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) |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of muscle spasm in patients with multiple sclerosis (MS) |
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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 |
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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 |
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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 compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-6; LLMT-6) in patients with MS |
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E.2.2 | Secondary objectives of the trial |
• 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 4; LLMT-4) in patients with MS • To evaluate the safety and tolerability of nabiximols after administration of multiple doses • To evaluate the pharmacokinetic (PK) profile 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion 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. • If currently receiving approved anti-spasticity therapy, it must be with a stable dosing regimen for at least 30 days prior to Visit 1. 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).
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E.4 | Principal exclusion criteria |
• Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal or recreational purposes in the 30 days prior to Visit 1 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. • 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 botulinum toxin injection for the relief of spasticity (within 6 months of Visit 1) 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. • 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 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 > 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. 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 (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN). 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 (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. Patients 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 or Visit 2), lactating, or planning pregnancy during the course of the trial or within 3 months thereafter. |
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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 The MAS scores are transformed using the following algorithm: MAS untransformed [to MAS transformed] scores; 0[0], 1[1], 1+[2], 2[3], 3[4], and 4[5]. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Day 1 predose to Day 21 and from Day 31 predose to Day 51 |
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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 Safety: • Frequency of treatment-emergent adverse events (TEAEs) • Change from baseline to each assessment time point by treatment period for the following: • Clinical laboratory parameters • Vital signs • Physical examination procedures • 12-lead electrocardiograms (ECGs) • Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, and at each subsequent time point with reference to the last assessment (since last visit) 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 (Visits 2, 4, 5, 6, 8, and 9) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: from Day 1 predose to Day 21 and from Day 31 predose to Day 51
Safety: Change from baseline to each assessment time point by treatment period; Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, and at each subsequent time point with reference to the last assessment (since last visit)
Pharmacokinetics: at distinct time points during each treatment period (Visits 2, 4, 5, 6, 8, and 9) |
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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 | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Spain |
Czechia |
United Kingdom |
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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
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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |