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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. Bob

    Bob

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    That finding has been repeated by the CDC recently (Out of 104 referred patients examined, 47% were found to have exclusionary illnesses, and 17% had insufficient symptoms for a CFS diagnosis):
    http://forums.phoenixrising.me/inde...illnesses-and-chronic-fatigue-syndrome.24627/
    user9876 likes this.
  2. user9876

    user9876 Senior Member

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    Its not just the matching of a set of symptoms but also the filtering of other diseases where care needs to be taken. The uncertainty around entry conditions makes me worry about small trials. For example if you have 10 patients but 4 of them have other problems such as a sleep disorder then 2/3rd sucess on the others would only leave 4 out of 10 giving a response with a probability of less.

    I guess this is the importance of having a good initial diagnostic process as part of a trial. Many trials seem to use mild and moderately affected patients as its easier. Do you have a preference? - I would have thought more severe patients would have easier to measure improvements and perhaps easier to see changes in any blood results.
    Bob likes this.
  3. Bob

    Bob

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    Jonathan Edwards

    I wonder if you are aware of Prof Mady Hornig's work re PANDAS (not the cuddly type, but 'pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection')?

    Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection
    K Yaddanapudi, M Hornig, R Serge, J De Miranda, A Baghban, G Villar and W I Lipkin
    Molecular Psychiatry 15, 712-726 (July 2010) | doi:10.1038/mp.2009.77
    http://www.nature.com/mp/journal/v15/n7/full/mp200977a.html

    Here is a short (lay) explanation of the above PANDAS research (from an article on this forum), which perhaps you may find interesting, if you haven't come across it already...

    The above extract is taken from a forum article by Simon:
    http://forums.phoenixrising.me/inde...ig-how-do-you-solve-a-problem-like-cfs.22182/




    Prof Mady Hornig is also currently working on a huge and expensive (multi-million-dollar) ME/CFS investigation with Prof Ian Lipkin, looking for any pathogens, proteins, DNA etc. that might be associated with ME/CFS. (Using a range of tissue types.)

    The latest very preliminary news is that the Lipkin/Hornig team say they may have found a 'possible' candidate in terms of finding something (protein, pathogen, DNA?) associated with ME.

    It's just a thought, but perhaps it would be worth contacting Mady Hornig, to see if she has any thoughts about potential biomarkers, that could be useful for your study?

    It's probably too early for her to share any info with you, but I just thought I'd mention it, in case helpful.
    voner, Simon, Marco and 1 other person like this.
  4. Legendrew

    Legendrew Content team

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    I think having a trial that includes both mild/moderate and severe patients is important. A greater severity may not necessarily mean more pronounced bloodwork. It would however be easier to objectively measure a symptom improvement in these patients.

    The trouble with a smaller study is that it puts more importance on the patient selection, The initial diagnostics will be important to rule out other illnesses but I don't doubt that this will be done to a high standard due to the experience of the group who will be carrying out the trial. After that, it is important to get a slightly wider range of diagnosed ME patients; with differing severity and symptoms groups. The most important thing for me has to be the preliminary work looking at B-cells and identifying whether any problems here correlate to patients who improve on the drug.
    Bob likes this.
  5. Ember

    Ember Senior Member

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    You may be aware that the ICC requires PENE which is operationalized this way in the ME Primer:

    * Exercise tolerance test with expired gas exchange - (2 consecutive days) – measure cardiovascular, pulmonary & metabolic responses at rest & during exercise: peak oxygen consumption VO2 or VO2 at anaerobic threshold (AT) - decline of 8% or greater on test 2 indicates metabolic dysfunction, post-exercise blood analysis - increase in sensory, adrenergic and immune genes - increase in metabolite receptors unique to ME

    Dr. Peterson uses biomarkers for entrance and outcome criteria, but using VO2 max as an outcome measure seems to be causing him a storyline problem anyway. His research assistant, Gunnar Gottschalk, says, “We'd like to investigate the mechanism of the increase in VO2 max as well, post and during Cidofovir treatment, and we'd like to do this in a multi-centre fashion (Recording 5, at 9:10 – 9:20).” Dr. Peterson notes:
    In his CPET Presentation Part II, Dr. Snell seems to be alluding to additional data that flows from the Stevens Protocol indicating subgroups:
    The ME Primer suggests using similar prominent-cluster subgroups, i.e., neurological, immune, metabolism/cardiorespiratory or eclectic (balanced). These are detailed in its Systems Review, Physical Examination and particularly in its Laboratory/Investigative Protocol:
    Dr. Broderick has yet to introduce the International Consensus Symptom Scale (ICSS). In Cort Johnson's interview two years ago, Marj van de Sande imagined a future when “the practice of comparing research results with prominent symptom clusters of the patients as indicated in their ICSS brought mutual confirmation and better treatment strategies.”​
  6. Marco

    Marco Old blackguard

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    Hi Bob - an excerpt from Simon's article :


    Rather intriguing that three studies have found impaired HSP response to exercise stress in ME/CFS :

    Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls.

    http://www.ncbi.nlm.nih.gov/pubmed/19032901

    Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses.

    http://www.ncbi.nlm.nih.gov/pubmed/19457057

    Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins.

    http://www.ncbi.nlm.nih.gov/pubmed/22112145

    .... and that HSPs also protect the brain against neurodegeneration :

    The findings of heat shock proteins at the site of neural ‘aggregations’ in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease might suggest they provide a protective response against neurodegeneration (Peter Csermely and Ichiro Yahara, 2003) and may protect the brain against glutamate induced excitotoxicity.

    Heat shock protein HSP70 increases the resistance of cortical cells to glutamate excitotoxicity.

    http://www.ncbi.nlm.nih.gov/pubmed/1625460

    Perhaps PANDAS is another potential model?
  7. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I continue to be intrigued by how many people want a big trial. If we think only 4 out of 10 will respond in a small trial, we have exactly the same problem for a large trial. We are not looking just for any responses but the proportion of responses, which should be the same - 40%. That immediately implies that the bigger the trial the more people will be given an inappropriate, and potentially risky, treatment. That makes it is essential that we do the smallest trial we can. With a bigger trial the statistical significance should improve for the same percentage response but there is a major problem with large trials - lots of people are diagnosing and assessing and that makes for much greater uncertainty about reliability. In my experience, response rates in large trials go down very considerably.

    I am generally in favour of treating severe cases in trials, on the basis that there is more to respond. However, there are several reasons why very severe cases may show poor responses, as I have mentioned before. In most rheumatic diseases we try to distinguish severity from 'activity', the latter being something we think is reversible. For ME that may be difficult.
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  8. Gemini

    Gemini Senior Member

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    Ian Lipkin's speaking on "Infection and Immunity in CFS" September 10 via a Patient Outreach Conference Call sponsored by the CDC. Perhaps he'll provide an update regards any findings at that time?

    Encouraging to me is that Dr. Lipkin is exploring the immune response, taking a much broader look than pathogens alone.
    Kati and Bob like this.
  9. Jonathan Edwards

    Jonathan Edwards Senior Member

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    One difficulty I see is that we do not have any particular reason to think that biomarkers of things like muscle metabolism will be useful for predicting a response to a B cell treatment. In a strange sense we are not looking for better 'markers of ME' but for better markers of illness that responds to rituximab, which is why I think that has to be something relevant to B cells. To my mind, at present, we have to stick as closely as possible to the way Drs Fluge and Mella selected patients, because that is the group we think responds quite well, and study B cell related ways of sharpening that up. We want to do that on as small a group as we think will give us an answer that gets us one step sharper. Then we can try for two steps.
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  10. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Thanks Bob. Yes I was aware of this approach. I heard Dr Hornig speak in London in May. I won't give a detailed analysis because much of what I might say has come up in previous discussion. One point I think may be worth making is that the self antigens they mention - C4, alpha2 macroglobulin and HSP-70 are not brain proteins. They are everywhere in the body and they are immunoregulatory proteins. Exactly how production of antibodies to these proteins comes about is I think still a very difficult call, as is the reason why the basal ganglia suffer after streptococci, along with skin, joints and kidneys in other post-streptococcal variants. The antibodies associated with RA, called rheumatoid factors, which are anti-antibody antibodies, also occur after acute bacterial infections but they do not persist. But these issues aside, I think the model provides another good example of just how many ways there might be to produce an illness like ME through B cell misbehaviour and so is good grist to the mill. All these approaches show just how plausible an immunological model for ME is.
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  11. Firestormm

    Firestormm Senior Member

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    Jonathan Edwards

    Today's announcement from IiME contained some - I think - additional data that appears to imply you will be seeking to replicate Bansal's work:

    Are you in a position to explain, a) if Bansal's findings are enough to pre-determine suitability for treatment with Rituximab; b) if indeed 'confirm' (in the above) equates to a replication effort and what the implications of non-replication might mean; and c) what 'extend' (in the above) might also mean?

    If a replication is what we are talking about, then what kind of size would be deemed suitable in terms of patients and controls; and is there any idea of a time-frame to get this done (presumably before embarking on any major Trial attempt)? I guess cost is not something that can be estimated at this point; but preliminary work - as we have been discussing - seems to be vital here.

    Bansal's study was well received, I'd just like to know if it is enough, and if not, then what else might you need. I appreciate you may not be in a position to go into detail about something you are still working on with UCL; but I'd like to better understand the significance and relevance of Bansal's work if you are able to help, as I have only been able to read the extract:

  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Phew - I am finally up to date with this thread again! Brain fog, eye fatigue and work have been getting in the way.

    Could not the fact that most people with DR1 do not get narcolepsy indicate a possible environmental trigger?
  13. Marco

    Marco Old blackguard

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    I'm not sure I'm following this line of argument. If HSP's are not brain proteins they do appear to play an active role?

    http://www.ncbi.nlm.nih.gov/pubmed/17645929
  14. Ember

    Ember Senior Member

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    Thanks! As Dr. Broderick observes on behalf of the International Consensus Panel, “One only has to question why 5 of 15 CFS patients in recent phase II clinical trials of rituximab were unresponsive to treatment to appreciate the need for more specific criteria.”
    Kati likes this.
  15. Jonathan Edwards

    Jonathan Edwards Senior Member

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    The presumption is that in the flu vaccine study the environmental trigger is the flu jab. Yet only one in 10,000 people getting the jab showed signs of narcolepsy afterwards. You could say that they had some other coincident trigger but I see no need to invoke another environmental trigger when we have a random mechanism for antibody generation. Consider the analogy to cancer. Exposure to cosmic rays increases the risk of cancer very slightly. The difference between those who get cancer and those who do not is a random mutation in DNA due to the irradiation that just happens by chance to muck up a growth regulator gene or some such. All antibodies are made by a strange mechanism that goes around punching holes in antibody DNA and sewing them up differently - at random. Everybody is happy with randomness in cancer. I think it is worth thinking about it here too.
    voner likes this.
  16. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I think it would be difficult to say much more just yet. Dr Bansal's data do not tell us who should have rituximab but we can work towards finding out whether his approach could do that. Technology improves all the time so I hope UCL can not only repeat his study, but go into more detail. The logistics are fairly straightforward. What I think is so encouraging is that less than two months after meeting up with IiME, all the necessary resources for getting this project started, including people, facilities, expertise and finance, look to be in place. Online communication, including on PR I guess, has played a major part in getting things to that point. I have to say that trying to get research up and running in this style is a bit new for me but if it works so well, I am all for it. It seems to be a remarkable example of 'patient power' driving the agenda and that must be a good thing.
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  17. Jonathan Edwards

    Jonathan Edwards Senior Member

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    HSPs are present in all cells as far as I know. The puzzle then is why antibodies to HSP-70 (which have also been reported in rheumatoid arthritis patients who have no brain problems) should be associated with a problem in one specific part of the brain. It is a particular puzzle because antibodies do not normally even get in to the brain because of the blood brain barrier. It would seem that maybe something else has affected that part of the brain to make the blood brain barrier leaky there. That raises the question whether this something else is actually all we need to explain the brain problem anyway. These are some of the almost endless tricky questions that beset our models of autoimmunity. We can never quite be sure what does what.
    MeSci likes this.
  18. Sasha

    Sasha Fine, thank you

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    I don't know that we in particular can claim much of the glory for that since it's very much a broad effort but I'd certainly say that the internet, and the growth of any number of online ME communities and networks must surely have extended the wider ME community's reach considerably in recent years in terms of fundraising. With a worthwhile project like this, we can all work together and get the word out to potential donors - the many small ones and the fewer big ones - very quickly.
    Dolphin likes this.
  19. Kati

    Kati Patient in training

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    By all means keep on being intrigued. An interesting read of the history of our disease, told from the US, is Osler's Web, from Hillary Johnson.

    It tell about decades of being ignored, being told it's in our head, being denied insurance benefits, being robbed of a life, getting married, having children and decades of being humiliated by physicians, especially in the UK.

    To this day we are being told that CBT and GET are the best treatments and this is what you should do whether you are too ill to feed yourself or you are 80% bedbound.

    Meanwhile patients keep on taking their own lives because there is no hope for them and nothing to look forward to when all that they could has been tried.

    You cannot imagine how rough living with this disease is, when family members think you are lazy, your employer thinks you are malingering and faking an illness in order to get benefits and your doctor doesn't believe what you say and when your country is denying research funding, turn around and grant millions if not billions in research for cancer and HIV AIDS.

    So you are asking me if I am willing to donate cerebro-spinal fluid, bonne marrow sample, muscle sample, blood, other fluids and if I will submit to a 2 ocnsecutive days VO2 max test, and agree to be a participant into a drug trial, may it be double blind, randomized or phase 1, never tested on humans, I will say to you, "Hell ya!"


    P.S. re-reading your first sentence, it sounds like you are surprised as of why pts want a BIG trial... Some of the above applies but I would argue that bigger sample provide more convincing results, no?

    P.S. #2 By all mean I am thankful for Dr Edwards's involvement and it is my hope that his efforts will be rewarded. I am also very thankful that he is sharing thoughts, knowledge and opinions over here.
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  20. voner

    voner Senior Member

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    that might be also phrased ."patient financing"?... a little quicker turnaround than government grants, eh?

    Prof. Edwards, I'm curious if someone is going to do very detailed patient histories?

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