Wednesday, 6 May 2015

Trial for PPMSers

People with Primary Progressive MS Progressive say we do not think about them and there is nothing for them to get involved with. However they are wrong.

If you are eligible please consider volunteering for: 

A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo


Laquinimod is a drug that was hoped to be a DMT in relapsing-remitting MS. Whilst it was well tolerated it was unfortunately found not to be a very good immunomodulator and only reduced the relapse rate by about 21% compared to placebo. This is worse than current DMT. However what was unusual was that despite being a poor immunomodulator with regard to slowing relapses it showed   a significant effect on disability confirmed after 3 months (34% risk reduction) and 6 months (46% risk reduction). Which suggests it may have some effect on slowing the rate of nerve loss. One of the mechanisms of this drug is through the inhibition of nuclear factor of activated T cells and so it blocks immune responses. Some of these may be microglial responses that are probably important in progressive MS.  Likewise some MSers also have problems with the immune response that causes relapsing disease and so  this element may also partially respond to MS.

This study is looking for 375 PPMSers in up to 105 sites in USA, Canada, Germany, Italy, the Netherlands,  Poland,  Russia, Spain, Ukraine, USA and the good old United Kingdom.  

We are one of the sites within the UK, and so if you are eligible for this trial (Details at www.clinical Trials.gov NCT02284568) contact your MS specialist team.

Other sites in the UK are Bristol, Edinburgh, Liverpool, Nottingham, Oxford, Plymouth, Stoke on Trent and Swansea.

Inclusion Criteria:
  • Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
  • Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
  • Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
  • Documented evidence of clinical disability progression in the 2 years prior to screening.
  • Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
  • Patients must be between 25 to 55 years of age, inclusive
  • Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.
  • Patients must sign and date a written informed consent prior to entering the study.
  • Patients must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:
  • Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
  • Progressive neurological disorder other than PPMS.
  • Any MRI record showing presence of cervical cord compression.
  • Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
  • Relevant history of vitamin B12 deficiency.
  • Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
  • Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
  • Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
  • Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
  • Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
  • Prior use of monoclonal antibodies ever, except for:
  • natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)
  • rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
  • Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
  • Previous use of laquinimod.
  • Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
  • Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
  • Previous total body irradiation or total lymphoid irradiation.
  • Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
  • Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
  • Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
  • Use of inducers of CYP3A4 within 2 weeks prior to baseline.
  • Pregnancy or breastfeeding.
  • Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
  • Serum direct bilirubin which is ≥2×ULN at screening.
  • Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
  • A known history of hypersensitivity to gadolinium (Gd).
  • Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
  • Inability to successfully undergo MRI scanning, including claustrophobia.
  • Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
CoI: We are investigators running this trial on behalf of Teva at Barts Health.

17 comments:

  1. It's no good just giving the gesture of thinking about PPMSers, they deserve tangible and efficacious medicinal treatments. For decades PPMSers have been in scientists thoughts but they remain without real hope. They have been failed and continue to be failed.

    ReplyDelete
    Replies
    1. Have you missed the simvastatin and phenytoin neuroprotection trial results? The situation you describe no longer holds and will improve markedly in the future.

      Delete
    2. It is clear some PPMSers respond in part to DMT also

      Delete
    3. If this is the case why are they not put on the stronger drugs such as lemtrada? Surely they have the most to gain

      Delete
  2. How long until phenytoin or others are available as a treatment?

    ReplyDelete
    Replies
    1. Maybe never. It will need more trials for phenytoin. If the optic neuritis trial was repeated it may help convince neuro-ophthalmologists of the value and maybe neuros as for STAT there is talk of STAT2, but will it need STAT3 also

      Delete
    2. oh great (not!) - so what is the sucess of the trials? incentives for pharma? do you think pharma will wake up and take your results into their labs to modify sodium channell blockers or is this a dead horse already?

      or is pharma not interested in progressive ms? i doubt that given that it's such a huge market of unmet needs.

      Delete
    3. 1. Yes, I think pharma will wake up to the fact that neuroprotection is possible in MS. They have lots of neuroprotectants they developed for stroke, which have gone through toxicity and phase I safety but were not successful in stroke as they couldn't be given soon enough. This will not be the case for MS.
      2. Pharma is definitely interested in progressive MS but up to now they've been looking at the existing immunomodulators and the results haven't been great. I think they will now realise that you need neuroprotectants perhpas in conjunction with a DMT.
      Hope that helps. We know pharma visit this blog regularly.

      Delete
    4. MD2 - thanks - I hope you're right.

      1. Perhaps you should lobby pharma with your (excellent) trial results - they may hesitate but I bet that if your results are replicable (and I am sure they are) pharma will jump on the bandwagon.

      2. Also, the new better model of progressive MS developed by MouseDoc should be advertised cos that's also a great success!

      3. I hope we MSers can take neuroprotectives without DMTs cos many progressives don't have problems with relapses so inflammation is not a priority, imho.

      Delete
    5. Anon 2.32 Biogen just spent $670 million buying a sodium channel blocker company, for example, one suspects there are a few useful agents in the cupboard.
      Anon 5:51 Would you just want a neuroprotective or a DMT plus neuroprotective as it is clear that many progressive MSers have inflammatory lesions in their CNS.

      Delete
    6. oh, I am both anons :-)) I'm ANNA btw.

      That is great news - I firmly believe in the validity of your results, they are just so clever,honest. So great to see pharma giving it a go.

      I would prefer one drug tbh cos they have so many side-effects and if you double the pills which in turn have different machanism of actions the risks increase as well as the cross-interactions between the drugs.

      A drug cocktail is not really something I'm crazy about - perhaps the regulation of the channels will do the trick without tons of other stuff.

      Delete
    7. In our hands regulation of the channels does one thing not both, but an induction therapy and then neuroprotective amintinence may be a way forward.

      Delete
  3. Gosh, the scientists running this blog expect PPMSers to be ecstatic because they're at least doing what they get paid for.

    These trail results are meaningless to a PPMSer decaying away right now. It might be good news to bearded academics and geeks, but it's not something you ought to expect us current PPMSers to be jubilant about. Get real!

    ReplyDelete
    Replies
    1. I understand your frustration, however, the docs on this blog are really good at what they're doing - if only everyone was of their league.

      We need to hope that 2015 with all its interesting results gives an impetus for greater and faster discoveries.

      I feel that the first domino has been set in motion.

      I'm a rather sceptical type generally but this years has already proved a good one.

      Delete
    2. But if the research and trials aren't done the situation for progressive MSers will never improve. No-one is expecting jubilation but some of us consider the glass to be half full. I would fervently hope that the pace of progress in this area will gather apace and the fact that (if I can be immodest) have been prime movers on this is a source of pride.

      Delete
  4. Md1003 is possible remylation. Definitely not out of the picture the next set of results could change the whole picture please god

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.