Should advocates be trying now to get a US rituximab trial started?

Sasha

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In the light of last week's new paper out of Norway supporting the exciting results of the earlier RCT of rituximab for PWME, should US advocates be trying to get a US rituximab trial underway now?

On another thread, UK MEA medical advisor Dr Charles Shepherd (who has ME himself) said:

charles shepherd said:
If the large scale clinical trials are just left to the Norwegians, and let's assume that their phase 3 clinical trial produces some positive results in the summer 2017 when it finishes (which probably won't get published till 2018) this may help to get the drug made available in Norway.

But it won't mean that Rituximab will then get a product license here in the UK and NICE will recommend its use in ME/CFS

For this to happen, the UK regulatory authorities will require sound evidence of both safety and efficacy of Rituximab in ME/CFS from a number of high quality, preferably multicentre, phase 3 cinical trials

Phase 3 clinical trials are randomised controlled trials, like the one the Norwegians are currently setting up, and they are, not surprisingly, extremely costly to carry out.

If we don't start looking at how this could be done here in the UK - and it's interesting to note that the comments from Professor Simon Wessely in the New Scientist which suggest that he would also support this type of large clinical trial - then we are probably creating a situation whereby there is no real possibility of this drug becoming available for use in the UK for at least another five years.

I base this assumption on a scenario whereby we wait for the (hopefully positive) results of the phase 3 Norwegian trial in 2017/2018, then set about organising a phase 3 clinical trial here, and hope that others may follow suit.

This will take another 2 to 3 years to plan, set up, carry out, and analyse the results.

Which takes us up to 2021 or 2022...…

A long time to wait!

Having said that, the work on B cell status being carried out at UCL is very important and could help us to identify people with ME/CFS who are more likely/less likely to respond to Rituximab.

[...]

But I do believe that we also need to making moves right now to try and get a large multicentre phase 3 clinical trial taking place here in the UK, just as is happening in Norway.

Which is why I will be raising this when the Board of the UK Research Collaborative meets at the MRC next week.

Because if we don't, it could well be a very long time before people with ME/CFS here in the UK, who could benefit from Rituximab, will have access to it.
Interested in your thoughts about the US, @charles shepherd, @Jonathan Edwards, @Simon...
 

heapsreal

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I think australia would also be well suited to a rituximab trial through the cfsme researchers at griffith university, who are in partnership with the government health system here (Queensland Health). With some of the world's best cancer researchers here, it would be well within their capacity to do some good research , trials and treatments .
 
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added: Cort's bit on the US situation, quoted by @Sasha

Yes - though not just advocates, very happy if some clincian/researchers pick this up instead though suspect pressure from both will help.

Though I suspect NIH/MRC won't actually sign up til there are results from Norway (they might accept provisional results from F&M, don't know); the pre-trial work on b-cell subtypes in the UK might help too.. They may also be willing to fund the work in preparing the detailed plans for such a large-scale study - sometimes that sort of thing gets funded too, as it takes a huge amount of work.

Sorry, thinking aloud here. Yes, I do think we and researchers/clinicians in US, UK (and anywhere else eg Oz) should think seriously about this, even if the most likely short-term outcomes is funding for preparation for a large scale study - pending results from elsewhere. It could still take a year or two off the time it takes to get results from such full studies, i.e. cut the time before the drug is available to patients generally (assuming the initial good results pan out).
 
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heapsreal

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The Australian cfs researchers have been interested in rituximab for a long time and have been following the Norwegian research very early on.

They have invested most of their research time in finding a diagnostic test. It wouldn't suprise me if once norway have their research completed, it wont take long at all for them to have a test and probably already have a good idea on how rituximab actually works in cfs.

Delays in treatment trials here would be more related to politics and lack of understanding , which i think is why they have proceeded in looking for physiological abnormalities, biomarkers etc to help prove ME exists but also possibly to show improvements from treatment,not just going by how one says they feel.

Its good to have many countries involved. I think once its sorted, everything will fall into place, i hope.
 

EtherSpin

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The Australian cfs researchers have been interested in rituximab for a long time and have been following the Norwegian research very early on.

They have invested most of their research time in finding a diagnostic test. It wouldn't suprise me if once norway have their research completed, it wont take long at all for them to have a test and probably already have a good idea on how rituximab actually works in cfs.
In the meantime I'm keen to do anything to advocate for a trial and hasten it (as I've detailed in some ideas in the Aussie Ritux thread ) - I think its possible for researchers to glean data without necessarily conducting their own full study - getting CFS docs here to monitor and of their patients who qualify for Ritux here for other conditions like Rheumatoid Arthritis . we have what.. over 200000 CFS people here ? that should be enough with R.A. to observe for example if their docs guided them through a ritux protocol.
 

Sasha

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In the meantime I'm keen to do anything to advocate for a trial and hasten it (as I've detailed in some ideas in the Aussie Ritux thread ) - I think its possible for researchers to glean data without necessarily conducting their own full study - getting CFS docs here to monitor and of their patients who qualify for Ritux here for other conditions like Rheumatoid Arthritis . we have what.. over 200000 CFS people here ? that should be enough with R.A. to observe for example if their docs guided them through a ritux protocol.
@Jonathan Edwards, do you think this idea has value? If so, this is something that should be being done in every country.
 

alex3619

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The other thing is countries can have plans ready to go, and consult with the Norwegian team, before final commitment. This would be an in-between position. I do think that some other countries need to get studies started, even if they are smaller ones than Norway.
 
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@Jonathan Edwards, do you think this idea has value? If so, this is something that should be being done in every country.
I certainly think it would be useful to document any cases given rituximab for other conditions who have coexisting ME. That may not always be easy to tease out but in some cases it should be. Nielk is a case in point. Unfortunately, since rituximab is only one of many treatments for RA we may be talking about one person in a million having rituximab for RA while also having ME. There should still be a few dozen around the world.
 

Sasha

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I certainly think it would be useful to document any cases given rituximab for other conditions who have coexisting ME. That may not always be easy to tease out but in some cases it should be. Nielk is a case in point. Unfortunately, since rituximab is only one of many treatments for RA we may be talking about one person in a million having rituximab for RA while also having ME. There should still be a few dozen around the world.
I don't want to derail the thread (which is about a US trial for rtx) but aren't Fluge & Mella also looking at cyclophosphamide (also used in RA) - can't remember if they're also looking at methotrexate (another RA drug)? If these other RA drugs would be expected to have a similar mechanism of action (including on T-cells, not just B-cells?) shouldn't we be looking at PWME getting treated with all of them for their RA? And their cancer? That would certainly bump the numbers up.
 

Scarecrow

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I don't want to derail the thread (which is about a US trial for rtx) but aren't Fluge & Mella also looking at cyclophosphamide (also used in RA) - can't remember if they're also looking at methotrexate (another RA drug)? If these other RA drugs would be expected to have a similar mechanism of action (including on T-cells, not just B-cells?) shouldn't we be looking at PWME getting treated with all of them for their RA? And their cancer? That would certainly bump the numbers up.
In theory this sounds great but how could you monitor it? (Costs / communication / organisation)
 

SOC

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I don't want to derail the thread (which is about a US trial for rtx) but aren't Fluge & Mella also looking at cyclophosphamide (also used in RA) - can't remember if they're also looking at methotrexate (another RA drug)? If these other RA drugs would be expected to have a similar mechanism of action (including on T-cells, not just B-cells?) shouldn't we be looking at PWME getting treated with all of them for their RA? And their cancer? That would certainly bump the numbers up.
Would the protocol be the same for RA or cancer and ME? If so, this could be useful, if not, it might be difficult to understand whether these drugs would help with ME or not. One condition may need higher dose, more frequent dosing, more repeated doses over longer time than another. If the RA treatment, for example, wasn't long enough to affect ME, then it would look like the treatment (given for RA) doesn't work for ME, when it might given the correct protocol. Or if the dose for some other condition was higher than needed for ME, the side effects might be worse and considered too much for PWME. If the protocols are exactly the same regardless of the condition being treated, these questions are all moot. :)

Nevertheless, it would be interesting to see if any clues can be extracted by gathering such information. It may be that the information is more vague and fuzzy than we would like. Clues can be valuable, but we know how good Certain People are at misinterpreting fuzzy data and using it against us. :cautious:
 
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Nielk

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If the goal is complete B cell depletion, couldn't this be monitored via blood test? As an example, I was given two infusions of Rituximab over a year ago for my RA. Two months later my CD 19 was 0. The depletion has lasted all year long. I am assuming that subsequent doses would have been useless, since there wereni B cells to kill. Why is there an assumption that all patients in a disease group will react the same way in reducing their B cells?
 

Hutan

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(sorry, further derailing the thread but perhaps relevant to the question about how rituximab treatment regimes differ for different diseases)

Hope you don't mind me using your case as an example @Nielk. It was so generous of you to share your experience with rituximab with us. I have been wondering if the treatment regime you followed for RA (two infusions only) was responsible for your lack of response regarding ME symptoms.

I think one non-responder in the first Norwegian trial responded in the second. I wonder what happened with the Norwegian trial patients' B cells over the trial period. Is that reported anywhere?

I wonder if the timing of B cell elimination tells us anything abut who responds. Is it possible that Nielk's plasma cells and/or specific antibodies persisted longer, even though the B cells that made the plasma cells were long gone?

I wonder if rituximab is actually doing something else, other than eliminating B cells, that helps ME patients. And so Nielk, if you had had a longer course, like that of the Norwegian patients, perhaps this other effect of rituximab might have kicked in.
 
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added: Cort's bit on the US situation, quoted by @Sasha

Yes - though not just advocates, very happy if some clincian/researchers pick this up instead though suspect pressure from both will help.

Though I suspect NIH/MRC won't actually sign up til there are results from Norway (they might accept provisional results from F&M, don't know); the pre-trial work on b-cell subtypes in the UK might help too.. They may also be willing to fund the work in preparing the detailed plans for such a large-scale study - sometimes that sort of thing gets funded too, as it takes a huge amount of work.

Sorry, thinking aloud here. Yes, I do think we and researchers/clinicians in US, UK (and anywhere else eg Oz) should think seriously about this, even if the most likely short-term outcomes is funding for preparation for a large scale study - pending results from elsewhere. It could still take a year or two off the time it takes to get results from such full studies, i.e. cut the time before the drug is available to patients generally (assuming the initial good results pan out).
I raised my observations (at the start of this thread) on the need for a large (ideally multicentre) UK RCT sooner rather than later as an agenda item at the UK Research Collaborative Board meeting on Wednesday this week

And there was actually a lot of support for trying to get something moving here in the UK right now, and not just waiting to do this until the Norwegian phase 3 trial has finished (in summer 2017) and been reported on (presumably in 2018).
 
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added: Cort's bit on the US situation, quoted by @Sasha

Yes - though not just advocates, very happy if some clincian/researchers pick this up instead though suspect pressure from both will help.

Though I suspect NIH/MRC won't actually sign up til there are results from Norway (they might accept provisional results from F&M, don't know); the pre-trial work on b-cell subtypes in the UK might help too.. They may also be willing to fund the work in preparing the detailed plans for such a large-scale study - sometimes that sort of thing gets funded too, as it takes a huge amount of work.

Sorry, thinking aloud here. Yes, I do think we and researchers/clinicians in US, UK (and anywhere else eg Oz) should think seriously about this, even if the most likely short-term outcomes is funding for preparation for a large scale study - pending results from elsewhere. It could still take a year or two off the time it takes to get results from such full studies, i.e. cut the time before the drug is available to patients generally (assuming the initial good results pan out).
There are other major funders here in the UK who could fund a large RCT - possibly with the charity sector as co-funders….
 

barbc56

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Fog horns sounding. I thought @Jonathan Edwards is setting up a trial in the UK? Possibly, consulting with Norway.

If I weren't so exhausted, I would try and find it.

Can anyone help?

Barb
 
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Difficult to do on an intentional basis but I think it would be extremely helpful if we had some form of registry that contained details of people with ME/CFS who have been prescribed Rituximab (for ME/CFS, or for another condition) outside a clinical trial setting

There are certainly some people here in the UK that I am aware of and I suspect that there may now be a rather more significant number in America