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

Andy

Andy

Retired committee member
Rintatolimod = Ampligen
A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2–8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance
Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. 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. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.
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Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403
 
butter. said:
what does this mean in plain?
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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.
 
butter. said:
what does this mean in plain?
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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.
 
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'

In order to decrease the likelihood of spontaneous remissions, the AMP-516 protocol required a diagnosis of ME/CFS for ≥1 year, which was extended to ≥2 years for performing the post-hoc analysis.

....Accordingly, we stratified the subsets based on a 2–8 year duration of symptoms vs <2 and >8 years. In the post-hoc data analysis patients having onset of symptoms between 2 and 8 years, PEM lasting more than 24 hours and the ability to walk on a moving treadmill for longer than one minute but less than 16 minutes (Target Subset, n = 75) were compared with the remainder of the ITT Population (Non-Target Subset, n = 133).
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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.
 
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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.
 
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.
 
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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
 
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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:
Patients enrolled in the Phase III clinical trial AMP-516 met both the original CDC 1988 [1] diagnostic criteria and the revised 1994 CDC case definition [2]. An international consortium proposed in 2011 that Myalgic Encephalomyelitis was a preferable term for the syndrome complex [3]. In 2015, the Institute of Medicine (IOM) recommended that PEM be required for a diagnosis of the disease [15]; we have incorporated PEM as a requirement for the Target Subset, although only one patient was excluded from the Target Subset because of a lack of PEM. The percentage of patients with PEM was well-balanced with no significant differences seen between the rintatolimod and placebo cohorts within the ITT population and within both of the subsets (Target and Non-Target).
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It would be nice if they measured PEM threshold, PEM duration, and PEM severity.
 
DigitalDrifter said:
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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From that quote they would seem to be using Fukuda with a requirement for PEM. How they are defining PEM is obviously important.
 
....Accordingly, we stratified the subsets based on a 2–8 year duration of symptoms vs <2 and >8 years. In the post-hoc data analysis patients having onset of symptoms between 2 and 8 years, PEM lasting more than 24 hours and the ability to walk on a moving treadmill for longer than one minute but less than 16 minutes (Target Subset, n = 75) were compared with the remainder of the ITT Population (Non-Target Subset, n = 133).
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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.
 
In the post-hoc data analysis patients having onset of symptoms between 2 and 8 years, PEM lasting more than 24 hours and the ability to walk on a moving treadmill for longer than one minute but less than 16 minutes (Target Subset, n = 75) were compared with the remainder of the ITT Population (Non-Target Subset, n = 133).
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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
 
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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.

We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246).

Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks.

We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static.

These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.
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https://advances.sciencemag.org/content/1/1/e1400121
 
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