| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Symptomatic treatment of spasticity in patients with multiple sclerosis (MS) | |
| E.1.1.1 | Medical condition in easily understood language | | Treatment of muscle spasm in patients with multiple sclerosis (MS) | |
| 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 | 20.0 | | 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.1.2 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-6; LLMT) in patients with MS who have not achieved adequate relief from spasticity with other antispasticity medications | |
| E.2.2 | Secondary objectives of the trial | • To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocitydependent
muscle tone in the lower limbs (Lower Limb Muscle Tone 4; LLMT-4) in patients with multiple sclerosis (MS) who have not achieved adequate
relief from spasticity with other antispasticity medications
• To evaluate the pharmacokinetic (PK) profile of nabiximols after administration of multiple doses
• To evaluate the safety and tolerability of nabiximols after administration of multiple doses
Exploratory objectives
• To evaluate the effect of nabiximols after administration of multiple doses on walking using the Timed 25-Foot Walk (T25FW) test
• To evaluate the effect of nabiximols after administration of multiple doses on the following patient-reported outcomes:
− The 11-point Numerical Rating Scale (NRS) spasticity score
− Daily spasm count
− The MS Spasticity Scale (MSSS-88) total and subdomain scores | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | For inclusion in the trial, patients 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 requirements.
• 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 an 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.
• Currently receiving optimized treatment with at least 1 oral antispasticity drug (baclofen, tizanidine, and/or dantrolene) that has been stable for at least 30 days prior to Visit 1. Despite optimization, the patient does not have adequate relief of spasticity 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 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 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 from the investigator.
Additional Inclusion Criteria at Randomization (Visit 2)
Patients are eligible for randomization in the trial if, in addition to
continuing to meet the Screening (Visit 1) inclusion criteria, they also
meet the following criterion prior to Visit 2 (Day 1):
• Completed at least 5 of 7 days of their electronic diary reporting during
the 7 days immediately preceding Visit 2 (Day 1). | |
| E.4 | Principal exclusion criteria | The patient may not enter the trial if:
•Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal or recreational purposes in the 30 days prior to Visit 1 and 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
•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 pt's spasticity
•Has had a relapse of MS within the 60 days prior to Visit 1
•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 doses and dosing regimen
have been stable for at least 30 days prior to Visit 1
•Clinically suspected to have a contracture in one of the muscle groups of the lower limbs, preventing assessment with the MAS
•Has any known/suspected hypersensitivity to cannabinoids or any of the excipients of the IMP
•Has experienced myocardial infarction or clinically significant cardiac dysfunction within the last 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 (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 or Visit 2
•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 (ALT) or aspartate aminotransferase (AST) >2 × upper limit of normal (ULN)
•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 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 (positive pregnancy test at Visit 1 or Visit 2), 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
•Has any other clinically significant disease or disorder (including
seizure 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, may
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 screening procedures
that, in the opinion of the investigator, would jeopardize the safety of the pt.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 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
(including opiate abuse) or dependence within 1 year prior to Visit 1
•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)
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Change in Lower Limb Muscle Tone-6 (LLMT-6; defined as the average of the 6 individual MAS transformed scores of knee flexors, knee extensors, and plantar flexors on both sides of the body) from Day 1 predose to Day 21 and from Day 31 predose to Day 51. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Day 1 predose & Day 21
Day 31 predose & Day 51 | |
| E.5.2 | Secondary end point(s) | Efficacy:
• Change in Lower Limb Muscle Tone-4 (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) from Day 1 predose to Day 21 and from Day 31 predose to Day 51
Pharmacokinetics:
• Plasma concentrations for Δ9-tetrahydrocannabinol (THC) and its relevant metabolites (11-hydroxy-Δ9-tetrahydrocannabinol and 11-carboxy-
Δ9-tetrahydrocannabinol) and cannabidiol (CBD) and its relevant metabolites (7-hydroxy-cannabidiol and 7-carboxy-cannabidiol) at distinct time points during each treatment period (Visit 2)
Safety:
• Frequency of treatment-emergent adverse events (TEAEs)
• Change from baseline to the last visit of each double-blind treatment period (i.e., Visits 4 and 7) for the following:
- Clinical laboratory parameters
- Vital signs
- Physical examination procedures
- 12-lead electrocardiograms (ECGs)
- Columbia-Suicide Severity Rating Scale (C-SSRS)
Exploratory end points
Efficacy:
• Difference between treatments in total and subdomain scores of the MSSS-88 at the end of the maintenance-dose phase of each double-blind treatment period
• Difference between treatments in average 11-point NRS spasticity score over the last 7 days of each double-blind treatment period
• Difference between treatments in average daily spasm count over the last 7 days of each double-blind treatment period
• Difference between treatments in the change in Timed 25-Foot Walk (T25FW) test from Day 1 predose to Day 21 and from Day 31 predose to Day 51 | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Efficacy: Day 1 predose to Day 21, Day 31 predose to Day 51 Pharmacokinetics: Day 1 predose & postdose, Day 15, Day 21, Day 31 predose & postdose, Day 45, Day 51.
Safety: all visits
Efficacy
• MSSS-88: Day 21 & Day 51
• NRS spasticity score: Day 1 predose, Day 15-31 & Day 45-51
• daily spasm count: Day 1 predose, Day 15-31 & Day 45-51
• T25FW: Day 1 predose, Day 21-31 & Day 5 | |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | | LVLS or last contact, whichever comes last | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
