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

Study Overview
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Brief Summary
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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.

Detailed Description
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Each period of this multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial includes a 7-day Baseline period, a 3-week treatment period (comprising a 2-week titration phase and a 1-week maintenance phase). Eligible participants will enter the 7-day baseline period of each treatment period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record their 11-point Numerical Rating Scale (NRS) spasticity score and spasm count using an electronic daily diary. On Day 1, eligible participants will be randomized to 1 of 2 treatment sequences, each composed of 2 treatment periods, with administration of multiple doses of nabiximols or placebo in a 1:1 ratio. Participants will be advised to titrate the investigational medicinal product (IMP), beginning with 1 spray/day, to an optimized dose or to a maximum of 12 sprays/day over the first 14 days of treatment. Participants should continue at the same dose level achieved at the end of the titration phase ±1 spray divided into a morning dose and an evening dose for the remainder of the treatment period. Lower limb muscle tone, health-related quality of life, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period. Participants who complete the trial will participate for a total of approximately 11 weeks (77 days), including the 7-day baseline period.

Official Title
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A Randomized, Double-blind, Placebo-controlled, 2-way Crossover Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Patients With Multiple Sclerosis

Conditions
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Spasticity With Multiple Sclerosis

Intervention / Treatment
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* Drug: Nabiximols
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nabiximols<br>Nabiximols is a complex botanical medicine formulated from extracts of the cannabis plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and also contains minor constituents, including other cannabinoid and non-cannabinoid plant components, such as terpenes, sterols, and triglycerides. Study dependent: Each spray delivers 100 microliters (μL) of nabiximols. A pre-determined number of sprays, but no less than 4 sprays, of nabiximols will be self-administered by participants as an oromucosal spray, under supervision of trial staff during 2 study visits to the trial site after they temporarily discontinued treatment with prescribed nabiximols (Sativex) as part of their regular medication. | Drug: Nabiximols<br>* oromucosal spray<br>* Other names: Sativex;|
| Placebo Comparator: Placebo<br>Placebo to match nabiximols is presented as an oromucosal spray containing the excipients ethanol and propylene glycol (50% v/v) with colorings and flavored with peppermint oil (0.05% v/v). Each spray delivers 100 μL containing no active ingredients. | Drug: Placebo<br>* oromucosal spray<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lower Limb Muscle Tone-6 (LLMT-6) from Day 1 predose to Day 21 (Treatment Period 1) and from Day 31 predose to Day 51 (Treatment Period 2) | 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. | predose on Days 1 and 31; Days 21 and 51 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LLMT-4 from Day 1 predose to Day 21 and from Day 31 predose to Day 51 | LLMT-4 is defined as the average of the 4 individual MAS transformed scores of knee flexors and knee extensors on both sides of the body. | predose on Days 1 and 31; Days 21 and 51 | 
| Number of participants with treatment-emergent adverse events |  | up to Day 58 | 
| Number of participants with clinically significant changes in clinical laboratory parameters from Baseline to Day 51 |  | Baseline; up to Day 51 | 
| Number of participants with clinically significant changes in vital sign values from Baseline to Day 58 |  | Baseline; up to Day 58 | 
| Number of participants with clinically significant changes in physical examination procedures from Baseline to Day 51 |  | Baseline; up to Day 51 | 
| Number of participants with clinically significant changes in 12-lead electrocardiogram parameters from Baseline to Day 51 |  | Baseline; up to Day 51 | 
| Columbia-Suicide Severity Rating Scale (C-SSRS) Score at Screening (Visit 1) and at each subsequent timepoint with reference to the last assessment (since last visit) |  | Screening; up to Day 58 | 
| Plasma concentrations for Δ9-tetrahydrocannabinol (THC) and its relevant metabolites (11-hydroxy-Δ9-tetrahydrocannabinol [11-OH-THC] and 11-carboxy-Δ9-tetrahydrocannabinol [11-COOH-THC]) | Days 1, 15, 21, 31, 45, and 51 | Day 1: predose; 0-2 and 2-4 hours (hr) postdose (PD). Day 15: 0-2 and 2-4 hr PD. Day 21: predose; 0-1 and 2-3 hr PD. Day 31: predose; 0-2 and 2-4 hr PD. Day 45: 0-2 and 2-4 hr PD. Day 51: predose; 0-1 and 2-3 hr PD | 
| Plasma concentrations for cannabidiol (CBD) and its relevant metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]) | Days 1, 15, 21, 31, 45, and 51 | Day 1: predose; 0-2 and 2-4 hr PD. Day 15: 0-2 and 2-4 hr PD. Day 21: predose; 0-1 and 2-3 hr PD. Day 31: predose; 0-2 and 2-4 hr PD. Day 45: 0-2 and 2-4 hr PD. Day 51: predose; 0-1 and 2-3 hr PD | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, MS, spasticity, velocity-dependent muscle tone, nabiximols