New Atmosphere, New Vision: Gibson and Whittemore Kick Off Invest in ME Conference 2016
Mark Berry reports on Dr. Gibson's introduction and Dr. Whittemore's keynote speech, at the 11th Invest in ME International ME Conference in London.
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Why do the Fluge/Mella trials seem to be more successful than off/trial reports?

Discussion in 'Rituximab: News and Research' started by Jesse2233, Feb 8, 2017.

  1. Jesse2233

    Jesse2233 Senior Member

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    @Jonathan Edwards

    Hi Professor, would you say that the reason for fewer successful outcomes in off-trial Rituximab treatments vs Fluge / Mella's trials is...

    1. An incorrect maintenance portocol?

    2. Specific patient selection criteria in the Norway trials (or a regionally definedl etiology)?

    3. An incorrect inital dosage rate/size?

    4. Lack of a controlled setting?

    5. A combination of the above?

    6. Another reason?

    Or is the premise of my question flawed in that we don't have a significant sample of off-trial treatments from which to draw a comparison?

    Anyone else feel free to jump in!

    Thank you!
     
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  2. deleder2k

    deleder2k Senior Member

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    To your question, who says that there are fewer successful outcomes for patients treated outside studies?

    I think we would expect the results from a multi-centred phase 3 trial to be slightly less positive than the previous ones that were conducted only at one hospital. I think that is pretty common.

    My sources say that the respond rate may be lower than what the studies have shown earlier, but that is speculation based on reports from some patients treated outside trials. We don't know whether these patients have ME according to the Canadian criteria - in fact we don't know much about anything. These are just reports from patients. I think you could be right in your assumption, but it is important to distinguish between a proper study and unofficial reports from patients that we know nothing about.
     
  3. Jesse2233

    Jesse2233 Senior Member

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    @deleder2k yes that's a fair point. I don't know if the rates are actually lower, but annecdotally that's how it seems. I'm of course hoping it's not the case.

    I remember reading a post that said you were going to trial Rituximab. Did that end up happening (if you're comfortable sharing)? Couldn't find the follow up
     
    Last edited: Feb 8, 2017
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  4. Hip

    Hip Senior Member

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    On these forums, the response rate of those who posted their rituximab results has not been very good. Out of the 14 people on this forum who I saw posted their results, only 1 person had a very good response, another 1 or 2 had moderate to mild responses, and the rest did not respond.

    However, in some cases there were only minimal details posted, so it was not clear what rituximab protocol they followed, how long they followed it for, nor even whether they had ME/CFS in the first place by the strict CCC definition.

    It's possible that there are others on the various ME/CFS forums that are getting some positive responses from rituximab, but they prefer not to post about it.

    I think there was some concern that posting your rituximab results on a public forum could affect the outcome of the Fluge and Mella phase III rituximab clinical trial, which is still ongoing, but I don't remember the reason for this.

    The rituximab results of the Kolibri Medical hospital in Norway are positive though, see this post. Not sure about the Open Medicine Institute's rituximab response rate.
     
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  5. Jesse2233

    Jesse2233 Senior Member

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    Interesting, Kolibri results matched Fluge / Mela's second trial. Do we know their population size / protocol?
     
  6. adreno

    adreno PR activist

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    As more and more studies are coming out showing ME to be a metabolic disorder, I have lost faith in rituximab as a reliable treatment. I don't think any of the researchers involved in those studies seriously considers rituximab as a viable treatment either. I am however optimistic that other treatment options will become available in the light of recent findings.
     
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  7. Hip

    Hip Senior Member

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    Being an energy metabolism disorder and being an autoimmune condition are not mutually exclusive: an autoantibody targeting the mitochondria could for example cause the energy metabolism dysfunction.
     
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  8. Jesse2233

    Jesse2233 Senior Member

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    Perhaps B-cell dysfunction is disrupting the metabolic system via some upstream mechanism

    What makes you say that?
     
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  9. Jesse2233

    Jesse2233 Senior Member

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    Yes are there other autoimmune diseases where this happens?
     
  10. deleder2k

    deleder2k Senior Member

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    If the body creates b-cells which turns into autoantibodies that attacks an enzyme that is required for the metabolic system to function properly then Rituximab is surely a very interesting drug to consider using. If the phase 3 trial shows a response rate of 50% for patients treated with rituximab, compared to say 10-20% for placebo group, that would be a fantastic result.


    Most absurd thing I've read in 2017. Where do you get your information? I don't want to be rude, but I think you have read up on why immunomodulatory drugs like rituximab works in diseases. It is 100% certain that all of us wont benefit from rituximab, but I think we know from a fact that quite a few of us would. We don't know how many before the study is published in early 2018, but the researchers are confident that a group of patients with ME respond to the drug. It would be great if they actually could link B-cell depletion to the believed metabolic dysfunction, but if they are on the wrong that it doesn't really make any difference for the rituximab study. We use many drugs that we don't know exactly why they work. The important thing with respect to treatment is that patients that receive the drug improves more than the placebo group, and that side effects are not an issue. Even why we don't know why it helps, if we're certain that rituximab does alleviate symptoms for ME patients, then we have something that can help many of us.

    I would also have a look at their latest presentation in Norwich which is available here:
     
    Last edited: Feb 9, 2017
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  11. Gingergrrl

    Gingergrrl Senior Member

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    If I do RTX in the future (which I will do 100% if I can get insurance approval) then I will post about it. I would be doing an autoimmune disease protocol of two doses given two weeks apart. If my B Cells are then at an undetectable level, then I would not require anything further. If B Cells return, then we would request another infusion at the 3, 6, or 12 month mark (only if needed at any of those points) to keep B Cells at an undetectable level for one year. So most likely, two doses total will be all that is needed.

    In my case, I have proven autoimmunity but do not suspect that I have a metabolic disorder (although anything is possible). If RTX is the thing that helps my remaining symptoms (in addition to the improvements I have had from IVIG) then I do not care what disease label I am given. For a while I was obsessed with the label but have found this is far less important than how I feel and my level of functioning.
     
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  12. deleder2k

    deleder2k Senior Member

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    @Gingergrrl, if you get maintenance infusions or not won't effect whether you'll respond or not, but the open phase 2 study showed that maintenance infusions delayed relapse significantly. I think almost no one relapsed why getting maintenance infusions, and it looked like the response lasted longer (way longer for some). That is something to consider - especially if your insurance pays.
     
  13. adreno

    adreno PR activist

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    I must have missed all the buzz and excitement about rituximab in the metabolomics studies.
     
  14. Gingergrrl

    Gingergrrl Senior Member

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    Thanks @deleder2k and ultimately I am going to do the protocol that my doctor's think is best (combined with whatever my insurance permits).

    It is interesting what you are saying re: that the maintenance infusions do not effect if you initially respond but could delay the relapse. That is definitely something to consider. I am so far from that point though and this is another purely theoretical discussion! But I am gathering all of this info and storing it in my brain for future reference!
     
    Last edited: Feb 11, 2017
  15. Gingergrrl

    Gingergrrl Senior Member

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    ETA- @deleder2k Do you know why maintenance infusions would delay relapse if the B Cells are already at an undetectable level? No worries if you do not know the answer!
     
  16. Hip

    Hip Senior Member

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    Yes, in chronic coxsackievirus B myocarditis (viral heart muscle infection), the virus appears to give rise to an autoantibody that targets the translocator protein in mitochondria, thereby causing mitochondrial dysfunction, and a low energy state in the heart. More info in this post.
     
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  17. deleder2k

    deleder2k Senior Member

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    I am sure @Jonathan Edwards can provide a better answer than I do. I think this is also discussed in their study published in 2015 in PLOSOne. If you haven't read it, you must read it :)

    @adreno, I think many of them has mentioned the studies, but we don't know for sure whether Rituximab works before the study is published in 2018. I think someone can explain this to you more thoroughly, but the point is that a metabolic dysfunction could go hand in hand with the use of rituximab. Rituximab could kill the potential autoantibodies that lead to the metabolic dysfunction.
     
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  18. Gingergrrl

    Gingergrrl Senior Member

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    I look forward to his answer and tbh at this point, I am not even sure which studies I have read and not read re: RTX b/c most of them are above my level of understanding!

    This makes sense to me and my Metabolon showed many different types of dysfunction but I was told that it did not match the dysfunction seen in the ME/CFS patients in the study (mine was done privately and not part of any study). I really cannot explain the differences, only that they were seen by the experts.

    I think this might be why I had so much muscle weakness that kept worsening (to where I could no longer open a bottle of water or my front door prior to IVIG) yet I feel no fatigue and can participate in activities all day long, every day, with no negative consequences as long as I am using wheelchair. So I think it is likely I am in the responder group to RTX even if we don't know what illness I have. I hope this relates to the original posters questions!
     
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  19. AndyPR

    AndyPR RIP PR :'(

    This is the final slide from Fluges recent presentation in Norwich, part of the video that Delder linked above.
    [​IMG]

    Rituximab stage 2 trials showed 65% of patients responded positively to the treatment, stage 3 results will be out in 2018. Earlier in the talk cyclophosphamide was discussed, results will be out later this year so all they would say was that they were getting positive results with that too.

    In the diagram, Fluge is illustrating their theory on how these treatments may work, in that the drugs impact on what is causing the upregulating of PDKs and SIRT4, which they believe are the reason that PDH function is down regulated and which then causes our problems in glucose conversion. Also note that the diagram indicates two potential areas for new treatments, first, alternatives to rituximab and cyclophosphamide and secondly, at the point of PDK-PDH interaction. I took many things from the talk, and one of them is that if they can find an alternative and better treatment to use then they will use it.
     
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  20. BurnA

    BurnA Senior Member

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    Yes, that's very interesting. I wonder if they already have ideas of new treatments or just speculating.
     

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