It has been a long time since I designed or conducted a research study, in nutrition, psychology, or marketing, but I remember the principles well, of how to come up with a hypothesis, design a small study to test it, design a bigger study to ensure results were not a fluke, then design a study of a size designed to confirm that results can be replicated in the population, not just a subset of it. After listening to Dr. Paolo Zamboni's interview on CBC Radio 1, it sounded to me like he had done and was doing just that and then some with his multiple sclerosis (MS) research.
After familiarizing yourself with the literature and latest research, you come up with a hypothesis. Zamboni asked, does opening up narrowed veins, which will improve blood flow, alleviate MS, as it logically should? "My initial idea was to understand, after this discovery, what happened when you, with a simple balloon dilatation -- angioplasty is a commonly used technique -- what happen," said Zamboni. He had begun looking at MS because his wife had it. There's nothing more motivating to a researcher than a vested interest. One could say that would create bias in his research; on the contrary, he wants a cure more than any objective researcher will and will not fake results because he has to live with them.
Once you have a hypothesis, you design a single-subject research study or tiny pilot study to test the hypothesis. The pilot study usually has a small number of patients.
Zamboni set about designing a pilot study for his original research (original research is a term used to mean that no one has ever looked at a particular hypothesis before, no one has tested a particular procedure or drug before -- much research is not original but an attempt to replicate results already achieved by the original researcher -- in the research community there is a lot of jealousy from the mediocres who copy old research towards those who do original work). His procedure consisted of dilating the narrowed jugular and azygos (drains the spinal cord) veins with balloon angioplasty. Some have exclaimed that this is terribly risky. Well, the arteries are trickier vessels to work in than veins, yet angioplasty in cardiac arteries is seen as routine. So exactly how is a stent in an artery routine, and a stent in a vein risky? And as he noted, there is no drug or injection that can open a closed vein, so an operation is it. We're talking of narrowed veins here, but I think narrow minds, closed minds are the biggest menace to good health and, in particular, good research.
Normally, it's difficult to introduce randomization within a pilot study group (although subjects can be selected randomly), have controls, or make it double blind because the numbers are so small and you're still essentially just testing a hypothesis. Also, in some kinds of research, doing a sham version of the treatment is tricky. How do you mimic a stent operation in a neck vein when the ethics committee is likely to say a big "no" to subjecting individuals to the risks of an operation? (Any operation has risk. All human research is subject to vetting by an ethics committee, whose requirements I hear are going from onerous to ridiculous.) However, if it's possible, you have a small control group, keeping in mind that this early in the research a control group can also end up not being a control. So you go ahead with this small study, say 1 or 6 or 10 people. Zamboni's pilot study had a bigger sample size, way bigger.
His team conducted 120 procedures of one-hour in length, each of which costs about $5,000. His wife was the fourth person to undergo it, back in 2007, that's 3 years ago. He states that she's doing well. In addition, they never suspended a patient's MS drugs. "We do not have any evidence that treating CCSVI, you may treat the MS." So, in essence, the control group was all the people around the world with MS who were taking the same drugs but did not have the procedure.
If your study shows statistically significant results, better than the placebo effect, then you move on to a small-size replication of the single subject study. Sometimes, you may adjust the methodology and/or the kind of control group based on the results. The sample size could be up to 10 people, or if you have dramatic results over 100.
Zamboni's pilot study had dramatic results. So dramatic, he's skipping the small-size replication and moving on to the big trial.
The success of Zamboni's "liberation" procedure depended on the neurological condition. Sixty percent of the 120 had relapsing-remitting MS. After 2 and a half years, 75 percent of those have shown improvement with no more attacks and no new lesions on MRI. Furthermore -- and as a person with a brain injury, I consider this most important -- there was an improvement in the quality of life and alleviation of the chronic fatigue associated with MS. (Patients marvel over and over again at the energy surge they experience right away. Man, I want some of that. I'm amazed at how oblivious many doctors seem to be to the crippling effects of fatigue, both physically and psychologically. Zamboni is clearly not oblivious.) The other 40 percent had secondary progressive and primary progressive and were more advanced cases. Here the results were not fantastic, as Zamboni put it. Still, there was more stability, improved quality of life, and more energy; sometimes the last symptom in the progression disappeared or improved. Also in a proportion of progressives, the progression seemed to stop.
These results not only point towards further study, but also offers possibilities to refine it in the case of those with progressive disease. Zamboni shows he's no fool in the research arena when he notes this:
However, there was a setback. Within about 18 months, the benefits for the most advanced cases disappeared. But it was not a random setback. Zamboni noted: "This was associated with the occurrence of restenosis [the veins narrowed again]." As he pointed out, sometimes there needs to be a second shot, second treatment. This is not out of line with other long-standing procedures for other conditions, which are considered "routine" and certainly not for something that's new. So obviously, he'll be continuing to observe these patients if they have a second shot, to see what happens. This is how research is done: conduct and observe; refine, conduct, and observe.
"Despite those limitations [no control group and independent assessment], the results and witness of people are very strong." Given that this was a pilot study, the limitations are inherent to standard research practice. Yet "MS sufferers were really enthusiastic of this research ... [because] it makes sense. And usually MS is a mystery but CCSVI can be diagnosed and can be treated. So you know a part of your enemy." Knowing exactly what you're dealing with is so important. He's so right when he points out that knowing your enemy makes a diff.
In assessing research, I also use the logic sniff test. And it doesn't seem logical to me that having narrowed veins would have no effect on the brain, otherwise why are the veins the size they are. Nature could've made them smaller. In other words, Zamboni's hypothesis and his study make logical sense.
Having "identified an unknown factor" in MS and showing in this pilot study that opening up these two veins treats this "unknown factor". Zamboni told The Current that "the results of this pilot study was so interesting that now we are planning a randomized, controlled trial."
He's skipping the usual second stage in research, which does happen when results from a single subject or pilot study are awesome, and moving on to large trials. Before him, nobody knew of CCSVI and this terrible association with MS; nobody had observed it in a pilot study. (I guess the critical neurologists are just miffed at being trumped.) But now the world has a good base on which to design a randomized, controlled trial to create a new tool in the fight against MS. While Canadian physicians and governments -- with the exception of Saskatchewan, the pioneer of medicare -- and the Canadian MS Society dither and criticize and run in fear of original research, Zamboni is moving ahead on his large randomized, controlled trial. While the fussbudgets in Canada nitpick, the Italian works to help the sufferers.
Again, if a researcher achieves significant results -- significant meaning that the results effected a change beyond what placebo would do and either equal to or better than current treatments -- then you set up a large study, trying not to get too excited and breaking out in the snoopy dance, although that's already happened in this case all over the world. As a researcher, you select subjects randomly, have a control group (having worked out how you treat the controls based on the small research study), randomize which subjects go into the treatment group and which into the control, and do it double blind, meaning that the people who treat the subjects don't evaluate them, and those who evaluate the results don't know who is control and who is treated. It can be more complicated than that in some cases. Minimally, you'll want 100 subjects for this kind of study, just for the treated group. Ideally, way more. But, again, it depends on what you're testing. Some diseases are not that prevalent, so you wouldn't be able to achieve that kind of group size. However, that's not an issue with MS, and as we've seen, Zamboni's pilot study began with 72 people with relapsing-remitting MS and 48 with secondary or primary progressive.
There are many questions raised by Zamboni's "miracle" cure. Are narrowed veins found in the general, healthy population? Why do they not suffer the same neurological deficits as people with MS? Or will they, given the "right" exposure to a virus or bug or micro-organism of some kind that can't be drained out of the brain fast enough and given enough time for negative results to emerge? Is a lack of blood flow the sole reason for MS? How does narrowed blood flow out of the brain affect other abnormal processes going on there? Does it impair healing? Is it the interaction of lowered blood drainage with perhaps some minor injuries that sets up the deteriorating process of some kinds of MS? Does the problem of narrowed veins only manifest itself over a long period of time? What are the implications of restored blood flow for other brain issues -- I'm thinking of how every person operated on talks about the instant alleviation of fatigue, the almost-immediate gain in energy. Since fatigue is such a huge problem in the brain injury population, can increasing blood flow through the brain help to alleviate that fatigue (there are non-invasive ways to increase blood flow too, beginning with the most basic: exercise)?
The neurologists are up in arms over this incursion into their territory by a vascular guy, but Zamboni points out "We know from a lot of years that a plaque... have always a vein running in the centre of the plaque. So there is a well-known association between veins, venous system that collect into the blocked vein and the myelinating disease [of multiple sclerosis]....From first hour, we knew of vascular component in MS...unknown the reason and where this condition was...so this is not great new. The great new is to understand why the venous function is [involved]."
Even though Zamboni has only conducted a pilot study, he's already shown that research in MS from now on must include the vascular component. He estimates that to respond to the urgency that worldwide attention has put on his work, 2 to 3 years of further study will be enough. He advises that "people with not advanced disease, probably may wait for further evidences that will derive from randomized, controlled trial. But people in which neurologist declare any response to the treatment or...like primary progressive or very rapid decline with any possibility to stop, I think that this can be proposed and offered [today]."
This is pretty good. Some research takes way longer to complete, and of course only time will show the long-term effects. Two to 3 years will not be enough for that, but it will be enough to know if one can achieve even 5 years of relief.
Those who sniff that Zamboni's procedure is unproven, who refuse to offer research dollars to test it, are allowing their egos to get in the way of helping people with MS, for they couldn't possibly be that ignorant of how original research is conducted and that Zamboni has been following it well.
"We discovered an association between narrowing in the main outflow route from the brain to the heart in the veins. This condition is called chronic cerebrospinal venous insufficiency [CCSVI], and it's strongly associated with multiple sclerosis....The transit time of the blood from the brain to the heart is longer, so the drainage system of the nervous system is worsening than expected. It's a chronic condition, very slow...and inflammatory. If you don't have a good drainage of toxins or infections, viruses, etc., certainly this is not a good thing for people," said Zamboni.
After familiarizing yourself with the literature and latest research, you come up with a hypothesis. Zamboni asked, does opening up narrowed veins, which will improve blood flow, alleviate MS, as it logically should? "My initial idea was to understand, after this discovery, what happened when you, with a simple balloon dilatation -- angioplasty is a commonly used technique -- what happen," said Zamboni. He had begun looking at MS because his wife had it. There's nothing more motivating to a researcher than a vested interest. One could say that would create bias in his research; on the contrary, he wants a cure more than any objective researcher will and will not fake results because he has to live with them.
Once you have a hypothesis, you design a single-subject research study or tiny pilot study to test the hypothesis. The pilot study usually has a small number of patients.
Zamboni set about designing a pilot study for his original research (original research is a term used to mean that no one has ever looked at a particular hypothesis before, no one has tested a particular procedure or drug before -- much research is not original but an attempt to replicate results already achieved by the original researcher -- in the research community there is a lot of jealousy from the mediocres who copy old research towards those who do original work). His procedure consisted of dilating the narrowed jugular and azygos (drains the spinal cord) veins with balloon angioplasty. Some have exclaimed that this is terribly risky. Well, the arteries are trickier vessels to work in than veins, yet angioplasty in cardiac arteries is seen as routine. So exactly how is a stent in an artery routine, and a stent in a vein risky? And as he noted, there is no drug or injection that can open a closed vein, so an operation is it. We're talking of narrowed veins here, but I think narrow minds, closed minds are the biggest menace to good health and, in particular, good research.
Normally, it's difficult to introduce randomization within a pilot study group (although subjects can be selected randomly), have controls, or make it double blind because the numbers are so small and you're still essentially just testing a hypothesis. Also, in some kinds of research, doing a sham version of the treatment is tricky. How do you mimic a stent operation in a neck vein when the ethics committee is likely to say a big "no" to subjecting individuals to the risks of an operation? (Any operation has risk. All human research is subject to vetting by an ethics committee, whose requirements I hear are going from onerous to ridiculous.) However, if it's possible, you have a small control group, keeping in mind that this early in the research a control group can also end up not being a control. So you go ahead with this small study, say 1 or 6 or 10 people. Zamboni's pilot study had a bigger sample size, way bigger.
His team conducted 120 procedures of one-hour in length, each of which costs about $5,000. His wife was the fourth person to undergo it, back in 2007, that's 3 years ago. He states that she's doing well. In addition, they never suspended a patient's MS drugs. "We do not have any evidence that treating CCSVI, you may treat the MS." So, in essence, the control group was all the people around the world with MS who were taking the same drugs but did not have the procedure.
If your study shows statistically significant results, better than the placebo effect, then you move on to a small-size replication of the single subject study. Sometimes, you may adjust the methodology and/or the kind of control group based on the results. The sample size could be up to 10 people, or if you have dramatic results over 100.
Zamboni's pilot study had dramatic results. So dramatic, he's skipping the small-size replication and moving on to the big trial.
The success of Zamboni's "liberation" procedure depended on the neurological condition. Sixty percent of the 120 had relapsing-remitting MS. After 2 and a half years, 75 percent of those have shown improvement with no more attacks and no new lesions on MRI. Furthermore -- and as a person with a brain injury, I consider this most important -- there was an improvement in the quality of life and alleviation of the chronic fatigue associated with MS. (Patients marvel over and over again at the energy surge they experience right away. Man, I want some of that. I'm amazed at how oblivious many doctors seem to be to the crippling effects of fatigue, both physically and psychologically. Zamboni is clearly not oblivious.) The other 40 percent had secondary progressive and primary progressive and were more advanced cases. Here the results were not fantastic, as Zamboni put it. Still, there was more stability, improved quality of life, and more energy; sometimes the last symptom in the progression disappeared or improved. Also in a proportion of progressives, the progression seemed to stop.
These results not only point towards further study, but also offers possibilities to refine it in the case of those with progressive disease. Zamboni shows he's no fool in the research arena when he notes this:
"We need more cases and to create a progression curve for the different patients to be sure of what we observed in the pilot study [with regards to stoppage of the progression in progressive MS]."
However, there was a setback. Within about 18 months, the benefits for the most advanced cases disappeared. But it was not a random setback. Zamboni noted: "This was associated with the occurrence of restenosis [the veins narrowed again]." As he pointed out, sometimes there needs to be a second shot, second treatment. This is not out of line with other long-standing procedures for other conditions, which are considered "routine" and certainly not for something that's new. So obviously, he'll be continuing to observe these patients if they have a second shot, to see what happens. This is how research is done: conduct and observe; refine, conduct, and observe.
"Despite those limitations [no control group and independent assessment], the results and witness of people are very strong." Given that this was a pilot study, the limitations are inherent to standard research practice. Yet "MS sufferers were really enthusiastic of this research ... [because] it makes sense. And usually MS is a mystery but CCSVI can be diagnosed and can be treated. So you know a part of your enemy." Knowing exactly what you're dealing with is so important. He's so right when he points out that knowing your enemy makes a diff.
In assessing research, I also use the logic sniff test. And it doesn't seem logical to me that having narrowed veins would have no effect on the brain, otherwise why are the veins the size they are. Nature could've made them smaller. In other words, Zamboni's hypothesis and his study make logical sense.
Having "identified an unknown factor" in MS and showing in this pilot study that opening up these two veins treats this "unknown factor". Zamboni told The Current that "the results of this pilot study was so interesting that now we are planning a randomized, controlled trial."
He's skipping the usual second stage in research, which does happen when results from a single subject or pilot study are awesome, and moving on to large trials. Before him, nobody knew of CCSVI and this terrible association with MS; nobody had observed it in a pilot study. (I guess the critical neurologists are just miffed at being trumped.) But now the world has a good base on which to design a randomized, controlled trial to create a new tool in the fight against MS. While Canadian physicians and governments -- with the exception of Saskatchewan, the pioneer of medicare -- and the Canadian MS Society dither and criticize and run in fear of original research, Zamboni is moving ahead on his large randomized, controlled trial. While the fussbudgets in Canada nitpick, the Italian works to help the sufferers.
Again, if a researcher achieves significant results -- significant meaning that the results effected a change beyond what placebo would do and either equal to or better than current treatments -- then you set up a large study, trying not to get too excited and breaking out in the snoopy dance, although that's already happened in this case all over the world. As a researcher, you select subjects randomly, have a control group (having worked out how you treat the controls based on the small research study), randomize which subjects go into the treatment group and which into the control, and do it double blind, meaning that the people who treat the subjects don't evaluate them, and those who evaluate the results don't know who is control and who is treated. It can be more complicated than that in some cases. Minimally, you'll want 100 subjects for this kind of study, just for the treated group. Ideally, way more. But, again, it depends on what you're testing. Some diseases are not that prevalent, so you wouldn't be able to achieve that kind of group size. However, that's not an issue with MS, and as we've seen, Zamboni's pilot study began with 72 people with relapsing-remitting MS and 48 with secondary or primary progressive.
There are many questions raised by Zamboni's "miracle" cure. Are narrowed veins found in the general, healthy population? Why do they not suffer the same neurological deficits as people with MS? Or will they, given the "right" exposure to a virus or bug or micro-organism of some kind that can't be drained out of the brain fast enough and given enough time for negative results to emerge? Is a lack of blood flow the sole reason for MS? How does narrowed blood flow out of the brain affect other abnormal processes going on there? Does it impair healing? Is it the interaction of lowered blood drainage with perhaps some minor injuries that sets up the deteriorating process of some kinds of MS? Does the problem of narrowed veins only manifest itself over a long period of time? What are the implications of restored blood flow for other brain issues -- I'm thinking of how every person operated on talks about the instant alleviation of fatigue, the almost-immediate gain in energy. Since fatigue is such a huge problem in the brain injury population, can increasing blood flow through the brain help to alleviate that fatigue (there are non-invasive ways to increase blood flow too, beginning with the most basic: exercise)?
The neurologists are up in arms over this incursion into their territory by a vascular guy, but Zamboni points out "We know from a lot of years that a plaque... have always a vein running in the centre of the plaque. So there is a well-known association between veins, venous system that collect into the blocked vein and the myelinating disease [of multiple sclerosis]....From first hour, we knew of vascular component in MS...unknown the reason and where this condition was...so this is not great new. The great new is to understand why the venous function is [involved]."
Even though Zamboni has only conducted a pilot study, he's already shown that research in MS from now on must include the vascular component. He estimates that to respond to the urgency that worldwide attention has put on his work, 2 to 3 years of further study will be enough. He advises that "people with not advanced disease, probably may wait for further evidences that will derive from randomized, controlled trial. But people in which neurologist declare any response to the treatment or...like primary progressive or very rapid decline with any possibility to stop, I think that this can be proposed and offered [today]."
This is pretty good. Some research takes way longer to complete, and of course only time will show the long-term effects. Two to 3 years will not be enough for that, but it will be enough to know if one can achieve even 5 years of relief.
Those who sniff that Zamboni's procedure is unproven, who refuse to offer research dollars to test it, are allowing their egos to get in the way of helping people with MS, for they couldn't possibly be that ignorant of how original research is conducted and that Zamboni has been following it well.
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