Trial Outcomes & Findings for Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS) (NCT NCT01709149)

NCT ID: NCT01709149

Last Updated: 2020-03-31

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 711 participants
• Primary outcome timeframe: Baseline, 8 weeks, 12 weeks
• Results posted on: 2020-03-31

Participant Flow

Patients with familial or sporadic amyotrophic lateral sclerosis were enrolled at 73 sites in Canada, France, Germany, Ireland, Netherlands, Spain, the United Kingdom, and the United States. The first patient was screened on 23 October 2012 and the last subject completed follow-up on 21 March 2014.

A total of 711 patients were enrolled in the study and began treatment with open-label tirasemtiv during the 7-day lead-in phase of the study. Patients who completed this phase were randomized (1:1) to receive either placebo (N=295) or tirasemtiv (N=301) in the double-blind treatment period.

Participant milestones

Measure	Open-label lead-in Treatment: Tirasemtiv Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.	Double-blind Treatment: Placebo Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Double-blind Treatment: Tirasemtiv Tirasemtiv 125 mg oral capsules administered twice daily. Minimum dose was 125 mg bid and patients were up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Open-label Lead-in Phase STARTED	711	0	0
Open-label Lead-in Phase COMPLETED	596	0	0
Open-label Lead-in Phase NOT COMPLETED	115	0	0
Double-blind, Placebo-controlled Phase STARTED	0	295	301
Double-blind, Placebo-controlled Phase COMPLETED	0	269	204
Double-blind, Placebo-controlled Phase NOT COMPLETED	0	26	97

Reasons for withdrawal

Measure	Open-label lead-in Treatment: Tirasemtiv Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.	Double-blind Treatment: Placebo Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Double-blind Treatment: Tirasemtiv Tirasemtiv 125 mg oral capsules administered twice daily. Minimum dose was 125 mg bid and patients were up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Open-label Lead-in Phase Adverse Event	109	0	0
Open-label Lead-in Phase Withdrawal by Subject	2	0	0
Open-label Lead-in Phase Death	1	0	0
Open-label Lead-in Phase Protocol Violation	3	0	0
Double-blind, Placebo-controlled Phase Adverse Event	0	12	78
Double-blind, Placebo-controlled Phase Withdrawal by Subject	0	7	12
Double-blind, Placebo-controlled Phase Physician Decision	0	2	5
Double-blind, Placebo-controlled Phase Death	0	2	0
Double-blind, Placebo-controlled Phase not defined	0	1	2
Double-blind, Placebo-controlled Phase Lost to Follow-up	0	2	0

Baseline Characteristics

Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS)

Baseline characteristics by cohort

Measure	Did Not Complete Open-label Lead-in Treatment n=115 Participants Tirasemtiv 125 mg oral capsules administered twice daily for 7 days. This group started open-label treatment but discontinued early and did not receive double-blind treatment.	Double-blind Treatment: Placebo n=295 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Double-blind Treatment: Tirasemtiv n=301 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.	Total n=711 Participants Total of all reporting groups
Age, Continuous	60.0 years STANDARD_DEVIATION 9.83 • n=93 Participants	56.9 years STANDARD_DEVIATION 11.10 • n=4 Participants	57.0 years STANDARD_DEVIATION 11.17 • n=27 Participants	57.5 years STANDARD_DEVIATION 10.98 • n=483 Participants
Sex: Female, Male Female	52 Participants n=93 Participants	88 Participants n=4 Participants	86 Participants n=27 Participants	226 Participants n=483 Participants
Sex: Female, Male Male	63 Participants n=93 Participants	207 Participants n=4 Participants	215 Participants n=27 Participants	485 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Asian	2 Participants n=93 Participants	2 Participants n=4 Participants	6 Participants n=27 Participants	10 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Black or African American	3 Participants n=93 Participants	8 Participants n=4 Participants	9 Participants n=27 Participants	20 Participants n=483 Participants
Race (NIH/OMB) White	102 Participants n=93 Participants	250 Participants n=4 Participants	259 Participants n=27 Participants	611 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=93 Participants	34 Participants n=4 Participants	26 Participants n=27 Participants	68 Participants n=483 Participants
Time since ALS symptom onset	24.0 months n=93 Participants	21.0 months n=4 Participants	23.0 months n=27 Participants	22.0 months n=483 Participants
Site of symptom onset Lower limb	43 Participants n=93 Participants	110 Participants n=4 Participants	116 Participants n=27 Participants	269 Participants n=483 Participants
Site of symptom onset Upper limb	51 Participants n=93 Participants	145 Participants n=4 Participants	149 Participants n=27 Participants	345 Participants n=483 Participants
Site of symptom onset Bulbar	20 Participants n=93 Participants	40 Participants n=4 Participants	35 Participants n=27 Participants	95 Participants n=483 Participants
Site of symptom onset Respiratory	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	2 Participants n=483 Participants
El Escorial Diagnostic Criteria for ALS Possible	9 Participants n=93 Participants	28 Participants n=4 Participants	31 Participants n=27 Participants	68 Participants n=483 Participants
El Escorial Diagnostic Criteria for ALS Probable, laboratory supported	15 Participants n=93 Participants	57 Participants n=4 Participants	63 Participants n=27 Participants	135 Participants n=483 Participants
El Escorial Diagnostic Criteria for ALS Probable	46 Participants n=93 Participants	119 Participants n=4 Participants	103 Participants n=27 Participants	268 Participants n=483 Participants
El Escorial Diagnostic Criteria for ALS Definite	45 Participants n=93 Participants	91 Participants n=4 Participants	104 Participants n=27 Participants	240 Participants n=483 Participants

PRIMARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Population: Modified Full Analysis Set

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.

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	-2.40 units on a scale Standard Error 0.246	-2.98 units on a scale Standard Error 0.277

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Population: Modified Full Analysis Set

MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	-4.27 L/min Standard Error 1.332	-3.79 L/min Standard Error 1.497

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Population: Modified Full Analysis Set

SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	-0.89 cm H2O Standard Error 1.103	-4.29 cm H2O Standard Error 1.243

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Population: Modified Full Analysis Set

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 the patients of similar demographic and baseline characteristics [eg, height, age, sex]).

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	-7.24 % predicted Standard Error 0.691	-2.98 % predicted Standard Error 0.780

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force.

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	-3.54 pounds Standard Error 0.640	-2.78 pounds Standard Error 0.714

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

Population: Modified Full Analysis Set

Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first.

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment	1.76 seconds Standard Error 2.863	2.01 seconds Standard Error 3.331

SECONDARY outcome

Timeframe: Baseline, 8 weeks, 12 weeks

A hand-held dynamometer (HHD), 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). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.

Outcome measures

Measure	Placebo n=210 Participants Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Tirasemtiv n=178 Participants Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment	-10.71 percent change Standard Error 2.108	-9.10 percent change Standard Error 2.425

Adverse Events

Open-label lead-in Treatment: Tirasemtiv

Serious events: 13 serious events

Other events: 525 other events

Deaths: 2 deaths

Double-blind Treatment: Placebo

Serious events: 16 serious events

Other events: 258 other events

Deaths: 3 deaths

Double-blind Treatment: Tirasemtiv

Serious events: 27 serious events

Other events: 291 other events

Deaths: 2 deaths

Serious adverse events

Measure	Open-label lead-in Treatment: Tirasemtiv n=711 participants at risk Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.	Double-blind Treatment: Placebo n=295 participants at risk Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Double-blind Treatment: Tirasemtiv n=301 participants at risk Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Psychiatric disorders Confusional state	0.28% 2/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.66% 2/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Depression	0.28% 2/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Delirium	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.66% 2/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.28% 2/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Pneumonia	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.66% 2/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Dysphagia	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.66% 2/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	1.0% 3/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Angina pectoris	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Atrial fibrillation	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Myocardial infarction	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Vascular disorders Deep vein thrombosis	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders cerebral haemorrhage	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Humerus fracture	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Joint dislocation	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Tachycardia paroxysmal	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Acute coronary syndrome	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Agitation	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Cerebrovascular accident	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Blood and lymphatic system disorders Coagulopathy	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Cardiac disorders Bradycardia	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Dysarthria	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Kidney infection	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Paresis	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Spinal haematoma	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Suicidal ideation	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Tremor	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.33% 1/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Face injury	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Faeces discoloured	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Parainfluenzae virus infection	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Post procedural infection	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Respiratory tract infection	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Renal and urinary disorders Urinary retention	0.00% 0/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.34% 1/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	0.00% 0/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.

Other adverse events

Measure	Open-label lead-in Treatment: Tirasemtiv n=711 participants at risk Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.	Double-blind Treatment: Placebo n=295 participants at risk Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.	Double-blind Treatment: Tirasemtiv n=301 participants at risk Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.
Nervous system disorders Dizziness	40.9% 291/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	19.7% 58/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	50.8% 153/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
General disorders Fatigue	15.6% 111/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	14.2% 42/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	33.2% 100/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Nausea	10.8% 77/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	7.8% 23/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	21.9% 66/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Headache	4.2% 30/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	11.2% 33/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	17.9% 54/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
General disorders Asthenia	5.6% 40/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	12.5% 37/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	15.9% 48/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	4.2% 30/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.4% 16/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	15.0% 45/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Somnolence	7.0% 50/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.7% 11/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	13.0% 39/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Muscular weakness	3.0% 21/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.8% 20/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	11.3% 34/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Confusional state	2.5% 18/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	1.0% 3/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	11.0% 33/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Insomnia	2.3% 16/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	4.1% 12/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	10.3% 31/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Metabolism and nutrition disorders Decreased appetite	3.2% 23/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.1% 9/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	10.0% 30/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.5% 11/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	2.7% 8/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	8.3% 25/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Dysarthria	1.8% 13/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	2.4% 7/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	7.6% 23/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Contusion	0.84% 6/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	8.5% 25/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	7.3% 22/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Diarrhoea	1.4% 10/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	7.3% 22/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Anxiety	2.1% 15/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	4.4% 13/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.6% 20/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Nasopharyngitis	0.98% 7/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.4% 19/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.3% 19/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Constipation	1.5% 11/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.3% 19/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.14% 1/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.3% 19/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
General disorders Oedema peripheral	0.70% 5/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.0% 18/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Laceration	0.84% 6/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.7% 11/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.0% 18/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Injury, poisoning and procedural complications Excoriation	0.28% 2/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.1% 15/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.6% 17/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Urinary tract infection	0.70% 5/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	4.7% 14/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.6% 17/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Tremor	1.1% 8/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	2.4% 7/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.6% 17/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Skin and subcutaneous tissue disorders Rash	0.42% 3/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	1.0% 3/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.6% 17/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Psychiatric disorders Depression	1.1% 8/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.4% 10/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.3% 16/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Gastrointestinal disorders Dysphagia	0.84% 6/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.4% 10/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.3% 16/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Muscle contractions involuntary	2.1% 15/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	2.7% 8/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.3% 16/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Back pain	1.3% 9/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	6.8% 20/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.0% 15/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Respiratory, thoracic and mediastinal disorders Cough	0.84% 6/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	4.1% 12/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.0% 15/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Nervous system disorders Balance disorder	1.4% 10/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	1.0% 3/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.0% 15/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	1.1% 8/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	4.7% 14/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.84% 6/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.8% 17/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.0% 9/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.
Infections and infestations Upper respiratory tract infection	0.42% 3/711 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	5.1% 15/295 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.	3.0% 9/301 • AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier. An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.

Additional Information

MD Cytokinetics

Cytokinetics, Inc.

Phone: 650-624-2929

Email: medicalaffairs@cytokinetics.com

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