Spasticity
Conditions
Brief summary
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.
Interventions
Sponsors
Acorda Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | Baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | Baseline and Day 5 | 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. |
| Assessing the Relationship Between Changes in the QTc Interval and Plasma Levels of Tizanidine Using Concentration-effect Modeling | Day 5, Day 14 | 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. |
| 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) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tizanidine | 72 |
| Initial Placebo and Crossover to Moxifloxacin Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected). | 32 |
| Initial Moxifloxacin and Crossover to Placebo Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected). | 32 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 | 1 |
| Overall Study | Classified as 'Other' | 5 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 1 |
Baseline characteristics
| Characteristic | Tizanidine | Initial Placebo and Crossover to Moxifloxacin | Initial Moxifloxacin and Crossover to Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 33.4 years STANDARD_DEVIATION 6.75 | 34.1 years STANDARD_DEVIATION 7.51 | 35.3 years STANDARD_DEVIATION 7.21 | 34.0 years STANDARD_DEVIATION 7.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 6 Participants | 12 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 26 Participants | 20 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 39 Participants | 17 Participants | 17 Participants | 73 Participants |
| Sex: Female, Male Male | 33 Participants | 15 Participants | 15 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 72 | 16 / 32 | 23 / 32 | 39 / 64 |
| serious Total, serious adverse events | 0 / 72 | 0 / 32 | 1 / 32 | 1 / 64 |
Outcome results
Primary
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.
Time frame: Baseline and Day 14
Population: QT/QTc Analysis set: Received at least 1 dose of study drug (including placebo), had measurements at baseline and on-treatment with at least 1 time point post-dose with at minimum triplicate measures giving rise to a QTc value for primary correction method. Effect of moxifloxacin was as expected. Therefore, no analysis required per Medical Monitor.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1.5 | -4.7 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 24 | 0.4 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 4 | 1.6 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 2 | -3.6 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | Timepoint (Hour) 0 | -4.3 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 12 | -2.0 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1 | -4.0 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 0.5 | -2.0 milliseconds (msec) |
| Tizanidine 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 8 | -2.4 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 2 | 2.9 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | Timepoint (Hour) 0 | -0.5 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 0.5 | 1.2 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1 | 2.6 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1.5 | 2.7 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 4 | 3.4 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 8 | 3.1 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 12 | 1.0 milliseconds (msec) |
| Tizanidine Placebo 24 mg | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 24 | 2.6 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1 | -6.6 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | Timepoint (Hour) 0 | -3.7 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 8 | -5.5 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 0.5 | -3.2 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 24 | -2.2 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 2 | -6.4 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 1.5 | -7.4 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 12 | -3.0 milliseconds (msec) |
| Tizanidine 24 mg Placebo-corrected | The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14. | 4 | -1.8 milliseconds (msec) |
Secondary
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.
Time frame: 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg)
Population: PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tizanidine 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. | 32.4 ng*hr/mL | Geometric Coefficient of Variation 65.1 |
| Tizanidine Placebo 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. | 115 ng*hr/mL | Geometric Coefficient of Variation 52.8 |
Secondary
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.
Time frame: Day 5, Day 14
Population: Pk/QTc Analysis set will include all subjects in the QT/QTc analysis set with at least one valid PK assessment. Effect of moxifloxacin was as expected. Therefore, no analysis required per Medical Monitor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tizanidine 24 mg | Assessing the Relationship Between Changes in the QTc Interval and Plasma Levels of Tizanidine Using Concentration-effect Modeling | -0.1209 msec per ng/mL |
Secondary
Maximum Plasma Concentration (Cmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State.
Time frame: 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg)
Population: PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tizanidine 24 mg | Maximum Plasma Concentration (Cmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. | 11.7 ng/mL | Geometric Coefficient of Variation 43.9 |
| Tizanidine Placebo 24 mg | Maximum Plasma Concentration (Cmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. | 27.4 ng/mL | Geometric Coefficient of Variation 42.7 |
Secondary
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.
Time frame: Baseline and Day 5
Population: QT/QTc Analysis set: Received at least 1 dose of study drug (including placebo), had measurements at baseline and on-treatment with at least 1 time point post-dose with at minimum triplicate measures giving rise to a QTc value for primary correction method. Effect of moxifloxacin was as expected. Therefore, no analysis required per Medical Monitor.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1.5 | 1.1 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 24 | -0.5 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 4 | 2.6 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 2 | -0.4 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | Timepoint (Hour) 0 | -0.8 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 12 | -0.1 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1 | 0.0 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 0.5 | -0.4 msec |
| Tizanidine 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 8 | -1.5 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 2 | 0.4 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | Timepoint (Hour) 0 | -0.9 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 0.5 | 0.4 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1 | 2.3 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1.5 | 1.3 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 4 | 1.0 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 8 | 0.6 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 12 | 0.7 msec |
| Tizanidine Placebo 24 mg | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 24 | 1.4 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1 | -2.3 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | Timepoint (Hour) 0 | 0.1 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 8 | -2.2 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 0.5 | -0.8 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 24 | -1.9 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 2 | -0.7 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 1.5 | -0.1 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 12 | -0.8 msec |
| Tizanidine 24 mg Placebo-corrected | The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint. | 4 | 1.6 msec |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State.
Time frame: 0.5, 1, 1.5, 2, 4, 8, 12 & 24 hours post dose on Days 5 (8 mg) and 14 (24 mg)
Population: PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tizanidine 24 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. | 1.35 hour |
| Tizanidine Placebo 24 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State. | 2.10 hour |