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Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year (VITALITY-ALS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02496767
Recruitment Status : Completed
First Posted : July 14, 2015
Results First Posted : June 19, 2020
Last Update Posted : September 9, 2020
Sponsor:
Information provided by (Responsible Party):
Cytokinetics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Amyotrophic Lateral Sclerosis
Interventions Drug: Tirasemtiv
Drug: Placebo tablets
Enrollment 744
Recruitment Details Patients with familial or sporadic amyotrophic lateral sclerosis were enrolled at 79 sites in Belgium, Canada, France, Germany, Great Britain, Ireland, Italy, Netherlands, Portugal, Spain, and the United States. The first patient was screened on 03 September 2015 and the last subject completed on 27 September 2017.
Pre-assignment Details All enrolled patients began open-label tirasemtiv (250 mg) in a 2-week lead-in phase. Completed patients were randomized (3:2:2:2) to placebo or tirasemtiv (250, 375, or 500 mg) for 48 weeks of double-blind treatment. After which, patients on tirasemtiv were re-randomized (1:1) to placebo or tirasemtiv (current dose) for a 4-week withdrawal phase.
Arm/Group Title Open-label Lead-in: 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Double-blind, Withdrawal: Placebo Double-blind, Withdrawal: Tirasemtiv to Placebo Double-blind, Withdrawal: Tirasemtiv
Hide Arm/Group Description Open-label tirasemiv (125 mg twice daily) for 2 weeks Day 1 through Week 48: 2 placebo tablets twice daily Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM Day 1 through Week 2: 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Following the 48-week double-blind, placebo-controlled phase of the study, patients in the placebo group continued placebo for an additional 4 weeks. Following the 48-week double-blind, placebo-controlled phase of the study, approximately half the patients in a tirasemtiv group were re-randomized to placebo treatment for 4 weeks. Following the 48-week double-blind, placebo-controlled phase of the study, approximately half the patients in a tirasemtiv group were re-randomized to remain on tirasemtiv treatment (at the same dose received at the end of the double-blind, placebo-controlled phase) for 4 weeks.
Period Title: Open-label Lead-in Phase
Started 744 0 0 0 0 0 0 0
Completed 565 0 0 0 0 0 0 0
Not Completed 179 0 0 0 0 0 0 0
Reason Not Completed
Adverse Event             176             0             0             0             0             0             0             0
Protocol Violation             2             0             0             0             0             0             0             0
Lost to Follow-up             1             0             0             0             0             0             0             0
Period Title: Double-blind, Placebo-controlled Phase
Started 0 188 126 126 125 0 0 0
Completed 0 132 80 65 59 0 0 0
Not Completed 0 56 46 61 66 0 0 0
Reason Not Completed
Adverse Event             0             13             23             43             43             0             0             0
Progressive disease             0             13             9             8             14             0             0             0
Death             0             10             6             2             4             0             0             0
Various             0             9             4             5             2             0             0             0
Withdrawal by Subject             0             4             3             1             2             0             0             0
Physician Decision             0             4             1             0             0             0             0             0
Lost to Follow-up             0             2             0             2             1             0             0             0
Protocol Violation             0             1             0             0             0             0             0             0
Period Title: Double-blind, Withdrawal Phase
Started 0 0 0 0 0 132 103 101
Completed 0 0 0 0 0 126 99 96
Not Completed 0 0 0 0 0 6 4 5
Reason Not Completed
Progressive disease             0             0             0             0             0             4             0             1
Adverse Event             0             0             0             0             0             1             2             1
Death             0             0             0             0             0             0             1             2
Withdrawal by Subject             0             0             0             0             0             1             1             1
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Total
Hide Arm/Group Description Day 1 through Week 48: 2 placebo tablets twice daily Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Total of all reporting groups
Overall Number of Baseline Participants 188 126 125 122 561
Hide Baseline Analysis Population Description
Baseline Characteristics are provided for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment (totaling 561 patients: 188, 126, 125, and 122 patients in Groups 1, 2, 3, and 4, respectively).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 188 participants 126 participants 125 participants 122 participants 561 participants
55.9  (10.63) 57.1  (10.20) 57.4  (9.09) 56.0  (10.81) 56.5  (10.24)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 126 participants 125 participants 122 participants 561 participants
Female
65
  34.6%
30
  23.8%
42
  33.6%
38
  31.1%
175
  31.2%
Male
123
  65.4%
96
  76.2%
83
  66.4%
84
  68.9%
386
  68.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 126 participants 125 participants 122 participants 561 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
3
   1.6%
3
   2.4%
0
   0.0%
4
   3.3%
10
   1.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
1
   0.8%
0
   0.0%
1
   0.2%
Black or African American
3
   1.6%
0
   0.0%
2
   1.6%
1
   0.8%
6
   1.1%
White
181
  96.3%
123
  97.6%
120
  96.0%
117
  95.9%
541
  96.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   0.5%
0
   0.0%
2
   1.6%
0
   0.0%
3
   0.5%
Riluzole use at baseline  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 126 participants 125 participants 122 participants 561 participants
141
  75.0%
95
  75.4%
94
  75.2%
92
  75.4%
422
  75.2%
1.Primary Outcome
Title Change From Baseline to Week 24 of the Double-blind, Placebo-controlled Phase in Percent Predicted Slow Vital Capacity (SVC)
Hide Description SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex], based on Knudson 83 normative values).
Time Frame 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data presented are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Least Squares Mean (Standard Error)
Unit of Measure: % predicted
-14.354  (1.2270) -12.648  (1.5165) -13.742  (1.6076) -13.927  (1.7213)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3782
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 1.707
Confidence Interval (2-Sided) 95%
-2.089 to 5.503
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.9365
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7625
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.612
Confidence Interval (2-Sided) 95%
-3.359 to 4.583
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.0245
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8394
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.428
Confidence Interval (2-Sided) 95%
-3.711 to 4.566
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.1081
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in the ALSFRS-R Respiratory Domain Score at the End of 48 Weeks of Double-blind, Placebo-controlled Treatment
Hide Description The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: bulbar functions, fine motor tasks, gross motor tasks, and respiratory function. Respiratory function consists of 3 of the 12 questions, which assess dyspnea, orthopnea, and respiratory insufficiency. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The sum of the response to these 3 questions represents the respiratory domain score. The respiratory domain score ranges from 0 to 12, with higher scores reflecting more normal function and lower scores reflecting more impaired function.
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.26  (0.258) -1.95  (0.320) -2.41  (0.340) -2.59  (0.355)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4521
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.31
Confidence Interval (2-Sided) 95%
-0.50 to 1.12
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.410
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7120
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.16
Confidence Interval (2-Sided) 95%
-1.00 to 0.68
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.426
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4510
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.33
Confidence Interval (2-Sided) 95%
-1.19 to 0.53
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.439
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Slope of Mega-score of Muscle Strength During the 48 Weeks of Double-blind, Placebo-controlled Treatment
Hide Description A hand-held dynomometer, with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). The muscle strength mega-score was calculated as the average of responses to all tested muscles as well as handgrip strength. The slope of muscle strength mega-score was the change over time (48 weeks) and analyzed using a mixed model that assumed a random slope effect. For this endpoint, negative values indicate a decline in muscle strength over time.
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Mean (95% Confidence Interval)
Unit of Measure: pounds/day
-0.1501
(-0.1729 to -0.1272)
-0.1512
(-0.1794 to -0.1230)
-0.1434
(-0.1742 to -0.1126)
-0.1413
(-0.1730 to -0.1095)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9505
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.0011
Confidence Interval (2-Sided) 95%
-0.0374 to 0.0351
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7336
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0066
Confidence Interval (2-Sided) 95%
-0.0317 to 0.0450
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6593
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0088
Confidence Interval (2-Sided) 95%
-0.0303 to 0.0479
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time to the First Occurrence of a Decline From Baseline in Percent Predicted SVC ≥ 20 Percentage Points or the Onset of Respiratory Insufficiency or Death All 48 Weeks of Double-blind, Placebo-controlled Treatment
Hide Description

This endpoint evaluated the time to occurrence of a decline in percent predicted SVC (as measured by spirometry) of ≥ 20 percentage points, or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 22 hours per day for ≥10 consecutive days), or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase.

Note: The median time to a ≥ 20% decline in percent predicted SVC, onset of respiratory insufficiency, or death was 302 days for the placebo group and 359, 334, and 337 days for the 250 mg, 375 mg, and 500 mg tirasemtiv groups, respectively. The data presented for this endpoint are the number and percent of patients who met the endpoint.

Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Measure Type: Count of Participants
Unit of Measure: Participants
98
  52.1%
58
  46.0%
58
  46.4%
57
  46.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2369
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.818
Confidence Interval (2-Sided) 95%
0.587 to 1.141
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9420
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.988
Confidence Interval (2-Sided) 95%
0.711 to 1.372
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6853
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.933
Confidence Interval (2-Sided) 95%
0.668 to 1.304
Estimation Comments Hazard ratio for tirasemtiv vs placebo
5.Secondary Outcome
Title Time to the First Occurrence of a Decline in SVC to ≤ 50% Predicted, or the Onset of Respiratory Insufficiency, or Death During the 48 Weeks of Double-blind, Placebo-controlled Treatment
Hide Description

This endpoint evaluated the time to occurrence of a decline in SVC (as measured by spirometry) to ≤ 50% predicted, or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 22 hours per day for ≥10 consecutive days), or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase.

Note: The median time to a decline in SVC to ≤ 50% predicted, onset of respiratory insufficiency, or death was not estimable for the placebo group or the 375 mg tirasemtiv group. The median time was estimated as 363 and 351 days for the 250 mg and 500 mg tirasemtiv groups, respectively. The data presented for this endpoint are the number and percent of patients who met the endpoint.

Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Measure Type: Count of Participants
Unit of Measure: Participants
57
  30.3%
39
  31.0%
30
  24.0%
32
  26.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7667
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.066
Confidence Interval (2-Sided) 95%
0.698 to 1.627
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6619
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.904
Confidence Interval (2-Sided) 95%
0.577 to 1.419
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5856
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.882
Confidence Interval (2-Sided) 95%
0.561 to 1.386
Estimation Comments Hazard ratio for tirasemtiv vs placebo
6.Secondary Outcome
Title Change From Baseline in the ALSFRS-R Total Score to the End of 48 Weeks of the Double-blind, Placebo-controlled Treatment
Hide Description The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function.
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-11.39  (0.695) -11.39  (0.859) -12.19  (0.903) -11.99  (0.937)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9991
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-2.17 to 2.17
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.103
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4808
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.80
Confidence Interval (2-Sided) 95%
-3.04 to 1.43
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.138
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6082
Comments [Not Specified]
Method Repeated-measures mixed model
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -0.60
Confidence Interval (2-Sided) 95%
-2.89 to 1.69
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.165
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time to the First Use of Mechanical Ventilatory Assistance or Death During All 48 Weeks of Double-blind, Placebo-controlled Treatment
Hide Description

This endpoint evaluated the time to occurrence of mechanical ventilatory assistance (defined as invasive or non-invasive ventilation for at least 2 hours over a 24-hour period for at least 5 consecutive days) or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase.

Note: The median time to first use of mechanical ventilatory assistance or death was not estimable for all but the 375 mg tirasemtiv group (with a value of 367 days). As such the number and percent of patients who met the endpoint (ie, had mechanical ventilatory assistance or died) are presented.

Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The data provided are for the Full Analysis Set, comprised of patients who received at least 1 dose of study drug during the randomized double-blind, placebo-controlled phase and had at least 1 post-randomization efficacy assessment.
Arm/Group Title Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv
Hide Arm/Group Description:
Day 1 through Week 48: 2 placebo tablets twice daily
Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM
Overall Number of Participants Analyzed 188 126 125 122
Measure Type: Count of Participants
Unit of Measure: Participants
60
  31.9%
31
  24.6%
37
  29.6%
33
  27.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2602
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.776
Confidence Interval (2-Sided) 95%
0.500 to 1.206
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6748
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.094
Confidence Interval (2-Sided) 95%
0.720 to 1.662
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Double-blind, Placebo-controlled: Group 1 - Placebo, Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7694
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.938
Confidence Interval (2-Sided) 95%
0.609 to 1.443
Estimation Comments Hazard ratio for tirasemtiv vs placebo
Time Frame AEs were collected from the first dose of open-label study drug through 28 days after the last dose of study drug.
Adverse Event Reporting Description

An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label [OL] or double-blind [DB] phases). The onset date of a TEAE in the OL phase that continued uninterrupted for ≥96 hours in the DB placebo-controlled phase was the date of the first dose of DB study drug.

For patients randomized in the DB withdrawal phase, the onset date was on or before the last dose of study drug in the DB placebo-controlled phase.

 
Arm/Group Title Open-label Lead-in: 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Double-blind, Withdrawal: Placebo Double-blind, Withdrawal: Tirasemtiv to Placebo Double-blind, Withdrawal: Tirasemtiv
Hide Arm/Group Description Open-label tirasemiv (125 mg twice daily) for 2 weeks Day 1 through Week 48: 2 placebo tablets twice daily Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM Following the 48-week double-blind, placebo-controlled phase of the study, patients in the placebo group continued placebo for an additional 4 weeks. Following the 48-week double-blind, placebo-controlled phase of the study, approximately half the patients in a tirasemtiv group were re-randomized to placebo treatment for 4 weeks. Following the 48-week double-blind, placebo-controlled phase of the study, approximately half the patients in a tirasemtiv group were re-randomized to remain on tirasemtiv treatment (at the same dose received at the end of the double-blind, placebo-controlled phase) for 4 weeks.
All-Cause Mortality
Open-label Lead-in: 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Double-blind, Withdrawal: Placebo Double-blind, Withdrawal: Tirasemtiv to Placebo Double-blind, Withdrawal: Tirasemtiv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/744 (0.13%)   17/188 (9.04%)   8/126 (6.35%)   10/126 (7.94%)   8/125 (6.40%)   5/132 (3.79%)   4/103 (3.88%)   5/101 (4.95%) 
Hide Serious Adverse Events
Open-label Lead-in: 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Double-blind, Withdrawal: Placebo Double-blind, Withdrawal: Tirasemtiv to Placebo Double-blind, Withdrawal: Tirasemtiv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   11/744 (1.48%)   53/188 (28.19%)   30/126 (23.81%)   30/126 (23.81%)   32/125 (25.60%)   15/132 (11.36%)   15/103 (14.56%)   11/101 (10.89%) 
Cardiac disorders                 
Arteriosclerosis coronary artery  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Atrial tachycardia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cardiac arrest  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cor pulmonale acute  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Stress cardiomyopathy  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Supraventricular tachycardia  1  0/744 (0.00%)  2/188 (1.06%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Tachycardia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Ventricular fibrillation  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Gastrointestinal disorders                 
Abdominal pain upper  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Constipation  1  1/744 (0.13%)  1/188 (0.53%)  0/126 (0.00%)  1/126 (0.79%)  2/125 (1.60%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Diarrhoea  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
Dysphagia  1  0/744 (0.00%)  9/188 (4.79%)  12/126 (9.52%)  7/126 (5.56%)  2/125 (1.60%)  2/132 (1.52%)  4/103 (3.88%)  3/101 (2.97%) 
Ileus  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
Intestinal polyp  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Nausea  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Oesophageal spasm  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pancreatitis  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Vomiting  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
General disorders                 
Asthenia  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Death  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  1/101 (0.99%) 
Device dislocation  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  1/101 (0.99%) 
Device malfunction  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Euthanasia  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  1/101 (0.99%) 
Sudden death  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  1/125 (0.80%)  2/132 (1.52%)  0/103 (0.00%)  0/101 (0.00%) 
Hepatobiliary disorders                 
Cholecystitis  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cholelithiasis  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Immune system disorders                 
Drug hypersensitivity  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Infections and infestations                 
Appendicitis  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Bacteraemia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Bronchitis  1  0/744 (0.00%)  2/188 (1.06%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Bronchitis bacterial  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Bronchopneumonia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cellulitis  1  0/744 (0.00%)  2/188 (1.06%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Device related sepsis  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Klebsiella bacteraemia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Lobar pneumonia  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Lower respiratory tract infection  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Otitis externa  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Otitis media acute  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pneumonia  1  0/744 (0.00%)  4/188 (2.13%)  0/126 (0.00%)  2/126 (1.59%)  2/125 (1.60%)  0/132 (0.00%)  3/103 (2.91%)  1/101 (0.99%) 
Respiratory tract infection  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Serratia bacteraemia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Tracheobronchitis  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Urosepsis  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Injury, poisoning and procedural complications                 
Accidental overdose  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Subdural haematoma  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Toxicity to various agents  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Traumatic arthritis  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  1/101 (0.99%) 
Traumatic fracture  1  1/744 (0.13%)  4/188 (2.13%)  2/126 (1.59%)  0/126 (0.00%)  0/125 (0.00%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Traumatic haematoma  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Traumatic intracranial haemorrhage  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Investigations                 
Liver function test abnormal  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Oxygen saturation decreased  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pulmonary function test decreased  1  0/744 (0.00%)  3/188 (1.60%)  1/126 (0.79%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Weight decreased  1  0/744 (0.00%)  2/188 (1.06%)  5/126 (3.97%)  4/126 (3.17%)  1/125 (0.80%)  0/132 (0.00%)  3/103 (2.91%)  1/101 (0.99%) 
Metabolism and nutrition disorders                 
Dehydration  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hypokalaemia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hyponatraemia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Malnutrition  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Musculoskeletal and connective tissue disorders                 
Intervertebral disc protrusion  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pain in extremity  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                 
Genital neoplasm malignant female  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
Lung cancer metastatic  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pancreatic carcinoma metastatic  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Testicular cancer metastatic  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Nervous system disorders                 
Amyotrophic lateral sclerosis  1  0/744 (0.00%)  4/188 (2.13%)  2/126 (1.59%)  1/126 (0.79%)  3/125 (2.40%)  3/132 (2.27%)  3/103 (2.91%)  0/101 (0.00%) 
Basal ganglia stroke  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cerebellar infarction  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Cerebrovascular insufficiency  1  0/744 (0.00%)  0/188 (0.00%)  1/126 (0.79%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Clonus  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Ischaemic stroke  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Loss of consciousness  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Muscle spasticity  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Somnolence  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Syncope  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Thalamic infarction  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Toxic encephalopathy  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Transient ischaemic attack  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Tremor  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Psychiatric disorders                 
Abnormal behaviour  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Adjustment disorder with anxiety  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Completed suicide  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hallucination, auditory  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hallucination, visual  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Mania  1  1/744 (0.13%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Mental status changes  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  2/125 (1.60%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Panic attack  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  2/126 (1.59%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Renal and urinary disorders                 
Cystitis interstitial  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Nephrolithiasis  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Urinary retention  1  1/744 (0.13%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Respiratory, thoracic and mediastinal disorders                 
Acute respiratory failure  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
Bronchial secretion retention  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Chronic obstructive pulmonary disease  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Dyspnoea  1  1/744 (0.13%)  1/188 (0.53%)  0/126 (0.00%)  2/126 (1.59%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hypercapnia  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Hypoventilation  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Increased bronchial secretion  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Pneumonia aspiration  1  1/744 (0.13%)  4/188 (2.13%)  0/126 (0.00%)  1/126 (0.79%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  2/101 (1.98%) 
Pulmonary embolism  1  1/744 (0.13%)  3/188 (1.60%)  3/126 (2.38%)  3/126 (2.38%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Respiratory depression  1  0/744 (0.00%)  1/188 (0.53%)  0/126 (0.00%)  0/126 (0.00%)  0/125 (0.00%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Respiratory distress  1  0/744 (0.00%)  0/188 (0.00%)  0/126 (0.00%)  0/126 (0.00%)  1/125 (0.80%)  0/132 (0.00%)  0/103 (0.00%)  0/101 (0.00%) 
Respiratory failure  1  1/744 (0.13%)  8/188 (4.26%)  5/126 (3.97%)  6/126 (4.76%)  6/125 (4.80%)  3/132 (2.27%)  3/103 (2.91%)  0/101 (0.00%) 
Sleep apnoea syndrome  1  0/744 (0.00%)  1/188 (0.53%)  1/126 (0.79%)  0/126 (0.00%)  1/125 (0.80%)  1/132 (0.76%)  0/103 (0.00%)  0/101 (0.00%) 
Vascular disorders                 
Deep vein thrombosis  1  1/744 (0.13%)  1/188 (0.53%)  0/126 (0.00%)  1/126 (0.79%)  0/125 (0.00%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Open-label Lead-in: 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 1 - Placebo Double-blind, Placebo-controlled: Group 2 - 250 mg Tirasemtiv Double-blind, Placebo-controlled: Group 3 - 375 mg Tirasemtiv Double-blind, Placebo-controlled: Group 4 - 500 mg Tirasemtiv Double-blind, Withdrawal: Placebo Double-blind, Withdrawal: Tirasemtiv to Placebo Double-blind, Withdrawal: Tirasemtiv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   640/744 (86.02%)   182/188 (96.81%)   125/126 (99.21%)   125/126 (99.21%)   125/125 (100.00%)   123/132 (93.18%)   100/103 (97.09%)   95/101 (94.06%) 
Ear and labyrinth disorders                 
Vertigo  1  19/744 (2.55%)  7/188 (3.72%)  13/126 (10.32%)  7/126 (5.56%)  4/125 (3.20%)  3/132 (2.27%)  0/103 (0.00%)  0/101 (0.00%) 
Gastrointestinal disorders                 
Abdominal distension  1  3/744 (0.40%)  2/188 (1.06%)  4/126 (3.17%)  5/126 (3.97%)  3/125 (2.40%)  2/132 (1.52%)  1/103 (0.97%)  5/101 (4.95%) 
Constipation  1  21/744 (2.82%)  40/188 (21.28%)  24/126 (19.05%)  21/126 (16.67%)  27/125 (21.60%)  17/132 (12.88%)  15/103 (14.56%)  13/101 (12.87%) 
Diarrhoea  1  24/744 (3.23%)  19/188 (10.11%)  7/126 (5.56%)  10/126 (7.94%)  9/125 (7.20%)  5/132 (3.79%)  5/103 (4.85%)  2/101 (1.98%) 
Dry mouth  1  10/744 (1.34%)  14/188 (7.45%)  8/126 (6.35%)  8/126 (6.35%)  7/125 (5.60%)  7/132 (5.30%)  5/103 (4.85%)  8/101 (7.92%) 
Dysphagia  1  9/744 (1.21%)  33/188 (17.55%)  28/126 (22.22%)  22/126 (17.46%)  16/125 (12.80%)  22/132 (16.67%)  17/103 (16.50%)  17/101 (16.83%) 
Gastrooesophageal reflux disease  1  5/744 (0.67%)  8/188 (4.26%)  6/126 (4.76%)  7/126 (5.56%)  6/125 (4.80%)  3/132 (2.27%)  4/103 (3.88%)  6/101 (5.94%) 
Nausea  1  108/744 (14.52%)  30/188 (15.96%)  20/126 (15.87%)  38/126 (30.16%)  26/125 (20.80%)  9/132 (6.82%)  7/103 (6.80%)  6/101 (5.94%) 
Salivary hypersecretion  1  3/744 (0.40%)  19/188 (10.11%)  14/126 (11.11%)  9/126 (7.14%)  3/125 (2.40%)  14/132 (10.61%)  5/103 (4.85%)  11/101 (10.89%) 
General disorders                 
Asthenia  1  42/744 (5.65%)  22/188 (11.70%)  12/126 (9.52%)  22/126 (17.46%)  22/125 (17.60%)  12/132 (9.09%)  10/103 (9.71%)  9/101 (8.91%) 
Fatigue  1  204/744 (27.42%)  61/188 (32.45%)  43/126 (34.13%)  54/126 (42.86%)  50/125 (40.00%)  32/132 (24.24%)  32/103 (31.07%)  23/101 (22.77%) 
Gait disturbance  1  19/744 (2.55%)  13/188 (6.91%)  12/126 (9.52%)  10/126 (7.94%)  9/125 (7.20%)  12/132 (9.09%)  7/103 (6.80%)  11/101 (10.89%) 
Oedema peripheral  1  8/744 (1.08%)  19/188 (10.11%)  9/126 (7.14%)  7/126 (5.56%)  10/125 (8.00%)  10/132 (7.58%)  10/103 (9.71%)  7/101 (6.93%) 
Peripheral swelling  1  2/744 (0.27%)  9/188 (4.79%)  9/126 (7.14%)  0/126 (0.00%)  3/125 (2.40%)  4/132 (3.03%)  6/103 (5.83%)  0/101 (0.00%) 
Infections and infestations                 
Nasopharyngitis  1  13/744 (1.75%)  30/188 (15.96%)  19/126 (15.08%)  20/126 (15.87%)  12/125 (9.60%)  7/132 (5.30%)  4/103 (3.88%)  5/101 (4.95%) 
Upper respiratory tract infection  1  4/744 (0.54%)  17/188 (9.04%)  3/126 (2.38%)  4/126 (3.17%)  9/125 (7.20%)  4/132 (3.03%)  1/103 (0.97%)  0/101 (0.00%) 
Urinary tract infection  1  3/744 (0.40%)  8/188 (4.26%)  12/126 (9.52%)  12/126 (9.52%)  9/125 (7.20%)  0/132 (0.00%)  2/103 (1.94%)  0/101 (0.00%) 
Injury, poisoning and procedural complications                 
Contusion  1  18/744 (2.42%)  34/188 (18.09%)  15/126 (11.90%)  23/126 (18.25%)  18/125 (14.40%)  5/132 (3.79%)  6/103 (5.83%)  0/101 (0.00%) 
Laceration  1  2/744 (0.27%)  13/188 (6.91%)  8/126 (6.35%)  13/126 (10.32%)  12/125 (9.60%)  5/132 (3.79%)  3/103 (2.91%)  2/101 (1.98%) 
Ligament sprain  1  4/744 (0.54%)  12/188 (6.38%)  6/126 (4.76%)  3/126 (2.38%)  2/125 (1.60%)  2/132 (1.52%)  0/103 (0.00%)  0/101 (0.00%) 
Post-traumatic pain  1  8/744 (1.08%)  26/188 (13.83%)  16/126 (12.70%)  14/126 (11.11%)  8/125 (6.40%)  6/132 (4.55%)  3/103 (2.91%)  3/101 (2.97%) 
Skin abrasion  1  7/744 (0.94%)  24/188 (12.77%)  22/126 (17.46%)  7/126 (5.56%)  12/125 (9.60%)  8/132 (6.06%)  4/103 (3.88%)  5/101 (4.95%) 
Traumatic fracture  1  3/744 (0.40%)  12/188 (6.38%)  6/126 (4.76%)  5/126 (3.97%)  2/125 (1.60%)  4/132 (3.03%)  2/103 (1.94%)  3/101 (2.97%) 
Head injury  1  3/744 (0.40%)  5/188 (2.66%)  8/126 (6.35%)  2/126 (1.59%)  4/125 (3.20%)  0/132 (0.00%)  1/103 (0.97%)  0/101 (0.00%) 
Investigations                 
Weight decreased  1  7/744 (0.94%)  40/188 (21.28%)  41/126 (32.54%)  41/126 (32.54%)  28/125 (22.40%)  26/132 (19.70%)  31/103 (30.10%)  35/101 (34.65%) 
Blood creatine phosphokinase increased  1  0/744 (0.00%)  3/188 (1.60%)  2/126 (1.59%)  2/126 (1.59%)  7/125 (5.60%)  2/132 (1.52%)  3/103 (2.91%)  2/101 (1.98%) 
Metabolism and nutrition disorders                 
Decreased appetite  1  45/744 (6.05%)  19/188 (10.11%)  16/126 (12.70%)  19/126 (15.08%)  21/125 (16.80%)  10/132 (7.58%)  5/103 (4.85%)  6/101 (5.94%) 
Musculoskeletal and connective tissue disorders                 
Arthralgia  1  4/744 (0.54%)  14/188 (7.45%)  4/126 (3.17%)  7/126 (5.56%)  4/125 (3.20%)  8/132 (6.06%)  4/103 (3.88%)  6/101 (5.94%) 
Back pain  1  3/744 (0.40%)  15/188 (7.98%)  11/126 (8.73%)  9/126 (7.14%)  9/125 (7.20%)  8/132 (6.06%)  7/103 (6.80%)  8/101 (7.92%) 
Muscle spasms  1  33/744 (4.44%)  34/188 (18.09%)  17/126 (13.49%)  24/126 (19.05%)  17/125 (13.60%)  22/132 (16.67%)  18/103 (17.48%)  17/101 (16.83%) 
Muscular weakness  1  54/744 (7.26%)  58/188 (30.85%)  52/126 (41.27%)  42/126 (33.33%)  34/125 (27.20%)  48/132 (36.36%)  45/103 (43.69%)  42/101 (41.58%) 
Musculoskeletal pain  1  5/744 (0.67%)  22/188 (11.70%)  9/126 (7.14%)  8/126 (6.35%)  6/125 (4.80%)  10/132 (7.58%)  10/103 (9.71%)  6/101 (5.94%) 
Myalgia  1  6/744 (0.81%)  12/188 (6.38%)  6/126 (4.76%)  3/126 (2.38%)  5/125 (4.00%)  6/132 (4.55%)  3/103 (2.91%)  5/101 (4.95%) 
Neck pain  1  2/744 (0.27%)  10/188 (5.32%)  3/126 (2.38%)  4/126 (3.17%)  4/125 (3.20%)  7/132 (5.30%)  3/103 (2.91%)  3/101 (2.97%) 
Pain in extremity  1  14/744 (1.88%)  17/188 (9.04%)  9/126 (7.14%)  12/126 (9.52%)  11/125 (8.80%)  11/132 (8.33%)  7/103 (6.80%)  8/101 (7.92%) 
Musculoskeletal stiffness  1  9/744 (1.21%)  6/188 (3.19%)  6/126 (4.76%)  3/126 (2.38%)  7/125 (5.60%)  3/132 (2.27%)  4/103 (3.88%)  1/101 (0.99%) 
Nervous system disorders                 
Balance disorder  1  19/744 (2.55%)  4/188 (2.13%)  3/126 (2.38%)  3/126 (2.38%)  6/125 (4.80%)  2/132 (1.52%)  6/103 (5.83%)  4/101 (3.96%) 
Dizziness  1  361/744 (48.52%)  45/188 (23.94%)  47/126 (37.30%)  55/126 (43.65%)  56/125 (44.80%)  11/132 (8.33%)  21/103 (20.39%)  15/101 (14.85%) 
Dysarthria  1  30/744 (4.03%)  18/188 (9.57%)  15/126 (11.90%)  8/126 (6.35%)  12/125 (9.60%)  13/132 (9.85%)  11/103 (10.68%)  10/101 (9.90%) 
Headache  1  36/744 (4.84%)  28/188 (14.89%)  13/126 (10.32%)  21/126 (16.67%)  19/125 (15.20%)  3/132 (2.27%)  12/103 (11.65%)  7/101 (6.93%) 
Muscle contractions involuntary  1  11/744 (1.48%)  9/188 (4.79%)  15/126 (11.90%)  8/126 (6.35%)  12/125 (9.60%)  5/132 (3.79%)  5/103 (4.85%)  7/101 (6.93%) 
Muscle spasticity  1  11/744 (1.48%)  4/188 (2.13%)  5/126 (3.97%)  10/126 (7.94%)  6/125 (4.80%)  4/132 (3.03%)  7/103 (6.80%)  7/101 (6.93%) 
Somnolence  1  90/744 (12.10%)  14/188 (7.45%)  19/126 (15.08%)  19/126 (15.08%)  18/125 (14.40%)  3/132 (2.27%)  5/103 (4.85%)  10/101 (9.90%) 
Tremor  1  22/744 (2.96%)  4/188 (2.13%)  4/126 (3.17%)  13/126 (10.32%)  11/125 (8.80%)  5/132 (3.79%)  5/103 (4.85%)  3/101 (2.97%) 
Parathesia  1  6/744 (0.81%)  3/188 (1.60%)  4/126 (3.17%)  1/126 (0.79%)  8/125 (6.40%)  1/132 (0.76%)  1/103 (0.97%)  1/101 (0.99%) 
Psychiatric disorders                 
Affect lability  1  8/744 (1.08%)  6/188 (3.19%)  5/126 (3.97%)  5/126 (3.97%)  6/125 (4.80%)  8/132 (6.06%)  2/103 (1.94%)  5/101 (4.95%) 
Anxiety  1  15/744 (2.02%)  19/188 (10.11%)  14/126 (11.11%)  13/126 (10.32%)  24/125 (19.20%)  13/132 (9.85%)  15/103 (14.56%)  10/101 (9.90%) 
Depression  1  21/744 (2.82%)  22/188 (11.70%)  8/126 (6.35%)  24/126 (19.05%)  23/125 (18.40%)  14/132 (10.61%)  9/103 (8.74%)  14/101 (13.86%) 
Insomnia  1  31/744 (4.17%)  25/188 (13.30%)  23/126 (18.25%)  25/126 (19.84%)  30/125 (24.00%)  19/132 (14.39%)  19/103 (18.45%)  18/101 (17.82%) 
Respiratory, thoracic and mediastinal disorders                 
Cough  1  3/744 (0.40%)  26/188 (13.83%)  12/126 (9.52%)  16/126 (12.70%)  7/125 (5.60%)  12/132 (9.09%)  5/103 (4.85%)  7/101 (6.93%) 
Dyspnoea  1  26/744 (3.49%)  35/188 (18.62%)  17/126 (13.49%)  22/126 (17.46%)  18/125 (14.40%)  22/132 (16.67%)  13/103 (12.62%)  13/101 (12.87%) 
Nasal congestion  1  4/744 (0.54%)  11/188 (5.85%)  12/126 (9.52%)  11/126 (8.73%)  7/125 (5.60%)  8/132 (6.06%)  5/103 (4.85%)  5/101 (4.95%) 
Respiratory failure  1  1/744 (0.13%)  12/188 (6.38%)  6/126 (4.76%)  6/126 (4.76%)  7/125 (5.60%)  6/132 (4.55%)  3/103 (2.91%)  2/101 (1.98%) 
Skin and subcutaneous tissue disorders                 
Rash  1  8/744 (1.08%)  9/188 (4.79%)  12/126 (9.52%)  3/126 (2.38%)  8/125 (6.40%)  3/132 (2.27%)  5/103 (4.85%)  3/101 (2.97%) 
Pruritis  1  10/744 (1.34%)  5/188 (2.66%)  4/126 (3.17%)  3/126 (2.38%)  7/125 (5.60%)  3/132 (2.27%)  4/103 (3.88%)  1/101 (0.99%) 
Hyperhidrosis  1  4/744 (0.54%)  6/188 (3.19%)  3/126 (2.38%)  3/126 (2.38%)  4/125 (3.20%)  4/132 (3.03%)  6/103 (5.83%)  0/101 (0.00%) 
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: MD Cytokinetics
Organization: Cytokinetics, Inc.
Phone: 650-624-2929
EMail: medicalaffairs@cytokinetics.com
Layout table for additonal information
Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT02496767    
Other Study ID Numbers: CY 4031
2014-005413-23 ( EudraCT Number )
First Submitted: July 10, 2015
First Posted: July 14, 2015
Results First Submitted: May 6, 2020
Results First Posted: June 19, 2020
Last Update Posted: September 9, 2020