in most cases due to resource constraints (meaning no controls in some cases) and to limit the risk of adverse events (meaning as few participants as possible).
Kitty
Senior Member (Voting Rights)
Yes, and we shouldn't forget that taking part in a trial inevitably changes people's thinking and behaviour. Changed behaviour is a risk in ME/CFS because it could lead to a nasty crash.
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