Embry: Actual data from PREMiSe suggests CCSVI is of value

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Embry: Actual data from PREMiSe suggests CCSVI is of value

Postby Cece » Fri Apr 12, 2013 10:49 am

http://www.direct-ms.org/sites/default/ ... 202013.pdf
The actual data from the PREMiSe Trial do not support the highly
publicized claim that CCSVI correction by angioplasty is not of value
for MS and may worsen disease activity. In sharp contrast, the data
suggest that CCSVI correction may well be of substantial value for
MS. The misleading claims made by University of Buffalo researchers
are based on irrelevant data from the failed Phase 2 portion of the
trial in which no one had their CCSVI corrected. The anti-CCSVI bias
and baseless claims may be explained by the conflicts of interest.

A lot of information in the article he's put together. Not sure what to think.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Squeakycat » Fri Apr 12, 2013 2:02 pm

Cece wrote:A lot of information in the article he's put together. Not sure what to think.

What to think is pretty clear.

Dr. Embry documents what others, and I believe you, have been saying that if there is no improvement in blood flow following treatment, then the treatment itself failed in Phase 2 of the trial and no conclusions can be drawn about the effectiveness of CCSVI treatment from the study.

I think this also raises a serious question about what the research team was up to with their highly publicized press release and YouTube presentation which drew conclusions unsupported by the data they presented.

Embry wrote:An inspection of the PREMiSe data on the poster presented by UB researchers at the recent AAN convention in San Diego reveals the following:
    1) All the subjects in the open label, Phase 1 portion of the PREMiSe trial had their CCSVI was corrected (>75% blood flow restored by venous angioplasty). They had very good clinical results over the 6 months with no relapses and only 2 new lesions among the ten subjects.
    2) The controlled and blinded Phase 2 portion of the PREMiSe trial was a failure because those receiving angioplasty did not have their CCSVI corrected (i.e. they did not have their blood flow restored to >75%).
    3) Among the nineteen, Phase 2 subjects, all of whom did not have their CCSVI corrected, there were a total of 4 relapses and 20 new lesions.
    4) The reason for the failure of the angioplasty procedure to correct CCSVI in any of the Phase 2 subjects is unknown and is of concern because there was 100% success in Phase 1.
    5) The failure of angioplasty to correct CCSVI in the Phase 2 patients means any comparison between the clinical outcomes of the angioplasty patients and sham ones has no scientific significance. Any detected differences between the clinical outcomes of the two groups are purely random and a consequence of the very small trial size and the acceptance of only persons with active MS into the trial.
    6) The excellent clinical results of Phase 1 subjects, all of whom experienced CCSVI correction, compared to the adverse clinical results of Phase 2 subjects, none of whom experienced CCSVI correction, suggest CCSVI treatment may be of substantial value for MS.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Cece » Fri Apr 12, 2013 2:26 pm

Squeakycat wrote:I think this also raises a serious question about what the research team was up to with their highly publicized press release and YouTube presentation which drew conclusions unsupported by the data they presented.

Yes, this. I don't know how much to be concerned about conflict of interest. I don't know what the BNAC team should have done when they realized that the procedures had been unsuccessful at restoring blood flow in the phase 2 group.

Also in an interview, Dr. Zivadinov said that the patients in phase 2 who had greater improvement to blood flow are the ones who had greater worsening of their MS; there was a correlation there and not the expected direction.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Squeakycat » Fri Apr 12, 2013 2:56 pm

Cece wrote:Yes, this. I don't know how much to be concerned about conflict of interest. I don't know what the BNAC team should have done when they realized that the procedures had been unsuccessful at restoring blood flow in the phase 2 group.

Also in an interview, Dr. Zivadinov said that the patients in phase 2 who had greater improvement to blood flow are the ones who had greater worsening of their MS; there was a correlation there and not the expected direction.
Dr. Embry's comments on the graph provided of blood flow seems to show the opposite of this in the sense that it does show "some" improvement at least in VHISS for both sham and treated groups:
Embry wrote:The VHISS scores of the two groups from Phase 2 are coloured in red (angioplasty group) and green (sham group). Note that the VHISS score of the angioplasty group was higher than sham group at both 1 month and 6 months after treatment and was almost the same at 3 months. These data reveal that, without a doubt, the subjects in the angioplasty group did not have their CCSVI corrected and that their blood flow remained as bad as that recorded for those in the sham group. The importance of this hard fact cannot be overstated.


Further, I wonder what throwing out the one outlier who had 8 new lesions would do to Dr. Zivadinov's statement? There seem to be two key differences between the treated and sham group. The first is that the treated group had more active disease in terms of an average of 1 previous relapse compared with only 0.4 for the sham group, half the number, and that one person in the treated group had 8 new lesions:
Embry wrote:Why the Angioplasty Group Had a Worse Outcome – One aspect of the PREMiSe trial is that the researchers only accepted persons with active MS into the trial (at least one relapse in the past year or at least one new enhancing lesion in the last three months). Notably, it turned out that the angioplasty group by pure chance through randomization got subjects with more active disease with an average of 1 previous relapse for the angioplasty subjects versus only .4 relapses for the sham group (i.e. more than twice as many relapses for the angioplasty group). It is worth noting that one person randomly assigned to the angioplasty group 50/50 chance) ended up with 8 new lesions which was almost as many as the total number of new lesions (12) developed by all other 18 people in Phase 2!
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby MrSuccess » Fri Apr 12, 2013 5:30 pm

same Organization .... same Researchers ..... different outcomes.

All in the Grand scheme . :wink:


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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Robnl » Sat Apr 13, 2013 4:38 am

MrSuccess wrote:same Organization .... same Researchers ..... different outcomes.

All in the Grand scheme . :wink:


MrSuccess


Agree, it's all about playing chess 8)
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby eveable » Sat Apr 13, 2013 10:24 am

The data suggests there is a measuring problem as well as too small sample size.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Squeakycat » Sat Apr 13, 2013 10:33 am

eveable wrote:The data suggests there is a measuring problem as well as too small sample size.
Where do you see a "measuring" problem?

It is a small study, but the size seems appropriate as a first step in terms of a blinded study with sham treatment.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby 1eye » Sat Apr 13, 2013 11:24 am

One outcome of using data from sources such as this, is that it seems, because of occasional positive results, that these trials are fair, and that nothing should be made of any conflicts of interest. This is not true. In cases where there is even an appearance of conflict, the evidence is of no value. The public, along with public organizations such as the Canadian Institute of Health Research and the FDA, not to forget the Health Ministry, must take a zero tolerance policy on publication bias, which is bound to exist when research groups self-publish, whether on paper, in private communications, or on the Internet, in words or video. Everyone must hold these powerful, supposedly unbiased professionals to the same standards. These studies affect peoples' life and death.

Those who break faith with patients will deserve the same, when disease strikes closer to home. My family doctor reminded me that most people, including doctors, researchers, drug company spokespeople, and government officials, will eventually be patients, often with very serious disease.

Drug company funding should be seen as what it is: clear conflict, likely to bias, and encourage fraud, sometimes at the cost of many thousands of lives. If we continue to accept it without question, it will be at our own peril. The cost of research is the cost of knowledge, and no short-cuts exist.

The truth is in everyone's interest. Bias, commercial and otherwise, helps nobody.

The figure of justice is blind, and does not have her hand out. :-x
"Try - Just A Little Bit Harder" - Janis Joplin
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'MS' is over - if you want it
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby ScutFarkus » Sun Apr 14, 2013 11:21 am

1eye wrote:One outcome of using data from sources such as this, is that it seems, because of occasional positive results, that these trials are fair, and that nothing should be made of any conflicts of interest. This is not true. In cases where there is even an appearance of conflict, the evidence is of no value.

This is where you misunderstand the scientific method. Scientifically, results live or die by their reproducibility, not by whether or not there is "appearance" of conflict. Furthermore, in most parts of the globe, there is very little research money available, so if you automatically reject all research that involves any researcher who has ever taken money from a health-related company, you will pretty much have to reject all science. But luckily for all of us, science doesn't depend in any way on the total purity of spirit of scientists. The way it works is that researchers publish their results, other researchers contemplate the results and try to reproduce (or improve upon) them, and if the results hold across multiple independent studies, we start to trust them! No single study can ever be the first and final word, as the authors of this paper clearly point out.

1eye wrote:Drug company funding should be seen as what it is: clear conflict, likely to bias, and encourage fraud, sometimes at the cost of many thousands of lives. If we continue to accept it without question, it will be at our own peril. The cost of research is the cost of knowledge, and no short-cuts exist.

Actually, the cost of research is lots and lots of MONEY, and this money has to come from somewhere. Don't be fooled into thinking money that comes from the government or wealthy private benefactors is free from bias. There are plenty of counter-examples. You're fooling yourself if you think you can figure out which results are true and which are biased just by knowing who provides the money.

/Scut
Last edited by ScutFarkus on Mon Apr 15, 2013 12:46 pm, edited 1 time in total.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby David1949 » Sun Apr 14, 2013 7:56 pm

Based on the graph on page 6 of http://www.direct-ms.org/sites/default/%20...%20202013.pdf
I'd say Ashton Embry is right.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Squeakycat » Sun Apr 14, 2013 9:43 pm

David1949 wrote:Based on the graph on page 6 of http://www.direct-ms.org/sites/default/%20...%20202013.pdf
I'd say Ashton Embry is right.

Is this the link you are referring to?

The only problem with this is that we are looking at an average of just nine people and as you can see from the graph, there is a wide variation from the highest to the lowest values at each point on the graph.

This means that just one person could change everything. For example, Dr. Embry points out that one of the treated patients had 8 new lesions out of a total of 12 for the other 18 for the treated and sham group.

Something may well have gone wrong for that one person. We don't know whether angioplasty made their blood flow worse which might account for this. Nor do we know whether they had very active disease just prior to angioplasty. But the numbers for just this one person might be enough to change the average for such a small group since this one person's data is 66% of the total.

I think we have to wait until all these details are released before we can come to any conclusions.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby ScutFarkus » Sun Apr 14, 2013 9:48 pm

David1949 wrote:Based on the graph on page 6 of http://www.direct-ms.org/sites/default/%20...%20202013.pdf
I'd say Ashton Embry is right.


You mean he's right in general? Or on some specific point? His paper makes a lot of claims, some I agree with, but many of which I don't.

I do agree that the ineffectiveness of the CCSVI procedure during the Phase II portion of the trial means that these results don't really say much about whether or not venous flow correction is helpful for MS.

Comparing the Phase 1 results with the Phase 2 results is interesting, but not scientifically valid, since it's effectively "cherry picking". That is, the strength of a proper scientific experiment is making a plan, determining your end points and metrics ahead of time, then collecting the data, and finally analyzing it. But if after collecting the data you open it up to post-hoc reinterpretation, it's easy to find all sorts of "results" that may or may not be real. That can be useful for getting ideas to suggest future experiments, but results achieved this way are no substitute for a proper experiment.

One huge difference between the Phase 1 and Phase 2 groups (as Embry even points out) is that the Phase 2 group was required to have active MS at the time of enrollment, while the Phase 1 group was not. So it's hardly surprising that the Phase 1 group had less disease activity during the followup period than the Phase 2 groups, since only the Phase 2 group was known to have ongoing disease activity right before the intervention! Claiming the difference in activity is due to the effectiveness of the venous intervention in Phase 1 is highly misleading, and Embry should know better.

It's also worth pointing out that stated goal of PREMiSe was "To investigate the safety and efficacy of percutaneous transluminal venous angioplasty (PTVA) for correcting
CCSVI in MS in the setting of a prospective, double-blind, sham-controlled, randomized pilot trial." Read this carefully. It states that their goal was to see if a specific technique (PTVA) was safe and effective at correcting CCSVI. Their results suggest it is pretty safe, but wasn't very effective as correcting CCSVI. As such, and contrary to what Embry claims, these results don't represent an "abject failure," and in fact represent success. Disappointing success, of course, since it means this specific intervention may not be as effective for CCSVI as hoped, plus the results don't give us good data on how MS responds to proper intervention, but these latter points were not the design of the trial!

/Scut
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby Squeakycat » Mon Apr 15, 2013 12:19 am

ScutFarkus wrote:This is where you misunderstand the scientific method. Scientifically, results live or die by their reproducibility, not by whether or not there is "appearance" of conflict.
Not when it comes to drugs.

There is a long history such as happened with Zoloft where the manufacturer pays for repeated studies in the hope of getting two that are positive which they then use to force FDA approval. There is well documented bias where manufacturer supported studies have positive results and studies that don't fit the marketing plan either never see the light of day or get buried in obscure publications.

As a result, I think there may be a three step process in science:

    1. Look at the results.
    2. See who the sponsor is and then
    3. If the sponsor is a pharmaceutical, look very carefully at the methodology.

The problem is that patients are usually not well-qualified to look at this kind of detail and medical professionals are for the most part, too busy to do anything other than look at the abstract or articles written about the study.

The companies and their academic spokesmen are not above flat out lying about things that most people simply don't have the time to check.

A classic MS example of this is in a Medscape video presentation about Aubagio by Dr. Mark Freedman.

He very glibly starts out by mentioning that the parent of Aubagio was given a black box warning by the FDA for liver problems which the FDA also insisted on for Aubagio.

Dr. Freedman dismisses this with the following statement:

Dr. Mark Freedman wrote:"Teriflunomide derives from leflunomide, which is used for treatment of rheumatoid arthritis. Unfortunately, leflunomide has a black box warning because of potential liver dysfunction. This actually never panned out but the warnings were there." [Emphasis added.]
Who, besides me, is going to take the time to look up the FDA's adverse drug reaction statistics to see whether Dr. Freedman is being truthful about this? Not many people. And in fact, the data show that liver problems are the most commonly reported side effects of leflunomide which makes Dr. Freedman's glib dismissal of this, his specific statement that "this actually never panned out . . ." to be a complete lie. [That's not to say that Dr. Freedman is a liar. He may well have been given this talking point by the manufacturer and simply didn't check it himself.]

That's the kind of science we are dealing with.

Drugs will be tested and tested until someone in the statistic group in marketing can figure out a way to spin the data or run a new trial to avoid the problems highlighted by the last one.

Take one look at the data at http://www.ClinicalTrials.gov. You will see hundreds of trials that have been completed for which there are no reported results. Bet you my last penny that every single one was a failure.

So if you rely solely on reproducibility as a way to weed out bad drugs, you are going to be completely misled by the published "science."

And the FDA is absolutely useless in acting on our behalf to use real science to stop this kind of crap. If I were to report Sanofi over Dr. Freedman's statement, I can tell you exactly what will happen. Nothing. Best case in doing this for over 30 years is that after 18 months of illegal promotion of a drug, the FDA will send a letter to the manufacturer telling them to stop doing it. Of course, the manufacturer at that point will have started a new illegal marketing campaign.

The system is completely broken. Science has been completely prostituted in pursuit of revenue and does not provide any guarantee of safety or efficacy when it comes to drugs.
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Re: Embry: Actual data from PREMiSe suggests CCSVI is of val

Postby NZer1 » Mon Apr 15, 2013 2:48 am

Many good points in the discussion ;)
BNAC has been looking at CCSVI from many angles and come up with some very good positive learning edges because of their broad thinking so far. CSF flows, Thalamus atrophy, Doppler trialling, combining with Zamboni for guidance, so why the reverse approach suddenly when so many CCSVI understandings make solid findings of Vascular involvement in MS?

I am wondering why the phase 2 leg was designed to find the failure point? To treat to an advertised 50% level of improvement is a very loose term and when you consider the before PTA figure one has to wonder what was physically done to achieve the outcome.
Active MS is one of the most impossible states of this disease to predict, timing the 'regular' relapsers so that you can treat when in the worst inflammatory cycle is an interesting ploy!
If the testing was done to find out why there are nil responders to treatment Internationally occurring, I would have 'assumed' would have been a stated purpose in the design of the trial.
To test if undertreating could in future be classified as less than 50% flow improvement from/at PTA appears to be the purpose of phase 2 in reality?
In phase 1 treating and achieving greater than 75% flow improvement was a success!
So why cherry pick the two phases PwMS? It appears to be purposeful and the outcome, predictable for that phase, to not improve the flow.
I keep coming back to 'why' and what pressures were happening when the trial was designed by BNAC?

Something purposeful by manipulation and attempted stealth happened in this trial, was it to disillusion the public, was it to see what they could get away with, was it about exposing bias, was it about profit at any cost?


This has become a test of the public's power to change the system, to introduce integrity, to speak up against fraudulent methods of deception, and to use the Internet to correct problems, imo!
;)
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