Safety and Effectiveness of Nabiximols Oromucosal Spray as Add-on Therapy in Participants With Spasticity Due to Multiple Sclerosis (RELEASE MSS3)

A Double-blind, Randomized, Placebo-controlled, Parallel-group Trial of the Efficacy and Safety of Nabiximols Oromucosal Spray as Add-on Therapy in Patients With Spasticity Due to Multiple Sclerosis

This trial is being conducted to demonstrate the efficacy of nabiximols, compared with placebo, when added to standard of care, in the treatment of muscle spasms associated with multiple sclerosis (MS).

Study Overview

• Status: Terminated
• Conditions: Multiple Sclerosis (MS)
• Intervention / Treatment: Drug: Nabiximols; Drug: Placebo

Detailed Description

This multicenter, double-blind, placebo-controlled trial includes a 28-day Baseline period, a 12-week treatment period (comprising a 2-week titration phase and a 10-week maintenance phase), and 2-week follow-up period.

Eligible participants will enter the 28-day baseline period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record spasm count using an electronic daily diary. At screening (Day 1), eligible participants will be randomized to either 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 may leave a gap between sprays of approximately 15 minutes. 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.

Daily spasm count, the participant's symptom experiences, clinician's assessment of spasticity, functional outcomes, health-related quality of life, changes in mood, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period.

Participants who complete the trial will participate for a total of approximately 18 weeks (127 days), including the 28-day baseline period. Participants will have a maximum duration of 85 (±7) days on IMP treatment.

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Hradec Králové, Czechia, 500 03
    • Neurologie Taláb Radomír Doc. MUDr., CSc
  • Jihlava, Czechia, 586 01
    • Nemocnice Jihlava
  • Praha 10, Czechia, 100 34
    • Fakultní nemocnice Královské Vinohrady
  • Teplice, Czechia, 415 29
    • Krajská Zdravotní - Nemocnice Teplice
  • Pardubice
    • Choceň, Pardubice, Czechia, 565 01
      • Poliklinika Choceň
• Poland
  • Lublin, Poland, 20-855
    • Centrum Medyczne Oporow
  • Plewiska, Poland, 62-064
    • Neurologiczny NZOZ Centrum Leczenia SM Ośrodek Badań Klinicznych im. dr n. med. Hanki Hertmanowskiej Witosław Cieślak
  • Wrocław, Poland, 51-685
    • Wromedica Centrum Zdrowia
  • Łódź, Poland, 90-001
    • SP ZOZ Uniwersytecki Szpital Kliniczny Nr 1 im. Norberta Barlickiego w Łodzi
  • Dolnoslaskie
    • Wrocław, Dolnoslaskie, Poland, 51-685
      • Wromedica Centrum Zdrowia
  • Kujawsko-Pomorskie
    • Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-163
      • Centrum Medyczne Neuromed - Ośrodek Badań Klinicznych
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-684
      • Centrum Medyczne NeuroProtect
    • Warszawa, Mazowieckie, Poland, 01-868
      • Centrum Medyczne Pratia - Warszawa
  • Slaskie
    • Katowice, Slaskie, Poland, 40-555
      • 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
• Romania
  • Caracal, Romania, 235200
    • Spitalul Municipal Caracal
  • Constanţa, Romania, 900123
    • Spitalul Clinic Cai Ferate Constanta
  • Câmpulung, Romania, 115100
    • Centrul Medical Clubul Sanatatii
  • Rădăuți, Romania, 725400
    • Spitalul Municipal Sf. Dr. Cosma si Damian Radauti
• United Kingdom
  • England
    • London, England, United Kingdom, E1 1BB
      • Barts Health NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham School of Medicine
  • Florida
    • Port Charlotte, Florida, United States, 33952
      • Neurostudies - Port Charlotte
    • Tampa, Florida, United States, 33613
      • University of South Florida
    • Tampa, Florida, United States, 33634
      • Accel Research Sites - Enterprise
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Shepherd Center
  • Illinois
    • Northbrook, Illinois, United States, 60062
      • Consultants in Neurology - Northbrook
  • Indiana
    • Avon, Indiana, United States, 46123
      • American Health Network of Indiana
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63131
      • The Multiple Sclerosis Center For Innovations In Care
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates - Raleigh Location
  • Ohio
    • Dayton, Ohio, United States, 45417
      • University of Cincinnati (UC) Health
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Neurology Clinic - Cordova
    • Knoxville, Tennessee, United States, 37922
      • Hope Neurology
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Round Rock, Texas, United States, 78681
      • Central Texas Neurology Consultants

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Criteria at screening:

1. Participant is male or female aged 18 years or above.
2. Participant has had a diagnosis with any disease subtype of multiple sclerosis (MS), by revised 2017 McDonald criteria, for at least 12 months prior to screening and is expected to remain stable for the duration of the trial.
3. Participant has had treatment with at least 1 optimized oral antispasticity therapy prior to Visit 1 that must include either oral baclofen or oral tizanidine (monotherapy or combination therapy).
4. Participant is currently receiving optimized treatment with at least 1 oral antispasticity medication (baclofen, tizanidine, and/or dantrolene) and has been stable for at least 30 days prior to screening.
5. If the participant is currently receiving an approved MS disease-modifying therapy, it must be at a stable dose for at least 3 months prior to screening and is expected to remain stable for the duration of the trial.

Exclusion Criteria:

1. Participant has any concomitant disease or disorder that has spasticity-like symptoms or that may influence the participant's level of spasticity.
2. Participant has had a relapse of MS within the 60 days prior to screening (Visit 1).
3. Participant is currently using or has used cannabis or a cannabinoid-derived product for medicinal or recreational use (within 30 days of screening) and is unwilling to abstain for the duration of the trial.
4. Participant is currently using botulinum toxin injection for the relief of spasticity (within 6 months of screening) and is unwilling to abstain for the duration of the trial.
5. Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP.
6. Participant is male and fertile unless willing to ensure that he uses male contraception or remains sexually abstinent during the trial and for 3 months thereafter.
7. Participant is female and of childbearing potential unless willing to ensure that she uses a highly effective method of birth control during the trial and for 3 months thereafter.
8. Participant is female and pregnant, lactating, or planning pregnancy during the course of the trial or within 3 months thereafter.
9. Participant has received an IMP within the 30 days prior to screening.
10. Participant has a history of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product.
11. Participant has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to screening.
12. Participant is currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7.
13. Participant is currently taking strong 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: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: 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 microliters (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.
Experimental: Nabiximols	Drug: 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.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.; Other Names: GW-1000-02; Sativex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	The change in the average daily spasm count was assessed compared to the baseline period.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Multiple Sclerosis Spasticity Scale (MSSS-88) Total Score	The MSSS-88 is a self-reported measure of the impact of spasticity (muscle stiffness and spasms) in MS. This 88-item scale captures the patient experience and impact of spasticity, including muscle stiffness, pain and discomfort, muscle spasms, effect on daily activities, ability to walk, body movement, patient feelings, and social functioning. Responses to individual questions can range from "1 - not at all bothered" to "4 - extremely bothered", ranging from 88 to 352 total score. Scores are summed and higher scores indicate poor clinical outcome. Least square means are being reported, with greater negative values indicating better outcome.	Week 8 and Week 12
Number of Patients Reporting Any Treatment-emergent Adverse Events	A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product.	From date of first dose of IMP up to 30 days after last dose, up to approximately 16 weeks
Change From Baseline in Clinical Laboratory Test Values		Baseline up to Week 12
Change From Baseline in Erythrocytes		Baseline up to Week 12
Change From Baseline in Hemoglobin		Baseline up to Week 12
Change From Baseline in Hematocrit Ratio	The hematocrit ratio measures the volume of red blood cells compared to the total blood volume.	Baseline up to Week 12
Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin		Baseline up to Week 12
Change From Baseline in Blood Pressure		Baseline up to Week 12
Change From Baseline in Heart Rate		Baseline up to Week 12
Change From Baseline in Electrocardiogram Parameters		Baseline up to Week 12
Change From Baseline in Electrocardiogram Pulse Rate		Baseline up to Week 12
Change From Baseline in Weight		Baseline up to Week 12
Change in Body Mass Index		Baseline up to Week 12
Number of Patients With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)	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.	Screening up to Week 12

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): February 10, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 18, 2019

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Spasticity
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Multiple Sclerosis; Sclerosis; Muscle Spasticity; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Nabiximols
• Other Study ID Numbers: GWSP18023; 2019-002623-14 (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