bootstrap trial design

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

bootstrap trial design

Postby Cece » Thu Oct 10, 2013 1:10 pm

http://multiple-sclerosis-research.blog ... udies.html
"As you can see in this picture the original daclizumab trial was an open-label study, i.e. everyone gets treated with daclizumab and you simply count the number of gadolinium-enhancing lesions on MRI before and after treatment with daclizumab to assess whether or not the treatment is effective. At the end of the study the MRI images are assessed blind by a radiologist and the number of enhancing lesions are counted. This is called a bootstrap study. The MRI experts have now developed well defined protocols with power calculations, which allows us to use this type of study in early proof-of-concept studies. They are called bootstrap studies as MSers cross over from a period of observation to active treatment and they are not necessarily blinded. Bootstrap proof-of-concept studies are typical for academic or investigator-led studies because they are relatively cheap to perform (~$1.0-1.5M). Industry on the other hand prefers to do parallel double-blind placebo-controlled studies, which cost about 5-10x more. The table below is from the article that gives the numbers of MSers needed in these studies to get enough power to test whether or not a drug is effective or not."

We have talked about the need for randomized controlled trials but those are expensive and difficult to control. Perhaps what we need are more bootstrap trials where the patient is aware of the treatment but there is a blinded assessment at the end. The blinded assessment would have to be of the CCSVI, not the MS, wouldn't it? Anyway it seems there is a precedence in neurology for levels of evidence that are lower than RCT but still evidence.
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Re: bootstrap trial design

Postby MarkW » Mon Oct 14, 2013 12:29 pm

Hello Cece,
An open label trial is essential for balloon venoplasty as we both know that you can feel the balloon being inflated. I convinced NICE in the UK that a double blind placebo controlled trial was not possible (see their guidance). The neuros want impossible trials so that we cannot show balloon venoplasty helps pwMS. I have never heard of bootstrap trials in published papers but it is a good name for what we need.
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: bootstrap trial design

Postby frodo » Mon Oct 14, 2013 11:24 pm

MarkW wrote:Hello Cece,
An open label trial is essential for balloon venoplasty as we both know that you can feel the balloon being inflated. I convinced NICE in the UK that a double blind placebo controlled trial was not possible (see their guidance). The neuros want impossible trials so that we cannot show balloon venoplasty helps pwMS. I have never heard of bootstrap trials in published papers but it is a good name for what we need.
Kind regards,
MarkW


That is true, but nature helps in this problem. As some of the treated patients re-stenose, every re-stenosis can be treated as a control for the study. I don't understand why they don't do it this way.
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Showing Balloon Venoplasty helps pwMS

Postby MarkW » Tue Oct 15, 2013 7:25 am

Hello Cece,
This meta-analysis shows that brain atrophy correlates with disabilty in MS. If an open label study showed that balloon venoplasty reduces brain atrophy that means balloon venoplasty benefits pwMS. No need for an impossible double blind trial................
Kind regards,
MarkW
=======================================================
Ann Neurol. 2013 Sep 5. doi: 10.1002/ana.24018. [Epub ahead of print]
Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis.
Sormani MP, Arnold DL, De Stefano N.
Source - Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy.
Abstract
Objective To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in Relapsing-Remitting Multiple Sclerosis (RRMS). Methods We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints: disability progression (defined as 6 or 3 months confirmed 1-point increase in the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Results: 13 trials including more than 13500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated both with treatment effects on brain atrophy (R2 =0.48, p=0.001) and on active MRI lesions (R2 =0.61, p<0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R2 =0.75, p<0.001) and both variables were retained as independently related to the treatment effect on disability progression. Interpretation: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the two MRI measures predict the treatment effect on disability more closely when used in combination. ANN NEUROL 2013. © 2013 American Neurological Association.
Copyright © 2013 American Neurological Association.
PMID: 24006277 [PubMed - as supplied by publisher]
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: bootstrap trial design

Postby MarkW » Tue Oct 15, 2013 7:31 am

frodo wrote:
MarkW wrote:Hello Cece,
An open label trial is essential for balloon venoplasty as we both know that you can feel the balloon being inflated. I convinced NICE in the UK that a double blind placebo controlled trial was not possible (see their guidance). The neuros want impossible trials so that we cannot show balloon venoplasty helps pwMS. I have never heard of bootstrap trials in published papers but it is a good name for what we need.
Kind regards,
MarkW

That is true, but nature helps in this problem. As some of the treated patients re-stenose, every re-stenosis can be treated as a control for the study. I don't understand why they don't do it this way.

Hello Frodo,
Treatment failures (re-stenosis) are not usually considered a control in science. Also if you accept Dr S's view (I do) then re-stenosis is usually due to sub-optimal initial treatment.
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: bootstrap trial design

Postby Cece » Wed Oct 16, 2013 7:53 am

Back when Dr. Siskin's trial was cancelled, there was mention of a possible bigger US trial in the making. Does anyone know anything about this? I would like to see a trial initiated that meets our high standards around here. (Treatment includes use of IVUS in diagnosis, experienced investigator, allowed to seek out stenosis and not look only at predetermined spots, left renal vein included in investigation, high pressure balloons used carefully with IVUS measurements so as to minimize potential vein damage, outcome measurements specific to CCSVI, any restenosis gets retreated, proper anticoagulation is used, any control group is a short-term control such as 6 months, any untreatable outflow obstructions such as hypoplastic jugulars means disinclusion from the study.)
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Re: bootstrap trial design

Postby CureOrBust » Thu Oct 17, 2013 2:31 am

There are medications that can make you forget what you experience during a procedure. Someone previously on this board had a treatment where he was told by the treating physician that he begged him stop due to the pain from ballooning. But, the patient had absolutely no memory of the procedure.

There was a belief that maybe the doc ballooned the wrong vein, and hence all the pain.
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Re: bootstrap trial design

Postby Cece » Thu Oct 17, 2013 8:44 am

But those medications that make you forget can have adverse effects of their own. Ethical concerns?

Ballooned the wrong vein? The collaterals can look as if they're the jugular but the IR only has to follow the "jugular" all the way to the dural sinus. Ballooning a collateral vein can lead to that collateral vein being injured, and there you are, worse off than you started. And this is by a well-intentioned IR with probably a reasonable amount of experience, and mistakes are still made. I am so sad about the current lack of strong trials underway.
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