Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

Discussion in 'Latest ME/CFS Research' started by Simon, Jul 1, 2015.

  1. Simon

    Simon

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    As posted by the ME Association (thank you!)

    - this is for RESEARCH discussion, go here to discuss media response -

    B-lymphocyte depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An open-label phase II study with rituximab maintenance treatment

    Øystein Fluge(1*), Kristin Risa(1), Sigrid Lunde(1), Kine Alme(1), Ingrid Gurvin Rekeland(1), Dipak Sapkota(2,1), Einar Kleboe Kristoffersen(3,4), Kari Sørland(1), Ove Bruland(5,1), Olav Dahl(4,1), Olav Mella(1,4*)
    1) Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
    2) Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway
    3) Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway
    4) Department of Clinical Science, University of Bergen, Haukeland University Hospital, Bergen, Norway
    5) Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
    * Correspondence: E-mail: oystein.fluge@helse-bergen.no (ØF); olav.mella@helse-bergen.no (OM)

    Trial registration: ClinicalTrials.gov; NCT01156909

    Abstract

    BACKGROUND

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS.

    METHODS

    In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months.

    FINDINGS

    Major or moderate responses, predefined as lasting improvements in self- reported Fatigue score, were detected in 18 out of 29 patients (intention to treat).

    Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders.

    At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8-66).

    Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study.

    Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity.

    CONCLUSION

    In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

    No sign of the paper itself, yet.
    PLOS ONE: B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment
     
    Last edited: Jul 1, 2015
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  2. Simon

    Simon

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    ME Association statement


    Further evidence of Rituximab’s effectiveness in treating ME/CFS | PlosOne publish results of Phase 2 trial | 1 July 2015
    The results of a phase 2 clinical trial into the treatment with the anti-lymphoma drug Rituximab of a group of 29 patients with ME/CFS are announced this evening in the US open access science journal, PloSOne. They have been welcomed by the ME Association as evidence of possibly “the first major advance” in the drug treatment of the illness.

    The trial is being carried out by the Norwegian group that first announced it was investigating the use of Rituximab in ME/CFS in 2011. Eighteen of the 29 patients– 64% – experienced major or moderate responses, and some have now been symptom-free for five years. Rituximab wipes out most of the B cells that make antibodies, yet patients don’t experience remissions of their symptoms until months later.

    STATEMENT BY DR CHARLES SHEPHERD, MEDICAL ADVISER, ME ASSOCIATION
    The Norwegian clinical trials (which are being followed closely by people with ME/CFS) indicate that Rituximab could be the first major advance in the drug treatment of ME/CFS.

    The findings are also support a key role for immune system dysfunction in the causation of ME/CFS and explain why (immunomodulatory) treatments that remove B cells from circulation could then be used in some cases.

    The downside is that Rituximab is a very expensive drug with a potential to cause serious side-effects.

    So, while a much larger phase 3 clinical trial is now taking place in Norway, we also need to set up up other multi-centre clinical trials to confirm the efficacy and safety of Rituximab in ME/CFS, and to obtain a clearer (clinical and immunological) profile of which patients respond to Rituximab and which do not.

    Otherwise, there will be a significant delay before what could be a very effective form of treatment becomes available here in the UK.

    Dr Charles Shepherd
    Hon Medical Adviser, ME Association


    NB:
    1 Researchers at University College London are currently carrying out further research on B cell dysfunction in ME/CFS in preparation for a UK clinical trial of Rituximab.

    2. Dr Øystein Fluge will be speaking at the CFS/ME Research Collaborative Conference in Newcastle on Wednesday, 14 October 2015.

    www.meassociation.org.uk/2015/03/early-bird-bookings-open-for-the-two-day-research-collaborative-conference-newcastle-13-14-october-2015/

    3 The Norwegian group are also looking at the use of another immunomodulatory drug, cyclophosphamide:

    www.meassociation.org.uk/2015/02/second-anti-cancer-drug-now-being-investigated-in-norway-for-treatment-of-mecfs-10-february-2015/
     
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  3. A.B.

    A.B. Senior Member

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    Open-label means both the researchers and participants know what they're receiving/administering. What is the purpose of doing an open label study? I suppose one thing we could learn is that the response rate in this open-label study (64%) did not differ greatly from the previous double-blind placebo controlled pilot study (67%), but I'm sure there are other reasons as well. Does anyone know?

    Note: there is no placebo group in this study so everyone knows they're getting Rituximab.

    To rephrase: 2/3 of the people who in the previous study failed to get better with a placebo, got better when receiving Rituximab. Did I understand this right?

    These seem to be pretty consistent findings so far. It's almost too good to be true :)
     
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  4. msf

    msf Senior Member

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    I'm confused, when is the large, double-blind study coming out?
     
  5. Scarecrow

    Scarecrow Revolting Peasant

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    I guess because it's a small study - so cheap to run - and indicates whether it might be worth doing a larger trial. In the case of this study it looks like it was a resounding 'yes'. Makes you wonder why they struggled to get funds for the Phase III trial.
     
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  6. Simon

    Simon

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    Full free text is here at PLoS One. It's a huge paper.

    PLOS ONE: B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

      • Øystein Fluge ,
      • Kristin Risa,
      • Sigrid Lunde,
      • Kine Alme,
      • Ingrid Gurvin Rekeland,
      • Dipak Sapkota,
      • Einar Kleboe Kristoffersen,
      • Kari Sørland,
      • Ove Bruland,
      • Olav Dahl,
      • Olav Mella
    [​IMG]
      • Published: July 1, 2015
      • DOI: 10.1371/journal.pone.0129898
    @Sasha and I hope to be bringing you a blog on this later this evening.
    hopefully this will answer some of the questions posted here - though by then the smart crowd here will probably have it all figured out
     
    Last edited: Jul 1, 2015
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  7. Scarecrow

    Scarecrow Revolting Peasant

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    It's all in the eye of the beholder. ;)
     
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  8. Bob

    Bob

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    The large multi-centre double-blind phase iii study won't be published for a year or two. I can't remember the exact time scale. This was a second phase II trial.

    The reason this study was open-label was so that Fluge and Mella could assess the most effective treatment regime as they carried out the study. I think it was to give them some flexibility and better insight into what was working best. i.e. the best dosage and the optimal intervals between infusions. That's my understanding of it anyway, but I might not have got the details exactly right.
     
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  9. Scarecrow

    Scarecrow Revolting Peasant

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    Oh, alright then. Now we're in agreement.
     
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  10. msf

    msf Senior Member

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    Well, from a quick glance at the paper I would say Ritux seems to be the answer for about a third, part of the answer for another third, and not the answer for the last third.
     
  11. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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  12. worldbackwards

    worldbackwards A unique snowflake

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    Anyone want a good laugh? This comes from @Firestormm on Twitter:

    Screen Shot 2015-07-01 at 20.33.43.png

     
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  13. msf

    msf Senior Member

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    Wow, I think Wessely just had a breakdown.
     
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  14. halcyon

    halcyon Senior Member

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    And also not an answer for all those who aren't a candidate for the treatment at all.
     
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  15. cigana

    cigana Senior Member

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    I think there is no placebo because in this study they wanted to focus on working out if they could keep the patients better for longer by giving them more rituximab (which seems to be true).
     
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  16. John Mac

    John Mac Senior Member

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    Maybe he needs to see a psychiatrist
     
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  17. Sidereal

    Sidereal Senior Member

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  18. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Yes, it is really all about kinetics and consistency. You need controlled studies to prove the thing works but you also want to get a feel for the practical detail of how long it works and whether you can repeat it and all sorts of other things. That is where open label follow on comes in. It still does not give us the hard proof that can only come from the big phase III study but it provides scrupulous accounting on a whole lot of issues that might have started to look problematic at this stage. I have not read the paper yet but from the preview information I have had it seems clear that no major roadblocks have been encountered. Thoroughly encouraging.
     
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  19. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    Ooh, and who would those be?
     
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  20. Sidereal

    Sidereal Senior Member

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