Sarizotan in the Treatment of Neuroleptic-induced Tardive Dyskinesia

NCT ID: NCT00310661

Last Updated: 2015-07-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-12-31
• Study Completion Date: 2008-03-31

Brief Summary

TD is a troublesome and potentially irreversible side effect associated with the use of neuroleptics. While the newer neuroleptics are improved in this regard, they all still carry the risk of TD.

The present study proposes that sarizotan is a potential agent for treating neuroleptic-induced TD based on preliminary data indicating efficacy in the management of dyskinesias associated with Parkinson's disease. Its efficacy is further substantiated by pre-clinical data obtained from the vacuous chewing movement (VCM) model in rats, a model we employ ourselves in investigating the relationship between D2 occupancy and TD. The present study also examines the effects of sarizotan on cognitive function, given the association between TD and cognitive deficits.

Detailed Description

The primary objective of the study is to assess the safety and the anti-dyskinetic properties of sarizotan at various dosages for neuroleptic-induced TD.

The secondary objective of the study is to assess the effects of sarizotan on cognitive function in patients with neuroleptic-induced TD.

The diagnosis of neuroleptic-induced TD will be confirmed by history and physical examination. Patients will be evaluated at baseline, 2, 4, 8, and 12 weeks. Safety will be assessed by vital signs, ECG, routine blood tests, the ACTH stimulation test, and the clinician's and patient's global impression of tolerability.

Procedures:

For efficacy, the primary outcome variable will be changes in the Abnormal Involuntary Movement Scale (AIMS), and a baseline score of >3 ('moderate') will be required for item 8 (Severity of Abnormal Movements). Quantitative evaluation of movements will be carried out in two ways. The first involves a series of instrumental and clinical measures that were developed as a battery for the assessment of antipsychotic-induced parkinsonism and TD. The second means of quantifying the movements involves the use of video recording, with independent evaluation by several raters (Appendix I). Such approaches have gained popularity in the quantification of movement disorders as a means of improving reliability.

Secondary measures will include the positive and negative syndrome scale (PANSS) and other movement disorder scales (Simpson-Angus Rating Scales) for acute extrapyramidal symptoms (EPS), and the Barnes Akathisia Rating Scale (BARS). Global impressions of efficacy and tolerability by the clinician (CGI) and by the patients (PGI) will be recorded at all study visits after the commencement of treatment. To assess potential cognitive changes that may occur in conjunction with TD changes, a battery of neuropsychological tests will be carried out at baseline and endpoint (see Appendix II). To assess the relationship with primary negative symptoms such as the deficit syndrome, the total and sub-scales of the Positive and Negative Syndrome Scale will be evaluated.

Conditions

Neuroleptic-induced Tardive Dyskinesia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Placebo hard gelatin capsules matching the investigational medication

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo for each patient randomized to the placebo arm will be given placebo (oral, twice daily) in a pill form for 12 weeks

Sarizotan HCI

Sarizotan HCI is administered at various doses ranging from 2-7mg.

Group Type: EXPERIMENTAL

Sarizotan

Intervention Type: DRUG

The dose of sariztan HCI for each patient in the drug arm will be given 2mg b.i.d. orally during the first 4 weeks of treatment. If efficacy is inadequate and there are no safety concerns, the option to raise the dose to 5mg b.i.d is given. After 8 weeks of treatment, the option to raise the dose to 7mg bid is given. Dose may remain the same or may be decreased again to the previous dose.

Interventions

Sarizotan

The dose of sariztan HCI for each patient in the drug arm will be given 2mg b.i.d. orally during the first 4 weeks of treatment. If efficacy is inadequate and there are no safety concerns, the option to raise the dose to 5mg b.i.d is given. After 8 weeks of treatment, the option to raise the dose to 7mg bid is given. Dose may remain the same or may be decreased again to the previous dose.

Intervention Type: DRUG

Placebo

Placebo for each patient randomized to the placebo arm will be given placebo (oral, twice daily) in a pill form for 12 weeks

Intervention Type: OTHER

Other Intervention Names

Sarizotan HCI; Sugar Pill

Eligibility Criteria

Inclusion Criteria

• The patient meets the Schooler and Kane Diagnostic Criteria (25) for Tardive Dyskinesia as established by history and physical examination.
• a score of 3 or above for item 8 of the AIMS scale (Severity of Abnormal Movements) at baseline.
• For female patients: either the patient is surgically sterile, has been post-menopausal for at least 12 months, or she is using a reliable method of contraception (single-barrier methods alone will not be considered sufficiently reliable) and provides a negative pregnancy test at the screening visit.
• on a stable dose of his/her current antipsychotic (either typical or atypical) and movement disorder medication (e.g. anticholinergics) for at least one month before randomisation. For depot antipsychotics, this period will be at least one dosing interval.
• The patient gives full written informed consent for participation in the study.
• The patient has a level of understanding of English or Tamil sufficient to communicate effectively with the investigator and study staff, and to be able to complete the computerised neurocognitive test battery where necessary

Exclusion Criteria

• Evidence of pre-existing tic disorders, neuroleptic-induced acute dystonia or neuroleptic-induced acute akathisia
• Risk of suicide (in the opinion of the investigator).
• Any of the following non-permitted concomitant medication: Metoclopramide in the 4 weeks before screening, Buspirone in the 4 weeks before screening, Azole antifungals (particularly ketoconazole), Etomidate, HIV proteinase inhibitors (e.g. indinavir, ritonavir), any tricyclic antidepressant in the 4 weeks before screening (SSRI antidepressants if at a stable dosage are permitted), Fludrocortisone, Intermittent therapy with oral corticoids, continuous therapy with <7.5mg/day (oral) prednisolone or an equivalent dose of a different corticoid (patients on continuous long-term therapy with a dose of >7.5mg prednisolone or equivalent may participate but should not undergo an ACTH challenge test).
• Treatment with electroconvulsive therapy within six months before the first study visit.
• Known history of drug dependence (except nicotine and caffeine) or alcohol dependence within the six months before the study (three months for known drug abuse).
• Evidence of any clinically significant endocrine, cardiac, renal, neurological, cerebrovascular, metabolic, gastrointestinal, immunological, allergic or respiratory disease. Patients who are not euthyroid.
• asthma or known hypersensitivity to antipsychotic drugs or ACTH
• Pregnancy or lactation.
• Any abnormal laboratory test result(s) of potential clinical significance at screening, including: Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) greater than 3 ´ upper limit of normal (ULN), Creatinine >2 ´ ULN, total bilirubin >2 ´ ULN
• Participation in another clinical study within the 30 days before the first visit of the present study.
• Plasma cortisol concentration below 18 µg/dL 60 minutes after stimulation with 250 µg ACTH1-24 (for procedure see Section 7.9). (NOTE: This exclusion criterion is waived, and the test should not be carried out, for patients on continuous long-term therapy with a dose of >7.5mg prednisolone or equivalent.
• Lack of legal capacity, or limited legal capacity.)
• Known previous diagnosis of learning disability.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

Centre for Addiction and Mental Health

OTHER

Sponsor Role: lead

Responsible Party

Gary Remington

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gary Remington, MD

Role: PRINCIPAL_INVESTIGATOR

Centre for Addiction and Mental Health

Locations

Centre for Addiction and Mental Health

Toronto, Ontario, Canada

Schizophrenia Research Foundation of India

Chennai, , India

Countries

Canada; India

References

Kleven MS, Barret-Grevoz C, Bruins Slot L, Newman-Tancredi A. Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats. Neuropharmacology. 2005 Aug;49(2):135-43. doi: 10.1016/j.neuropharm.2005.02.005. Epub 2005 Apr 1.

Reference Type: BACKGROUND

PMID: 15996562 (View on PubMed)

Related Links

http://camh.net

CAMH web site

Other Identifiers

005/2004

Identifier Type: -

Identifier Source: org_study_id