None listed
Conditions
Brief summary
The CRISP study is a blinded, placebo-controlled clinical trial of clozapine and risperidone administration in secondary progressive multiple sclerosis (SPMS) patients. The aim of the CRISP trial is to assess the safety and acceptability of clozapine and risperidone in SPMS patients. Thirty-six patients with SPMS will be recruited through the Neurology Department at Wellington Hospital with the expectation of 33 completing the trial. Baseline clinical and laboratory investigations will be taken and patients (n = 12/group) will receive oral clozapine titrated to a final dose of 150 mg/day (1, 2), risperidone titrated to a final dose of 3.5 mg/day, or no study medicine. Over the course of the 6 month participation in the trial, patients will have regular clinical review and blood sampling. The primary outcome measure is the safety and tolerability of clozapine and risperidone treatment. Secondary outcome measures include disability progression.
Interventions
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
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
Sponsors
Victoria University of Wellington
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 70 Years
Healthy volunteers
No
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
Exclusion criteria
1. Relapsing-remitting MS 2. Pregnant or lactating women 3. Patients unable to undergo regular blood tests or MRI scans 4. Patients with contraindications to clozapine or risperidone 5. Known hypersensitivity to clozapine, risperidone or to any of the excipients thereof 6. Reported past intolerance to clozapine or risperidone 7. Postural hypotension, defined as a reduction in systolic blood pressure (BP) of 20 mmHg within 2 – 5 minutes of standing up 8. Dysphagia 9. Current diagnosis of substance abuse or history of alcohol or drug abuse in the past 3 months 10. Concomitant disease likely to interfere with the trial medication (e.g. capable of altering absorption, metabolism or elimination of the trial drug) 11. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy) 12. Impaired bone marrow function 13. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions 14. History of circulatory collapse and/or CNS depression of any cause 15. Moderate or severe renal or cardiac disorders (e.g. myocarditis) 16. Hepatic impairment; active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure 17. Paralytic ileus 18. History of cardiovascular disease 19. Elevated glycosylated haemoglobin levels (HbA1c greater than or equal to 41mmol/mol) 20. Hyperthyroidism 21. Serious medical co-morbid illness or any other disease or condition which, in the opinion of the investigator, means that it would not be in the patient’s best interests to participate in the study 22. A white blood cell (WBC) and differential blood count taken within 10 days of starting treatment shows a WBC count of < 3500/mm3 and absolute neutrophil count (ANC) of < 2000/mm3 23. An abnormal platelet count taken within 10 days of starting treatment 24. Concomitant use of medications known to affect clozapine treatment: a. Fluvoxamine, ciprofloxacin, or enoxacin b. Oral contraceptives c. Cimetidine, escitalopram, erythromycin, paroxetine, buproprion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline 25. Concomitant use of medications known to reduce the effectiveness of clozapine treatment, including phenytoin, carbmazepine, St John’s wort, rifampin 26. Patients taking drugs that increase the risk of agranulocytosis, including carbamazepine, phenylbutazone, azapropazone, co-trimoxazole, penicillamine, cytotoxic agents, sulphonamide antibiotics, or chloramphenicol 27. Patients taking medications that prolong the QT interval or inhibit clozapine metabolism, including ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin, quinidine, procainamide, amiodarone, sotalol, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol, or tacrolimus. 28. Patients taking other medications that may potentiate the side effects of treatment with atypical antipsychotics, including frusemide or anti-cholinesterase treatment 29. Treatment with cyclophosphamide or mitoxantrone within 12 months; systemic corticosteroid therapy within 30 days; treatment with interferon beta, glatiramer acetate, natalizumab, plasmapheresis, or intravenous immunoglobulin within 60 days
Outcome results
None listed