New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[jimells]

Surely, beyond the clinical trials that are currently being done, the extensive safety data for Rituximab for RA is likely to be sufficient? It would be strange to argue that the safety of the drug in ME patients could be much worse.

Beyond that, all that is really necessary is data of efficacy which does not require such large sample sizes for statistical significance when the effect size is strong.

What I find particularly infuriating about the foot-dragging which we know will continue is that lack of efficacy is no impediment to approval and mass marketing when it comes to drugs like SSRIs and statins.

 

[jimells]

As far as individuals are concerned I don't think there is anything in the way of campaigning, writing to MPs etc that should be done at the moment

It's a funny thing about governments - when regular folks try to prod them into action, not much happens. When the right people ask their bought-and-paid-for officials for a favor, it can happen overnight. If disability insurers were to demand that their beneficiaries be given access to these drugs, we would see a lot of red tape disappear in a hurry. Of course there is no way for regular folks to influence insurers since their decision makers are completely isolated from the peons.

I wonder how much it would cost to hire Sir Simon to lobby the insurers to get behind real treatments. He could save them billions in disability payments and present himself as a hero to the patient community. We know he has the connections, and by now he and his gang must be looking for the exit to the dead end they have backed themselves into.

I doubt very much that disability insurers stonewalled access to AIDS treatments when it became apparent that those patients could return to work and stop collecting benefits.

 

[greeneagledown]

Not sure if this has been posted yet. This was a cool figure that I didn't see in the body of the article but was in the appendix:

These are the "norm-based" SF-36 sub-component scores, as opposed to the raw scores. In the norm-based SF-36, a score of 50 is the average for the entire US population in 1998, so this is a handy way to see how the patients compared to the typical person, although we don't know what the standard deviation is, so it's tough to tell how significant it is that a patient is a certain distance away from 50.

Vitality is the measure I'm paying the most attention to because it's the best proxy for feeling energetic instead of fatigued. It would seem to capture both physical energy and mental energy.

The mean vitality score for major responders was about equal to the US population as a whole throughout most of the follow-up period. At 30-month follow-up, the mean for major responders was slightly higher than the US population mean. (Say what?!?) Even at 36 month follow-up, the mean for major responders appears to be just 5 points off the population mean, although again, that's somewhat difficult to interpret.

Looking at the left chart, which plots individuals, you can see that at 36-month follow-up, 8 patients were either above the population mean or fairly close to it.

One note of caution: I believe the mean of 50 is for the entire US population, not just the healthy population. So "50" probably doesn't mean perfectly healthy. But most people without ME/CFS don't have debilitating fatigue, so I don't think the mean for the healthy population would be that much higher than the mean for the population overall.

Good stuff!

 

[SOC]

This was a cool figure that I didn't see in the body of the article but was in the appendix:

It's good to see that the Mental Health scores of these patients was at the population average before treatment, contrary to what many people would have the world believe about PWME.

I find it interesting that the major responders started off slightly higher than the moderate and non-responders in Physical Function, Bodily Pain, and Social Function which suggests less severe patients may do better with Ritux. However, the initial scores are close enough that the differences may not be statistically significant. More interesting, though, is that major responders had noticeably lower initial scores than moderate and non-responders in Vitality and Mental Health. So the major responders initially had better physical function and less pain, but lower mental health scores (on average) than the others. I wonder what that means?

I'm very much looking forward to some studies with more objective measures of success so we're not reliant on self-report, which can be affected by hopefulness and discouragement, as well as overall personality differences, all of which alter how one answers questionnaires.

Lots of information in those figures that raise many potentially interesting questions and observations.

 

[greeneagledown]

More interesting, though, is that major responders had noticeably lower initial scores than moderate and non-responders in Vitality and Mental Health. So the major responders initially had better physical function and less pain, but lower mental health scores (on average) than the others. I wonder what that means?

I noticed that as well. Could easily be random. But maybe in the subset that Rituximab helps a lot, the underlying pathology that is causing CFS is also causing some mood deterioration. We could think of any number of mechanisms for that which have nothing to do with nonsense like "unhelpful beliefs" and, instead, depend entirely on brain chemistry, neurotransmitters, etc. The Norwegians think nitric oxide may be implicated in CFS, and I believe nitric oxide has some sort of role in regulating mood-related neurotransmitters. And if blood flow and blood volume are impaired in a subset, that could easily cause mild depression due to lack of blood flow to the brain.

 

[SOC]

I noticed that as well. Could easily be random. But maybe in the subset that Rituximab helps a lot, the underlying pathology that is causing CFS is also causing some mood deterioration. We could think of any number of mechanisms for that which have nothing to do with nonsense like "unhelpful beliefs" and, instead, depend entirely on brain chemistry, neurotransmitters, etc. The Norwegians think nitric oxide may be implicated in CFS, and I believe nitric oxide has some sort of role in regulating mood-related neurotransmitters. And if blood flow and blood volume are impaired in a subset, that could easily cause mild depression due to lack of blood flow to the brain.

Agreed. I also wonder if it might be a matter of neuroinflammation or something autoimmune related to neurotransmitter receptors.

 

[Simon]

...it appears that 6 of the patients in this study had mono (glandular fever) upfront when they first got ME/CFS, and of those 6, 3 of them responded very well and went into long-term remission. The 3 patients who went into long-term remission all came down with ME/CFS as teenagers, while the 3 mono patients who didn't go into long-term remission came down with ME/CFS much later in life. Obviously a tiny sample size, but I'll be interested to see what happens in the big phase 3 trial. Maybe patients whose ME/CFS was precipitated by a mono infection during adolescence or early adulthood are especially likely to benefit from Rituximab.

Really neat observation. A large chunk of new mecfs cases are from people who develop it after glandular fever at teens (see this incidence graph from Norway), which means potentially this is a large and important group. Though anecdotally initial recovery rates from mecfs post-glandular fever in teens are high - so maybe there aren't so many people left with mecfs in their twenties (as applied to all three cases here) after mono in their teens.

Also, recovery rates may naturally be higher for mecfs after mono - see my blog on this recent study (Norwegian again), so perhaps prognosis generally after mono is better than for mecfs after other triggers, which could be why they respond better to rtx. On the other hand, that same Norwegian study found that age didn't predict recovery from post-mono.

Anyway, something to watch out for in the new trial, for sure.

Also, I ran some stats, comparing outcomes for those three cases of mecfs-post-mono-as-teens (3/3 'megaresponders') vs all other trial particpants (4/25) -and it was statistically significant (p=0.005). Though that's a pretty extreme post hoc analysis so maybe best not to read too much into it.

Finally, posted this on the other (blog) thread looking at how patients responded depending on their origin (had rtx before v in placebo group before v new patients). Pics below, details here.

 

[Rich D]

So if I found a willing doctor, couldn't he/she put me on Rituximab? In other words, aside from the obvious dangers at this point due to lack of knowledge, is some sort of approval unnecessary as long as I am willing to pay out-of-pocket?

 

[Nielk]

So if I found a willing doctor, couldn't he/she put me on Rituximab? In other words, aside from the obvious dangers at this point due to lack of knowledge, is some sort of approval unnecessary as long as I am willing to pay out-of-pocket?

As long as your dictor is willing to prescribe it and you are willing to pay for it, there should be no problem.

I know of some patients in the US that have done this.

 

[Rich D]

It would be interesting to hear about the experience of the patients you describe.

 

[alex3619]

It would be interesting to hear about the experience of the patients you describe.

This has been written about several times on PR.

 

[Sasha]

Cort (thanks to @Simon for giving me a link!) has written about the paper for his Simarron blog and what interests me about his article is what he says about the US situation in regards to a US trial.

Major target for some US advocacy, I'd have thought!

The Big Lug
Much of the innovative research, both inside and outside the public sphere, is occurring in the U.S. but the Rituximab trials might never have happened for all the work that’s been done here. That’s something that ought to give one pause. A possible new treatment for a disorder with no FDA-approved drugs occurs and the biggest and richest country in the world does nothing.


The country with the biggest medical system in the world doesn’t figure in Rituximab yet

How does that happen? Norway got funding from both advocates and the government. UK advocates have raised $600,000 by themselves. No group has mounted a serious effort in the U.S. and federal funding for clinical trials is difficult to achieve.

It’s pretty clear right now that nothing’s going to happen around Rituximab in the U.S. until the Norwegian trial ends up in mid 2017. Say the Norwegian results published in 2018 are impressive and the U.S. gets a major year-long trial started in early 2019. The results are in by mid-2020, they’re submitted for publication in early 2021, are published in mid-2021. The FDA examines the data from the US, Norwegian and UK trials and in early 2022 seven years from now, approves Rituximab for use in a subset of ME/CFS patients.

When U.S. – because of bureaucratic or institutional barriers or whatever, is simply sitting on the its hands everything takes longer. In another disorder the Oct 2011 Fluge/Mella study might have sparked an extensive U.S. treatment trial in 2012. The first results of that multi-year trial might have been published in say 2015. In this scenario with the big Norwegian study underway we’d have enough data to apply for FDA approval in two years.

- See more at: http://simmaronresearch.com/2015/07...hronic-fatigue-syndrome/#sthash.vRedySRN.dpuf

The Open Medicine Institute had an expensive ($7.56m) 2x2 rituximab/valcyte trial as their top research priority but I haven't heard anything about it since I wrote about it here exactly two years ago.

 

[anniekim]

any passing out in your teens ? that was my first signal. 2 or 3 times, particularly if constrained to a standing position where I couldn't move my legs much and was under bright light, singing in groups on stage did it twice though once I made it off with out actually blacking out.

Thanks, no, no passing out in my teens. My OI symptoms now are more extreme racing heart if I try to be upright. I don't think I have the low blood pressure or dizziness. I am bedridden so too ill to attend hospital for tilt table testing so I don't have a confirmed POTS diagnosis but I haven't been able to sit in a chair or stand now for five years. My body does not like being upright!

 

[Hutan]

Re the US situation regarding a rituximab trial:

The NIH is currently funding a Phase 2 rituximab trial for myasthenia gravis patients. Myasthenia gravis is an autoimmune illness affecting around 20 people in 100,000.

The parties involved in the Myasthenia gravis trial are NIH’s National Institute of Neurological Disorders and Stroke (and NeuroNEXT, its neurological research network); Yale University; and Genentech Pharmaceuticals who is providing the rituximab). See http://www.neuronext.org/nn103-rituximab-mg.

ME/CFS is estimated to affect at least 200 people per 100,000, ten times that of Myasthenia gravis. The US government has an urgent need to show some real action on ME/CFS following the IOM and P2P reports.

I hope that patient advocate institutions in the US will knock on the doors of NIH, the National Institute of neurological disorders and stroke, Yale University (Richard Nowak) and especially Genentech, armed with the Fluge and Mella results and strongly suggesting that a rituximab trial for ME/CFS would be relatively easy to do and would meet with enormous patient approval.

I note that the summary for the Myasthenia trial says “this work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanism underlying treatments of MG with rituximab leading to new ways to treat the disease”. This is exactly what is needed for ME/CFS.

 

[Nielk]

Some drugs get FDA approval even though the clinical trials take place in a foreign country. This, as long as it meets US FDA regulations.

http://www.fda.gov/RegulatoryInformation/Guidances/ucm124932.htm

 

[EtherSpin]

Re the US situation regarding a rituximab trial:

The NIH is currently funding a Phase 2 rituximab trial for myasthenia gravis patients. Myasthenia gravis is an autoimmune illness affecting around 20 people in 100,000.

I think worldwide we should be trying to get people conducting these studies to survey or make note of how many CFS patients are within their group and then request that those patients undertake a once monthly CFS symptom diary.
In Australia Ritux goes from $2030 and infusion down to 37 for severe rheumatoid arthritis cases - I can see a way to co-opt some research here (I mentioned this in the Aussie ritux discussion thread) , a researcher could contact all the well known doctors who claim to treat CFS specifically here in Australia and have them offer to step any of their CFS patients with Rheumy arthritis through ritux treatment whilst filling out details again to track their CFS symptoms. it gets treatment immediately to people who qualify and then gets safety data for Aussie authorities to use moving forward

 

[Sasha]

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.

Just wondering if the meeting has happened and if you're able to give us any kind of update?

Thanks very much for raising this - it's a hugely important issue.

 

[Sasha]

@charles shepherd, did you mean to post your replies on this thread?

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).

There are other major funders here in the UK who could fund a large RCT - possibly with the charity sector as co-funders….

 

[alex3619]

At 30-month follow-up, the mean for major responders was slightly higher than the US population mean. (Say what?!?)

To be expected. The population mean includes lots of sick and old people, so fully healthy would be a little higher than the mean. Further, you have spent years able to do nothing, suddenly you can do a lot, what do you do? You do stuff! Whatever stuff you want! Enthused, vitalised!

 

[alex3619]

Something that occurred to me just a few minutes ago, what do we know about rates of post cancer fatigue after Rituximab for lymphoma?