secretive Canadian clinical trial green-lighted

[Cece]

http://www.theprovince.com/health/clini ... z1sijrfwmn

Federal Health Minister Leona Aglukkaq says the government will fund a clinical trial for "liberation treatment," an experimental vein therapy for multiple sclerosis developed by an Italian doctor.

The MS Society of Canada, a co-funding partner of the project, said it's "thrilled" by the announcement that may bring answers about the controversial treatment developed by Dr. Paolo Zamboni.

The trial is subject to an ethics approval in Canada in "a way that balances our hunger for innovation and research with respect for dignity of human life," Savoie said.

The government is withholding the names of the researchers and institutions involved in the project "to protect the independence" of the ethics review, according to CIHR.

The trial is greenlighted by the government but not yet by the ethics review, if I understand this right. And the researchers and institutions involved are being kept secret to protect the independence of the ethics review? What are they concerned about? Media articles? Us? Will they be giving us all the details once the ethics review is done? We already agreed a few years ago here that the ethics of sham trials were questionable, and that CCSVI patients are savvy and difficult to sham. But it may be the fastest way to prove the efficacy of angioplasty for congenital venous malformations of the jugulars.

If they are withholding the names of researchers and institutions involved, can we assume that there are researchers (plural) and institutions (plural) involved? Putting the multicenter in multicenter prospective randomized controlled trial?

[PointsNorth]

Sounds like a bunch of indignant neuros using public funds to design a trial which will ultimately disprove all dissenters wrong. With the full support of the venerable MS Society of course. I think we need to mobilize our friends with other CCSVI-related conditions to push some buttons.

I will join a few forums where I think I will have some street-cred.

[Cece]

Imagine if Mark Freedman were involved in the CCSVI trial. I could see the incentive in keeping that quiet.

[MarkW]

A trial of any CCSVI procedure cannot be fully randomised as patients can feel if the are having a balloon inflated or not. I agree with PointsNorth this sounds like a neuro scheme. Unless the trial design is subject to open review then it will be meaningless.
MarkW

[tiltawhirl]

There will be nothing secretive about me submitting my receipts to the gov upon my return next week. ;)

tilt

[1eye]

Given the Conservatives' shameful performance with Kirsty Duncan's bill, which can only mean they are unquestionably in the pockets of the likes of Serono and other shady operators, and given the gutting of the CBC, closing their Radio Drama unit -- I am inclined not to give them the benefit of the doubt. So I won't. It would take too much suspension, of too much disbelief, but nothing can be done about them until election time. We should be glad we still have that questionable power. The problem is, in a democracy, as Hunter Thompson said, the people get the government they deserve. Let's hope we even still have a democracy.

Dr. Sclafani has pointed out that randomized trials are unethical because the patients should not be asked to risk placebo.. To be really sure, opponents are saying, you would have to take them off other DMDs they might be on. That in itself is probably unethical, given that that might deprive them of the only benefit they get from interferons: the placebo effect. Even then it would have to be pretty clearly not a remission, and I don't know how you could tell, especially on those who are still expected to have them, occasionally. (Isn't that argument still applicable to the DMD trials? What if those in the interferon and other drug trials who benefited, were really only having remissions?)

It is only possible to make this trial bulletproof if the subjects are put to sleep. That requires an anesthetist, and they are expensive. You could probably get Dr. Code. The guy who did my gall-bladder operation anesthesia said I would be on ten different drugs, at different times. Finding volunteers will not be difficult, if the researcher is someone trustworthy. Anyway I have to wait, so I wait.

[MarkW]

To be ethical a trial has to use all subjects already on DMDs and leave them on the DMDs (Prof Zamboni did this in an early trial) or have subjects who are not on DMDs. It is not ethical to put people to sleep unless it is medically required. Trial design for surgical procedures is very complex, probably the reason that NICE did not give details of the research required.
I agree with Prof Sclafani (title used at SIR 2012), randomised trial are unethical, especially when many trials are patient funded. Hence trial design is vital.
MarkW

[Cece]

http://www.globalregina.com/federal+gov ... story.html

Now, the federal government has made another step towards their own trial here at home. A research team has been chosen and is now awaiting approval by an ethics committee.

“Once the approval has been given, which we don't expect will take too long, the funding can be released and the researchers can begin their work which we expect to begin in the fall of this year,” explained Tom Lukiwski, Member of Parliament for Regina Lumsden-Lake Centre.

The national study is co-sponsored by the MS Society of Canada who have donated half a million dollars to phase one and two of the trial.

“Phase one trials are really to determine safety,” said Janet Nicolson with the Saskatchewan branch of the MS Society of Canada. “We have seen cases across the world where people who’ve gone for CCSVI, Liberation Therapy, have seen complications with that and we really want to minimize that risk if this procedure is approved in Canada.”

So they are beginning with phase one, to determine safety?
I am pretty well versed in complications and there are things that can be done to minimize complications:
1 - use IVUS to diagnose stenoses and determine sizing of balloons
2 - prescribe true anticoagulants, and not antiplatelets along like aspirin or Plavix, post-procedure
3 - do not exceed vein size by more than about 10% when ballooning
4 - keep duration of ballooning short to minimize time that the vein is cut off from its own blood supply but repeat if necessary
5 - use high pressure balloons only if properly sized according to the measurements of the vein as measured by IVUS
6 - have a one-month doppler ultrasound to check for clotting; and if clotting is found, have a second procedure to manually remove clot
7 - hypoplasias can be left alone due to their likelihood of clotting if treated
8 - avoid perforations of the veins by using a softer guidewire, backing off quickly, and going slow
9 - do not compress the femoral vein entry point excessively hard or for too long, as clots can happen there
10 - keep stent use to a minimum, when absolutely necessary, which should be less than 5% of the time
11 - treat patients locally to better facilitate follow-up care
12 - in the upper jugular, do not balloon stenoses against bone, because it can damage the vein against the bone
13 - do not stent a physiological narrowing, where if it expands, the stent can migrate
14 - do not begin the trial with a doctor who has treated fewer than fifty patients, because there is a learning curve to the procedure
15 - exercise extra caution if the patient has a clotting disorder
16 - what did I miss?

[1eye]

I think various arguments are made against the CCSVI. Placebo, remission, and DMDs are the main ones, I think, used to explain improvements. Remission seems like a kind of Catch-22. I don't see how CCSVI can be thoroughly "proven", except on people who are not expected to have remissions ('SP'' and 'PP'). They don't use DMDs as a rule, either. Then what you are doing is testing its efficacy in promoting remission where none was expected. That actually is what happened to me. I know that 'RR' patients have persistent symptoms which don't usually remit. Should we only accept remission of those, if the patient is 'RR', given they were not expected to improve?

Phase II will likely not be a trial of the procedure's efficacy on CCSVI, using only bloodflow testing, as Dr. Sclafani does it.. It will be a full-bore test of the efficacy of the procedure for CCSVI to treat 'MS': lesions, disability, debilitating symptom, aphasia, cognition, the whole enchilada. Perhaps it should first be acknowledged by the research community, that CCSVI does happen, and causes problems, which can be understood, and happens in others too, not just pw'MS'. If the procedure is shown to be effective at treating problems that are not being caused by something that is undoubtedly 'MS', in people who have not had a diagnosis of 'MS', the procedure that treats these symptoms can be approved as a precaution or palliation, by people who just want their veins to get, and stay, healthy. pw'MS' are just the ones who need it most.

[MarkW]

Hello 1eye,
Below is the process I prepared for NICE(UK) for percutaneous venoplasty. Step F is six months old and needs updating (more veins included). My method is high level of the actual process. You need to decide if you are going to offer pre/post procedure guidance.
The first question is 'what is the trial testing ?' CCSVI is not an realistic answer.
Good luck,
MarkW

Leading practice comes largely from the USA, with unpublished findings (personal communications) developing at a rapid pace. I continue to monitor these communications and share my understanding, hopefully to improve NICE’s guidance:
A – Entry is best made through the saphenous vein rather than the femoral vein. This reduces the patient’s risk of a thrombosis in the femoral vein. Local anaesthesia is used. The puncture site is compressed manually at the end of the procedure, which is generally more successful than if the femoral vein was used.
B – A guide tube (called catheter tube in UK, sheath in USA) is advanced through the heart into the superior vena cava. The tube remains in place during the procedure and catheter, balloons and intravascular ultrasound (IVUS) are introduced, removed, and re-introduced many times through the tube.
C – Diagnosis of CCSVI syndrome requires the use of both catheter venography and intravascular ultrasound (IVUS). Latest research shows that some problems are missed if catheter venography is used alone.
D – Treatment is largely confined to venoplasty of vein valves in leading practice, which follows Prof Zamboni’s recent paper. This reduces, probably eliminating, vein dissection and vein rupture. This area requires future research before any CCSVI syndrome treatment procedure is finalized.
D - Correct sizing of the balloon in relation to the vein value being treated is best evaluated using IVUS. Pressure in the balloon of up to 20 atmospheres may be required, although lower pressure of up to 5 atmospheres is often sufficient.
E - Recording the valve or vein with IVUS, pre and post venoplasty, permits assessment of the outcome of each intervention.
F – Diagnosis of CCSVI syndrome must include major veins in the neck and trunk. CCSVI invasive diagnosis and/or treatment has included vena cava, transverse & dural sinuses, with internal jugular, azygous, hemi-azygous, iliac, and left renal veins, also being investigated.
Mark Walker
12th October 2011
--------------------------------------------------------------

[1eye]

Dr. Zamboni had end points. Here I see a procedure that doesn't even say how we will know what we're looking at. Researchers want to know why, as well as what. This sounds like an all-inclusive fishing trip. Or will they just tell us when we get there?

[MarkW]

Dr. Zamboni had end points. Here I see a procedure that doesn't even say how we will know what we're looking at. Researchers want to know why, as well as what. This sounds like an all-inclusive fishing trip. Or will they just tell us when we get there?

Yes 1eye, research and diagnosis can be described 'like a fishing trip'. Unless interventionalists have read Prof Zamboni's review paper then they would not know Prof Zamboni's description of stenoses, webs septums etc. I would expect any interventionalist to have studied Prof Zamboni's work before considering research or diagnosis or 'going fishing'.
1eye you said "Dr Zamboni had end points". I don't understand what you mean.
Research means looking for stenoses (what) using a stated method (how) in named veins (where). The results are what is found or not. Discussion may include attempts to answer 'why'. Most CCSVI syndrome papers are weak in the 'why' area. Neuro papers conclude 'we did not find flow problems so CCSVI does not exist and does not cause MS'. I call that junk science, which makes me very popular.
I wrote a list of questions on another thread. We still need the 'where' and 'how' answered, provided everyone accepts Prof Zamboni's definition of 'what are stenoses'.
Reaseach is slow, which is why I advocate 'treating the symptom of stenoses' before completing the research programme.
MarkW

My simple series of questions on 'CCSVI syndrome' asks:
Who, When, What, Where, How. The final 'why' is left until the first five are answered.

1 - WHO has CCSVI syndrome? - pwMS (all/many/most?) and which other diseases ?
2 - WHEN is CCSVI syndrome seen? at birth? at diagnosis? 5/10 years after MS diagnosis?
3 - WHAT is seen in CCSVI syndrome? stenosis of vein valves? webs/septums? restricted veins?
4 - WHERE is CCSVI syndrome found? veins involved?
5 - HOW is CCSVI syndrome seen? Screening test by? full diagnosis requires (tools+methods)?
When the above are fully answered then:
6 - WHY does CCSVI syndrome develop ? Not important for patients but usually the focus for reseachers.

My NICE submission was guidance on 'How is CCSVI syndrome seen?'

[Cece]

I love the work and activism you've put into this.

A – Entry is best made through the saphenous vein rather than the femoral vein. This reduces the patient’s risk of a thrombosis in the femoral vein. Local anaesthesia is used. The puncture site is compressed manually at the end of the procedure, which is generally more successful than if the femoral vein was used.

This one is Dr. Sclafani's technique. I have not heard any of the other IRs pick up on it. It seems logical because we are likely to repeat procedures over a lifespan of managing our venous malformations and this protects the femoral vein from injury. If the saphenous vein is injured, it is of less consequence. Using the saphenous instead of the femoral might be minor in comparison to some of the more major differences in technique, such as doctors not checking the left renal vein.

D – Treatment is largely confined to venoplasty of vein valves in leading practice, which follows Prof Zamboni’s recent paper. This reduces, probably eliminating, vein dissection and vein rupture. This area requires future research before any CCSVI syndrome treatment procedure is finalized.

Septums too. Dr. Fox's autopsy study found more septal abnormalities than valvular abnormalities. I am curious about this because we don't hear much talk about septums or about how the treatment of a septum differs than a valve. Septums may be more resistant to treatment. 'Intraluminal abnormalities' would be a more encompassing term than vein valves for this point. And vein dissection and rupture can be due to overaggressive ballooning such as oversizing or excessively long or repeated balloonings. I believe this can happen as easily at the area of the valves as anywhere else in the vein. They have always been treating the area of the valves, even if they did not know it was the valves that they were treating.

D - Correct sizing of the balloon in relation to the vein value being treated is best evaluated using IVUS. Pressure in the balloon of up to 20 atmospheres may be required, although lower pressure of up to 5 atmospheres is often sufficient.

In Dr. Sclafani's abstract on high pressure balloons, the range went as low as 4 atms, which surprised me. I do not think 5 atms is sufficient for most of us.
http://www.ccsvicare.org/outreach_update03.html
His conclusions were that high pressures are required to completely dilate the lesions of CCSVI and that IVUS reduces the risk of vein injury.
And who wants incomplete dilation of the lesions of CCSVI or vein injury.

[1eye]

It is not ethical to put people to sleep unless it is medically required.

While the medical necessity doctrine is used routinely to justify non-payment of insurance claims, no-one would deny a newborn the use of anesthetic for circumcision, based on necessity. There the decision is often in the hands of the parents, although the anesthesiologist (and the doctor) are within their rights to decide ahead of time not to participate. For a CCSVI trial, I think a case could be made for both necessity and a high benefit/risk ratio, when the use of anesthetic helps prove efficacy. Here I think the belief is that the intervention may improve on other methods, and anesthesia is seen as the only way to prove that. I think patients will be eager to give their informed consent. Note that it also helps prove necessity for future patients.

[MarkW]

While the medical necessity doctrine is used routinely to justify non-payment of insurance claims, no-one would deny a newborn the use of anesthetic for circumcision, based on necessity. There the decision is often in the hands of the parents, although the anesthesiologist (and the doctor) are within their rights to decide ahead of time not to participate. For a CCSVI trial, I think a case could be made for both necessity and a high benefit/risk ratio, when the use of anesthetic helps prove efficacy. Here I think the belief is that the intervention may improve on other methods, and anesthesia is seen as the only way to prove that. I think patients will be eager to give their informed consent. Note that it also helps prove necessity for future patients.

I submitted these comments to NICE on 20th Sept 2011: - Trials comparing venoplasty against sham is a research dream. Real life patient experiences, including my own, report that balloon venoplasty (inflation of the balloon) is felt during treatment. In some cases pain is reported and local pain killers (eg Fentanyl via catheter) are used. Heavy sedation of patients in order to facilitate a sham trial would place trial subjects under increased risk, due to the sedative drug. I doubt that heavy sedation of patients would be accepted by any UK ethics committee and it is certainly not in the best interests of the trial subjects (people with Multiple Sclerosis).

I am confident of the situation in the UK but it could be different in Canada.
MarkW