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 With Multiple Sclerosis
- Sponsor
- Jazz Pharmaceuticals
- Enrollment
- 56
- Locations
- 29
- Primary Endpoint
- Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief 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.
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 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.
Investigators
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)
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. 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.
Intervention: Nabiximols
Placebo
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.
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 Electrocardiogram Pulse Rate(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))
- 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 Electrocardiogram Parameters(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)(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))
- Number of Participants With Suicidal Ideation or Behavior Based on The Columbia Suicide Severity Rating Scale (CSSRS)(Baseline, Day 15, and Day 21)
- 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))
- 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 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 Hematocrit Ratio(Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2))