Clinical trial NCT04984278: Evaluation of the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Participants With Multiple Sclerosis
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Spasticity With Multiple Sclerosis
Keywords: multiple sclerosis
MS
spasticity
velocity-dependent muscle tone
nabiximols
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-07-30
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Change From Baseline in Lower Limb Muscle Tone-6 (LLMT-6)
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
Secondary outcomes:
measure: Change From Baseline in Lower Limb Muscle Tone-4 (LLMT-4)
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Number of Participants With Any Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Blood Pressure
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Heart Rate
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Clinical Laboratory Test Values
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Erythrocytes
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Hemoglobin
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Hematocrit Ratio
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Erythrocyte Mean Corpuscular Volume
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Electrocardiogram Parameters
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Change From Baseline in Electrocardiogram Pulse Rate
timeFrame: Baseline (predose Day 1 of Treatment Period 1) up to Day 51 (end of treatment of Treatment Period 2)
measure: Number of Participants With Suicidal Ideation or Behavior Based on The Columbia Suicide Severity Rating Scale (CSSRS)
timeFrame: Baseline, Day 15, and Day 21
Other outcomes:
Locations:
city: Denver
country: United States
facility: Mountain View Clinical Research
state: Colorado
city: Naples
country: United States
facility: Collier Neurologic Specialists
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Consultants in Neurology - Northbrook
state: Illinois
city: Greer
country: United States
facility: Premier Neurology Research, PC
state: South Carolina
city: Cordova
country: United States
facility: Neurology Clinic-Cordova
state: Tennessee
city: Choceň
country: Czechia
facility: NeuropsychiatrieHK
city: Hradec Králové
country: Czechia
facility: NeuropsychiatrieHK
city: Teplice
country: Czechia
facility: Krajská Zdravotní - Nemocnice Teplice
city: Bydgoszcz
country: Poland
facility: Centrum Medyczne Neuromed - Ośrodek Badań Klinicznych
state: Kujawsko-Pomorskie
city: Lublin
country: Poland
facility: Indywidualna Praktyka Lekarska Dr Hab Konrad Rejdak
state: Lubelskie
city: Kraków
country: Poland
facility: Małopolskie Centrum Kliniczne
state: Malopolskie
city: Oświęcim
country: Poland
facility: Instytut Zdrowia dr Boczarska-Jedynak
state: Malopolskie
city: Warszawa
country: Poland
facility: Centrum Medyczne Pratia - Warszawa
state: Mazowieckie
city: Warszawa
country: Poland
facility: Szpital Wolski im dr. Anny Gostyńskiej Samodzielny Publiczny Zakład Opieki Zdrowotnej
state: Mazowieckie
city: Katowice
country: Poland
facility: MA-LEK A.M. Maciejowscy S.C. Centrum Terapii SM
state: Slaskie
city: Katowice
country: Poland
facility: DENDRYT Centrum Medyczne
state: Slaskie
city: Katowice
country: Poland
facility: Neuro-Medic Janusz Zbrojkiewicz
state: Slaskie
city: Zabrze
country: Poland
facility: Wielospecjalistyczne Centrum Medyczne Ibismed
state: Slaskie
city: Kielce
country: Poland
facility: RESMEDICA Poradnia Neurologiczna
state: Swietokrzyskie
city: Poznań
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej NEURO - KARD
state: Wielkopolskie
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
state: Madrid
city: Barcelona
country: Spain
facility: Institut Hospital del Mar d'Investigacions Mèdiques
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Sevilla
country: Spain
facility: Hospital Vithas Nisa Sevilla
city: North London
country: United Kingdom
facility: Panthera Biopartners - North London
state: England
city: Plymouth
country: United Kingdom
facility: ReCognition Health - Plymouth
state: England
city: Preston
country: United Kingdom
facility: Panthera Biopartners - Preston
state: England
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
state: England
city: Inverness
country: United Kingdom
facility: NHS Highland
state: Scotland
Study officials:
References: