UK small trial planned - Dr Hunter

[Cece]

http://clinicaltrials.gov/ct2/show/NCT0 ... svi&rank=6

It's a small study with 6 pwMS in a treatment group and 6 in a control group. Looking at functional changes after venoplasty.
Here is their plan to get around the ethical challenges of having a sham group:

A common concern raised is the ability to prevent any possible placebo effect and like any other clinical trial should offer a sham procedure to a matched control group. The difficulty with this option are the ethical issues associated with an invasive sham treatment and also the practical issues of masking a potentially painful treatment such as venoplasty. Another option is to use dependent measures that are unaffected by motivational or psychological influences which avoids any placebo effect issue. One such dependent measure is motor unit firing behaviour whilst contracting at a submaximal target force. Typically clinicians have used this to manage motor disorder patients but have used cumbersome invasive technology that can only measure a few motor units with limited accuracy. However, De Luca et al recently developed a high density surface electromyographic (HDsEMG) system that can measure 30-40 motor units with 92-97% accuracy. From this it has been proposed as a highly effective tool for evaluating efficacy of therapeutic interventions for upper motoneuron disorders such as MS.

Can CCSVI venoplasty be expected to have an effect on 'motor unit firing behavior while contracting at a submaximal target force'?

It's listed again in the methods:

Methods
•
Four (first two to establish baseline variability of measures) repeat visits to the laboratory at University of Stirling to establish neuromuscular measures:
1.HDsEMG pre and post tetanic induced fatigue
2.Muscle fibre conduction velocity as previously described (Hunter et al., 2011)
3.Ultrasound for CCSVI determination on visits 1 and 3
4.DEXA scans for alterations in body composition on visits 2 and 4

•With the use of accelerometers monitor free living activity on days 0-7 and 9-42 (post venoplasty).

They've also got nonambulatory as the only exclusion criteria.

Not sure what to think. I am not familiar with the measurement tool for muscle fibre conduction velocity. Does that measure a CCSVI symptom or an MS symptom? If only six patients are undergoing treatment, what are the odds that they'll get super-responders like Tilt, and what are the odds that they'll get nonresponders? It's a small sample size.

[1eye]

Not to worry before the barn door is closed, or something... But it does sound like promising technology.

[Cece]

some previous work by Dr Hunter:
http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract

Surface EMG characteristics of people with multiple sclerosis during static contractions of the knee extensors

Summary
Objectives:  This study was designed to determine whether any alterations existed in surface electromyography (sEMG) in people with multiple sclerosis (MS) during isometric contractions of the knee extensors.

Methods:  Fifteen people with MS and 14 matched controls (mean ± SD age and body mass index 53·7 ± 10·5 versus 54·6 ± 9·6 years and 27·7 ± 6·1 versus 26·5 ± 4, respectively) completed 20%, 40%, 60% and 80% of their maximal voluntary contraction (MVC) of the knee extensors. sEMG was recorded from the vastus lateralis where muscle fibre conduction velocity (MFCV) and sEMG amplitude (RMS) were assessed. Body composition was determined using dual-energy X-ray absorptiometry and physical activity with the use of accelerometry.

Results:  People with MS showed significantly (P<0·05) faster MFCV during MVC (6·6 ± 2·7 versus 4·7 ± 1·4 m s−1) and all submaximal contractions, while RMS was significantly (P<0·05) less (0·11 ± 0·03 versus 0·24 ± 0·06 mV) in comparison with the controls. MVC along with specific thigh lean mass to torque, rate of force development and mean physical activity were significantly (P<0·01) less in PwMS.

Conclusion:  People with MS have elevated MFCV alongside reduced RMS during isometric contraction. This elevation in MFCV should be accounted for when interpreting sEMG from people with MS.

[MarkW]

The work at Sterling is in conjunction with EHC. MarkW

[CureOrBust]

I do not understand how this test is better at weeding out the placebo effect than an MRI?

[MarkW]

Not to worry before the barn door is closed, or something... But it does sound like promising technology.

The barn door is wide open in the UK for CCSVI research. It is called IPG420 from NICE. The NICE guideline does not require a sham arm in a UK trial.............MarkW

[MarkW]

I do not understand how this test is better at weeding out the placebo effect than an MRI?

MRI does not correlate changes in the MS brain with MS disability (find meta data analysis if you do not accept my words). So this test could measure a change in pwMS after a de-stenosis procedure for CCSVI syndrome.
MarkW

[Mossmanor]

So...what is wrong with a sham treatment arm? The PREMiSe trial by the University at Buffalo Neurosurgery & BNAC is testing 20 people, all get catheter venograms with IVUS, and 10 also get venoplasty. Among a battery of other tests, all of which are the most extensive I have ever received in 10 years after MS dx. I will be there today for my 1 year follow-up exam. I truly do not know which arm of the study I am in. I'd prefer to find out I was in the sham arm, as I have seen no positive change since my procedure. So hope is still alive!

I feel any risk I have undertaken in minimal, the neurosurgeons involved are world class, the follow up care is terrific.

The payoff in research is worth my risk. I would feel far more at risk in a drug trial where the side effects are unknown, and even less is known about long term effects.

[tiltawhirl]

So...what is wrong with a sham treatment arm? The PREMiSe trial by the University at Buffalo Neurosurgery & BNAC is testing 20 people, all get catheter venograms with IVUS, and 10 also get venoplasty. Among a battery of other tests, all of which are the most extensive I have ever received in 10 years after MS dx. I will be there today for my 1 year follow-up exam. I truly do not know which arm of the study I am in. I'd prefer to find out I was in the sham arm, as I have seen no positive change since my procedure. So hope is still alive!

I feel any risk I have undertaken in minimal, the neurosurgeons involved are world class, the follow up care is terrific.

The payoff in research is worth my risk. I would feel far more at risk in a drug trial where the side effects are unknown, and even less is known about long term effects.

I appreciate your willingness to be one of the pioneers on the patient side of the equasion. I also hope you got the sham procedure since you haven't seen any benefits, and that the real deal will give you symptom relief. Thanks for updating the community!

tilt

[1eye]

The PREMiSe trial by the University at Buffalo Neurosurgery & BNAC is testing 20 people, all get catheter venograms with IVUS, and 10 also get venoplasty.

It being a randomized, placebo-controlled, prospective trial, I hope they filed the right paperwork with the FDA.

[Cece]

The work at Sterling is in conjunction with EHC. MarkW

And they are experienced and use ivus. Great news or reminder if I happen to have known and forgotten about this one.

Mossmanor, BNAC's trial is a good one, and it's good to know that the risks felt acceptable to you, your doctor, and your doctor's IRB! There is the concern about an invasive procedure for a patient who is not getting the treatment (what if something went wrong??) or the need to unnecessarily sedate patients who are getting the procedure to blind them to whether they had it or not. And the practical logistics: neck soreness alone might give it away, although not every patient reports neck soreness afterwards. These days I am in favor of randomized controlled trials, with whatever design passes the IRB, since we need to make progress on getting CCSVI treatment universally accepted as legitimate.

And I agree about drug trials. Some of them are really scary.

If Dr. Hunter's muscle fibre conduction velocity can measure improvements when patients have physical therapy or rehab, then perhaps it will work as a measurement of physical improvements after ccsvi venoplasty. I'm eager for the results.

[CureOrBust]

And the practical logistics: neck soreness alone might give it away, although not every patient reports neck soreness afterwards.

I once talked to a research assistant that was recruiting for a trial that had an arm using the test medication, another on Rebif and the placebo arm on saline solution. I scoffed at how it could be blinded as to who had Rebif and who was on saline because of Rebifs' side effects. She said I would be surprised how many people on saline solution had Rebif like side effects.

The sore neck could also be attributable to the investigative side, if it was explained to them as such.

[1eye]

I once talked to a research assistant that was recruiting for a trial that had an arm using the test medication, another on Rebif and the placebo arm on saline solution. I scoffed at how it could be blinded as to who had Rebif and who was on saline because of Rebifs' side effects. She said I would be surprised how many people on saline solution had Rebif like side effects.

This is the beginning and end of the science proving placebo effect exists, is it? Yes, I would be surprised. I think people who believe that nocebos and placebos go hand-in-hand merrily around every research trial, well I guess you can fool some of the people all of the time. You should have demanded numbers. Or somebody should have. I can't believe all the hokum I hear in support of some unmeasurable, pseudo-scientific poppycock used to justify so many medical 'proofs'. I'm sorry, but unless somebody shows me a placebo, I will deny its existence.

The sore neck could also be attributable to the investigative side, if it was explained to them as such.

The more intelligent among them (or the more dubious, which in the case of placebo amounts to the same thing) will strongly suspect the lie.

[1eye]

So...what is wrong with a sham treatment arm? The PREMiSe trial by the University at Buffalo Neurosurgery & BNAC is testing 20 people, all get catheter venograms with IVUS, and 10 also get venoplasty. Among a battery of other tests, all of which are the most extensive I have ever received in 10 years after MS dx. I will be there today for my 1 year follow-up exam. I truly do not know which arm of the study I am in. I'd prefer to find out I was in the sham arm, as I have seen no positive change since my procedure. So hope is still alive!

I'll give you strong odds you are. It is not hope. I have had the procedure, and unless you are not at all like me you were in the sham arm. That's how I knew in the MBP8298 trial that either the 'drug' didn't work or I was on saline. It turned out both were true. My disability progressed significantly. That is not monitored, due to 'diagnose and adios', unless you complain to the doctor that 'hey I need a wheelchair now'. You can withdraw, but that won't stop the trial. Yes hope is still alive but like many before you may have been duped into being on nothing, because some doctors thought they could prove something.

I feel any risk I have undertaken in minimal, the neurosurgeons involved are world class, the follow up care is terrific.

Unless you have been given a sham, and during that year you have joined the 'SPMS' crowd. I think it inhuman to say placebo is not more risky than angioplasty.

The payoff in research is worth my risk. I would feel far more at risk in a drug trial where the side effects are unknown, and even less is known about long term effects.

To be honest the same is true of this procedure. Fortunately you have the uncounted many who have already had it to prove safety except to the idiots at the FDA and elsewhere. The payoff we will have to see. I hope it stops a few barking dogs.

It is not true that sedation is unethical. Especially if you have consented already to having a catheter in your veins. Which has been proven safe, maybe safer than general anaesthetic, but we are all adults, aren't we? Valium is the least of our worries.

[MarkW]

So...what is wrong with a sham treatment arm? The PREMiSe trial by the University at Buffalo Neurosurgery & BNAC is testing 20 people, all get catheter venograms with IVUS, and 10 also get venoplasty.

There is nothing wrong with a sham treatment arm for a trial Mossmanor if it is really sham treatment. In the PREMiSe trial you describe the untreated people have a catheter and IVUS passed through their veins. This could rupture a septum or web or open a sticky vein valve so you get unintentional treatment on some of untreated arm of the study. Also the treated arm of the study needs to show that all instances of stenoses are treated. A sham trial of CCSVI syndrome is highly unlikely to be valid.
NICE UK listened to these arguments and removed the requirement for a sham trial, which was placed in the discussion document (at the behest of Neuros?). UK trials by Sterling/EHC must be robust and controlled not double blind, a big difference.
MarkW