Trial to Evaluate 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 as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) in participants with multiple sclerosis (MS) who have not achieved adequate relief from spasticity with other antispasticity medications.

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 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 maximum of 90 days, which consists of a maximum 29-day screening period and a maximum 61-day treatment period (s), including washout between periods, and safety follow-up.

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 in Participants 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) 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 and is expected to remain stable for the duration of the trial Has a 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 Currently receiving optimized treatment with at least 1 oral antispasticity drug (baclofen, tizanidine, and/or dantrolene) that has been stable for at least 30 days prior to Visit 1. Despite optimization, the participant does not have adequate relief of spasticity symptoms, including muscle spasms. Optimization of antispasticity medications is defined as having reached the most efficacious and best tolerated dose according to the relevant local prescribing information. 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 and is 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 and is expected to remain stable for the duration of the trial. For 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 and 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 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 Currently using botulinum toxin injection for the relief of spasticity (within 6 months of Visit 1) and 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 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 or Visit 2), 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 Has any history of suicidal behavior in the 5 years prior to Visit 1 or a score of 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the month prior to Visit 1 Has donated blood during the 3 months prior to Visit 1 and is unwilling to abstain from donation of blood during the trial Has been previously randomized into this trial Has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to Visit 1 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

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. Each spray delivers 100 microliters (μL) of nabiximols. Nabiximols will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks. | Drug: Nabiximols<br>* oromucosal spray<br>* Other names: Sativex;|
| Placebo Comparator: Placebo<br>Placebo to match nabiximols will be 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 will deliver 100 μL containing no active ingredients. Placebo will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks. | 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 From Baseline in Lower Limb Muscle Tone-6 (LLMT-6) | 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. Transformed MAS ranges from 0 (no increase in muscle tone) to 5 (affected part rigid in flexion or extension). The combined (treatment period 1 and treatment period 2) least square mean change from baseline in LLMT-6 score is being reported. Negative values indicate an improvement in muscle tone. | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lower Limb Muscle Tone-4 (LLMT-4) | 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. Transformed MAS ranges from 0 (no increase in muscle tone) to 5 (affected part rigid in flexion or extension). The combined (treatment period 1 and treatment period 2) least square mean change from baseline in LLMT-4 score is being reported. Negative values indicate an improvement in muscle tone. | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Number of Participants With Any Treatment-Emergent Adverse Events (TEAEs) | A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product. | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Blood Pressure |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Heart Rate |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Weight |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Body Mass Index |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Clinical Laboratory Test Values |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Erythrocytes |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Hemoglobin |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Hematocrit Ratio | Hematocrit was measured in whole blood samples. The ratio of packed cells to total volume was assessed. Normal ratio ranges from 0.350-0.470 female and 0.400-0.540 male (normal ranges per our central lab), 0.37 (or 37%) to 0.52 (or 52%) in adults. Lower hematocrit ratios indicate worse clinical outcome. | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Erythrocyte Mean Corpuscular Volume |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Electrocardiogram Parameters |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Change From Baseline in Electrocardiogram Pulse Rate |  | Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2) | 
| Number of Participants With Suicidal Ideation or Behavior Based on The Columbia Suicide Severity Rating Scale (CSSRS) | The C-SSRS is a short questionnaire that is used to assess suicidal ideation (5 questions) and behavior (5 questions) since last patient visit. The questionnaire is completed by participants answering yes or no to each question. | Baseline, Day 15, and Day 21 | 
| Plasma Concentrations for Δ9-tetrahydrocannabinol (THC) | Plasma concentrations were assessed using blood samples collected at the timepoints specified. | Period 1: Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. | 
| Plasma Concentrations for Relevant Metabolites, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), for Δ9-tetrahydrocannabinol (THC) | Plasma concentrations were assessed using blood samples collected at the timepoints specified. | Period 1: Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. | 
| Plasma Concentrations for Cannabidiol (CBD) | Plasma concentrations were assessed using blood samples collected at the timepoints specified. | Period 1: Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. | 
| Plasma Concentrations for Relevant Metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and 7-carboxy-cannabidiol (7-COOH-CBD), for Cannabidiol (CBD) | Plasma concentrations were assessed using blood sample collected at the timepoints specified. | Period 1: Day 1: predose,0-2 and 2-4 hours (hr) postdose. Day 15: 0-2 and 2-4 hr postdose. Day 21: predose,0-1 and 2-3 hr postdose. | 

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