Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04657666

Acronym

RELEASE MSS1

Enrollment

Registered

2020-12-08

Start date

2020-12-21

Completion date

2022-05-10

Last updated

2023-07-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Spasticity in Participants With Multiple Sclerosis

Keywords

spasticity, multiple sclerosis, nabiximols, adjunctive therapy, velocity-dependent muscle tone

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.

Interventions

DRUGNabiximols

oromucosal spray

DRUGPlacebo

oromucosal spray

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)	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

Measure	Time frame	Description
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)	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.
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)	A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product.
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	Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)	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.
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	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.
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 were assessed using blood samples collected at the timepoints specified.
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 were assessed using blood samples collected at the timepoints specified.
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.	Plasma concentrations were assessed using blood samples collected at the timepoints specified.
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.	Plasma concentrations were assessed using blood sample collected at the timepoints specified.

Countries

Czechia, Poland

Participant flow

Recruitment details

A total of 68 participants who met all inclusion and no exclusion criteria were randomized to treatment at 9 clinic centers in Poland and 1 center in Czech Republic.

Pre-assignment details

Randomized participants completed 2 treatment periods with administration of study drug for 21 days per period. A washout period of at least 7 days separated the 2 treatment periods. During the washout period, participants continued their current MS anti-spasticity medications. Each treatment period included a dose titration phase (\ 14 days) followed by a maintenance-dose phase (\ 7 days), where the optimized dose level remained unchanged for the remainder of the period after titration.

Participants by arm

Arm	Count
Nabiximols First, Then Placebo Participants who were randomized to receive GW-1000-02 (nabiximols) self-administered as an oromucosal spray for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received matching placebo treatment for 21 days (starting at Day 31; Treatment Period 2).	33
Placebo First, Then Nabiximols Participants who were randomized to receive matching placebo self-administered for 21 days (starting on Day 1; Treatment Period 1), followed by at least a 7-day wash out period, and then received GW-1000-02 (nabiximols) self-administered as an oromucosal spray in the morning and evening for 21 days (starting on Day 31; Treatment Period 2).	35
Total	68

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1	Administrative decision by investigator, GW, or a regulatory authority	0	1
Period 1	Withdrawal of participant consent	2	1
Period 1	Withdrawn/discontinued due to AE	1	0
Period 2	Other	2	0
Period 2	Withdrawn/discontinued due to AE	0	3

Baseline characteristics

Characteristic	Nabiximols First, Then Placebo	Placebo First, Then Nabiximols	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	0 Participants	2 Participants
Age, Categorical Between 18 and 65 years	31 Participants	35 Participants	66 Participants
Age, Continuous	49.7 years STANDARD_DEVIATION 9.9	49.7 years STANDARD_DEVIATION 9.7	49.7 years STANDARD_DEVIATION 9.7
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	33 Participants	35 Participants	68 Participants
Region of Enrollment Czechia	0 participants	1 participants	1 participants
Region of Enrollment Poland	33 participants	34 participants	67 participants
Sex: Female, Male Female	19 Participants	24 Participants	43 Participants
Sex: Female, Male Male	14 Participants	11 Participants	25 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 66	0 / 65
other Total, other adverse events	19 / 66	3 / 65
serious Total, serious adverse events	1 / 66	1 / 65

Outcome results

Primary

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.