Evaluation of the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis (RELEASE MSS5)

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

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.

Study Overview

• Status: Terminated
• Conditions: Spasticity With Multiple Sclerosis
• Intervention / Treatment: Drug: Nabiximols; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Choceň, Czechia, 565 01
    • NeuropsychiatrieHK
  • Hradec Králové, Czechia, 503 41
    • NeuropsychiatrieHK
  • Teplice, Czechia, 415 29
    • Krajská Zdravotní - Nemocnice Teplice
• Poland
  • Kujawsko-Pomorskie
    • Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-163
      • Centrum Medyczne Neuromed - Ośrodek Badań Klinicznych
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-016
      • Indywidualna Praktyka Lekarska Dr Hab Konrad Rejdak
  • Malopolskie
    • Kraków, Malopolskie, Poland, 30-149
      • Małopolskie Centrum Kliniczne
    • Oświęcim, Malopolskie, Poland, 32-600
      • Instytut Zdrowia dr Boczarska-Jedynak
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-868
      • Centrum Medyczne Pratia - Warszawa
    • Warszawa, Mazowieckie, Poland
      • Szpital Wolski im dr. Anny Gostyńskiej Samodzielny Publiczny Zakład Opieki Zdrowotnej
  • Slaskie
    • Katowice, Slaskie, Poland, 40-571
      • MA-LEK A.M. Maciejowscy S.C. Centrum Terapii SM
    • Katowice, Slaskie, Poland, 40-684
      • DENDRYT Centrum Medyczne
    • Katowice, Slaskie, Poland, 40-686
      • Neuro-Medic Janusz Zbrojkiewicz
    • Zabrze, Slaskie, Poland, 41-800
      • Wielospecjalistyczne Centrum Medyczne Ibismed
  • Swietokrzyskie
    • Kielce, Swietokrzyskie, Poland, 25-726
      • RESMEDICA Poradnia Neurologiczna
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 61-853
      • Niepubliczny Zakład Opieki Zdrowotnej NEURO - KARD
• Spain
  • Barcelona, Spain, 8003
    • Institut Hospital del Mar d'Investigacions Mèdiques
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Sevilla, Spain, 41009
    • Hospital Vithas Nisa Sevilla
  • Madrid
    • Getafe, Madrid, Spain, 289005
      • Hospital Universitario de Getafe
• United Kingdom
  • England
    • North London, England, United Kingdom, EN1 1LJ
      • Panthera Biopartners - North London
    • Plymouth, England, United Kingdom, PL6 8BT
      • ReCognition Health - Plymouth
    • Preston, England, United Kingdom, PR2 9QB
      • Panthera Biopartners - Preston
    • Sheffield, England, United Kingdom, S10 2JF
      • Sheffield Teaching Hospitals NHS Foundation Trust
  • Scotland
    • Inverness, Scotland, United Kingdom, IV2 3UJ
      • Nhs Highland
• United States
  • Colorado
    • Denver, Colorado, United States, 80209
      • Mountain View Clinical Research
  • Florida
    • Naples, Florida, United States, 34105
      • Collier Neurologic Specialists
    • Tampa, Florida, United States, 33613
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60062
      • Consultants in Neurology - Northbrook
  • South Carolina
    • Greer, South Carolina, United States, 29650
      • Premier Neurology Research, PC
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Neurology Clinic-Cordova

Participation Criteria

Eligibility Criteria

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

Description

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)
• 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 [Screening] or Visit 2 [Day 1]), 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 (Screening)
• Has any other clinically significant disease or disorder (including seizure disorder) that, in the opinion of the investigator, may put the participant, other participants, or site staff at risk because of participation in the trial, influence the interpretation of trial results, or may affect the participant's ability to take part in the trial
• Has any abnormalities identified following a physical examination, clinical laboratory, serology, or other applicable screening procedures that, in the opinion of the investigator, would jeopardize the safety of the participant or the conduct of the study if he or she took part in the trial
• Has any history of suicidal behavior in the 5 years prior to Visit 1 (Screening) or a score of 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the month prior to Visit 1 (Screening)
• Has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to Visit 1 (Screening)
• 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
• Currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7
• Currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's Wort)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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. 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.	Drug: Nabiximols; oromucosal spray; Other Names: GW-1000-02; Sativex
Placebo Comparator: 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.	Drug: Placebo; oromucosal spray

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 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 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	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.	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)	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.	Baseline, Day 15, and Day 21
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.	Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2021
• Primary Completion (Actual): November 11, 2022
• Study Completion (Actual): November 11, 2022

Study Registration Dates

• First Submitted: July 14, 2021
• First Submitted That Met QC Criteria: July 29, 2021
• First Posted (Actual): July 30, 2021

Study Record Updates

• Last Update Posted (Estimated): December 11, 2024
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: MS; multiple sclerosis; spasticity; nabiximols; velocity-dependent muscle tone
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Muscle Spasticity; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Analgesics; Nabiximols
• Other Study ID Numbers: GWSP20105; 2020-003271-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No