Saturday, 1 November 2014

PROXIMUS has been given the green light!

PROXIMUS (Oxcarbazepine) neuroprotection study in early SPMS is starting recruitment

History

This is another crack at the neuroprotection concept by us neurologists (NB: we're affiliated with this trial). The story starts with the good old 'Lamotrigine trial in SPMS' - Kapoor et al. Lancet 2010; which dashed our budding hopes for a neuroprotection strategy in SPMS. But further data analysis, in particular of the blood and CSF samples monitoring for the release of neurofilament proteins (damage/injury marker of axons), showed it to be less in participants on lamotrigine vs placebo/dummy tablet (Gnanapavan et al. PLOS One 2013). From this came the spin off trial 'Phenytoin in optic neuritis' - protection of vision in optic neuritis (now fully recruited) and the PROXIMUS study in early SPMS (the name by the way was picked by you guys after posting on this blog!).

Rationale


Although demyelination is an early feature in MS, axonal loss also occurs very early on (this is why a stand alone remyelination strategy in MS will never work - you can't myelinate what is not there!). And axonal loss for all intents and purposes is permanent, and is the predominant cause of loss in neurological function (the God farther of Neuroscience, Ramon y Cajal is oft quoted to have said: 'But the functional specialization of the brain imposed on the neurones two great lacunae; proliferative inability and irreversibility of intraprotoplasmic differentiation. It is for this reason that, once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably'). 

Over the past decade (see figure below) there has been a growing body of work demonstrating that nitric oxide (a free radicle released during inflammation can shut down the energy producing cells of axons (the mitochondria). This energy deficiency in turn leads to axonal breakdown (there is increased influx of sodium into axons triggering a reversal of the sodium/calcium exchanger which unwittingly ends up with toxic levels of calcium entering into axons). Blockade of the sodium channels has been shown to prevent nitric oxide-induced axonal breakdown in laboratory and animal models. Sodium channel blockers include lamotrigine, phenytoin, flecanide and carbamazepine/oxcarbazepine.


Clinical trial details


The study is going to be carried out at the Clinical Research Centre at Barts Health NHS Trust & Queen Mary University of London. It is a randomised controlled study of Oxcarbazepine vs placebo (participants will be randomly assigned to either the active drug or the dummy tablet). There has to be evidence of active axonal loss; a lumbar puncture will be performed at the start to check neurofilament levels. If your neurofilament levels are raised then you'll be randomised. Another LP is then performed at the start of the study, at 6 months and lastly an year later. The study's aim is to see if those on Oxcarbazepine have a reduction in their neurofilament levels compared to placebo.

Eligibility criteria
- Age 18-60 years old.
- Early SPMS (secondary progressive MS); EDSS 3.5-6.0 (i.e. maximum level of disability is the requirement of a single aid to walk 100 meters, either a cane, crutch or a brace).
- On a disease modifying therapy (any) and no relapses or steroid use for the past 6 months.
- A history of slow progression over at least 6 months.

Exclusion criteria (cannot participate if any of these apply to you)

- Pregnant or breastfeeding or unwilling to use adequate contraception.
- Participants who do not take a disease modifying therapy for MS.
- A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
- Participants presenting with medical disorder deemed severe or unstable, such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the participant.
- Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
- Participants receiving other sodium or calcium channel blockers in the previous 12 weeks.
- Exposure to any other investigational drug within 30 days of enrolment in the study.
- Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS).
- Prior history of malignancy unless an exception is granted by the Chief Investigator.
- History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
- Past untoward reactions to Oxcarbazepine or Carbamazepine.


So ladies and gentleman, returning to Ramon y Cajal, is also noted to have said: 'Reflecting on the nature of valid hypotheses, one may note that they are usually fortunate generalizations or daring inductions that allow one provisionally to consider the recently discovered data as one instance of a general principle...'

20 comments:

  1. I'm curious as to list exclusions, not that I'd qualify as I have RRMS, but I notice that you have to be on a DMT too. Surely that skewers the results to begin with?

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    1. In order to allow axons to heal you need to also dampen down the inflammation. You have to both have an anti-inflammatory and a neuroprotectant on board for the strategy to succeed. As the placebo arm will also be on a DMT, this can be controlled for in the analysis.

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    2. OK, I understand but why then is the proposed Riluzole trial excluding people on DMTs?

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    3. Our view is that it inflammation is still part of progression and to get optimal effect you try to deal with the events driving progression and those that drive the inflammation

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    4. So the opposite of what Neuro Doc Gnanapavan is stating for being on a DMT in the trial above? Wow, must be hard not to feel cognitive dissonance sometimes in medical research:)

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    5. Not sure what you mean

      Exclusion criteria; Participants who do not take a disease modifying therapy for MS so the people eligable will be on a DMT as it states

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    6. I was referring to the MS-SMART Study trial that states in its list of exclusions:
      'Use of immunosupressants (e.g. azathioprine, methotrexate, cyclosporine) or first generation disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
      Use of fingolimod/fumarate/teriflunomide/laquinomod/or other experimental disease modifying treatment (including research in an investigational medicinal product) within 12 months of baseline visit
      Use of mitoxantrone/natalizumab/alemtuzumab/daclizumab if treated within 12 months of baseline visit'

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    7. The two studies point to differences in scientific/clinical opinion. Not everyone believes that you need to immunsuppress in addition in the progressive phase of the disease. In terms of trial design there are also added complexities of controlling for the effects of these highly active agents on brain atrophy, which in majority of neuroprotection studies is the primary outcome. In our case, as we're using neurofilaments this is less of a problem. Time will tell who's in the right or not as the case may be!

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  2. I'm also curious as to what happened to the inosine studies a few years back, this also works in a similar way, as does melatonin to some extent. No money in it for the pharmas?

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    1. The more I do this, the more I realise that clinicians, scientists and MS societies with the backing of patients/funding etc need to push the earlier promising Phase I studies into Phase II. We have been doing this with the sodium channel/calcium channel blockers in neuroprotection and the experience has been invaluable. At some point, it will crack and we'll be there to see it!

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    2. I hope so. In the meantime, I will continue taking inosine (14 years) and melatonin (a few years), who knows if these help but I have extremely mild sensory MS, in fact it's actually a lot better now than when first diagnosed, or before then in limbo hell. Though the MS is active, unfortunately! Given the side affects are negligible, compared to taking a DMT or an anti-epileptic drug, it's impossible to tell if this works as it seems the mantra these days is the less side affects the less efficacy.

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  3. Good luck with the study! :-)
    In the part about suicidal risk in exclusion criteria... I guess you mean LOW suicidal risk judged clinically?
    J

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    1. I hope so, otherwise that is an extremely weird trial, maybe it's to mitigate being on a DMT -you know balance it out;)

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    2. Oxcarbazepine is also an anti-epileptic agent and there is a supposed association between the use of anti-epileptics and suicide-related behaviour. Although personally I think its the epilepsy itself which is attributable. However, we're stuck with this disclaimer.

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    3. Years ago I was given Tegretol to alleviate the excruciating pain from pins and needles. It worked wonderfully, but unfortunately I had an allergy to the drug. I wasn't on it long enough to notice depression, I was too euphoric to think something worked.

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  4. How many people with SPMS don't fall into the exclusion criteria? They are very lucky. No wonder there isn't much for us.

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  5. 2 questions.
    As far as mobility. I am a T-10 paraplegic previous to MS Dx. Why would I not qualify?
    and
    Being a self clearing Hep-C Pt. with normal alts. for last 30 years what would be the dangers?

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    1. In answer to your first question, the inclusion is based on EDSS for both trials, which is 6.0-6.5. You either have to be able to walk using assistance of one or two sticks or crutches. For the second question, Hep C is in the exclusion criteria because these drugs can cause hepatitis, the risk of which is greater in people with Hep B and C. Hope this helps?

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  6. I'm secondary progressive, but unable to tolerate DMTs (had a very short trial of Rebif) had to come off due to intolerance. I've had MS for over 20 yrs, diagnosed for 19 yrs, I'm very worried that us SPMS'ers will be lforgotten about.

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    1. Studies like PROXIMUS are designed specifically to address SPMS and hopefully stop/slow its development, however, recrutitment is very slow, which is frustrating. This study need to be done rigorously so the results are robust, which is what we need to up the pace of the development of neuroprotectives for MS.

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