Open Norway: Plasma cell aimed treatment with daratumumab in ME/CFS (ResetME) - Haukeland University Hospital

[V.R.T.]

It’s not 72 months, it’s 72 weeks including a 3 month run in period before the intervention.

I totally forgot that! Of course. Well lets say 9 months then, so six months after for unbinding. Why does the follow up have to remain blinded six months after the injection is given?

Im just curious why you need such a long blinded follow up period, and when you could unblind after 6 months post treatment, do preliminary results and then follow up for as long as you liked after that.

 

[Peter T]

Changing a pre written protocol during the study, not for objective scientific reasons but rather to assuage our wish for an answer sooner is a potentially worrying precedent.

I understand it is hard to wait: it was hard to wait for the new NICE ME/CFS guidelines, it was hard to wait for the DecodeME prepublication draft, etc. However I strongly feel, with so much poor quality and inconclusive ME/CFS and Long Covid research, ensuring not only the best quality research but also the unquestionable appearance of unimpeachable results is more important than speed. Not only does good science need to done.

I have always found the idea of seeking a drug treatment by a largely scattergun approach before we have developed an understanding of the underlying aetiology strange. Obviously I would not reject a treatment that is demonstrated to work because we have not yet demonstrated why it works, and an effective medication would give us important information relevant to progressing an explanation of the disease mechanism. However for me this feels like jumping the gun.

 

[V.R.T.]

Changing a pre written protocol during the study, not for objective scientific reasons but rather to assuage our wish for an answer sooner is a potentially worrying precedent.

To be crystal clear:

I am not advocating for the study protocol to be changed now, I'm asking why they chose 72 months.

 

[V.R.T.]

also the unquestionable appearance of unimpeachable results is more important than speed.

This is true, but if hypothetically there was a way that with more funding the trial could finish six months sooner with the same rigorousness we need, then we have to find it, because it may mean a significant proportion of that six months worth of post viral suicides and deaths will be responders and be saved.

That's what we're discussing here.

If there's no way to do that then fine but we need to at least discuss it.

 

[Kitty]

Why does the follow up have to remain blinded six months after the injection is given?

Presumably because that's in their protocol. The reasons they've designed it the way they have might not be obvious, but they know what they're doing. We're probably best letting them get on with it.

 

[Utsikt]

I totally forgot that! Of course. Well lets say 9 months then, so six months after for unbinding. Why does the follow up have to remain blinded six months after the injection is given?

Im just curious why you need such a long blinded follow up period, and when you could unblind after 6 months post treatment, do preliminary results and then follow up for as long as you liked after that.

Because all of the bias comes into play for the unblinded followup period, and bias makes it a lot harder to figure out what’s a real effect and what’s not.

 

[ryanc97]

I have always found the idea of seeking a drug treatment by a largely scattergun approach before we have developed an understanding of the underlying aetiology strange. Obviously I would not reject a treatment that is demonstrated to work because we have not yet demonstrated why it works, and an effective medication would give us important information relevant to progressing an explanation of the disease mechanism. However for me this feels like jumping the gun.

I do think it’s impossible to find the underlying biology of the disease with current science.

To me trialing different drugs and seeing what works let’s you work backwards the underlying mechanism, from a data first perspective.

I think FM are on to something that it’s definitely immune system related.

Look at current research. They just pull out thousands of biomarkers and symptoms and find so many different things. It’s quite clear none of them are the true upstream cause.

 

[Sasha]

Thinking about how the responders and non-responders were separated by the responders having higher NK levels, possibly indicating a subset of PwME with a mechanism that daratumumab tackles, is it weird that we haven't seen reliably raised average NK levels in PwME? Or have we?

 

[ryanc97]

Thinking about how the responders and non-responders were separated by the responders having higher NK levels, possibly indicating a subset of PwME with a mechanism that daratumumab tackles, is it weird that we haven't seen reliably raised average NK levels in PwME? Or have we?

Don’t think anyone has done a large scale study of the NK cell distribution in healthy people vs ME patients.

But it would seem the 100-200 range which a lot of us fall into is quite low relative to healthy people.

So nobody knows. I checked the literature.

The blueberry study got healthy athletes from 300 to 600 with blueberry powder.

 

[forestglip]

is it weird that we haven't seen reliably raised average NK levels in PwME?

Well nothing indicated that people with high NK cells had worse ME/CFS. There's the possibility that NK count doesn't have much to do with the illness itself, it's just if you happen to be a person with high numbers, dara can work more effectively.

An imaginary related example is if there was a treatment applied as a skin cream. The study finds that those who wash their skin with a certain brand of soap had better responses, where it might just be that this soap allows the cream to be absorbed more easily. Whether you wash with this soap might have nothing to do with the disease, and no study would find an association between the two.

Though it's not the only possibility for why responders had high NK cells, as has been discussed elsewhere.

 

[ryanc97]

Well nothing indicated that people with high NK cells had worse ME/CFS. There's the possibility that NK count doesn't have much to do with the illness itself, it's just if you happen to be a person with high numbers, dara can work more effectively.

An imaginary related example is if there was a treatment applied as a skin cream. The study finds that those who wash their skin with a certain brand of soap had better responses, where it might just be that this soap allows the cream to be absorbed more easily. Whether you wash with this soap might have nothing to do with the disease, and no study would find an association between the two.

Though it's not the only possibility for why responders had high NK cells, as has been discussed elsewhere.

This is my hope. If the P2 trial is successful and the NK cell correlation holds a lot of PWME are going to want to boost NK cells.

In fact no harm doing it right now, since high NK cells help fight illness and cancer.

 

[Jaybee00]

This is my hope. If the P2 trial is successful and the NK cell correlation holds a lot of PWME are going to want to boost NK cells.

Are you going to open a tropical blueberry farm in Singapore to cash in? There actually are heat tolerant blueberry varieties.

Maybe the real trick is mixing blueberries with durian and rambutan—could be the secret to unlocking sky high NK levels.

 

[ryanc97]

Are you going to open a tropical blueberry farm in Singapore to cash in? There actually are heat tolerant blueberry varieties.

Maybe the real trick is mixing blueberries with durian and rambutan—could be the secret to unlocking sky high NK levels.

well sadly or not sadly I don’t know anyone else in my country with this disease.

Zero media coverage also.

Anyway in my non scientific opinion, I have a gut feeling that high dose Vit D is the most improrant thing out of all supplements you can take for NK cells.

I only quote blueberries because of the study. It’s the only study that was done in humans and not cell lines.

There’s also a study on the Indian herb Neem and Ashwagandha. And some Chinese herbs.

The neem study injected neem extract in mice and got like a 2.2x increase in blood NK cells.

Ashwagandha was in humans and got like a 1.3x increase.

In general there are a lot more studies on NK cell function than count. Nobody seems to study counts as much.

 

[Kitty]

Nobody seems to study counts as much.

I seem to recall Jonathan saying that it varies a lot and doesn't usually mean very much. If I've got that right, it could be why no one's spent time and money doing it.

It might mean something here, but it looks as if we'd have to base our understanding on the eventual study outcomes.

 

[rapidboson]

Can anybody point me to the study protocol?

 

[Sasha]

Can anybody point me to the study protocol?

It would be good to have that edited into the first post of the thread.

 

[hotblack]

These?

Trial info in Norwegian

Plasmacelle-rettet behandling med daratumumab ved ME/CFS

Hensikten med denne studien er å undersøke om behandling med daratumumab gir klinisk gunstig effekt på symptomer hos pasienter med moderat til alvorlig ME/CFS sammenlignet med placebo, og hente inn ytterligere data om toleranse og bivirkninger.

www.helse-bergen.no

English language fundraising page with 3 documents (the two useful ones linked directly below)

English The ME-fund

ME-fondet is a Norwegian non-profit foundation dedicated to supporting biomedical research on Myalgic Encephalomyelitis (ME/CFS). We raise funds for high-quality, independent studies that seek to uncover the underlying mechanisms of this severe disease and bring hope for better treatments.

www.me-foreningen.no

Clinical trial information – Daratumumab treatment for ME/CFS
Detailed information for those considering participation in the Daratumumab drug study

 

[V.R.T.]

Thought I'd mention something that occurred to me that made me hopeful. If the daratumumab effect is real, it's heartening that the pilot participant in the social media video who went back to work from mod/severe said it was exercise that put her in a wheelchair in the first place when she spoke about being able to exercise again.

I have heard very few spontaneous improvement or recovery stories from people who worsened a lot from GET etc, and have always been concerned that perhaps we have had some change from the repeated crashing/overexertion that means we couldn't improve again. So if this effect is real, it is an indication that this isnt the case.

 

[OrganicChilli]

They've updated their website: https://www.me-foreningen.no/om-oss/stott-me-foreningen/me-fondet/english-me-fund/

And claim this:

The Haukeland team believes that ME is caused by an immune response after an infection involving autoantibodies that disrupt the regulation of blood circulation in the body, especially during exertion and stress. Lactic acid builds up very quickly even with little exertion, patients become dizzy and experience brain fog. The drug used in the study, daratumumab, is used especially in bone marrow cancer (myeloma). Because the myeloma cells share the same antigens as normal plasma cells, daratumumab can reduce plasma cells and their products: antibodies.

I'm confused about the lactic acid statement? Iirc we don't have evidence for that.

 

[Utsikt]

An interesting report.
Sjogren's is a difficult condition to interpret but it may be a good target for an anti-plasma cell agent because it is associated with hypergammaglobulinaemia.
It will be interesting to see how far this approach can be extended to other autoimmune diseases. If it works in Ro and Sm positive lupus there would be quite a good case for trying it in a small group of ME cases (maybe with positive ANA initially).

The reason for picking people with ANA is that going back over the last twenty years of B cell/plasma cell depletion for autoimmune disease (I did the first formal proof of concept trial in RA in 2001 and the first trial in lupus a bit later) it has become clear that although ANAs directed against protein antigens are likely pathogenic they do not go down much with anti-CD20 and clinical benefit is uncertain. A significant minority of people have such ANA - including healthy people - and I think if ME is autoantibody driven at all it is likely to involve such antibodies in at least a few cases. The story is very complicated.

I am not particularly suggesting that Oystein Fluge changes his current study. But I think if one is going to select cases at all something like ANA is about the only marker of B cell involvement likely to be useful. The same probably applies to Long Covid. I am not impressed by the various reports of other autoantibodies in Long Covidor even any evidence that it involves B cell activation.

Most side effects from rituximab are transient. The only major issue I am aware of, apart from infection, which will occur with any of these agents if Ig levels go down, is sterile pneumonitis with ritux. We identified that very early but the drug company was slow to document it. It may be that sever side effects are less with daratumumab but do we actually know that? I am not sure what you mean by 'heavy' ritux? If daratumumab is going to be better it will have to be 'heavier' in terms of Ig reduction I think.

I was looking for something else and found these comments. Do you still think ANA might be relevant in the context of Dara for ME/CFS?