Evaluation of the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis

Inclusion Criteria:

Screening (Visit 1)

• Willing and able to give informed consent for participation in the trial

• Willing and able (in the investigator's opinion) to comply with all trialrequirements

• Has had a diagnosis with any disease subtype of multiple sclerosis (MS), by revised 2017 McDonald criteria, for at least 12 months prior to Visit 1 (Screening) and isexpected to remain stable for the duration of the trial

• Has an Modified Ashworth Scale (MAS) untransformed score of at least 2 in 2 or moreof 6 muscle groups (right knee flexors, left knee flexors, right knee extensors,left knee extensors, right plantar flexors, or left plantar flexors) at Visit 1 (Screening)

• If currently receiving approved anti-spasticity therapy, it must be with a stabledosing regimen for at least 30 days prior to Visit 1 (Screening). The participantmust be willing to maintain the same antispasticity medication and not plan toinitiate a new course of physiotherapy for the duration of the trial.

• If currently receiving an approved MS disease-modifying therapy, it must be at astable dose for at least 3 months prior to Visit 1 (Screening) and be expected toremain stable for the duration of the trial.

• If currently receiving dalfampridine or fampridine, it must be at a stable dose forat least 3 months prior to Visit 1 (Screening) and is expected to remain stable forthe duration of the trial.

Additional Inclusion Criteria at Randomization (Visit 2)

• Completed at least 5 of 7 days of their electronic diary reporting during the 7 daysimmediately preceding Visit 2 (Day 1)

Exclusion Criteria:

• Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal orrecreational purposes in the 30 days prior to Visit 1 (Screening) or unable toabstain for the duration of the study

• Did not tolerate or did not respond adequately to treatment with nabiximols oranother cannabis-based medication if exposed at any time before the 30-day periodprior to Visit 1 (Screening)

• Any concomitant disease or disorder that has spasticity-like symptoms or that mayinfluence the participant's level of spasticity

• Medical history suggests that relapse/remission is likely to occur during the trial,which, in the opinion of the investigator, is expected to influence theparticipant's spasticity

• Has had a relapse of MS within the 60 days prior to Visit 1 (Screening)

• Currently using botulinum toxin injection for the relief of spasticity (within 6months of Visit 1 [Screening]) or is unwilling to abstain for the duration of thetrial

• Currently taking antipsychotic medication

• Currently taking benzodiazepines unless doses and dosing regimen have been stablefor at least 30 days prior to Visit 1 (Screening)

• Clinically suspected to have a contracture in one of the muscle groups of the lowerlimbs, preventing assessment with the MAS

• Has any known or suspected hypersensitivity to cannabinoids or any of the excipientsof the investigational medicinal product (IMP)

• Male and fertile (i.e., after puberty unless permanently sterile by bilateralorchiectomy) unless willing to ensure that he uses male contraception (condom orvasectomy) or remains sexually abstinent during the trial and for 3 monthsthereafter

• Female and of childbearing potential (i.e., following menarche and until becomingpostmenopausal for ≥ 12 consecutive months unless permanently sterile byhysterectomy, bilateral salpingectomy, or bilateral oophorectomy) unless willing toensure that she uses a highly effective method of birth control (e.g., intrauterinedevice/hormone-releasing system, bilateral tubal occlusion, vasectomized partner, orsexual abstinence) during the trial and for 3 months thereafter. Participants usingcombined hormonal methods or a progestogen-only pill or injection or implant shoulduse an additional barrier method such as a male condom or diaphragm during the trialand for 3 months thereafter.

• Female and pregnant (positive pregnancy test at Visit 1 [Screening] or Visit 2 [Day 1]), lactating, or planning pregnancy during the course of the trial or within 3months thereafter.

• Has received an IMP within the 30 days prior to Visit 1 (Screening)

• Has any other clinically significant disease or disorder (including seizuredisorder) that, in the opinion of the investigator, may put the participant, otherparticipants, or site staff at risk because of participation in the trial, influencethe interpretation of trial results, or may affect the participant's ability to takepart in the trial

• Has any abnormalities identified following a physical examination, clinicallaboratory, serology, or other applicable screening procedures that, in the opinionof the investigator, would jeopardize the safety of the participant or the conductof the study if he or she took part in the trial

• Has any history of suicidal behavior in the 5 years prior to Visit 1 (Screening) ora score of 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in themonth prior to Visit 1 (Screening)

• Has any known or suspected history of alcohol or substance abuse (including opiateabuse) or dependence within 1 year prior to Visit 1 (Screening)

• Currently using an illicit drug or current nonprescribed use of any prescriptiondrug

• Has a history of psychiatric or neurologic disorder that, in the opinion of theinvestigator, may interfere with trial participation, data interpretation, orconduct of trial procedures

• Has a history of severe psychiatric disorder that may be exacerbated by the use of acannabinoid-containing product

• Has any planned clinical interventions or intends to change any or all medicationsthat may have an effect on spasticity or MS during the trial

• Currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7

• Currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin,phenobarbital, St. John's Wort)