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

Teva Pharmaceuticals

Status and phase

Completed

Phase 2

Phase 1

Conditions

Muscle Spasticity

Treatments

Drug: Tizanidine (sublingual or oral)

Study type

Interventional

Funder types

Industry

Identifiers

NCT00358293

Protocol C2/5/TZ-MS-05

Details and patient eligibility

About

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.

Full 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.

Sex

All

Ages

20 to 65 years old

Volunteers

No Healthy Volunteers

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