| 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 |
The Secondary objectives are:
- To evaluate the effect of nabiximols relative to placebo using the following patient-reported outcome measures 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
. The Lower Limb Muscle Tone 6
. The Lower Limb Muscle Tone 4
- To evaluate the effect of nabiximols relative to placebo on functional outcome as reflected by walking ability using the T25FW test
- 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 |
|
| 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 nonambulatory)
- 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 antispasticity therapy prior to Visit 1 that must include either oral baclofen or oral tizanidine (monotherapy or combination therapy).
- 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 Visit 1. Despite optimization,
the patient does not have adequate relief of spasticity 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 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.
- 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 28-day baseline period
immediately prior to Visit 2:
- Completed at least 90% and at least 26 completed days of their electronic daily diary reporting during the baseline period.
- Has an average daily spasm count of ≥ 4 during the baseline period, as recorded by the patient.
- Has no more than 24 spasms on any single day of the baseline period, as recorded by the patient.
- Does not have > 7 consecutive days without experiencing any spasm during the baseline period. |
|
| E.4 | Principal exclusion criteria |
The patient may not enter the trial if ANY of the following apply:
- 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, in the opinion of the investigator, is expected to influence the patient's spasticity.
- Has had a relapse of MS within the 60 days prior to Visit 1.
- Currently using or has used cannabis or a cannabinoid-derived product for medicinal or recreational use (within 30 days of Visit 1) and is unwilling to abstain for the duration of the trial.
- 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 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, in the opinion of the investigator, 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 > 160 mmHg (when measured in a sitting position at rest for 5 minutes) or a postural drop in the systolic
blood pressure of > 20 mmHg at Visit 1. All measurements will be performed singly and can be repeated once, if any are outside the reference range but not considered clinically significant.
- Has clinically significant impaired renal function at Visit 1, as evidenced by an estimated creatinine clearance lower than 50 mL/min. All measurements will be performed singly and can be repeated once, if any
are outside the reference range but not considered clinically significant.
- Has moderately impaired hepatic function at Visit 1, defined as serum alanine aminotransferase or aspartate aminotransferase > 2 × upper limit of normal. All measurements will be performed singly and can be
repeated once, if any are outside the reference range but not considered clinically significant.
- 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, in the opinion of the investigator, 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, in the opinion of the investigator, 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 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 abuse or dependence within 1 year prior to Visit 1.
- Currently using an illicit drug or current nonprescribed use of any prescription drug.
- 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 currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort). |
|
| 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 efficacy endpoints are measurements of spasticity, the patient’s symptom experiences, clinician’s assessment of spasticity, functional outcomes, health-related QoL, changes in mood, safety, tolerability, and PK during the double-blind treatment period. Change from baseline refers to the change at the specified post-randomization time point compared with baseline, assessed at Visit 2 (Day 1).
Key secondary endpoint:
Efficacy:
- Change from baseline in total 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-carboxycannabidiol [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.
. Physical examination procedures.
. 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 period 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 LLMT 6 (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) at
Visit 6
- Change from baseline in LLMT 4 (defined as the average of the 4 individual MAS transformed scores of knee flexors and knee extensors on both sides of the body) at Visit 6
- Change from baseline in Timed 25-Foot Walk (T25FW) test at Visit 6.
- Change from baseline in the SF-36 total score at Visit 6. |
|
| 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 | 5 |
| 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 |
| Czech Republic |
| Poland |
| Romania |
| United Kingdom |
| United States |
|
| 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 | 3 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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