Friday, 31 August 2012

Team G: Maria's leaving us today

Today is Maria Espasandin's last day in our group! She has worked as our clinical research manager for over 10 years. Dependable, thorough, highly-skilled and an asset we are can't afford to be losing. Ask Maria to get a trial or study protocol written and through ethics and bingo it is done. Maria was also the person responsible for arranging our annual research days. We are going to find it difficult replacing Maria's skills. 

We hope the grass is greener on the pharma side if not you can always change your mind and come back.

Maria about to run the London Marathon!

Maria at her MSc graduation! 
 Good Luck! 

Team G News: Leaving us

Bye Bye Beki from Shift MS, who is moving on to pastures new.

Nurse Maria Espasandin Research Manager has also jumped Ship to work with the Enemy (:-)) ..Oops sorry Pharma. 
Missing You Already

We wish them well in their New Jobs

Research: Mixing statins with Interferons do not add up

PURPOSE: The efficacy of statins in combination with interferon therapy in patients with multiple sclerosis (MS) is reviewed. METHODS: A systematic literature search was conducted through September 2011 to identify randomized controlled trials that evaluated the effect of combination statin-interferon therapy compared with interferon therapy alone in patients with MS. Trials had to report at least one of the following outcomes of interest: clinical relapse rate, disease progression, or Expanded Disability Status Scale (EDSS) score. 
RESULTS: Four unique trials were included in the analysis (n = 463 subjects; range of follow-up, 9-24 months). All trials evaluated patients with relapsing-remitting MS (RRMS). Most trials enrolled patients taking interferon beta therapy either twice or three times weekly. The mean baseline EDSS scores ranged from 1.2 to 3.4. Evaluated statins included simvastatin and atorvastatin. No significant difference was found between the statin and control groups in the incident rate ratio for clinical relapse (0.72; 95% confidence interval [CI], 0.17 to 3.11), risk of relapse (relative risk [RR], 0.99; 95% CI, 0.53 to 1.85], disease progression (RR, 1.31; 95% CI, 0.73 to 2.36), or difference in the change in the EDSS score from baseline (weighted mean difference, -0.06; 95% CI, -0.30 to 0.19). 
CONCLUSION A meta-analysis revealed that the addition of statins to interferon therapy did not significantly influence the relapse risk, disease progression, or EDSS scores in patients with RRMS.

The conclusions say it all. There is no good evidence that statins really make an influence on RRMS by themselves and appear to add nothing when used as an add-on to beta interferon.

Research: time to relapse - a new outcome for RR trials

Epub: Sormani et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2012.

BACKGROUND: The increasing number of effective therapies to treat MS raises ethical concerns for the use of placebo in clinical trials, suggesting that new clinical trial design strategies are needed.
OBJECTIVES: To evaluate time to first relapse as an endpoint for MS clinical trials.
METHODS: A recently-developed model fitting the distribution of time to first relapse in MS was used for simulations estimating the sample sizes of trials using this as an outcome, and for comparison with the size of trials using the annualized relapse rate (ARR) as the primary outcome.
RESULTS: Trials based on time to first relapse were feasible, requiring sample sizes that were similar or even smaller than if the study was based on ARR instead. In the case of low ARR (0.4 relapses/year), as is expected in future trials, the 1-year trials designed to detect a treatment effect of 30%, with 90% power, require fewer MSers when based on time to first relapse (470 MSers/arm) than if based on ARR (540 MSers/arm).
CONCLUSIONS: Our simulations show that time to first relapse is not less powerful than ARR in MS trials; thus, this measure would be a potentially useful primary outcome offering the advantage of an ethically sound design, as the MSers randomized to placebo can then switch to the active drug, once they relapse. A potential drawback is the loss of information for other endpoints collected at fixed time points.

"This analysis supports what we have been saying for sometime we need to be more imaginative in how we undertake trials so that they can speed up the  thoughput of new drugs and expose fewer MSers to trial conditions. Let's hope the regulators see the advantage of this!"

Research: Clinical Improvement after Venoplasty of CCSVI.

Purpose: This study proposed to prospectively evaluate safety and clinical changes in outpatient endovascular treatment in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI).

Materials and Methods: Two hundred fifty-nine patients with MS were followed with the Multiple Sclerosis Impact Scale (MSIS-29) before and for 1and 6 months after treatment of extracranial internal jugular vein and azygos vein stenoses and occlusions using venous angioplasty, as well as stent placement in 2.5% of patients. Before treatment, the patients were tested with magnetic resonance (MR) venography and flow quantification.

Results: We found statistically significant improvements in the MSIS-29 scores (P < .01) at both 1 and 6 months. At 1 and 6 months, 67.9% and 53.6% were improved on the physical scale, respectively, and 53.0% and 44.4% were improved on the psychological scale, respectively. Women showed greater improvement than did men on the physical scale at 6 months (P = .01). Patients with primary progressive MS (PPMS) showed less improvement than did those with relapsing-remitting MS (RRMS) on the psychological scale at 1 month, and venoplasty treatment of more vein sites versus fewer vein sites showed greater improvement on the physical scale at both 1 and 6 months. Fifteen patients (6.3%) reported recurrent symptoms after clinical improvement and were treated again. There was one serious adverse event, a deep venous thrombosis at the catheter insertion site, which resolved with treatment.

Conclusions :Endovascular treatment of CCSVI in patients with MS appears to be a safe procedure resulting in significant clinical improvement.

Well you can all read and so the conclusions say it all. This is not a clinical trial but a retrospective look at people who have had venoplasy and 70% felt better at 1 month after treatment.

Therefore if the trials ongoing look at one month then it should be a breeze to show an effect. But at 6 months only 50% better or no effect/worse. If one looks at 12 months then maybe it is going to be touch and go. The BRAVE DREAMS trial of Zamboni is baseline and 12 months, maybe months too far.

We need to see data from placebo controlled trials. The pro-side should be confident and say "bring it on". Let us hope it works.

This study is by David Hubbard of the Hubbard Foundation, which investigates the vascular component of neurological disorders, such as Chronic Cerebrospinal Venous Insufficiency. So no conflict of interest in showing CCSVI as a disease entity then :-)

Unrelated Blogger Comments August

Sometimes you want to say something that is unrelated to the threads. This is a spot for you
"If you are a MSer at the Royal London Hospital please sign-up for our cognition study!"

We may be slow at answering this Month 


  1. Alemtuzumab will no longer be sold in the UK

    I guess it will return at a much higher price when it is licensed for MS
  2. I think the new posting format is better because I couldn't read the code numbers sometimes, now it's quicker.

    If people want to spam, they will regardless let's hope they discover some other blog to do so.

    Also, could someone please tell the other researchers from Team G to increase the typing size of their articles? Thanks.


    1. Maybe time to turn the codes back on?

      There is alot of useless traffic about viagra, penile enlargement and windows operating system spam. It may be it is autoamatically generated on key words. May an experiment is in order.
  3. Have increased font size of past recent posts.

    Code numbers?
  4. Return at higher price.

    Yes I suspect so.
  5. I have been trying to remotely assess comments from Kindle 3G that is why some of the comment access changed. It was a hopeless case
  6. Oh MouseDoc:-) No code numbers just the stuff you had to type (letters+numbers) so that your post got through - now, how do you name that?

    Anyway, thanks for increasing the font, very helpful!!
  7. Another not Campath-related:-) question but perhaps some of the docs has time to answer - can you tell how much a blood test for Aquaporin-4 would cost me if I were to cover for it privately - just roughly need to know if I need to sell my car or something ;-) thanks.
  8. Can a Zoster or a Herpes encephalitis easily be distinguished from MS?
    Both are rarer than MS. And I wonder if a certain percentage of MSers have a Herpes or Zoster encephalitis.
  9. This article will cheer up Prof G:
  10. This article will cheer up Prof G

    Not sure why it would cheer us up, we have no real axe to grind with the Zamboni hypothesis except that we want definative proof the CCSVI hypothesis has legs, which is increasingly unlikely. We are saddened by the false hope and resource and human costs that this so called "eccentric and maverick" (by an A from Cambridge) idea has appeared to consume.

    That MS suceptibility genes are largely immune related is not new we have known about this for years...therefore it is not news. The generation of this information has likewise not smelt of roses along its history.

    However if I said I dont think that progressive MS is not anything to do with autoimmunity this could be true and this could still require immune related genes in its trigger. The question is can the vascular protagonists build the fact into their ideas, with something that is not a shaggy dog hypothesis. This has always been a problem with the CCSVI story that it brushes many on the known facts about MS aside.
  11. This one - in my view - is way more interesting:
  12. Re: "Can a Zoster or a Herpes encephalitis easily be distinguished from MS?"

    Yes, zoster causes an encephalitis and is sudden in onset. Very different to MS.
  13. From Prof G's twitter feed on 15 November 2010

    -a successful MS prevention strategy will destroy the MS DMT market! Whoopee bring it on

    -A small molecule DMTs coming off patent may do it sooner or maybe not as they are not that effective. A cure is what we want!

    Could BG12 be the small molecule DMT that eventually destroys the MS market?
  14. BG12 destroying the market? Why not, you can buy fumaric acid over the counter. It could become a health or food supplement.
  15. Could BG12 be the small molecule DMT that eventually destroys the MS market?

    Unlikely...try iv cladribine..any white knights out there?


    1. What would be required of a white knight in this context? Funding or time (or both?). I'm willing but whether I'm able is a different matter... Surely an IV Cladribine trial would be a prime fund raising opp given it is a generic drug that could be as effective as the many (very expensive) DMTs. Wouldnt the various MS charities consider this?

      As an aside, we're any results ever gathered from the Oracle trial of Clad for CIS or was the plug pulled before they could be obtained? Was there any informal sense of how effective it had been? Prof G?
    2. In this context...
      A consultant neurologists with an iron back with the time and energy to co-ordinate a safety trial and organise the funding for the trial (could be MS Charities or Government) and presumably subsequent licencing. (This is not Prof G).
    3. How can it be that there isn't a neuro interested in taking this on? A drug with comparable effectiveness to the newer induction agents, potentially less side effects and no patent. Surely that's a very significant potential drug just sat gathering dust or being used in the odd off-label use? If its safety could be proved, then the neuro responsible would receive huge plaudits. Back to my earlier question - does anyone know what happened to the Oracle trial for this drug? Were any results gathered?
    4. Re: "Oracle" - yes the data is being collected and will be presented. I suspect next year sometime.
  16. Interesting that Oracle was CIS. If the results are promising, that's taking early, aggressive to a new level (i.e. induction treatment at CIS stage). Is off label IV clad a reasonable strategy for new CISers to consider with their neuros? If it can be shown to significantly reduce risk of conversion to MS then it could be extremely important.

    Who is responsible for Oracle? Presumably not Merck given they've abandoned oral Clad?
  17. Oral Cladribine in Early Multiple Sclerosis (MS) (ORACLE MS)NCT00725985 is Merck Serono trial July 2011 (Final data collection date for primary outcome measure Jul 2011) n = 617. Endpoint time to MS conversion

    Oral Cladribine binned by EMS23 June 2011.....What's the interest from EMS in putting resource into study to tell us the result?

    If Movecto was on the agenda still I suspect it would have been all over ECTRIMS this year if it had I bet it will make as much of a splash as pin dropping in to a big lake.

    IV clad needs safety study to be done, remember it did not get FDA/European approval because of potential cancer signature.
  18. Do you expect we'll get the results at ECTRIMS? Are we certain this data is being collated? I can't see why EMS would do this given Oral Clad has been binned? Safety aside, it will be interesting to see the results. I'm certainly considering IV Clad off-label - cancer risk or not - now Alem is off the agenda for the time being.
  19. Do you expect we'll get the results at ECTRIMS? ...No.....Not this year. If you look at the ECTRIMS website you can see titles of most of the presentations

    Are we certain this data is being collated?....No...But I don't know..should be

    I can't see why EMS would do this given Oral Clad has been binned? ...It will not be high on the agenda I'm sure but will come out at some stage..Prof G thought next year


    1. EMS has not binned it; they are simply not developing it further. I suspect if someone came along with the right price they may sell the oral cladribine portfolio. The buyer would have to do another trial to get safety data; by the time there is sufficient safety data the patent would have expired and there would be no window to may their money back. This is an example why patents and incentives are so important to get pharma to invest and develop drugs for MS.
  20. Thanks. On a different topic - what's the most anticipated 'release' at ECTRIMS? Are there any really exciting trial result or developments expected to be revealed for the first time??
  21. I think there will be the Pharam Jamboree, but you know most of what they are serving up

    Here is the preliminary programme

    Prof G will no doubt we sending updates from Lyon


    1. I have no doubt that Prof G and his colleagues will be eating out at Michelin starred restaurants in Lyon care of Big Pharma. Disgraceful as most of us are facing benefit cuts!
    2. This is a rude and unnecessary comment. And you don't even have the guts to put your name to the post.
      I hope Prof G does have a lovely meal in Lyon. Why go to Lyon otherwise?
      But the deeper point is this: Prof G and his team don't have to run this blog. They don't have to be engaged and passionate as they clearly are. So slagging them off on it is not only counter productive (they might just stop posting) but it really is pathetic. Yes, you (I) have a crap disease. Yes, it makes you (me) feel bad. But this isn't Prof G's fault. So lay off the insults.
    3. Thanks Iain O. Well said. More sensitive people would see a comment like that and wonder why we bother. Fortunately we aren't. We totally understand MSers frustration but slagging off people who really do care is really not the way to go. Team G actually look forward to the day when MS is cured and we put ourselves out of a job.
      Have no worries, we won't stop posting!
    4. I agree entirely. This blog is an invaluable source of info and commentary and the time Prof G and MouseDoctor take to reply to questions and comments is incredible and generous. As a newly diagnosed MSer, I'd be completely lost without this site.
  22. Amen Iain. You said it right.

    Anon 11:15 pls (out of respect to us) control your emotions.
    I know its tough with mood swings in MS - but do count to 10 before you post.
  23. Dear Anon 11.15
    Saw Prof G at lunch time and mentioned your comment, it reminded him to think about food in France as he thinks Lyon will have some nice places to eat..after all it will be french food.


    1. Prof G - go to one of the city's bouchons if you get the chance. They serve things like donkey nose and lots and lots of offal but the taste is a lot better than the sound.

      Ground fish dumplings at Le Poelon d'Or is a nice place to start. 29 rue des Remparts d'Ainay (+33 (0)4 78 42 43 42).

      Trust me - it's worth it.
  24. Good luck & a big thank you to Maria & Beki!
    Both of them will be missed

Thursday, 30 August 2012

Research: sativex can alleviate spasticity in mice

This study investigated the anti-spasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were administered and the "stiffness" of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity up to approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Sativex was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS. 

The compounds within Sativex can inhibit spasticity in mice. Well no big shakes there Sativex has been licenced for the treatment of spasticty in Msers for a few years. Yes I know few PCT are funding it because it is too expensive. 

Well members of Team G showed that this should happen many moons ago and this study confirms this. The important thing is that mice can not talk to us and so if we can measure benefit, it is not that they are conned because of mind-altering effects, which is a comment often aimed at MSers who take cannabis. 

However, the reason why this is important is that the regulators such as the FDA like to see that drugs work in pre-clinical models. This works because it acts on a biology that is involved in the control of spasticity.

CoI: Work was undertaken by Team G and supported by GW Pharmaceuticals the makers of Sativex.  Other Members of Team G have generated potentially competing chemicals

Research: Further evidence that Neurofilaments are a useful biomarker to detect damage

BACKGROUND: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest.
OBJECTIVE: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS).
METHODS: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them.
RESULTS: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients' NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load.
CONCLUSION:  Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage.

This study looks at neurofilament an internal protein of nerves and examines its content in spinal fluid in people with their first symptoms of MS. This shows that neurofilament notably neurofilament light correlates with the occcurrance of disability, which suggests nerve damage.

Wednesday, 29 August 2012


The 14th paralympics start in London today and this week many people will see wheelchair users (and blade runners, blind, deaf and walking enabled etc.) in a whole new light.

Best of Luck to Everyone

What do you expect from an effective DMT in progressive MS?

In clinic yesterday I was discussing the natalizumab SPMS trial with a SPMSer. It dawned on the MSer, after some discussion, that even if the trial was positive and they were randomised to active agent they would probably not notice any discernible effects at a personal or individual level. The reason for this is that we, the clinicians, don’t expect an effective drug for progressive MS to stop disease progression but to merely slow the rate at which SPMS (or PPMS) progresses. In other words if you were progressing a rate X before the drug you now progress at rate Y, which is simply a slower rate of progression than before. If this was the case you would have no indication the drug was necessarily working. Of course we would like the drug to stop disease progression all together, i.e. stabilise your disease, or hopefully improve your neurological functioning, but this seems unlikely based on observations from other progressive trials and in animal models of SPMS. I have already discussed this issue in some detail before on this blog (see previous survey), but would like to revisit it as I am not sure how to best communicate this information to potential trial participants in a clinical situation. I don't want to MSers volunteering for progressive trials to have unrealistic expectations.

Any ideas or suggestions would be helpful?

Other posts of interest on progressive disease

27 Apr 2012
Survey results: neuroprotection. "I am reassured that 55% of MSers expect and effective neuroprotective therapy to stabilise of improve their disability progression; this is a realistic expectation and something that may be ...

01 Apr 2012
A few weeks back one of the readers posted this comment: "Sick of conferences like MS Life. It's pure spin on the scientists' part. Firstly, how about you introduce truly efficacious therapies for progressive MS and then you'll ...
18 Mar 2012
I also spoke to them about the need for better trial designs for progressive MS and described the study design we are promoting using frequent lumbar punctures and neurofilament levels as an outcome measure. They were ...
24 Aug 2012
Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for ...
17 Aug 2012
Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS). Clin Proteomics. 2012;9(1):9. "The methods of this study ...
15 Aug 2012
Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients. Study Population: Adult, untreated patients with ...
19 Jul 2012
Giovannoni. Primary progressive MS. ACNR 2012;12(3):9-12. Although PPMS is relatively uncommon it remains a significant clinical problem both diagnostically and therapeutically. PPMS is almost certainly part of the MS ...

07 Jul 2012
Our strategic plan 2012-2016 identifies progressive MS as one of the three key priority areas for MSIF's international MS research going forward (along with paediatric MS and stem cells). This important research area has also ...
21 Jul 2012
But perhaps we should also introduce the Clinical Trials Network (CTN), which was set up specifically for Progressive MSers. This has been reported in some places but may not be common knowledge. As you know all too ...
28 Aug 2012
We compared OB+ versus OB- patients regarding progression to expanded disability status scale (EDSS) of 6.0 and to secondary progressive MS (SPMS). Cox proportional hazard models were used to compare the outcome ...
16 Jun 2012
BACKGROUND: Treatment options for MSers suffering from progressive forms of MS remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various ...
29 May 2012
Participants and treatments: 493 MSers with primary or secondary progressive MS were recruited to the study from 27 centres across UK between May 2006 and July 2008. It was a requirement for participants entering the trial ...
30 Jun 2012
Background:It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent.
13 Jul 2012
Thus, to develop safe therapeutic approaches for patients with progressive MS, it is essential to elucidate how mitoxantrone exerts it benefits. Accordingly, we initiated a prospective single-arm open-label study with 19 ...
16 Feb 2012
Challenging the dogma (1): progressive MS and remyelination. In response to a comment concerning dogma in the field of MS, I am going to publish a series of posts that are designed to "challenge the dogma". Dogma: ...