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Cardiac Toxicity in Chronic Fatigue Syndrome : Trial of Rintatolimod

Discussion in 'Latest ME/CFS Research' started by George, Nov 8, 2010.

  1. George

    George waitin' fer rabbits

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    http://www.jarcet.com/articles/Vol10Iss3/Vol10%20Iss3Stouch.pdf

    I don't know how to copy and paste the article it's one of those that won't let you just highlight and copy. Sorry, if anyone knows how to do that it would be great to get the text available for everybody. I figured somebody would post it before now. If not I'll type up at least the first part of it later today.

    I was told that this was an oral form of Ampligen but I haven't been able to establish that from reading the study. If anyone has anymore information on this it would be great!
  2. Mark

    Mark Acting CEO

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    PDF is a right PITA; this road-block to accessing and reviewing research papers comes up time and again. It would be most useful if anyone can recommend a free solution for accessing text from PDF files - or alternatively, I think the paid-for version of Acrobat Reader has that function so people with access to that software could rip the text from PDFs as a service to the rest of us. Maybe I'll look into it one day soon...but if anybody has a neat solution for us, do shout up...

    Regarding this paper: first, it turns out to be important to have a basic definition of "QT" which is referred to throughout:

    So: QT interval is basically a measure of certain risk factors for heart disease, which is a leading cause of death in CFS patients.

    The abstract of the study says it (AMP-516) is: "a double-blind placebo-controlled study in CFS patients to evaluate the effectiveness of rintatolimod (Ampligen (R))"...including "repeated QT interval measurements"

    So yes, it is a double-blind placebo-controlled study of ampligen for CFS, basically.

    Results: "A greater proportion of the placebo patients were found to have significant QT prolongation, compared to patients receiving rintatolimod. The increase in QT in the placebo group was associated with continued use of concomitant medications known to prolong QT; patients randomised to receive rintatolimod were able to significantly reduce their dependance on these same medications".

    "Reducing the risk of cardiac toxicity by reducing fatigue and the use of concomitant medications with serious side effects is an important clinical objective and underscores the seriousness of CFS."

    "The increase in the placebo patients can be directly attributable to the use of concomitant medications known to prolong QT, coupled with a sedentary lifestyle known to be a risk factor for heart disease."

    "In both AMP-502 and AMP-516, rintatolimod resulted in a statistically significant (p < 0.05) increase in mobility and stamina (exercise tolerance)."

    "Given more patients in the placebo group continue with their use of medications, compared to patients receiving rintatolimo, it is indeterminate as to the exact contribution the increase in exercise tolerance had on abrogating QT prolongation in the rintatolimod group."

    SO: in short, this is a double-blind placebo controlled ampligen trial in CFS patients, which found improvements in heart function for the patients receiving ampligen. Those patients reduced their use of other medications, some of which are known to cause QT prolongation. Those patients also benefited from increased mobility and improved exercise tolerance.

    It wasn't clear how much of the improvement in QT measurements was due to direct benefits of ampligen, and how much was due to the indirect benefits of discontinuing other medications. But in either case, it's a double-blind placebo-controlled confirmation that Ampligen is beneficial to CFS patients. Sounds very significant to me.

    Finally: ampligen is described as a "TLR3 agonist, which modulates innate and adoptive immunity". Given that this study shows that ampligen is beneficial to CFS patients, it seems to me that this might also be seen as strong evidence regarding what CFS actually is: it seems to imply that immune modulation is significant, which comes as no great surprise of course...
  3. George

    George waitin' fer rabbits

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    Hey Mark the person who sent me the link indicated they thought this was for "Oral" Ampligen but I can't find anything in the study that would indicated that this was oral rather than IV. Do you see anything???

    Great synopsis by the way! Go Mark!
  4. lansbergen

    lansbergen Senior Member

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    Mark
    Not if it is password protected like this one.
  5. Mark

    Mark Acting CEO

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    Afraid not George; I was vaguely mindful that you were interested in whether the ampligen was orally administered and read the whole paper but I didn't notice anything about that. It was also administered as placebo of course, if that gives any clues...
  6. Mark

    Mark Acting CEO

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    Thanks for clarifying that it's password-protected: in that circumstance I guess there's no easy way to get to the text. One could use OCR software on the printed image I suppose: that could be a pretty reliable solution. If one had some OCR software...

    So annoying: I do get wound up by this sort of thing. At the risk of sounding like a stuck record: how can scientists complain about public ignorance about science, and complain that we don't just accept their verdict on the science, but give credence to supposedly irrational therapies like homeopathy, and yet at the same time all the published science on which we're supposed to form rational conclusions is locked behind firewalls and requiring subscriptions to journals? They're basically expecting us to just take it all on faith and trust them just because they're scientists, while at the same time bemoaning anyone who forms conclusions without seeing the evidence.

    How can we be expected to trust science that the public can't see and which can't be publicly scrutinised? If the 'quackbuster' style lobbies were really serious about engaging the public with science and encouraging people to be more rational, they would take on the journal system and work for open access to science and genuine public engagement with the scientific process. Unless and until they do that, they are obviously just interested in strengthening their own position as a new kind of priesthood. Sorry...off topic...but it really does wind me up...
  7. Mark

    Mark Acting CEO

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    Just came across Lucinda Bateman's OFFER presentation, at the start of which she describes a placebo, double-blind Ampligen study. Assuming it's the same study we're talking about here: it was IV, twice a week, 1-2 hours each session, for 40 weeks!!! Here's a link to Dr Bateman's presentation:
    http://www.screencast.com/users/OFF...os/media/3d6472a2-33de-4a22-bc47-113266a9965d
    and just in case that link doesn't work:
    http://www.screencast.com/users/OFFERUtah/folders/2010 Conference Videos

    ETA: Ah, moving on through the video, looks like a different study: sorry!

    ETA: No, not a different study after all, just checked the video again and it's AMP-516: so the answer to your question, George, is: IV. :D
  8. George

    George waitin' fer rabbits

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    Well drat! and I was on the edge of my er, monitor there for a minute thinking your excellent research had figured it out. (big grins) Great rant by the way and one of my pet peeves right now too. I have this "delusion" that if you get any public funding at all you should make the articles available after 30 days to the people who are funding you. In my "delusion" the voice of the great gods of the medical establishment call out from the vast dark void and say, "why do stupid lay people need to know any of this stuff anyway? You will just misinterpret the words and meanings." The thing I hate is that for the most part they are right a lot of stuff wouldn't be understood by the public.

    HOWEVER, (big grins) for the groups of patients educating themselves, for that minority that takes the time to learn the talk there really should be some way that we can get access to the articles to discuss, learn and interpret the results since our lives hang in the balance of cutting edge science. Maybe we could pool our resources and get a um, er, like a forum subscription for the next year, or maybe we could write the various journals and get them to donate a year subscription to this or that journal.

    With the NIH CFS web site going offline yesterday (and I mean they pulled the entire thing down which kinda surprised me!) and with the obvious reference to renaming it ME/CFS and the reference Dennis Mangan made to possible "recoding" the numbers used in medical billing and charts this opens up a chance for me to go back to my doctor and start a new conversation with him in the coming year. My doctor is an A, number one, proctologist's dream so I'm going to need to have printed and highlighted information from reputable websites and journals when I go back to see him. Plus I think he hates me cause I'm a medicare patient. (sigh) So I've got to have a very coherent argument for him. The ability to access and print studies would be a huge help. I doubt that I'm the only one that is going to have this problem.

    And on another rant (grins) the BWG promised to make the information from Phase II available but there is still no info. I hope it's not buried in a journal somewhere. Anybody here anything?? anything at all???
  9. Mark

    Mark Acting CEO

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    Just edited my previous post to confirm that Dr Bateman was referring to AMP-516 after all, and the administration was indeed IV.
  10. George

    George waitin' fer rabbits

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    Now see that's why you are "King of the Lab" er, forum. (big grins)

    Thanks Mark, I never even thought of look at the videos I keep trying to find the information from Hemisphere Biopharma's web site. Duhhhhh!
  11. Mark

    Mark Acting CEO

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    Regarding the idea of a forum subscription, I'm not too keen on that actually, unless they were to donate it. I'm more interested in challenging the concept that we pay (through taxes and fundraising) for researchers to conduct research, which they then conceal from us and expect us t just accept their conclusions about what it all means.

    I agree that there is an issue with most people not being able to understand it all, but I really don't think that's an insurmountable problem: surely those that can't understand it will at least learn (if they look at the papers) how much they don't understand it, and those that can understand it partly will be motivated to learn more. So I can't really see a justification for the status quo there.

    I know there are movements within the academic community to try to encourage open-access to publications, and sometimes to make that a condition of funding: I think all that should be encouraged through pressure because I think the case is really open-and-shut: we pay their wages, we fund their research, some of us are capable of reading and understanding it, to varying degrees, but it's unacceptable that we aren't given that opportunity.

    The reasons behind it all are the history of the journal system, and the way that works for funding, and that whole system needs completely rethinking for the internet age. It's in everybody's interests to do so, with the possible exception of the journals themselves...

    Finally, regarding a solution to getting hold of abstracts: actually we do have a solution to that, which is that somebody who has access to the journals posts significant papers in the member's library...that's rather broken down lately for want of 'librarians', so if anybody reading this has access, through a university or elsewhere, this is a hugely valuable job that somebody could volunteer to help with...
  12. Mark

    Mark Acting CEO

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    Thanks George but really you're far too kind, I'm nothing of the sort of course: it's very rare that I actually answer a question with useful, novel and correct factual information! It was really pleasing to be able to do so for a change - the rants and speculation are far more common I'm afraid, as I'm sure you know. :)

    In this case, I didn't even go looking for it: it just fell into my lap when I happened to watch Dr Bateman's OFFER video and she mentioned it about a minute in. Just a nice bit of dumb luck to end a fascinating session: the OFFER videos, and Dr Singh's video, were definitely the highlights.
  13. Francelle

    Francelle Senior Member

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    I am too tired right now to read through this paper and this will be evident by my ill-informed questions!

    Was it a cross over trial? If it wasn't, I'd have been definitely unhappy if I sat there having saline IV infusions for forty weeks in the randomised placebo group! LOL!

    Was there evidence of a greater opt-out rate of subjects in the placebo group compared to the treatment group over the course of such a demanding study? I'm sure the placebos felt they were no better considering the amazing results of some like Kelvin Lord!!

    And Mark I'm with you - I baulk at paying such prices for full text papers that should be in the public domain!
  14. Mark

    Mark Acting CEO

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    Yes, it was, this is also mentioned in Dr Bateman's video from the OFFER conference. For the last 20 weeks (or something like that) they all got Ampligen. The video is worth watching for the details like this, which aren't in the paper as far as I can see. It's just a few minutes near the start of her talk, which is quite an inspiring and positive talk in general.

    I think Dr Bateman said that every single patient in the trial continued with the treatment through to the end, and that most of them were so sick this was an enormous trial for them to do so. Some of them arriving in wheelchairs, having to travel some distance to attend, each treatment session taking 1-2 hours, twice a week for 40 weeks...it sounds like really heavy stuff! One of the themes of her talk is praise for these brave pioneers who volunteer for these trials, and of course we all have good reason to feel profoundly grateful to those people. I do hope they all get lasting benefit from the treatment, as reward for the risks they have taken with their health on behalf of all of us.
  15. JohnnyD

    JohnnyD Senior Member

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    Hemispherx held a conference call this morning and this peer reviewed paper about the Ampligen 516 study and the heart (QT prolongation) data will be published this week. here is the link again: http://www.jarcet.com/articles/Vol10Iss3/Vol10 Iss3Stouch.pdf

    The company also has new data about XMRV+ patients and ampligen, also collected retrospectively from the AMP516 trial. The most surprising thing said in this mornings conference call is that they will submit these studies this week to the FDA and ask them "to keep their NDA open" iow, they are going to ask the FDA to reconsider the complete response letter they received a year ago in light of the new data. Which would prevent patients from being subjected to treadmill tests again in a new study, which is barbaric considering the seriousness of the illness.
  16. Rafael

    Rafael XMRV+ Member

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    Well, it seems there is only security needed for people that don't have Macs.
    But maybe I'm not understanding the issue. Is this helpful ? Should I continue ? But why not just follow link to read the abstract and see the nice graphs ? I don't know what you see.

    ABSTRACT: The sedentary life-style caused by extreme fatigue is a significant risk factor for heart disease which is a leading cause of death in Chronic Fatigue Syndrome (CFS) patients. AMP-516, a 40-week double-blind, placebo- controlled study in CFS patients to evaluate the effectiveness of rintatolimod (Ampli- gen) included repeated QT interval mea- surements. A ≥5 ms post-treatment mean increase in QT prolongation was observed
    in the placebo group, while a <5 ms mean post-treatment increase in QT prolongation was observed in the rintatolimod patients. A greater proportion of the placebo patients were found to have significant QT prolonga- tion, compared to patients receiving rintato- limod. The increase in QT in the placebo group was associated with continued use of concomitant medications known to prolong QT; patients randomized to receive rintato- limod were able to significantly reduce their dependence on these same medications. Reducing the risk of cardiac toxicity by reducing fatigue and the use of concomitant medications with serious side effects is an important clinical objective and underscores the seriousness of CFS.
    INTRO: Chronic Fatigue Syndrome (CFS) is a severe disorder consisting of profound fatigue and a variety of other debilitating symptoms that affects up to 4 million Americans1, 2. Heart failure is a major cause of death with CFS, even in the female population where the
    age of disease onset is typically 38-42 years of age3. Currently, there are no approved treatments for this disease, and severely af- flicted patients often become sedentary and bedridden. To evaluate the investigational drug rintatolimod (a TLR3 agonist, which modulates innate and adoptive immunity) for CFS, Study AMP-516 was conducted as a 40-week double-blind, randomized, multi- center, placebo-controlled trial (n=234)4. Table 1 contains a summary of the patients enrolled and treated in AMP-516. The mean duration of symptoms of CFS was 9.64
    years, and patients had been suffering with Safety Population evaluated for QT prolon- CFS for over 5 years prior to enrollment. gation consisted of 190 subjects (91 received
    The profound inability of CFS patients to exercise and the chronic duration of their sedentary life-style is a significant risk factor for heart disease. Heart failure is a leading cause of death in patients with CFS3. Over 20% of the total deaths of CFS subjects in- vestigated by Jason, et al. were secondary to heart failure, which is known to induce QT prolongation most likely through upregula- tion of KCNE15. For patients with CFS, more than twice as many women die from heart failure compared to men.
    MATeRIAlS And MeThodS
    A comprehensive analysis of QT interval assessments including the QTc interval was performed in AMP-516 per ICH E14 Guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Anti-arrhythmic Drugs (October 2005, ICH). In AMP-516, the
    rintatolimod (Poly I : Poly C12U) and 99 placebo) with a baseline and post-baseline QT interval determination performed under standardized conditions. The clinical ECG database consisted of over 1,000 12-lead surface ECGs obtained during baseline (twice) and at weeks 20, 34, and 40. All ECGs were obtained by an experienced team headed by an exercise physiologist. The team traveled to each site and obtained the ECGs prior to administering the treadmill tolerance test. The same ECG analysis equipment (Pulse Biomedical, Inc., Norris- town, Pennsylvania USA) was utilized for all subjects at all study sites throughout the duration of the AMP-516 study.
    Data was recorded and differences in proportions were analyzed using a 2-tailed Fisher’s exact test. Intra-arm differences from baseline in continuous parameters were analyzed using a paired-difference t-test.
  17. Rafael

    Rafael XMRV+ Member

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    I now see the comment about putting in Members Library - I'll look into that later tonight but for those that can't wait to read endings:
    CONCLUSIONS:
    The QT interval prolongation results from the AMP-516 study provide a head-to-head comparison between patients randomized to receive either rintatolimod or placebo. The increase in QT prolongation observed in the placebo group provides concurrent validation of the design, given a ≥5 ms post-treatment increase was observed in the placebo group of CFS patients. The increase observed in the placebo patients can be di- rectly attributable to the use of concomitant medications known to prolong QT, coupled with a sedentary life-style known to be a risk factor for heart disease.
    Increased stamina and tolerance to ex- ercise are important factors in reducing the cardiovascular risk associated with CFS. In both AMP-502 and AMP-516, rintatolimod resulted in a statistically significant (p<0.05) increase in mobility and stamina (exercise tolerance). Reducing the sedentary influ- ence of CFS through increased stamina, coupled with the reduced dependence on medications that can prolong QT, is an important step in the management of this chronic disease. The analysis of the intra- patient QT interval data from AMP-516, where over 1,000 EKGs were recorded during the course of the study re- vealed evidence of an increased risk of pro- arrhythmic potential in the placebo group, compared to the rintatolimod treated group. Given more patients in the placebo group continue with their use of medications, compared to patients receiving rintatolimod, it is indeterminate as to the exact contribu-tion the increase in exercise tolerance had on abrogating QT prolongation in the rintato-
    limod group. Regardless, based on the thresholds published in the FDA guidelines
    for all new drugs, there were significantly more intra-patient measurements in placebo patients that were prolonged, compared to the rintatolimod treated patients.
    Rintatolimod treatment allowed CFS subjects to reduce their dependence on con- comitant medications used to treat debilitat- ing symptoms of CFS, coincidentally reduc-
    ing exposure to drugs known to prolong the QT interval. This may suggest a new thera- peutic strategy to potentially mitigate the incidence of heart failure/sudden death in
    this relatively young, predominantly female, population by reducing their dependency on palliative medications associated with increased risk of TdP/sudden death. Further Clinical Trial with a Specifically Configured RNA
    clinical studies should provide more insight into the potential relationship between poly- pharmacy (as practiced in alleviating CFS symptomatology), QT interval prolongation, and the relative incidence of catastrophic cardiovascular events in this population.

    Oh yes, the credits (at beginning): Cardiac Toxicity in Chronic Fatigue Syndrome: Results from a Randomized 40-Week Multicenter Double-blind Placebo Control Trial of Rintatolimod
    Bruce C. Stouch, Ph.D1 David Strayer, M.D2. William Carter, M.D2.
    1Philadelphia College of Osteopathic Medicine Philadelphia, PA 19131
    2Hemispherx Biopharma, Inc. Philadelphia, PA 19103
  18. LaurelW

    LaurelW Senior Member

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    Anybody know what this means in plain English? This is beyond me.
  19. JohnnyD

    JohnnyD Senior Member

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    The FDA is very concerned with heart problems with new drugs (QT prolongation). This was a concern contained in the CRL received by the company. The company did a retrospective of their 516 clinical trial and found that ampligen reduced QT prolongation because patients were able to exercise and were less dependent on concomitant medications... e.g. ampligen improved heart health.
  20. LaurelW

    LaurelW Senior Member

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    Thanks! That is easy to understand. That was certainly my experience of being on it.

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