A Study to Assess the Effect of CK-2127107 on Physical Function in Subjects With Chronic Obstructive Pulmonary Disease

• ClinicalTrials.gov Identifier: NCT02662582
• Recruitment Status: Completed
• First Posted: January 25, 2016
• Results First Posted: February 5, 2021
• Last Update Posted: March 24, 2021
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborator: Cytokinetics
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease (COPD)
• Interventions: Drug: Reldesemtiv; Drug: Placebo
• Enrollment: 46

Participant Flow

Recruitment Details
Pre-assignment Details	Participants with a clinical diagnosis of moderate to severe chronic obstructive pulmonary disease (COPD) between 40 to 75 years of age inclusive and met all of the inclusion and none of the exclusion criteria were enrolled in this study.

Arm/Group Title	CK-2127107 1000 mg, Then Placebo	Placebo, Then CK-212710 1000 mg
Arm/Group Description	Participants received CK-2127107 500 mg, orally, twice daily for 2 weeks in treatment period 1 followed by matching placebo orally, twice daily for 2 weeks in treatment period 2. A washout period of 2 weeks was maintained between the two treatment periods.	Participants received matching placebo orally, twice daily for 2 weeks in treatment period 1 followed by CK-2127107 500 mg orally, twice daily for 2 weeks in treatment period 2. A washout period of 2 weeks was maintained between the two treatment periods.
Period Title: Treatment Period 1 (14 Days)
Started	23	23
Completed	18	19
Not Completed	5	4
Reason Not Completed
Adverse Event	3	2
Miscellaneous	0	1
Protocol Deviation	1	0
Withdrawal by Subject	1	1
Period Title: Washout Period (14 Days)
Started	18	19
Completed	18	19
Not Completed	0	0
Period Title: Treatment Period 2 (14 Days)
Started	18	19
Completed	18	19
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		CK-2127107 1000mg, Then Placebo	Placebo, Then CK-2127107 1000mg	Total
Arm/Group Description		Participants received CK-2127107 500 mg, orally, twice daily for 2 weeks in treatment period 1 followed by matching placebo orally, twice daily for 2 weeks in treatment period 2. A washout period of 2 weeks will be maintained between the two treatment periods.	Participants received matching placebo orally, twice daily for 2 weeks in treatment period 1 followed by CK-2127107 500 mg, orally, twice daily for 2 weeks in treatment period 2. A washout period of 2 weeks will be maintained between the two treatment periods.	Total of all reporting groups
Overall Number of Baseline Participants		23	23	46
Baseline Analysis Population Description		The safety analysis set (SAF) consisted of all randomized participants who took ≥ 1 dose of study medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	23 participants	23 participants	46 participants
		62.8 (7.9)	63.1 (8.3)	63 (8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	Female	13 56.5%	12 52.2%	25 54.3%
	Male	10 43.5%	11 47.8%	21 45.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	Hispanic or Latino	0 0.0%	1 4.3%	1 2.2%
	Not Hispanic or Latino	23 100.0%	22 95.7%	45 97.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	23 participants	23 participants	46 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 21.7%	8 34.8%	13 28.3%
	White	18 78.3%	14 60.9%	32 69.6%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	1 4.3%	1 2.2%
Constant work rate (CWR) Endurance Time [1]; Mean (Standard Deviation); Unit of measure: Seconds
	Number Analyzed	23 participants	23 participants	46 participants
		334.5 (80.0)	346.4 (89.1)	340.4 (84.0)
		[1] Measure Description: The CWR defines how long it takes until the participant reaches symptom limitations while simultaneously being monitored and is called "CWR time to intolerance," which determines the "CWR endurance time".

Outcome Measures

1. Primary Outcome

Title	Change From Period Baseline at Week 2 in Constant Work Rate (CWR) Endurance Time Relative to Placebo
Description	The CWR defines how long it takes until the participant reaches symptom limitations while simultaneously being monitored and is called "CWR time to intolerance," which determined the "CWR endurance time". Positive change indicates an improvement from baseline (i.e., a favorable outcome).
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) consisted of all participants who were randomized and received ≥ 1 dose of study drug and had ≥ 1 baseline measurement and 1 post baseline measurement within a period. FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: seconds
	-1.4 (22.2)	-13.4 (21.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Least square means (LSMeans), LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.734
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-12.0
	Confidence Interval	(2-Sided) 90%; -71.2 to 47.2
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Oxygen Uptake (VO2)
Description	VO2 was defined as volume of O2 extracted from inspired air in a given period of time. VO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Liter per minute (L/min)
Peak	-0.0054 (0.0193)	-0.0273 (0.0182)
Isotime	-0.0006 (0.0155)	-0.0330 (0.0147)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.438
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean Difference
	Estimated Value	-0.0219
	Confidence Interval	(2-Sided) 90%; -0.0694 to 0.0256
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.114
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean Difference
	Estimated Value	-0.0325
	Confidence Interval	(2-Sided) 90%; -0.0663 to 0.0014
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Ventilation (VE)
Description	VE was defined as volume of gas exhaled from the lungs in 1 minute, also called 'ventilation' or 'minute ventilation. VE was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: L/min
Peak	-0.17 (1.04)	0.58 (0.98)
Isotime	0.04 (0.84)	0.34 (0.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.612
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 90%; -1.75 to 3.24
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.789
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 90%; -1.55 to 2.14
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Ventilatory Equivalent for Carbon Dioxide (VE/VCO2)
Description	VE/VCO2 was a ratio of VE to VCO2. It is a dimensionless quantity. This ratio indicates how many liters of air exhaled were breathed to eliminate 1 liter of CO2. VE/VCO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: ratio
Peak	0.05 (0.37)	0.77 (0.36)
Isotime	0.05 (0.37)	0.97 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.225
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 90%; -0.26 to 1.70
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.064
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.92
	Confidence Interval	90%; 0.11 to 1.174
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Inspiratory Capacity (IC) Change From Peak to Rest
Description	IC was defined as the volume of air that can be inspired after a normal expiration; it is the sum of the tidal volume (VT) and the IRV.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Liters
	-0.008 (0.051)	0.044 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.447
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 90%; -0.063 to 0.167
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Perceived Exertion for Dyspnea and Leg Discomfort (BORG CR10)
Description	The Borg Scale (Borg CR10) is a simple 10-item method of rating perceived exertion and collects information on perceived exertion in an individual's rating of exercise intensity. Participants were asked to use this scale to rate the intensity of their breathing and leg discomfort before, during, and after exercise. Scores range from 0 (Complete Rest) to 10 (Extremely Hard (almost maximal)). BORG CR10 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title		Placebo	CK-2127107
Arm/Group Description:		Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed		32	35
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Borg (Dyspnea) at Peak	Number Analyzed	32 participants	35 participants
		0.5 (0.4)	-0.3 (0.3)
Borg (Dyspnea) at isotime	Number Analyzed	32 participants	35 participants
		0.4 (0.4)	-0.1 (0.3)
Borg (Leg Effort) at Peak	Number Analyzed	32 participants	35 participants
		-0.1 (0.3)	-0.3 (0.3)
Borg (Leg Effort) at isotime	Number Analyzed	31 participants	35 participants
		0.1 (0.3)	-0.2 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Borg (Dyspnea) at Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.099
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 90%; -1.7 to 0.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Borg (Dyspnea) at isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.255
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 90%; -1.3 to 0.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Borg (Leg Effort) at Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.651
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -1.1 to 0.6
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Borg (Leg Effort) at isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.591
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 90%; -1.0 to 0.5
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Respiratory Exchange Ratio (RER)
Description	The respiratory exchange ratio is equal to the VCO2 / VO2 [RER = VCO2 (L/min) / VO2 (L/min)]. RER was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: ratio
Peak	-0.0036 (0.0125)	0.0250 (0.0119)
Isotime	-0.0042 (0.0102)	0.0143 (0.0097)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.040
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.0286
	Confidence Interval	(2-Sided) 90%; 0.0061 to 0.0511
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.155
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean differencce
	Estimated Value	0.0185
	Confidence Interval	(2-Sided) 90%; -0.0031 to 0.0401
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Carbon Dioxide Output (VCO2)
Description	VCO2 was defined as volume of CO2 exhaled from the body per unit of time; also called the rate of elimination of CO2. VCO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: L/min
Peak	-0.0129 (0.0231)	-0.0119 (0.0219)
Isotime	-0.0115 (0.0188)	-0.0232 (0.0179)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.972
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.0010
	Confidence Interval	(2-Sided) 90%; -0.0459 to 0.0479
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.578
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.0118
	Confidence Interval	(2-Sided) 90%; -0.0471 to 0.0236
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change From Period Baseline at Week 2 in End-tidal PCO2 (PETCO2)
Description	PETCO2 was defined as partial pressure of carbon dioxide in the expired gas at the end of an exhalation. This represents the mean partial pressure of carbon dioxide in the pulmonary alveoli. PETCO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: mmHg
Peak	-0.12 (0.34)	-0.77 (0.33)
Isotime	-0.07 (0.33)	-0.64 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.235
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 90%; -1.55 to 0.26
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.215
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean differencce
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 90%; -1.33 to 0.19
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Change From Period Baseline at Week 2 in End-tidal PO2 (PETO2)
Description	PETO2 was defined as Partial pressure of oxygen in the expired gas at the end of an exhalation. This represents the mean partial pressure of oxygen in the pulmonary alveoli. PETO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: mmHg
Peak	0.38 (042)	1.08 (0.40)
Isotime	0.30 (0.40)	0.75 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.280
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 90%; -0.38 to 1.77
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.424
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 90%; -0.49 to 1.40
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Tidal Volume (VT)
Description	VT was defined as tidal volume is the volume of gas exhaled in each respiratory cycle. Tidal volume is typically measured as an average value over several respiratory cycles, and is expressed in liters. VT was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Liters
Peak	-0.0689 (0.0216)	-0.0299 (0.0204)
Isotime	-0.0582 (0.0289)	-0.0093 (0.0273)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.187
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.0390
	Confidence Interval	(2-Sided) 90%; -0.0099 to 0.0879
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.213
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.0488
	Confidence Interval	(2-Sided) 90%; -0.0163 to 0.1140
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Breathing Frequency (Bf)
Description	Bf was defined as the number of breaths (i.e., an entire inspiratory and expiratory respiratory cycle) per minute. Bf was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	34
Least Squares Mean (Standard Error); Unit of Measure: Breaths/min
Peak	1.6 (0.6)	1.2 (0.6)
Isotime	1.4 (0.7)	0.7 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.640
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.4
	Confidence Interval	90%; -2.1 to 1.2
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.487
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 90%; -2.5 to 1.1
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Inspiratory Capacity (IC)
Description	IC was defined as the volume of air that can be inspired after a normal expiration; it is the sum of the VT and the IRV. IC was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Liters
Peak	-0.047 (0.048)	0.048 (0.046)
Isotime	-0.09 (0.045)	0.042 (0.043)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.100
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.095
	Confidence Interval	(2-Sided) 90%; 0.000 to 0.189
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.008
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.133
	Confidence Interval	(2-Sided) 90%; 0.053 to 0.213
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Period Baseline to Week 2 in Inspiratory Reserve Volume (IRV)
Description	The Inspiratory reserve volume was equal to VT - IC measured in liters [IRV (L) = VT (L) - IC (L)]. IRV was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Liters
Peak	0.026 (0.049)	0.077 (0.047)
Isotime	-0.042 (0.050)	0.052 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.408
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 90%; -0.052 to 0.154
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.058
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 90%; 0.013 to 0.174
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Ventilatory Reserve (VE/MVV)
Description	VE/MVV provides the rate of expired ventilation to the capacity. VE/MVV was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	34
Least Squares Mean (Standard Error); Unit of Measure: percentage of expired ventilation
Peak	2.19 (2.18)	3.62 (2.10)
Isotime	2.67 (2.34)	3.52 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.648
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 90%; -3.85 to 6.73
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.775
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 90%; -4.12 to 5.82
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Heart Rate (HR)
Description	HR was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: Beats/min
Peak	-1.6 (1.5)	-0.5 (1.5)
Isotime	-1.5 (1.7)	0.7 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.544
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 90%; -1.9 to 4.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.216
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 90%; -0.7 to 5.0
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Systolic Blood Pressure (SBP)
Description	SBP was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: mmHg
Peak	3.0 (3.5)	-4.5 (3.3)
Istotime	0.2 (4.2)	0.4 (4.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.171
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-7.4
	Confidence Interval	(2-Sided) 90%; -16.5 to 1.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.976
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; -10.3 to 10.7
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Diastolic Blood Pressure (DBP)
Description	DBP was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	32	35
Least Squares Mean (Standard Error); Unit of Measure: mmHg
Peak	0.3 (2.1)	-0.3 (2.0)
Isotime	-1.0 (2.0)	-2.0 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.844
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 90%; -6.1 to 4.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.751
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 90%; -5.8 to 4.0
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Arterial Oxygen Saturation From Pulse Oximetry (SpO2)
Description	SPO2 was defined as the noninvasive estimation of arterial hemoglobin (Hb) oxygen saturation, using a device that utilizes the combined principles of spectrophotometry and pulse plethysmography. SPO2 was reported at isotime and peak exercise during CWR test.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	31	34
Least Squares Mean (Standard Error); Unit of Measure: percentage of oxygen saturation
Peak	-0.4 (0.3)	-0.2 (0.2)
Isotime	-0.3 (0.3)	0.0 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.590
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.399
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.9
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Forced Vital Capacity (FVC)
Description	Change From Period Baseline in FVC was reported.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	33	34
Least Squares Mean (Standard Error); Unit of Measure: Liters
	0.00 (0.05)	-0.10 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.151
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 90%; -0.20 to 0.01
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Forced Expiratory Volume 1 (FEV1)
Description	Change From Period Baseline in FEV1 was reported.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	33	34
Least Squares Mean (Standard Error); Unit of Measure: Liters
	-0.030 (0.028)	-0.037 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.857
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	-0.007
	Confidence Interval	(2-Sided) 90%; -0.070 to 0.056
	Estimation Comments	[Not Specified]

22. Secondary Outcome

Title	Change From Period Baseline at Week 2 in FVC/FEV1 Ratio
Description	Change From Period Baseline in FVC/FEV1 Ratio was reported.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	33	34
Least Squares Mean (Standard Error); Unit of Measure: ratio
	-1.10 (0.71)	0.47 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.110
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 90%; -0.05 to 3.17
	Estimation Comments	[Not Specified]

23. Secondary Outcome

Title	Change From Period Baseline at Week 2 in Activation of Accessory Respiratory Muscles
Description	Activation of accessory respiratory muscles was assessed by electromyogram. Data was reported at peak and isotime.
Time Frame	Baseline and week 2 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS population with available data at each specified time point.

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	31	32
Least Squares Mean (Standard Error); Unit of Measure: percentage of activation
Peak	4.84 (4.76)	6.91 (4.65)
Isotime	1.04 (4.39)	3.98 (4.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Peak: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.766
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	2.07
	Confidence Interval	(2-Sided) 90%; -9.57 to 13.71
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CK-2127107
	Comments	Isotime: LSMeans, LSMean difference of CK-2127107 minus placebo, and 90% confidence intervals are based on a mixed effect model with treatment and period as fixed effects, subject as a random effect, and a compound symmetry covariance structure.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.642
	Comments	Statistical comparison was performed at a 2-sided 0.10 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSMean difference
	Estimated Value	2.94
	Confidence Interval	(2-Sided) 90%; -7.66 to 13.54
	Estimation Comments	[Not Specified]

24. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	TEAEs were defined as any AE that started or worsened in severity after the first dose of study drug up to 14 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participant administered a study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, physical examination) an AE only if the abnormality meets 1 of the following criteria: Induces clinical signs or symptoms, Requires active intervention, Requires interruption or discontinuation of study drug, The abnormality or test value is clinically significant in the opinion of the inves
Time Frame	From first dose of study drug up to 14 days after last dose of study drug (8 weeks)

Outcome Measure Data

Analysis Population Description

SAF population

Arm/Group Title	Placebo	CK-2127107
Arm/Group Description:	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.	Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed	41	42
Measure Type: Number; Unit of Measure: Participants
	15	21

25. Secondary Outcome

Title	Plasma Concentration of CK-2127107 at Day 1 Predose, Day 14 Lowest Concentration (Ctrough), and Day 14 Concentration Predose 6 Hours (C6h)
Description	Plasma concentration of CK-2127107 was reported.
Time Frame	Day 1 predose, day 14 Ctrough, day 14 C6h

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set (PKAS) consisted of the administered population for which ≥ 1 quantifiable plasma trough concentration or concentration at 6 hours was available for CK-2127107, or its metabolite CK-2127106.

Arm/Group Title		CK-2127107
Arm/Group Description:		Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed		33
Mean (Standard Deviation); Unit of Measure: Nanogram per milliliter (ng/mL)
Day 1 predose	Number Analyzed	17 participants
		0 (0)
Day 14 Ctrough	Number Analyzed	32 participants
		2620 (2100)
Day 14 C6h	Number Analyzed	33 participants
		3290 (2000)

26. Secondary Outcome

Title	Plasma Concentration of CK-2127106 (Metabolite of CK-2127107) at Day 1 Predose, Day 14 Ctrough, Day 14 C6h
Description	Plasma concentration of CK-2127106 (metabolite of CK-2127107) was reported.
Time Frame	Day 1 predose, day 14 Ctrough, day 14 C6h

Outcome Measure Data

Analysis Population Description

PKAS population

Arm/Group Title		CK-2127107
Arm/Group Description:		Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
Overall Number of Participants Analyzed		33
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 1 predose	Number Analyzed	17 participants
		0 (0)
Day 14 Ctrough	Number Analyzed	32 participants
		1760 (1710)
Day 14 C6h	Number Analyzed	33 participants
		1770 (1620)

Adverse Events

Time Frame	From first dose of study drug up to 14 days after last dose of study drug (8 weeks)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo		CK-2127107
Arm/Group Description	Participants received matching placebo orally, twice daily for 2 weeks in treatment periods 1 and 2.		Participants received CK-2127107 500 mg orally twice daily for 2 weeks in treatment periods 1 and 2.
All-Cause Mortality
	Placebo		CK-2127107
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/41 (0.00%)		0/42 (0.00%)
Serious Adverse Events
	Placebo		CK-2127107
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/41 (2.44%)		2/42 (4.76%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma † 1	0/41 (0.00%)	0	1/42 (2.38%)	1
Nervous system disorders
IIIrd nerve paralysis † 1	0/41 (0.00%)	0	1/42 (2.38%)	1
Renal and urinary disorders
Haematuria † 1	1/41 (2.44%)	1	0/42 (0.00%)	0
1 Term from vocabulary, MedDRA 17.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		CK-2127107
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/41 (2.44%)		3/42 (7.14%)
Nervous system disorders
Dizziness † 1	1/41 (2.44%)	1	3/42 (7.14%)	3
1 Term from vocabulary, MedDRA 17.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure
• Organization: Astellas Pharma Global Development, Inc.
• Phone: 800-888-7704
• EMail: astellas.resultsdisclosure@astellas.com

• Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• ClinicalTrials.gov Identifier: NCT02662582
• Other Study ID Numbers: 3318-CL-3002
• First Submitted: January 20, 2016
• First Posted: January 25, 2016
• Results First Submitted: January 16, 2021
• Results First Posted: February 5, 2021
• Last Update Posted: March 24, 2021