Trial Outcomes & Findings for A Study for Patients Who Completed VITALITY-ALS (CY 4031) (NCT NCT02936635)

NCT ID: NCT02936635

Last Updated: 2021-06-15

Results Overview

The number of participants with adverse events was used as the measure for the long-term safety and tolerability of tirasemtiv.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 280 participants
• Primary outcome timeframe: From the first dose of tirasemtiv through 28 days after the last dose
• Results posted on: 2021-06-15

Participant Flow

Patients with ALS were enrolled at 69 sites in Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, the United Kingdom, and the United States. The study was conducted from 17 October 2016 (date first patient enrolled) through 26 October 2018 (date of last patient contact).

Eligible patients completed participation in Study CY 4031 on study drug and had completed the scheduled follow-up visit for that study.

Participant milestones

Measure	Delayed Start Treatment The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Overall Study STARTED	115	165
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	115	165

Reasons for withdrawal

Measure	Delayed Start Treatment The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Overall Study Adverse Event	43	25
Overall Study Progressive Disease	10	18
Overall Study Sponsor Discretion	10	16
Overall Study Death	9	15
Overall Study Withdrawal by Subject	8	15
Overall Study Physician Decision	2	9
Overall Study Lost to Follow-up	1	2
Overall Study Protocol Violation	1	0
Overall Study Lack of effect/Entry into other study	31	65

Baseline Characteristics

A Study for Patients Who Completed VITALITY-ALS (CY 4031)

Baseline characteristics by cohort

Measure	Delayed Start Treatment n=111 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=162 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.	Total n=273 Participants Total of all reporting groups
Age, Continuous	55.7 years STANDARD_DEVIATION 10.07 • n=5 Participants	57.7 years STANDARD_DEVIATION 9.13 • n=7 Participants	56.9 years STANDARD_DEVIATION 9.56 • n=5 Participants
Sex: Female, Male Female	35 Participants n=5 Participants	46 Participants n=7 Participants	81 Participants n=5 Participants
Sex: Female, Male Male	76 Participants n=5 Participants	116 Participants n=7 Participants	192 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	105 Participants n=5 Participants	158 Participants n=7 Participants	263 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Time since ALS symptom onset at screening in parent study	23.60 months STANDARD_DEVIATION 17.078 • n=5 Participants	19.15 months STANDARD_DEVIATION 11.041 • n=7 Participants	20.96 months STANDARD_DEVIATION 13.961 • n=5 Participants

PRIMARY outcome

Timeframe: From the first dose of tirasemtiv through 28 days after the last dose

Population: The data are presented for the Safety Analysis Set, which consisted of all patients who enrolled and received at least 1 dose of tirasemtiv in Study CY 4033.

The number of participants with adverse events was used as the measure for the long-term safety and tolerability of tirasemtiv.

Outcome measures

Measure	Delayed Start Treatment n=115 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=165 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Number of Participants With Adverse Events	112 Participants	157 Participants

SECONDARY outcome

Timeframe: baseline and 24 weeks

Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had slow vital capacity results at Week 24.

Slow vital capacity (SVC) was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, 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 percent predicted values (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex]).

Outcome measures

Measure	Delayed Start Treatment n=48 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=94 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033	-28.79 change in % predicted SVC Standard Error 2.845	-32.69 change in % predicted SVC Standard Error 2.285

SECONDARY outcome

Timeframe: baseline and 48 weeks

Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had slow vital capacity results at Week 48.

Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, 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 percent predicted values (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex]).

Outcome measures

Measure	Delayed Start Treatment n=28 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=45 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033	-35.55 percent predicted slow vital capacity Standard Error 3.332	-40.87 percent predicted slow vital capacity Standard Error 2.667

SECONDARY outcome

Timeframe: baseline and 24 weeks

Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had an ALSFRS-R total score at Week 24.

The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 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. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function.

Outcome measures

Measure	Delayed Start Treatment n=75 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=120 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Change From CY 4031 Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score at Week 24	-13.78 scores on a scale Standard Error 0.934	-14.35 scores on a scale Standard Error 0.767

SECONDARY outcome

Timeframe: baseline and 48 weeks

Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had an ALSFRS-R total score at Week 48.

The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 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. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function.

Outcome measures

Measure	Delayed Start Treatment n=38 Participants The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=62 Participants The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Change From CY 4031 Baseline in ALSFRS-R Total Score at Week 48	-17.61 scores on a scale Standard Error 1.171	-17.82 scores on a scale Standard Error 0.956

Adverse Events

Delayed Start Treatment

Serious events: 32 serious events

Other events: 111 other events

Deaths: 21 deaths

Early Start Treatment

Serious events: 53 serious events

Other events: 155 other events

Deaths: 28 deaths

Serious adverse events

Measure	Delayed Start Treatment n=115 participants at risk The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=165 participants at risk The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Respiratory, thoracic and mediastinal disorders Respiratory failure	5.2% 6/115 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.8% 8/165 • Number of events 8 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.2% 7/165 • Number of events 7 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 4 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Bronchial secretion retention	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.8% 3/165 • Number of events 4 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.6% 3/115 • Number of events 3 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.87% 1/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Respiratory distress	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Aspiration	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Hypoventilation	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Increased bronchial secretion	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Lower respiratory tract congestion	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Obstructive airways disorder	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Pneumonia	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	5.5% 9/165 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Bronchitis	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.2% 2/165 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Lower respiratory tract infection	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Lung infection	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Sepsis	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Upper respiratory tract infection	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Abscess	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Bronchitis viral	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Bronchopneumonia	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Influenza	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Lobar pneumonia	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Staphylococcal bacteraemia	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Tracheobronchitis	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Amyotrophic lateral sclerosis	3.5% 4/115 • Number of events 4 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	7.9% 13/165 • Number of events 14 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Dizziness	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Encephalopathy	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Hypoaesthesia	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Ischaemic stroke	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Metabolic encephalopathy	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Dysphagia	1.7% 2/115 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.8% 3/165 • Number of events 3 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Constipation	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.2% 2/165 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Irritable bowel syndrome	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Pneumoperitoneum	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Traumatic fracture	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.8% 3/165 • Number of events 3 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Traumatic intracranial haemorrhage	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Subdural haematoma	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Euthanasia	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Asthenia	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Chest discomfort	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Chest pain	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Feeling abnormal	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Non-cardiac chest pain	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Cardiac disorders Cardiac arrest	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.2% 2/165 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Cardiac disorders Cardio-respiratory arrest	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Cardiac disorders Acute myocardial infarction	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Cardiac disorders Atrial fibrillation	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Mental status changes	1.7% 2/115 • Number of events 3 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Depression	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Vascular disorders Deep vein thrombosis	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.2% 2/165 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	1.2% 2/165 • Number of events 2 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Hepatobiliary disorders Cholelithiasis	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Renal and urinary disorders Calculus urinary	0.87% 1/115 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.00% 0/165 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Investigations Weight decreased	0.00% 0/115 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	0.61% 1/165 • Number of events 1 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.

Other adverse events

Measure	Delayed Start Treatment n=115 participants at risk The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033.	Early Start Treatment n=165 participants at risk The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.
Nervous system disorders Dizziness	42.6% 49/115 • Number of events 73 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	26.7% 44/165 • Number of events 63 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Somnolence	24.3% 28/115 • Number of events 33 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	16.4% 27/165 • Number of events 35 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Headache	7.0% 8/115 • Number of events 8 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	8.5% 14/165 • Number of events 17 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Nervous system disorders Dysarthria	6.1% 7/115 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	3.6% 6/165 • Number of events 7 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Constipation	17.4% 20/115 • Number of events 26 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	20.0% 33/165 • Number of events 38 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Nausea	16.5% 19/115 • Number of events 21 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	13.3% 22/165 • Number of events 28 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Dysphagia	10.4% 12/115 • Number of events 13 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	5.5% 9/165 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Salivary hypersecretion	7.0% 8/115 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	6.1% 10/165 • Number of events 12 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Diarrhoea	2.6% 3/115 • Number of events 3 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	7.3% 12/165 • Number of events 14 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.2% 6/115 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 4 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Fatigue	36.5% 42/115 • Number of events 58 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	30.9% 51/165 • Number of events 65 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Asthenia	12.2% 14/115 • Number of events 17 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.8% 8/165 • Number of events 11 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Oedema peripheral	5.2% 6/115 • Number of events 8 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	3.6% 6/165 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
General disorders Feeling abnormal	5.2% 6/115 • Number of events 7 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Musculoskeletal and connective tissue disorders Muscular weakness	13.9% 16/115 • Number of events 25 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	20.0% 33/165 • Number of events 45 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Musculoskeletal and connective tissue disorders Muscle spasms	15.7% 18/115 • Number of events 20 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	6.1% 10/165 • Number of events 12 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Musculoskeletal and connective tissue disorders Pain in extremity	3.5% 4/115 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	5.5% 9/165 • Number of events 12 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Musculoskeletal and connective tissue disorders Back pain	7.8% 9/115 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.2% 7/165 • Number of events 7 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Fall	19.1% 22/115 • Number of events 44 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	13.9% 23/165 • Number of events 45 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Contusion	9.6% 11/115 • Number of events 17 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	7.9% 13/165 • Number of events 20 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Skin abrasion	7.8% 9/115 • Number of events 11 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Injury, poisoning and procedural complications Post-traumatic pain	5.2% 6/115 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 4 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Anxiety	13.9% 16/115 • Number of events 19 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	7.3% 12/165 • Number of events 13 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Insomnia	13.9% 16/115 • Number of events 16 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	8.5% 14/165 • Number of events 16 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Depression	13.9% 16/115 • Number of events 19 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	6.1% 10/165 • Number of events 11 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Psychiatric disorders Confusional state	7.0% 8/115 • Number of events 10 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.8% 8/165 • Number of events 8 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.9% 16/115 • Number of events 17 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	9.7% 16/165 • Number of events 20 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Cough	6.1% 7/115 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	4.2% 7/165 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Choking	6.1% 7/115 • Number of events 8 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	2.4% 4/165 • Number of events 5 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Respiratory, thoracic and mediastinal disorders Increased upper airway secretion	5.2% 6/115 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	3.0% 5/165 • Number of events 5 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Nasopharyngitis	7.0% 8/115 • Number of events 10 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	10.9% 18/165 • Number of events 22 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Infections and infestations Urinary tract infection	4.3% 5/115 • Number of events 6 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	6.1% 10/165 • Number of events 10 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Investigations Weight decreased	11.3% 13/115 • Number of events 15 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	5.5% 9/165 • Number of events 9 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.
Metabolism and nutrition disorders Decreased appetite	13.9% 16/115 • Number of events 19 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.	7.9% 13/165 • Number of events 15 • Adverse events (AEs) were collected from the first administration of tirasemtiv through 28 days after the last dose of tirasemtiv. An AE was treatment-emergent if it started after initiation of study drug dosing in CY 4033 or was present at initiation of study drug dosing in CY 4033 and subsequently worsened in severity.

Additional Information

MD Cytokinetics

Cytokinetics, Inc.

Phone: 650-624-2929

Email: medicalaffairs@cytokinetics.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place