2.6. Assessments

At the screening visit, participants will be asked to provide sociodemographic information, their medication use, and their comorbidities. Furthermore, compulsive use and the individual’s preoccupation with cannabis use will be assessed by the Severity Dependence Scale, a self-reported questionnaire (40). The Structured Clinical Interview for DSM-5 Disorders will be administered to assess substance use disorders, including alcohol and other substances (41). The heart condition will be reviewed by electrocardiography. A pregnancy test and birth control questionnaire will be conducted in women aged ≤50 years with no sign of menopause and who did not undergo surgical contraception. A MS neurologist will evaluate the participants’ eligibility and will assess spasticity and disability with the Modified Ashworth Scale and the Expanded Disability Status Scale, respectively (42, 43).

The primary outcome (i.e., patient-reported spasticity) will be assessed using the mNRS (22, 44). The main outcome will be the difference in mNRS recorded for 7 days prior to the visit at week 4 and the visit at baseline. NRS is the most used tool to assess spasticity in most previous RCTs of treatment, including cannabinoid-based therapy, for MS-related spasticity (22). It is represented on a 0–10 scale, where 0 means no spasticity and 10, the worst possible spasticity (22). The NRS has been shown to be more robust than the Ashworth Scale for the test–retest reliability and highly correlative of the Patient Global Impression of Change scores (22, 44). Most studies investigating cannabis-derived products enrolled MS patients who have NRS ≥4 on the 0–10 scale (22). To include patients with moderate spasticity, we also enrolled those who have mNRS ≥2 on the 0–10 scale (17, 22, 44).

All the secondary – efficacy and safety – outcomes will be assessed at baseline, at week 4 and 12 weeks after the initial treatment period. Clinical efficacy outcomes are presented in Table 2. In addition, we will assess the success of participants’ blinding after the initial treatment period with the James Blinding Index (69). Blood tests will be conducted only at baseline and at week 4 to measure immunological and neurobiological markers. Safety measures will include all reported or observed adverse events and serious adverse events (AEs and SAEs). Pregnancy and birth control will be re-evaluated every 4 weeks.

Secondary and exploratory efficacy assessments.

ClinRO, clinician-reported outcome; PRO, patient-reported outcome; PerfO, performance outcome. ^aWe adapted the Multiple Sclerosis Quality of Life Inventory for the CANSEP trial, by excluding two of its ten scales: (1) The Impact of Visual Impairment Scale was not included, because it is not widely used in clinical practice and not relevant to the CANSEP trial; (2) instead of the Mental Health Inventory, we considered the Hospital Anxiety and Depression Scale, a widely used instrument in clinical practice, but also a validated scale in the MS population (55, 67, 68). Furthermore, we added the Cannabis Experience Questionnaire for the subjective effects of cannabinoids (56, 57). ^bAll tests will be conducted at baseline, at week 4, and at week 16. However, participants who never used cannabis in their lifetime will not complete the Cannabis Experience Questionnaire at baseline.