Evaluation of the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis
Condition: Spasticity With Multiple Sclerosis
MeSH terms: Muscle Spasticity; Multiple Sclerosis; Sclerosis
Intervention: Nabiximols; Placebo
Intervention description: oromucosal spray; oromucosal spray
Intervention MeSH terms: Nabiximols
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: multiple sclerosis; MS; spasticity; velocity-dependent muscle tone; nabiximols

Summary:

      This study will be conducted to evaluate the effect of multiple doses of nabiximols compared
      with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs
      (Lower Limb Muscle Tone-6 [LLMT-6]) in participants with multiple sclerosis (MS). LLMT-6 is
      defined as the average of the 6 individual Modified Ashworth Scale (MAS)-transformed scores
      of knee flexors, knee extensors, and plantar flexors on both sides of the body.
    

Eligibility criteria:

        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 trial requirements

          -  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 is
             expected to remain stable for the duration of the trial

          -  Has an Modified Ashworth Scale (MAS) untransformed score of at least 2 in 2 or more of
             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 stable
             dosing regimen for at least 30 days prior to Visit 1 (Screening). The participant must
             be willing to maintain the same antispasticity medication and not plan to initiate a
             new course of physiotherapy for the duration of the trial.

          -  If currently receiving an approved MS disease-modifying therapy, it must be at a
             stable dose for at least 3 months prior to Visit 1 (Screening) and be expected to
             remain stable for the duration of the trial.

          -  If currently receiving dalfampridine or fampridine, it must be at a stable dose for at
             least 3 months prior to Visit 1 (Screening) and is expected to remain stable for the
             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 days
        immediately preceding Visit 2 (Day 1)

        Exclusion Criteria:

          -  Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal or
             recreational purposes in the 30 days prior to Visit 1 (Screening) or unable to abstain
             for the duration of the study

          -  Did not tolerate or did not respond adequately to treatment with nabiximols or another
             cannabis-based medication if exposed at any time before the 30-day period prior to
             Visit 1 (Screening)

          -  Any concomitant disease or disorder that has spasticity-like symptoms or that may
             influence 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 the participant'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 6
             months of Visit 1 [Screening]) or is unwilling to abstain for the duration of the
             trial

          -  Currently taking antipsychotic medication

          -  Currently taking benzodiazepines unless doses and dosing regimen have been stable for
             at least 30 days prior to Visit 1 (Screening)

          -  Clinically suspected to have a contracture in one of the muscle groups of the lower
             limbs, preventing assessment with the MAS

          -  Has any known or suspected hypersensitivity to cannabinoids or any of the excipients
             of the investigational medicinal product (IMP)

          -  Male and fertile (i.e., after puberty unless permanently sterile by bilateral
             orchiectomy) unless willing to ensure that he uses male contraception (condom or
             vasectomy) or remains sexually abstinent during the trial and for 3 months thereafter

          -  Female and of childbearing potential (i.e., following menarche and until becoming
             postmenopausal for ≥ 12 consecutive months unless permanently sterile by hysterectomy,
             bilateral salpingectomy, or bilateral oophorectomy) unless willing to ensure that she
             uses a highly effective method of birth control (e.g., intrauterine
             device/hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or
             sexual abstinence) during the trial and for 3 months thereafter. Participants using
             combined hormonal methods or a progestogen-only pill or injection or implant should
             use an additional barrier method such as a male condom or diaphragm during the trial
             and 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 3
             months thereafter.

          -  Has received an IMP within the 30 days prior to Visit 1 (Screening)

          -  Has any other clinically significant disease or disorder (including seizure disorder)
             that, in the opinion of the investigator, may put the participant, other participants,
             or site staff at risk because of participation in the trial, influence the
             interpretation of trial results, or may affect the participant's ability to take part
             in the trial

          -  Has any abnormalities identified following a physical examination, clinical
             laboratory, serology, or other applicable screening procedures that, in the opinion of
             the investigator, would jeopardize the safety of the participant or the conduct of 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) or a
             score of 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the
             month prior to Visit 1 (Screening)

          -  Has any known or suspected history of alcohol or substance abuse (including opiate
             abuse) or dependence within 1 year prior to Visit 1 (Screening)

          -  Currently using an illicit drug or current nonprescribed use of any prescription drug

          -  Has a history of psychiatric or neurologic disorder that, in the opinion of the
             investigator, may interfere with trial participation, data interpretation, or conduct
             of trial procedures

          -  Has a history of severe psychiatric disorder that may be exacerbated by the use of a
             cannabinoid-containing product

          -  Has any planned clinical interventions or intends to change any or all medications
             that 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)