Ampligen study published in PLoS One 14mar2012

Esther12

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Thanks. I'll just post up my instinctive thoughts to reading it, to get the discussion going.

I couldn't really tell, at first glance, how significant the improvement was.

Their primary outcome measure was treadmill exercise tolerance, and I'm not familiar with this as a measure of disability.

By week 40, the rintatolimod cohort (n = 100) had a mean change increase in ET of 96 seconds to 672, corresponding to a group mean increase of 16.6% and an intra-patient mean increase of 36.5%. In contrast, the placebo group (n = 108) increased ET by 28 seconds to 616 corresponding to an intra-group mean increase of 4.8% and an intra-patient mean increase of 15.2%. The placebo-adjusted intra-group and intra-patient increases in the rintatolimod ITT cohort were 11.8% and 21.3%, respectively (p = 0.047). For the patients who completed all 40 weeks (Table 1B) of the study (n = 194), mean baseline ET was 583 seconds for the rintatolimod cohort (n = 93) compared to 587 seconds for the placebo group (n = 101). At week 40, the rintatolimod patients had increased mean ET by 108 seconds (18.6%) to 691 compared to an increase of 27 seconds (4.6%) to 614 in the placebo cohort. The placebo-adjusted, intra-group and intra-patient increases were 14.0% and 24.6%, respectively.
They kept mentioning their protocol, and following PACE I recognise how important it is for researchers to present their data and outcome measures as was laid out prior to conducting their trial.

As I was reading it, I was aware of how instinctively cynical I've become about those claiming to have a meaningful treatment for CFS since we saw how PACE was spun. Hermispherx clearly have a big incentive to demonstrate efficacy, but this look like they've done so, to some extent, in a blinded RCT.

It will be interesting to see other's views on this.

The fact that it's PLoS ONE might dampen down my excitement too, although post-XMRV, I wouldn't be surprised if lots of bigger journals were keen to avoid CFS. There's lots of good research on PLoS ONE too, and lots of crap in Science and Nature.
 

Sean

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The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies.
Compare and contrast with the best result on the only objective measure reported for PACE (6 minute walking distance for the GET arm), which didn't even reach minimal clinical significance.
 

Mark

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It's a Phase III, prospective, double-blind, placebo-controlled, randomised trial, in 234 patients, of a drug treatment for severe ME/CFS, replicating and extending previous positive research results with this drug, and finding a difference between the placebo control and treatment groups roughly twice the size considered medically significant by regulatory agencies! That deserves at least three exclamation marks, surely?!!!

The primary endpoint measure of exercise tolerance (presumably based on the Lights' work) seems to me like a more relevant and objective measure than the traditional measures, but they also showed significant improvement on the other, secondary, endpoints, which included drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). So the more typical SF36 figures are there as well.

Unless I'm missing something, the fact that it's Phase III puts it firmly in the frame to be considered as a scientifically validated treatment option. Surely it should now be on the table for NICE to consider? Do we have any other treatments that have got through a Phase III trial? I don't think so...

I think this is very exciting news. I imagine it was published in PloS ONE at least partly to get the news out there as quickly as possible. It should not require a major traditional journal to gain considerable attention for this study.

This news should really be in all the papers in the next few days...and in the next BMJ...but being UK-based, I'm not holding my breath on that one. It should also be up for consideration by NICE now; even though I doubt it would be approved (it is not cheap), that argument should now begin, if only to be advanced is clear evidence that ME is indeed (and of course) a physical illness, but I don't know how realistic that expectation is.

Of course we should view all research with a sceptical eye, and I'm sure members will dissect the paper in the coming days and weeks, but they will have to come up with something fairly major to dampen my enthusiasm...
 

Mark

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Correction: the ET test is a standard test recognised as a regulatory standard, not the Lights' test:

"Cardiopulmonary exercise tolerance (ET) testing is an objective measurement of treatment efficacy for fatigue and is accepted as a regulatory standard for drugs ameliorating exertional fatigue by exhibiting an average improvement of at least a 6.5% in intra-group, placebo-adjusted ET [16][19]."
 
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I haven't properly read this yet, but a few initial thoughts:

I feel ETT is still an unusual choice for a primary outcome.
Looking at the secondary outcomes, the effects are either small to modest, or only a subset of patients responded, but I haven't yet read enough to see if there is such analysis.
The safety assessment discussion is rather colourful.
 

Mark

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Ah...another correction, we have kind of had a successful Phase III before...last time round with Ampligen - Wikipedia:

Hemispherx reports that it completed a Phase III clinical trial for CFS in 2004 and filed a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS,[1] but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy
But this time round, the FDA were involved in the study design, and auditing of the study...so hopefully that 8-year delay to the rollout of an effective treatment has now been overcome...

This study was funded, designed, and analyzed by Hemispherx Biopharma with oversight by the Food & Drug Administration (FDA) including statistical analysis. Following completion of FDA audits, the decision to publish was made.
The design of the study, including endpoint, and the statistical method used to define efficacy were all reviewed by the FDA prior to receipt of FDA authorization for the initiation of the study.
A potential source of bias exists since a commercial entity, Hemispherx Biopharma, Inc. funded and conducted this trial using independent investigators. This concern is mitigated since this study remained blinded to all Hemispherx clinical trial staff involved with the study until data base lock and the clinical data and statistical analysis were reviewed and audited by the FDA. This audit included a comparison if the data utilized for the statistical analysis versus the data contained in source documents at the investigator sites.
 

Mark

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I feel ETT is still an unusual choice for a primary outcome.
They do say it's a regulatory standard for fatigue treatments, and I think there was a line suggesting that the FDA were involved in the choice of this measure (?)

Looking at the secondary outcomes, the effects are either small to modest, or only a subset of patients responded, but I haven't yet read enough to see if there is such analysis.
I got the impression that the drug use outcome was just as positive, and maybe the Karnovsky, but I didn't find the detail of all the other measures, which was a little disappointing. I was hoping to compare the SF36 figures favourably with PACE; that would seem to be an important point of comparison but I couldn't find the figures. Perhaps I didn't read it thoroughly enough...

The safety assessment discussion is rather colourful.
Quite! :eek:

But nothing indicating safety concerns or indicating significant harms, as I read it.
 

Persimmon

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During a quick scan of the article, one thing caught my attention.

Table 4 reported secondary performance scores (Karnofsky; Activities of Daily Living; and 2 of the SF-36 sub-categories). If I've got this right,
(i) Those patients on Ampligen (as a group) had statistically significant improvements on all of the secondary measures except for the SF-36 measure of how they perceived their health (ie they improved but didn't feel that they'd improved);
while
(ii) Those patients on placebo (as a group) had no statistically significant improvement on any of the secondary measures except for the SF-36 measure of how they perceived their health (ie they didn't improve but felt as if they had).

Pt (ii) is unsurprising: a placebo-effect.
However, the contrast between Pts (i) & (ii) would suggest that the blinding was effective.
 

CBS

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During a quick scan of the article, one thing caught my attention.

Table 4 reported secondary performance scores (Karnofsky; Activities of Daily Living; and 2 of the SF-36 sub-categories). If I've got this right,
(i) Those patients on Ampligen (as a group) had statistically significant improvements on all of the secondary measures except for the SF-36 measure of how they perceived their health (ie they improved but didn't feel that they'd improved);
while
(ii) Those patients on placebo (as a group) had no statistically significant improvement on any of the secondary measures except for the SF-36 measure of how they perceived their health (ie they didn't improve but felt as if they had).

Pt (ii) is unsurprising: a placebo-effect.
However, the contrast between Pts (i) & (ii) would suggest that the blinding was effective.
I noticed the same thing. Subjects given Ampligen also had higher rates of "adverse events." Could the adverse events have effected perception of their health status while not being severe enough (or of a particular type) to have limited performance on the Exercise Testing?
 

Persimmon

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Adverse effects is a possible explanatory factor.

Another might be that more of the Ampligen cohort than the placebo-cohort reduced their other medications during the course of the trial (see Table 3). That is, if you felt able to cut back on other meds, then you might be improving while the feel-good aspect of that improvement is counter-balanced by the withdrawal of meds that were focused on superficial symptom amelioration.
 

Marco

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Just a few points :

If I understand correctly, the Ampligen story has been ongoing for some time but are these dates correct?

This study was initiated on 12/17/98, and ended following full enrollment on 8/16/04 when the last patient completed.
Given that the FDA was intimately involved in the study design and analysis, what held up publication for 8 years?

I do like the use of intra-patient measures which strike me as much more preferable to group means, particularly if you suspect that your cohort contains sub-sets. Its a pity the 'gold standard' PACE trial didn't report such measures.

I'm a little concerned though at the lack of a strong theoretical underpinning for the use of and efficacy of Ampligen in ME/CFS beyond suspected viral triggers and some sort of immune dysfunction. Tying the exercise results and self reported measures to some immune parameters would have been much more persuasive. I appreciate that many drugs may work without knowing the exact mode of action but I would have expected some, even post-hoc, discussion that was a little more specific.
 

Nielk

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Hi Marco, that must be the previous study, this study wasn't even applied for till 2005 if you follow the link in the paper for clinical trial approval. Bye, Alex
Why does it say:
This study was initiated on 12/17/98, and ended following full enrollment on 8/16/04 when the last patient completed.
, right in the trial design? the last patient completed on 8/16/04?
 

LaurelW

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I was in that study, which did indeed end in 2004. I'm pretty sure the study results have been published before, but I think they must have repackaged them to be more in line with the FDA requirements that were outlined when the NDA was rejected just over a year ago.

As far as exercise testing being the measure of improvement, I think they used that because there really isn't much else they could have used that is objective. I remember the criteria being solely how long you could walk on the treadmill, but I don't think that tells the whole story. For example, being on Ampligen raised my aerobic threshhold, reduced pain, gave me a lot more energy and made life in general much easier. I remember having to wear an activity monitor several times, but I don't know what they did with that data.

Personally, I wish to heck they'd approve the darn drug so that insurance would pay for it--it's incredibly expensive and is still the only viable option.
 

Rooney

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I was in that study, which did indeed end in 2004. I'm pretty sure the study results have been published before, but I think they must have repackaged them to be more in line with the FDA requirements that were outlined when the NDA was rejected just over a year ago.

As far as exercise testing being the measure of improvement, I think they used that because there really isn't much else they could have used that is objective. I remember the criteria being solely how long you could walk on the treadmill, but I don't think that tells the whole story. For example, being on Ampligen raised my aerobic threshhold, reduced pain, gave me a lot more energy and made life in general much easier. I remember having to wear an activity monitor several times, but I don't know what they did with that data.
Personally, I wish to heck they'd approve the darn drug so that insurance would pay for it--it's incredibly expensive and is still the only viable option.
Speaking of expense, are you able to have a reduced dose?
 

LaurelW

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I personally don't want a reduced dose, since I do fine on the full dose. I've heard of some people that get less, though, but since the bottles come in 200 mg sizes, if you get 100 mg you still have to pay for the 200 mg bottle since it can't be saved or shared.
 

Nielk

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The fact that Ampligen has not been approved yet by the FDA is another one of the big "mysteries" of this disease.
 
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Hi Marco, that must be the previous study, this study wasn't even applied for till 2005 if you follow the link in the paper for clinical trial approval. Bye, Alex
Hi Alex,

I think we need Hemispherx to clarify whether this is in fact a new study; the following is taken from the "Competing Interests" section of the paper: "A patent for the use of rintatolimod for CFS was granted to Hemispherx during the conduct of this study (patent number is 6,130,206 and the date is October 10, 2000).

ETA: reading Laurel's post above it looks like this is a re-analysis of data from an old study.