A Double-Blind, Placebo-Controlled, Randomized, Clinical Trial of the TLR-3 Agonist Rintatolimod in Severe Cases of CFS, Strayer et al, 2012

Background

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C12U), in patients with debilitating CFS/ME.

Methods and Findings

A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites.

The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET).

Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36).

Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies.

The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048).

Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04).

Rintatolimod at 400 mg twice weekly was generally well-tolerated.

Conclusions/Significance

Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

Trial Registration

NCT00215800

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031334

 

This is the phase 3 clinical trial of Ampligen that ran from December 1998 to August 2004.

It is unclear to me why the investigators chose intra-patient difference in percentage as the primary endpoint rather than the absolute inter-group difference, although this choice was approved by the FDA before the trial.

If my understanding is correct, the inter-group difference in percentage is what they call “placebo-adjusted intra-group difference”:

In total, in the full set analysis (every participant including dropouts), those in the rintatolimod arm had an 11.8% increase in walking time over the IV saline arm, which was barely statistically significant (p = 0.047). The rintatolimod arm achieved on average an increase of just over one minute in walking time (68 s) over IV saline.

For the participants who completed all 40 weeks of treatment, the result improved to 14% in the rintatolimod arm relatively to the IV saline arm (p = 0.019), meaning the rintatolimod arm achieved just 9 more seconds (77 s) on average than in the full set analysis result.

I believe the drop-out rate was similar in both groups, although more adverse events were reported in the rintatolimod arm, specifically flu-like syndrome, chills, vasodilation and dyspnea of mild and moderate intensity at frequencies of 4 to 7% higher than IV saline.

Importantly, there were barely any improvements on the secondary outcomes such as activities of daily living and the general health perception subscale of the SF-3 6questionnaire.

Overall, it seems there is nothing much to write home about. I don’t understand the hopes (and anger at the FDA’s refusal of approval) that Ampligen continues to elicit to this day.

That being said, we now know that IV saline can be effective for relieving orthostatic intolerance in ME/CFS (independently of the presence of POTS or orthostatic hypotension) and thus for slightly improving exertion tolerance. It may well be that the Ampligen is slightly more effective at increasing exertion tolerance compared to usual care than compared to IV saline.

 

I'm not sure - it just makes me sad the limitations of how these trials might be read.

A 14% increase in exercise tolerance over 40weeks, with an 11% interim indicates to me that (like a few other things) longer timescales, as well as, the improvement as it is is well-worth having.

First 14% is massive for those who are severe - I work on the basis of 'if something gives me just 5-10% more health it is a huge leap forward in a survivable baseline'.

Second I note personally the 5-10% because when I couldn't watch TV for 10mins and a shower crashed me for weeks I was in a health no-win (you need to keep clean but no way of doing so without slow downward spiral). Getting 5-10% more just broke that quite scarily quick revolving cycle to be able to survive whilst doing nothing without breaching baseline so much I never got back to before. It 'turned the circle'. Another 5-10% could mean I can actually shower near decent hygeine amounts or do other really basic things I can't that will also make a difference to my health.

It would insulate me from the variability of noise from neighbours or others shouting at me sending me downhill because it is 'surprise exertion' I can't compensate for if I have a bit more spare and it just means going a week without showers or meal prep instead of having little to cut out. I could make an appointment and not breach so far beyond baseline I'm not sure if I'll recover in 3months. And so on. the baseline vs uncontrollable and unavoidable vs amount of rest needed to get back vs amount of rest likely to ever get becomes more close to adding up.

And it seems the more 'health' you have the less 'naturally self-perpetuating itself downwards' it is.

So after a few years 14% could actually be huge differences in outcome directly (in my mind) and/or indirectly (if people are having to be strict)

I think the intra-person measure is more powerful for me personal seeing it, because I'm so convinced by the bucket/umbrella/types but also because of severity and situation having such an impact. I'd like to think if a good chunk got a reasonably significant and solid improvement that would make it worthy of consideration - I'd be more concerned about the yellow-carding personally.

I just hope there will be a parallel one day where people nail the PEM-vocab list and measures so we can know who is in 'PEM' or 'max exertion' and all those other things when we go into experiments too. I doubt there is like-for-like or matched pair possibilities currently easily done without knowing more about these things.

 

I do not think it is possible to extrapolate a 10-15% improvement in walking time to a general health improvement. The secondary outcomes show that it did not seemingly translate into an improvement in the activities of daily living and in general quality of life.

 

It feels like we are missing some measures doesn't it. We need objective, but then there is the issue of it not being a 2-day CPET (but that not being a great one to get people to do lots health-wise), or including the PEM/amount of PEM people are in before or after ie compensation.

I think ability to 'exert' matters somewhat (or must) because/if it can be equated to 'max wall', but having a higher one of those doesn't equate to how bad someone's PEM might be (for many reasons including pushing through etc, but also individual differences for various reasons). We can't even cleanly measure or interpret either of these - which might be relevant if they had any bearing on 'baseline max' or something (just because it would be useful to have the bar raised for the 'unexpected/unavoidable') but as you say perhaps less bearing on the daily living as other factors come into play.

I know this is an old one and I'm getting off-track/theoretical. But on the other hand it is an old one and these questions were/should have been begging then in the right culture which makes me sad slightly to see the wasted years. And I find an example easier to bend my mind around to think what angles we need to come at this from than blank sheet of paper..

 

I agree in some regards. To me, the main problem of this trial is the control arm — in hindsight, we now know, thanks to research on POTS (and less reliably from anecdotal accounts), that IV saline can help with orthostatic intolerance. If the participants had received an infusion just before their second treadmill walking test, they may well have done better than if they hadn’t.

Interestingly, the treadmill tests were administered by the Workwell Foundation — I didn’t know they existed before 2003/4 — and they had the courage to travel between 12 different study centres. I would like to think that if they knew about 2 day CPETs back then, they would have proposed this test as the primary outcome.

In any case, it seems to me that this trial was well conducted and reported — surely the most important part was the FDA’s involvement in the study design to maximize the chances of getting Ampligen approved, even if the FDA are by no means knowledgeable about ME/CFS — and, of course, I wish more trials like these were taking place nowadays.

 

I’m not sure Workwell had come up with the idea of the 2 day CPET back then — I believe the earliest study on it dates from 2010 or thereabouts.

Both fair points (the outcome and the reported improvement). I don’t know if actimeters were easily available and not overly cumbersome 20+ years ago, though I wouldn’t believe so.

What is strange, then, is that Hemispherx / AIM ImmunoTech never raised funds for a third trial that the FDA asked them to do. If they were confident they could replicate their results (after all, they reached twice the minimally important difference required by the FDA in this trial), I don’t think it would have been excessively hard to convince investors — but I may be wrong. They really just seem to have dropped Ampligen after the FDA’s refusal of approval in 2012. They might have gotten fed up with dealing with the FDA as the process dragged on for years.

Perhaps the most important point would have been to identify who responded best, and why. The investigators tried to do so in a post-hoc analysis published in 2020 but as you pointed out, @Hutan, it looked more like an exercise in cherry-picking with the aim of hyping their drug for long Covid than anything else.

In the end, it is hard to reach a definitive conclusion as to what direction to take. On the one hand, a 1m 17s mean increase in walking time relatively to placebo that is not associated with improvements in quality of life, after 10 months of treatment, is rather off-putting. On the other hand, no other treatment to date has produced such an improvement, though it seems reasonable to conjecture that, apart from pyridostigmine (Mestinon), medication for orthostatic intolerance such as midodrine or propanolol could get there.

From a more pragmatic point of view, now that 10 years mostly devoid of important developments around Ampligen have passed (if not for its approval in Argentina in 2016), I doubt AIM ImmunoTech will ever run this third trial. They have expanded their open-label study AMP 511 to include long Covid patients who meet ME/CFS criteria, but I’m not convinced they will be able to progress to a RCT for long Covid, even though there are fairly clear signs they are trying to make it happen.

 

Lately, they seem to be trying to push Ampligen as an antiviral against Covid (as a nasal spray prophylactically and as a treatment). Plus a bunch of different cancers, in flu vaccines and HIV. It doesn't really inspire confidence.

 

Some patient advocates are just incompetent. This also seems to be tied to the belief that ME/CFS is a continued infection by one specific virus. The antiviral Ampligen fits with that belief, and that the results are really weak, with terrible cost-benefit profile doesn't seem to register. If the tiny positive effects are even real.

 

Were the tests done on patients who were severe? If not, the results might not apply to severe patients. I'm really skeptical about the precision of the results (14% rather than ~15%). To me that reported precision means they may have cranked out the numbers with no real feel for what they meant, meaning they really don't know what they're talking about.

 

This makes me think, and rightly ask the question from a patient perspective: why on earth do we not have ME clinics that offer these as standard where applicable to the patient and measure the impact (those it works for and doesn't), probably along with other things that some report help them (B12, yes I know some people's views, and things like antihistamines, being others where the improvements for some are real, the harm is limited ie worth a try).

I'm currently trying to suppress outrage at the idea money is funnelling in our name still into places that offer useless therapies probably not to people who have ME and have no medics at all in them. Whilst they claim there are no cures - which is not the same as 'nothing could help these people'.

I feel the attitude really quite sharply watching it all of others putting themselves (and their little cushy niche they've built) well ahead of taking our health and lives seriously (and still being allowed to claim the eponymous 'good intentions' which I think needs to be called out as a phrase too to hide behind, instead of having to look up whether what they offer is harming the people they are funded to prioritise, and there are other things that maybe they don't offer that would help them).

 

I'd hope they weren't done on patients who were severe putting them on a treadmill. They might not, and the methodology would need to be significantly different - ie looking at essential ADLs exertion-wise rather than treadmills. This seems to be one area that @PhysiosforME was looking at with the heart rate studies, how you could measure certain things without creating additional exertion to what someone would have to go through (safety and ethics).

What I am saying is that for someone more severe that could be the difference between an essential task making you permanently worse or being recoverable from at 14%. And that being able to live more weeks without such 'heavy PEM' knocking someone downwards could indeed stop that inherent self-perpetuating deterioration and be life-saving if combined with a set-up where they were surrounded by people who insulated them from things which were avoidable, giving their body more chance to recover.

I'm not saying this is perfect methodologically, I'm saying 14% is massive if anything can reach that level with good methodology and should have funding that reflects that life-saving and life-changing impact - and it makes me sad that neither the implication of the illness at that end is producing such urgency that it should deserve given this. I'm also saying that picking up these types of things from before research got trampled by the BPS treatment hegemony and seeing if there is anything to give clues as to where to pick back up from on potential interim directions to look for supportive therapies for some isn't a bad idea, and will certainly inform future methodology (given one thing that has progressed in the time interval is knowing more about PEM, 2-day CPETs so there are innovations begging which could add weight to replications). I like it as an idea to look back at these.

I also agree that methodology is more important than many illnesses as my comment further up discusses, than for many other conditions, due to the weird cardinal symptom of ME (PEM) making the ideas of baseline measures utter wildcard nonsense without knowing what stage of PEM you've put people into.

Then we get into types and how we can manage to not stymie all research by insisting on the lowest common denominator approaches that are prevalent in the 'straight to trial' approach combined with a bucket diagnosis a health system won't adhere to criteria for. I'm no fan of 'post-hoc' if it is not merely for the purpose of proper follow-up and improving methodology and understanding of mechanisms and types (BPS are the worst for then applying these to skew their samples they then claim are representative). But if trials are done where there are 10% (who can all be confirmed as having similarities/differences/potential for cluster analysis) who improve significantly from something over a sustained time period with objective measures that can underline this ... should that inform an overarching research strategy?

ie there is a bit to be learned from papers like these above and beyond whether 'Ampligen is it'

 

Two notes on IV saline:

1) The paper does not mention when the last infusion was given to participants, and more precisely whether it was administered on the day that they did the treadmill walking test. If not, given that the effects of IV saline are short-lived, they would not have carried over to the day of the test.

2) The trial protocol mentions that Ampligen is dosed at 200mg per 80mL vial. Patients in the intervention arm received two vials (400mg) at each administration, and those in the control group received an equivalent volume of IV saline, i.e. 160mL (1.44g of salt). Given that a regular bag of saline contains 1L for a total of 9g salt, this amount is unlikely to have had a clinically significant effect on increasing blood volume and thus on improving patients’ performance on the walking test.

 

Interestingly, the protocol (April 2003 version) mentions actigraphy coupled with an activity diary as a secondary endpoint (pages 2-3 & 11). Patients were to wear a waist-worn actimeter, with data being collected over 15 day cycles, and add an entry to their diary if an activity was sustained for more than 5 minutes. This seems to have been dropped altogether from the trial; or at least the results were not reported in this paper.

 

> What I am saying is that for someone more severe that could be the difference between an essential task making you permanently worse or being recoverable from at 14%. And that being able to live more weeks without such 'heavy PEM' knocking someone downwards could indeed stop that inherent self-perpetuating deterioration and be life-saving if combined with a set-up where they were surrounded by people who insulated them from things which were avoidable, giving their body more chance to recover.

when you are bedridden and have tjhousands of crises that others doulw not even eelive possible all at the same time having such a team of isulators and accomplishers pf things needing doing couold ake aoll the difference.