Sativex

Pharmacotherapeutic Group: Other Analgesics and Antipyretics ATC Code: N02BG10 The European Medicines Agency has deferred the obligation to submit the results of studies with Sativex in one or more subsets of the paediatric population in spasticity. See section 4.2 for information on paediatric use. Mechanism of action As part of the human endocannabinoid system (ECS), cannabinoid receptors, CB 1 and CB 2 receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function. THC acts as a partial agonist at both CB 1 and CB 2 receptors, mimicking the effects of the endocannabinoids, which may modulate the effects of neurotransmitters (e.g. reduce effects of excitatory neurotransmitters such as glutamate). In animal models of MS and spasticity CB receptor agonists have been shown to ameliorate limb stiffness and improve motor function. These effects are prevented by CB antagonists, and CB 1 knockout mice show more severe spasticity. In the CREAE (chronic relapsing experimental autoimmune encephalomyelitis) mouse model, Sativex produced a dose-related reduction in the hind limb stiffness. Clinical experience Sativex has been studied at doses of up to 48 sprays/day in controlled clinical trials of up to 19 weeks duration in more than 1500 patients with MS. In the pivotal trials to assess the efficacy and safety of Sativex for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) the primary efficacy measure was a 0 to 10 point Numeric Rating Scale (NRS) on which patients indicated the average level of their spasticity related symptoms over the last 24 hours where 0 is no spasticity and 10 is the worst possible spasticity. In a first Phase 3 placebo controlled trial over a 6-week treatment period the difference from placebo reached statistical significance but the difference between treatments of 0.5 to 0.6 points on the 0-10 point NRS was of questionable clinical relevance. In a responder analysis 40% Sativex and 22% placebo responded to treatment using the criterion of greater than a 30% reduction in NRS score. A second 14 week Phase 3 study failed to show a significant treatment effect. The difference from placebo on the NRS score was 0.2 points. It was postulated that a clinically useful treatment effect in some patients might be partly masked by data from non-responders in the analyses of mean changes. In analyses comparing NRS scores with patient global impression of change (PGI), a 19% NRS response was estimated to represent a clinically relevant improvement on the PGI and a response of 28% “much improved” on the PGI. In post hoc exploratory combined analyses of the above two studies, a 4-week trial period using a 20% NRS response threshold was predictive of eventual response defined as a 30% reduction. A third Phase 3 trial incorporated a formalised 4-week therapeutic trial period prior to randomisation. The aim of the trial was to assess the benefit of continued treatment for patients who achieve an initial response to treatment. 572 patients with MS and refractory spasticity all received single blind Sativex for four weeks. After four weeks on active treatment 273 achieved a reduction of at least 20% on the spasticity symptom NRS, of which 241 met the entry criteria for randomisation, with a mean change from the start of treatment of -3.0 points on the 10 point NRS. These patients were then randomised to either continue to receive active or switch to placebo for the 12 week double-blind phase, for a total of 16 weeks treatment overall. During the double-blind phase the mean NRS scores for patients receiving Sativex generally remained stable (mean change from randomisation in NRS score -0.19), while the mean NRS scores for patients switched to placebo increased (mean change in NRS score was +0.64 and median change was +0.29). The difference* between treatment groups was 0.84 (95% CI -1.29, -0.40). * Difference adjusted for centre, baseline NRS and ambulatory status Of those patients who had a 20% reduction from screening in NRS score at week 4 and continued in the trial to receive randomised treatment, 74% (Sativex) and 51% (placebo) achieved a 30% reduction at week 16. The results over the 12-week randomised phase are shown below for the secondary endpoints. The majority of secondary endpoints showed a similar pattern to the NRS score, with patients who continued to receive Sativex maintaining the improvement seen from the initial 4-week treatment period, while patients switching to placebo declined: Modified Ashworth Score for spasticity: Spasm frequency (per day): Sleep disruption by spasticity: (0 to 10 NRS) Timed 10 metre walk (seconds): Motricity index (arm and leg): Barthel Activities of Daily Living: Sativex -0.1; Placebo +1.8 ; Adjusted Difference -1.75 (95% CI -3.80, 0.30) Sativex -0.05; Placebo +2.41 Adjusted Difference -2.53 (95% CI -4.27, -0.79) Sativex -0.25; Placebo +0.59 ; Adjusted Difference -0.88 (95% CI -1.25, -0.51) Sativex -2.3; Placebo +2.0; Adjusted Difference -3.34 (95% CI -6.96, 0.26) No differences between treatment groups were seen. Odds ratio for improvement: 2.04 Subject global impression of change (OR=1.71), carer global impression of change (OR=2.40) and physician global impression of change (OR=1.96) all showed statistically significant superiority of Sativex over placebo. The benefit of continued treatment in the long-term was studied in a placebo controlled, parallel group, randomised withdrawal trial in subjects taking long-term Sativex. Thirty six patients with a mean duration of Sativex use prior to the trial of 3.6 years were randomised to either continue with Sativex treatment or switch to placebo for 28 days. The primary endpoint was time to treatment failure, defined as the time from the first day of randomised treatment to a 20% increase in NRS or premature withdrawal from randomised treatment. Treatment failure was experienced by 44% of Sativex patients, and 94% of placebo patients, hazard ratio 0.335 (95% CI 0.16, 0.69). In a study designed to identify its abuse potential, Sativex at a dose of 4 sprays taken at one time did not differ significantly from placebo. Higher doses of Sativex of 8 to 16 sprays taken at one time did show abuse potential comparable to equivalent doses of dronabinol, a synthetic THC. In a QTc study a dose of Sativex 4 sprays over 20 minutes twice daily was well-tolerated, but a substantially supratherapeutic dose of 18 sprays over 20 minutes twice daily resulted in significant psychoactivity and cognitive impairment. Paediatric population The efficacy and safety of Sativex was evaluated in a 12-week randomised, double-blind, placebo-controlled study involving 72 children and adolescents aged from 8–18 years with cerebral palsy or traumatic central nervous system injury. The placebo controlled phase was followed by a 24-week open label extension phase. The maximum permitted daily dose in this trial was 12 sprays and was titrated for 9 weeks. At baseline, most patients had severe impairment of motor function (Gross Motor Function Classification Scale level IV or V). The primary efficacy endpoint was the change in spasticity severity 0–10 numerical rating scale (NRS) score from baseline which is a carer reported outcome measure. After 12 weeks of treatment, the mean change from baseline for Sativex-treated participants' spasticity severity NRS scores was −1.850 (SD 1.9275) and for placebo participants −1.573 (SD 2.0976). The least square mean difference between the two groups (−0.166, 95% CI −1.119, 0.787) was not statistically significant (p=0.7291). No new safety findings were identified in this study. No data are available in children below 8 years (see section 4.2 for information on paediatric use).