Interview: Dr Rebecca Spain – AAN Meeting 2016

AMERICAN ACADEMY OF NEUROLOGY (AAN) MEETING 2016

INTERVIEW WITH DR REBECCA SPAIN – OREGON HEALTH AND SCIENCES UNIVERSITY (OHSU), VA PORTLAND HEALTH CARE SYSTEM

BD: Brett Drummond, MStranslate
RS: Dr Rebecca Spain, OHSU

BD:  Welcome everyone today to our MStranslate interview with Dr Rebecca Spain.  Dr Spain is joining us from the American Academy of Neurology conference that is currently being held in Vancouver, Canada.  Dr Spain is an MS researcher from the Oregon Health and Sciences University, as well as the VA Portland Health Care System.  Thanks for joining us today Dr Spain.  I wonder if you would mind just starting by giving us a little introduction to yourself and the work that you have been doing.

RS:  Ok, well I’m a neurologist and I’m fellowship trained in multiple sclerosis and I joined the faculty at OHSU and the Portland VA about 8 years ago.  The work that I’ve been doing is based on research from Dr Dennis Bourdette’s laboratory, he is the chairman at OHSU and one of the co-directors of the MS Center of Excellence West, part of the Portland VA system.  So, he has been studying the effects of lipoic acid, an oral antioxidant, in the animal model of MS and found that it reduced inflammation and conferred some neuroprotection in this animal model.  He and Dr Vijay Yadav also looked at blood levels of lipoic acid and came across a dose that compared well with the effective doses in the mouse model.  They also found that it was safe and tolerated in people with MS.

So based on this foundation work, I conducted an interventional trial, a randomised, placebo-controlled trial, of lipoic acid, particularly in a secondary progressive population.  Now there really are no effective treatments to slow the course of secondary progressive MS right now and so, this is an area that I would really like to focus my research on.  So we conducted a 96 week interventional trial of lipoic acid, 1200mg daily versus placebo – we had 51 participants in the study, 27 were on lipoic acid and 24 were on placebo.  We had only 5 dropouts during the study, which is a very good retention in a study.  Overall, the medication was safe and tolerated.  Now our primary outcome for the study was to look at whole brain atrophy.  This is currently the gold standard outcome measure in a progressive MS trial and so this is what we used for our primary outcome for lipoic acid.  At the end of 96 weeks, there was a significant reduction in brain atrophy in the lipoic acid group, it was highly statistically significant and so we fulfilled our primary outcome.

We also looked at clinical measures as well, the neurologic exam, walking speed, quality of life and cognition.  The study was really too small to fully answer the question whether or not lipoic acid provided any clinical benefit, however, there was a trend towards improved walking speed in the people on lipoic acid and fewer falls in the people on lipoic acid.  So it’s possible that with a larger study, we would be able to determine if there was a clinical benefit, as well as the reduction in whole brain atrophy.  So, we were quite excited by this outcome and look forward to confirming these results in a larger trial that can then answer the question whether or not lipoic acid, in addition to reducing brain atrophy, improves clinical outcomes.

BD:  Ok, fantastic.  I think it’s really important that you have both those arms in terms of outcomes that you are looking at.  Often, I think we have one or the other when we are doing research, but to look at the effect on atrophy, but as well at the effect on quality of life, is really important and a really good part of the study, I thought, when I read it.

RS:  Well absolutely, I think that any MS medication – we first look at MRI surrogate outcomes, but ultimately if we think it is going to be effective, people have to feel better when they take it.

BD:  Certainly.  Do you have any idea as to how the lipoic acid could be working to have this effect?

RS:  There are some ideas – it is an antioxidant, it is a key cofactor in an enzyme that works in our mitochondria (mitochondria are our powerhouses of our cells and produce energy for the cell) and evidence that mitochondrial failure is part of the process of progressive MS.  So, improving mitochondrial function may enhance the energy and the life of neurons, that may provide the neuroprotection that we are seeing.  There is also some evidence that lipoic acid can suppress microglial activation – microglia are small immune cells that become abnormally activated in progressive MS.  So by suppressing this abnormal activation, that may be another mechanism by which it works.

BD:  Ok, that’s really interesting.  So you mentioned that this was a smaller study and that the plan or the hope would now be to continue onto a larger study, is that the next step for this research?

RS:  Yeah, absolutely.  For one, we just need to replicate the study at other centres – so maybe do a multi-centre trial, so that we don’t think it’s just what we found in our patients at our one site.  Then, we also want to see is there a clinical benefit – so what we can do is use the data from this study to say what size of the next study do we need to do to answer the question ‘does the neurologic exam get better?’ or ‘does walking time truly improve?’ like we think it does based on our small study.  So we can use this pilot data to determine what the size of the next study is going to be.

BD:  Do you have any idea yet on when the next study will be beginning or that’s really in the process of being planned at the moment?

RS:  That’s definitely in the planning process, but you know, as soon as possible.

BD:  Ok, so I have a few questions that have been submitted by people in the MStranslate community.  So one of the questions that we had was, this current trial was performed in people with secondary progressive MS, as we’re slightly unclear as to the differences or what causes the differences between them, are there thoughts on whether or not it would be effective in other types of MS?  Or any plans to trial it in other forms – such as primary progressive or relapsing-remitting?

RS:  That’s a great question.  In the animal model of MS, lipoic acid had anti-inflammatory properties and there is an ongoing trial also at Oregon Health and Science University looking at lipoic acid after acute optic neuritis.  That is going to answer the question of whether it can work for acute inflammation in more of a relapsing population.  You know the reason I limited the current study to just secondary progressive and didn’t include primary progressive is kind of an interesting one.  At the time that, this was 6 years ago when I was setting up this study, the general trends at the time were to separate the different types of MS and study them each separately.  Now, it is more common to group progressive forms of MS as opposed to relapsing forms of MS in trials and I think, in upcoming trials, I will follow that trend because it makes sense to me to look at both secondary and primary progressive MS in the same trial, since we are looking for neuroprotection in both of these populations.

BD:  Certainly, often it can be difficult to get a large enough study number of people with primary progressive MS, considering it’s a rare form.

RS:  Yeah, that’s a real challenge.

BD:  Another question we had…the people involved in this trial, what was the washout period for if they were on any disease modifying therapies before the trial began?

RS:  Good question.  So, actually we allowed people to continue their interferons or glatiramer acetate if they were on it already.  I would say that about half of the participants were on one of these two medications, the other half were not on any disease modifying therapy and that stayed true through the 96 weeks.  You know, interferons and glatiramer acetate have not been found to be particularly effective in secondary progressive populations so we didn’t think that that would end up confounding our results in any way.

BD:  The next question that we had was based on the safety, so there was a few adverse events reported throughout the 2 years, but generally reasonably moderate and I think it was only a very small number that dropped out due to adverse events.  With things like infections and gastrointestinal problems throughout the time of 2 years, the question was, these are things that can come up naturally in people anyway, was there any way of knowing whether or not those events were directly related to lipoic acid or were they just separate and just things that happened as a natural event during the course of the trial?

RS:  Yeah, well absolutely.  We looked at the total number of adverse events, which were a little bit higher in the lipoic acid group, but not statistically different from the placebo group.  Then, we looked at a breakdown of each category of events, so for instance, infection rate was the same in lipoic acid as placebo group, so when they are the same we don’t think that there is any increased risk of infection or decreased risk of infection with one versus the other.  The areas where there were significant differences between the groups, the lipoic acid group had more stomach upset, some nausea, some stomach upset than the placebo group.  This is a well-known adverse effect of the lipoic acid and has been reported in our previous trials at OHSU and also in other studies of lipoic acid.  I should back up and mention that lipoic acid is actually used as a treatment for diabetic neuropathy, particularly in Germany.  So, there have been safety studies done already on lipoic acid and overall it has been determined to be pretty safe.  So there was more stomach upset with the lipoic acid, so we advised people to take it with food or split up their dose into a morning and afternoon dose if they needed to.  The other place where there were significant differences were in falls and, in fact, there was almost half as many falls in the people on the lipoic acid than the people on the placebo.  Again, this was unexpected and that’s why we have to repeat these trials to see whether it was just one of those statistical flukes or whether there truly is some benefit to reducing falls with lipoic acid.

As far as serious adverse events, and by serious, I mean that people had to be hospitalised or even withdraw from the study because of a medical condition, there were similar numbers in both groups, but there were a couple that were concerning.  There was one person who went into kidney failure and there was another person who had a new diagnosis of glomerular nephritis, which is another kidney disease just in the lipoic acid group.  Again, we don’t know if it’s just a fluke that that happened or whether this is truly due to the lipoic acid – this is definitely when you need to have a larger trial to determine the long-term safety of it.  That said, the same dose of lipoic acid (1200mg that we used in this trial) has been used in 2 year studies looking at diabetic neuropathy in Germany, so we think it’s fairly safe, it was very well tolerated – people took their medicine as prescribed, over 80% compliance with all participants.  In general, I would say that it was well tolerated and people didn’t have problems taking it every day.

BD:  And those kidney problems that you described, they weren’t seen in the German study at all?

RS:  They were not seen, no.

BD:  Ok well, that’s good news and it’s good that it was quite well tolerated across the time of study, because that’s obviously going to be something that people with MS are going to be particularly interested in if they are going to take part or take this as a potential therapy.

The last question that we have is based on obtaining lipoic acid through the diet and obviously we may be talking about doses that used in this trial that are beyond what is possible to achieve through dietary intake, but the question was what are the best food sources for lipoic acid?

RS:  Well, so you can get trace amounts of lipoic acid from foods like liver, spinach, broccoli, dark green leafy vegetables, but these are trace amounts.  Most of our production of lipoic acid is actually within our own bodies and then to get enough into us to achieve blood levels that we think are the therapeutic levels necessary to cause these changes or have these effects, you really have to take a synthetically manufactured version of lipoic acid.  So I don’t think it’s possible to get it from diet alone.

BD:  Ok and lipoic acid as a supplement is currently available?

RS:  It is, it is available over the counter and people have often taken it for general antioxidant reasons or for perhaps if they have a painful neuropathy, particularly diabetic neuropathy.  However, I would encourage people to see what the trial actually shows because a lot of vitamins do get tested and initially they seem promising, but then either they don’t work or they have adverse effects that we aren’t aware of at the beginning.  So, I think this is very promising, but I would like to see the results of a larger trial to confirm this before people start taking it left and right.

BD:  Alright, fantastic.  As you are at the conference and you are a few days in, as we discussed before, we thank you very much for taking the time at the end of what has no doubt been an exceptionally busy day to talk to us.  We won’t take up any more of your time, we’ll let you get some rest for the few days left of the conference.  Once again, thank you very much for taking the time to talk to us today, we very much appreciate it and I’m sure that all of the people with MS that are part of our community appreciate it as well.  We’d like to wish you luck for all of your future research.

RS:  Well thank you very much.  Thanks for having me today.