Safety and Effectiveness of Nabiximols Oromucosal Spray as Add-on Therapy in Participants With Spasticity Due to Multiple Sclerosis

Study Overview
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Brief Summary
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This trial is being conducted to demonstrate the efficacy of nabiximols, compared with placebo, when added to standard of care, in the treatment of muscle spasms associated with multiple sclerosis (MS).

Detailed Description
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This multicenter, double-blind, placebo-controlled trial includes a 28-day Baseline period, a 12-week treatment period (comprising a 2-week titration phase and a 10-week maintenance phase), and 2-week follow-up period. Eligible participants will enter the 28-day baseline period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record spasm count using an electronic daily diary. At screening (Day 1), eligible participants will be randomized to either 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 may leave a gap between sprays of approximately 15 minutes. 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. Daily spasm count, the participant's symptom experiences, clinician's assessment of spasticity, functional outcomes, health-related quality of life, changes in mood, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period. Participants who complete the trial will participate for a total of approximately 18 weeks (127 days), including the 28-day baseline period. Participants will have a maximum duration of 85 (±7) days on IMP treatment.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Parallel-group Trial of the Efficacy and Safety of Nabiximols Oromucosal Spray as Add-on Therapy in Patients With Spasticity Due to Multiple Sclerosis

Conditions
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Multiple Sclerosis (MS)

Intervention / Treatment
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* Drug: Nabiximols
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Criteria at screening: Participant is male or female aged 18 years or above. Participant has had a diagnosis with any disease subtype of multiple sclerosis (MS), by revised 2017 McDonald criteria, for at least 12 months prior to screening and is expected to remain stable for the duration of the trial. Participant has had treatment with at least 1 optimized oral antispasticity therapy prior to Visit 1 that must include either oral baclofen or oral tizanidine (monotherapy or combination therapy). Participant is currently receiving optimized treatment with at least 1 oral antispasticity medication (baclofen, tizanidine, and/or dantrolene) and has been stable for at least 30 days prior to screening. If the participant is currently receiving an approved MS disease-modifying therapy, it must be at a stable dose for at least 3 months prior to screening and is expected to remain stable for the duration of the trial. Exclusion Criteria: Participant has any concomitant disease or disorder that has spasticity-like symptoms or that may influence the participant's level of spasticity. Participant has had a relapse of MS within the 60 days prior to screening (Visit 1). Participant is currently using or has used cannabis or a cannabinoid-derived product for medicinal or recreational use (within 30 days of screening) and is unwilling to abstain for the duration of the trial. Participant is currently using botulinum toxin injection for the relief of spasticity (within 6 months of screening) and is unwilling to abstain for the duration of the trial. Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP. Participant is male and fertile unless willing to ensure that he uses male contraception or remains sexually abstinent during the trial and for 3 months thereafter. Participant is female and of childbearing potential unless willing to ensure that she uses a highly effective method of birth control during the trial and for 3 months thereafter. Participant is female and pregnant, lactating, or planning pregnancy during the course of the trial or within 3 months thereafter. Participant has received an IMP within the 30 days prior to screening. Participant has a history of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product. Participant has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to screening. Participant is currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7. Participant is currently taking strong 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nabiximols<br> | Drug: 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.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.<br>* Other names: Sativex;|
| Placebo Comparator: Placebo<br> | Drug: 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 microliters (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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in the Average Daily Spasm Count (from Days 57 to 84 Compared to the Average Daily Spasm Count for the Baseline Period) |  | Baseline, Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in The Multiple Sclerosis Spasticity Scale (MSSS-88) Total Score at Day 85 |  | Baseline, Day 85 | 
| Number of Participants with Treatment-emergent Adverse Events |  | Baseline through Day 99 | 
| Number of Participants with Clinically Significant Changes from Baseline in Clinical Laboratory Test Values at Days 29 and 85 |  | Baseline, Days 29 and 85 | 
| Number of Participants with Clinically Significant Changes from Baseline in Vital Sign Values at Days 15, 29, 57, 85, and 99 |  | Baseline, Days 15, 29, 57, 85, and 99 | 
| Number of Participants with Clinically Significant Changes from Baseline in Physical Examination Values at Day 85 |  | Baseline, Day 85 | 
| Number of Participants with Clinically Significant Changes from Baseline in 12-lead Electrocardiogram (ECG) Values at Days 29 and 85 |  | Baseline, Days 29 and 85 | 
| Mean Columbia-Suicide Severity Rating Scale (C-SSRS) Score at Days 15, 29, 57, and 85 |  | Days 15, 29, 57, and 85 | 
| Plasma Concentrations for Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Relevant Metabolites at Days 1 (Predose), 15, 29, 57, and 85 | Sparse pharmacokinetic (PK) sampling option, blood samples will be taken as follows: Day 1, predose; Days 15, 29, 57, and 85, any time during the visit. Semi-intensive PK sampling option, blood samples will be taken as follows: Day 1, predose. At 1 visit (either Days 15, 29, or 57, 1 sample predose (i.e., prior to administration of investigational medicainal product [IMP] at the investigational site), 1 sample between 2 and 3 hours postdose, 1 sample between 4 and 6 hours postdose, and 1 sample between 6 and 8 hours postdose | Days 1, 15, 29, 57, and 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spasticity