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Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for [ME/CFS], 2020, Mitchell et al

Discussion in 'BioMedical ME/CFS Research' started by Andy, Oct 30, 2020.

  1. Andy

    Andy Committee Member & Outreach

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    Rintatolimod = Ampligen
    Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403
     
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  2. butter.

    butter. Senior Member (Voting Rights)

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    what does this mean in plain?
     
  3. Kitty

    Kitty Senior Member (Voting Rights)

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    "The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response* to rintatolimod under the dosing conditions utilized in this Phase III clinical trial."

    * More than half reported some response, but it didn't appear to be a huge game changer. The fact that they used a modified exercise programme suggests the cohort didn't include severely ill patients, to whom even small gains might make a significant difference.
     
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  4. Simon M

    Simon M Senior Member (Voting Rights)

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    The makers of Ampligen see treating long Covid as a huge potential market opportunity for them, and have produced an exploratory (so not reliable) analysis of existing data that conveniently supports this.

    That said, the idea that people who have been ill for less time are more likely to respond to treatment is plausible. I’ve no idea of the quality of this work.
     
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  5. Hutan

    Hutan Moderator Staff Member

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    Sorry for my skepticism, but this looks like a lesson in 'how to get around the problems created by a blinded placebo controlled trial'. Answer 1: 'very detailed post hoc stratification'



    The measure, exercise treadmill tolerance, as measured once at baseline and once at trial end seems less than ideal. Activity monitoring would be a much better measure.


    Screen Shot 2020-10-31 at 12.15.02 AM.png

    To be fair, there does seem to be an improvement in the seconds Rintatolimod participants spent on the treadmill compared to the placebo.

    But what's going on with the standard deviations and the 95% confidence intervals? The report says the results were distributed normally, and so a 95% confidence interval should be about two times the standard deviation either side of the mean*. Look at the top left result (ITT population, with the Rintatolimod treatment). The mean change was about 96, with a huge standard deviation of 251. So wouldn't the 95% confidence interval be from (96 -502 = 406) seconds to (96 +502= 598) seconds? Instead, it's reported as 64 to 229 seconds. It look weird to me; I'm happy to be corrected through.

    I'm wrong (see Trish's note below). But the standard deviations are still very big relative to the means.
     
    Last edited: Oct 30, 2020
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  6. Trish

    Trish Moderator Staff Member

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    It's a post hoc analysis, which means it wasn't part of the original plan to analyse the data in this way. It seems to me that they realised that overall the results weren't significant, so they looked at the data and found most of those who showed some improvement were in the 2 to 8 years illness duration. So they looked just at those and found half of them improved a bit. Seems pretty unimpressive to me, but maybe I'm missing something.
     
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  7. Trish

    Trish Moderator Staff Member

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    I think you need to divide the SD by the square root of the sample size, to get the standard error of the mean.
    https://www.statisticshowto.com/pro...l for the mean is a way of,and 7 is the upper.
     
  8. Hutan

    Hutan Moderator Staff Member

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    Answer #2 in how to market results from a blinded placebo controlled trial: focus on something entirely different from the planned outcomes.

    Here are the main results, comparing improvements in cohorts with the treatment and a placebo:
    Screen Shot 2020-10-31 at 12.48.23 AM.png
    So, it looks as though more patients treated with rintatolimod were able to increase their time on the treadmill by more than 25% than those patients treated with the placebo. Even if you don't buy the post hoc stratification and look at the left-hand bars for the whole trial populations, rintatolimod seems a bit better.

    But then there is a chart (using exactly the same purple and grey colours) and lots of discussion comparing those patients who were able to increase their treadmill time by 25%, not with controls, but with those who were not able to increase their time by 25%.

    For example, see this:

    Screen Shot 2020-10-31 at 12.55.26 AM.png
    So, they are telling us that those patients treated with rintatolimod who increased their time on the treadmill by more than 25% also had improvements in two secondary endpoints, not against the controls, but against the patients treated with rintatolimod who didn't increase their time by more than 25%.

    They don't report the secondary endpoints for controls at all. And one of those secondary endpoints is just a part of the SF-36, so who knows how many secondary endpoints were measured and not reported.

    To me, it looks like a very modest average improvement (in an outcome that isn't that relevant to ME/CFS) (that may possibly include a very small group who really did respond, but might just be chance or measurement bias), wrapped up in a lot of marketing.
     
    Last edited: Oct 30, 2020
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  9. Hutan

    Hutan Moderator Staff Member

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    Here are the scatter plots so you can make up your own mind.

    The first one is for the so-called 'target population', the second one is for everyone else. Illness duration is on the x axis, with different scales for each chart. % change in the time on the treadmill (from baseline to end of treatment) is on the y axis.

    The blue dots are the patients treated with rintatolimod, the red dots are the placebo.

    Screen Shot 2020-10-31 at 1.36.35 AM.png

    Screen Shot 2020-10-31 at 2.04.29 AM.png
     
    Last edited: Oct 30, 2020
  10. butter.

    butter. Senior Member (Voting Rights)

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    still dont get it.
     
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  11. Kitty

    Kitty Senior Member (Voting Rights)

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    "Not much to see here, to be honest."
     
  12. DigitalDrifter

    DigitalDrifter Senior Member (Voting Rights)

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    Does any one know what criteria for ME they are using? They reference Holmes 1988, CDC 1994, and I think the CCC 2003 criteria.

    I've just read the following:
    It would be nice if they measured PEM threshold, PEM duration, and PEM severity.
     
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  13. Andy

    Andy Committee Member & Outreach

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    From that quote they would seem to be using Fukuda with a requirement for PEM. How they are defining PEM is obviously important.
     
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  14. Hutan

    Hutan Moderator Staff Member

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    One of the criteria to be included in the 'Target Population' was 'PEM lasting more than 24 hours'. The participants in the non-target population presumably either didn't have PEM or had PEM that lasted less than 24 hours. It's not clear how the PEM criteria was determined, but it looks as though it was patient self-report during trial eligibility screening.
     
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  15. Creekside

    Creekside Senior Member (Voting Rights)

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    Maybe if they subdivided the groups based on astrological signs, or first letters of their names (or their pet's names), or some other such random divisions, they'd eventually find an even stronger statistical correlation. :rolleyes:
     
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  16. Michiel Tack

    Michiel Tack Senior Member (Voting Rights)

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    If you only look at patients with a short disease duration for example and find a much larger response than those with longer disease duration, there might be something there.

    But here they used so many selection criteria to define their 'target population' (why did the onset of symptoms had to be longer than 2 years? why did patients need to wall longer than one minute but less than 16 on the treadmill?) that it looks like p-harking or fishing for a significant result.

    The original Phase III trial results look more interesting, seems that for the primary outcome there was a statistically significant improvement but the p-value was very close to 0.05 (for the secondary outcomes they strangely only report significance for improvement over time, instead of compared to the placebo group). https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031334
     
    Last edited: Nov 3, 2020
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  17. John Mac

    John Mac Senior Member (Voting Rights)

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    Lipkin et al released a study in 2015 that showed different immune signatures depending on illness duration i.e less than 3 years compared with more than 3 years.

    https://advances.sciencemag.org/content/1/1/e1400121
     

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