European Journal of NeurologyVolume 18, Issue 9 p. 1122-1131 A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis A. Novotna, A. Novotna Krajska nemocnice Pardubice, Neurologicke odd, Paradubice, Czech RepublicSearch for more papers by this authorJ. Mares, J. Mares Neurologicka Klinika, Olomouc, Czech RepublicSearch for more papers by this authorS. Ratcliffe, S. Ratcliffe MAC UK Neuroscience Ltd, Manchester, UKSearch for more papers by this authorI. Novakova, I. Novakova MS Centrum, Neurologicka klinika, Prague, Czech RepublicSearch for more papers by this authorM. Vachova, M. Vachova MS centre of Hospital Teplice, Teplice, Czech RepublicSearch for more papers by this authorO. Zapletalova, O. Zapletalova Neurologicka klinika FN Ostrava, Ostrava, Czech RepublicSearch for more papers by this authorC. Gasperini, C. Gasperini Reparto Neurologico LANCISI Day Hospital, Centro Sclerosi Multipla, Rome, ItalySearch for more papers by this authorC. Pozzilli, C. Pozzilli Dipartimento di Scienze Neurologiche, Universita’ degli Studi, Rome, ItalySearch for more papers by this authorL. Cefaro, L. Cefaro Sant’Andrea Multiple Sclerosis Centre, University La Sapienza, Rome, ItalySearch for more papers by this authorG. Comi, G. Comi Centro Sclerosi Multipla Ospedale S. Raffaele, Milan, ItalySearch for more papers by this authorP. Rossi, P. Rossi Centro Sclerosi Multipla Ospedale S. Raffaele, Milan, ItalySearch for more papers by this authorZ. Ambler, Z. Ambler Neurologicka klinika FN Plzen, Plezn, Czech RepublicSearch for more papers by this authorZ. Stelmasiak, Z. Stelmasiak Katedra i Klinika Neurologii Akademii Medycznej, Lublin, PolandSearch for more papers by this authorA. Erdmann, A. Erdmann Pain Clinic F, Edith Cavell Hospital, Peterbrough, UKSearch for more papers by this authorX. Montalban, X. Montalban Hospital Universitari de la Vall d’Hebron, Antigua Escuela de Enfermeria, Barcelona, SpainSearch for more papers by this authorA. Klimek, A. Klimek Klinika Neurologii i Epileptologii z Oddzialem Udarowym, Lodz, PolandSearch for more papers by this authorP. Davies, P. Davies Department of Neurology, Northampton General Hospital, Northampton, UKSearch for more papers by this authorthe Sativex Spasticity Study Group, the Sativex Spasticity Study GroupSearch for more papers by this author A. Novotna, A. Novotna Krajska nemocnice Pardubice, Neurologicke odd, Paradubice, Czech RepublicSearch for more papers by this authorJ. Mares, J. Mares Neurologicka Klinika, Olomouc, Czech RepublicSearch for more papers by this authorS. Ratcliffe, S. Ratcliffe MAC UK Neuroscience Ltd, Manchester, UKSearch for more papers by this authorI. Novakova, I. Novakova MS Centrum, Neurologicka klinika, Prague, Czech RepublicSearch for more papers by this authorM. Vachova, M. Vachova MS centre of Hospital Teplice, Teplice, Czech RepublicSearch for more papers by this authorO. Zapletalova, O. Zapletalova Neurologicka klinika FN Ostrava, Ostrava, Czech RepublicSearch for more papers by this authorC. Gasperini, C. Gasperini Reparto Neurologico LANCISI Day Hospital, Centro Sclerosi Multipla, Rome, ItalySearch for more papers by this authorC. Pozzilli, C. Pozzilli Dipartimento di Scienze Neurologiche, Universita’ degli Studi, Rome, ItalySearch for more papers by this authorL. Cefaro, L. Cefaro Sant’Andrea Multiple Sclerosis Centre, University La Sapienza, Rome, ItalySearch for more papers by this authorG. Comi, G. Comi Centro Sclerosi Multipla Ospedale S. Raffaele, Milan, ItalySearch for more papers by this authorP. Rossi, P. Rossi Centro Sclerosi Multipla Ospedale S. Raffaele, Milan, ItalySearch for more papers by this authorZ. Ambler, Z. Ambler Neurologicka klinika FN Plzen, Plezn, Czech RepublicSearch for more papers by this authorZ. Stelmasiak, Z. Stelmasiak Katedra i Klinika Neurologii Akademii Medycznej, Lublin, PolandSearch for more papers by this authorA. Erdmann, A. Erdmann Pain Clinic F, Edith Cavell Hospital, Peterbrough, UKSearch for more papers by this authorX. Montalban, X. Montalban Hospital Universitari de la Vall d’Hebron, Antigua Escuela de Enfermeria, Barcelona, SpainSearch for more papers by this authorA. Klimek, A. Klimek Klinika Neurologii i Epileptologii z Oddzialem Udarowym, Lodz, PolandSearch for more papers by this authorP. Davies, P. Davies Department of Neurology, Northampton General Hospital, Northampton, UKSearch for more papers by this authorthe Sativex Spasticity Study Group, the Sativex Spasticity Study GroupSearch for more papers by this author First published: 01 March 2011 https://doi.org/10.1111/j.1468-1331.2010.03328.xCitations: 312 MU Dr. A. Novotna, Krajska nemocnice Pardubice, Neurologicke odd., Kyjevska 44, 632 03 Pardubice, Czech Republic (tel.: +420 467 434701; fax: +420 466 014702; e-mail: [email protected]). † See editorial by Claudio Solaro, on page 1113. ‡ Sativex does not yet have an INN, but the product does have a US Adopted Name (USAN): ‘nabiximols’. Therefore, we use ‘nabiximols’ in preference to the full product name throughout the text. § Trial registration: The details of this study were registered on clinicaltrials.gov (Ref. NCT00681538). Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Background: 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. Methods: 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 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks 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. Conclusions: 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. References 1 Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmer TL. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler 2004; 10: 589– 595. 2 Vukusic S, Van Bockstael V, Gosselin S, Confavreux C. Regional variations of multiple sclerosis prevalence in French farmers. J Neurol Neurosurg Psychiatry 2007; 78: 707– 709. 3 Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis (Cochrane Review). In: The Cochrane Library. 2001; Issue 3. 4 Smith CR, La Rocca NG, Giesser BS, Scheinberg LC. High-dose oral baclofen: experience in patients with multiple sclerosis. Neurology 1991; 41: 1829– 1831. 5 Beard S, Hunn A, Wright J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 2003; 7: iii, ix-x, 1-111. 6 House of Lords Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. Session 1997–98, 9th report. 7 Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 129– 180. 8 Pertwee RG. Neuropharmacology and therapeutic potential of cannabinoids. Addict Biol 2000; 5: 37– 46. 9 Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000; 404: 84– 87. 10 Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006; 66: 234– 246. 11 Wade D, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomised, placebo controlled study on 160 patients. Mult Scler 2004; 10: 434– 441. 12 Collin C, Davies P, Mutiboko IK, Ratcliffe S for the Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007; 14: 290– 296. 13 Wade DT, Collin C, Stott C, Duncombe P. Meta-analysis of the efficacy and safety of Sativex, on spasticity in people with multiple sclerosis. Mult Scler 2010; 16: 707– 714. 14 Farrar JT, Troxel AB, Stott C, Duncombe P, Jensen MP. Validity, reliability and clinical importance of change in a 0-10 numeric rating scale measure of spasticity: a post-hoc analysis of a randomized, double-blind, placebo-controlled trial. Clin Ther 2008; 30: 974– 985. 15 Anwar K, Barnes MP. A pilot study of a comparison between a patient scored numeric rating scale and clinician scored measures of spasticity in multiple sclerosis. NeuroRehabilitation 2009; 24: 333– 340. 16 Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomised, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010; 32: 451– 459. 17 Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 2001; 15: 300– 302. 18 Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 9395: 1517– 1526. 19 Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005; 76: 1664– 1669. 20 Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003; 17: 21– 29. 21 Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006; 12: 639– 645. 22 Vaney C, Heinzel-Gutenbrunner M, Jobin P, Tschopp F, et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler 2004; 10: 417– 424. 23 Sackett DL. Turning a blind eye: why we don’t test for blindness at the end of our trials. BMJ 2004; 328: 1136. 24 McQuay HJ, Derry S, Moore RA, Poulain P, Legout V. Enriched enrolment with randomised withdrawal (EERW): time for a new look at clinical trial design in chronic pain. Pain 2008; 135: 217– 220. Citing Literature Volume18, Issue9September 2011Pages 1122-1131 ReferencesRelatedInformation

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