How can we design a trial to test efficacy of the surgery?

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

Postby thisisalex » Tue May 11, 2010 12:53 pm

here you can take a look at the kuwait treatment's methodology. What they measure before and after... trying to measure unmeasurable things like fatigue....
http://www.ccsvikuwait.com/uploads/all%20tables.pdf
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Postby fogdweller » Tue May 11, 2010 4:14 pm

Here are some measures of MS disease that might be used for trials to asses MS disease from research out today:

progressiona: http://www.ncbi.nlm.nih.gov/pubmed/20437181

meaningful measure of disability: http://www.ncbi.nlm.nih.gov/pubmed/20421572

Health related Quality of Life: http://www.ncbi.nlm.nih.gov/pubmed/20421570

All could be used, and if any were was statistically significant you could claim the treatment was justified
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Postby Billmeik » Tue May 11, 2010 4:41 pm

you know maybe the only time something like the sci-am study idea would work is in Canada now. People are so desperate for liberation they'll sign on to a half and half deal. I think that's an answer.
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Postby se1956 » Tue May 11, 2010 11:19 pm

May be the combination of my recent proposal and the sci-am idea would be better:


1st step: 50% liberation - 50% get a placebo liberation
2nd step: Every patient calculates his MSIS value every week
3rd step: Control checkup every (2-3) month(s) (Doppler/MRV?)

The patient doesn't know the results of the controls and the physician doesn't get the MSIS-values.

4th step: After 12 month, on unblinding:

- the group with liberation shows clear improvements but these improvements often vanish
- the vanishing curve and the restenosis curve should have similar shape

It is important to include some type of restenosis monitoring, because it will mask the positive effects.
I think, in the future stents will become the "Gold Standard".

R.
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Re: Use restenosis as controls

Postby frodo » Wed May 12, 2010 2:47 am

Cece wrote:
frodo wrote:The only ethically possible way to have controls is to use the restenosis cases as such.

I think however that everyone who feels better and then restenoses is immediately aware of feeling worse and quite desperate to get the procedure done again.


Well, the procedure could be changed to prevent this behaviour. As soon as anybody feels bad, he goes back to the doctors performing the study. They check his veins and fix them in case of restenosis. Then the number of visits with and without restenosis are counted.

Finally the conclusion would be probably that people with restenosis is more likely to go back complaining. Enough to prove that blood flow affects health in MS patients, and enough to request universal treatment.
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Postby Billmeik » Wed May 12, 2010 5:12 am

you know I think the sci am idea is great but something ptients might be able to pull off on their own would be proving restenosis causes ms attacksl.

I saw an add on tv last night for a prenatal ultrasound for $50 and it would have to be cheap because you need one every day. When the ms attack happens you need dated images to show you already had restenosis.

Just 3 patient that prove this would be an interesting paper.

So would 20 people with before and after mri's to be compared.
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Postby frodo » Wed May 12, 2010 11:01 am

Billmeik wrote:you know I think the sci am idea is great

What is the sci am idea?
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Postby fogdweller » Wed May 12, 2010 3:25 pm

se1956 wrote:1st step:

50% liberation - 50% get a placebo liberation

R.


I still don't know how one could possibly do a placebo liberation. The angioplasty involves an incision, running a catheter from the incision (probably in the shoulder, maybe in the groin) up past the stenosis, inflating the balloon, rechecking the flouroscope to make sure the stenosis had resolved, removing the catheter and closing the incision. Generally done with the patient awake but under sedation.

How would you convincingly fake this, without acting unethically? I think sedation and incision on a patient not getting any treatment would be unethical, much less running a catheter through the veins.

I am not sure about that. Does anyone KNOW if informed consent would allow this?
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Postby Billmeik » Wed May 12, 2010 5:09 pm

I think what is unethical is not liberating anyone ever. If it takes a test like this to get rolling make it so!
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Postby Billmeik » Wed May 12, 2010 8:13 pm

I still don't know how one could possibly do a placebo liberation



full anaesthesia on all patients

1 doc who does bedsides stuff doesn't know who is liberated.

1 doc who does the liberation.


leave a small scar on everyone and shave em.
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Postby NZer1 » Thu May 13, 2010 1:02 am

I believe that the restenosis that the patient notices is some of the key here. It indicates that placebo doesn't currently exist and retesting will support that. This is also proof that the treatment works if the patient knows they have regressed.
If the changes that treatment made can be measured then you have a tool for overcoming the placebo debate.
Now taking the opposite angle, could the symptoms be recreated in another patient who is CCSVI free. That is to say to recreate the same style/type of stenosis that on the treatment table created immediate improvements for a CCSVI treated patient.
This may open a nest of possibilities and provide some insights. It most likely will show the variety of outcome that the blocked veins can create and the effects of time will be even more interesting.
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Postby frodo » Thu May 13, 2010 1:53 am

NZer1 wrote:I believe that the restenosis that the patient notices is some of the key here

The patient does not feel the restenosis. Only can feel its effects. That's why it can be used as control

NZer1 wrote: It indicates that placebo doesn't currently exist and retesting will support that.

Do you refer to the placebo effect or to the possible placebo group in a trial? Placebo effect exists and always has to be considered.

NZer1 wrote: This is also proof that the treatment works if the patient knows they have regressed.
If the changes that treatment made can be measured then you have a tool for overcoming the placebo debate.

If we count restenosis vs. non-restenosis among the people that regressed we will have prove that wrong venous flow affects health among MS patients.

NZer1 wrote: Now taking the opposite angle, could the symptoms be recreated in another patient who is CCSVI free. That is to say to recreate the same style/type of stenosis that on the treatment table created immediate improvements for a CCSVI treated patient.
This may open a nest of possibilities and provide some insights. It most likely will show the variety of outcome that the blocked veins can create and the effects of time will be even more interesting.

Are you proposing to create artificial MS in patients? Obviously is completely unethical. About creating MS in animals is a problem because we are the only two-legs mammal, and we have a special neck area. This will probably will make difficult to reproduce the effect in other animals. Besides animals cannot tell you how they feel and the lesion presence that could be found in them is not the whole story about CCSVI.
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Study Methods

Postby MarkW » Thu May 13, 2010 8:44 am

I have not designed clinical trials but have reviewed many trials. CCSVI and MS are difficult to study as RRMS varies in an untreated but statistically normal MS population. I suggest that using cross over trial design would be useful. How about de-stenosis and CBT (Cognitive Behavioural Therapy) ?? Also we need to find a short term change after de-stenosis, maybe look at 'purple feet' and measure temperature or blood flow. Fatigue is measurable, using techniques employed by Clinical Psychologists for investigating Chronic Fatigue Syndrome.
I am not convinced that re-stenosis is a valid control group. We need to measure re-stenosis rates over time in an open label or cross over study to know how often to check CCSVI.
Interesting topic, it requires some 'outside the box' thinking.
Kind regards,
MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Study Methods

Postby fogdweller » Thu May 13, 2010 9:07 am

MarkW wrote:CCSVI and MS are difficult to study as RRMS varies in an untreated but statistically normal MS population.

Also we need to find a short term change after de-stenosis, maybe look at 'purple feet' and measure temperature or blood flow. Fatigue is measurable, using techniques employed by Clinical Psychologists for investigating Chronic Fatigue Syndrome.

Interesting topic, it requires some 'outside the box' thinking.
Kind regards,
MarkW


I think RRMS even varies within the same subject...relapses for a couple years then free of relapses for a couple years. This makes weeding out the random behavior even tougher.

A short, immediate change after de-stenosis would be nice, but I fear that instead we will need to follow the test patients for a long time or use a huge number of test subjects. Also the fact that the symptoms vary from patient to patient is a confounding issue. For example, I do not have purple feet, or heat sensitivity, or even the sort of fatigue that seems to be what people are discussing. So if we were using that as the measure, I would be useless. Plus people change over time and also learn to adapt to problems. I have less fine motor co-ordination problems now than I have at some times.

You are right, a real headache to design some test!! Even MRI lesions are not real indicative of debility.
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Postby CureIous » Thu May 13, 2010 9:52 am

fogdweller wrote:
Billmeik wrote:I guess if the patients were under full sedation during the angio?


You would also have to make an incision. I think the risk, even slight, of placing a patient under anesthesia and making an incision when you know you are not going to treat would be unethical.

However, I am not sure. Could informed consent allow this? If so that could be an anwer!!


That's precisely how Stanford is proposing to structure their study. The patient won't know if the balloon was fully inflated or not. All patients post-study that were in the "non-inflated" category will then have the option of getting the real deal. Simple and eloquent.
Mark
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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