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
Overview
- Phase
- Phase 3
- Intervention
- Nabiximols
- Conditions
- Spasticity in Participants With Multiple Sclerosis
- Sponsor
- Jazz Pharmaceuticals
- Enrollment
- 68
- Locations
- 4
- Primary Endpoint
- Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
- •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)
Arms & Interventions
Nabiximols
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.
Intervention: Nabiximols
Placebo
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.
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)
Time Frame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of 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. 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.
Secondary Outcomes
- 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 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 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 Hemoglobin(Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2))
- Plasma Concentrations for Cannabidiol (CBD)(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.)
- Change From Baseline in Hematocrit Ratio(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)(Baseline, Day 15, and Day 21)
- Plasma Concentrations for Δ9-tetrahydrocannabinol (THC)(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)(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)(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.)
- Number of Participants With Any Treatment-Emergent Adverse Events (TEAEs)(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 Erythrocytes(Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2))
- Change From Baseline in Lower Limb Muscle Tone-4 (LLMT-4)(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))