Embry: Actual data from PREMiSe suggests CCSVI is of value

[cheerleader]

It is essential to compare the data from phase 1 and phase 2-- Because that's exactly what BNAC does in their poster.
It is apples to apples. Dr. Siddiqui did all of the venoplasty. It was done in Buffalo. People had a diagnosis of CCSVI. They were treated with venoplasty. And the poster says this:
• In phase 1 (Figure 1), there was significant improvement of VHISS (p<0.0001) over 6-months that resulted in >75% restoration of the venous outflow compared to baseline.

• In phase 2, improvement was observed also in treatment (p=0.02) and sham (p=0.04) arms at month 1 but did not reach >75% restoration of the venous outflow compared to baseline. No differences in VHISS improvement were detected between phase 2 treated and sham groups (p=0.894).

It does not matter what any of us think. It matters what the research shows. Hopefully, there will someday be a paper to go along with this poster. Until then,
cheer

[NZer1]

Thanks Joan.
It opens all sorts of thoughts, especially when you ask what flow was achieved by BNAC compared with a normal person when studies show the MS patients have less flow than normals?

The planning of how to choose patients must be a challenge, do you pick from MS criteria or CCSVI criteria?

Are patients chosen for consistency in the treatment required? For example two patients having a valve issue at the same position in one jugular and therefore you are working on equal footing, or are you looking at purely total flow in individual veins which may have multiple or complex problems and therefore outcomes that require two stages of treatment to be able to say the treatment is complete and achieved the desired flow?
If one treatment is used for the purpose of the trial when two or more were said to be proven more successful, are trials actually the way to go? Or should the specific treatment such as for a fixed valve issue only be compared, rather than the flow rate or percentage improvement from a one time PTA through a specific vein?

Complex reasons for having the trial and I guess the link to symptom improvements is the final goal of trials of this type.
Define the cause of symptom improvement with the appropriate test measures?
Design the tests that will define an improvement?
Define the flow improvement required to create improvements?
Define the time frame that improvements need to have occurred?
Decide which disease to use as the trial focus?
Decide which symptom to focus on?

All these criteria will end up being to define if Insurance or Governments will pay the cost!

;)

[centenarian100]

Interesting thread.

special kudos to scut for several good points. You can't just disregard a study because you don't like the results. Everyone has bias. Maybe Dr. Zamboni wants to be famous for a paradigm-shifting discovery. Maybe some interventionalists want to cash in on a lucrative procedure. Maybe we all want to believe that morbidity from MS will decrease by 90% in the next 5 years due to venous procedures. I sure do.

check out this video series:

do you really think that these people are biased AGAINST CCSVI? Really?

The reality is that it is extremely common for hyped treatments to fail miserably in randomized blinded trials.

Here are some vascular examples...

Percutaneous intervention for stable angina in coronary artery disease has no mortality benefit or myocardial infarction prevention benefit (COURAGE trial: http://www.slideshare.net/theheartorg/c ... evaluation)

endovascular thrombecomy revealed no benefit in acute stroke when added to standard therapy (IMS3 trial: http://bmctoday.net/evtoday/2013/01/art ... conference)

Who would have thought!? Correcting a stenosis in the coronary arteries doesn't prevent heart attacks!? But we know for sure that atherosclerosis in the coronary arteries causes heart attacks...and these procedures are relatively safe!

Taking out the clot in the relevant artery within five hours of an acute stroke doesn't improve outcome measured by a blinded observer at 3 months!? How could that be!?

Most clinical trials for novel treatments are failures. Treatments which seem intuitive and reasonable sometimes don't work. Did the trial fail because restoration of venous flow was insufficient? Maybe so. Maybe not. It definitely leaves some questions unanswered.

Dr. Zivadinov and Dr. Siddiqui recommend more larger blinded randomized trials.

Hopefully large enough so that people won't whine about a single treated patient who did particularly poorly in their nonsense a posteriori analysis.

In the mean time, they recommend against excessive treatments outside of a clinical trial. They think that liberation should not be considered the standard of care for MS but that it still holds some promise and that we should attempt to learn more. I agree.

[Robnl]

Is it stupid to say: Phase 1 & 2 treatments were alike, but in Phase 1 the dilation was more thorough??
a.k.a. look at the differences in results between all the ccsvi-centers??

[cheerleader]

Is it stupid to say: Phase 1 & 2 treatments were alike, but in Phase 1 the dilation was more thorough??
a.k.a. look at the differences in results between all the ccsvi-centers??

it's not stupid, Robni...but the answer is, we really don't know why phase 1 and phase 2 results in correcting VHISS were so different, and it's anyone's guess. Until we have a full paper, it's just shots in the dark. The poster does not clarify the difference. It's not about liking or disliking scientific results, or comparing this to other PTA trials, it's about using all the information on the poster.
VHISS--Venous Henodynamic Insufficiency Severity Score, is a measurement BNAC created, to show how badly CCSVI was affecting blood flow.

BNAC compares phase 1 and phase 2 on their poster. And phase 2 patients did not have their VHISS corrected. In fact, their VHISS improvement was the same in the untreated arm of the trial. That doesn't sound very successful.

• In phase 1 (Figure 1), there was significant improvement of VHISS (p<0.0001) over 6-months that resulted in >75% restoration of the venous outflow compared to baseline.

• In phase 2, improvement was observed also in treatment (p=0.02) and sham (p=0.04) arms at month 1 but did not reach >75% restoration of the venous outflow compared to baseline. No differences in VHISS improvement were detected between phase 2 treated and sham groups (p=0.894).

full paper ahead--
cheer

[centenarian100]

VHISS--Venous Henodynamic Insufficiency Severity Score, is a measurement BNAC created, to show how badly CCSVI was affecting blood flow.

Does anyone know the criteria for VHISS?

[cheerleader]

VHISS--Venous Henodynamic Insufficiency Severity Score, is a measurement BNAC created, to show how badly CCSVI was affecting blood flow.

Does anyone know the criteria for VHISS?

yes, it's a scoring system based on Zamboni's original doppler criteria

Here is the BNAC paper which used VHISS---
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462121/

The five VH criteria evaluated are: Criterion 1) reflux in the IJVs and/or in the VVs assessed in both sitting and supine postures, Criterion 2) reflux in the deep cerebral veins (DCVs), Criterion 3) B-mode detection of stenoses in the IJVs in the form of annuli, webs, septa, or malformed valves, Criterion 4) absence of ECD signal in the IJV and/or in the VVs, even after forced deep breaths, and Criterion 5) presence of a negative difference in the cross sectional area (CSA) of the IJV.
The severity of CCSVI was measured by VHISS, as previously reported [3]. VHISS is based on the sum of pathologic parameters measured for each of the 5 criteria examined. VHISS is ranging from 0 to 16.

As expected, VHISS was significantly higher for MS patients diagnosed with CCSVI (Mean±SD: 4.20±1.4) than for subjects without CCSVI (Mean±SD: 1.28±1.0; p<.001 from a Mann–Whitney test). Table2 gives the distribution of VHISS for the MS disease groups. The MS disease groups (p<0.001, Kruskall-Wallis) significantly differed in VHISS.

Here is the patient-friendly outline of the PREMiSe trial, in pdf form.
http://www.bnac.net/wp-content/uploads/ ... 7-2011.pdf

One marker of PREMiSe was "restoration of venous outflow to 75% or better to normal proximal venous diameter and resolve pressure gradient and flow disruption." page 29 That did not happen in phase 2, and the lack of change in VHISS scores reflect this.
cheer

[centenarian100]

The graph of VHISS (scroll to page 6; http://www.direct-ms.org/sites/default/ ... 202013.pdf) is very unusual

I wonder what the explanation is for the discrepancy between phase I and phase II. The baseline data look very similar, and I presume that the criteria were unchanged. It could be that there was some bias introduced into phase I because it was known that all of the participants were treated. I would like to learn more about the methodology VHISS

Embry's criticism of the baseline characteristics is totally reasonable. The sham arm had a lower recent relapse rate: 0.4 vs 1 in the last year and a higher duration on DMT (81.5 vs 47.4). There were also more women in the sham group. This kind of thing happens in an n= 20 study.

I don't really buy Embry's accusation that Dr. Siddiqui may have "purposely did a poor job so as to ensure those receiving angioplasty would not have normal blood flow restored and would not have a better result than the patients in the sham group."

Would he deliver the same type of skepticism if the trial had heavily favored liberation treatment?

I also like how he claims that he is an "objective scientist" when the entire paper is heavily slanted against the trial an involves biting vitriol and accusations of outright fraud.

[centenarian100]

The five VH criteria evaluated are: Criterion 1) reflux in the IJVs and/or in the VVs assessed in both sitting and supine postures, Criterion 2) reflux in the deep cerebral veins (DCVs), Criterion 3) B-mode detection of stenoses in the IJVs in the form of annuli, webs, septa, or malformed valves, Criterion 4) absence of ECD signal in the IJV and/or in the VVs, even after forced deep breaths, and Criterion 5) presence of a negative difference in the cross sectional area (CSA) of the IJV.
The severity of CCSVI was measured by VHISS, as previously reported [3]. VHISS is based on the sum of pathologic parameters measured for each of the 5 criteria examined. VHISS is ranging from 0 to 16.

Thanks

[centenarian100]

Further, I wonder what throwing out the one outlier who had 8 new lesions would do to Dr. Zivadinov's statement?

I can roughly estimate this by taking out the worst data point in the treatment group...

For cumulative # of T2 lesions:

Sham arm (10 pts):

mean new T2 lesions: 0.3; SD 0.7

Treatment arm (9 pts): mean new T2 lesions: 2.1; sd 2.9.

Taking out the one patient with 8 new T2 lesions in the treatment arm, the adjusted mean would be (9(2.1) -8)/8 = 1.3625

Obviously, this is still worse than the sham arm, but the difference would be less dramatic, and the p value would be larger.


For T2 lesion volume change


Sham group mean change: -4.7

Treatment group mean change: 13.9

adjusted treatment group mean change: (9(13.9)-45./8 = 9.9125 (still worse than sham)


For contrast enhancing lesion number

Sham group mean: 0.3

treatment arm number : 2.4

adjusted treatment group mean number (9(2.4)-9)/8) = 1.575 (still worse than sham)

-------------

That patient obvious had a significant effect, but s/he wasn't entirely driving the fact that this is a negative study. You can't just throw out outliers in clinical trials. Even if his/her results were the result of some kind of complication, they still should count in the trial. That is what happens in real-world clinical medicine-complications sometimes negate benefits of otherwise beneficial procedures.

Maybe he would have removed or softened the "may worsen disease activity" part of the statement if it weren't for that patient.

[cheerleader]

Thanks

sure. I think Dr. Embry's anger may come from the fact his charity gave $125,000 to PREMiSe, and as we've noted:
• In phase 1 (Figure 1), there was significant improvement of VHISS (p<0.0001) over 6-months that resulted in >75% restoration of the venous outflow compared to baseline.
• In phase 2, improvement was observed also in treatment (p=0.02) and sham (p=0.04) arms at month 1 but did not reach >75% restoration of the venous outflow compared to baseline. No differences in VHISS improvement were detected between phase 2 treated and sham groups (p=0.894).

No mention of this discrepancy has been noted outside of Dr. Embry's write up or online patient forums like TIMS.
it's a problem,
cheer

[ScutFarkus]

I think Dr. Embry's anger may come from the fact his charity gave $125,000 to PREMiSe,

Interesting. So, had the results been positive, I assume we'd have to accuse the researchers of blatant pro-CCSVI bias due to all that cash from "big-CCSVI". I jest, of course!

and as we've noted:
• In phase 1 (Figure 1), there was significant improvement of VHISS (p<0.0001) over 6-months that resulted in >75% restoration of the venous outflow compared to baseline.
• In phase 2, improvement was observed also in treatment (p=0.02) and sham (p=0.04) arms at month 1 but did not reach >75% restoration of the venous outflow compared to baseline. No differences in VHISS improvement were detected between phase 2 treated and sham groups (p=0.894).

No mention of this discrepancy has been noted outside of Dr. Embry's write up or online patient forums like TIMS.
it's a problem

I don't understand why you claim that this discrepancy was not noted, right after you quote the poster where it clearly notes the discrepancy. Unless I'm really confused about the sources, what you quote above is from the poster presented by BNAC, as included in Appendix 1 of Embry's rant. Or are you complaining that this wasn't noted in press releases? Honestly, I didn't pay much attention to those, since the press tends to mangle "sciency" stuff pretty badly, so I don't know what they did or didn't say there. But I do know that news coverage of science items, especially the headlines, is generally horrendous and often gets things completely backwards. Here's an interesting article I just found on this topic: http://www.nature.com/embor/journal/v7/ ... 00862.html

Also, you took me to task for suggesting we can't compare Phase 1 with Phase 2. What I mean is that we cannot (meaningfully) compare them the way Embry does, e.g. treating Phase 1 like the treatment arm of a study, and Phase 2 as the placebo controls, and then conclude the treatment improved symptoms. That's pure speculation. But we can absolutely look at the clearly noted differences in VHISS scores and wonder what caused them. It seems reasonable to expect the treatment groups in Phase 1 and Phase 2 would have similar responses to treatment. That said, since the groups were selected using different criteria, we can't draw firm conclusions about why this discrepancy exists (specifically, it's grossly premature and inappropriate to claim bias, fraud, or surgical incompetence). Hopefully the final paper will shed more light on this.

/Scut

[ScutFarkus]

Thanks all,
I do understand the outcomes, my point has always been the same, WHY design a trial the way they have?

The trial design is very typical for evaluating a medical intervention, as far as I can tell. You might check out a few other published medical trial results, and I think you'll see that the most robust studies tend to have similar designs (small unblinded Phase 1 for safety, then somewhat larger Phase 2 that is randomized, double-blinded and placebo controlled).

I wonder why in Phase 2 there was a constraint on the treatment that it was only to achieve a maximum of 50% improvement, no more?

I'm pretty sure the 50% VHISS improvement in Phase 2 was not intentional. I'd imagine there was a fair bit of head-scratching when the researchers were finally allowed to analyze the data.

The safety research concept as a stand alone Phase 1 and not inclusive part of the entire trial appears to be an expensive waste of money available and potential for finding a deeper understanding, when the task is performed anyway.
If 75% gives one outcome, why was 75% chosen and not any other figure to experiment with the safety concept?

Again, I think they do the surgery, and then measure the VHISS improvement, hoping to achieve the 75% threshold.

Regarding the Phase 1 portion of the trial, this safety trial was almost certainly required (by the University, or by the FDA, I'm not sure). You cannot ethically do a trial to see how effective a procedure is until you have demonstrated that the procedure is safe. BNAC doesn't make these rules, but they do have to play by them. Now, back in the good old days (ahem!) before these rules were in place, you could just round up some prisoners or patients from the free clinic, and go right into a big effectiveness trial. That saved money, but had some horrendous outcomes. Be thankful that's forbidden now, even if sometimes the new rules seem wasteful.

And in Phase 2 50% tops is used with differently selected patients from Phase 1, it gives a purposeful impression OR it gives an impression that separate theories were being tested.
Were the researchers united in both the trial stages or was there complete separation of Phase 1 and Phase 2 projects?

Again, Phase 1 and Phase 2 trials have different goals. To make the Phase 2 results (where you compare outcomes between groups), you want the people in the two groups to be as similar as possible at the start. So you use very restrictive enrollment criteria. But those strict criteria make it hard to get enough patients, so for Phase 1 you use more relaxed criteria. I beleive this is also very typical.

Could the trial have been planned differently and achieved more CCSVI understandings if there had been more progression of treatment stages with the same criteria for patient selection and then the safety finding would have been based on boarder knowledge of degrees of risk with percentage of resizing, blinded or not.

I don't entirely follow what you're suggesting, but keep in mind that there is a standard, well established way to organize trials. If you deviate from that design, it makes it more likely that your results will not be trusted by other scientists (getting these things right is hard), and that in turn likely makes it harder to get funding. So researchers have good reasons to stick to tried and true study designs.

In fact, I believe the reason people were so excited about this study is precisely because it was the first to use the "gold standard" of study designs: the randomized, double-blind, placebo controlled study.

The safety understanding would have evolved with trial and outcome in Phase 2 rather than selecting a set figure Phase 1 with no other criteria and saying one percentage was safe on 10 subjects that were picked by 'xyz' screening?

No, you can't do that. You want as many people as possible in Phase 2, but it's not ethical to submit a large group of people to a treatment whose safety hasn't been demonstrated (according to some specific requirements).

What percentage and criteria will be chosen for Phase 3, will it match Phase 2 in some regard and what is the purpose of the patient picking criteria with a disease with an unknown disease progression?

You should read up on clinical trials. There will be no Phase 3. Those terms, e.g. "Phase 1" and "Phase 2", have specific meanings specified by the FDA for medical trials. See http://en.wikipedia.org/wiki/Phase_1_clinical_trial

My favourite question,
WHY? WHY? WHY?

My favorite answer: Google it!

/Scut

[NZer1]

ScutFarkus I see you use the mindset to discredit anything that I ask rather than see that there is logic in what I ask.
The outcome of the recent BNAC trial which has been done to the sets of standards that you require upheld has created the responses from Direct MS and The Hubbard Foundation in writing and of course there is the many, many debates happening around the Globe regarding personal opinions.
The Youtube link that centenarian100 placed on this thread shows the intention of BNAC to publicly be communicative where possible and also to be transparent on a previous study. This appears to have changed for this Phase 1 and Phase 2 study.

My questions lists are not about following the general pattern of past Studies in Research, my questions are why have they made this 'pair' of studies more expensive and separate from each other which causes incongruence in the task. Also why have they chosen figures for PTA outcomes and criteria for patients without explanations or data to show the purpose through outcomes. This makes a huge difference to the value of the outcomes knowledge and the ability to learn from the study in a broad context. Whether Phase 1 is blinded or not makes no difference when you want to understand what the 75% flow change choice is about. If you then chose less than 50% for the next Phase with different patient criteria you skew the outcome of a potential learning curve, making it worthless other than to say that "less than 50% flow improvement will not improve the measurements used to assess if there was changes from having the treatment".

Expensive way to prove that under treating won't benefit the patient and will be at huge cost and waste of a persons time, and energy, therefore causing stress, and probable disease flare!

Is there literature on MS that shows what criteria to use when choosing Trial patients, literature or relevance to lesion activity, type/classification of MS as two simple questions on the methodology BNAC has used. The methodology must have reason or it would not apply.

Thinking out side the box you live in opens up the World for greater experiences and purposes!

Thanks again Joan I see why Franz Schelling often refers that, Head banging on Walls as tiresome!
;)
Nigel

[ScutFarkus]

ScutFarkus I see you use the mindset to discredit anything that I ask rather than see that there is logic in what I ask.

OK, fine, I give up. I was sincerely trying to be helpful in my reply to your post, and I thought the tone was friendly, but it's clear that what we have here is a failure to communicate.

/Scut