Saturday, 1 November 2014

Fumarates in progressive MS

Is it ethical to perform uninformative clinical trials? #MSBlog #MSResearch

"This exploratory study of fumarates in progressive MS is a step in the right direction. On balance it is impossible to stay whether or not there is any treatment effect as this study not designed to look for a treatment effect and was under-powered; i.e. too few patients to assess whether there is a treatment effect or not. This study is essentially an observational study with no control group. To be able to assess a treatment effect you need a decent baseline period of observation and then a period of observation on the treatment. A better design is a blinded placebo-controlled arm. In addition, to clinical observation it would have been appropriate to see objective biomarkers in this study; i.e. MRI and/or spinal fluid biomarkers to assess if there is any effect of fumarates on the biology of MS. Interestingly, the FDA demands double-blind placebo-controlled studies as the gold standard, but how easy is it to double-blind fumarate studies? It is probably impossible as the majority of MSers get flushing and gastrointestinal symptoms on the drug."

"Some would argue that studies of this nature that have no hope of providing an answer are unethical. They consume resources and provide MSers with a sense of false hope. What do you think?"

"The good news is that Biogen-Idec is planning a secondary progressive trial of dimethyl fumarate (DMF or Tecfidera). Let's hope they design the trial to be long enough to take into account the potential for therapeutic lag and the asynchronous progressive MS hypothesis."


Strassburger-Krogias et al. Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther Adv Neurol Disord. 2014;7(5):232-8. 

OBJECTIVES: Therapeutic options in progressive forms of multiple sclerosis (MS) are still limited. Dimethyl fumarate (DMF) has immunomodulatory properties but may also exert antioxidative cytoprotective effects. Hence, it may be a therapeutic option for progressive MS. The aim of this observational study was to evaluate safety, adherence and efficacy of fumarates in patients with primary progressive MS (PPMS) or secondary progressive MS.


METHODS: Patients with progressive MS whose condition had failed to respond to standard therapies and had worsened received the fumarate mixture Fumaderm, licensed for psoriasis therapy in Germany, or DMF by pharmaceutical preparation (Bochum ethics approval no. 4797-13). At regular follow-up visits, tolerability and disease course were assessed.


RESULTS: Twenty-six patients [age 54 ± 7.8 years; female = 13 (50%); PPMS = 12 (46.2%); Expanded Disability Status Scale (EDSS) = 6.0 ± 0.4 (range 3.5-8.0); disease duration = 14.1 ± 8.7 years] were initiated on treatment with Fumaderm (n = 18) or pharmacy-prepared DMF (n=8). During a mean follow-up period of 13.2 ± 7.5 months (range 6-30) only five patients (19.2%) reported minor complaints. In 15 patients (57.7%) EDSS remained stable. In five cases (19.2%) there was even a decrease in EDSS while in six patients (23.1%) there was an increase in EDSS of more than 0.5 points, reflecting deterioration. Laboratory values were controlled for lymphopenia, renal and hepatic values, without any safety problems. We observed no significant differences between the two pharmaceutical forms.


CONCLUSION: Our pilot data indicate that fumarate therapy appears to be safe and well tolerated by patients with progressive MS. In more than 75% of cases no further disease progression was evident. However, controlled studies are warranted to evaluate the detailed therapeutic potential of fumarates and their long-term effects in progressive MS.


CoI: multiple

Its all in the family


Up to 20% of all multiple sclerosis (MS) cases are familial. The concordance rates for monozygotic and dizygotic twins are 25-30% and 3-5% respectively. Certain isolated regions have a higher prevalence of MS. An estimated 30% of the disease heritability is accounted for, mostly by common risk alleles. Interpretation of risk alleles, gene-gene and gene-environment interactions is challenging, but all are believed to be important factors in the development of MS. Isolates and MS families are warranted for further research concerning these issues.


Although it is often said that MS is not a genetic disease, it is very clear that indeed there is a strong genetic component to MS. At Ms life when we get to speak to alot of MSers it is is amazing how many people have a family member affected. Now this does not mean that if you have MS your children will, if fact the likelihood is that it willl not. However the chance is greater than if you did not have MS. In this Danish study one in five of the referrals was some on who had an affected family member. There are now about 160 genes that have been identfied only another 250 to go.

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...'

Unrelated Blogger Comments November

Sometime you want to say some thing that is unrelated to the posts. This is the spot for you.