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

Phase 2

• Conditions: progressive multiple sclerosis; Neurological - Multiple sclerosis

• Registration Number: ACTRN12616000178448
• Lead Sponsor: Victoria University of Wellington

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-02-11
• Last Update Posted: 13 January 2020

Recruitment & Eligibility

• Status: Stopped early
• Sex: All
• Target Recruitment: 36

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

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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. [At each weekly visit/phone call post-screening through to Week 18, then at Weeks 22 and 26 (end of Treatment), and at final visit at Week 32.];Acceptability of clozapine and risperidone in a PMS population, using the Treatment Satisfaction Questionnaire for Medication (TSQM-9) [At Months 3 and 6 (End of Treatment)]

Secondary Outcome Measures

Name	Time	Method
Efficacy of clozapine and risperidone in PMS using the MS Functional Composite (MSFC) [Months 0, 3 and 6 (End of Treatment)];Efficacy of clozapine and risperidone in PMS using the Expanded Disability Status Score (EDSS) [Months 0, 3 and 6 (End of Treatment)];Efficacy of clozapine and risperidone in PMS using the Fatigue Severity Scale (FSS) [Months 0, 3 and 6 (End of Treatment)];Phenotypic analysis of the circulating leukocytes by flow cytometry [Months 0, 3 and 6 (End of Treatment)];Assess cytokine levels by cytometric bead array [Months 0, 3 and 6 (End of Treatment)];Determine study medication levels in serum, using mass spectrometry[Months 0, 3 and 6 (End of Treatment)];Functional tests by stimulating the PBMC in vitro to assess cytokine production. [Months 0, 3 and 6 (End of Treatment)]