TQT: 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

• Sponsor: Acorda Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01839279
• Collaborator: (none)
• Enrollment: 136
• Location: 1
• Arms: 3
• Duration (Months): 13
• Patients Per Site Per Month: 10.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Spasticity	Drug: Tizanidine; Drug: Placebo; Drug: Moxifloxacin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tizanidine Oral dose of 2 and 4 milligram (mg) tablets	Drug: Tizanidine; Other Names: Zanaflex
Placebo Comparator: Placebo Placebo followed by a single dose 400 mg moxifloxacin tablets.	Drug: Placebo; Drug: Moxifloxacin
Active Comparator: Moxifloxacin Single dose of 400 mg moxifloxacin followed by placebo.	Drug: Placebo; Drug: Moxifloxacin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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)]

4. 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)]

5. 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)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance- Dallas	Dallas	Texas	United States	75247

Sponsors and Collaborators

• Acorda Therapeutics

Investigators

• Study Director: Mathews Adera, MD, Acorda Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acorda Therapeutics
• ClinicalTrials.gov Identifier: NCT01839279
• Other Study ID Numbers: ZAN-QT-1006
• First Posted: Apr 24, 2013
• Last Update Posted: Mar 23, 2021
• Last Verified: Mar 1, 2021

• Additional relevant MeSH terms: Muscle Spasticity; Moxifloxacin; Tizanidine

Study Results

Participant Flow

Arm/Group Title	Tizanidine	Initial Placebo and Crossover to Moxifloxacin	Initial Moxifloxacin and Crossover to Placebo
Arm/Group Description	Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).	Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
Period Title: Overall Study
STARTED	72	32	32
QT/QTc Analysis Set	72	32	32
PK Analysis Set	70	0	0
Moxifloxacin/Placebo Analysis Set	0	31	30
PK/QTc Analysis Set	70	0	0
COMPLETED	59	30	30
NOT COMPLETED	13	2	2

Baseline Characteristics

Arm/Group Title	Tizanidine	Initial Placebo and Crossover to Moxifloxacin	Initial Moxifloxacin and Crossover to Placebo	Total
Arm/Group Description	Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).	Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).	Total of all reporting groups
Overall Participants	72	32	32	136
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.4 (6.75)	34.1 (7.51)	35.3 (7.21)	34.0 (7.03)
Sex: Female, Male (Count of Participants)
Female	39 54.2%	17 53.1%	17 53.1%	73 53.7%
Male	33 45.8%	15 46.9%	15 46.9%	63 46.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	30 41.7%	6 18.8%	12 37.5%	48 35.3%
Not Hispanic or Latino	42 58.3%	26 81.3%	20 62.5%	88 64.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tizanidine 24 mg	Tizanidine Placebo 24 mg	Tizanidine 24 mg Placebo-corrected
Arm/Group Description	60 subjects Tizanidine 24 mg single dose	61 subjects placebo used for the analysis.	60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
Measure Participants	60	61	121
Timepoint (Hour) 0	-4.3	-0.5	-3.7
0.5	-2.0	1.2	-3.2
1	-4.0	2.6	-6.6
1.5	-4.7	2.7	-7.4
2	-3.6	2.9	-6.4
4	1.6	3.4	-1.8
8	-2.4	3.1	-5.5
12	-2.0	1.0	-3.0
24	0.4	2.6	-2.2

2. Secondary Outcome

Title	The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tizanidine 8 mg	Tizanidine Placebo 8 mg	Tizanidine 8 mg Placebo-corrected
Arm/Group Description	70 subjects Tizanidine 8 mg single dose.	63 subjects placebo used for analysis.	70 subjects Tizanidine 8 mg single dose, 63 subjects placebo used for analysis.
Measure Participants	70	63	133
Timepoint (Hour) 0	-0.8	-0.9	0.1
0.5	-0.4	0.4	-0.8
1	0.0	2.3	-2.3
1.5	1.1	1.3	-0.1
2	-0.4	0.4	-0.7
4	2.6	1.0	1.6
8	-1.5	0.6	-2.2
12	-0.1	0.7	-0.8
24	-0.5	1.4	-1.9

3. Secondary Outcome

Title	Assessing the Relationship Between Changes in the QTc Interval and Plasma Levels of Tizanidine Using Concentration-effect Modeling
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Tizanidine
Arm/Group Description
Measure Participants	70
Number (90% Confidence Interval) [msec per ng/mL]	-0.1209

4. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment

Arm/Group Title	Day 5 (Tizanidine 8 mg)	Day 14 (Tizanidine 24 mg)
Arm/Group Description
Measure Participants	70	60
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	11.7 (43.9)	27.4 (42.7)

5. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment

Arm/Group Title	Day 5 (Tizanidine 8 mg)	Day 14 (Tizanidine 24 mg)
Arm/Group Description
Measure Participants	70	60
Median (Full Range) [hour]	1.35	2.10

6. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

PK Analysis set: all subjects from Group 1 who received at least one study drug and have at least one valid PK assessment

Arm/Group Title	Day 5 (Tizanidine 8 mg)	Day 14 (Tizanidine 24 mg)
Arm/Group Description
Measure Participants	70	60
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	32.4 (65.1)	115 (52.8)

Adverse Events

Time Frame	Up to 23 days
Arm/Group Title	Tizanidine		Initial Placebo and Crossover to Moxifloxacin		Initial Moxifloxacin and Crossover to Placebo		Placebo and Moxifloxacin Groups Combined
Arm/Group Description	Tizanidine Arm		Placebo/Moxifloxacin Arm		Moxifloxacin/Placebo Arm		Combined Moxifloxacin Arm
All Cause Mortality
	Tizanidine		Initial Placebo and Crossover to Moxifloxacin		Initial Moxifloxacin and Crossover to Placebo		Placebo and Moxifloxacin Groups Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tizanidine		Initial Placebo and Crossover to Moxifloxacin		Initial Moxifloxacin and Crossover to Placebo		Placebo and Moxifloxacin Groups Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/72 (0%)		0/32 (0%)		1/32 (3.1%)		1/64 (1.6%)
Pregnancy, puerperium and perinatal conditions
Ectopic Pregnancy	0/72 (0%)		0/32 (0%)		1/32 (3.1%)		1/64 (1.6%)
Other (Not Including Serious) Adverse Events
	Tizanidine		Initial Placebo and Crossover to Moxifloxacin		Initial Moxifloxacin and Crossover to Placebo		Placebo and Moxifloxacin Groups Combined
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/72 (61.1%)		16/32 (50%)		23/32 (71.9%)		39/64 (60.9%)
Gastrointestinal disorders
GASTROINTESTINAL DISORDERS	21/72 (29.2%)		8/32 (25%)		10/32 (31.3%)		18/64 (28.1%)
NAUSEA	9/72 (12.5%)		4/32 (12.5%)		5/32 (15.6%)		9/64 (14.1%)
DRY MOUTH	10/72 (13.9%)		0/32 (0%)		3/32 (9.4%)		3/64 (4.7%)
General disorders
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	24/72 (33.3%)		9/32 (28.1%)		9/32 (28.1%)		18/64 (28.1%)
FATIGUE	13/72 (18.1%)		1/32 (3.1%)		1/32 (3.1%)		2/64 (3.1%)
APPLICATION SITE PRURITUS	5/72 (6.9%)		1/32 (3.1%)		4/32 (12.5%)		5/64 (7.8%)
APPLICATION SITE IRRITATION	5/72 (6.9%)		3/32 (9.4%)		1/32 (3.1%)		4/64 (6.3%)
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS	10/72 (13.9%)		2/32 (6.3%)		3/32 (9.4%)		5/64 (7.8%)
BACK PAIN	4/72 (5.6%)		2/32 (6.3%)		1/32 (3.1%)		3/64 (4.7%)
MUSCULOSKELETAL CHEST PAIN	4/72 (5.6%)		0/32 (0%)		1/32 (3.1%)		1/64 (1.6%)
Nervous system disorders
NERVOUS SYSTEM DISORDERS	32/72 (44.4%)		8/32 (25%)		8/32 (25%)		16/64 (25%)
SOMNOLENCE	20/72 (27.8%)		4/32 (12.5%)		4/32 (12.5%)		8/64 (12.5%)
DIZZINESS	17/72 (23.6%)		2/32 (6.3%)		4/32 (12.5%)		6/64 (9.4%)
HEADACHE	10/72 (13.9%)		5/32 (15.6%)		3/32 (9.4%)		8/64 (12.5%)
PARAESTHESIA	7/72 (9.7%)		0/32 (0%)		1/32 (3.1%)		1/64 (1.6%)
DIZZINESS POSTURAL	4/72 (5.6%)		0/32 (0%)		1/32 (3.1%)		1/64 (1.6%)
Skin and subcutaneous tissue disorders
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	8/72 (11.1%)		4/32 (12.5%)		7/32 (21.9%)		11/64 (17.2%)
RASH	5/72 (6.9%)		1/32 (3.1%)		1/32 (3.1%)		2/64 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor (Acorda) has right to review and comment on proposed publications within a specified time frame, up to 60 days; multi-center trials require joint publication unless specifically permitted otherwise.