Ampligen study published in PLoS One 14mar2012

I'm not sure there was another paper from this cohort except this one:

Definitely. The clinical trial notification says:
Study First Received: September 16, 2005
Last Updated: September 16, 2005
i.e. it was posted in 2005 with the status:

Concerns about using saline infusions as a placebo

I've heard concerns before about using saline infusions as a placebo in ME/CFS trials as it might help patients. I don't know if we can tell much from this? But it would have been interesting if they had a "no treatment group" (although distinguishing what were the effects from saline as opposed to placebo effects might be hard. Maybe one could simply have a non-saline/water infusion? Although again, some might feel that would help with blood volume issues.

History of changes: http://clinicaltrials.gov/archive/NCT00215813

Thanks for that. When I tried to access it the history didn't go beyond 2005.

Just working through it. Cornish Mizzle-day so am particularly slow today :In bed: So some observations I guess:

'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].

The Phase III multi-center, double-blind, placebo controlled trial reported here uses ET as its primary endpoint and the reduction in drug usage for symptom relief as one of several secondary endpoints in the evaluation of rintatolimod in the treatment of CFS/ME.'

Ok. So in order to prove this drug was effective at reducing fatigue the results of ET had to exceed the average improvement of 6.5%. Doesn't seem much does it? I mean if you are bed-bound i.e. KPS 30 (see below), then it probably is but this assumes of course that fatigue is the most important measure of the condition.

Although, in addition, if (and I haven't yet seen this mentioned) the Ampligen removes PEM then any improvement above 6.5% would certainly be welcomed - as would sustained ET over a significant period.

Like Esther though, I have to ask why this drug is seemingly so effective. What is happening within the body to improve performance.

They do talk generally about Ampligen of course and I suppose I can look it up again specifically:

'The rationale for the initial trials with rintatolimod (Poly I:C12U) in CFS/ME were based on its recognized antiviral and immunomodulatory properties and as an inducer of interferon [13]. These properties are mediated by its activity as a selective toll-like receptor 3 (TLR-3) agonist in the induction of innate immune responses [14]. Toll-like receptors, as primordial transmembrane, pattern recognition receptors, trigger alarm signals against invading pathogens by modulating cytokine cascades.'

One of the inclusion criteria (other than KPS below) was:

'Ability to walk (minimum of 20 seconds) on the moving treadmill (grade=0%; belt speed=1 mph) on a minimum of two (2) occasions during the twelve (12) weeks immediately preceding study entry.'


The definition of 'severe' prompted me to look up the Karnosfky score. We were not talking bed-bound patients then:

KPS score 40-60 was needed for inclusion i.e.

100 Normal activity; no complaints; no evidence of disease.
90 Able to carry on normal activity; minor signs or symptoms of disease.
80 Normal activity with effort; some signs or symptoms of disease.
70 Cares for self, unable to carry on normal activity or do active work.
60 Requires occasional assistance but is able to care for most of needs.
50 Requires considerable assistance for daily care.
40 Disabled; unable to care for self, requires special care and assistance.
30 Severely disabled; bedridden although death is not imminent.
20 Very sick; hospitalization and/or nursing care is necessary; active support treatment is necessary.
10 Moribund; fatal processes progressing rapidly.
0 Dead.

'The primary endpoint was ET on a treadmill (Trackmaster TM 225, Full Vision, Inc., Newton, KS) with ECG monitoring performed by a team of exercise physiology specialists who traveled to each of the trial sites (Workwell Physiology Services, Inc., Ripon, CA). Secondary endpoints included changes in the use of concomitant medications to treat CFS/ME symptoms, Karnofsky Performance Score (KPS) (Table S3), Activities of Daily Living (ADL), and the Vitality and General Health Perceptions subscales from the Short Form 36-Health Survey (SF-36).'

'Patients underwent treadmill ET testing according to a standardized protocol (Table S4). Subjects rated their perceived exertion, generally considered to be a reliable indicator of fatigue [20], using the Borg Scale and progressed through stages successively until they could no longer continue.'

Presumably that means until they felt they could no longer continue. Is that objective enough? Is it better than say GET objectivity? I don't know.

Results then:

'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%.'

So - on this measure - Ampligen appears what 3-4 times more effective at improving ET than placebo. Not bad. Or roughly twice as effective on the 'intra-patient mean increase'.

'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.'

So roughly 4 times again in terms of ET for those on the drug compared to those on placebo. Again, I wonder if this ability is maintained long-term.

Enough for now. Need a rest....

With this, the speed was set for you by the treadmill, while it's not with the 6 minute walking test (6MWT) (distance walked).

It's important to point out that with CBT in the PACE Trial, there was no improvement on the 6MWT - indeed the control group did a tiny little bit better when adjusted to baseline factors (1.5m, p=0.87 i.e. not close to statistical significance).

The GET group did walk further than the other groups in PACE. However, GET is about exercising so we can't be sure that this didn't bring in biases e.g. the people who did GET might push themselves harder on the 6MWT or might be better able to judge what speed they could walk at for 6 minutes from doing lots of walks while in the APT and SMC, some people might do few if any continuous 6 minute walks so might go "too fast" or "too slow" initially. Such concerns don't apply in a trial like this.

Yes, it would be interesting to know how people do when they go off the drug. I have heard anecdotally some disimprove.

Thanks D.

PEM is a good point too don't you think? And I need to see about this 'coming off other drugs because Ampligen seems to warrant it' - business. Do they quantify what drugs? That would be interesting. If as Laurel mentioned these patients felt able to surrender or reduce their e.g. pain medications - then that is brilliant. BUT - what does it mean? That somehow Ampligen works on pain receptors? There is - I seem to recall - a link between the immune system and pain.... anyway if Ampligen e.g. enabled me to reduce my Neurontin or co-codamol safely, then cool. But I'd like to know why....

There was this separate study on the change in drugs used: http://forums.phoenixrising.me/show...hronic-Fatigue-Syndrome-Trial-of-Rintatolimod . I can't remember the details.

Cheers. Am running out of 'juice' but will check it out tomorrow (as well as the paper) I think.

Ampligen 'GET in a bottle'!!

Ahh... I can see the adverts now

If PACE and FINE proved (in addition) how costly such interventions were I wonder how Ampligen stacks up in that respect? I think you're 'lucky' to get six weeks (six sessions) of GET/CBT PACE-style on the NHS but in order to be as 'effective' as they were purported to be you'd need far more.

If (as has been said) Ampligen were to be approved (and I think there will need to be more trials by the regulatory authorities in the UK) then presumably a pill in a bottle will prove more economic? Unless of course one needs to remain on the drug for many years to prevent relapse. Mass production would reduce the unit cost and post-patent it would become generic.

Still, a long way to go and I remain uncertain that the results amount to much. Can't wait for the critiques to appear. I can hear White now and that bloke from Holland....

As an interesting side note if you follow the links on clinical trials you get to: http://clinicaltrials.gov/ct2/results?cond="Myalgic Encephalomyelitis"

This page has a list of recorded studies on ME. You can also run a search for CFS.

Bye, Alex

An oral form would certainly make it cheaper and more accessible. I recall hearing suggestions that they were working on it.

One of the biggest problems in terms of us accessing useful drugs is the hype around CBT and GET. It's probably likely that they will continue to be seen as relatively safe. And especially with the clinic structure, the figures can probably be "worked" to claim they are value for money even if this depends on non-objective measures.

CBT and GET being seen as front line treatments is a big problem in terms of us getting access to effective drugs. I heard indirectly that one drug company decided not to run a major drug trial after the NICE CFS/ME guidelines came out as they figured it would be hard to them to get their money back. A lot of us have reflected on this which is one of my big motivations anyway for spending a lot of time scrutinising CBT, GET and similar research. Drugs tend to be "naturally" regulated and scrutinised more tightly.

All the suggestions that we can be rehabilitated back to normal, as well as even lesser efficacy claims, mean there is less of a focus on working out the underlying biological causes. Some drugs may work well for some people but work at all for others but this can be hard to spot without more biomedical progress.

The issue here is that the FDA's complete response letter is not a public document. All we know is the conclusion from the agency that the drug did not "show credible evidence of efficacy" but we don't know the reasoning of the FDA panel.

The FDA has made a number of unfortunate decisions with respect to Ampligen. The drug should have been fast-tracked and given priority review status because there are no approved treatments for this disease. This was not done. The FDA selected unusual criteria for evaluating the efficacy of this treatment. Then, they appeared to make the standards for drug approval and safety more and more stringent after the drug scandals of 2001.

The company also made bad design decisions. First, they chose a study length of 6 months when it is well known that patients are hardly responding by 6 months- the optimum responses to Ampligen are seen between 18-24 months of treatment. And, the most dramatic effect of the drug is on cognitive functioning, and there was no cognitive testing done as an outcome measure.

I have been treated with Ampligen for one year and got significant improvement in cognitive function, objectively measured, and modest improvement in physical function. The flu-like side effects of the drug were significant, but it had no toxic effects. It is not a miracle drug but it was worth every penny (it's not that expensive anymore). The worst thing about it is the inconvenient twice a week infusions and that you can only get it in a few places in the country. XD

I am not sure how much ml is mixed with Ampligen- but let's take the example of RItuximab- which is as far as I remember given in 250 ml saline. That's 1 cup of water, given over 5 hours for the first infusion, and over 1.5 hours all subsequent infusions. Not significant.

But then all the patients, on the study drug and the placebo control receive the same amount of saline- so the fact that patients on the trial drug do better is comparative to placebo control patients. And let's be honest here: there is always be a few patients responding on whatever is given to them. (Look at the craze of the minute, and the hype it gets on forums. If it were that good, the size of the forum would be much decreased, we'd all be playing outside)

Have reviewed that thread. It would seem to me that one of the reasons for the delay then in publication, was because the FDA expressed concern about the effects of such medications on patient's heart-function.

So they went back and looked at the effect of Ampligen on the heart, and found that as it improved the ability to exercise (and reduced dependence on other medications that might have been placing patients more at risk in relation to their hearts), Ampligen passed this test.

I haven't read that paper but from the comments/extracts on the thread there would appear to have been little information about what these other drugs were. But I'll get around to looking once I've finished with this latest paper.

I have a feeling that in order to review what Ampligen is actually doing to patients i.e. how it works in allowing greater ability to exercise, one might have to go back at look at previous studies about the drug itself. These eight years or so appear to be clinical trials concerned with safety and quantifying the benefits in blinded testing.

But the inference is there, is it not? Something is screwed with the immune system. Something that appears to limit ability to exercise, tolerance of exercise, 'energy'? What 'it' is might be revealed by previous study, but like Rituximab I suppose, this drug is being marketed because of it's perceived results - not because it would seem they've nailed what is 'wrong' with us.

I have to say that it (like Rituximab) makes me uncomfortable. But, hey, I am not the one who has to approve this drug. And if when I visit my specialist he eventually prescribes it to me - then what do I care?

Whether or not this latest paper will satisfy the FDA etc. is not a call I can make of course. It's been a long and rocky road for Hemispherex. I must check their share price following the publication. Not much in the way of news coverage - I wonder why?

Edit:

Share price: http://finance.yahoo.com/echarts?s=...=on;ohlcvalues=0;logscale=on;source=undefined

Nada!

Oooppsss! Bit of an injustice there. When the publication was accepted in January the share price did peak, probably not a coincidence actually: http://finance.yahoo.com/echarts?s=...=on;ohlcvalues=0;logscale=on;source=undefined

Look's like - at a guess - some further 'profit-taking' since that time. A favorable FDA pronouncement would be the key to further gains of course. I wonder when they are likely to pass a verdict?

My last resource - wikipedia - has this to say and carries references. Don't know if it helps you blue or not:

'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."[2][3]'

So I am only surmising that this latest publication was a further attempt at proving 'efficacy'. But whether it will be enough, is down to the FDA of course. Anyway, there might be more on good old Wiki...

Journal of Virology, 2007, talks more about how Ampligen is supposed to help stimulate the immune system to better fight viral infections. It also refers to the Stage III clinical trial for CFS - the one that was not sufficient for the FDA - viz.

From the Discussion: http://www.jimmunol.org/content/178/8/5200.long

'To this end, it has successfully completed a large double-blind, placebo-controlled, phase 3 clinical trial for the treatment of chronic fatigue syndrome under the trade name, Ampligen. The primary end point of exercise tolerance achieved statistical significance and was highly correlated with an increase in oxygen use. Moreover, poly(I:C12U) was generally well tolerated, and there was no significant difference in the number of serious adverse events in the poly(I:C12U)-treated group compared with the placebo control group.'

Whilst they appear to have tried very hard to prove 'efficacy' for Ampligen in CFS and HIV as a treatment; until I can find it - there does seem to be a lack of 'What exactly is happening in these patient's bodies?'

Why, for example, in the study just published, weren't the patients on Ampligen and the controls tested pre and post medication for immune system activity etc.? And (layman speaking) if Ampligen 'works' what does it imply is happening within these patient's bodies? A dysfunctional system caused by a previous viral stressor, or the presence of some ever-present virus?

It seems - from the little I have read - that Ampligen has the effect of a scatter-gun. It is marketed as being effective for a whole host of viral infections and yet I haven't read of comparison's with other anti-viral agents.

So what makes Ampligen unique - if anything? From this latest (re)-publication it doesn't appear to be a 'fix' for the condition - but if one considers the ability to sustain exercise and 'fatigue-reduction' to be the biggest objective measure: then you have to ask if these results are 'good enough' I guess to justify the cost for example...

All good 'fun' isn't it?

I don't understand the reasoning of the above posts. Who cares if Hemispherx has no idea how or why Ampligen helps CFS patients? This shouldn't be relevant to the FDA!

The FDA has approved *reams* of medicines where the drug companies have no clue why they work. For example, Prozac and all it's cousins to treat depression. These drugs were approved even though they were barely more effective than placebo and long-term safety was not shown.

Again, we do not know what the FDA's reasoning was for rejecting Ampligen. But, the safety standards are more stringent for a first-in-class new drug (i.e. there are no other drugs anything like Ampligen on the market, so it is a scary new thing). And, as I discussed, they didn't give the drug priority status on account of the fact that there is no approved treatment for CFS.

We don't know how it works, but Ampligen is the *only* CFS treatment that has shown efficacy in multicenter randomized double-blind controlled trials.

Intellectual curiousity.

You're right of course, it shouldn't matter and reams of drugs to get approval without the mode of action being fully or even partly understood.

But we like to speculate and muse over these things in lieu of having 'the answer'.

Plus having a plausible explanation lends a certain credence to the published results.

I don't think you have this right. The FDA isn't like NICE for example - it can use unpublished data. As I read it, the FDA was shown the data from this study already but it doesn't consider it sufficient.

Hear, hear! It so burns my butt that drugs like Viagra get out of the chute with hardly a nod, and we are left to languish for decades. I still maintain that if CFS was a male-majority illness, this wouldn't be happening. In the midst of claims of equality, there are still a lot of ways in which women get marginalized. (end of soap box).