| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptomatic relief of spasticity in Multiple Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of muscle spasm in Multiple Sclerosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028245 |
| E.1.2 | Term | Multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028335 |
| E.1.2 | Term | Muscle spasticity |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to establish the efficacy of nabiximols relative to placebo in reducing spasm count as part of the presentation of spasticity when used as adjunctive therapy in patients with multiple sclerosis (MS) who have not achieved adequate relief from other antispasticity agents. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
The Secondary objectives are:
- To evaluate the effect of nabiximols relative to placebo using the
following patient-reported outcome measure of spasticity:
. The MS Spasticity Scale (MSSS-88) total score
- To evaluate the pharmacokinetics (PK) of nabiximols
- To evaluate the safety and tolerability of nabiximols
The Exploratory objectives are:
- To evaluate the effect of nabiximols relative to placebo using the
following patient-reported outcome measures and clinician-administered
assessments of spasticity:
. The 8 MS Spasticity Scale (MSSS-88) subscale scores
. The 11-point NRS for spasm severity
. The 11-point NRS for spasticity
- To evaluate the effect of nabiximols relative to placebo on health
related
quality of life, as reflected by the 36-Item Short Form Health
Survey
- To evaluate the effect of nabiximols relative to placebo on functional
outcome as reflected by walking ability using the T25FW test |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Screening (Visit 1)
For inclusion in the trial, patient must fulfill ALL of the following criteria:
- Male or female aged 18 years or above.
- 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 requirement (With the exception of the T25FW test, if the patient is non-ambulatory)
- Has had a diagnosis with any disease subtype of 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 had treatment with at least 1 different optimized oral MS antispasticity therapies prior to Visit 1 that must include at least oral baclofen or oral tizanidine (monotherapy or combination therapy).
- Currently receiving optimized treatment with at least 1 oral antispasticity medication (baclofen, tizanidine or dantrolene) and has been stable for at least 30 days prior to Visit 1. Despite optimization, the patient does not have adequate relief of spasticity and signs and 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 patient 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 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.
- Willing to allow the responsible authorities to be notified of participation in the trial, if mandated by local law.
- Willing to allow his or her primary care practitioner (if he or she has one) and/or treating neurologist (if he or she has one) to be notified of participation in the trial, if the primary care practitioner/treating neurologist is different than the investigator.
Additional Inclusion Criteria at Randomization (Visit 2)
The patient is eligible for randomization in the trial if, in addition to
continuing to meet the Screening (Visit 1) inclusion criteria, they also
meet ALL of the following criteria during the first 28-days of the baseline
period (Note: patients are expected to start completing their electronic
diary in the evening of their screening visit):
- In the opinion of the investigator the patient is able to interpret and
report spasm count data accurately
- Completed their electronic diary for at least 25 of the first 28 days of
the baseline period
- Has an average daily spasm count of ≥ 4 during the first 28 days of the
baseline period, as recorded by the patient.
- Has no more than 35 spasms on any single day of the first 28 days of
the baseline period, as recorded by the patient
- Does not have > 7 consecutive days without experiencing any spasm
during the first 28 days of the baseline period.
If, for any reason, the patient is unable to attend the site for
randomization within the visit window, the site should contact the
Medical Monitor or the sponsor to discuss. In addition to meeting the
Screening (Visit 1) inclusion criteria and additional inclusion criteria
above (apart from last bullet point), any patient with more than 28 days
between Visit 1 and Visit 2 would need to meet ALL of the following
criteria prior to randomization:
- Completed their electronic diary for at least 85% of days between Visit 1 and Visit 2
- Has an average daily spasm count of ≥ 4 between Visit 1 and Visit 2
(randomization), as recorded by the patient
- Has no more than 35 spasms on any single day between Visit 1 and
Visit 2, as recorded by the patient
- Does not have > 7 consecutive days without experiencing any spasm
between Visit 1 and Visit 2. |
|
| E.4 | Principal exclusion criteria |
Previously participated in a clinical trial of nabiximols or has had a poor previous response or intolerance to nabiximols or other cannabinoid-containing products used for therapeutic purposes
- Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the patient’s level of spasticity
- Medical history suggests that relapse/remission is likely to occur during the trial which is expected to influence the patient’s spasticity
- Has had a relapse of MS within the 60 days prior to Visit 1
- Has taken cannabis, or a cannabis-derived product for medicinal or recreational use within the 30 days prior to screening or a positive blood drug test for THC at screening
- Is unwilling to abstain from use of cannabis or a cannabis-derived product for medicinal or recreational purposes for the duration of the trial
- Currently using botulinum toxin injection for the relief of spasticity
- Is unwilling to abstain from the use of botulinum toxin injection for the relief of spasticity for the duration of the trial
- Currently taking antipsychotic medication
- Currently taking benzodiazepines unless the doses and dosing regimen have been stable for at least 30 days prior to Visit 1
- Has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP
- Has experienced myocardial infarction or clinically significant cardiac dysfunction within the 12 months prior to Visit 1 or has a cardiac disorder that would put the patient at risk of a clinically significant arrhythmia or myocardial infarction
- Has a diastolic blood pressure of < 50 mmHg or > 105 mmHg or systolic blood pressure < 90 mmHg or > 150 mmHg, or a postural drop in the systolic blood pressure of > or = 20 mmHg or in diastolic blood pressure of > or = 10 mmHg at Visit 1
- Has clinically significant impaired renal function at Visit 1 as evidenced by an estimated creatinine clearance lower than 50 mL/min
- Has moderately impaired hepatic function at Visit 1 defined as serum alanine aminotransferase or aspartate aminotransferase >2 × upper limit of normal
- Male and fertile unless willing to ensure that he uses male contraception or remains sexually abstinent during the trial and for 3 months thereafter
- 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. Patients using combined hormonal methods or a progestogen-only pill or injection or implant should use an additional barrier method such as a condom or diaphragm during the trial and for 3 months thereafter
- Female and pregnant, lactating, or planning pregnancy during the course of the trial or within 3 months thereafter
- Received an IMP within the 30 days prior to Visit 1
- Has any other clinically significant disease or disorder that may put the patient, other patients, or site staff at risk because of participation in the trial, influence the interpretation of trial results, or may affect the patient’s ability to take part in the trial
- Has any abnormalities identified following a physical examination, clinical laboratory, serology, or other applicable screen procedures that would jeopardize the safety of the patient 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 or a suicidal ideation score of 3, 4, or 5 on the C-SSRS in the month prior to Visit 1
- Has a history of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product
- 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 use disorder within 1 year prior to Visit 1
- Currently using an illicit drug or current nonprescribed use of any prescription drug. A positive drug test at Visits 1 or 2 for a prescribed medication is not exclusionary at the investigator’s
discretion. A positive drug test at Visit 1 or predose at Visit 2 for illicit drugs may be repeated locally at the investigator’s discretion
- 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/UGT2B7
- Currently taking strong CYP3A4 inducers
- There is an expectation that the participant will require a new course of treatment with strong CYP3A4 inhibitors during the study duration
- Patients who receive a positive coronavirus disease 2019 antigen test result before randomization may be screen failed, at the discretion of the investigator
- Individuals who do not meet the criteria for participation in this trial (screen failure) can be rescreened once, at the discretion of the investigator or designee, with sponsor approval.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change from baseline in the average daily spasm count (from Days 57 to 84 compared to the average daily spasm count for the baseline period). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Days 57 to 84 and for baseline period. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are change in MS Spasticity Scale (MSSS-88) total score, safety, tolerability, and pharmacokinetics (PK).
Key secondary endpoint:
Efficacy:
- Change from baseline in the spasm subscale score of the MSSS-88 at Visit 6.
Pharmacokinetics:
- Plasma concentrations for THC and its relevant metabolites (11-hydroxy-Δ9-tetrahydrocannabinol [11-OH-THC] and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol [11-COOH-THC]) and CBD and its relevant metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]) at Visits 2 (predose), 3, 4, 5, and 6.
Safety:
- Frequency of treatment-emergent adverse events (AEs).
- Change from baseline to each assessment timepoint by treatment arm for the following:
. Clinical laboratory tests.
. Vital signs.
- 12-lead electrocardiograms (ECGs).
. Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, and at each subsequent timepoint with reference to the last assessment (since last visit)
Exploratory Endpoint(s):
Efficacy:
- Change from baseline in the 8 subscale scores of the MSSS-88 at Visit 6
- Change from baseline in average daily 11 point NRS spasm severity
score to Days 57 to 84
- Change from the last 7 days of baseline in average daily 11-point NRS
spasticity score to Days 78 to 84
- Change from baseline in the SF-36 total score at Visit 6 (Day 85)
- Change from baseline in Timed 25-Foot Walk (T25FW) test at Visit 6
(Day 85). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At Day 1 and Day 85, and during the 85 days of the double-blind treatment period for pharmacokinetics and safety above listed outcomes. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Poland |
| Romania |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient last visit or last contact, whichever occurs last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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