What to watch out for: placebo-controlled trials

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

What to watch out for: placebo-controlled trials

Postby Cece » Mon Jun 07, 2010 2:57 pm

I have been thinking about this ever since I heard about a NY doctor who is in the IRB stages for a placebo-controlled trial (but without his permission I can't say who). Thought about it some more when Dr. Sclafani mentioned that he'd been invited to join a group of doctors pulling together a randomized trial but declined. I'm guessing the trial I'd heard about and the one he mentioned are one and the same.

Then today at the Masters of MS website, I read about the 30-person Buffalo trial, which will also have a placebo group.
"Our group in Buffalo is undertaking a larger placebo-controlled trial (PTA versus a “fake” treatment) in 30 RRMS patients," Dr. Zivadinov,

http://mastersofms.com/masters_qas.php
And there was talk earlier about Dr. Dake that he too will have a placebo group when his study gets underway.

I'm trying to make a list of things to think about before joining a placebo-controlled trial:

1) how long of a trial is it...if you are in the placebo group, how long until the end of the trial...will treatment be done at that time?

2) how confident are you in CCSVI theory...the more confident, the more you should be looking for straight-up treatment to avoid the risk of not being treated...the less confident, then maybe leaving it up to chance might feel more okay...

3) how much do you typically progress in the amount of time the trial will take (if you are more likely to progress, then the risk of no treatment would seem to be higher)

4) what other options do you have, have you been able to find your way onto the lists of a doctor doing straight-up treatment or approach local doctors (if you haven't any other options, then the risk of no treatment is where you'd be anyways, and here you'd have a gambler's chance at treatment)

5) do you have insurance? (I think randomized trials are free to participants, which would benefit those who are uninsured or underinsured or anyone who is shut out from treatment due to cost)

6) would you genuinely be okay with it if you ended up in the group that does not receive the venoplasty treatment?

I'd say, let's not gamble with our health, but it's all a bit of a gamble...an educated gamble, hopefully.

I'm not looking to argue about whether placebo-controlled trials should or shouldn't be done; from all appearances, they are in the works.

For me the complexity is this: I believe randomized trials are important if we want this to be proven as quickly and completely as possible, which I very much do...but at the same time I would not sign up for one...we all have to look out for ourselves...and I worry for anyone here who does sign up for such a trial.

Dr. Sclafani's response to this awhile back was something along the lines of, who knows, maybe the placebo group will fare better than the venoplasty treatment group? ... which I guess goes back to #2 above, confidence in the treatment.
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Postby ikulo » Mon Jun 07, 2010 3:10 pm

Even if the trial is set for a long duration, it may be ended early if the placebo group gets much worse. I've read about such results before.
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Postby garyak » Mon Jun 07, 2010 3:36 pm

Placebo controls are obviously necessary for this science to be proven. Since I personally am progressing every few weeks I cannot afford the chance that I would end up in a placebo group. MSers like me are likely to be less willing to partipate especially if we have access to funds for treatment abroad.
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Postby HappyPoet » Mon Jun 07, 2010 4:10 pm

ikulo wrote:Even if the trial is set for a long duration, it may be ended early if the placebo group gets much worse. I've read about such results before.

A trial also may be ended early if the treatment group shows a highly statistically significant response... the reason being that it would be unethical to make the placebo group wait until the end of the trial before being offered the 'proven' treatment.
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Postby Cece » Mon Jun 07, 2010 5:02 pm

If we look at the results from Dr. Zamboni's treatment trial, if there had been a control-placebo group included alongside it, do you suppose those results have been big enough to stop the trial and treat the control group?
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Postby 1eye » Mon Jun 07, 2010 6:52 pm

I think you all are in the area of exit criteria. Where there is placebo, there should be a clear way to exit from the trial. Most folks have a really good idea when they have progressed. I have no problem with self-reported improvements or disease progression. The patient should be encouraged to self-report. If the treatment is efficacious, most of the placebo group will have exited and be on their way to treatment in short order. But self-assessment is not enough, and that is why I suggest the usual triumvirate of three-monthly tests: 10 M timed walk (with an attempt at a 500 M timed walk), 9-hole peg test, and PASAT. Progression criteria for these three tests should also be there, and a specific criterion for each that leads to exit. If done right, even a placebo-controlled trial can be relatively humane. Neurological examinations should be sensitive enough to detect worsening or improvement, leading to exit or further periodic retesting to determine limits of efficacy. Personally, I expect continung improvement in many cases, asymptotically toward health.
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Postby Cece » Mon Jun 07, 2010 7:05 pm

I wonder if any of those three studies have an exit strategy as you describe in place. It puts the researcher and the patient at cross purposes...I am not sure how they crunch the data if there are a large number of dropouts, particularly if they're all dropping out because they progressed? or maybe that progression is considered an end point?
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Postby eric593 » Mon Jun 07, 2010 7:12 pm

You have to remember too, the placebo group DOES experience a benefit, that's what placebo IS, even to the point of less lesions than the natural history group.

The placebo benefit for all of the CRABS was quite significant.

Have a look at the article that just came out today from Rocky Mountain MS Center on Placebo with the chart on the placebo effect for the CRABS. It's not like placebo group doesn't benefit from the experience, they too have a benefit. Hopefully, just not as great a benefit as the real procedure, otherwise the procedure has no merit:

http://www.mscenter.org/images/stories/ ... LowRes.pdf
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Postby elyse_peace » Mon Jun 07, 2010 7:55 pm

Cece -
Thank you yet again. :)
My cog/fog has great respect for your presence. :)
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Postby Cece » Mon Jun 07, 2010 9:44 pm

ok, so with the placebo effect being real (to around 30%), that is I guess a consolation prize...granted I'm coming at this quite well convinced by the CCSVI research, theory, and testimonies.

I'm with garyak, because even those of us who are relapsing-remitting instead of obviously progressing...there is research that shows gray matter damage is still going on even in times of remittance.

There are people who will choose to go into placebo-controlled trials and this is not necessarily a wrong choice...if treatment is otherwise unavailable, if they're ok with being slotted into the placebo group, if finances dictate the course of action...it's a big decision and I hope that anyone considering it has time to think it through. It is easy to fall into the gambler's fallacy and assume that getting slotted into the placebo group is for other people, not you.
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Postby eric593 » Mon Jun 07, 2010 10:02 pm

Cece wrote:ok, so with the placebo effect being real (to around 30%), that is I guess a consolation prize...granted I'm coming at this quite well convinced by the CCSVI research, theory, and testimonies.

I'm with garyak, because even those of us who are relapsing-remitting instead of obviously progressing...there is research that shows gray matter damage is still going on even in times of remittance.

There are people who will choose to go into placebo-controlled trials and this is not necessarily a wrong choice...if treatment is otherwise unavailable, if they're ok with being slotted into the placebo group, if finances dictate the course of action...it's a big decision and I hope that anyone considering it has time to think it through. It is easy to fall into the gambler's fallacy and assume that getting slotted into the placebo group is for other people, not you.


Cece,

If you are so convinced of the treatment of CCSVI ameliorating MS, then you shouldn"t have any problem being in a blinded trial. If the results of the CCSVI treated arm are overwhelmingly superior to the placebo arm, the trial will be halted in short order with everyone receiving treatment, as happens in trials where efficacy is so demonstrably superior to placebo. So you'd be treated rather soon anyway if the treatment is obviously far and away beneficial. So you shouldn't have to wait long anyway even if you get the initial placebo if treatment is as amazing as is being expressed by some.

People join blinded trials for many reasons, often simply for the desire to further research and to be a part of the process to help others. Sometimes, it's for the potential for treatment earlier than the public or if they couldn't afford it. Many reasons.

They are certainly to be commended as we wouldn't have an objective understanding of a treatment's impact without it.
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Postby NZer1 » Mon Jun 07, 2010 10:15 pm

I 'd pick people who didn't have access to the net. At least they wouldn't be second guessing or have high expectations.
People who are in the trial purely for research to benefit.
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Postby Leonard » Tue Jun 08, 2010 5:48 am

Zamboni treated 120 patients.
All of them must have had expectations, and I guess most of them improved.
After a while, some got worse.
Tests then revealed that they had restenosed.
They were treated again and improved (e.g. the heart surgeon from Northern Ireland).

What else do "they" want?
This is not a test of the effectiveness of one or the other molecule.
The rules for mechanical surgery are at least here in Europe very different.
Treat a person with a broken leg through sham surgery?
Hope that the placebo effect will then heal his leg?
They ought to be deeply ashame.

It is unethical and I can only hope that doctors will not cooperate.
Apart from that, what if the patient later on finds out that he was not helped and has detoriated further? Who can be held liable?
Will "they" let you sign a declaration with so many small letters, cleverly drafted by lawfirm?
This is unfiar, unethical etc.

The practices for testing MS medication can not be simply carried over like that.
They should think first and then speak.
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Postby eric593 » Tue Jun 08, 2010 7:38 am

These days, with other treatments available, they generally have everyone, placebo and treatment groups alike, on an existing treatment as well so that the trial does not deprive those taking part of an existing treatment. So everyone would need to be on a CRAB and its impact on health would be the same for both groups and thus the only difference between the two groups is the new treatment or placebo.

In this way, they avoid any ethical problems that would arise if one group was entirely deprived of even available treatments because they agreed to participate in the trial.
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Postby BooBear » Tue Jun 08, 2010 7:52 am

I have to say something here (and CeCe, I have no intent of hijacking your thread, but it is relevant to your topic).

What exactly are we looking to perform a clinical trial against?

We have those that think the stenosis itself is junk science. Do we try and prove that CCSVI itself is real?

Or, is the concern more that CCSVI causes or contributes to MS? If so, why do we need a double-blind trial? To me, if you acknowledge the existence of CCSVI, then go ahead and treat some MS patients and track improvement over a control group of MS patients who do not receive the treatment.

I still struggle with the notion of a double-blind, placebo trial of a surgical procedure. Do surgical procedures go through the same process as drugs do? I am not sure that is the case, but I welcome thoughts here.
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