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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
oromucosal spray
oromucosal spray
Clinical Trial Site
Choceň, Czechia
Clinical Trial Site 2
Poznan, Greater Poland Voivodeship, Poland
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.
Time frame: 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)
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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
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Clinical Trial Site 1
Poznan, Greater Poland Voivodeship, Poland
Clinical Trial Site
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland
Clinical Trial Site 1
Krakow, Lesser Poland Voivodeship, Poland
Clinical Trial Site
Oświęcim, Lesser Poland Voivodeship, Poland
Clinical Trial Site 2
Warsaw, Masovian Voivodeship, Poland
Clinical Trial Site 1
Warsaw, Masovian Voivodeship, Poland
Clinical Trial Site
Gdansk, Pomeranian Voivodeship, Poland
Clinical Trial Site
Chorzów, Silesian Voivodeship, Poland
...and 6 more locations
Change From Baseline in Weight
Time frame: 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
Time frame: 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
Time frame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
Change From Baseline in Erythrocytes
Time frame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
Change From Baseline in Hemoglobin
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Baseline, Day 15, and Day 21
Plasma Concentrations for Δ9-tetrahydrocannabinol (THC)
Plasma concentrations were assessed using blood samples collected at the timepoints specified.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.