Is it time for T cell targeting clinical trials in ME/CFS?

Jonathan Edwards said:
I don't see any problem with this. When I did the first trial of rituximab I made up the drug myself, and monitored the infusions myself, taking the patients' blood pressure and pulse. i could have done that in their home without any problem. I would have liked to have full backup for anaphylactic reactions but in reality these are almost non-existent if you monitor infusions carefully. A single infusion over a couple of hours would be much easier than taking a drug that might produce severe nausea and liver function abnormality over a period of months.

My gut feeling is that treating moderate patients in a pilot study would produce a lemon - no further on. Too many uncertainties. If moderate means able to leave the house and do a certain amount of normal activities outside I don't think that is the right population to test. It is a difficult call but having been through all these considerations before several times I am fairly sure an initial pilot study should recruit severe/very severe cases.
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As I said earlier, if there’s a reason to believe that severe would give a different result than moderate, I’m not against a trial of severe.

I think we had some discussions earlier about why going to the hospital is required for these kinds of treatments. If you think it isn’t, including (very) severe becomes a lot easier.
EndME said:
The current trial is also for severe patients
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Realistically? ResetME requires quite a lot of trips to the hospital. Far more than I’d be willing to commit to even when I was borderline moderate, but still severe.
EndME said:
Rituximab trials included severe patients so did Cyclo, even if they were fewer (https://pmc.ncbi.nlm.nih.gov/articles/PMC11265720/), so we do have some data.
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Thanks for finding the link. I don’t know how they classified the participants. It would be interesting to see the baseline step data for the severe ones to get a rough estimate of their level of functioning.
 
Utsikt said:
I think we had some discussions earlier about why going to the hospital is required for these kinds of treatments
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These treatments require supervision by a hospital based physician well-informed on immunodynamics. How you fix that for routine use is still a debate worth having bt for a pilot study on a few cases the logistics are different, especially if you have a principal investigator personally supervising treatment administration. That may now seem old fashioned but some old fashioned things are worth preserving!
 
V.R.T. said:
From what JE has said, Campath would be one infusion, so that would make it much more viable even without home visits.
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Ooh, that changes things!

You’d still have baseline and follow up assessments, but maybe those could be done at home. So just one trip for the infusion.

I could do that I think.
Jonathan Edwards said:
These treatments require supervision by a hospital based physician well-informed on immunodynamics. How you fix that for routine use is still a debate worth having bt for a pilot study on a few cases the logistics are different, especially if you have a principal investigator personally supervising treatment administration. That may now seem old fashioned but some old fashioned things are worth preserving!
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That’s useful info. I’d prefer the old ways.
 
Utsikt said:
Thanks for finding the link. I don’t know how they classified the participants. It would be interesting to see the baseline step data for the severe ones to get a rough estimate of their level of functioning.
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In their other study it has been discussed that step counts via Fitbit were high in all severity groups (often higher than the average population in mild/moderate and still relatively high in severe), which might reflect inaccuracies of Fitbit, inaccuracies in the proxy of step count for severity (for example not addressing neurocognitive symptoms) or certain severites not accurately capturing what others thinks of better severity classifications.

But generally I agree, patients participating in trials will often be fitter than one perhaps often wants.

Utsikt said:
You’d still have baseline and follow up assessments, but maybe those could be done at home. So just one trip for the infusion.
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I think the largest complication would be medical assessments to ensure accurate diagnosis, not the fairly few infusions itself. Even if there are probably some severe cases who still have regular medical assessments, I think the sample sizes might become rather small very quickly if one has to rely on this.
 
EndME said:
In their other study it has been discussed that step counts via Fitbit were high in all severity groups (often higher than the average population in mild/moderate and still relatively high in severe), which might reflect inaccuracies of Fitbit, inaccuracies in the proxy of step count for severity (for example not addressing neurocognitive symptoms) or certain severites not accurately capturing what others thinks of better severity classifications.

But generally I agree, patients participating in trials will often be fitter than one perhaps often wants.
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Good points!
EndME said:
I think the largest complication would be medical assessments to ensure accurate diagnosis, not the fairly few infusions itself. Even if there are probably some severe cases who still have regular medical assessments, I think the sample sizes might become rather small very quickly if one has to rely on this.
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A small pilot would probably still be feasible in Bergen (where Fluge and Mella are), but perhaps this is a good reason to try to get larger countries involved.

Perhaps the Germans would be interested?
 
Utsikt said:
Good points!

A small pilot would probably still be feasible in Bergen (where Fluge and Mella are), but perhaps this is a good reason to try to get larger countries involved.

Perhaps the Germans would be interested?
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Yes the Germans might be well placed to do this, especially with the National Decade funding. And I believe funding isn't exclusive to German projects, so they might fund something in another country.

I wonder if it would be at all feasible to get something up and running in the UK. If there was a pilot at Addenbrokes I might even put my money where my mouth is and apply to participate!

There was a joke about Polybio earlier but I am surprised that nothing like this has even been attempted in the states, with their more gung ho approach to medical ethics (not an endorsement of said approach)
 
On the subject of the states, does this information about BTN mutations in MECFS being likely function impairing

jnmaciuch said:
View attachment 32121
The PRY-SPRY domain is that purple and green box section starting at ~330.

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It looks like the mutation 982G>A changes the splice junction acceptor (in the diagram below, it removes the right hand splice site). [Edit: I have to double check the exact effect but either way it means the relevant protein binding domain won’t end up where it should be]

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This is an almost guaranteed loss of function. Between that and the Pro486Thr mutation, I think it's clear that the story here is function-impairing mutations.
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Imply that depleting T cells could actually be counterproductive and that Naths Keytruda trial revving up T cells could have some merit after all?

Or could campath still induce a 'hard reset' and break a revved up t cell signalling issue and return immune function to normal

Or is it not as simple as lost function in the gene = underactive t cells, gene working too well = overactive? (I'm pretty positive this is the case because its never simple and genetics is mind bogglingly complex)
 
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neophyte32 said:
Is this a clinical trial that would be expensive?
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Shouldn't be overly expensive, should it? S4ME involvement could save a lot of staff time with getting access stuff right and designing outcome measures.

It might quite hard to get approval, at least in the UK. It's a bit of a long shot, and it would be a team that doesn't even have a track record in ME/CFS (nobody does).

The Germans might find it a bit easier within their existing research programme, or the Norwegians if they had the capacity / interest.
 
Kitty said:
Shouldn't be overly expensive, should it? S4ME involvement could save a lot of staff time with getting access stuff right and designing outcome measures.

It might quite hard to get approval, at least in the UK. It's a bit of a long shot, and it would be a team that doesn't even have a track record in ME/CFS (nobody does).

The Germans might find it a bit easier within their existing research programme, or the Norwegians if they had the capacity / interest.
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I was thinking they could just copy Fluge and Mella’s design.

The cost per participant in ResetME is roughly 200k NOK excluding the cost of Dara. That’s 19k EUR or 16k GBP.

If we can extrapolate from that (which is a big if), an unblinded pilot of 10 participants would cost ~200k EUR + the cost of the drug.

There might be some added costs for home visits if it’s for the severe.

Even at 500k EUR, it would be well within the norm of PolyBio. They’ve had multiple trials >1M EUR.
 
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