Embry: Actual data from PREMiSe suggests CCSVI is of value

[Cece]

However, the results do provide relevant data on a question patients should be asking, which is "if I have this procedure, will I see improvement." Failure of the treatment itself, just like restenosis following successful treatment, is a real possibility. This study suggests it may be a high probability result, but until we have more info on what went wrong here, we don't really know.

/Scut

A high probability result when done by a neurosurgeon without experience in CCSVI endovascular interventions.
It does not inform on the results when done by an IR with experience.

[cheerleader]

The trial objective was "Correcting CCSVI in MS." Correcting CCSVI is measured by improving VHISS (venous insufficiency severity score) scores. This was a trial endpoint, and it was not met.
BNAC phase 2 DID NOT improve VHISS scores in the poor people who were treated. They went from 6 to 5.5.

The Phase one group did fantastically well....they went from a 6 to a 3. But their results (reduced EDSS, lack of relapses, etc) were not publicized by BNAC.

BNAC publicized a failed trial. They made it sound like venoplasty doesn't help MS. But the truth is, insufficient CCSVI treatment, which doesn't change VHISS, doesn't help MS.
cheer

[NZer1]

If 'failure of treatment' is instead languaged as 'undertreating the participants in a BNAC CCSVI PTA treatment trial does not give positive results or outcomes' there will be some learning happen.
If the word 'failure' and 'CCSVI treatment' continues to be the catch cry then BNAC win, it's propaganda by PR skills to the unlearned and unaware! It's subliminal training!

When words a specifically chosen and used in Media instead of peer reviews then warning bells should be ringing!

;)
Nigel

[NZer1]

I had a look on the Media blurb from the BNAC trial (http://www.wivb.com/dpp/news/health/UB_ ... S_20091014)
and suddenly have the opinion that BNAC IS looking at the flow and volume issues found to be less in PwMS BUT not the reflux and back jets issues that have been the core reason that Franz Schelling and Dr Zamboni have been 'shouting' about for some time. The symptoms originate from BBB leakage due to 'hydraulicing' return flow, against natural flow and then immune system involvement/clean up activities, as well there is a risk of infection within the normally protected BBB.
If BNAC wants to undertreat PwMS with known CCSVI flow and volume issues then they are not confronting the actual problem, reflux/back jets,(in symptom development and also in MRI image findings of Lesions to WM and GM).
If this is correct then there is a genuine reason to suspect the involvement of outside influences in the design and treatments performed at BNAC in this Trial, imo!
The Trial has become a distraction from the actual problems of concern, WHY?
Is the BNAC study only focusing on neck veins as was said in the interview so that any GENUINE reason for blood flow and volume decreases causing reflux and back jets in ANY veins returning blood to the Heart is down played or misinterpreted?
Will there be further interconnected studies by BNAC to genuinely seek knowledge on CCSVI involvement in de-generative diseases?
Who is going to financially benefit from protracting this search for 'Knowledge'?
Stealth? WHY?
;) Nigel

[ScutFarkus]

The trial objective was "Correcting CCSVI in MS." Correcting CCSVI is measured by improving VHISS (venous insufficiency severity score) scores. This was a trial endpoint, and it was not met.
BNAC phase 2 DID NOT improve VHISS scores in the poor people who were treated. They went from 6 to 5.5.

The Phase one group did fantastically well....they went from a 6 to a 3. But their results (reduced EDSS, lack of relapses, etc) were not publicized by BNAC.

BNAC publicized a failed trial. They made it sound like venoplasty doesn't help MS. But the truth is, insufficient CCSVI treatment, which doesn't change VHISS, doesn't help MS.
cheer

Here's the entry on clinicaltrials.gov: http://clinicaltrials.gov/ct2/show/NCT01450072
It says the purpose of the study is "to evaluate the safety and effectiveness of intravascular angioplasty for the treatment of venous narrowing in the treatment of Multiple Sclerosis (MS)." That's also what the poster says, in slightly different language.
The Primary Outcome measure was safety. The Secondary Outcome measure was restoration of flow, with a 75% target.

In the experiment, the primary outcome was positive (seems safe), but the secondary outcome was negative (the procedure didn't improve flow versus sham controls). They have every reason to report these results, since it wasn't a failed trial, it was a successful trial with negative results.

Didn't someone in this thread complain about drug companies conducting 20 studies and suppressing all the negative ones until they get two that are positive? If BNAC failed to publish the results of this study for that reason, they'd be no better.

That said, I agree with you that the press release makes it sound like actually correcting flow doesn't help MS, which does a disservice to the CCSVI effort. I think the press release is technically correct but quite misleading. So they deserve blame for that, especially since most science reporting seems to involve publishing press releases as-is, which means the press release will get much wider distribution than the actual paper ever will.

/Scut

[NZer1]

I had the thought earlier and haven't started going on about it yet. Thanks to Carol Schumacher for reminding me . So I will start,
Dr Zivadinov has spoken frequently about the Thalamus pathway and the atrophy found in the Thalamus region in PwMS. It may have give some credibility to the recent study if it linked genuine other recent MS findings rather than the methods of measurement used which are said to be inappropriate for MS studies by the Ebers paper! The other aspect of recent finding the Fox pathology and silicon visual proof of Vascular issues is another milestone for CCSVI which would create test insights for future measurement options in CCSVI research projects.
Both of items of measurement of defined issues have been avoided in the BNAC Phase 1 and Phase 2 stages, WHY?

Abstract
Arterial spin labeling (ASL) is a noninvasive technique that can measure cerebral blood flow (CBF). To our knowledge, there is no study that examined regional CBF of multiple sclerosis (MS) patients by using this technique. The present study assessed the relationship between clinical presentations and functional imaging data in MS using pseudocontinuous arterial spin labeling (pCASL). Twenty-seven patients with MS and 24 healthy volunteers underwent magnetic resonance imaging and pCASL to assess CBF. Differences in CBF between the two groups and the relationships of CBF values with the T2-hyperintense volume were evaluated. Compared to the healthy volunteers, reduced CBF was found in the bilateral thalami and right frontal region of the MS patients. The volume of the T2-hyperintense lesion was negatively correlated with regional CBF in some areas, such as both thalami. Our results suggest that demyelinated lesions in MS mainly have a remote effect on the thalamus and that the measurement of CBF using ASL could be an objective marker for monitoring disease activity in MS.
http://www.sciencedirect.com/science/ar ... 5X13001021

** Why was this NOT an outcomes measurement in the recent BNAC trial where they were testing 'safety' and then the minimum amount of PTA treatment required for the change in symptoms or other measurement?
It is getting to the point where egos seem to be flexing towards saying that CSF flow changes matter more than the original Franz Schelling findings and the Dr Zamboni assessment systems of reflux/back jets that are observed in MS and seen on Fonar Upright MRI.**


Nigel

[NZer1]

I think it is a good time to review some very important details about what researchers are using as yard sticks in MS research such as the BNAC 'study/trail'.
Quote
" To emphasize this critical point I have to quote Dr George Ebers, one of the
premier MS researchers in the world on this. Dr Ebers states “Clinical trials of
multiple sclerosis have been uniform in utilising invalidated outcome measures.
This has occurred to a degree to which it is difficult to find parallels in medicine in
general. It is quite clear from natural history studies that relapses have very
little if anything to do with long term outcome. Similarly, MRI measures have
been thoroughly evaluated within large datasets and found to be similarly
non-predictive for meaningful outcomes.” These are conclusions from hard
science and have to be respected and used when it comes to actions regarding
the CRAB drugs."
and
". In fact it was found those with fewer attacks progressed faster and
farther! "
http://www.direct-ms.org/sites/default/ ... c%2010.pdf

So I have to ask what was BNAC up to when they selected the criteria for their measurement system of this Trial?

WHY?

;)
Nigel

[NZer1]

And another quote from George Ebers on the problem of “widespread embracing
of dubious and poorly validated outcomes by some MS investigators, often
in contexts where there are egregious conflicts of interest, threaten
academic credibility not to mention long term professional autonomy.”

[centenarian100]

These are conclusions from hard science and have to be respected and used when it comes to actions regarding
the CRAB drugs."

Ashton Embry makes the following statement in the link that you posted: "3) The CRAB drugs do not have any effect on MS disease progression."

While it is true that copaxone has failed to meet the sustained disability endpoint in many studies, the beta-interferons have met this endpoint time and time again. Here is some data from the trials....





source: 1. PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498-1504.



glatiramer acetate decreases the risk of progression to MS after CIS:



source: "PreCISe" trial

How about the new drugs?

BG12 easily met confirmed disability...



as did tysabri...



My point is that with the exception of copaxone, there is level 1a evidence (multiple randomized blinded prospective clinical trials) favoring that MS drugs do have benefit in preventing progression of disability. There is currently no high quality evidence for the disability benefit of the liberation procedure.

With regards to presumed benefit on disability progression, Dr. Embry states that "...it is mainly based on the clinical trials which tested the effect of the drugs using frequency of MS relapse and number of new MS lesions as proxies for determining if a given drug affected progression or not"

As I have shown above, it is not based on assumptions or proxies but rather is based on actually doing EDSS measurements on blinded patients. Whether or not these modest benefits are worth the enormous cost of the drugs is a different debate, and I agree with Dr. Embry's statements such as the following:

“widespread embracing of dubious and poorly validated outcomes by some MS investigators, often in contexts where there are egregious conflicts of interest, threaten academic credibility not to mention long term professional autonomy.”

However, when he is criticizing CRAB drugs and stating that they don't do anything to prevent disability progression, he is going against several high quality and well designed studies.

[NZer1]

Thanks for the thoughts above.

What I think is the deciding factor is Time. It is well known and documented that the relapse rate and progression cannot be mapped and predicted. It is cyclical and there are factors such as stress and injury that shorten the cycle.

Any assumptions regarding DMD's are unsubstantiated by tests and stat assessments. The figures above in the graphs are proof that limiting the time capture shows one impression, if the time frame was expanded to 5-10 years you would have a more realistic picture for assessment of the theory.

That is a sad but true fact and is used and manipulated by Manufacturers to present a picture for Sales purposes rather than patient well-being!


Nigel

This study feel into my inbox just now and is a graphic of the point I make, the shorter the assessment time for DMD's the larger the assumption of their effects;
http://www.msif.org/global-ms-research/ ... trial.aspx
If you look with an open mind the statements can mean more than what is said and for that matter why it is said,
** billions of dollars drive integrity in these studies!**

[MarkW]

My point is that with the exception of copaxone, there is level 1a evidence (multiple randomized blinded prospective clinical trials) favoring that MS drugs do have benefit in preventing progression of disability. There is currently no high quality evidence for the disability benefit of the liberation procedure.

Hello Centenarian 100,
It is not either drugs or CCSVI de-stenosis. Prof Zamboni describes MS as a multifactorial disease and treats it using drugs as well as de-stenosis.
MarkW

[centenarian100]

The figures above in the graphs are proof that limiting the time capture shows one impression, if the time frame was expanded to 5-10 years you would have a more realistic picture for assessment of the theory.

Do you have any reason to believe that drugs which have unambiguous disability progression benefit over 2-3 years lose such a benefit over the very long term.

Allow me to cite one article which Dr. Embry mentions in his article:

http://msj.sagepub.com/content/15/11/1286.full.pdf+html

Source: Veugelers et al, 2009

Scroll down to page 1290 to see the graph to which he is referring which clearly shows that patients progressed to EDSS 6 slower after 1998 when the treatment program was in effect. This is statistically significant (CI hazard ratio 0.59-0.91) and even more so after adjusting for confounders (CI hazard ratio 0.35-0.55), presumably because the clinic received more subspecialty referrals after 1998.

Obviously, this is an unblinded observational study which is not a high quality study in terms of making serious claims about drug efficacy. Nonetheless, Dr. Embry misinterprets this study as being non-significant because "the 95% confidence intervals [of the time to EDSS 6 in the two groups] overlap"

Is this guy serious!? I guess all medical treatments where the bottom 5 percent of treated patients do worse than the top 5 percent of untreated patients show "no real statistical difference."

Dr. Embry is obviously a very intelligent and passionate man who has done a lot of research on MS, but it is hard for me to take him seriously when he makes statements such as this.

At the current time, there is much better evidence for even the least efficacious pharmaceuticals compared to the liberation procedure. I personally believe copaxone and beta-interferons are not very effective overall and are not changing the face of the disease, but to say that they have no effect on disability progression is simply wrong and in contradiction to large amounts of high quality evidence. The drugs have a small but measurable effect. Again, the benefit may not be worth the side effects and extraordinary cost, but that is a different debate.

[centenarian100]

By the way, please PM me if you have questions about interpreting hazard ratios, t tests, and survival curves as I am fairly knowledgeable about these topics

[centenarian100]

By the way, here is Dr. Embry's article on "new studies show the MS drugs don't slow progression" which I was criticizing:

http://www.direct-ms.org/sites/default/ ... 7%2010.pdf

[centenarian100]

It is not either drugs or CCSVI de-stenosis. Prof Zamboni describes MS as a multifactorial disease and treats it using drugs as well as de-stenosis.
MarkW

I was talking about Dr. Embry rather than Dr. Zamboni.

Here are a few quotes from Dr. Embry which suggest he does not hold this view:

"The CRAB drugs do not have any effect on MS disease progression."

"Do not use any of the CRAB drugs."

Source: http://www.direct-ms.org/sites/default/ ... c%2010.pdf

These are bold statements which I feel are not correct and against a very impressive preponderance of evidence.