Tuesday, 29 August 2017

Minocycline as a neuroprotectant

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

Luanne M. Metz, M.D., David K.B. Li, M.D., Anthony L. Traboulsee, M.D., Pierre Duquette, M.D., Misha Eliasziw, Ph.D., Graziela Cerchiaro, Ph.D., Jamie Greenfield, M.P.H., Andrew Riddehough, B.Sc., Michael Yeung, M.D., Marcelo Kremenchutzky, M.D., Galina Vorobeychik, M.D., Mark S. Freedman, M.D., Virender Bhan, M.D., Gregg Blevins, M.D., James J. Marriott, M.D., Francois Grand’Maison, M.D., Liesly Lee, M.D., Manon Thibault, M.D., Michael D. Hill, M.D., and V. Wee Yong, Ph.D., for the Minocycline in MS Study Team

N Engl J Med 2017; 376:2122-2133June 1, 2017DOI: 10.1056/NEJMoa1608889

Background

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.

Methods

During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI [“enhancing lesions”], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]).

Results

A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.

Conclusions

The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887.)




It is important to pay attention. 

To what specifically you might ask? Why, to everything... 

Neurologists are notorious for paying attention to detail, some may consider this peculiar - even borderline autistic. So, in this fashion and not simply for diegetic entertainment, I'm able to say that the Yong group have trialed minocycline as a neuroprotectant in just about every neurological disorder they can get their hands on. In science this is tantamount to using the same run of numbers in the national lottery to improve the odds. But they've seem to have hit the jackpot with this one - the disorder being, multiple sclerosis.

Minocycline is a semi-synthetic tetracycline (antibiotic, commonly used for acne treatment), but also has additional biological actions, including anti-inflammatory properties and anti-apoptotic effects (process by which cell death occurs in the body). In short, potentially a good neuroprotectant.

Metz et al. gave 100mg twice a day of minocycline to 72 subjects and placebo (dummy treatment) to 70 subjects. There was some imbalance between the two groups at the start of the trial, in that the placebo group were more likely to have their first symptom in the spinal cord (increased likelihood of being disabling) and have more than one enhancing lesion on their baseline MRI head scan (i.e. more active). At the end of the study, 23 in the minocycline group and 41 in the placebo group reached the primary outcome of conversion to multiple sclerosis from clinically isolated syndrome (i.e. a single demyelinating event only) - see figure below. The adjusted risk difference of 18.5 % at 6 months is similar to that with other disease-modifying therapies for multiple sclerosis (24% for IFNb-1b, 26% IFNb-1a, 18% teriflunomide, 25% cladrabine). MRI scans were not available in ~37% of participants after month 3 in the placebo group which may have introduced bias in the MRI analysis which favoured minocycline in terms of change in T2 lesion load and mean GAD enhancing lesions.



Figure Participants Who Reached the Outcome of Conversion to Multiple Sclerosis (MS) over the Course of 24 Months.

There were more adverse events in the minocycline group (86% vs 61% in placebo) and included rash, teeth discolouration and dizziness.

Overall, despite the underpowered study, the minocycline trial is a success for MS. Here is a toast to the Yong group for their tenacity and gumption, and to all neurologists and scientists out there who keep going! I would say watch this space as the minocycline saga unwinds.

27 comments:

  1. So 20% reduction?
    Dont you think its weak?
    Thanks luis

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    1. Not at all, minocycline will be working on a specific aspect of the disease process - possibly the innate immune system (it has been noted to dampen the prounflammatory cytokines release from macrophages in infections), and therefore may not affect the whole process. The potential for it would be to add it onto an existing immunomodulatory therapy, which may provide an additive effect.

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    2. The risk of conversion froms CIS to MS lacks any meaning within 24 months since:
      a. MS is a life-time disease with unpredictable behavior. The afforementioned risk is only meaningful after a life fully-lived.
      b. Both CIS and MS are words out of a neurologist's mouth on clinical grounds only. The underlying process could be missed completely.

      "minocycline will be working on a specific aspect of the disease process - possibly the innate immune system"

      provided there is one and is proved abnormal. Strangely, the innate immune respond in MS is quite normal according to Prineas et al.
      https://www.ncbi.nlm.nih.gov/pubmed/20035511

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    3. Hi Vasilis, if we ignore the pretext of the clinical jargon and take it to mean the time to next clinical event - then minicycline is impacting on this and therefore applicable even in RRMS.

      As for the role of the innate immune system in MS, the idea that macrophages are simply scavenging is an old idea. Microglia and macrophages contribute to antigen presentation and cytokine release - it's not possible to demonstrate this simply by looking at fixed tissues. In fact Rasmussen showed that activated microglia are involved in the loss of neuronal synapses. They all express Toll like receptors 1-9 which are important in the development of neuroimmune responses. So there's more to them than meets the eye..

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    4. Talk about M1 and M2 macrophages...Please

      Wath are they doing?
      Obrigado

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    5. The next clinical event is bound to happen, if you have MS. 6 months sooner or later means nothing in the long run and should not be attributed to drugs of any kind.

      As for microglia, yes they are found near degenerating axons as microglial nodules. Still, this is exactly what's going on in stroke and Traumatic Brain Injury too. Nothing special in MS, therefore one is urged to speculate that MS damage is of the same kind, meaning NOT autoimmune.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611040/

      All in all, the scaveging action of macrophages has not been refuted. To the contrary, even the microglial behavior support it.

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    6. Luis, the M1/M2 paradigm seeks to divide macrophages in a similar way to the T cell population based around activating factors, and their effects. So the main stimuli for an M1 response is IFNgamma leading to Th1 style immune responses. Whilst M2 are mainly activated by IL4 leading to Th2 style responses. So it is thought that M1 macros are pro inflammatory and M2 are anti-inflammatory, both the T cell and mac working in a coordinated fashion. But attempts to pigeon hole macrophages into these two categories have failed. Macrophages are very flexible and depending on the challenge faced they adapt to it leading to a myriad of expression profiles unlike that seen in T cells.

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    7. Thanks for reply
      "Macrophages are very flexible and depending on the challenge faced they adapt to it"
      It that the hallmark of the innate immune system?
      Ie:First line of defense required very rapid and flexible mechanisms?
      Obrigado

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    8. Evolutionarily speaking macrophages or macrophage-like cells are the oldest. They've evolved with the host and have a number of different defence mechanisms (recognition and effector molecules) that allow for a fast response to different infections. The additional adaptive immunity (T/B cells) are there to supplement the innate response. The latter are more highly specific, require antibody maturation, and have memory. Scientists who study ontogeny think that the development of the adaptive immunity in higher vertebrates (us!) allowed us to reduce the number innate responses originating from evolution. There are whole books devoted to this stuff, with scientists waiting to see which new cell is going to pitch up in the evolutionary tree. I suspect this would driven by viruses such as HIV which have a faster mutation capacity than can be fought with our modern drugs!

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  2. I remember back in 2010 when I was first researching MS, there was talk about minocycline then

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    1. It's also cheap costing a under a pound per tablet.

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    2. Is it possible the minocycline is actually killing or suppressing an infection like staph until it becomes resistant and it's losing its effect? I've been diagnosed with ms for over 20 years. I've had limited success with the MS drugs. Over the years I have been treated for nasal multiple antibiotic resistant staph with biofilms, with dramatic results. Every single time I felt the difference after about 5 days. Several times I went from using a cane to running. Only to have the staph become resistant to the next antibiotic. Last one was applied only intra nasal and I went from the wheelchair to walking. It took over a year but I did it. Only to have the staph again become resistant to the gentamicin and I'm now very sick again.
      Someone from the MS community needs to please look further into Frederick Gays research. Also into Ritchie Shoemakers research who treated biotoxin exposure. He has shown that the staph with the biofilm is making polycyclic toxins that are similar to the biotoxins he has found cause many of his Chronic Fatigue patients to have abnormal brain MRI results that resemble MS. Thank you very much for this blog. As a patient who is trying to be my own advocate, I really appreciate the candid exchange of information. I believe this exchange will be the only possible solution to the discovery of the cause of this very complex disease. It gives me hope.

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  3. I feel awkward reducing yet again a detailed scientific post to such a simplistic level, but as a lay person, fortunate enough to have an excellent and open-minded GP the question in my head is 'Is it worth me asking my GP to prescribe this antibiotic on an on-going basis?'

    My GP has also mentioned Fecal Microbiota Transplant, as he's so convinced by the evidence of positive outcomes with a number of auto-immune conditions and is going to start using it for the benefit of some patients. He confirmed I may not be eligible having received Alemtuzumab, but proposed I research it.
    Having been diagnosed less than two years ago I'm keen to avoid falling foul of chasing the quick fix. I want to focus on being the best I can be in living with this disease, and using the appropriate means available to me to facilitate this!

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    1. As a rule of thumb always wait for the phase III study findings (performed in a larger group of patients and therefore more reliable) before jumping onto a product. A classic example of this is simvastatin, which showed promising effects on brain atrophy and is now funded for a larger study in secondary progressive MS.

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    2. That's helpful- thank you.
      If you or any of the team have a view on Fecal Microbiota Transplant I'd appreciate knowing it.
      Thanks

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    3. Fecal transplant...treat it as a pampering exercise....there is no evidence that it is of any value. (No evidence its not too) but you are being sold a pup.

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    4. There are times when this blog depresses me or upsets me but I do appreciate when it makes me laugh! Thanks for the reply MD... and your phraseology.

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  4. "the unadjusted risk difference over a 24 month period was not significantly different"...what am I missing here that suggests minocycline is effective in the long run?

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    1. Over time there would be a certain percentage of people converting to MS. In a small study it is therefore easier to show a difference in the first 6 months. They did do a posthoc analysis and showed that the difference remained significant at 12 months. Looking at their power calculations (used to determine the size of each group) was sufficient to show changes beyond 6months. They therefore need to look at this in their next study as you're right it's more important to have stable disease in the long run than the short run.

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  5. NDG:

    1) If this is a "good" neuro-protectant and this drug has been around for decades, why does Metz et al not study this on a progressive MS population, as this is sorely needed? Why choose as CIS to definitive MS and not PPMS or SPMS patients?

    2) I am not sure why this study is published in NEJM as it clearly has failed to meet its endpoint at 24 months and is no different to placebo at the end of 2 years. What am I missing? Who cares if it has an effect at 6 months if in the long run it is no different than placebo?

    If this is the best that our Canadian researchers can offer with recycled drugs and recycled ideas, progressive MS patients are in fact doomed. It is no wonder why MS patients seek their own answers and treatments outside of phase 3 trials. What do you offer your progressive MS patients at this time in your clinics NDG?

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    1. If you like a glass half-empty you can read my take on the same publication

      http://multiple-sclerosis-research.blogspot.com/2017/06/minocycline-as-short-term-success-or.html

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    2. The NEJM is all about "who you know". Content is not always their #1 priority IMO.

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    3. Thanks MD for taking the time to do this blog. I appreciate all Bart's MS blog greatly, especially your brutally honest posts with constructive criticism.

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    4. Ta...Brutally honest...I get a salty-feeling coming on in the next couple of days:-)

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  6. NDG, would the neuroprotective effect of minocycline be obtained on a per-cycle basis or given concomitantly to DMT, or when the pwMS was in an outbreak where a corticoid pulse therapy was given and administered along with minocycline?

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    1. So this study only looked at treatment vs naive. Steroids were given for the CIS presentation but this was not significantly different between the treatment of placebo arms.

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