Official Title: “Long Term Clinical Efficacy and Safety of Novel Sublingual Tizanidine HCl (12 mg) for the Treatment of Spasticity in Patients With Multiple Sclerosis - Open Label Extension Study”

Open label, one year extension study to evaluate the clinical efficacy and safety of 12 mg sublingual tizanidine administered once nightly in MS patients who successfully completed Phase I/II protocol C2/5/TZ:MS-05 at the Tel Aviv Sourasky Medical Center, Department of Neurology, Dr. Arnon Karni, PI.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2008

The previous study, Protocol C2/5/TZ-MS-05, using 12 mg sublingual tizanidine, confirmed that administration of once nightly sublingual tizanidine before sleep results in a statistically and clinically significant reduction in next-day spasticity, as compared to placebo. The clinical effect following 12 mg sublingual tizanidine was larger (4-5 units on the Ashworth scale) and more sustained (up to 18-20 hours post-dose) than was seen for 8 mg tizanidine (earlier study, Protocol C2/5/TZ:MS-03z). This study also reconfirmed that the increased improvement in next-day reduction of spasticity following overnight sublingual tizanidine dosing is not accompanied by a concomitant increase in next-day somnolence.

This study, a 12 month open label extension, will allow those patients who successfully completed Protocol C2/5/TZ-MS-05 and who found tizanidine to be beneficial, to continue treatment under close medical supervision. The study will provide long-term (12 months) clinical efficacy and safety data re: the use of once daily sublingual tizanidine, administered at night, just before bedtime.

Intervention(s) in this Clinical Trial

• Drug: sublingual tizanidine 12 mg
  • Single sublingual tizanidine 12 mg tablet, to be administered once nightly, via sublingual administration for 12 months

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Sublingual tizanidine
  • Once nightly dosing of 12 mg sublingual tizanidine tablet

Primary Measures

• Clinical Efficacy- reduction in next-day spasticity (Ashworth scores)
  • Time Frame: 12 months
    Safety Issue?: No
• Safety- No increase in next-day somnolence/fatigue, measured via Epworth Sleepiness Scale (ESS) and Fatigue Severity Scale (FSS) questionnaires
  • Time Frame: 12 months
    Safety Issue?: Yes

Secondary Measures

• Additional Safety Measures: Clinical Laboratories (hematology and clinical chemistry, with special emphasis on liver function tests); Blood pressure monitoring (standard vital signs: BP and pulse at every monthly visit, + 24 hour Holter ambulatory Blood
  • Time Frame: 12 months
    Safety Issue?: Yes

Inclusion Criteria:

• Successful completion of previous protocol, Study C2/5/TZ:MS-05
• Have a definitive diagnosis of Multiple Sclerosis
• Patients may be allowed to take other anti-spasticity medication during the study (other than Baclofen pump)as per their individual daily dosing regimen, with the following qualification: (1) No dose after 18:00 on any study day (2) No dose at all on a clinic evaluation day
• Females must agree to use a medically accepted form of birth control, be surgically sterile, or be two years post-menopausal. Oral contraception in NOT acceptable as it is contraindicated for tizanidine use.
• Patients must meet criteria for stable 24 hour BP values based on the screening ABPM monitorings (with and without tizanidine challenge) as determined by the study's BP consultant

Exclusion Criteria:

• Use of CYP1A2 inhibitors [e.g. ciprofloxacin or fluvoxamine as well as zileuton, other fluroquinolones (norfloxacin), antiarrythmics (amiodarone, mexiletine, propafenone), cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine] from baseline and for the duration of the study
• Taking medications from baseline and for the duration of the study that would potentially interfere with the actions of the study medication or outcome variables as determined by the PI
• Previous history of dementia, unstable psychiatric disease or current signs and symptoms of significant medical disorders such as severe, progressive or uncontrolled renal, hepatic hematological, endocrine, pulmonary, cardiac, neurological or cerebral disease
• Significant abnormalities in screening laboratory parameters as described below:
• ALT > 2xULN
• AST > 2xULN
• Creatinine > 2.0 mg/dL
• Bilirubin > 2xULN
• WBC < 2,300/mm3
• Platelets < 80,000/mm3
• History of allergy to tizanidine or any inactive component (including lactose intolerance) of the sublingual tizanidine tablet
• History of substance abuse within past 12 months
• Patients who are non-cooperative or unwilling to sign consent form

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 20 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Teva R&D Initiative

Overall Clinical Trial Officials and Contacts

Arnon Karni, MD Principal Investigator Tel-Aviv Sourasky Medical Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00464958

Study ID Number: Protocol C2/5/TZ:MS-05 EXT

ClinicalTrials.gov Identifier: NCT00464958

Health Authority: Israel: Ministry of Health

ClinicalTrials.gov Identifier: NCT00358293