Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000178448
Ethics application status
Approved
Date submitted
8/02/2016
Date registered
11/02/2016
Date last updated
8/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Clozapine and risperidone for the treatment of progressive multiple sclerosis (CRISP)
Scientific title
Clozapine and risperidone for the treatment of progressive multiple sclerosis (CRISP)
Secondary ID [1] 288407 0
None
Universal Trial Number (UTN)
U1111-1173-2770
Trial acronym
CRISP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
progressive multiple sclerosis 297419 0
Condition category
Condition code
Neurological 297605 297605 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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
Intervention code [1] 293721 0
Treatment: Drugs
Comparator / control treatment
Comparator / control treatment is a placebo.
Control group
Placebo

Outcomes
Primary outcome [1] 297146 0
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.
Timepoint [1] 297146 0
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.
Primary outcome [2] 297153 0
Acceptability of clozapine and risperidone in a PMS population, using the Treatment Satisfaction Questionnaire for Medication (TSQM-9)
Timepoint [2] 297153 0
At Months 3 and 6 (End of Treatment)
Secondary outcome [1] 320173 0
Efficacy of clozapine and risperidone in PMS using the MS Functional Composite (MSFC)
Timepoint [1] 320173 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [2] 320174 0
Efficacy of clozapine and risperidone in PMS using the Expanded Disability Status Score (EDSS)
Timepoint [2] 320174 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [3] 320175 0
Efficacy of clozapine and risperidone in PMS using the Fatigue Severity Scale (FSS)
Timepoint [3] 320175 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [4] 320663 0
Phenotypic analysis of the circulating leukocytes by flow cytometry
Timepoint [4] 320663 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [5] 320665 0
Assess cytokine levels by cytometric bead array
Timepoint [5] 320665 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [6] 320666 0
Determine study medication levels in serum, using mass spectrometry
Timepoint [6] 320666 0
Months 0, 3 and 6 (End of Treatment)
Secondary outcome [7] 320667 0
Functional tests by stimulating the PBMC in vitro to assess cytokine production.
Timepoint [7] 320667 0
Months 0, 3 and 6 (End of Treatment)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All site study staff will be blinded except for Pharmacy and the research nurse. The research nurse will be responsible mainly for visit organisation however will review the participant diary, check compliance with study medication and ask about adverse events and concomitant medications. She may also collect blood pressure, heart rate, weight and temperature data at study visits Months 0, 3 and 6. While the research nurse will be blinded to the treatment allocation of the participants, some aspects of the study medicine formulation may allow the allocation to be guessed. However, although the research nurse will collect adverse event information, this outcome measure will be verified by the clinical investigator, who will be blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Participants will be randomly assigned to one of three treatment groups (N=12 for each treatment): clozapine suspension titrated to a final dose of 150 mg/day, risperidone tablets titrated to a final dose of 3.5 mg/day, or placebo.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A sample size of 12 per treatment group is proposed to allow comparison of the acceptability and safety of clozapine and risperidone treatment to placebo and to provide preliminary data on potential effects on disease parameters (i.e. MSFC, EDSS). The sample size has been calculated based upon the validation of the TSQM-9 by Bharmal et al. This study demonstrated that medium compliers had a significantly higher TSQM-9 score than low compliers, and compliance was assessed by the Modified Morisky scale, which evaluates self-reported patient adherence. Based upon this data, if we assume a similar effect size as that shown between medium to low compliers (81.25 +/- 15.19 compared to 69.82 +/-19.82 for global satisfaction) occurs between either drug treatment compared to placebo over the 6-month treatment, then 11 patients will give us an 80% power of observing a statistically significant result. Thus, a group size of 12 would slightly overpower the study.

While the main comparison is between drug-treatment (clozapine or risperidone) and placebo, if clozapine or risperidone is found to be superior in terms of acceptability and safety and to show efficacy on disease parameters, a phase 2 randomized, placebo-controlled trial can be run to evaluate the efficacy of this superior drug at reducing disease parameters.

The proportion of patients with SAE and AE in each group will be compared (clozapine vs risperidone) by Fisher’s exact test. TSQM-9, change in EDSS, change in FSS, and change in MSFC will be analyzed by Wilcoxon signed-rank test for paired participant analyses. To compare TSQM-9 between placebo, clozapine, and risperidone treatment, a Kruskal-Wallis test (non-parametric; multiple comparison correction) will be used.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
After reviewing the results form our interim analyses, it was clear that our primary outcome was achieved.
Date of first participant enrolment
Anticipated
14/03/2016
Actual
6/05/2016
Date of last participant enrolment
Anticipated
1/03/2018
Actual
16/06/2017
Date of last data collection
Anticipated
Actual
9/11/2017
Sample size
Target
36
Accrual to date
Final
9
Recruitment outside Australia
Country [1] 7553 0
New Zealand
State/province [1] 7553 0
Wellington

Funding & Sponsors
Funding source category [1] 292777 0
Government body
Name [1] 292777 0
Ministry for Business, Innovation, and Employment
Country [1] 292777 0
New Zealand
Primary sponsor type
University
Name
Victoria University of Wellington
Address
PO Box 600
Wellington 6140
Country
New Zealand
Secondary sponsor category [1] 291513 0
Other
Name [1] 291513 0
Capital and Coast District Health Board (CCDHB)
Address [1] 291513 0
Riddiford Street, Newtown, Wellington 6021,
Country [1] 291513 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294248 0
Central Health and Disabilitiy Ethics Committe
Ethics committee address [1] 294248 0
Ethics committee country [1] 294248 0
New Zealand
Date submitted for ethics approval [1] 294248 0
Approval date [1] 294248 0
18/12/2015
Ethics approval number [1] 294248 0
15/CEN/216

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63026 0
Dr David Abernethy
Address 63026 0
Department of Neurology
Wellington Hospital
Capital and Coast District Health Board
Riddiford Street
Wellington 6021
Country 63026 0
New Zealand
Phone 63026 0
+64 4 385 5999
Fax 63026 0
Email 63026 0
[email protected]
Contact person for public queries
Name 63027 0
Anne La Flamme
Address 63027 0
Professor, School of Biological Sciences
Victoria University of Wellington
PO Box 600
Wellington 6140
Country 63027 0
New Zealand
Phone 63027 0
+64 4 463 6093
Fax 63027 0
Email 63027 0
[email protected]
Contact person for scientific queries
Name 63028 0
Anne La Flamme
Address 63028 0
Professor, School of Biological Sciences
Victoria University of Wellington
PO Box 600
Wellington 6140
Country 63028 0
New Zealand
Phone 63028 0
+64-4-463-6093
Fax 63028 0
Email 63028 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSafety and acceptability of clozapine and risperidone in progressive multiple sclerosis: A phase I, randomised, blinded, placebo-controlled trial.2020https://dx.doi.org/10.1136/bmjno-2020-000060
Dimensions AIOpportunities for Molecular Imaging in Multiple Sclerosis Management: Linking Probe to Treatment2022https://doi.org/10.1148/radiol.211252
N.B. These documents automatically identified may not have been verified by the study sponsor.