A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex (R)), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis

Krajska nemocnice Pardubice, Neurologicke odd, Paradubice, Czech Republic.
European Journal of Neurology (Impact Factor: 4.06). 03/2011; 18(9):1122-31. DOI: 10.1111/j.1468-1331.2010.03328.x
Source: PubMed


  Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design.
  A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase.
  Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols.
  The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

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Available from: Paolo Rossi, Jul 06, 2015
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    • "However, very little is known about potential neuroprotective effects of these compounds on complex models of neurodegenerative diseases, which represent the complexity of the human diseases more faithfully. Sativex ® is a cannabinoid-based medicine already approved for the treatment of spasticity in multiple sclerosis [22] [23]. Sativex ® is a mixture of 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). "

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    • "This could suggest that Δ9-THC is the major therapeutic chemical within cannabis, based on the reports that cannabis in North America may have a low CBD content (ElSohly et al. 2000; Wilkinson et al. 2003; EMCDD 2008). However, pharmaceutical, medical cannabis extracts being developed (Sativex & Cannador) contain essentially equal proportions of Δ9-THC and CBD (Novotna et al. 2011; Zajicek et al. 2012; Langford et al. 2013). Although it has been reported that CBD may limit the side-effect potential of Δ9-THC within cannabis (Dalton et al. 1976; Russo and Guy 2006), little direct evidence has been provided for such a specific ratio and contrasts with the low CBD:Δ9-THC ratio (1:10–1:200) in many recreational cannabis extracts (Burgdorf et al. 2011). "
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    ABSTRACT: Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.
    Full-text · Article · Dec 2014 · Journal of Neuroimmune Pharmacology
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    • "The largest study of Sativex® published to date addressed this problem by adopting an 'enriched' design. Novotna et al. [49] recruited 572 refractory MS patients into a 4-week, single-blind period of treatment with Sativex® in addition to their existing medicine. Only those subjects who demonstrated at least a 20% improvement from baseline in spasticity over this period progressed into the second phase of the study. "
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    ABSTRACT: Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology. In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders. Copyright © 2013 John Wiley & Sons, Ltd.
    Preview · Article · Feb 2014 · Drug Testing and Analysis
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