|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Symptomatic treatment of spasticity in patients with MS
|Medical condition in easily understood language
|Diseases [C] - Nervous System Diseases [C10]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10029205 - Nervous system disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To establish the efficacy of nabiximols relative to placebo on spasm frequency in MS patients with spasticity.
|Secondary objectives of the trial
1. To evaluate the effect of nabiximols on spasticity using the 11-point NRS for spasticity.
2. To evaluate the safety and tolerability of nabiximols after administration of multiple doses.
1. To evaluate the effect of nabiximols on spasm severity using the 11-point NRS spasm severity scale
2. To evaluate the effect of nabiximols relative to placebo on other symptoms associated with MS, using the following patient-reported outcomes:
− To evaluate the effect of nabiximols on the impact of spasticity in MS
|Trial contains a sub-study
|Principal inclusion criteria
|1. Patient is male or female, aged 18 years or above.
2. Patient is willing and able to give informed consent for participation in the trial.
3. Patient is willing and able (in the investigator’s opinion) to comply with all trial requirements.
4. Willing to allow the responsible authorities to be notified of participation in the trial, if mandated by local law.
5. Patient is willing to allow his or her primary care practitioner (if they have one) or consulting neurologist (if they have one) to be notified of participation in the trial, if the primary care practitioner/consultant is different to the investigator.
6. Patient has a diagnosis with any disease subtype of MS, by revised 2017 McDonald criteria, for at least 12 months before Visit 1 (screening) and is expected to remain stable for the duration of the trial.
7. For patients not receiving any current antispasticity medications they must have been off of any antispasticity medication (e.g., oral or intrathecal baclofen, tizanidine, and/or oral dantrolene) for 30 days prior to Visit 1 (screening) and is not planning to start any antispasticity medication during the trial; and must not plan to initiate a new course of physiotherapy for the duration of the trial.
8. For those on antispasticity medication (oral or intrathecal baclofen, oral tizanidine, and/or oral dantrolene) these medications must be optimized and 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.
9. 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.
10. 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.
Patients are eligible for the treatment period if, in addition to continuing to meet the screening (Visit 1) inclusion criteria, they also meet ALL of the following criteria immediately prior to Visit 2:
11. Patient has completed at least 12 of the last 14 days of their eDiary reporting immediately prior to Visit 2.
12. Patient has an average daily spasm count of ≥ 4 during the screening period, as recorded in the eDiary.
13. Patient has no more than 35 spasms on a single day of the screening period, as recorded in the eDiary.
14. Patient does not have > 7 consecutive days without experiencing any spasm during screening.
15. Patient completed at least 12 of the last 14 days of their eDiary reporting immediately prior to Visit 4.
|Principal exclusion criteria
|The patient may not enter the trial if ANY of the following apply:
1. History of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product.
2. Relapse of MS within the 60 days prior to Visit 1.
3. Patient’s 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.
4. Any concomitant disease or disorder that has spasticity-like symptoms that may influence the patient’s level of spasticity.
5. Planned clinical interventions or intention to change any medications that may have an effect on spasticity or MS during the trial.
6. Plans to initiate a new course of physiotherapy during the course of the trial.
7. Patient has any known or suspected hypersensitivity to cannabinoids or any of the excipients of nabiximols, or any other cannabinoid-containing products used for therapeutic purposes.
8. Currently taking antipsychotic medications.
9. 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.
10. Received an IMP within the 30 days prior to Visit 1.
11. Patient has travel outside the country and/or US state of residence planned during the trial, unless the patient has confirmation that the IMP is permitted in the destination country/state.
12. Current use or use of cannabis or a cannabinoid-derived product for medicinal or recreational use within 30 days of Visit 1, or is unwilling to abstain for the duration of the trial.
13. Currently taking benzodiazepines, unless doses and dosing regimen have been stable for at least 30 days prior to Visit 1.
14. Previous participation in a clinical trial of nabiximols.
15. Have been in close contact with persons with diagnosed or suspected COVID-19 in the last 2 weeks.
|E.5 End points
|Primary end point(s)
- Change in the average daily spasm count (the last 14 days prior to Visit 7) compared to the average daily spasm count at baseline.
|Timepoint(s) of evaluation of this end point
|- Spasm count recorded in ediary from visit 1 to 7.
- Change in the average daily spasm count (the last 14 days prior to Visit
7) compared to the average daily spasm count at baseline (the last 14 days prior to the date of randomization
|Secondary end point(s)
- Change from baseline in average daily 11-point NRS spasticity to the last 14 days prior to Visit 7.
- To evaluate the safety and tolerability of multiple dose administrations of nabiximols
Change from baseline to each assessment timepoint by treatment period for the following:
− Adverse Events (AE's) − Clinical laboratory parameters (hematology, coagulation, biochemistry, and urinalysis)
− Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, and body temperature)
− Physical examination − 12-lead ECGs
- C-SSRS at screening (Visit 1), and at each subsequent timepoint with reference to the last assessment (since last visit)
The exploratory endpoints are as follows:
• Change from baseline in the PSQI at 14 days prior to Visit 7
• Change from baseline in OAB-q-SF at 14 days prior to Visit 7
• Change from baseline in MSISQ19 at 14 days prior to Visit 7
• Change from baseline in the MSSS-88 at 14 days prior to Visit 7
• Change from baseline in average daily 11-point NRS spasm severity score to the last 14 days prior to Visit 7
|Timepoint(s) of evaluation of this end point
|- AE's - visit 1-8, Clinical lab tests visit 1,2,4,5 and 7.
- Vital signs and ECG visit 1 and 2 and visits 4-7.
- Physical examination visit 1 and 7.
- CSSR and NRS (ediary) visit 1-7.
- PSQI, OAB-q-SF, MSISQ19, MSSS-88 visits 2,4,5 and 7
- For eDiary endpoints, baseline is defined as the last 14 days prior to the date of randomization.
- For visit-based endpoints, baseline is defined as the last measurement collected prior to the first dose of randomized IMP.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
|Other trial design description
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial days