Monday, 3 October 2016

Neuroprotection from ECTRIMS2016

Lipoic acid for neuroprotection in secondary progressive multiple sclerosis: results of a randomised placebo-controlled pilot trial
R.I. Spain, K. Powers, C. Murchison, E. Heriza, F.B. Horak, J. Simon, D.N. Bourdette. ECTRIMS2016

Objective: To determine if Lipoic acid (LA) is neuroprotective, reduces disability and improves quality of life, and is safe in a secondary progressive multiple sclerosis (SPMS) population.
Background: LA is an inexpensive and readily-available oral antioxidant. In the animal model of MS, LA decreases inflammation and reduces optic nerve and spinal cord atrophy. LA reaches therapeutic blood levels and is tolerated at high doses in people with MS. The LA/dihydrolipoic acid redox couple is a key co-factor for pyruvate dehydrogenase in mitochondria which may relate to its mechanism of action in MS.
Methods: A 96 week, double-blind, randomised controlled trial of 1200mg daily LA versus placebo. Primary outcome was reduction in MRI whole brain atrophy. Secondary outcomes included atrophy of brain substructures and spinal cord, retinal and macular atrophy, changes in neurological exam, walking, cognition, fatigue, and quality of life. Adverse events (AEs) and safety laboratory measures were monitored throughout. Intention-to-treat analysis utilised linear mixed-models to evaluate the effect of LA on per 48 week rates of change in outcomes.
Results: Of the 54 randomised participants, 51 (27 LA and 24 placebo) took at least one dose of study drug and were included in analysis. Study arms were overall matched with an average age of 58.5±5.9 (40-69) years, 61 % female, disease duration of 29.6±9.5 (9-51) years, and median EDSS of 6.0 (3.0-9.0). Five participants (9.8 % of total), all taking LA, terminated early. Total and serious AEs were similar between groups, however there was significantly higher gastrointestinal upset and lower numbers of falls in LA participants. 
Compliance, measured by pill counts, was >80 %. Annualised rate of whole brain atrophy was significantly lower at 96 weeks in the LA group compared to placebo (slope= -0.22 vs. -0.65, p=0.004). On treatment two year volume loss was -0.4 % (0.7) for LA and (-1.3 % (1.1) for placebo (p=0.006). Walking speed (25 foot walk) nearly improved in the LA group (p=0.057). 
Conclusions: This highly promising pilot trial of LA demonstrated a significant reduction in whole brain atrophy and suggested a clinical benefit in SPMS while maintaining safety, tolerability, and high compliance over 96 weeks. A larger trial is necessary to confirm the neuroprotective effects, explore clinical benefits, and ensure the safety of LA in progressive MS populations.

Lipoic acid is an neutriceutical that was reported at ECTRIMS2016. The atrophy rate over the trial (NCT01188811) in the placebo group was 0.65% decrease per year and the lipoic acid group went to 0.22 decrease a year, so not stopping but significant P=0.004 (66%) reduction. 
However there was no other outcome that changed like grey matter volume or EDSS (stable or improved in 61% on LA and 71% on placebo, but walking nearly improved. 
The main side effects are stomach upsets and stinky pee was mentioned in this stud.y 17% had stomach upsets verses 3 % on placebo. There was kidney failure and protein in urine in two people, but whether this is related required further study. 
So this is promising but the question is what next? 
We have been here so many times before, the statin trial had promise 6 years ago and still no phase III and surely the neuros attached with this trial need to get the finances to follow this up. But who will fund it? 
The NIH have committed to start the process, so one would hope they would continue because, if not surely it is unethical to start. If this is to be worthwhile they will have to do a much larger study likely to involve more than just over 50 and if the FDA want a clinical endpoint which this study was not powered to do, will they get a effect as the EDSS had an increase by 1.33. 
 There was a suggested effect on walking but this is surely a subset analysis with EDSS up to 9 included. A larger study is needed. 
They did not report on the 9 hole peg test so remember #think hand.
However, before we get too excited, I do not believe this is a signal to go down to the health food shop. Time and time again we see small neutriceutical trials going no where. Hopefully this will be different. Will the Progressive Alliance get behind this?
There does appear to be mileage in this. Choi KH, Park M S, Kim JT, Kim HS, Kim JH, Nam TS, Choi SM, Lee SH, Kim BC, Kim MK, Cho KH.Lipoic Acid Use and Functional Outcomes after Thrombolysis in Patients with Acute Ischemic Stroke and Diabetes. PLoS One. 2016;11(9):e0163484
More when it is published.

13 comments:

  1. It's cheap and maybe effective. Should it take (a normal daily recommendation or trial dose) an RRMS patient, with a disease modifying drug. Is there any contraindication with any DMD?

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    1. We do not know about contra-indications because there is insufficient evidence

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    2. it is contra-indicated for people with thyroid conditions, though

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  2. There has been another recent study that also seems to point to ALA as being neuro-protective and had an impact on walking speed - albeit not reaching significance: 1200 mg/day lipoic acid supplementation decreases ‘Timed Up and Go’ completion time by about 2 seconds

    https://www.youtube.com/watch?v=UWZtAf8U2v8

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    1. As it says not significant = not different.

      If you measure twenty outcomes, by chance one may change

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  3. Surely - but surely - there is more information on safety out there. It is prescribed in Germany in high doses for diabetes patients, for example. Unless I am very much mistaken.

    So we can't be sure about efficacy yet, but if someone such as I with PPMS has nothing else to take...?

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    1. So should we report these types of nutriceutical study ..because as you say if people can get their hands on it they may try it if the safety profile looks OK.

      If we report on them is that legitimising them

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    2. I think it is definitely positive that you report on this sort of thing - in a responsible, proportionate way, i.e. pointing out what is still not known. (Not in a Daily Mail fashion, with headlines like "Cheap Health Food Store Pills Stop Brains Shrinking!")

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  4. Co-factor for pyruvate dehydrogenase in the mitochondria similar to biotin. Probably ameliorates mitochondrial stress and promotes neuro-protection. Who will fund large studies for these nutraceuticals when there is no money to be made?

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    1. The only people are governments and charities but not sure that many charities have the resource.

      Also worth bearing in mind is the effect of marginal importance or really something impressive.

      I wonder how much has been spent on vitamin D trials...there are loads upon loads of underpowered studies. Could a multi national focused study have addressed the issue once and for all.

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  5. A few years ago I started taking it after hearing a dr saying it helps with diabetic neuropathy. I almost felt it helped with my neuropathic pain but it might have been wishful thinking. I didn't have any side effects and would have continued taking it but it is expensive. I don't know why I keep reading it is inexpensive - it isn't.

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  6. Here in Brazil the ALA and Coenzyme Q10 are a little more expensive than other nutraceuticals.

    ALA, Biotin, Coenzyme Q10, Methylcobalamin, N-Acetyl-L-Cysteine ... Nutraceuticals with possible neuroprotective effects, antioxidants ...

    The problems of studies involving nutraceuticals are the duration of the study and the doses administered, since it is very difficult to create a aparâmetro to know which dose the nutraceutical begin or will to do the expected effect, and how long the measured dose or achieved will to be administered and wherein when start their therapeutic effects.
    These are, in my view, the obstacles amiores why has not reached a consensus on vitamin D...


    From what I've been researching it's well founded that Creatine has action with a co-factor for pyruvate dehydrogenase in the mitochondria too?

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  7. "The chemical structure of biotin is similar to that of LA [lipoic acid], and there is some evidence that high concentrations of LA can compete with biotin for transport across cell membranes"

    http://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid

    This snippet of information makes me wary of lipoic acid supplementation.

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