PREMISE negative results

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

PREMISE negative results

Postby frodo » Mon Sep 15, 2014 2:58 am

Somehow I missed this. It looks like bad news, though now the question is why some people are responders while others are not.


http://www.ncbi.nlm.nih.gov/pubmed/24975855

OBJECTIVE:
We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072).

METHODS:
Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life.

RESULTS:
No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected.

CONCLUSION:
Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity.

CLASSIFICATION OF EVIDENCE:
This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty. This study also includes a Class IV phase 1 study of safety in 10 patients receiving the angioplasty procedure.
© 2014 American Academy of Neurology.
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Re: PREMISE negative results

Postby Cece » Mon Sep 15, 2014 4:40 am

Did you see this one? http://www.ncbi.nlm.nih.gov/pubmed/24531803
It used the same VHISS scale as the Premise study and concluded that responders have better post-procedure results on the VHISS scale than the nonresponders, at 3 months post-procedure.
The Premise study had no reduction in VHISS post-procedure in phase 2, thus they were nonresponders?
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PREMISE a flawed study

Postby MarkW » Mon Sep 15, 2014 6:56 am

Cece wrote:Did you see this one? http://www.ncbi.nlm.nih.gov/pubmed/24531803
It used the same VHISS scale as the Premise study and concluded that responders have better post-procedure results on the VHISS scale than the nonresponders, at 3 months post-procedure.
The Premise study had no reduction in VHISS post-procedure in phase 2, thus they were nonresponders?

Hello Cece,
I suggest that the non-responders on the VHISS scale have not been fully treated by venoplasty. The VHISS scale should be used to indicate if the subject was fully treated or not ie was the method successful. It is the same logic as D3. Doing some venoplasty does not mean that all CCSVI symptoms were corrected. The trial design of Premise is flawed as they are not treating subjects with a demonstrated methodology. The truly scientific study would investigate what venoplasty needs to be performed to achieve a significant response on the VHISS scale, then looking for changes in the brain (probably size changes not lesions).
The folks at Buffalo appear to have re-joined the neuro camp rather than investigating venoplasty for CCSVI with open minds.
Kind regards,
MarkW
Mark Walker - Oxfordshire, England. Retired Pharmacist. 16 years of study about MS.
CCSVI Comments:
http://www.telegraph.co.uk/news/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: PREMISE negative results

Postby frodo » Mon Sep 15, 2014 11:05 am

Cece wrote:Did you see this one? http://www.ncbi.nlm.nih.gov/pubmed/24531803
It used the same VHISS scale as the Premise study and concluded that responders have better post-procedure results on the VHISS scale than the nonresponders, at 3 months post-procedure.
The Premise study had no reduction in VHISS post-procedure in phase 2, thus they were nonresponders?


I didnt know that one. Thanks.
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Re: PREMISE negative results

Postby cheerleader » Mon Sep 15, 2014 4:04 pm

Cece's got it---Premise phase 2 did not meet its endpoint of >75% improvement in VHISS---therefore it was a failure. Still not sure how or why the conclusion can say CCSVI treatment isn't effective---when the patients weren't treated effectively. (???)

I compared the two phases of Premise head to head on my blog:
A Tale of Two Studies

Dr. Robert Zivadinov is the lead investigator in both studies.

Cine/CSF Study (phase 1)
Published in the Journal of Vascular Radiology March 2013
No publicity
Discussed at International Society for Neurovascular Disease Conference
http://www.ncbi.nlm.nih.gov/pubmed/23523158

PREMiSe Study (phase 2)
Poster/Publicity at American Academy of Neurology March 2013
Press conferences, videos, lots of news coverage all over the world.
http://www.buffalo.edu/news/releases/2013/03/021.html

Both are Venoplasty studies in mainly RRMS patients.

Phase 1--Dr. Robert Galleotti, treating IR
has worked with Dr. Zamboni for many years, has treated hundreds of CCSVI patients
an expert in venoplasty for CCSVI.

Phase 2-- Dr. Adnan Siddiqui, treating IR, relatively new to CCSVI venoplasty


Phase 1 Lower number of lesions on MRI for treated patients, less relapses.
"Improved venous parenchyma drainage" More studies are warranted! PTA is good for the brain.

Phase 2-- headlines read, Liberation Therapy may make MS worse!
Nine patients treated, showed 19 new lesions on MRI. PTA is bad.
"more sizable changes in venous outflow [were] associated with increased disease activity primarily noted on MRI," Dr. Zivadinov and his colleagues concluded.

How are we to know what to believe?
Is venoplasty helpful or harmful? Is this about experience in the treating IR?
Is this about how research is framed for the different audiences of vascular vs. neurological conferences?

Because one study shows the venoplasty for CCSVI reduces lesions, relapses and improves CSF and venous drainage---
while the other study shows the exact opposite.

http://ccsviinms.blogspot.com/2013/03/b ... march.html
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: PREMISE negative results

Postby CureIous » Sun Oct 05, 2014 2:22 pm

Zivadinov is IMO the worst thing that ever happened to CCSVI study. He's held us closer than his friends from the very start. These guys just don't get it, CCSVI is as variable and changing as the wind. Even attempting to effect an imaging study (let alone treatment studies) with fluctuating parameters, fluctuating pathologies, by preselecting particular points in time, is doomed before it begins.

Once the medical community has THAT aha moment, all bets are off. That requires too much time and patience and money up front though.

White matter lesions, pfft. Got a ton of those, big deal. Why no symptoms? Ridiculous. Using pharmaceutical study markers to assess efficacy of structural defects and/or correction thereof?
Yeah okay, why bother doing the study? Why not just write out the preordained conclusion and save the participants the headache?

How about assessing QOL and cognitive function in those who are known to have long term patency, say people writing mid afternoon posts in 95 degree heat outside 5 years post op? Lol
RRMS Dx'd 2007, first episode 2004. Bilateral stent placement, 3 on left, 1 stent on right, at Stanford August 2009. Watch my operation video: http://www.youtube.com/watch?v=cwc6QlLVtko, Virtually symptom free since, no relap
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Re: PREMISE negative results

Postby 1eye » Sun Oct 05, 2014 6:51 pm

I propose that nobody should run any more half-assed trials of CCSVI patients, or patients with CCSVI that have also been diagnosed with "MS", without following the
Recommendations for Multimodal Noninvasive and Invasive Screening for Detection of Extracranial Venous Abnormalities Indicative of Chronic Cerebrospinal Venous Insufficiency: A Position Statement of the International Society for Neurovascular Disease
.
DOI: http://dx.doi.org/10.1016/j.jvir.2014.07.024

Once these people have been properly screened, "MS"/CCSVI prevalence can be assessed, and the hard work of determining efficacy and measuring things like changes to MRI outcomes and blood biomarkers and CSF changes can proceed.
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Re: PREMISE negative results

Postby MrSuccess » Fri Oct 10, 2014 4:28 pm

I wouldn't be too quick to condem the efforts and " conflicting results " of the people
involved in CCSVI research.

I have yet to see any idea , plan or theory , acted on without masterfully manipulating
those with the power to " make it happen " .... come to believe that it was THEIR idea.

That is how it works.

I think Dr.Zivadinov is way ahead of the curve. And knows what he is doing.

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Re: PREMISE negative results

Postby 1eye » Sat Oct 11, 2014 6:03 pm

I learned this from a pike. If you want to stop the guy from trolling for a little while, bite his line in two.

International Society for Neurovascular Disease -- a lot of them have their names on this document. If you need something spelled out in minute detail, that would be the place to look. Personally, I think if you have not read this document you are blowing smoke. Read it, and then talk to me.

Zivadinov's is the first name on it.
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Re: PREMISE negative results

Postby CureIous » Sat Oct 11, 2014 7:14 pm

Iff'n I were a smart guy, and wanted to grab all the research funding I could, but at the same time was predisposed against CCSVI from the git go, well I would just keep my big fat trap shut for the time being, give a few nods in the general direction thereof, bask in the research dollars for as long as possible, then without fanfare, quietly let it die on the vine by the same study I accreted said funding for in the first place.

But that's just me, and my lesion riddled pea sized brain is incapable of grasping such concepts. Must be the brain damage. Yeah, that's it..
RRMS Dx'd 2007, first episode 2004. Bilateral stent placement, 3 on left, 1 stent on right, at Stanford August 2009. Watch my operation video: http://www.youtube.com/watch?v=cwc6QlLVtko, Virtually symptom free since, no relap
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