Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

[Evergreen]

Did anyone look at the recruitment of Ritux P2? Is there any info on this?

I just think on a first principles basis it is impossible to go from 3k to 9k steps consistently on a pure placebo effect. How many of you would be able to do that, and consistently hold it for a year?

Therefore, IMO this deduction leads to me thinking there is something wrong with the Ritux P2 step count measurement. Especially given the step counts in P3.

Either recruitment or the measurement was wrong. Again this argument is built on the idea of tripling step count over a year being not possible unless being cured.

Here's what Fluge et al. themselves write in the 2019 paper on the phase III trial (RituxME):

This discrepancy between results of RituxME and previous trials has several possible explanations.
First, placebo mechanisms…
Second, …natural symptom variation over time…
Third, unintended patient selection effects may have contributed to the positive results, especially in our open-label rituximab maintenance study (7)…[that's the 2015 phase II study, bolding added]
[Fourth] In the RituxME trial, the rituximab maintenance doses were 50% to 60% lower than those in the previous maintenance study. However, rituximab dose reductions are not a plausible main cause for the lack of clinical efficacy because early responses should nevertheless have been more frequent in the rituximab group than in the placebo group.

That third point is the one that is relevant to your question about recruitment. They're saying that the way they selected patients in the phase II trial may have been what created a (false) positive result in 2015.

All 29 patients in the 2015 study fulfilled both Fukuda and Canadian criteria, but if I've counted correctly, 22/29 had participated in previous studies by Fluge et al. That might make them an unrepresentative sample. For example, those early trials might have attracted more people with an autoimmune family history, because Fluge et al's hypothesis that "ME/CFS in a subgroup is associated with a variant of an autoimmune pathomechanism" was in the public domain. Or they might differ from the wider ME/CFS population in some other way.

On the idea that massive increases in step count are not possible unless someone has been genuinely cured by an effective treatment, I don't agree. If you look at actual data of people with ME/CFS, there are always some whose physical function scores shoot up by a large amount, even though we don't have effective treatments yet. Some drop back over time, but more remain at the higher level.

 

[Jonathan Edwards]

IF the Ptwo study ultimately turns out successful, would it be any use to ask patients what symptoms improved first?

It's an interesting idea. My guess is that the pathways linking one to the other operate more or less in real time day be day so that you won't get much differential observing over weeks but that might be wrong.

 

[hotblack]

I figured people would improve slightly differently just as they’re ill slightly differently.

That each of us has slightly different symptoms we see as dominant is reflective of that along with what @Kitty says about noticing different things (I sometimes take painkillers for a headache and realise bits of me I didn’t realise were hurting feel better). And of course we live different lives and many have been ill for many years so may have picked up other things along the way. We may well all get better in the same fundamental way as we got ill, but may experience it differently.

 

[Rick Sanchez]

I figured people would improve slightly differently just as they’re ill slightly differently.

We just don`t know though, since no intervention in MECFS has ever been found to work.

Having a questionnaire ask what the first sign of improvement was could be very low effort for high reward. But maybe you don`t want to burden patients with too much.

But yeah the most likely outcome would probably be that the questionnaire wouldn`t be of much if any use, and that it would just end up as noise. It`s just the recent genetic studies that have gotten me curious. It feels like we are narrowing in for sure now.

 

[hotblack]

We just don`t know though, since no intervention in MECFS has ever been found to work.

Agreed. I think it would be difficult to tell if a symptom is a ‘brain’ symptom given how little we understand about what is ‘brain’ and ‘not brain’ (my view is it’s very blurry) and given all the other points I mentioned that may confuse how people report what/how they improve. But that’s just an opinion and I agree getting information from a questionnaire may be interesting.