Trial Outcomes & Findings for 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 (NCT NCT01839279)
NCT ID: NCT01839279
Last Updated: 2021-03-23
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
136 participants
Primary outcome timeframe
Baseline and Day 14
Results posted on
2021-03-23
Participant Flow
Participant milestones
| Measure |
Tizanidine
|
Initial Placebo and Crossover to Moxifloxacin
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
Initial Moxifloxacin and Crossover to Placebo
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
|---|---|---|---|
|
Overall Study
STARTED
|
72
|
32
|
32
|
|
Overall Study
QT/QTc Analysis Set
|
72
|
32
|
32
|
|
Overall Study
PK Analysis Set
|
70
|
0
|
0
|
|
Overall Study
Moxifloxacin/Placebo Analysis Set
|
0
|
31
|
30
|
|
Overall Study
PK/QTc Analysis Set
|
70
|
0
|
0
|
|
Overall Study
COMPLETED
|
59
|
30
|
30
|
|
Overall Study
NOT COMPLETED
|
13
|
2
|
2
|
Reasons for withdrawal
| Measure |
Tizanidine
|
Initial Placebo and Crossover to Moxifloxacin
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
Initial Moxifloxacin and Crossover to Placebo
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
|---|---|---|---|
|
Overall Study
Adverse Event
|
4
|
1
|
1
|
|
Overall Study
Withdrawal by Subject
|
4
|
1
|
1
|
|
Overall Study
Classified as 'Other'
|
5
|
0
|
0
|
Baseline Characteristics
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
Baseline characteristics by cohort
| Measure |
Tizanidine
n=72 Participants
|
Initial Placebo and Crossover to Moxifloxacin
n=32 Participants
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
Initial Moxifloxacin and Crossover to Placebo
n=32 Participants
Dosing of moxifloxacin will only be analyzed for cause (if the effect of moxifloxacin is not as expected).
|
Total
n=136 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
33.4 years
STANDARD_DEVIATION 6.75 • n=99 Participants
|
34.1 years
STANDARD_DEVIATION 7.51 • n=107 Participants
|
35.3 years
STANDARD_DEVIATION 7.21 • n=206 Participants
|
34.0 years
STANDARD_DEVIATION 7.03 • n=157 Participants
|
|
Sex: Female, Male
Female
|
39 Participants
n=99 Participants
|
17 Participants
n=107 Participants
|
17 Participants
n=206 Participants
|
73 Participants
n=157 Participants
|
|
Sex: Female, Male
Male
|
33 Participants
n=99 Participants
|
15 Participants
n=107 Participants
|
15 Participants
n=206 Participants
|
63 Participants
n=157 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
30 Participants
n=99 Participants
|
6 Participants
n=107 Participants
|
12 Participants
n=206 Participants
|
48 Participants
n=157 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
42 Participants
n=99 Participants
|
26 Participants
n=107 Participants
|
20 Participants
n=206 Participants
|
88 Participants
n=157 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
0 Participants
n=157 Participants
|
PRIMARY outcome
Timeframe: Baseline and Day 14Population: 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.
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.
Outcome measures
| Measure |
Tizanidine 24 mg
n=60 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
n=61 Participants
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
n=121 Participants
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
Timepoint (Hour) 0
|
-4.3 milliseconds (msec)
Interval -6.3 to -2.3
|
-0.5 milliseconds (msec)
Interval -2.5 to 1.4
|
-3.7 milliseconds (msec)
Interval -6.6 to -0.9
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
0.5
|
-2.0 milliseconds (msec)
Interval -4.0 to 0.1
|
1.2 milliseconds (msec)
Interval -0.8 to 3.2
|
-3.2 milliseconds (msec)
Interval -6.0 to -0.3
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
1
|
-4.0 milliseconds (msec)
Interval -6.0 to -2.0
|
2.6 milliseconds (msec)
Interval 0.6 to 4.5
|
-6.6 milliseconds (msec)
Interval -9.4 to -3.8
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
1.5
|
-4.7 milliseconds (msec)
Interval -6.9 to -2.6
|
2.7 milliseconds (msec)
Interval 0.6 to 4.8
|
-7.4 milliseconds (msec)
Interval -10.5 to -4.4
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
2
|
-3.6 milliseconds (msec)
Interval -5.6 to -1.6
|
2.9 milliseconds (msec)
Interval 0.9 to 4.8
|
-6.4 milliseconds (msec)
Interval -9.2 to -3.6
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
4
|
1.6 milliseconds (msec)
Interval -0.4 to 3.6
|
3.4 milliseconds (msec)
Interval 1.4 to 5.4
|
-1.8 milliseconds (msec)
Interval -4.6 to 1.0
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
8
|
-2.4 milliseconds (msec)
Interval -4.1 to -0.7
|
3.1 milliseconds (msec)
Interval 1.4 to 4.8
|
-5.5 milliseconds (msec)
Interval -7.9 to -3.1
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
12
|
-2.0 milliseconds (msec)
Interval -3.5 to -0.5
|
1.0 milliseconds (msec)
Interval -0.5 to 2.5
|
-3.0 milliseconds (msec)
Interval -5.1 to -0.8
|
|
The Primary Endpoint Will be the Baseline-adjusted, Placebo-corrected Effect on QTc (ΔΔQTc) on Day 14.
24
|
0.4 milliseconds (msec)
Interval -1.3 to 2.2
|
2.6 milliseconds (msec)
Interval 0.9 to 4.4
|
-2.2 milliseconds (msec)
Interval -4.6 to 0.2
|
SECONDARY outcome
Timeframe: Baseline and Day 5Population: 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.
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.
Outcome measures
| Measure |
Tizanidine 24 mg
n=70 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
n=63 Participants
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
n=133 Participants
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
Timepoint (Hour) 0
|
-0.8 msec
Interval -2.5 to 0.8
|
-0.9 msec
Interval -2.7 to 0.8
|
0.1 msec
Interval -2.3 to 2.5
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
0.5
|
-0.4 msec
Interval -2.3 to 1.4
|
0.4 msec
Interval -1.5 to 2.3
|
-0.8 msec
Interval -3.5 to 1.8
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
1
|
0.0 msec
Interval -1.9 to 1.9
|
2.3 msec
Interval 0.3 to 4.3
|
-2.3 msec
Interval -5.1 to 0.4
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
1.5
|
1.1 msec
Interval -0.7 to 2.9
|
1.3 msec
Interval -0.6 to 3.1
|
-0.1 msec
Interval -2.7 to 2.4
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
2
|
-0.4 msec
Interval -2.0 to 1.3
|
0.4 msec
Interval -1.3 to 2.1
|
-0.7 msec
Interval -3.1 to 1.6
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
4
|
2.6 msec
Interval 1.2 to 4.0
|
1.0 msec
Interval -0.5 to 2.5
|
1.6 msec
Interval -0.4 to 3.6
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
8
|
-1.5 msec
Interval -3.1 to 0.0
|
0.6 msec
Interval -1.0 to 2.3
|
-2.2 msec
Interval -4.4 to 0.1
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
12
|
-0.1 msec
Interval -1.6 to 1.4
|
0.7 msec
Interval -0.9 to 2.3
|
-0.8 msec
Interval -3.0 to 1.5
|
|
The Baseline-adjusted, Placebo-corrected (ΔΔQTc) on QTc Method Not Selected as Primary Endpoint.
24
|
-0.5 msec
Interval -2.0 to 1.0
|
1.4 msec
Interval -0.1 to 3.0
|
-1.9 msec
Interval -4.1 to 0.3
|
SECONDARY outcome
Timeframe: Day 5, Day 14Population: 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.
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.
Outcome measures
| Measure |
Tizanidine 24 mg
n=70 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
Assessing the Relationship Between Changes in the QTc Interval and Plasma Levels of Tizanidine Using Concentration-effect Modeling
|
-0.1209 msec per ng/mL
Interval -0.1894 to -0.0524
|
—
|
—
|
SECONDARY outcome
Timeframe: 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
Outcome measures
| Measure |
Tizanidine 24 mg
n=70 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
n=60 Participants
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
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
|
27.4 ng/mL
Geometric Coefficient of Variation 42.7
|
—
|
SECONDARY outcome
Timeframe: 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
Outcome measures
| Measure |
Tizanidine 24 mg
n=70 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
n=60 Participants
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
Time to Reach Maximum Plasma Concentration (Tmax) of Single Doses of 8 and 24 mg Tizanidine After Reaching Steady State.
|
1.35 hour
Interval 0.6 to 4.1
|
2.10 hour
Interval 0.6 to 4.1
|
—
|
SECONDARY outcome
Timeframe: 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
Outcome measures
| Measure |
Tizanidine 24 mg
n=70 Participants
60 subjects Tizanidine 24 mg single dose
|
Tizanidine Placebo 24 mg
n=60 Participants
61 subjects placebo used for the analysis.
|
Tizanidine 24 mg Placebo-corrected
60 subjects Tizanidine 24 mg single dose, 61 subjects placebo used for the analysis.
|
|---|---|---|---|
|
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
|
115 ng*hr/mL
Geometric Coefficient of Variation 52.8
|
—
|
Adverse Events
Tizanidine
Serious events: 0 serious events
Other events: 44 other events
Deaths: 0 deaths
Initial Placebo and Crossover to Moxifloxacin
Serious events: 0 serious events
Other events: 16 other events
Deaths: 0 deaths
Initial Moxifloxacin and Crossover to Placebo
Serious events: 1 serious events
Other events: 23 other events
Deaths: 0 deaths
Placebo and Moxifloxacin Groups Combined
Serious events: 1 serious events
Other events: 39 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Tizanidine
n=72 participants at risk
Tizanidine Arm
|
Initial Placebo and Crossover to Moxifloxacin
n=32 participants at risk
Placebo/Moxifloxacin Arm
|
Initial Moxifloxacin and Crossover to Placebo
n=32 participants at risk
Moxifloxacin/Placebo Arm
|
Placebo and Moxifloxacin Groups Combined
n=64 participants at risk
Combined Moxifloxacin Arm
|
|---|---|---|---|---|
|
Pregnancy, puerperium and perinatal conditions
Ectopic Pregnancy
|
0.00%
0/72 • Up to 23 days
|
0.00%
0/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
1.6%
1/64 • Up to 23 days
|
Other adverse events
| Measure |
Tizanidine
n=72 participants at risk
Tizanidine Arm
|
Initial Placebo and Crossover to Moxifloxacin
n=32 participants at risk
Placebo/Moxifloxacin Arm
|
Initial Moxifloxacin and Crossover to Placebo
n=32 participants at risk
Moxifloxacin/Placebo Arm
|
Placebo and Moxifloxacin Groups Combined
n=64 participants at risk
Combined Moxifloxacin Arm
|
|---|---|---|---|---|
|
Nervous system disorders
NERVOUS SYSTEM DISORDERS
|
44.4%
32/72 • Up to 23 days
|
25.0%
8/32 • Up to 23 days
|
25.0%
8/32 • Up to 23 days
|
25.0%
16/64 • Up to 23 days
|
|
Nervous system disorders
SOMNOLENCE
|
27.8%
20/72 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
12.5%
8/64 • Up to 23 days
|
|
Nervous system disorders
DIZZINESS
|
23.6%
17/72 • Up to 23 days
|
6.2%
2/32 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
9.4%
6/64 • Up to 23 days
|
|
Nervous system disorders
HEADACHE
|
13.9%
10/72 • Up to 23 days
|
15.6%
5/32 • Up to 23 days
|
9.4%
3/32 • Up to 23 days
|
12.5%
8/64 • Up to 23 days
|
|
Nervous system disorders
PARAESTHESIA
|
9.7%
7/72 • Up to 23 days
|
0.00%
0/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
1.6%
1/64 • Up to 23 days
|
|
Nervous system disorders
DIZZINESS POSTURAL
|
5.6%
4/72 • Up to 23 days
|
0.00%
0/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
1.6%
1/64 • Up to 23 days
|
|
Gastrointestinal disorders
GASTROINTESTINAL DISORDERS
|
29.2%
21/72 • Up to 23 days
|
25.0%
8/32 • Up to 23 days
|
31.2%
10/32 • Up to 23 days
|
28.1%
18/64 • Up to 23 days
|
|
Gastrointestinal disorders
NAUSEA
|
12.5%
9/72 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
15.6%
5/32 • Up to 23 days
|
14.1%
9/64 • Up to 23 days
|
|
Gastrointestinal disorders
DRY MOUTH
|
13.9%
10/72 • Up to 23 days
|
0.00%
0/32 • Up to 23 days
|
9.4%
3/32 • Up to 23 days
|
4.7%
3/64 • Up to 23 days
|
|
General disorders
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
|
33.3%
24/72 • Up to 23 days
|
28.1%
9/32 • Up to 23 days
|
28.1%
9/32 • Up to 23 days
|
28.1%
18/64 • Up to 23 days
|
|
General disorders
FATIGUE
|
18.1%
13/72 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
3.1%
2/64 • Up to 23 days
|
|
General disorders
APPLICATION SITE PRURITUS
|
6.9%
5/72 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
7.8%
5/64 • Up to 23 days
|
|
General disorders
APPLICATION SITE IRRITATION
|
6.9%
5/72 • Up to 23 days
|
9.4%
3/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
6.2%
4/64 • Up to 23 days
|
|
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
|
13.9%
10/72 • Up to 23 days
|
6.2%
2/32 • Up to 23 days
|
9.4%
3/32 • Up to 23 days
|
7.8%
5/64 • Up to 23 days
|
|
Musculoskeletal and connective tissue disorders
BACK PAIN
|
5.6%
4/72 • Up to 23 days
|
6.2%
2/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
4.7%
3/64 • Up to 23 days
|
|
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL CHEST PAIN
|
5.6%
4/72 • Up to 23 days
|
0.00%
0/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
1.6%
1/64 • Up to 23 days
|
|
Skin and subcutaneous tissue disorders
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
|
11.1%
8/72 • Up to 23 days
|
12.5%
4/32 • Up to 23 days
|
21.9%
7/32 • Up to 23 days
|
17.2%
11/64 • Up to 23 days
|
|
Skin and subcutaneous tissue disorders
RASH
|
6.9%
5/72 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
3.1%
1/32 • Up to 23 days
|
3.1%
2/64 • Up to 23 days
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER