Sunday, 2 November 2014

Riluzole: another neuroprotection failure

Riluzole in MS: not another negative neuroprotective trial. #MSBlog #MSResearch


"Riluzole is only the second licensed neuroprotective drug and the only one licensed to treat a neurodegenerative disease, ALS (amyotrophic lateral sclerosis) or MND (motor neurone disease), commonly know as Lou Gehrig's disease. The other neuroprotective drug is nimodipine that is licensed to treat stroke in the setting of subarachnoid haemorrhage (SAH); in this setting nimodipine, which is a calcium channel blocker, is given prophylactically before the stroke occurs. Whether nimodipine works as a true neuroprotectant or simply prevents or reduces the amount of arterial spasm triggered by the blood around the arteries at the base of the brain, is a moot point."


"Riluzole works mainly via blocking sodium channels and also has an effect on glutamate receptors. A preliminary trial in PPMS suggested riluzole may be an effective neuroprotective drug in MS, which is why we are very keen to test it in a larger study. The results of the study below are very disappointing in that riluzole had no effect on brain atrophy when added onto interferon-beta in MSers with very early disease. Unfortunately, the study groups were not balanced at baseline with the riluzole group having higher baseline brain atrophy than the placebo group. This is not a trivial problem in that baseline brain atrophy in CIS and early MS is a poor prognostic factor and predicts a greater likelihood of disease progression in the immediate future. When these baseline imbalances were taken into account the brain atrophy rates were essentially similar in the groups randomised to either placebo or riluzole. This statistical correction however does not necessarily take into account the rate of atrophy between the two groups may differ. Hence I have to conclude that this study is not definitive and we still don't know if riluzole has  the potential to work as a neuroprotective drug in MS or not. This is very important for our group. Why? Because riluzole is one of the drugs we are testing in the MS-SMART study in the UK. This trial is comparing 3 active drugs against a placebo in SPMS. Recruitment for this study will be opening in December. The good news is that the PROXIMUS and MS-SMART studies will be recruiting patients in parallel and will be providing patients different options."


The following are the inclusion and exclusion criteria for the MS-SMART Study (ClinicalTrials.gov: NCT01910259):

Eligibility:

  1. Ages Eligible for Study: 25 Years to 65 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Inclusion Criteria:
  1. Confirmed diagnosis of SPMS at randomisation
  2. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years. Progression can be evident from either an increase of at least one point in EDSS or clinical documentation of increasing disability in patients notes
  3. EDSS 4.0-6.5
  4. Aged 25 to 65
  5. Men or Women of childbearing age must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the 3 drugs from time of consent, to 6 weeks after treatment inclusive
  6. Females have a negative pregnancy test within 7 days prior to being enrolled (baseline visit) unless not of child bearing potential e.g. have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy or they are postmenopausal
  7. Willing and able to comply with the trial protocol and have the ability to understand and complete questionnaires
  8. Willing and able to give full written informed consent
  9. Able to undertake MRI
Exclusion Criteria:
  1. Pregnancy or breast feeding females
  2. Patients unable to tolerate baseline MRI scan or scan not of adequate quality for analysis (e.g. too much movement artefact)
  3. Patients fitted with pacemakers or permanent hearing aids
  4. Significant organ co-morbidity (e.g. malignancy or renal or hepatic failure)
  5. Routine screening blood values (LFT) >/ 3 x upper limit of normal (ULN) of site reference ranges (AST/ALT, bilirubin, ˠGT)
  6. Potassium >5.5mmol/l
  7. Sodium <125mmol/l
  8. Creatinine >130µmol/l
  9. Neutrophil count <1.0 x109 /l
  10. Platelet count <100 x109 /l
  11. Relapse within 3 months of baseline visit
  12. Patients who have been treated with iv or oral steroids within 3 months of baseline visit (these patients can undergo future screening visits once the 3 month window has expired)
  13. Commencement of Fampridine within 6 months of baseline visit
  14. Use of immunosupressants (e.g. azathioprine, methotrexate, cyclosporine) or first generation disease modifying treatments (β-interferons, glatiramer) within 6 months of baseline visit
  15. 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
  16. Use of mitoxantrone/natalizumab/alemtuzumab/daclizumab if treated within 12 months of baseline visit
  17. Primary progressive MS
  18. Relapsing-remitting MS
  19. Known hypersensitivity to the active substances and their excipients to any of the active drugs for this trial
  20. Use of: lithium, chlorpropamide, triamterene, spironolactone,
  21. Use of potassium supplements

Epub: Waubant et al. A randomized controlled phase II trial of riluzole in early multiple sclerosis. Ann Clin Transl Neurol. 2014 May;1(5):340-7.

OBJECTIVES: We evaluated the effect of riluzole versus placebo added to weekly IM interferon beta-1a in early multiple sclerosis (MS).

METHODS: This is a randomized (1:1), double-blind, placebo-controlled trial of riluzole 50 mg twice daily in subjects with MS onset less than 1 year prior. Trial participation was up to 3 years. The primary endpoint was change in percent brain volume change. Secondary endpoints included changes in normalized gray and normal-appearing white matter volumes, retinal nerve fiber layer thickness (RNFL), MS Functional Composite and Symbol Digit Modalities Test scores. Mixed model regression analysis was used to compare the changes over time between groups.

RESULTS: Forty-three subjects were randomized to study drug (22 riluzole, 21 placebo). Baseline characteristics were overall similar between groups except for older age (P = 0.042), higher normalized cerebrospinal fluid volume (P = 0.050), lower normalized gray matter volume (P = 0.14), and thinner RNFL (P = 0.043) in the riluzole group. In the primary analysis, percent brain volume change in the placebo group decreased at a rate of 0.49% per year whereas the riluzole group decreased by 0.86% per year (0.37% more per year; 95% CI -0.78, 0.024; P = 0.065). Although age did not influence the rate of brain volume decline, the difference between groups was attenuated after adjustment for baseline normalized gray matter and lesion volume (0.26% more per year in riluzole group; 95% CI -0.057, 0.014; P = 0.22). Analyses of secondary outcomes showed no differences between groups.


INTERPRETATION: This trial provides class 1 evidence that riluzole treatment does not meaningfully reduce brain atrophy progression in early MS.

2 comments:

  1. What is the reasoning to study riluzole, a drug with little benefit in preventing motor neuron degeneration in ALS, in neurodegeneration in MS? I realize that ALS is not MS but there must be some similarities in the pathology of neurodegeneration between these two diseases. Secondly, are neurodegeneration and brain atrophy synonymous?

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    Replies
    1. There is a before and after study in PPMS done in Holland and this gave the hit that progression was slowed.

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