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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00358293
Recruitment Status : Completed
First Posted : July 31, 2006
Last Update Posted : January 21, 2009
Information provided by:
Teva GTC

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.

Condition or disease Intervention/treatment Phase
Muscle Spasticity Drug: Tizanidine (sublingual or oral) Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double
Primary Purpose: Treatment
Official Title: 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
Study Start Date : December 2006
Actual Study Completion Date : February 2007

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. Clinical efficacy - improvement in next-day spasticity (Ashworth scores)
  2. 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

Secondary Outcome Measures :
  1. Secondary clinical efficacy - objective measure of sleep (actigraphy measures)

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00358293

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Tel Aviv Sourasky Medical Center- Neurology Department
Tel Aviv, Israel
Sponsors and Collaborators
Teva GTC
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Principal Investigator: Arnon Karni, MD Department of Neurology, Tel Aviv Sourasky Medical Center
Layout table for additonal information Identifier: NCT00358293    
Other Study ID Numbers: Protocol C2/5/TZ-MS-05
First Posted: July 31, 2006    Key Record Dates
Last Update Posted: January 21, 2009
Last Verified: April 2007
Keywords provided by Teva GTC:
Multiple Sclerosis
Sublingual Tizanidine
Ashworth Scores
Spasticity in Multiple Sclerosis Patients
Additional relevant MeSH terms:
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Muscle Spasticity
Multiple Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Muscular Diseases
Musculoskeletal Diseases
Muscle Hypertonia
Neuromuscular Manifestations
Neurologic Manifestations
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Muscle Relaxants, Central
Neuromuscular Agents
Autonomic Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action