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Study of Nighttime Dosing of Sublingual Tizanidine (12 mg) in Multiple Sclerosis (MS) Patients With Significant Spasticity

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ClinicalTrials.gov Identifier: NCT00358293
Recruitment Status : Completed
First Posted : July 31, 2006
Last Update Posted : January 21, 2009
Sponsor:
Information provided by:
Teva GTC

Tracking Information
First Submitted Date  ICMJE July 27, 2006
First Posted Date  ICMJE July 31, 2006
Last Update Posted Date January 21, 2009
Study Start Date  ICMJE December 2006
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2006)
  • Clinical efficacy - improvement in next-day spasticity (Ashworth scores)
  • Safety - no increase in next-day somnolence (measured objectively using PVT psychomotor vigilance task monitoring) and subjectively, using Epworth Sleepiness Scale (ESS) and Fatigue Severity Scale (FSS) questionnaires
Original Primary Outcome Measures  ICMJE
 (submitted: July 27, 2006)
  • Clinical Efficacy-Improvement in Next-Day Spasticity (Ashworth scores)
  • Safety- No increase in Next-Day Somnolence (measured objectively using PVT Psychomotor Vigilance Task Monitoring) and subjectively, using Epworth Sleepiness Scale (ESS) and Fatigue Severity Scale (FSS) questionnaires
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2006)
Secondary clinical efficacy - objective measure of sleep (actigraphy measures)
Original Secondary Outcome Measures  ICMJE
 (submitted: July 27, 2006)
Secondary Clinical Efficacy- Objective Measure of Sleep (Actigraphy Measures)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Nighttime Dosing of Sublingual Tizanidine (12 mg) in Multiple Sclerosis (MS) Patients With Significant Spasticity
Official Title  ICMJE A Double-Blind, Randomized, Crossover Study to Evaluate the Clinical Efficacy and Safety of Oral Tizanidine HCl (12 mg) Versus Novel Sublingual Tizanidine HCl (12 mg) for the Treatment of Spasticity in MS Patients
Brief Summary Nightly administration of 8 mg of a unique sublingual (under the tongue) formulation of tizanidine, a known anti-spasticity medication, has been shown in a previous study to improve next-day spasticity, about 12 hours following dosing in 20 multiple sclerosis (MS) patients. This improvement was statistically significant when compared to oral tizanidine dosing. The current study is being undertaken to see if increasing the dose to 12 mg once nightly will result in an even greater improvement, with a longer effect, i.e., next day improvement in spasticity both in the morning as well as in the late afternoon.
Detailed Description

Sublingual tizanidine, a novel test formulation of the known effective antispasticity agent, has been shown to have a unique pharmacokinetic profile [(i.e., nearly twice the bioavailability/AUC), but with little or no increase in peak plasma levels (Cmax) as compared to oral tizanidine (Zanaflex)]. When administered nightly to 20 MS patients, at a dose of 8 mg, it was shown to improve next-day spasticity (statistically significant improvement in Ashworth scores) about 12 hours post-dosing), improvement in nighttime (first quartile) sleep efficiency (as demonstrated by actigraphic measurement), and no increase in daytime somnolence.

Current study is being undertaken to evaluate if increased dosing (12 mg once nightly) of sublingual tizanidine (vs. oral) will show a concomitant increase in clinical effect, i.e., longer improvement, with next-day spasticity score improvement both in AM (as previously) as well as at PM (late afternoon) evaluation, with no increase in daytime somnolence.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE Muscle Spasticity
Intervention  ICMJE Drug: Tizanidine (sublingual or oral)
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Enrollment  ICMJE
 (submitted: July 27, 2006)
20
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 2007
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female patients between the ages of 20-65
  • Definitive diagnosis of MS, with Expanded Disability Status Scale (EDSS) less than 6.5 at screening
  • Has significant spasticity (total Ashworth => 6) at screening
  • Can maintain sleep regimens of at least 5 hours nightly for study duration
  • May be allowed to take other anti-spasticity medication during study (including oral baclofen) as per individual dosing regimen, with the following qualifications:

    • No dose after 6pm on any study day
    • No dose at all on a clinic evaluation day (Visits 3, 4, 5)
  • Females must agree to use a medically accepted form of birth control, be surgically sterile, or be two years post-menopausal. Oral contraception is contraindicated with tizanidine use.

Exclusion Criteria:

  • Acute MS exacerbation requiring treatment with steroids within 30 days of screening
  • Initiation of discontinuation of interferon beta within 30 days of screening
  • Use of baclofen pump
  • Use of CYP1A2 inhibitors during study
  • Taking medications that would potentially interfere with the actions of the study medication or outcome variables, including: sedatives, stimulants, anti-hypertensives, tricyclic antidepressants, etc.
  • Previous diagnosis of a sleep disorder, distinct from MS, such as obstructive sleep apnea or narcolepsy
  • Score >18 on Beck Depression Inventory at screening
  • Changes in chronic oral medications within 2 weeks of baseline and during study
  • Significant abnormalities in screening lab parameters (ex: ALT, AST, bilirubin > 2 x upper limit of normal [ULN]; creatinine > 2 mg/dl; white blood cell [WBC] < 2,300; platelets < 80,000).
  • 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
  • History of allergy to tizanidine or any inactive component (including lactose intolerance) of test or reference formulation
  • History of substance abuse within the past 12 months
  • Within 30 days of baseline, worked a rotating or nighttime shift
  • Participation in another clinical trial within 30 days of baseline
  • Patients who are uncooperative or unwilling to sign consent form
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00358293
Other Study ID Numbers  ICMJE Protocol C2/5/TZ-MS-05
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE Teva GTC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Arnon Karni, MD Department of Neurology, Tel Aviv Sourasky Medical Center
PRS Account Teva GTC
Verification Date April 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP