A Multicenter, Randomized, Fixed Sequence, Cross-over Study to Assess the Safety, Tolerability, and Pharmacokinetics of MRX-4TZT TDS (Tizanidine Transdermal Delivery System) versus Oral Tizanidine in Multiple Sclerosis Patients with Established Spasticity

Exclusion Criteria26

• Acute MS exacerbation requiring treatment within 3 months prior to Day 1.
• Any concomitant disease or disorder that has symptoms of spasticity, or may influence the participant’s level of spasticity, or results in an inability to rate the participant’s level of MS spasticity including infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement in the opinion of the investigator.
• History of unstable psychiatric disease, or current signs or symptoms of significant medical disorders such as severe, progressive, or uncontrolled pulmonary, cardiac, gastrointestinal, hepatic, renal, genitourinary, hematological, endocrine, immunologic, or neurological disease.
• History of seizures at any time in the past, excluding childhood febrile seizures.
• History of significant cognitive deficit, severe or untreated anxiety, or severe or untreated depression in the opinion of the investigator.
• Any positive responses on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening or Day 1 that indicates the individual may be at increased risk by participating in this study or may cause potential interference with study conduct or results, at investigator discretion.
• History of malignancy that has not been in remission for >/=5 years, except effectively treated basal cell skin carcinoma.
• Known or suspected substance abuse disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Diagnostic Criteria for Drug and Alcohol Abuse, within the 12 months prior to screening in the opinion of the investigator, or positive drug or alcohol test at Screening or Day 1.
• History of significant dermatologic disease or conditions such as atopy, psoriasis, vitiligo, or condition known to alter skin appearance or physiologic response (e.g., diabetes, porphyria).
• Obvious difference in skin color between proposed TDS application sites or the presence of a skin condition, excessive hair, scar tissue, tattoo, open sores, raised moles, or damaged skin in or around the proposed TDS application sites (including sunburn, uneven skin tones), body piercings, or other disfigurations that would interfere with placement of the TDS, dermal irritancy assessment, drug absorption, or reactions to drug, in the opinion of the investigator.
• Inability to swallow or tolerate oral medications.
• Any other significant disease, disorder or significant laboratory finding which, in the opinion of the investigator, places the individual at risk as a result of their study participation, may influence the results of the study, or affect the individual’s ability to participate.
• Planned elective surgery or other procedures requiring general anesthesia during the study.
• For female participants of childbearing potential, use of oral or implanted hormonal contraception within 28 days prior to Day 1.
• Use of baclofen within 7 days prior to Day 1.
• Use of intravenous methylprednisolone within 3 months prior to Day 1.
• Use of botulinum toxin A or B within 3 months prior to Day 1, with the exception of treatment for neurogenic bladder or cosmetic Botox.
• Use of long-acting opioids or round the clock use of short-acting opioids for the treatment of pain within 28 days prior to Day 1.
• Use of benzodiazepines within 7 days prior to Day 1.
• Use of gabapentin or pregabalin that has not been stable for >/=3 months prior to Day 1.
• Use of dantrolene within 7 days prior to Day 1.
• Use of clonidine within 7 days prior to Day 1.
• Use of any product containing tetrahydrocannabinol (THC) within 28 days prior to Day 1 (non-THC containing CBD oil/products are permitted).
• Use of any other concomitant medications that may potentially interfere with the actions of the study drug or outcome variables, in the opinion of the investigator.
• Known or suspected allergy to any of the formulation components of tizanidine HCl capsules (Zanaflex® or generic equivalent) or MRX-4TZT.
• Current participation in any other investigational drug study or receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) before Day 1.