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How likely is a UK rituximab trial?

Discussion in 'Rituximab: News and Research' started by veganmua, Aug 28, 2016.

  1. veganmua

    veganmua Senior Member

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    What can we do to increase this likelihood? When would it be likely to happen?
     
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  2. alex3619

    alex3619 Senior Member

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    There are threads on this here somewhere. A trial has been in the planning phase for years now. @Jonathan Edwards would possibly be up to date on this.
     
  3. charles shepherd

    charles shepherd Senior Member

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    The following background information may be helpful

    1 Summary of points relating to Rituximab from Dr Amolak Bansal's prsentation at the Sussex Research and Management meeting in May:



    RITUXIMAB
    During the Question and Answer session Dr Bansal provided a comprehensive update on the current situation regarding the proposal to carry out a clinical trial of rituximab here in the UK to see if this could replicate the benefits that have been reported from the Norwegian trial.

    However, feedback relating to people in the UK who have been treated with rituximab in America, as well as US citizens who have been treated with rituximab, has been nowhere near as positive as the results that have been reported from Norway. Consequently, questions are now being asked as to how a UK trial could/should proceed and whether this is the right time to commence a UK trial.

    Dr Bansal noted that it is possible that the failure of these people to respond to rituximab could be explained by different trigger factors being involved in the Norwegian population, and/or that there is something different about the patient selection process in Norway.

    These concerns and uncertainties about the UK trial are due to be discussed with US colleagues shortly.

    Dr Shepherd pointed out that the MEA Ramsay Research Fund still has around £60,000 of ring-fenced money to help fund a UK clinical trial of rituximab – if a suitable protocol can be developed by the group concerned (which includes Dr Bansal) and there is a definite intention to move forward with a clinical trial, and a formal application is received.

    However, if a UK trial of rituximab is not going to take place, or it is going to be delayed until the results from the phase 3 clinical trial in Norway are published, the MEA Ramsay Research Fund will have to reconsider our position. This is because we have other requests for funding, including a commitment to keep the ME Biobank going for the next two years (at a cost of around £40,000 per year), which will need to be taken into consideration.

    Full report here:

    http://www.meassociation.org.uk/201...ghlights-of-burgess-hill-meeting-14-may-2016/


    2 My notes from the presentation by Dr Jo Cambridge at the 2016 Invest in ME Conference:

    DR GERALDINE (JO) CAMBRIDGE – PRINCIPAL RESEARCH FELLOW INFLAMMATION, DIVISION OF MEDICINE, FACULTY OF MEDICAL SCIENCES, UNIVERSITY COLLEGE LONDON (UCL) AND FANE MENSAH
    B-cell biology and Rituximab treatment in patients with ME/CFS

    Dr Jo Cambridge gave an excellent and easy-to-understand presentation on B-cell function in general, how B-cell dysfunction and the production of autoantibodies might relate to the immunopathology of ME/CFS, and the practical aspects of using rituximab to treat non-malignant conditions.

    She explained that she belonged to a group of researchers at UCL – including Professor Jonathan Edwards – who have a particular interest in how a drug called rituximab, which was originally used to treat a malignant condition called lymphoma, depletes the population of a specific type of immune cells called B-cells. Rituximab was then found to effectively treat some cases of rheumatoid arthritis (RA) and other autoimmune conditions such as SLE/lupus where inflammation is an important part of the underlying disease process.


    Among the key points made in relation to the use of rituximab in RA and to the way in which it might also act in ME/CFS:

    * This research has produced information about how rituximab can produce a significant remission of symptoms (in around 70% of RA patients) and the resumption of symptoms (in around 60% of RA patients) once the B-cell population has been restored.

    * Patients with high levels of autoantibodies (= antibodies that attack the body’s own tissues) have a far more pronounced and predictable response than those with no evidence of autoantibodies.

    * B-cells are killed off very quickly by rituximab; the drug binds to cells that express what is called a CD-20 receptor. This usually occurs within a week of the infusions which are given intravenously over 6 hours. The B-cells therefore start to disappear from the blood within days and from other tissues at varying rates. But the dynamics of the clinical response – which takes from 1 to 5 months after depletion of the B-cells – suggests that for remission to occur it is the constantly generated B-cell product (possibly an autoantibody) and not the B- cells themselves that need to be reduced.

    * A considerable proportion of the B-cells are not depleted and remain in protective sites in lymphoid and inflamed tissues.

    * Levels of autoantibodies can therefore remain raised, even in the presence of an improvement in clinical symptoms.

    * These observations suggest that only a proportion of parent B-cells and autoantibodies are actually ‘pathogenic’ (that is involved in disease causing mechanisms). And, as a proportion of patients then relapse, the autoimmune response underlying the disease causing process must be self-sustaining.

    * Patients are not therefore normally ‘cured’ by rituximab and symptoms can worsen when the B-cells start regenerating within 6 to 9 months after the infusion. However, some patients have a more extended period of remission after the B-cells return.

    * Side-effects are rare and, although there are reductions in serum antibody levels (which provide protection against infections) , the effects on protective immunity are mild and serious infections are not a problem.

    In relation to the use of rituximab in ME/CFS, we are very much at the beginning of a learning process which follows on from the clinical trials that have been carried out and published by Drs Fluge and Mella in Norway.

    The UCL research team is concentrating on investigating B-cell biology in order to try and identify differences between people with ME/CFS and healthy controls to see if this can help identify people with ME/CFS who are more likely to respond to this drug.

    The group has hypothesised that rituximab may be reducing fatigue levels in ME/CFS as a result of decreasing the production of immune system chemicals called cytokines (i.e interferon alpha) through the removal of autoantibody containing (pro-inflammatory) immune complexes. Rituximab would therefore be working by stopping the production of (as yet) only tentatively identified pathogenic antibodies.

    Fane Manesh, a PhD student at UCL, then spoke about the work that has been carried out into phenotyping sub-populations of naïve and memory-B cells in people with ME/CFS.

    The group has published data on these B-cells and this shows that a specific cell maturation marker called CD-24 is upregulated or retained by the newly generated B-cells. As a result, they have been using cells from patients and healthy controls to follow B-cell development patterns, and interactions with T-cells, in response to certain stimuli. The group has also established an in vitro system (i.e. it is performed in a test tube) where they can compare the metabolic function of B-cells in ME/CFS patients and in healthy controls as well as what is termed mitochondrial mass.

    Dr Cambridge did not put any ‘meat on the bone’ regarding which clinicians might/would be involved in a UK trial; where the trial might/would take place; the development of the protocol; and when a clinical trial might/would take place here in the UK until the Q and A session, where she explained the difficulties involved in setting up a UK trial for a drug like rituximab.

    According to Dr Cambridge, it is going to be very hard to get a clinical trial going here in the UK due to a combination of developing a protocol, obtaining ethical approval, finding committed clinicians to carry out the work, the work being expensive in both cost and time, and the lack of pharmaceutical backing for a drug that is quite expensive to use. This has also occurred in other clinical trials involving rituximab.

    Dr Cambridge also repeated the advice that has come from Drs Fluge and Mella in Norway that in our present state of knowledge rituximab should not be used on patients with ME/CFS outside proper clinical trials.

    [CS note: I was going to ask Dr Cambridge over lunch what she thought about the less positive patient evidence from people with ME/CFS who have been treated with rituximab in America outside the Norwegian clinical trial (an important point that was raised during the clinical and research meeting in Sussex with Dr Amolak Bansal and myself three weeks ago) but wasn’t able to do so.

    Further information:

    Mensah F et al. Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
    Clinical Experimental Immunology. 2016,184 :237-47.

    Full conference report here:

    http://www.meassociation.org.uk/201...y-for-sharing-ideas-on-research-20-june-2016/


    3 Follow up comments from Prof Edwards on PR discussion:

    Thanks CS, especially liked the information from UCL.

    One thing though: Why should it be hard to make a protocol for a rtx-study, in light of Haukeland already having one?
    Maybe I should comment here. Dr Cambridge has never been directly involved in the setting up of a trial, only in background research. Speakers at the IiME meeting were often asked questions that had nothing to do with their talks at all. There was a question to Dr Cambridge about setting up trials and she did her best to give her thoughts on the difficulties but only because she felt she ought to produce some sort of answer. She was not speaking for those involved in trial planning.

    In relation to Marky90's question we need to distinguish a treatment protocol from a trial design. Haukeland have devised a treatment protocol. It would be sensible to use the same protocol in other studies until we know more, but that has nothing to do with designing a trial that will answer a question. The size of trial that there is a budget for in the UK would not provide statistically powerful evidence just for efficacy over and above the Norwegian phase 3 study. It was always assumed that a UK trial would address a different scientific question - perhaps about markers of response or dose ranging - which could usefully be assessed in a relatively small trial.

    Dr Cambridge is right to point out that it is essential to have a dedicated principle investigator with a team that understands both ME/CFS and rituximab. Trials run by subcontractors are not a good idea. At present it is not clear that there is a suitable PI in the UK to take a trial forward.

    Although Fane Mensah has been working hard at detailing B cell subsets in ME/CFS we do not yet have a replicated marker that could be used look for correlation with response. That means that it is not clear what scientific question a UK trial would answer. I appreciate the enthusiasm for a UK trial but we cannot treat people with a drug with potential harmful effects without justifying that with a clear scientific objective. Drs Fluge and Mella would not wish that. Discussions continue but my own view is that setting up a trial in the UK should wait until either we have new findings that provide a clear direction or until we have a positive outcome from Norway phase 3, which would justify a small dose ranging study. Above all we need some handle on a B cell abnormality that we can follow so that we know what is going on.

    As people will realise, I have been through this mill once before (more than once in fact) and it is far from simple. It is not a question of if things go wrong but when, and how best to pick up pieces when they do, to ensure the best outcome. That does not mean getting cold feet, it just means being patient about when is the right time to move forward. Pharmaceutical support can be helpful but only if the science has been well sorted out in advance. Company trials can distort design in ways that are not in the patients' interests. The Norwegians have done everything by the book and all credit to them for getting this far. I do not think we should be muddying the waters with underpowered or badly controlled studies done in haste.

    An important part of exploring use of rituximab in other countries is to get a feel for clinical response outside a trial setting, which is a legitimate objective at this stage. Quite a large number of people with ME/CFS have now been treated in the USA, Germany and Norway at least and it would be useful to have published reports from these centres. Unfortunately at present we only have hearsay.

    4 The most recent (May 2016) MEA statement on the £60,000 we have reserved in the Ramsay Research Fund to help fund a UK trial - if a protocol can be prepared. and there is a UK PI and a clinical trial unit that wants to proceed with a trial, and formal research grant application is submitted to the RRF:

    http://www.meassociation.org.uk/2016/05/rituximab-update-by-the-me-association-23-may-2016/

    Dr Charles Shepherd
    Hon Medical Adviser, MEA
     
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  4. charles shepherd

    charles shepherd Senior Member

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    It would also be very useful if those physicians in the USA (and possibly elsewhere) who are treating ME/CFS with Rituximab outside a clinical trial could publish some information on what has been happening to these patients - rather than relying on (the often negative) anecdotal reports that appear on the internet and via the medical grapevine
     
  5. Aurator

    Aurator Senior Member

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    Though I risk sounding heretical, we still need to be cautious about how we interpret reports from physicians who are using Rituximab for ME/CFS outside of clinical trials - possibly even more cautious, given the financial interest some of these physicians may well have in giving Rituximab a more positive appraisal than the facts really permit.
     
  6. charles shepherd

    charles shepherd Senior Member

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    I would fully agree that we need to be cautious when interpreting this sort of information

    But it should be reported as both patient evidence and clinician evidence to add to the 'Gold Standard' evidence from clinical trials that are taking place/have taken place in Norway.
     
  7. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Honestly we can`t trust clinician evidence without any sort of obligatory patient reporting (questionnaires or the like). There is so much at stake for clinicians giving rituximab before phase 3 is out, and therefore all sorts of reasons for them not to report accurately. And even if they wanted to, how could they without tracking the progress of each patient?

    We have discussed this before Charles, and agreed to disagree, so do not feel obliged to respond.

    In a perfect world physicans would have to document relapses and recoveries before initiating experimental treatment, but one could argue that such added work either should be paid for, or conducted by the public health service.
     
  8. RL_sparky

    RL_sparky Senior Member

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    Well if they choose not to do a Rituximab trial why not do a cyclophosphamide trial. I read somewhere where Dr Øystein Fluge and Prof Olav Mella thought this would end up being the drug of choice anyway. It appears from the 1st trial to take a shorter time frame to work. The Norwegians are wrapping up a 40 patient trial next month , I believe with publication due early in 2017. It's a more affordable drug making it potentially accessible to more patients.
     
  9. Gingergrrl

    Gingergrrl Senior Member

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    I also wish that patients could be tested for autoantibodies (like those in Germany plus tests like the Mayo Clinic runs) before RTX b/c I think this issue will really help us with figuring out sub-groups or responders. And the autoantibodies could be measured before and after RTX (in addition to patients reporting that they have symptom improvement). I would want a trial to specify patients with and without antibodies (in an ideal world).
     
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  10. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Although the problems with the results from germany on antibodies pointed out by JE, is that you cant know for sure that clinical responses from rtx, that correlated with a drop in antibodies,is due to that drop, as rituximab also reduces other antibodies.
     
  11. Gingergrrl

    Gingergrrl Senior Member

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    I just think it would be an extra component that would be interesting to track if there were ever a large-scale trial or trials in different countries. I don't even think the person would need to have an ME/CFS diagnosis vs. certain antibodies (although I realize this might have to be a totally separate trial). I don't think we can say for sure what ME/CFS is but we can say for sure if an individual is positive for a certain auto-antibody, if the Ab reduces or disappears with RTX, and if the person reports a subjective improvement in symptoms plus something measurable like with an EMG, Neuro exam, spirometry test, six minute walk test, etc.
     
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  12. veganmua

    veganmua Senior Member

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    Thanks for your replies. What, if anything, can we as patients do to help a rituximab (or indeed cyclophosphamide) trial happen in the UK?
     
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  13. charles shepherd

    charles shepherd Senior Member

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    Following on from the information that is already in the public domain (see my original contribution), it seems to me that we may now be in a position where any firm decision regarding the development of a protocol for a UK trial, and finding a PI who wants to carry out a trial, AND finding a suitable location for a UK clinical trial, may have to wait until we have the results of the phase 3 clinical trial that is now taking place in Norway

    I think this is planned to conclude in the summer of 2017. But the results will not appear till later.

    What happens after that will clearly depend on the results from Norway

    If the phase 3 trial confirms the positive results that have already been reported from Norway, there would then be a very strong case to try and replicate these results in another (preferably large) RCT (randomised controlled trial clinical trial) that was completely independent of the Norwegian group

    As rituximab is a fairly expensive drug that has to be carefully administered in hospital, this would cost a considerable amount of money (far more than has been raised so far by the charity sector)

    However, I think that any application would receive serious and sympathetic consideration from a major funding body such as the MRC

    The MEA has co-funded research with the MRC and we would be very happy to do so again in the case of a rituximab trial

    If the results from the Norway phase 3 trial are disappointing, there will have to be a serious reconsideration of the possible role of rituximab in the treatment of ME/CFS......…

    So my gut feeling right now is that we may not see a UK trial taking place until later next year or early 2018

    Latest MEA statement on rituximab:
    http://www.meassociation.org.uk/2016/05/rituximab-update-by-the-me-association-23-may-2016/

    Dr Charles Shepherd
    Hon Medical Adviser, MEA
     
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  14. BurnA

    BurnA Senior Member

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    Thanks as always for your contribution here Dr.Shepherd.
    I agree at this stage it probably makes sense to wait and see the results from Norway.
    The only comment I'd like to make is a very general one about cost.
    Whilst I know you compared the cost of a trial to the monies currently raised, on any topic of cost, it is wise to consider all costs to paint an accurate picture.

    I am sure when one factors in the amount of money currently wasted on bogus treatments and pseudoscientific research in the UK the cost of a rituximab trial would seem like very good value. I think this is a message worth getting across and one that is often overlooked.

    PS think of how much money will be saved when they close down all those GET / CBT clinics.
     
  15. charles shepherd

    charles shepherd Senior Member

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    Fair point about the cost benefit analysis

    The MEA Ramsay Research Fund has around £60,000 set aside to help fund a clinical trial of rituximab

    Our preference is to use this money help researchers here in the UK (if the money is required) but we are also willing to consider a research grant proposal from an overseas group if there is a reputable clinical trials group who want to get involved with this approach to management

    The jury is clearly still out on the use of this drug in ME/CFS in our current state of knowledge

    But given the cost, and the potential to cause serious side effects, the UK licensing authorities and NICE will need sound evidence on both efficacy and safety from several large clinical trials before they even consider making a drug like this available on the NHS for ME/CFS

    So, even if all goes to plan, it is difficult to see how rituximab could become available on the NHS for the treatment of at least some people with ME/CFS before 2020 here in the UK
     
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  16. FTY

    FTY

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    Hi, this is very interesting. I'm a bit confused because Dr Bansal has said that there is no chance of a UK rituximab trial starting any time soon. We don't know the results of the Norwegian phase 3 trial yet, and it may very well not be positive. @Jonathan Edwards has spoken (sensibly) on here about how there would be no use in starting a UK trial at this point in time. @charles shepherd's comments above also suggest that a UK trial won't happen in the near future. And yet this seems to be going on: future.cofeforme.eu/IIME-Newslet-1611-03.shtml suggesting planning for a Norwich based trial is happening currently (as far as I can gather). Will the commencement of the Norwich trial be dependent on Norwegian results? Anyone any ideas?
     
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  17. veganmua

    veganmua Senior Member

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    Well, judging from the link, Dr Fluge is involved in these plans, so (hopefully) it could be an early indicator that good results are expected!? Or preliminary results are looking good? Oh god, do I even dare to be hopeful?!?

    I have a lot of brain fog, so excuse me if I'm wrong, but is this saying the trial will no longer be conducted by UCL? In that case, where will the participants be sourced? (Which clinic do I need to be a patient of?) I sought out Dr Berkovitz specifically with the rituximab trial in mind.

    Thanks for bringing this to our attention, @FTY .
     
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  18. FTY

    FTY

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    Thanks @veganmua I think this is encouraging - I trust the team working on this. I think the realistic hope is that rituximab research will lead to a much better understanding of this disease which will in time lead to treatments. But I also think it's also good to dare to hope for everything (cure) asap - let's both dare to hope :)

    - I think the UCL team will be involved (but I really don't know much).
     
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  19. Cinders66

    Cinders66 Senior Member

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    If ME was properly respected as the devasting illness it is and the powers that be acknowledged their appalling to date neglect then I don't think the logical decision IS to delay rituximab trials until the third phase trial is in, that is just what happens with an illness ranked low importance on shoe string budget. I remember reading the PET scan schizophrenia research (yes we are still waiting for OUR confirmation of PET scan inflammation confirmation studies) and how the MRC funded scientists were immediately rushing off, based on these results, to trial an experimental drug to address that inflammation. That's how things work for illnesses taken Seriously with reasonable budget. In ME the MRC should have done some rituximab research instead of the wait and see approach which had the inevitable consequence of wasting yet more of the precious lives of the severely ill. But who cares about us.

    In U.K. We need now a movement to lobby the MRC to give us ring-fenced the £7m was it? Gibson inquiry parliamentarians said we should get fair due in 2007 but MRC refused. We need rapid headway in this illness and MRC approach ain't cutting it , and the chsarities which won't lobby on this are failing generations of uk patients.
     
  20. Cinders66

    Cinders66 Senior Member

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    Because uk researchers aren't interested in a medical approach to this illness when CBT Get are so over promoted, because MRC refuse to ring-fence to stimulate research that's otherwise languishing and because charities can't fundraise or incentivise for a stigmatised illness. U.K. State funders have shown no urgency in trying to find treatments for the two decades worth of patients disabled by their hopeless NHS past approach to CFS , even with B12 drs are more likely to get struck off for using it than get money to actually research it. Prof Mella was saying at the recent IACFSME conference his disappointed that so little treatment research was going on. I think they're very much researchers moved by their hearts to alleviate suffering, not enough of those around, indeed I think the suffering aspect, both in terms of severity and multi symptom nature has been pretty much white-washed by the uk CBT MUS fatigue models.
     
    Last edited: Nov 29, 2016
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