Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis (RELEASE MSS1)

• ClinicalTrials.gov Identifier: NCT04657666
• Recruitment Status: Completed
• First Posted: December 8, 2020
• Last Update Posted: June 30, 2022
• Sponsor: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Jazz Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Spasticity in Participants With Multiple Sclerosis	Drug: Nabiximols; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 21, 2020
• Actual Primary Completion Date: May 4, 2022
• Actual Study Completion Date: May 10, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Nabiximols; oromucosal spray; Other Names: GW-1000-02; Sativex
Placebo Comparator: 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.	Drug: Placebo; oromucosal spray

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline in Lower Limb Muscle Tone-6 (LLMT-6) to Day 21 and Day 51 [ Time Frame: Baseline (predose Day 1 of Treatment Period 1 [TP1]; predose Day 31 [TP2]); Days 21 (TP1) and 51 (TP2)] ]
   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.

Secondary Outcome Measures :

1. Change from Baseline in Lower Limb Muscle Tone-4 (LLMT-4) to Day 21 and Day 51 [ Time Frame: Baseline (predose Day 1 [TP1]; predose Day 31 [TP2]); Days 21 (TP1) and 51 (TP2)] ]
   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.
2. Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: up to Day 58 ]
3. Number of Participants with a Clinically Significant Change from Baseline in Clinical Laboratory Test Values at Days 21 and 51 [ Time Frame: Baseline (Day 1 of TP1; Day 31 of TP2); Day 21 (TP1) and Day 51 (TP2) ]
4. Number of Participants with a Clinically Significant Change from Baseline in Vital Sign Values at Days 15, 21, 45, 51, and 58 [ Time Frame: Baseline (Day 1), Day 15, and Day 21 of TP1; Baseline (Day 31), Day 45, and Day 51 of TP2; Day 58 ]
5. Number of Participants with a Clinically Significant Change from Baseline in Physical Examination Values at Days 21 and 51 [ Time Frame: Baseline (Day 1 of TP1; Day 31 of TP2); Day 21 (TP1) and Day 51 (TP2) ]
6. Number of Participants with a Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Values at Days 21 and 51 [ Time Frame: Baseline (Day 1 of TP1; Day 31 of TP2); Day 21 (TP1) and Day 51 (TP2) ]
7. Mean Columbia-Suicide Severity Rating Scale (C-SSRS) Score at Days 15, 21, 45, 51 and 58 [ Time Frame: Baseline (Day 1 of TP1; Day 31 of TP2); Day 15 (TP1), Day 21 (TP1), Day 45 (TP2) and Day 51 (TP2); Day 58 ]
8. Plasma Concentrations for THC at Days 1, 15, 21, 31, 45, and 51 [ Time Frame: Baseline (Day 1), Day 15, and Day 21 of TP1; Baseline (Day 31), Day 45, and Day 51 of TP2 ]
   Day 1: predose and at 0-2 and 2-4 hours postdose. Day 15: 0-2 and 2-4 hours postdose. Day 21: predose and at 0-1 and 2-3 hours postdose. Day 31: predose and at 0-2 and 2-4 hours postdose. Day 45: 0-2 and 2-4 hours postdose. Day 51: 0-2 and 2-4 hours postdose
9. Plasma Concentrations for CBD at Days 1, 15, 21, 31, 45, and 51 [ Time Frame: Baseline (Day 1), Day 15, and Day 21 of TP1; Baseline (Day 31), Day 45, and Day 51 of TP2 ]
   Day 1: predose and at 0-2 and 2-4 hours postdose. Day 15: 0-2 and 2-4 hours postdose. Day 21: predose and at 0-1 and 2-3 hours postdose. Day 31: predose and at 0-2 and 2-4 hours postdose. Day 45: 0-2 and 2-4 hours postdose. Day 51: 0-2 and 2-4 hours postdose
10. Plasma Concentrations for Relevant Metabolites for THC at Days 1, 15, 21, 31, 45, and 51 [ Time Frame: Baseline (Day 1), Day 15, and Day 21 of TP1; Baseline (Day 31), Day 45, and Day 51 of TP2 ]
    Day 1: predose and at 0-2 and 2-4 hours postdose. Day 15: 0-2 and 2-4 hours postdose. Day 21: predose and at 0-1 and 2-3 hours postdose. Day 31: predose and at 0-2 and 2-4 hours postdose. Day 45: 0-2 and 2-4 hours postdose. Day 51: 0-2 and 2-4 hours postdose
11. Plasma Concentrations for Relevant Metabolites for CBD at Days 1, 15, 21, 31, 45, and 51 [ Time Frame: Baseline (Day 1), Day 15, and Day 21 of TP1; Baseline (Day 31), Day 45, and Day 51 of TP2 ]
    Day 1: predose and at 0-2 and 2-4 hours postdose. Day 15: 0-2 and 2-4 hours postdose. Day 21: predose and at 0-1 and 2-3 hours postdose. Day 31: predose and at 0-2 and 2-4 hours postdose. Day 45: 0-2 and 2-4 hours postdose. Day 51: 0-2 and 2-4 hours postdose

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

Contacts and Locations

Locations

Czechia

Clinical Trial Site

Choceň, Czechia, 565 01

Poland

Clinical Trial Site

Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-163

Clinical Trial Site 1

Kraków, Malopolskie, Poland, 30-539

Clinical Trial Site

Oswiecim, Malopolskie, Poland, 32-600

Clinical Trial Site 2

Warszawa, Mazowieckie, Poland, 01-211

Clinical Trial Site 1

Warszawa, Mazowieckie, Poland, 01-868

Clinical Trial Site

Gdansk, Pomorskie, Poland, 80-803

Clinical Trial Site

Chorzow, Slaskie, Poland, 41-500

Clinical Trial Site 3

Katowice, Slaskie, Poland, 40-123

Clinical Trial Site 1

Katowice, Slaskie, Poland, 40-571

Clinical Trial Site 2

Katowice, Slaskie, Poland, 40-684

Clinical Trial Site

Kielce, Swietokrzyskie, Poland, 25-726

Clinical Trial Site 2

Poznan, Wielkopolskie, Poland, 61-853

Clinical Trial Site 1

Poznan, Wielkopolskie, Poland, 62-064

Clinical Trial Site

Kraków, Poland, 30-149

Clinical Trial Site

Zabrze, Poland, 41-800

Sponsors and Collaborators

Jazz Pharmaceuticals

More Information

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04657666
• Other Study ID Numbers: GWSP19066; 2019-002625-29 ( EudraCT Number )
• First Posted: December 8, 2020
• Last Update Posted: June 30, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jazz Pharmaceuticals:

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

Additional relevant MeSH terms:

Muscle Spasticity; Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Nabiximols; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs