Sativex^® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial

Abstract

Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex^®) as add-on therapy to optimised standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity.

Methods: Sativex^® as add-on therapy vs. further optimised first-line ANTispastics (SAVANT) was a two-phase trial. In Phase A, eligible patients received add-on THC:CBD spray for 4 weeks to identify initial responders [≥20% improvement from baseline in spasticity 0–10 numerical rating scale (NRS) score]. Following washout, eligible initial responders were randomised to receive THC:CBD spray or placebo for 12 weeks (double-blinded, Phase B). Optimisation of underlying antispasticity medications was permitted in both groups across all study periods.

Results: Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on THC:CBD spray (n = 53) or placebo (n = 53). The proportion of clinically relevant responders after 12 weeks (≥30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD spray than placebo (77.4 vs. 32.1%; p < 0.0001). Compared with placebo, THC:CBD spray also significantly improved key secondary endpoints: changes in mean spasticity NRS (p < 0.0001), mean pain NRS (p = 0.0013), and mean modified Ashworth’s scale (p = 0.0007) scores from Phase B baseline to week 12. Adverse events, when present, were mild/moderate and without new safety concerns.

Conclusions: Add-on THC:CBD oromucosal spray provided better and clinically relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone.

Keywords:

• Multiple sclerosis
• spasticity
• Sativex^®
• THC:CBD
• nabiximols

Acknowledgements

The authors wish to express their sincere thanks for the collaboration of participating patients and investigators [CZ: Y. Benešová (Brno), M. Dufek (Brno), P. Hradílek (Havířov), L. Janů (Plzeň), H. Lachmann (Prague), B. Luběnová (Olomouc), E. Meluzínová (Prague), I. Nováková (Prague), O. Škoda (Pelhřimov), I. Štětkářová (Prague), R. Taláb (Hradec Králové), M. Vachová (Teplice), M. Vališ (Choceň); AT: M. Guger (Linz)], all team members at study sites, Easthorn CRO, and Almirall S.A. Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Almirall S.A. (Barcelona, Spain).

Disclosure statement

J. Markovà has received fees as consultant or investigator in projects sponsored by Almirall, Amgen, Biogen, Merck, Novartis, Pfizer, Teva and other pharmaceutical companies. U. Essner and A. Lenschat are consultants for Almirall Hermal GmbH. B. Akmaz and C. Trompke are fulltime employees of Almirall Hermal GmbH. M. Marinelli and C. Vila are fulltime employees of Almirall S.A.

Additional information

Funding

This study was sponsored by Almirall Hermal GmbH and Almirall S.A.