Clozapine and risperidone for the treatment of progressive multiple sclerosis (CRISP)

INTERVENTION: Patients will be randomised to one of three treatment groups: 1. clozapine suspension for oral administration ‐ Participants will be started on clozapine at a dose of 5 mg/day and titrated over 2 weeks to an interim daily dose of 100 mg/day for 2.5 months. The dose will be held at the same level across the weekends. After the 3‐month clinical visit, the dose of clozapine will then be further titrated over 2 weeks to a final dose of 150 mg/day. This dose will be used until study completion at 6 months. 2. risperidone tablets for oral administration ‐ Participants will be started on risperidone at a dose of 0.5 mg/day and titrated over 2 weeks to an interim daily dose of 2.0 mg/day for 2.5 months. Following the 3 month clinical visit, the dose of risperidone will then be titrated over 2 weeks to a final dose of 3.5 mg/day. This dose will be used until study completion at 6 months. 3. Or to a placebo To check compliance, at each site visit participants will be asked to bring all their study medication (used and unused) plus their dairy in which dates and time of dosing is to be recorded CONDITION: progressive multiple sclerosis PRIMARY OUTCOME: Acceptability of clozapine and risperidone in a PMS population, using the Treatment Satisfaction Questionnaire for Medication (TSQM‐9) Safety of clozapine and risperidone in a PMS population as assessed by the incidence of adverse events (AEs). AEs will be assessed by querying the study participant at their weekly visit/phone call, review of their daily diary and observations by site staff. The most common AEs associated with clozapine treatment, and occurring in more than 1 in 10 patients are weight gain, drowsiness, sedation, dizziness, tachycardia, constipation, and hypersalivation. The most AEs associated with risperidone treatment, and occurring in more than 1 in 10 patients are weight gain, dizziness, vomiting, dry mouth, nausea, anxiety, constipation, and hypersalivation. SECONDARY OUTCOME: Assess cytokine levels by cytometric bead array Determine study medication levels in serum, using mass spectrometry Efficacy of clozapine and risperidone in PMS using the Expanded Disability Status Score (EDSS) Efficacy of clozapine and risperidone in PMS using the Fatigue Severity Scale (FSS) Efficacy of clozapine and risperidone in PMS using the MS Functional Composite (MSFC) Functional tests by stimulating the PBMC in vitro to assess cytokine production. Phenotypic analysis of the circulating leukocytes by flow cytometry INCLUSION CRITERIA: Progressive multiple sclerosis with the continuous worsening of neurological impairment over at least 6 or 12 months; aged 18 years to 70 years; EDSS at baseline of 3.5 to 7.0; willing and able to participate in the trial and provide written, informed consent