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

Sponsor:	Teva R&D Initiative
Information provided by:	Teva R&D Initiative
ClinicalTrials.gov Identifier:	NCT00358293

Purpose

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	Intervention	Phase
Muscle Spasticity	Drug: Tizanidine (sublingual or oral)	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double-Blind, Active Control, Crossover Assignment, Safety/Efficacy Study
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

Resource links provided by NLM:

MedlinePlus related topics: Multiple Sclerosis

Drug Information available for: Tizanidine Tizanidine hydrochloride

U.S. FDA Resources

Further study details as provided by Teva R&D Initiative:

Primary Outcome Measures:

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

Secondary Outcome Measures:

Secondary clinical efficacy - objective measure of sleep (actigraphy measures)

Estimated Enrollment:	20
Study Start Date:	December 2006
Study Completion Date:	February 2007

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.

Eligibility

Ages Eligible for Study:	20 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00358293

Locations

Israel
Tel Aviv Sourasky Medical Center- Neurology Department
Tel Aviv, Israel

Sponsors and Collaborators

Teva R&D Initiative

Investigators

Principal Investigator:

Arnon Karni, MD

Department of Neurology, Tel Aviv Sourasky Medical Center

More Information

No publications provided

Study ID Numbers:	Protocol C2/5/TZ-MS-05
Study First Received:	July 27, 2006
Last Updated:	January 20, 2009
ClinicalTrials.gov Identifier:	NCT00358293 History of Changes
Health Authority:	Israel: Ministry of Health

Keywords provided by Teva R&D Initiative:

Multiple Sclerosis
Spasticity
Sublingual Tizanidine
Ashworth Scores
Spasticity in Multiple Sclerosis Patients

Additional relevant MeSH terms:

Parasympatholytics
Neurotransmitter Agents
Adrenergic Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuromuscular Agents
Adrenergic Agonists
Signs and Symptoms
Multiple Sclerosis
Musculoskeletal Diseases
Muscle Hypertonia
Sensory System Agents
Muscle Relaxants, Central
Therapeutic Uses
Tizanidine

Analgesics
Autoimmune Diseases of the Nervous System
Neuromuscular Manifestations
Autoimmune Diseases
Adrenergic alpha-Agonists
Immune System Diseases
Demyelinating Diseases
Nervous System Diseases
Pharmacologic Actions
Muscle Spasticity
Muscular Diseases
Autonomic Agents
Neurologic Manifestations
Demyelinating Autoimmune Diseases, CNS
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on November 25, 2009