The UK Rituximab Trial: A Study in a Hurry

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by Sasha


London: site of the proposed UK Rituximab trial
Photo by fussy onion/Flickr

On June 6, the Norwegian Medical Research Council agreed to give a large enough grant to the Haukeland Rituximab trial for the study to begin. Later that day, the charity Invest in ME announced that they were initiating a UK Rituximab trial. It seemed to come out of nowhere. There were no details – cost, size, location, research team – but there didn’t need to be. The ME community started throwing money at the trial and trusted Invest in ME when it said it could be done.

This trust was surely based on the reputation that Invest in ME has established for itself in its few short years of existence. The newest UK ME charity, run entirely by volunteers, it set up in 2006 an international annual conference on biomedical research into ME – not CFS, but WHO-defined ME – that is now attended by most of the major research groups from all over the world and is a focus for information-sharing and collaboration-building among ME researchers.

At the most recent conference, Drs Fluge and Mella presented their follow-up study of a new Rituximab dosing schedule on the control patients from their Norwegian pilot study. The results are still embargoed until publication but apparently positive. Drs Kogelnik and Scheibenbogen, who are planning US and German Rituximab studies, respectively, were also there. No-one could doubt Invest in ME’s sources of expertise and support in setting up a trial.

The community’s trust quickly paid off as the charity was able to make public a major coup. Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College London (UCL), had agreed to advise Invest in ME on all aspects of running a Rituximab trial (read his statement on the trial here). It was Professor Edwards who proposed in 1999 that self-perpetuating B lymphocytes drive autoimmune disease. He went on in 2004 to conduct the trials of Rituximab for rheumatoid arthritis that established the role of B cell depletion in treating autoimmune disorders, the same mechanism that Drs Fluge and Mella believe is operating in the treatment of ME with Rituximab.

Fresh from that victory, Invest in ME went on to announce their plans to have the trial conducted by an expert team led by Dr Jo Cambridge at UCL, with the intention of including other London sites and other collaborating researchers such as Dr Amalok Bansal, an immunologist with a research interest in B-cell abnormalities in ME.

Further details were announced. To the surprise of many, the proposed trial would not be of the magnitude of the 140-patient Haukeland confirmatory study but, with about 30 patients, would be roughly the same size as the Norwegian pilot trial. Professor Edwards explained that a small trial is appropriate when a large effect is expected, as indicated by the Haukeland pilot trial in which 67% of patients treated with Rituximab improved, compared to 13% of controls. A successful small trial would make a strong case for further studies that themselves may not need to be big. Several independent confirmatory trials will be needed if Rituximab is to be licensed for ME.

The small size of the trial makes for a relatively low-cost project. Details of the study protocol are still being hammered out but the current estimate is £350,000 ($540,000; €410,000). This is potentially a very achievable sum to raise within a short timeframe.

The UK has several advantages here. It has several large ME charities and, in a very welcome move, the ME Association has pledged nearly £60,000 to the trial, subject to its normal independent peer-review procedure. Action for ME have announced that their board of directors will be considering collaboration on the trial; the Irish ME Trust has pledged £1,000, setting a good example for smaller charities; and there are other UK charities that might also be expected to donate. Working together with Invest in ME, who have more support pledged, a very substantial chunk of that £350,000 could be found in short order.

Also, Invest in ME has many supporters and have already racked up about £20,000 in donations even though there has been no big launch or fanfare for the study. The Medical Research Council, thanks to years of pressure, is now finally funding biomedical ME research and might look favourably on this trial, if applied to.

And of course, Maria Gjerpe’s MEandYou Foundation raised something close to the total sum needed for the UK trial in only three months in a country with a tenth of the population of the UK. Her positive, fun, feelgood campaign made people want to join in and expanded the support base well beyond the ME community and into the general public. She raised awareness so effectively that the entire Norwegian football Champions’ League – the healthiest of the healthy – aligned themselves with us, some of the most stigmatised of the sick, and donated signed shirts for auction. We in the UK need to follow her example, work together, be ambassadors for our community, and welcome people in.

Not all elements of the trial are yet in place and Invest in ME, like MEandYou, have sensibly been transparent about what happens if, for some reason, the trial does not go forward. In that case, donations to their Rituximab fund will go into their general Biomedical Research Fund, where there’s no doubt they’ll do some very good things with it. But many - probably most of us - feel the same urgency as Invest in ME to get the money raised and in place, so that things can proceed as soon as possible, and with the £20,000 donated to Invest in ME and the £60,000 pledged by the ME Association, we’re already nearly a quarter of the way there. What can the rest of us do to help?

• Donate! There are now two Rituximab funds raising money for this trial: Invest in ME's fund and the ME Association's fund (scroll down for donation instructions), and we can probably expect each collaborating ME charity to set up its own fund for the trial as they join in. UK taxpayers should Gift Aid their donations.
• Join The Matrix (long black coat optional): be one of 100 people to make a pledge to raise £1,000.
• Fundraise: people are doing all sorts of things to fundraise, from selling crafts to sponsored walks. Think about what you can do.
• Raise awareness of the trial. Many people in the UK who have ME don’t belong to any of the charities and won’t know that there’s a trial to donate to or raise money for. Help them find out.

We’re very fortunate that Professor Edwards has joined the forums here on Phoenix Rising. He has already been giving fascinating answers to our many questions (on this thread, starting here) and has generously agreed to answer some more about the trial and how Rituximab might make sense for ME. If you have such a question, please post it in the comments section. I will collate the questions and present them to Professor Edwards for an interview article with him to appear later.

In the meantime, let’s get cracking. We can have a superb trial in the UK, one that will benefit patients all over the world – let’s get on with making it happen!

Remember that Phoenix Rising costs money to run and needs your donations to support it. Please hit the button below and donate!


Further resources

Invest in ME’s Rituximab trial website

Discover magazine’s April 2013 article on Rituximab, including comments by Professor Edwards

Fluge and Mella’s 2011 PLoSOne pilot trial of Rituximab

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Simon said: ↑

I still don't really understand why the study is so small. I know there is extensive discussion of this on the main thread - which I've only dipped into - and Jonathan Edwards seems to be saying that a small study can be more tightly controlled than a large multi-centre one. I can see the logic that a smaller replication study would have been a better place to start, but given that the large study is already largely funded and plans are well-developed for it, I do wonder how much 'value' a smaller study will add in practice.​

Hi Simon, Jonathan Edwards addresses these questions here:
http://forums.phoenixrising.me/inde...uximab-trial-30-july.24499/page-8#post-377254

Thanks, Bob

Though it might help if I summarise that Jonathan Edwards interesting post below. He was replying to a post by Esther12 about the value of a small study given the larger Norwegian one.

His answer seems to boil down to a concern that the larger Norwegian study might find a lesser effect next time around [which often happens after a big bang initial result], and that could derail Rituximab. Wheras if that did happen, but a UCL study found a clear sub-group that responded well to Rituximab, then it would still be a live game.

If the total response rate for unselected ME turned out to be 40% (or less), taken with all the uncertainties about objective monitoring I think regulatory authorities would be very cagy about licensing until there was other information to help the case. For this sort of reason my view is that we should try very hard to find a different sort of trial design.

...So one of my main thoughts about design is not to do a mini-Norway. It would be much better if we could find a way of testing whether rituximab works for some people with ME from a different angle and one that might get at least one step further towards finding out who those people might be and why they respond.

... what I would like to see is a focus on the longer term objective of making sense of a B cell story for some of ME. In that sense I agree with a lot of other people’s comments, especially Firestormm. If the big Norway study is a bit disappointing we want to make sure the real value of a B cell approach, if there is one, is not lost. In five years time there may not be the same mix of people in a position to collaborate.

So it seems to me the argument for a small UK study is partly as insurance in case five years down the line the Norwegian results are 'complicated', and partly to better understand how the B-cell approach fits different patients.

Please correct me if I have got this wrong.

 

Sasha, FYI, your article is quoted, and linked to, by the NICE Guidelines blogspot:
http://niceguidelines.blogspot.co.uk/2013/08/professor-jonathan-edwards-b.html

 

If it was a question of a small trial costing a relatively small amount of money and a big trial costing the size of the current proposed study (in the ball park of £350,000-400,000), then there would be a stronger case for a bigger trial. However, a bigger trial at the moment would likely cost £1m+, the sort of money which might be too much to raise, or might only be raised with virtually nothing else being funded for a period. So the situation is maybe more a case of a small study in the UK versus no study in the UK.

I'm hoping that because it's a small trial, there will be a reasonable number of biological measurements taken at baseline (useful to try to work out characteristics of responders/non-responders) and ideally a few biological measurements during and after the trial. By having small numbers, this would seem more affordable.

 

Thanks, Bob

Though it might help if I summarise that Jonathan Edwards interesting post below. He was replying to a post by Esther12 about the value of a small study given the larger Norwegian one.

His answer seems to boil down to a concern that the larger Norwegian study might find a lesser effect next time around [which often happens after a big bang initial result], and that could derail Rituximab. Wheras if that did happen, but a UCL study found a clear sub-group that responded well to Rituximab, then it would still be a live game.


So it seems to me the argument for a small UK study is partly as insurance in case five years down the line the Norwegian results are 'complicated', and partly to better understand how the B-cell approach fits different patients.

Please correct me if I have got this wrong.

Seems correct to me.

One of my thoughts about this would be whether or not samples could be taken from the initial Norway trial, by UCL and used to drill-down and try and better understand why those who responded did so.

What I mean to say is, would rituximab need to be tested again on UK patients in a replication trial; or could UCL 'simply' perform a better analysis of the existing data?

If on the other hand, a UK n=30 attempt at replication is being estimated as costing c. £400k - and this is deemed necessary to gain data before you can better analyse reasons: then we might be looking at more money, not less?

If you intended gathering better data, perhaps you could spend less on a smaller replication, in order to spend more on data analysis and in trying to discover the reason why?

Hard to know really at this point. Am certainly awaiting news from UCL with baited breath. All very exciting.

 

Independent replication by several different investigators is going to be key to getting Rituximab licensed, if the good results are confirmed - it won't be enough to analyse the Haukeland data or samples over and over. One way or another, we need more studies and it's important that there's also a German and US one planned.

The US (OMI) study will cost $7.65 million so I suspect the UK one will be underway faster...

I've got no info on the German trial.

 

Seems correct to me.

One of my thoughts about this would be whether or not samples could be taken from the initial Norway trial, by UCL and used to drill-down and try and better understand why those who responded did so.

What I mean to say is, would rituximab need to be tested again on UK patients in a replication trial; or could UCL 'simply' perform a better analysis of the existing data?

If on the other hand, a UK n=30 attempt at replication is being estimated as costing c. £400k - and this is deemed necessary to gain data before you can better analyse reasons: then we might be looking at more money, not less?

If you intended gathering better data, perhaps you could spend less on a smaller replication, in order to spend more on data analysis and in trying to discover the reason why?

Hard to know really at this point. Am certainly awaiting news from UCL with baited breath. All very exciting.

I think the real value is in the people at UCL thinking through the autoimmune angle and using their experience to interpret it. In the past they have been shown to have good intuition and forming the right questions and hypothesis is the hard part of science (running the experiment is easy). But its the intuitions with the knowledge of auto immunity that will lead to taking the right measurements that can be used to give greater understanding.

Fluge and Mella are oncologists and as such were using Rituximab for treating cancer which I get the impression is quite different. So it seems very important to have additional, very good, people with different backgrounds and understanding involved in a study. I suspect the things they will measure will be very different from that which Fulge and Mella would have measured when they designed their protocol many years ago.

 

I think the real value is in the people at UCL thinking through the autoimmune angle and using their experience to interpret it. In the past they have been shown to have good intuition and forming the right questions and hypothesis is the hard part of science (running the experiment is easy). But its the intuitions with the knowledge of auto immunity that will lead to taking the right measurements that can be used to give greater understanding.

Fluge and Mella are oncologists and as such were using Rituximab for treating cancer which I get the impression is quite different. So it seems very important to have additional, very good, people with different backgrounds and understanding involved in a study. I suspect the things they will measure will be very different from that which Fulge and Mella would have measured when they designed their protocol many years ago.

Morning User

So you thinking they'd run a smaller replication Trial but with their angle of expertise it would be 'better' designed and measured? If so, then yeah I can see that too I guess.

Fingers are crossed

 

Morning User

So you thinking they'd run a smaller replication Trial but with their angle of expertise it would be 'better' designed and measured? If so, then yeah I can see that too I guess.

Fingers are crossed

I wouldn't necessarily use the phrase better designed but rather designed to explore a different angle from Fluge and Mella. And an angle that might lead to explanation.

Thats a very different thing from a multi-site trial exploring a hypothesis of the amount of benefit to be gained by Rituximab.

Both types of research are interesting. Unfortunately its hard (or costly) in science to do a mega experiment that answers all questions well.

 

I wouldn't necessarily use the phrase better designed but rather designed to explore a different angle from Fluge and Mella. And an angle that might lead to explanation.

Thats a very different thing from a multi-site trial exploring a hypothesis of the amount of benefit to be gained by Rituximab.

Both types of research are interesting. Unfortunately its hard (or costly) in science to do a mega experiment that answers all questions well.

Thanks.

I am thinking that we have Rituximab, right, and we know something about how it works and what it does, right? So we are starting our search for why it should help those it did - with something more than we might have had before in other research seeking to determine mechanisms.

From what Prof. Edwards has been saying though, we don't know everything about Rituximab and how it can effect individuals: so we can't entirely say that if Ritux. is believed to have resulted in e.g. remission from a diagnosis of ME, that it is down to X. Like we might be better able to do with Rheumatoid Arthritis.

But we can begin with the drug itself and that's a start. Though we would still need to screen patients before and after treatment: but UCL know what to look for and with help from Norway - the search is narrowed.

To what extent patient selection at this point will matter - beyond the means by which they were selected in Norway - I don't know. It would make sense to select based on e.g. NICE on the one hand, then separately on other criteria perhaps: thinking ahead and down the road.

Also to have a further set known who have recognised abnormalities (with an ME diagnosis) that are deemed more/most likely to respond to Ritux.

Just thinking...

 

Oh and a cohort who have abnormalities in a control group perhaps - but don't have a diagnosis of ME.

Hmm... if the abnormalities were the same in the control and in that part of the ME cohort; I think this might work - wonder if they might have e.g. RA patients in a control or another disease that has the abnormalities and is known to respond?

My thinking being, that you need to try and equate response to Ritux. to remission in ME symptoms (and what is considered the disease known and diagnosed as ME); if you see what I mean?

Can treatment and remission with Rituximab mean something else other than remission in ME? As we don't know what ME is really - or the mechanisms behind it or in each individual case: I think it would be good to know more.

 

To what extent patient selection at this point will matter - beyond the means by which they were selected in Norway - I don't know. It would make sense to select based on e.g. NICE on the one hand, then separately on other criteria perhaps: thinking ahead and down the road.

I think NICE is extremely broad. But all the diagnositic guidelines are predicated on an exclusion diagnosis (i.e. the removal of people with other diseases). To me this is where things get difficult as its often unspecified. NICE lists a set of blood tests and also says anything else that seems relavent to the particular case but I think this last bit often gets lost. The problem is that the semantics of the ME, CFS labels come from the diagnositic system that includes these undefined or poorly defined exclusions.

Personally I would start a trial with severe cases as where there is remission the effects should be blindingly obvious (non of this statistical significance and very small movement in measures) and also as I would expect markers to be more obvious with greater changes.

 

Yeah I realise that about NICE. But they also break down the illness into categories. My point really would be that this study could be an opportunity to also demonstrate if the NICE criteria adequately select those most likely to respond to this treatment (compared to other criteria such as CDC and CCC).

Of course the more complex the recruitment protocol the more expensive. But we are talking about a UK Trial with one aim being UK approval for the drug. So... NICE should be considered in some definite way, (though it could be argued CDC equates to NICE I suppose).

 

..... has anyone got any questions for Prof. Edwards that they'd like to put to him for the interview I'll be doing with him in the follow-up article?

Also: has anyone got any good ideas for fundraising projects for the trial? Is anyone doing anything special?

I'm really really enjoying reading Prof Edwards ongoing dialogue on the ' invest-in-me-prof-jonathan-edwards-statement-on-uk-rituximab-trial-30-july' thread. It is generous of him to spend so much time in these discussions. A very refreshing change to feel we are being treated like a group of sane adults with varying views and knowledge; being respected in other words.

What I would like to know is what he is getting out of his presence on PR? is it working for him? is there anything else we can do that will be useful to him (aside from fundraising).

I hope that some of our questions are thought provoking for him. From my own experience I know that teaching is sometimes a good way to clarify my thoughts on a subject.

OTH

 

IiME's Quick Overview of the IiME/UCL Clinical Trial
http://www.ukrituximabtrial.org/IIMEUKRT Summary Sep13.htm

I wasn't sure which thread to post this on!
Not much new info, but perhaps a little new info, as follows...

• Invest in ME have agreed to fully fund the preliminary study by UCL which is a pre-requisite to the full clinical trial. This will begin shortly.

• The preliminary study will be a small study which will confirm the earlier work of Dr Amolak Bansal [1] on B-cells but using a different cohort of ME patients.

• Professor Edwards believes this is a useful study in its own right and a pre-requisite for the clinical trial.

• Meanwhile work is continuing on the design of a protocol which will be finalised after the trip to Bergen that IiME and Professor Edwards have arranged.

 

Meanwhile, the fundraising Matrix is taking shape:
http://www.ukrituximabtrial.org/IIME UK Rituximab Trial Matrix 01.htm