A Study to Define the ECG Effects of Tizanidine Compared to Placebo and the Positive Control, Moxifloxacin, in Healthy Men and Women Using a Blinded ECG Evaluator: A Thorough ECG Trial

Study Overview
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Brief Summary
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This is a single-center, partial-blind, randomized, placebo-controlled, parallel design study with a nested crossover comparison to define the ECG effects of tizanidine compared to placebo and the positive control, moxifloxacin, in healthy men and women. The study will be conducted in a Phase 1 unit with sufficient facilities to house subjects as required by the protocol.

Official Title
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A Partial-Blind, Randomized, Parallel Design Study With a Nested Crossover Comparison to Define the ECG Effects of Tizanidine Compared to Placebo and the Positive Control, Moxifloxacin, in Healthy Men and Women Using a Blinded ECG Evaluator: A Thorough ECG Trial

Conditions
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Spasticity

Intervention / Treatment
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* Drug: Tizanidine
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women of childbearing potential should have a negative urine pregnancy test prior to Screening and Day -2 of the trial All subjects of childbearing potential must practice a highly effective method of birth control excluding oral contraceptives for the duration of the trial and up to 3 months after the last dose of investigational product. Oral contraceptives are not allowed, based on the precaution listed in the Zanaflex package insert. Have a body mass index (BMI) ranging between 19 and 30 kg/m2 Comprehend and be able to provide written informed consent Be willing and able to comply with all trial requirements Exclusion Criteria: Female who is either pregnant, breastfeeding or planning to become pregnant History of hypersensitivity or allergic reaction to tizanidine or moxifloxacin or any of the tablet components Any condition possibly affecting drug absorption, metabolism or excretion including previous surgery for removal of parts of stomach, bowel, liver, gall bladder, or pancreas History of Long QT Syndrome or a first-generation relative with this condition Evidence or history of clinically significant allergies except for untreated, asymptomatic, seasonal allergies at time of dosing, hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, renal, psychiatric, or neurological disease. Determination of clinical significance is to be made at the Investigator's discretion History or presence of any malignant or benign neoplasm considered by the investigator to be clinically significant History of drug or alcohol abuse or dependence within the last year Have an active infectious disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tizanidine<br>Oral dose of 2 and 4 milligram (mg) tablets | Drug: Tizanidine<br> <br> * Other names: Zanaflex;|
| Placebo Comparator: Placebo<br>Placebo followed by a single dose 400 mg moxifloxacin tablets. | Drug: Placebo<br> <br> Drug: Moxifloxacin<br> <br> |
| Active Comparator: Moxifloxacin<br>Single dose of 400 mg moxifloxacin followed by placebo. | Drug: Placebo<br> <br> Drug: Moxifloxacin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | Change from baseline in Cardiac Repolarization (QTc Interval) at Day 14 (Tizanidine 24 mg). Moxifloxacin was not investigational drug, it was used to assess the sensitivity of the study. | Baseline and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | Change from baseline in Cardiac Repolarization (QTc Interval) at Day 5 (Tizanidine 8 mg). Moxifloxacin was not investigational drug, it was used to assess the sensitivity of the study. | Baseline and Day 5 | 
| Assessing the Relationship Between Changes in the QTc Interval and Plasma Levels of Tizanidine Using Concentration-effect Modeling | The relationship will be quantified using a linear mixed effects model with an intercept. Data from Day 5 and Day 14 were fitted into regression model to obtain a slope of change. The measure type 'Number' followed by (90% Confidence Interval) shown in results is the slope from the linear fit. | Day 5, Day 14 | 
| Maximum Plasma Concentration (Cmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. |  | 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg) | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. |  | 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg) | 
| Area Under the Plasma Concentration-time Curve During a Dosing Interval (AUCt) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. |  | 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg) |