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Outline

• Key Words

• Abstract
• Introduction
• Pivotal Studies of THC:CBD Oromucosal Spray
• Effect on Cognition and Mood
• Disclosures/Conflict of Interest
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

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 Key Words


• Cognition
• Mood
• Pivotal trial
• Phase 4 study
• Spasticity
• THC:CBD oromucosal spray

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 Introduction
Spasticity is a common and frequently disabling complication of multiple sclerosis (MS) and its prevalence increases as MS evolves; after 9-10 years of MS, approximately 50% of patients have greater than mild spasticity and 30% have greater than moderate spasticity [1]. MS patients with spasticity experience significantly worse symptomatology in terms of spasms, urinary dysfunction and sleep disturbances than those without spasticity [2].
THC:CBD oromucosal spray (Sativex®) is indicated for symptom improvement in adult patients with moderate to severe MS spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial 4-week trial of therapy. In the EU, treatment algorithms for management of MS spasticity include the use of THC:CBD oromucosal spray [3,4].
 
 Pivotal Studies of THC:CBD Oromucosal SprayThe THC:CBD oromucosal spray clinical trials program included three large pivotal phase III trials involving MS patients with treatment-resistant spasticity [5,6,7] (table 1). In the first two studies, mean changes from baseline in scores on the spasticity 0-10 numerical rating scale (NRS) were in favor of THC:CBD oromucosal spray compared with placebo, but differences between treatments did not reach statistical significance in the intent-to-treat populations [5,6]. Subsequent responder analyses indicated that 40% [5] and 36% [6] of patients, respectively, treated with THC:CBD oromucosal spray had achieved the threshold for clinically relevant improvement (≥30% NRS improvement from baseline) in the spasticity 0-10 NRS score.

Table 1. Pivotal studies of THC:CBD oromucosal spray for MS spasticity

An enriched-design study demonstrated the utility of a trial of therapy approach to identify responders to THC:CBD oromucosal spray [7]. After a 4-week trial of therapy with active medication, 47% of patients were initial responders (≥20% NRS improvement). At the end of the 12-week, randomized, double-blind phase, the NRS score had improved a further 0.04 points in the group treated with THC:CBD oromucosal spray and deteriorated 0.81 points in the group assigned to placebo; the difference was highly significant (p = 0.0002). Moreover, the proportion of clinically relevant responders at week 12 was significantly higher with THC:CBD oromucosal spray than with placebo (74 vs. 51%; p = 0.0003).
THC:CBD oromucosal spray was well tolerated in pivotal studies. Dizziness and fatigue were the most common treatment-related adverse events but were generally mild and resolved quickly; withdrawal rates due to adverse events were low. The incidence of adverse events was further reduced by introduction of a gradual ‘up titration’ schedule. Importantly, in clinical trials of THC:CBD oromucosal spray, there was no evidence of effects typically associated with recreational cannabis use.
 
 Effect on Cognition and MoodThe effects of THC:CBD oromucosal spray on cognition and mood were investigated in a randomized, double-blind, parallel-group, post-approval study in 120 patients with at least moderate MS spasticity [8]. After 50 weeks’ treatment with THC:CBD oromucosal spray or placebo, no statistically differences were observed between treatment groups for change from baseline in the Paced Auditory Serial Addition Test (cognitive ability) or the Beck Depression Inventory (mood). Patient, physician and caregiver Global Impression of Change scores indicated that efficacy was maintained over the long term (fig. 1). THC:CBD oromucosal spray was well tolerated; the most common adverse events during 50 weeks of use were vertigo, dizziness, fatigue and muscle spasticity. Study withdrawals were few and similar for THC:CBD oromucosal spray and placebo (12 vs. 11 patients).

Fig. 1. Patient, physician, and caregiver global impression of change (GIC) in spasticity after 50 weeks’ treatment with THC:CBD oromucosal spray or placebo [8]. *** p < 0.001; ** p = 0.0014; * p = 0.0042.

 
 Disclosures/Conflict of InterestOF has received honoraria as a consultant on advisory boards and as chairman or lecturer in meetings, and has also participated or is currently participating in clinical trials and other research projects promoted by Actelion Pharmaceuticals Ltd, Allergan, Almirall SA, Biogen-Idec Inc, Bayer-Schering, Merck Serono, Novartis Pharmaceuticals Corporation, Teva Neuroscience Inc.
Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Laboratorios Almirall SA (Barcelona, Spain).

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 References

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 Author Contacts
Dr. O. Fernández
Neurology Department, Hospital Regional Universitario de Málaga
Universidad de Málaga
Avda. de Carlos Haya s/n, 29010 Málaga (Spain)
E-Mail oscar.fernandez.sspa@juntadeandalucia.es

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 Article Information
Published online: September 26, 2014
Number of Print Pages : 3
Number of Figures : 1, Number of Tables : 1, Number of References : 8

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 Publication Details
European Neurology
Vol. 72, No. Suppl. 1, Year 2014 (Cover Date: September 2014)
Journal Editor: Bogousslavsky J. (Montreux)
ISSN: 0014-3022 (Print), eISSN: 1421-9913 (Online)
For additional information: http://www.karger.com/ENE

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Copyright / Drug Dosage / Disclaimer

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