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Anakinra/Kineret (IL-1 inhibitor) in ME/CFS - Dutch study + discussion

Discussion in 'Active Clinical Studies' started by Anne, Sep 23, 2014.

  1. Anne

    Anne Senior Member

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    Creating a thread specifically for discussion of the potential of the IL-1 inhibitor Anakinra/Kineret as a treatment for ME/CFS (I hope I'm not double-posting, found mentions of this study but no specific thread)

    http://clinicaltrials.gov/show/NCT02108210


    Cytokine Inhibition in Chronic Fatigue Syndrome Patients (CiCFS)

    Radboud University

    Purpose

    Rationale: Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. Although derangements of the cytokine network in CFS are controversial, a major problem is that many studies did not use adequate controls. In addition, all studies have been performed on peripheral venous blood of the patients. As cytokines mainly act in the tissues, e.g., the brain, the information that can be derived from peripheral blood cells is limited. The only information regarding the possible role of cytokines in the pathophysiology of CFS could come from intervention studies in which pathogenetically important cytokines are inhibited. A potentially relevant cytokine which can be blocked in humans without severe side effects is IL-1. Although it is plausible that these cytokines play a role in CFS, there is limited evidence for this.

    Objective: To investigate the effect on symptomatology of interference with IL-1 in CFS patients.

    Study design: A randomized placebo controlled study will be performed to determine whether interference with IL-1 is able to reduce fatigue and disabilities in CFS patients.

    Study population: Female CFS patients without psychiatric co-morbidity will be included in this study. Patients of the outpatient clinic of the Department of General internal medicine and the Expert Centre for Chronic Fatigue (ECCF) will be asked to participate in the study. Patients will be asked to bring a healthy neighbourhood control to their first study visit.

    Intervention: After inclusion patients will be randomized to receive one of the following treatments:

    • interleukin-1 inhibitor Anakinra (IL-1Ra) for 4 weeks (N=25);
    • placebo for 4 weeks (N=25).
    Main study parameters/endpoints: The primary outcome measure will be fatigue severity measured with the Checklist Individual Strength (CIS) at 4 weeks, measurement will be repeated up to 26 weeks.

    Secondary outcome measures will be:

    • level of functional impairment measured with the Sickness Impact Profile (SIP8) total score;
    • physical and social functioning assessed with the subscale physical functioning and social functioning of the SF-36;
    • level of psychological distress assessed with the total score on the Symptom Checklist-90 (SCL-90);
    • pain severity assessed with a Visual Analog Scale (VAS);
    • cytokine measurement in blood (plasma and blood in Pax-gene tubes) and saliva (at protein and mRNA level);
    • cortisol measurement in saliva and hair;
    • microbiome determination in faeces;
    • body temperature and pulse rate.

    Estimated Enrollment: 50

    Study Start Date: June 2014

    Estimated Study Completion Date: December 2015

    Estimated Primary Completion Date: December 2015 (Final data collection date for

    primary outcome measure)

    Experimental: Anakinra

    This therapy will consist of once daily subcutaneous injections (100mg/day) during a period of 4 weeks. Patients will be monitored at week 1 and week 4 after starting medication for development of side effects. Therapy will be stopped in case of severe side effects, interfering disease or pregnancy.
     
  2. Anne

    Anne Senior Member

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    From another thread:
    @Jonathan Edwards

    Dear Prof Edwards, first of all: many thanks for your engagement in the ME field, your participation on this forum and everything you are teaching us!

    If you have the time, I have some questions about Anakinra/Kineret and its possible effects (and risks) in ME/CFS:

    1. I have discussed off-label treatment with Anakinra/Kineret for my ME/CFS with a couple of physicians. One says it's feasible that it might have a positive effect, the other claims that it's only useful in disorders with clear inflammatory signs and since I (like most ME patients) don't have elevated CPR or a high fever it's unlikely Anakinra/Kineret would be effective.

    While I don't have objective test results showing inflammation, I get the feeling that inflammatory processes are going on in my body in various ways. In addition to a very typical clinical picture for ME (infectious onset, extreme fatigue and flu-feeling, swollen glands, sore throat, muscle pain and weakness, susceptibility to infections, sleep problems, etc) I have what physicians and physiotherapists have labelled muscle attachment inflammations in neck, hips and knees, causing me severe pain. When I received intramuscular injections of gammaglobulin (sadly with no positive effect on my ME) the injected muscles got inflamed (?) and became so painful I had severe problems lying on my side for a year afterwards. I have had two biopsies done, on from my toes due to acrocyanosis and one from my thyriod - both showed signs of inflammation.

    Do you think it worthwhile to try Anakinra/Kineret even in the absence of elevated CRP or fever? Could inflammatory processes be present anyway and possibly be affected by IL1-inhibition?

    2. Like many ME patients I am very sensitive to medication and prone to side-effects. I also belong to the subgroup of ME patients where susceptability to infection is a major symptom. One physician argues I have signs of reactivated EBV and I definitely do have re-curring candida infections. So I worry a bit about the fact that Anakinra/Kineret has increased risk for infection as a side-effect.

    Do you think this ME subgroup, prone to infections and with recurrent infections, would be less suitable candidates for Anakinra/Kineret?

    I would be immensely grateful for your thoughts on this (though I fully understand if you don't have the time or possibility to reply).

    I am a longtime friend of Invest in ME and I marvel at what IiME are achieving, not least now since you have come onboard and the biomedical research is gaining such speed.

    Many thanks for what you do for us ME patients and many greetings from Stockholm, Sweden
    Anne
     
    Last edited: Sep 23, 2014
    Johannawj, Bob, Kati and 4 others like this.
  3. deleder2k

    deleder2k Senior Member

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    Has anyone tried this before?

    "Patients will be asked to bring a healthy neighbourhood control to their first study visit."

    What does this mean? That one should bring a healthy friend from the neighborhood ? :wide-eyed:
     
    catly and NK17 like this.
  4. Ninan

    Ninan Senior Member

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    Yes. They need help collecting samples for the control group.
     
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  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The absence of raised CRP probably does reduce the theoretical chances of benefit but IL-1 might be produced locally without generating an IL-6 response affecting the liver (the CRP driver). I think it is worth trying these agents in ME/CFS. It would be best to do that within a controlled trial but that may depend on feasibility.

    My understanding is that infection risk is not as great with anakinra as it is with TNF inhibitors. It is something that needs to be discussed with the physician involved but I suspect it would not be prohibitive. The main issue for TNF inhibitors is dormant tuberculosis, which reactivates.
     
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  6. NK17

    NK17 Senior Member

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    I don't want to derailed this thread, but I'd love to hear Dr. Edwards opinion on latent TB reactivation during therapies with biologics.
    @Jonathan Edwards can you tell us what are the risks of latent TB reactivation during Rituximab therapy? I'm talking about proven latent TB with Quantiferon Gold blood test.
    Did you ever had any such case in your Rituximab treated RA population?
    Should a patient with latent TB infection undergo multiple antibiotic therapy before embarking on Rituximab treatment?
    I understand you can only bring your extensive experience on the forum and that in no way your opinions on PR should be taken as medical advice.
     
  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    As I understand it, there is no theoretical reason why rituximab should lead to TB reactivation since antibodies to bacteria remain unchanged with rituximab therapy. Moreover, I am unaware of any case of TB reactivation attributed to rituximab.
     
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  8. NK17

    NK17 Senior Member

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    Thank you for your prompt reply, I greatly appreciate it.
     
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  9. Valentijn

    Valentijn Senior Member

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    The principal investigator for the trial is Jos van der Meer, one of the Dutch psychobabblers. So it'll primarily include chronic fatigue patients, the results will be spun to obey the prime directive that only CBT can be helpful, and even if they're forced to publish any indication of improvement, they'll conclude that the treatment is too dangerous for patients with something as non-serious as CFS and that CBT is still the superior treatment.

    Anyone wanna place some bets? :D
     
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  10. NK17

    NK17 Senior Member

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    I'm afraid that you're right @Valentijn, in fact when I first read about this study a few months ago and read a bit about Jos Van der Meer school of thoughts, I was surprised and suspicious at the same time.
    So I'll be the second one to bet that this study is a wolf in sheep's skin, you'll be the first one to have placed the bet ;).
    We can expect the titles say: "another pharmacological intervention in CFS bites the dust".
     
    Last edited: Sep 24, 2014
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  11. Anne

    Anne Senior Member

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    Oh, that's sad to hear, @Valentijn . I was hoping that maybe they were realizing the tide is changing, were getting worried to look stupid once the biomedical research has outweighed the flawed psychosocial research and wanted to start changing their approach....

    Too hopeful?
     
    Last edited: Oct 20, 2014
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  12. Anne

    Anne Senior Member

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    Thank you so much for your reply @Jonathan Edwards !

    I have a follow-up question, if you have the time:

    I have read that Kineret is effective in cold urticaria (see http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=47045 )

    This is interesting to me, since I have major problems with urticaria, burning skin and allergic reactions, triggered by a number of things, among them heat. Even before my ME I had “heat allergy” leading to urticaria, once causing an anaphylactic shock including unconsciousness and hospitalization for several days. So I have some kind of allergy triggered by heat – but my grandmother had cold urticaria, so it’s in the family. A few years into my ME my skin problems escalated to a whole new level with constantly burning skin and allergic reactions in response to a large number of triggers (heat, sun, chemicals, most textile fabrics, etc).

    My question(s): Do you know anything about how the disease mechanisms in cold urticaria and other types of urticaria relate to eachother? Is all cold urticara IL1 mediated? Is there raised CRP in all cold urticaria or are there cases without raised CRP? Could the mechanisms in heat allergy/urticaria be similar and therefore also responsive to Kineret?

    Many, many thanks for all you do for us!
     
  13. A.B.

    A.B. Senior Member

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    He has done research on cytokines before, in particular IL-1. In the study, a variety of objective parameters will be measured. It's randomized and double blinded. From this angle, it looks pretty good. I'm not convinced that the outcome of this study is predetermined.
     
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  14. Valentijn

    Valentijn Senior Member

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    So ... the bet is on? :D
     
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  15. A.B.

    A.B. Senior Member

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    Hey, I just said that I'm not convinced the outcome is predetermined, not that it will show abnormalities. It could go either way.
     
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  16. NK17

    NK17 Senior Member

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    The bet is still on as far as I'm concerned @Valentijn, but I wish that in the end @A.B. will be right.
    Nothing will be sweeter for PWME than an old foe converted finally into a friend and of course any knowledge turned into therapeutical intervention is the best reward.
     
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  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I am afraid I know very little about cold urticaria.
     
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  18. Anne

    Anne Senior Member

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    Any news from patients in Holland participating in this trial?
    @Valentijn @A.B. , others?
     
  19. Valentijn

    Valentijn Senior Member

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    I'm not. They're associated with the Nijmegen group, which recruits from their psychosomatic "fatigue" center. I wouldn't go anywhere near them, for any reason.
     
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  20. lansbergen

    lansbergen Senior Member

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    Neither will I
     
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