Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Chronic Obstructive Pulmonary Disease CK-2127107 COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the effect of CK-2127107 relative to placebo on cycle ergometer exercise tolerance, assessed as change from period baseline in constant work rate (CWR) endurance time, utilizing a breath-by-breath metabolic measurement system with integrated electrocardiogram (ECG). The time to intolerance was assessed by a stopwatch and verified from electronic recordings of the cycle ergometer.

This study assessed cardiopulmonary and neuromuscular effects of CK-2127107 relative to placebo; the effect of CK-2127107 on resting spirometry relative to placebo; the safety and tolerability of CK-2127107 as well as the pharmacokinetics of CK-2127107.

Detailed description:
Enrolled participants were randomly assigned to 1 of 2 treatment sequences and received both CK-2127107 and matching placebo over 2 treatment periods.

Arms:
arm 1: Participants received CK-2127107 500 milligram (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. arm 2: Participants received matching placebo orally, twice daily for 2 weeks in treatment period 1 followed by CK-2127107 500 mg in treatment period 2. A washout period of 2 weeks was maintained between the two treatment periods.

Interventions: intervention 1: Reldesemtiv intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol document:
Prot_000.pdf: 
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two 
Period, Crossover Study to Assess the Effect of CK-2127107 on 
Physical Function in Subjects with Chronic Obstructive 
Pulmonary Disease
ISN/Protocol 3318-CL-3002
ClinicalTrials.gov Identifier: NCT02662582
Date of Protocol v3.1: 29 Nov 2017
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 3318-CL-3002
- CONFIDENTIAL -
29 Nov 2017
Astellas
Page 1 of 100
Version 3.1 Incorporating Non-Substantial Amendment 1
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two 
Period, Crossover Study to Assess the Effect of CK-2127107 
on Physical Function in Subjects with Chronic Obstructive 
Pulmonary Disease
ISN/Protocol 3318-CL-3002
Version 3.1
Incorporating Non-Substantial Amendment 1 [See Attachment 1]
29 November 2017
IND 127897
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History: 
Version 1.0 [24Nov2015]
Version 2.0 Incorporating Substantial Amendment 1 [22Mar2016]
Version 3.0 Incorporating Substantial Amendment 2 [13Mar2017]
Investigator:  Investigator information is on file at Astellas
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.


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Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································14
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································22
1
INTRODUCTION·················································································26
1.1
Background ····················································································26
1.2
Nonclinical and Clinical Data ·······························································27
1.2.1
Nonclinical Data·········································································28
1.2.2
Clinical Data ·············································································29
1.3
Summary of Key Safety Information for Study Drugs ···································31
1.4
Risk-Benefit Assessment·····································································32
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS···································32
2.1
Study Objectives ··············································································32
2.2
Study Design and Dose Rationale···························································33
2.2.1
Study Design·············································································33
2.2.2
Dose Rationale···········································································35
2.3
Endpoints·······················································································35
2.3.1
Primary Endpoints·······································································35
2.3.2
Secondary Endpoints····································································35
2.3.3
Exploratory Endpoints··································································36
2.3.4
Safety Endpoints·········································································36
2.3.5
Pharmacokinetic Endpoints ····························································37
3
STUDY POPULATION··········································································37
3.1
Selection of Study Population ·······························································37
3.2
Inclusion Criteria··············································································37
3.3
Exclusion Criteria·············································································39
4
TREATMENT(S)··················································································41
4.1
Identification of Investigational Product(s) ················································41
4.1.1
Study Drug(s) ············································································41
4.1.2
Comparative Drug(s)····································································41


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4.1.3
Rescue Drug(s) ··········································································41
4.2
Packaging and Labeling······································································41
4.3
Study Drug Handling ·········································································42
4.4
Blinding ························································································42
4.4.1
Blinding Method·········································································42
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················42
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································43
4.4.4
Breaking the Treatment Code for Emergency ·······································43
4.4.5
Breaking the Treatment Code by the Sponsor ·······································43
4.5
Assignment and Allocation ··································································44
5
TREATMENTS AND EVALUATION························································44
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················44
5.1.1
Dose/Dose Regimen and Administration Period ····································44
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································44
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································44
5.1.4
Treatment Compliance··································································45
5.2
Demographics and Baseline Characteristics ···············································46
5.2.1
Demographics············································································46
5.2.2
Medical History··········································································46
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease ··············46
5.3
Efficacy | Exploratory | Pharmacokinetics Assessment···································46
5.3.1
Efficacy Assessment ····································································46
5.3.1.1
IET and CWR ······································································47
5.3.1.2
EMG·················································································47
5.3.1.3
Borg CR10··········································································48
5.3.1.4
Physical Activity···································································48
5.3.1.5
Spirometry··········································································48
5.3.2
Exploratory Assessment ································································48
5.3.2.1
MIP and MEP ······································································48
5.3.2.2
SGRQ-C ············································································49
5.3.2.3
SF-36················································································49
5.3.2.4
SPPB ················································································49
5.3.3
Pharmacokinetics Assessment ·························································50


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5.4
Safety Assessment ············································································50
5.4.1
Vital Signs················································································50
5.4.2
Adverse Events ··········································································50
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································50
5.4.2.2
Adverse Events of Possible Renal Origin·······································51
5.4.3
Laboratory Assessments································································51
5.4.4
Physical Examination···································································51
5.4.5
Electrocardiogram (ECG) ······························································51
5.5
Adverse Events and Other Safety Aspects ·················································51
5.5.1
Definition of Adverse Events (AEs) ··················································51
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································52
5.5.3
Criteria for Causal Relationship to the Study Drug ·································53
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························53
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································53
5.5.6
Follow-up of Adverse Events··························································55
5.5.7
Monitoring of Common Serious Adverse Events ···································55
5.5.8
Procedure in Case of Pregnancy·······················································55
5.5.9
Emergency Procedures and Management of Overdose ·····························56
5.5.10
Supply of New Information Affecting the Conduct of the Study··················56
5.6
Study Drug Concentration ···································································56
5.7
Other Measurements, Assessments or Methods ···········································56
5.7.1
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis) ····························································56
5.7.2
Exploratory Biomarker Analysis Using Metabolomics and Proteomics··········57
5.8
Total Amount of Blood·······································································57
6
DISCONTINUATION············································································57
6.1
Discontinuation of Individual Subject(s)···················································57
6.2
Discontinuation of the Site···································································58
6.3
Discontinuation of the Study ································································58
7
STATISTICAL METHODOLOGY ···························································58
7.1
Sample Size····················································································59
7.2
Analysis Set····················································································59
7.2.1
Full Analysis Set ········································································59
7.2.2
Safety Analysis Set······································································59


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7.2.3
Pharmacokinetic Analysis Set ·························································59
7.3
Demographics and Other Baseline Characteristics········································59
7.4
Analysis of Efficacy ··········································································60
7.4.1
Analysis of Primary Endpoint ·························································60
7.4.1.1
Primary Analysis···································································60
7.4.1.2
Sensitivity Analysis ·······························································60
7.4.1.3
Subgroup Analysis·································································60
7.4.2
Analysis of Secondary Endpoints ·····················································60
7.4.3
Analysis of Exploratory Endpoints····················································60
7.5
Analysis of Safety·············································································60
7.5.1
Adverse Events ··········································································61
7.5.2
Laboratory Assessments································································61
7.5.3
Vital Signs················································································61
7.5.4
ECGs······················································································61
7.6
Analysis of Pharmacokinetics ·······························································61
7.7
Protocol Deviations and Other Analyses···················································61
7.7.1
Protocol Deviations ·····································································61
7.7.2
Other Analyses···········································································62
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················62
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········62
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················62
8.1
Procedure for Clinical Study Quality Control ·············································62
8.1.1
Data Collection ··········································································62
8.1.2
Specification of Source Documents···················································63
8.1.3
Clinical Study Monitoring······························································63
8.1.4
Direct Access to Source Data/Documents············································63
8.1.5
Data Management ·······································································64
8.1.6
Protocol Deviations ·····································································64
8.1.7
End of Trial in All Participating Countries···········································65
8.2
Ethics and Protection of Subject Confidentiality··········································65
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································65
8.2.2
Ethical Conduct of the Study···························································65
8.2.3
Informed Consent of Subjects ·························································65


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8.2.3.1
Subject Information and Consent················································65
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························66
8.2.4
Subject Confidentiality ·································································66
8.3
Administrative Matters ·······································································67
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····67
8.3.2
Documents and Records Related to the Clinical Study·····························67
8.3.3
Protocol Amendment and/or Revision················································67
8.3.4
Insurance of Subjects and Others······················································68
8.3.5
Signatory Investigator for Clinical Study Report····································68
9
QUALITY ASSURANCE········································································68
10
STUDY ORGANIZATION······································································69
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ···········69
10.2
Other Study Organization ····································································69
11
REFERENCES ····················································································70
12
APPENDICES ·····················································································72
12.1
List of Excluded Concomitant Medications/Foods ·······································72
12.2
List of Concomitant Medication to be Used With Caution ······························73
12.3
Liver Safety Monitoring and Assessment··················································74
12.4
Renal Safety Monitoring ·····································································77
12.5
Common Serious Adverse Events···························································78
12.6
Clinical Laboratory Tests ····································································79
12.7
Retrospective PGx Substudy·································································81
12.8
mMRC Scale···················································································83
12.9
Borg CR10 ·····················································································84
13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1···························85
14
SPONSOR’S SIGNATURES·································································· 100
List of Tables
Table 1
Schedule of Assessments·····································································23
Table 2
Treatment Sequence ··········································································33
Table 3
Pharmacokinetic Timepoints ································································56


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I.
SIGNATURES
1.
SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in [Section 14, Sponsor’s Signatures]; e-signatures (when applicable) are located at 
the end of this document.




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3
INVESTIGATOR’S SIGNATURE
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two Period, 
Crossover Study to Assess the Effect of CK-2127107 on Physical Function in 
Subjects with Chronic Obstructive Pulmonary Disease
ISN/Protocol 3318-CL-3002
Version 3.1 / Incorporating Non-Substantial Amendment 1
29 November 2017
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and 
applicable local regulations. I will also ensure that subinvestigator(s) and other relevant members of 
my staff have access to copies of this protocol and the ICH GCP guidelines to enable them to work in 
accordance with the provisions of these documents.
Principal Investigator:
Signature:
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
API
active pharmaceutical ingredient
AST
aspartate aminotransferase
ATS
American Thoracic Society
BMI
body mass index
C-PPAC
clinical visit version of PROactive physical activity in COPD
Ca2+
calcium
COPD
chronic obstructive pulmonary disease
CRO
contract research organization
CSR
clinical study report
CWR
constant work rate
CYP
cytochrome P450
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture
EMG
electromyogram
EOT
end of treatment
ERS
European Respiratory Society
FAS
full analysis set
FEV1
forced expiratory volume in 1 second
FUV
follow-up visit
FVC
forced vital capacity
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GMP
Good Manufacturing Practice
IB
investigator’s brochure
IC
inspiratory capacity
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IET
incremental exercise test
INR
international normalized ratio
IRB
institutional review board
IRT
Interactive Response Technology
LA-CRF
liver abnormality case report form
LFT
liver function tests
LHRH
luteinizing hormone-releasing hormone


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Abbreviations
Description of Abbreviations
MATE
multidrug and toxin extrusion
MEP
maximal expiratory pressure
MIP
maximal inspiratory pressure
mMRC
Modified Medical Research Council
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OCT
organic cation transporter
PKAS
pharmacokinetic analysis set
PRO
patient reported outcome
QoL
quality of life
RPE
rating perceived exertion
RV
residual volume
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SDD
spray dried dispersion
SF-36
Short Form-36
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SOP
standard operating procedure
SPPB
short physical performance battery
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TLC
total lung capacity
ULN
upper limit of normal
VE
ventilation
VE/VCO2
ventilatory equivalent for carbon dioxide
VO2
oxygen uptake
WHO
World Health Organization
WR
work rate


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Definition of Key Study Terms
Terms
Definition of Terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison.
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics).
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the study drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the study drug or comparative drug.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the study drug or 
comparative drug (sometimes without randomization) is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
29 November 2017 / Version 3.1
Sponsor:
Astellas Pharma Global Development Inc. (APGD)
Protocol Number:
3318-CL-3002
Name of Study Drug:
CK-2127107
Phase of Development:
2a
Title of Study:
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two Period, Crossover Study to Assess
the Effect of CK-2127107 on Physical Function in Subjects with Chronic Obstructive Pulmonary 
Disease
Planned Study Period:
From 1Q2016 to 1Q2017
Study Objective(s): 
Primary Objective
●
To assess the effect of CK-2127107 relative to placebo on cycle ergometer exercise tolerance, 
assessed as change from period baseline in constant work rate (CWR) endurance time, utilizing a 
breath-by-breath metabolic measurement system with integrated electrocardiogram (ECG). The 
time to intolerance is assessed by a stopwatch and verified from electronic recordings of the 
cycle ergometer.
Secondary Objectives
●
To assess cardiopulmonary and neuromuscular effects of CK-2127107 relative to placebo on:
o The change from period baseline in oxygen uptake (VO2), ventilation (VE), ventilatory 
equivalent for carbon dioxide (VE/VCO2) and other breath-by-breath cardiometabolic 
variables, inspiratory capacity (IC) and perceived exertion for dyspnea and leg discomfort 
(Borg CR10), at isotime* and peak during CWR test
o Activation of accessory respiratory muscles (by electromyogram [EMG]) at isotime* and 
peak exercise during CWR test
●
To assess the effect of CK-2127107 on resting spirometry relative to placebo
●
To assess the safety and tolerability of CK-2127107
●
To assess the pharmacokinetics of CK-2127107
*Isotime is the shortest duration of all of the CWR tests performed before and after treatment, not 
including screening.
Exploratory Objectives
●
To explore the effects of CK-2127107 relative to placebo on:
o Patient reported outcomes (PROs)
o Physical performance via a short physical performance battery (SPPB) 
o Respiratory muscle strength by maximal inspiratory pressure (MIP) and maximal expiratory 
pressure (MEP)
Planned Total Number of Study Centers and Location(s):
Approximately 4 sites located in the United States and possibly Canada or the United Kingdom


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Study Population:
Male and female subjects aged 40 to 75 years old with COPD
Number of Subjects to be Enrolled/Randomized:
Approximately 40 subjects are planned to be randomized.
Study Design Overview:
This is a phase 2a, randomized, double-blind, placebo-controlled, two period, crossover study to
assess the potential effects on physical function and safety of CK-2127107 in subjects with COPD.
Enrolled subjects will be randomly assigned to 1 of 2 treatment sequences and will receive both 
CK-2127107 and matching placebo over 2 treatment periods as per the following schedule.
Sequence
Treatment Period 1
Treatment Period 2
1
CK-2127107
Placebo
2
Placebo
CK-2127107
Each treatment period consists of 14 days dosing of CK-2127107 or matching placebo.  Each 
medication period is separated by a 14-day washout period.  The total study duration including 
screening period and follow-up visit (FUV) for an individual subject will be approximately 12 weeks 
(see Flow Chart and Schedule of Assessments).
Subjects will attend up to 3 screening visits (between days -28 and day -1) prior to randomization at 
day 1 of treatment period 1. At screening visits 1 and 2 between days -28 and -8, each subject will 
undergo standard screening procedures: Subjects will undergo spirometry before and after 
administration of a bronchodilator. Postbronchodilator forced expiratory volume in 1 second (FEV1) 
expressed as a percent of predicted and as the ratio of FEV1/forced vital capacity (FVC) will be an 
inclusion criterion. Subjects will perform 1 incremental exercise test (IET) on a bicycle to 
characterize the individual subject’s cardiopulmonary responses and also to determine the peak work 
rate (WR). After the IET, a CWR exercise test will be performed, which is set at a level that brings 
the subject to intolerance at between 4 to 8 minutes using a WR calculated from IET results.  The 
CWR test will be completed at least 24 hours after IET. At visit 3 a weekly PRO assessment (clinical 
visit version of PROactive physical activity in COPD [C-PPAC]) will be completed using a 7-day 
recall online 12-item questionnaire. Visit 3 will be considered optional if the subject successfully 
completes the CWR at visit 2.  On day 1 (visit 4) at baseline, all subjects will complete 
postbronchodilator spirometry, respiratory muscle strength tests (MIP and MEP), a resting ECG, 
CWR test with cardiopulmonary and respiratory muscle EMG measurements, quality of life (QoL) 
assessments (St. George’s Respiratory Questionnaire for COPD patients [SGRQ-C], Short Form-36 
[SF-36]), and SPPB to establish period baseline measurements, and will be randomly assigned to 1 of 
2 treatment sequences in a 1:1 ratio.
To achieve steady-state exposure to CK-2127107, subjects will receive CK-2127107 (500 mg) or 
matching placebo twice daily for 14 days, except on day 1 and day 14.  On day 1, subjects will take 
active or placebo drug once in the evening, and on day 14, subjects will take active or placebo drug 
once in the morning.  The subjects will return to the study site again on day 14 (visit 6) for the main 
assessment day (MAD) visit for treatment period 1. Physical activity assessment will be completed 
using a 7-day (days 7 to 13) recall online 12-item questionnaire.


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The exercise testing and the evaluation of the respiratory system will be conducted in the same 
chronologic order (spirometry, MIP/MEP, CWR, SPPB) at day 1 and day 14.  Subsequent visits for 
baseline (visit 7) and treatment period 2 will then follow as per the schedule of assessments.
During the study, blood samples will also be collected at predefined time points for the assessment of 
plasma concentrations of CK-2127107 and possible metabolite(s) (if applicable). One optional blood 
sample for pharmacogenomics will also be taken prior to first dose at day 1 of treatment period 1 
(predose) if the subject specifically consents to this sample collection.
For all subjects, safety will be assessed through the monitoring of adverse events (AEs), concomitant 
medication, vital signs (including blood pressure, heart rate and body temperature), clinical laboratory 
assessments, physical examination and ECG parameters.  Stopping rules for renal and liver safety are 
implemented.
Upon completion of 2 treatment periods each subject will attend a FUV (visit 10), 7 to 14 days after 
the last dose or early withdrawal.
An overview and planning of all assessments can be found in the flow chart and schedule of 
assessments.
Inclusion/Exclusion Criteria:
Inclusion:
A subject is eligible for the study if all of the following apply:
1.
Institutional review board (IRB)-/independent ethics committee (IEC)-approved written informed 
consent and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act [HIPAA] Authorization for US sites) must be obtained from the subject or 
legally authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Male or female aged 40 to 75 inclusive, at the signing of the informed consent.
3.
Subject has a body mass index (BMI) of 18 to 35 kg/m2 inclusive
4.
Subject must have all of the following:
a.
Clinical diagnosis of moderate to severe COPD, with a postbronchodilator FEV1/FVC ratio
< 70% and 30% ≤FEV1 < 80% predicted at screening.  The predicted values for normal 
spirometry will be those recommended by the American Thoracic Society (ATS) / 
European Respiratory Society (ERS) [Miller et al, 2005].
b.
General stable health with no change in medication (including non-COPD agents and 
dietary aids/food supplements) within 2 weeks prior to screening, no systemic corticosteroid 
administration (topical or inhaled corticosteroids are allowed) within 6 weeks prior to 
screening, no exacerbations or hospitalization within 6 weeks prior to screening.
c.
Current or ex-smokers with a smoking history of at least 10 pack years*.
d.
Grade of 2 or 3 on the Modified Medical Research Council (mMRC) Dyspnea Scale at 
screening:
Grade 2: walks slower than people of the same age on the level because of 
breathlessness or has to stop for breath when walking at own pace on the level
Grade 3: stops for breath after walking about 100 meters or after a few minutes on the 
level
5.
Subject is able to complete technically acceptable respiratory muscle strength tests, spirometry,
physical performance test and exercise tests.
6.
This criterion has been deleted.


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7.
Female subject must either:
●Be of non-child bearing potential:
●Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
●Documented surgically sterile
●Or, if of childbearing potential,
●Agree not to try to become pregnant during the study and for 28 days after the last dose,
●And have a negative serum pregnancy test at screening,
●And, if heterosexually active, agree to consistently use 2 forms of highly-effective birth 
control** (at least 1 of which must be a barrier method) starting at screening,
throughout the study, and for 28 days after the last dose.
8.
Female subject must agree not to breastfeed starting at screening and throughout the study and for 
28 days after the last dose.
9.
Female subject must not donate ova starting at screening, throughout the study and for 28 days 
after the last dose.
10. Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective form of contraception consisting of 2 forms of birth control** (at least 1 of which 
must be a barrier method) starting at screening, and continuing throughout the study and for 
90 days after the last dose.
11. Male subject must not donate sperm starting at screening, throughout the study and for 90 days 
after the last dose.
12. Subject agrees not to participate in another interventional study from screening through the FUV 
of the study.
*Pack year is calculated by multiplying the number of packs of cigarettes smoked per day by the 
number of years the person has smoked. For example, 1 pack year is equal to smoking 1 pack per 
day for 1 year, or 2 packs per day for half a year, and so on.
**Highly effective forms of birth control include:
●Consistent and correct usage of established oral contraception
●Established intrauterine device (IUD) or intrauterine system (IUS)
●Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/suppository
Waivers to the Inclusion Criteria will NOT be allowed.
Exclusion:
Subjects will be excluded from participation if any of the following apply:
1.
Subject has previously enrolled in a clinical study of CK-2127107.
2.
Subject has any clinically significant abnormality following the investigator’s review of the 
physical examination, ECG and protocol-defined clinical laboratory tests at screening.  A 
significant abnormality is defined as an abnormality which, in the opinion of the investigator, 
may (i) put the subject at risk because of participation in the study, (ii) influence the results of the 
study or (iii) cause concern regarding the subject’s ability to participate in the study.
3.
Subject has any of the liver function tests (LFTs; i.e., aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], γ-glutamyl transferase [GGT] and/or total 
bilirubin [TBL]) above 1.5 times the upper limit of normal (ULN) at screening. These 
assessments may be repeated once at the investigator’s discretion (within the screening window).
4.
Subject has an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 by the 
Cockcroft-Gault equation at screening.


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5.
Subject has a serious cardiovascular disease, including a current New York Heart Association 
(NYHA) class III or IV congestive heart failure or clinically significant valvular disease, history 
of cardiac arrest, uncontrolled angina or arrhythmia, untreated serious conduction disorder (e.g., 
third-degree heart block), or acute myocardial ischemic condition suspected on the ECG at 
screening (e.g., ST-segment elevation, ST-segment depressions > 2 mm).
6.
Subject has had a myocardial infarction or other acute coronary syndrome, major heart surgery 
(i.e., valve replacement or bypass surgery), stroke, deep vein thrombosis or pulmonary embolus 
in the 6 months prior to screening.
7.
Subject has known active tuberculosis.
8.
Subject has undergone thoracotomy with pulmonary resection (except for sub-lobar resection).
9.
Subject has resting pulse < 40 bpm or > 100 bpm; resting systolic blood pressure > 160 mm Hg or 
< 90 mm Hg; resting diastolic blood pressure > 100 mm Hg at screening.  These assessments may 
be repeated once at the investigator’s discretion (within the screening window).
10. Subject desaturates to SpO2 < 85% for at least 1 minute on screening IET.
11. Subject has a limitation of exercise performance as a result of factors other than fatigue or 
exertional dyspnea/shortness of breath (considered to be due to COPD), such as arthritis in the 
leg, angina pectoris, heart failure, claudication or morbid obesity.
12. Subject has a CWR cycle ergometry endurance time less than 4 or greater than 8 minutes after 
WR adjustment procedures at screening visit 2.
13. Subject has used the following drugs within 14 days prior to day -1: 
a. Strong cytochrome P450 (CYP)3A4 inhibitor (e.g., itraconazole, clarithromycin).
b. Strong CYP3A4 inducer (e.g., barbiturates, rifampin).
14. Subject has hemoglobin (Hb) concentration below 10.0 g/dL at screening.
15. Subject has a cancer requiring treatment currently or in the past 3 years (except primary non-
melanoma skin cancer, carcinoma in situ or cancers that have an excellent prognosis such as early 
stage breast or prostate cancer).
16. Subject giving a history of asthma, allergic rhinitis or atopy shall be evaluated by the investigator 
to determine whether the subject’s predominant diagnosis is COPD rather than asthma.
17. Subject has neurological conditions or neuromuscular diseases that are causing impaired muscle 
function or mobility.
18. Subject has a current diagnosis of schizophrenia, other psychotic disorders or bipolar disorder.
19. Subject in the active phase of pulmonary rehabilitation or had completed pulmonary rehabilitation 
or exercise training within the 13 weeks prior to screening.
20. Subject has severe and/or uncontrolled medical conditions that could interfere with the study 
(e.g., severe neurological deficit after stroke, developed diabetic peripheral neuropathy, 
respiratory diseases requiring daytime supplemental oxygen, infection, gastrointestinal disorder, 
uncontrolled pain or any other non-stable illness) as judged by the medical investigator.
21. Subject has a known history of positive test for hepatitis B surface antigen (HBsAg) or hepatitis C 
antibody or history of a positive test for human immunodeficiency virus (HIV) infection.
22. Subject has a history of alcoholism or drug/chemical substance abuse within 2 years prior to 
screening.


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23. Subject has used any medications known to affect physical function or muscle mass including
androgen supplements, anti-androgens (such as luteinizing hormone-releasing hormone [LHRH]
agonists), anti-estrogen (tamoxifen, etc.), recombinant human growth hormone (rhGH), oral beta 
adrenergic agonists, megestrol acetate, dronabinol or other drugs which, in the opinion of the 
investigator, might influence physical function or muscle mass within 6 weeks prior to screening.
24. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 28 days or 5 half-lives whichever is longer, prior to the initiation of 
screening.
25. Subject has any other condition that in the opinion of the investigator precludes the subject’s 
participation in the trial.
Waivers to the Exclusion Criteria will NOT be allowed.
Investigational Product(s):
CK-2127107-C 250 mg tablets, film-coated
Dose(s):
1000 mg (500 mg twice daily)
Mode of Administration:
Oral doses to be taken in the morning and evening within 2 hours after meals (approximately 12 hours 
apart).
Comparative Drug(s):
Matching placebo tablets
Dose(s):
Matching placebo for CK-2127107 (500 mg twice daily)
Mode of Administration:
Oral doses to be taken in the morning and evening within 2 hours after meals (approximately 12 hours 
apart).
Rescue Therapy: 
In the event of bronchospasm, albuterol is allowed to be self-administered by the subject, except for 
testing days. Subjects requiring rescue albuterol on testing days (beyond the dose administered with 
spirometry) before completing all assessments must return to the clinic as soon as possible to repeat 
the entire study day.
NOTE: During the scheduled spirometry assessments the subjects will receive 2 puffs of albuterol in 
the laboratory 10 to 15 minutes prior to the spirometry assessment on each study day.  Requirement of 
additional “rescue” doses would indicate that that the subject’s disease is not stable.
Dose(s):
180 μg (2 puffs)
Mode of Administration:
Inhaled by mouth every 4 to 6 hours; not to exceed 12 inhalations/24 hours


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Concomitant Medication/Food Restrictions or Requirements:
The following concomitant medications and treatments will not be allowed during the study:
●Systemic corticosteroids
●Strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, grapefruit juice, Seville oranges)
●CYP3A4 inducers (e.g., barbiturates, rifampin, St. John’s wort),
●Cannabis/tetrahydrocannabinol (THC)-based medication,
●Skeletal muscle relaxants,
●OCT1/OCT2 substrates:  oxaliplatin, pindolol, varencicline, pilisicainide and dofetilide,
●Any medications known to affect physical function or muscle mass including androgen 
supplements, anti-androgens (such as LHRH agonists), anti-estrogen (tamoxifen, etc.), rhGH,  oral 
beta adrenergic agonists, megestrol acetate, dronabinol or other drugs which, in the opinion of the 
investigator, might influence physical function or muscle mass.
Caution is recommended for concomitant administration of the organic cation transporter OCT1 
substrates (e.g., aciclovir, ganciclovir) and in particular the OCT1/2 substrate metformin
(antidiabetic), as CK-2127107 may have the potential to inhibit OCT1 and OCT2-mediated transport.
Chronic medications including COPD and non-COPD agents and dietary aids/food supplements are 
permitted, but change in the dose regimen or dosage, or starting any new medication is not allowed.  
All concomitant medication usage will be noted and recorded during each study visit.
Albuterol (180 μg) is to be administered by inhalation 10 to 15 minutes prior to spirometry 
assessment on each study day.
In case non-permitted treatment is necessary, withdrawal of the subject from the study should be 
considered by the authorized medical personnel.
Duration of Treatment:
Two 14-day treatment periods separated by a 14-day wash out period.
Endpoints for Evaluation:
Primary:
●Change from period baseline in CWR endurance time relative to placebo
Secondary:
●Change from period baseline in VO2, VE, VE/VCO2, IC, as well as other cardiometabolic variables 
and perceived exertion for dyspnea and leg discomfort (Borg CR10) at isotime* and peak during 
CWR as compared to placebo
●Change from period baseline in activation of accessory respiratory muscles (by EMG) at isotime* 
and peak exercise during CWR compared to placebo
●Change in resting spirometry compared to placebo
*Isotime is the shortest duration of all of the CWR tests performed before and after treatment, not including 
screening.
Exploratory:
●Change from period baseline in QoL outcomes (SGRQ-C, SF-36) relative to placebo
●Change from baseline in physical activity using a 7-day recall online 12-item questionnaire
●Change from period baseline in physical performance tests battery score (SPPB) relative to 
placebo
●Change from period baseline in MIP and MEP relative to placebo.  This test is performed before 
exercise testing and is part of the resting assessment.


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Safety:
●Adverse events (AEs) /serious adverse events (SAEs)
●Vital signs (blood pressure, heart rate, body temperature)
●Clinical laboratory tests (serum chemistry, hematology and urinalysis)
●12-lead ECG
Pharmacokinetics:
●Pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable): 
Day 1 (only treatment period 2): predose plasma concentration
Day 14 (of both treatment period 1 and 2): Ctrough and C6h
Statistical Methods:
Sample Size Justification:
A sample size of 40 subjects will provide 84% power to detect a difference of 60 seconds in CWR 
duration from period baseline for CK-2127107 versus placebo with a 1-sided alpha error of 0.05, 
assuming the standard deviation for change from period baseline is 100 seconds.  In order to maintain 
the statistical power of 80%, approximately 36 subjects would need to complete period 1.  Should the 
discontinuation rate in the first treatment period exceed 10% (approximately 5 subjects), additional 
subjects will need to be recruited to account for the discontinued subjects.
Efficacy:
Change from period baseline in CWR endurance time at the end of each period will be analyzed by a 
mixed effect model for the primary endpoint. The model includes subject as a random effect and 
treatment and period as fixed effects. Analysis of secondary endpoints will be performed based on a 
similar model as the primary endpoint.
Pharmacokinetics:
Descriptive statistics (e.g., number of subjects, mean, standard deviation, minimum, median, 
maximum, coefficient of variation and geometric mean) will be provided for pharmacokinetic 
parameters of CK-2127107 and possible metabolite(s) (if applicable).
Pharmacodynamics:
Not applicable.
Safety:
All variables will be summarized descriptively by treatment.
Interim Analyses: 
Not applicable.




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Table 1
Schedule of Assessments
Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 2
Follow-up
Day
-28 to -9
-27 to -8
-19 to -1
1
6
14
14 days
1
6
EOTa/
ED
7 days after 
EOT/ED
Window 
-
-
-
-
+3
+3
+7
-
+3
+3
+7
Visit Number
1
2
3b
4
5
6
-
7
8
9
10
Informed consent
X
Inclusion/Exclusion 
X
Medical history
X
X
X
Demographics
X
Drug and alcohol screenc
X
X
X
Randomization
X
Dispense/Collect study drug
X
X
X
X
Administration of study 
drugd
Physical examinatione
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Serum chemistries
X
X
Xg
X
X
Xf
X
X
Serology
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy test
X
X
X
Spirometryh
X
X
X
X
X
X
Respiratory muscle strength 
tests (MIP, MEP)
X
X
X
X
12-lead ECG
X
X
X
X
X
X
CWR exercise test
Xi
X
X
X
X
QoL outcomes 
(SGRQ-C, SF-36)
X
X
X
X
Physical performance test 
(SPPB)
X
X
X
X
IET
X
Table continued on the next page


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Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 2
Follow-up
Day
-28 to -9
-27 to -8
-19 to -1
1
6
14
14 days
1
6
EOTa/
ED
7 days after 
EOT/ED
Window 
-
-
-
-
+3
+3
+7
-
+3
+3
+7
Visit Number
1
2
3b
4
5
6
-
7
8
9
10
PRO (C-PPAC)
X
X
Blood sampling for 
pharmacokineticsj
Predose 6h
Predose
Predose 6h
Optional blood sampling 
for pharmacogenomicsk
X
Concomitant medication
X
X
X
X
X
Xl
X
X
Xl
X
X
Adverse events assessment
X
X
X
X
X
Xl
X
X
Xl
X
X
C-PPAC: clinical visit version of PROactive physical activity in COPD; CWR: constant work rate; ECG: electrocardiogram; ED: early discontinuation; EOT: end of treatment; IET: 
incremental exercise test; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; PRO: patient reported outcome; SF-36: Short Form-36; SGRQ-C: St. George’s 
Respiratory Questionnaire for COPD; SPPB: short physical performance battery
a. EOT: day 14 of treatment period 2.
b. Visit 3 will be considered optional if the subject successfully completes the CWR at visit 2.  Subjects who do not attend visit 3 will resume their visit schedule with visit 4.
c. A standard urine screen for drugs of abuse (e.g., cannabinoids, cocaine and amphetamines) and benzodiazepines, and blood, urine, or breathalyzer alcohol screen will be performed 
by a central laboratory.
d. The time of daily study drug dosing is to be recorded in the paper diary.  Subjects will take study drugs as follows: once a day after dinner at day 1, twice a day within 2 hours after 
breakfast and dinner between day 2 and day 13 and once a day within 2 hours after breakfast at day 14.  In order to collect the trough pharmacokinetic sample on day 14, the subject 
is to wait and take the morning dose at the site after pharmacokinetic sample collection has been performed.
e. A full physical examination will be performed at screening visit 1 and follow-up visit 10. Body systems to be evaluated include general appearance, skin, lymphatic, head and neck, 
ears, nose and throat, chest and lungs, cardiovascular, abdomen, extremities, musculoskeletal, and neuromuscular. At visits 4, 6, 7, and 9, a symptom-directed physical exam will be 
performed.
f.
Vital signs include blood pressure, heart rate and body temperature.
g. Specifically for the monitoring of creatinine, blood urea nitrogen (BUN), cystatin C and liver enzymes (renal and liver safety assessments) at visits 5 and 8.
h. At screening visit, subjects perform spirometry both pre and postbronchodilator, but only postbronchodilator thereafter: Subjects will receive 2 puffs of albuterol in the laboratory 
10 to 15 minutes prior to the spirometry assessment on each study day.
Footnotes are continued on the next page


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i.
At screening CWR will be completed at least 24 hours after IET at visit 2 and may be retested within the next 5 days at the investigator’s discretion (within the visit window) if 
target exercise duration is not obtained. If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be classified as a screen failure and no additional 
assessments completed.  All exercise tests (IET and CWR) will record heart rate and ECG simultaneously with breath-by-breath gas exchange and ventilatory variables during all 
exercise performance.  Borg CR10 is performed with CWR at all of the time points shown in the schedule.  The Electromyogram (EMG) is also performed with the CWR, but only 
at visits 4, 6, 7 and 9/EOT.
j.
Blood samples for pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable) will be collected from EVERY subject.  A single pharmacokinetic sample will be 
collected at each of the following time points: prior to evening dose at day 1 of treatment period 2, prior to morning dose (trough) and then approximately 6 hours postmorning dose
at day 14 of both treatment period 1 and 2.
k. Sample to be collected 1 time prior to first dose at day 1 of treatment period 1.
l.
If a subject experiences an AE or change in concomitant medications during days 7 to 13 or washout, they should call the study site to inform them of this change.


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1
INTRODUCTION
CK-2127107 is a small molecule activator of the fast-skeletal-muscle troponin complex, a 
sarcomere-directed therapy intended to improve skeletal muscle function in conditions 
associated with muscular weakness.  Although it is derived from a different structural class of 
compounds, CK-2127107 has the same mechanism of action as that of tirasemtiv (formerly 
known as CK-2017357), another fast-skeletal-muscle activator currently in a phase 3 study of 
subjects with amyotrophic lateral sclerosis and for which evidence of a pharmacodynamic 
effect already exists [Shefner et al, 2012].
CK-2127107 selectively activates the fast-skeletal-muscle troponin complex by increasing its 
sensitivity to calcium, thereby increasing skeletal muscle force in response to neuronal input 
and delaying the onset and reducing the degree of muscle fatigue.  CK-2127107 is selective for 
the troponin complex in fast skeletal muscle and does not activate the slow skeletal troponin 
complex or the cardiac troponin complex. CK-2127107 is orally bioavailable in nonclinical 
species and healthy humans; consequently, oral administration is the intended route of 
administration in subjects.  
CK-2127107 is hypothesized to reduce the energy cost of exercise by reducing the adenosine 
triphosphate demands associated with calcium ion pumping.
For more details about the investigational product, refer to the current Investigator’s Brochure
(IB).
1.1
Background
Chronic obstructive pulmonary disease (COPD) is an obstructive and progressive airway 
disease. The leading cause of COPD is smoking. According to the World Health Organization 
(WHO), COPD is the fifth leading cause of death in the world, with approximately 3 million 
deaths per annum, or 5% of deaths [WHO, 2015].  People with COPD experience limitations in 
expiratory airflow to their lungs, resulting in a significant reduction in physical activity and 
psychological problems, all of which contribute to the patient’s disability and poor quality of 
life. Standard treatments are bronchodilators, corticosteroids and pulmonary rehabilitation.
Overall, poor exercise capacity in COPD patients or overall low levels of physical activity 
are indicated to correlate with increased mortality [Waschki et al, 2011; Garcia-Aymerich et 
al, 2006; Oga et al, 2003].  The patho-physiological processes underlying the relationship 
between physical activity and survival in chronic diseases such as COPD are complex and 
not well understood [Aguilaniu, 2010]. To date, only a few drugs have been shown to 
enhance exercise capacity of patients with COPD, including beta2 agonists, tiotropium and 
low-density gas mixtures [O’Donnell et al, 2004; Palange et al, 2004; Celli et al, 2003].  
There is currently no pharmacological treatment available for skeletal muscle dysfunction 
and wasting in chronic pulmonary disorders. Troponin modulators and calcium sensitizers 
such as tirasemtiv and CK-2127107 sensitize fast skeletal muscle to calcium (Ca2+) and slow 
the rate of Ca2+ release from the regulatory troponin complex of fast skeletal muscle, 
resulting in a sensitization of the contractile apparatus to calcium. 


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The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have 
recently updated their statement on limb muscle dysfunction in COPD, recognizing this to be 
a key systemic consequence of COPD [Maltais et al, 2014]. According to this official 
statement of the ATS, assessment of limb muscle function could serve to identify patients at 
increased risk of poor clinical outcomes such as exercise intolerance and premature mortality.  
Current treatment options for limb muscle dysfunction include rehabilitative exercise training 
or neuromuscular electrical stimulations, particularly in patients who are severely impaired or 
suffering exacerbations.
A variety of interventions have been tested in order to improve muscle function in patients 
with COPD such as oxygen, nutritional supplements with or without exercise, anabolic 
steroids such as testosterone, growth hormone and other bioactive nutrients. Exercise 
training appears to improve muscle strength, endurance and fatigability, but the magnitude of 
response to exercise is highly variable.
In contrast to the respiratory system, limb muscles demonstrate plasticity in response to 
exercise and could therefore provide an opportunity for novel drug targets. The aim is to find 
treatment options to improve limb muscle function and reduce overall disability [Ribeiro et 
al, 2013]. CK-2127107 is hypothesized to selectively activate the fast skeletal muscle 
troponin complex by increasing its sensitivity to calcium. CK-2127107 slows the rate of 
calcium ion release from the regulatory troponin complex of fast skeletal muscle resulting in 
a sensitization of the contractile apparatus to calcium. It is selective for fast skeletal muscle 
over slow or cardiac muscle and may produce benefit in patients by increasing skeletal 
muscle force in response to neuronal input and delaying the onset and potentially reducing 
the degree of muscle fatigue.
There are a variety of exercise tests available in order to quantify changes in exercise 
capacity in COPD patients such as timed walk tests (6-minute walk test, shuttle walk test) or 
incremental cardiopulmonary exercise testing and constant work rate exercise testing.  
Constant work rate cycle ergometry has been found useful to detect improvements in exercise 
tolerance after an intervention [Borel B et al, 2013; Casaburi R, 2005; Oga T et al, 2000].  In 
the currently proposed study CK-2127107 is hypothesized to improve the physiological 
ability to sustain endurance exercise by demonstrating an increase in constant work rate 
(CWR) endurance time.
1.2
Nonclinical and Clinical Data
CK-2127107 is currently in 2 phase 2 clinical evaluations for chronic obstructive pulmonary 
disease and spinal muscular atrophy following completion of 5 phase 1 studies.  Nonclinical 
evaluations include a series of safety studies in rat and monkey, including single- and repeat-
dose (28-day and 13-week) toxicity studies, a core battery of safety pharmacology studies, 
reproductive and developmental toxicity studies, in vitro and in vivo genotoxicity tests, and 
an in vivo phototoxicity study.  To date, suspension formulations of CK-2127107, either of 
the crystalline active pharmaceutical ingredient (API) of an amorphous spray dried dispersion 
(SDD) and a tablet formulation comprised of API, have been used in nonclinical and clinical 
studies. 


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1.2.1
Nonclinical Data
Dosing of CK-2127107 increased running performance in healthy rats and rats with heart 
failure produced by myocardial infarction under slowly accelerating conditions on a rotarod 
apparatus.  Additionally, studies were conducted in human diaphragm obtained from 
biopsies.  CK-2127107 restored the reduced contractile force of muscle fibers from subjects 
on mechanical ventilation to that of control muscle fibers.  The pharmacological profile of 
CK-2127107, acting as a direct functional activator of fast skeletal muscle, could be of 
benefit to subjects with a wide variety of disorders characterized by muscle weakness.  
The toxicology studies conducted mainly in rats and cynomolgus monkeys, selected on the 
basis of in vitro metabolism studies with CK-2127107 demonstrate a favorable safety profile.  
In 28-day repeat-dose toxicity and toxicokinetic studies, the no observed adverse effect level 
(NOAEL) for CK-2127107 SDD was 600 mg/kg per day, the highest dose level evaluated, in 
both rats and monkeys.  
In both species, there were modest reversible changes in clinical chemistries, hematology, 
and coagulation that, in the absence of correlating macroscopic or microscopic findings, were 
considered to represent non-adverse effects of the test article.  While no microscopic findings 
were noted in monkeys, some reversible non-adverse microscopic changes were noted in the 
kidneys, liver and thyroid of rats.  These findings are recognized rat-specific patterns of 
histological changes.  
A 13-week repeat-dose toxicity and toxicokinetic study was conducted in rats at doses of 0, 
10, 30, 150 and 600 mg/kg per day by oral gavage.  All animals survived until scheduled 
termination.  There were microscopic findings observed in the liver, kidney, pancreas, 
adrenal gland and thyroid gland.  Organ weight and macroscopic/microscopic findings were 
reversible or partially reversible following the 4-week recovery period.  None of the findings 
observed were considered adverse and the NOAEL was considered to be at the highest repeat 
dose tested of 600 mg/kg per day for both sexes.
A 13-week repeat-dose toxicity and toxicokinetic study was conducted in cynomolgus 
monkeys at doses of 0, 30, 150 and 600 mg/kg per day by oral gavage. CK-2127107-related 
clinical chemistry changes included increases in creatinine and triglyceride concentrations in 
both sexes at dose levels ≥150 mg/kg and changes in urine color with an increased incidence 
in urine bilirubin in males and females across all dose levels. At 600 mg/kg per day, there 
were increases in the incidence of urine protein and, in a few females, detectable urine 
glucose. CK-2127107-related microscopic findings of minimal to mild follicular cell 
hypertrophy and hyperplasia were observed in the thyroid gland of males at dose levels 
≥150 mg/kg per day. Significant increases in liver weights were observed in females at 
600 mg/kg per day and in males at dose levels ≥150 mg/kg per day.  These liver weights had 
no microscopic correlate.  All of these findings were reversible after the 4-week recovery 
period.  None of the findings in this study were considered adverse and the NOAEL for 
CK-2127107 was considered to be 600 mg/kg per day for both sexes. 


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The core battery of safety pharmacology studies conducted with CK-2127107 indicated no 
functional changes in vital organs or systems which are likely to be of importance in clinical 
testing of CK-2127107.  Similarly, an effect of CK-2127107 on the human Ether-à-go-go 
Related Gene (hERG) channel was noted (half-maximal inhibitory concentration 
[IC50] = 230.8 μM), but no effect was noted on the QT interval in cynomolgus monkeys.
No effects of CK-2127107 on fertility or early embryonic development were observed in rats 
treated at 0, 30, 150 and 600 mg/kg per day.  In an embryo-fetal development toxicity study 
in rats (0, 30, 150 and 600 mg/kg/day), a delayed ossification ascribable to a maternal 
toxicity (decreases in body weight and food consumption) was observed at 150 and 
600 mg/kg, but no teratogenicity was indicated. In an embryo-fetal development toxicity 
study in rabbits (0, 10, 30 and 100 mg/kg/day), resorption and a decreased fetal body weight 
ascribable to a maternal toxicity (decreases in body weight and food consumption) were 
noted at 100 mg/kg, but no teratogenic potential was indicated.
The results of testing CK-2127107 and CK-2127106 in the bacterial reverse mutation, in 
vitro cytogenetic and in vivo rodent bone marrow micronucleus (in this last test, 
CK-2127106 is an abundant metabolite formed after dosing CK-2127107) studies indicated a 
lack of genotoxic hazard.  
CK-2127107 has detectable absorbance in the UVA-UVB/visible range, but an in vitro 
phototoxicity study was negative.
While CK-2127107 is a substrate for cytochrome P450 (CYP)3A4, CK-2127107 did not inhibit 
CYP isozyme activity (1A2, 2C9, 2C19, 2D6 or 3A4) in vitro, either directly or in a time-
dependent manner.  CK-2127107 (10 μM) did not activate transcription of human pregnane X 
receptor or aryl hydrocarbon receptor-regulated genes (i.e., CYP3A4 and CYP1A genes) 
compared with control compounds in vitro indicating no evidence for induction of these 
enzymes. CK-2127107 inhibited organic cation transporter (OCT)1, OCT2, multidrug and 
toxin extrusion (MATE)1, and organic anion transporter (OAT)1 activities in a concentration-
dependent manner.  CK-2127107 inhibited OCT1 and OCT2 with (IC50) values of 2.63 μmol/L 
and 2.59 μmol/L, respectively. The IC50 values for other transporters such as MATE1, OAT1, 
MATE2-K, OAT2, and OAT3 activity were > 100 μmol/L. The IC50 values for the metabolite, 
CK-2127106, against the same group of transporters were > 100 μmol/L.
1.2.2
Clinical Data
Five phase 1 studies have been completed.  Two studies were primarily directed toward 
evaluating the pharmacokinetics and tolerability of single- and multiple ascending doses of 
CK-2127107.  In a first-in-human study conducted in 35 healthy men (Study CY 5011), 
single oral doses of CK-2127107 SDD suspension ranging from 30 to 4000 mg were all well 
tolerated and no maximum tolerated dose was established.  In Study CY 5012, multidose 
administration of 300 and 500 mg twice daily for either 10 or 17 days was well tolerated by 
59 young and elderly healthy subjects and allowed the steady-state pharmacokinetic profile 
to be described.  A review of electrocardiograms (ECGs) obtained at baseline and various 


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time points at all dose levels revealed no clinically significant and/or obvious dose-dependent 
changes in QT interval vs. placebo.
Two other studies were directed toward comparing the pharmacokinetics and tolerability of 
different physical forms or formulations of CK-2127107.  In Study CY 5014, the relative oral 
bioavailability and pharmacokinetic profiles of the stabilized amorphous form of 
CK-2127107 as an SDD in suspension and the crystalline form of CK-2127107 API in 
suspension were compared following single doses of 300 mg and 1000 mg administered to 
25 healthy men.  Both dose levels were well tolerated.  Similar oral bioavailability of 
CK-2127107 SDD and API was demonstrated at the 300 mg dose level, but not at the 
1000 mg dose level.  Across the dose range 300 to 1000 mg, SDD but not API was dose 
proportional for both AUCinf and Cmax.  In Study CY 5015, the pharmacokinetics of a tablet 
formulated with CK-2127107 API was compared to CK-2127107 API suspension and found 
to have adequate bioavailability for use in future studies.
Finally, a 4-way crossover single dose pharmacokinetic/pharmacodynamic study 
(Study CY 5013) performed with placebo, 300, 1000 and 3000 mg demonstrated a dose- and 
concentration-dependent increase in the force-frequency relationship of the tibialis anterior 
muscle with transcutaneous electric stimulation of the common peroneal nerve. 
The primary objective of this study was to determine the change in the force-frequency 
profile and its relationship to dose and plasma concentrations when CK-2127107 is 
administered orally to healthy male subjects.
The effect of CK-2127107 on changes from baseline in force-frequency response showed 
significant increases relative to placebo. At 1, 3, 5 and 7 hours after administration of the 
1000 and 3000 mg doses of CK-2127107, the changes from baseline in normalized AUC 
force (based on the sum of all frequencies) were statistically significantly greater than 
changes following placebo dosing. The 300 mg dose of CK-2127107 produced changes from 
baseline that were significantly different from changes following placebo dosing at 1 and 
7 hours postdose. For all dose groups, the greatest changes from baseline were observed at 
3 hours postdose, which coincided with Cmax. 
The terminal half-life (t1/2) of CK-2127107 was generally around 12 hours with a tmax of 2 to 
3 hours.  The increase in exposure was largely dose-proportional although exposure was 
more variable at doses ≥3000 mg.  The exposure of CK-2127107 was higher at steady-state 
than after a single dose on day 1 with an accumulation ratio of approximately 3 to 4 at 
300 mg and 4 to 5 at 500 mg (CY 5012). The inactive metabolite (CK-2127106) was present 
at 4% to 19% of the parent in plasma.  Exposure to CK-2127106 was higher at steady-state 
than after a single dose with mean accumulation ratios > 20, consistent with its longer t1/2 of 
about 40 hours (CY 5012).  Cmax and AUC values increased somewhat greater than 
dose-proportionally following multiple dosing. There were no differences in 
pharmacokinetic parameters between young and elderly subjects but mean exposure was 
slightly higher in women versus men.


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CK-2127107 was well tolerated at all dose levels with no serious adverse events (SAEs) or 
discontinuations due to an adverse event (AE).  The most common (> 10%) AEs observed 
with CK-2127107 versus placebo were dizziness and headache. Gastrointestinal symptoms 
as a whole also exceeded the 10% incidence but the individual symptoms did not (abdominal 
pain, diarrhea, nausea, vomiting). Dizziness and headache appeared to be dose-related and 
their incidence increased at doses of 2250 mg and above. None of the AEs were classified as 
severe. Four subjects in the multiple dose study, CY 5012 (1 treated with placebo and 
3 treated with CK-2127107 500 mg), had an AE of “increased alanine aminotransferase 
(ALT)/hepatic enzymes”; an additional 3 subjects (all treated with CK-2127107 500 mg) had 
at least 1 elevated liver enzyme during treatment with study drug that was not reported as an 
AE.  Of these 7 subjects, some of whom also had modest bilirubin elevations, none had 
values that met Hy’s Law criteria.  Other laboratory tests remained normal and consistent 
with baseline values following dosing, with the exception of elevated serum creatinine values 
in most subjects treated with CK-2127107.  This was observed consistently across all studies. 
CK-2127107 has been demonstrated to inhibit OCT2, a mediator of renal tubular secretion of 
creatinine in the human kidney, with an IC50 of 2.59 μmol/L [see the last paragraph of 
Section 1.2.1, above].  Consequently, it is believed that inhibition of renal tubular OCT2 by 
CK-2127107 is the most likely reason for these generally small and reversible increases in 
serum creatinine during treatment with CK-2127107.  
1.3
Summary of Key Safety Information for Study Drugs
There were no differences in steady-state pharmacokinetics of CK-2127107 between young 
and elderly subjects. Thus no dose adjustment in the elderly appears necessary. Exposure to 
the inactive metabolite, CK-2127106, was higher in the elderly, but the clinical significance 
of this finding, if any, is not known.  
Although not observed in single dose studies, a total of 7 subjects in the multidose study 
CY 5012 had an abnormal liver function test (LFT), whether reported as a treatment-
emergent adverse event (TEAE) or as a laboratory value. Of the 7 subjects, some also had 
modest bilirubin elevations, but none had values that met Hy’s Law criteria for drug-induced 
liver injury (ALT or aspartate aminotransferase [AST] > 3 x the upper limit of normal 
[ULN], associated with total bilirubin [TBL] > 2 x ULN, with or without increases in alkaline 
phosphatase [ALP]). The clinical significance of these findings is not known at this time.  In 
nonclinical toxicology studies conducted out to 13 weeks in rat and monkey, there have been 
no adverse histological changes noted in the liver up to the highest dose of 600 mg/kg, which 
is also the NOAEL.  See [Appendix 12.3 Liver Safety Monitoring and Assessment] for 
detailed information on liver abnormalities, monitoring and assessment.
A concentration-dependent increase in serum creatinine levels during treatment with 
CK-2127107 that returned to baseline after discontinuation of treatment has also been 
observed.  No renal toxicity had been observed in nonclinical toxicology studies although a 
similar increase in creatinine during dosing was noted in monkey and rats after 13 weeks of 
exposure that was reversible.  At this time, it is believed that this finding is likely due to 
inhibition of renal tubular OCT2 by CK-2127107, as OCT2 mediates renal tubular creatinine 


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secretion (see Section 1.2.1, above) a mechanism which has been reported with other drugs 
[Agarwal, 1993; Hilbrands et al, 1993; Payne, 1993; van Acker et al, 1993; Schutzer et al, 
2010].  Interference with the creatinine assay by CK-2127107 or 1 of its metabolites could 
also be a potential factor underlying these transient increases in serum creatinine [Ducharme 
et al, 1993].
1.4
Risk-Benefit Assessment
Given the early stage of development and focus on obtaining initial safety data for 
CK-2127107, the AE profile seen to date appears acceptable for proceeding into clinical studies 
in subjects with muscle-wasting diseases as well as additional studies in healthy subjects as 
needed. Both LFTs and serum creatinine will be obtained at baseline and during dosing with 
CK-2127107 in order to further characterize these findings.  In addition, stopping rules have 
been implemented to ensure the safety of subjects enrolled into this study [Section 5.4.2.2].
Study 3318-CL-3002 will include COPD patients in stable condition meeting detailed entry 
criteria and who are required to follow restrictions for concomitant medications.
As a safety precaution, patients shall be discontinued from the study drug* should their 
serum creatinine demonstrate an increase of 1.5 to 2.0 times above baseline (Common 
Terminology Criteria for Adverse Events [CTCAE] grade 1) in concordance with an increase 
in serum cystatin C levels.
* Patients should be evaluated first for potential other reasons of elevated serum creatinine and 
cystatin C levels (i.e., dehydration, concomitant medication or any underlying pathology that could 
explain the increase in renal markers).
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objectives
To assess the effect of CK-2127107 relative to placebo on cycle ergometer exercise tolerance, 
assessed as change from period baseline in CWR endurance time, utilizing a breath-by-breath 
metabolic measurement system with integrated electrocardiogram (ECG). The time to 
intolerance is assessed by a stopwatch and verified from electronic recordings of the cycle 
ergometer.
There are several secondary objectives and exploratory objectives for this study.
Secondary Objectives
●
To assess cardiopulmonary and neuromuscular effects of CK-2127107 relative to 
placebo on:
o The change from period baseline in oxygen uptake (VO2), ventilation (VE), 
ventilatory equivalent for carbon dioxide (VE/VCO2) and other breath-by-breath 
cardiometabolic variables, inspiratory capacity (IC) and perceived exertion for 
dyspnea and leg discomfort (Borg CR10), at isotime* and peak during CWR test


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o Activation of accessory respiratory muscles (by electromyogram [EMG]) at isotime* 
and peak exercise during CWR test
●
To assess the effect of CK-2127107 on resting spirometry relative to placebo
●
To assess the safety and tolerability of CK-2127107
●
To assess the pharmacokinetics of CK-2127107
*Isotime is the shortest duration of all of the CWR tests performed before and after 
treatment, not including screening.
Exploratory Objectives
●
To explore the effects of CK-2127107 relative to placebo on:
o Patient reported outcomes (PROs) 
o Physical performance via a short physical performance battery (SPPB) 
o Respiratory muscle strength by maximal inspiratory pressure (MIP) and maximal 
expiratory pressure (MEP)
2.2
Study Design and Dose Rationale 
2.2.1
Study Design
This is a phase 2a, randomized, double-blind, placebo-controlled, two period, crossover study 
to assess the potential effects on physical function and safety of CK-2127107 in subjects with 
COPD.  Approximately 40 subjects are planned to be randomly assigned to 1 of 2 treatment 
sequences and will receive both CK-2127107 and matching placebo over 2 treatment periods 
as per the following schedule [Table 2].  If the discontinuation rate in the first treatment 
period exceeds 10%, additional subjects will be recruited to ensure a total of at least 36 
subjects completing the study.
Table 2
Treatment Sequence
Sequence
Treatment Period 1
Treatment Period 2
1
CK-2127107
Placebo
2
Placebo
CK-2127107
Each treatment period consists of 14 days dosing of CK-2127107 or matching placebo. Each 
medication period is separated by a 14-day washout period.  The total study duration 
including screening period and follow-up visit (FUV) for an individual subject will be 
approximately 12 weeks (see Flow Chart [Figure 1] and Schedule of Assessments [Table 1]).
Subjects will attend up to 3 screening visits (between day -28 and day -1) prior to 
randomization at day 1 of treatment period 1. At screening (visits 1 and 2 between days -28 
to -8) each subject will undergo standard procedures including resting spirometry before and 
after administration of a bronchodilator. Postbronchodilator forced expiratory volume in 
1 second (FEV1) expressed as a percent of predicted, and as the ratio of FEV1/forced vital 
capacity (FVC) will be an inclusion criterion. Subjects will perform resting ECG and 1
incremental exercise test (IET) to characterize the individual subject’s aerobic capacity (VO2
peak), lactate threshold, ventilatory efficiency (VE/VCO2 nadir) and peak work rate (WR), 
followed by a CWR exercise test, both assessed on a cycle ergometer.


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The CWR test will be completed at visit 2 at least 24 hours after the IET. The CWR exercise 
test will be performed at 80% peak WR (rounded to the nearest 5 watts). This screening test is 
used to confirm the correct WR selection for the rest of the study and to familiarize the subject 
with the testing procedure.  Subjects are expected to tolerate this WR for durations in the range 
of 4 to 8 minutes. Establishing a WR that will achieve this specific duration is critical if 
constant work rate testing is deemed to detect treatment effects in interventional studies 
[Casaburi R, 2005; Puente-Maestu et al, 2016]. In the event that the tolerable duration is 
outside this range, a second CWR is performed within the next 5 days at ± 5 watts to determine 
whether this adjusted WR will result in an endurance time in the desired range.  If this cannot 
be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be classified as a 
screen failure and no additional assessments completed. Once the WR is established that leads 
to intolerance in 4 to 8 minutes, all subsequent tests use the WR that led to intolerance. No 
additional WR adjustments can be made once the WR intolerance level is set. 
On day 1 (visit 4) at baseline, all subjects will complete postbronchodilator spirometry, 
respiratory muscle strength tests (MIP and MEP), a resting ECG, CWR test (including 
breath-by-breath cardiometabolic measurements and respiratory muscle EMG), quality of life 
(QoL) assessments (St. George’s respiratory questionnaire for COPD patients [SGRQ-C] and 
short form-36 [SF-36]), physical activity assessments (7-day recall online 12-item 
questionnaire), and a SPPB to establish period baseline measurements, and will be randomly 
assigned to 1 of 2 treatment sequences in a 1:1 ratio.
To achieve steady-state exposure to CK-2127107, subjects will receive CK-2127107 
(500 mg) or matching placebo twice daily for 14 days, except on day 1 and day 14.  On day 1,
subjects will take active or placebo drug once in the evening, and on day 14, subjects will 
take active or placebo drug once in the morning. At visit 5, subjects will also have renal and 
liver safety assessments.
The subjects will then be invited back to the study site again on day 14 (visit 6) for the main 
assessment day (MAD) visit for treatment period 1. Subsequent visits for the second period 
baseline (visit 7) and treatment period 2 will then follow as per the Schedule of Assessments
[Table 1].
During the study, blood samples will also be collected at predefined time points for the 
assessment of plasma concentrations of CK-2127107 and possible metabolite(s) (if 
applicable) [See Section 5.6]. One (voluntary) blood sample for pharmacogenomics will also 
be taken prior to first dose at day 1 of treatment period 1 (predose).
For all subjects, safety will be assessed through the monitoring of AEs concomitant 
medications, vital signs (including blood pressure, heart rate and body temperature), clinical 
laboratory assessments, physical examination and ECG parameters.
Upon completion of 2 treatment periods or ED, each subject will attend a FUV (visit 10), 7 to 
14 days after the last dose or early withdrawal.
An overview and planning of all assessments can be found in the Flow Chart [Figure 1] and 
Schedule of Assessments [Table 1].


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2.2.2
Dose Rationale
The optimal dose for CK-2127107 has not yet been determined, but CK-2127107 is expected 
to improve the physical (skeletal muscle) function in subjects at the same dose range and 
plasma concentration as those in healthy subjects (Study CY 5013).  The nonclinical studies 
conducted in human diaphragm obtained from biopsies indicated that CK-2127107 restored 
the contractile force of muscle fibers from subjects on mechanical ventilation to that of 
control muscle fibers.  In an assessment of running performance (NCD11-055), CK-2127107 
increased running time in healthy rats and rats with heart failure under slowly accelerating 
conditions on a rotarod apparatus.
In the CY 5013 pharmacokinetic-pharmacodynamic study, the change in the force-frequency 
profile of the tibialis anterior muscle during transcutaneous stimulation of the common 
peroneal nerve and its relationship to CK-2127107 dose and plasma concentrations 
CK-2127107 was evaluated in healthy male subjects.  CK-2127107 (300 and 1000 mg single 
dose) was associated with statistically significantly greater changes in the force generated by 
the tibialis anterior muscle from baseline to all time points evaluated (1, 3, 5 and 7 hours 
postdose) versus placebo.  The mean increase in force from baseline relative to placebo in 
CK-2127107 plasma concentration range > 1000 to 2000 ng/mL was 31.57%.  Thus, 
maintaining CK-2127107 plasma concentration in the range of 1000 to 2000 ng/mL or higher 
is expected to produce a pharmacodynamic effect with CK-2127107 in humans. The 500 mg
twice daily (daily dose of 1000 mg) was chosen based on the results of study CY 5013.
The results of the CY 5012 multiple ascending dose study, demonstrated that steady-state 
CK-2127107 mean plasma Ctrough of 500 mg twice daily was higher than 2000 ng/mL, and 
was therefore considered an appropriate dose to be explored in a proof of pharmacology
study while maintaining plasma exposures proven to be efficacious in the pharmacokinetic-
pharmacodynamic study (CY 5013).
2.3
Endpoints
2.3.1
Primary Endpoints
The primary endpoint is the change from period baseline in CWR endurance time relative to 
placebo.  The CWR defines how long it takes until the subject reaches symptom limitations 
while simultaneously being monitored and is called “CWR time to intolerance” which 
determines the “CWR endurance time”.  
CWR endurance time will be performed during screening and on day 1 and day 14 during 
each of the 2 treatment periods or at early discontinuation (ED) [Table 1].
2.3.2
Secondary Endpoints
The secondary endpoints are as follows:
●
Change from period baseline in VO2, VE, VE/VCO2, IC, as well as other cardiometabolic 
variables and perceived exertion for dyspnea and leg discomfort (Borg CR10) at 
isotime* and peak during CWR as compared to placebo


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●
Change from period baseline in activation of accessory respiratory muscles (by EMG) at 
isotime* and peak exercise during CWR
●
Change in resting spirometry compared to placebo
*Isotime is the shortest duration of all of the CWR tests performed before and after treatment, 
not including screening.
These endpoints relate to the isotime physiologic measurements that underpin the increase in 
exercise tolerance and represent an integrated examination of cardiopulmonary measurements. 
The analysis of variables that are recorded breath-by-breath (e.g., VO2, VE, VE/VCO2) are 
facilitated by averaging data over 20 second intervals within the metabolic cart system 
(recorded by the Vmax breath-by-breath metabolic measurement system). Surface accessory 
muscle EMG activity is recorded throughout the exercise and analyzed over the same time 
intervals as the breath-by-breath data.  IC is recorded every 2 minutes during exercise; its 
measurement requires the subject to produce a maximum inspiration (from end-inspiration) on 
command every 2 minutes during the exercise test.  This allows the determination of whether 
IC is reduced during exercise as a consequence of dynamic hyperinflation, which is common 
during exercise in COPD.  The exercise system software stores this maneuver and facilitates 
post-test examination of each maneuver to assess quality. Therefore IC assessment of dynamic 
hyperinflation is obtained with 2-minute resolution.
Resting spirometry is measured before exercise but after inhalation of albuterol. It is measured 
at approximately the same time of day, at the same duration after the subjects’ morning dose 
of normal bronchodilator medications. Subjects will receive 2 puffs of albuterol in the 
laboratory 10 to 15 minutes prior to the spirometry assessment on each study day.
2.3.3
Exploratory Endpoints
The exploratory endpoints are as follows:
●
Change from period baseline in QoL outcomes (SGRQ-C, SF-36) relative to placebo
●
Change from baseline in physical activity using a 7-day recall online 12-item 
questionnaire.
This will be assessed during only the first treatment period. Therefore, this will 
represent the response to placebo for half the subjects and the response to the study drug 
for the other half of subjects.
●
Change from period baseline in physical performance tests battery score (SPPB) relative 
to placebo
●
Change from period baseline in MIP and MEP relative to placebo. This test is performed 
before exercise testing and is part of the resting assessment.
2.3.4
Safety Endpoints
●
AEs/SAEs
●
Vital signs (blood pressure, heart rate, body temperature)
●
Clinical laboratory tests (serum chemistry, hematology and urinalysis)
●
12-lead ECG


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2.3.5
Pharmacokinetic Endpoints
●
Pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable):
o
Day 1 (only treatment period 2): predose plasma concentration
o
Day 14 (of both treatment period 1 and 2): Ctrough and C6h
3
STUDY POPULATION
3.1
Selection of Study Population 
This study will randomize subjects with a clinical diagnosis of moderate to severe COPD 
between 40 to 75 years of age inclusive. Approximately 40 subjects are planned to be 
randomized to 1 of 2 treatment sequences in a crossover fashion. Enrollment for this study 
will be at approximately 4 sites in the United States and possibly Canada or the United 
Kingdom.
The inclusion/exclusion criteria are to screen for the appropriate subjects to enroll in this 
study.  If a subject fails to meet these parameters the subject will not be included in the study. 
3.2
Inclusion Criteria
A subject is eligible for the study if all of the following apply:
1.
Institutional review board (IRB)-/independent ethics committee (IEC)-approved written 
informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must 
be obtained from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable). 
2.
Male or female aged 40 to 75 inclusive, at the signing of the informed consent.
3.
Subject has a body mass index (BMI) of 18 to 35 kg/m2 inclusive.  
4.
Subject must have all of the following:
a. Clinical diagnosis of moderate to severe COPD, with a postbronchodilator 
FEV1/FVC ratio < 70% and 30% ≤FEV1 < 80% predicted at screening. The 
predicted values for normal spirometry will be those recommended by the ATS/ERS 
[Miller et al, 2005]. 
b. General stable health with no change in medication (including non-COPD agents and 
dietary aids/food supplements) within 2 weeks prior to screening, no systemic 
corticosteroid administration (topical or inhaled corticosteroids are allowed) within 
6 weeks prior to screening, no exacerbations or hospitalization within 6 weeks prior 
to screening.
c. Current or ex-smokers with a smoking history of at least 10 pack years*.


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d. Grade of 2 or 3 on the Modified Medical Research Council (mMRC) Dyspnea Scale
[Appendix 12.8] at screening:
●Grade 2: walks slower than people of the same age on the level because of 
breathlessness or has to stop for breath when walking at own pace on the level
●Grade 3: stops for breath after walking about 100 meters or after a few minutes 
on the level
5.
Subject is able to complete technically acceptable respiratory muscle strength tests, 
spirometry, physical performance test, and exercise tests.
6.
This criterion has been deleted.
7.
Female subject must either:
●Be of non-child bearing potential:
●Postmenopausal (defined as at least 1 year without any menses) prior to 
screening, or
●Documented surgically sterile
●Or, if of childbearing potential,
●Agree not to try to become pregnant during the study and for 28 days after the 
last dose,
●And have a negative serum pregnancy test at screening,
●And, if heterosexually active, agree to consistently use 2 forms of highly-
effective birth control** (at least 1 of which must be a barrier method) starting 
at screening, throughout the study, and for 28 days after the last dose.
8.
Female subject must agree not to breastfeed starting at screening and throughout the 
study and for 28 days after the last dose.
9.
Female subject must not donate ova starting at screening, throughout the study and for 
28 days after the last dose.
10. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective form of contraception consisting of 2 forms of birth control** 
(at least 1 of which must be a barrier method) starting at screening, and continuing 
throughout the study and for 90 days after the last dose.
11. Male subject must not donate sperm starting at screening, throughout the study and for 
90 days after the last dose.
12. Subject agrees not to participate in another interventional study from screening through 
the FUV of the study.
*Pack year is calculated by multiplying the number of packs of cigarettes smoked per 
day by the number of years the person has smoked.  For example, 1 pack year is equal 
to smoking 1 pack per day for 1 year, or 2 packs per day for half a year, and so on.


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**Highly effective forms of birth control include:
●
Consistent and correct usage of established oral contraception
●
Established intrauterine device (IUD) or intrauterine system (IUS)
●
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Waivers to the Inclusion Criteria will NOT be allowed.
3.3
Exclusion Criteria
Subjects will be excluded from participation if any of the following apply:
1.
Subject has previously enrolled in a clinical study of CK-2127107.
2.
Subject has any clinically significant abnormality following the investigator’s review of 
the physical examination, ECG and protocol-defined clinical laboratory tests at 
screening. A significant abnormality is defined as an abnormality which, in the opinion 
of the investigator, may (i) put the subject at risk because of participation in the study, 
(ii) influence the results of the study, or (iii) cause concern regarding the subject’s ability 
to participate in the study.
3.
Subject has any of the LFTs (i.e., AST, ALT, ALP, γ-glutamyl transferase [GGT] and/or 
TBL) above 1.5 times the ULN at screening.  These assessments may be repeated once at 
the investigator’s discretion (within the screening window).
4.
Subject has an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2
by the Cockcroft-Gault equation at screening.
5.
Subject has a serious cardiovascular disease, including a current New York Heart 
Association (NYHA) class III or IV congestive heart failure or clinically significant 
valvular disease, history of cardiac arrest, uncontrolled angina or arrhythmia, untreated 
serious conduction disorder (e.g., third-degree heart block), or acute myocardial 
ischemic condition suspected on the ECG at screening (e.g., ST-segment elevation, 
ST-segment depressions > 2 mm).
6.
Subject has had a myocardial infarction or other acute coronary syndrome, major heart 
surgery (i.e., valve replacement or bypass surgery), stroke, deep vein thrombosis or 
pulmonary embolus in the 6 months prior to screening.
7.
Subject has known active tuberculosis.
8.
Subject has undergone thoracotomy with pulmonary resection (except for sub-lobar 
resection).
9.
Subject has resting pulse < 40 bpm or > 100 bpm; resting systolic blood pressure 
> 160 mm Hg or < 90 mm Hg; resting diastolic blood pressure > 100 mm Hg at 
screening.  These assessments may be repeated once at the investigator’s discretion 
(within the screening window).
10. Subject desaturates to SpO2 < 85% for at least 1 minute on screening IET.


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11. Subject has a limitation of exercise performance as a result of factors other than fatigue 
or exertional dyspnea/shortness of breath (considered to be due to COPD), such as 
arthritis in the leg, angina pectoris, heart failure, claudication or morbid obesity.
12. Subject has a CWR cycle ergometry endurance time less than 4 or greater than 8 minutes 
after WR adjustment procedures at screening visit 2.
13. Subject has used the following drugs within 14 days prior to day -1: 
a. Strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin).
b. Strong CYP3A4 inducer (e.g., barbiturates, rifampin).
14. Subject has hemoglobin (Hb) concentration below 10.0 g/dL at screening. 
15. Subject has a cancer requiring treatment currently or in the past 3 years (except primary 
non-melanoma skin cancer, carcinoma in situ or cancers that have an excellent prognosis 
such as early stage breast or prostate cancer).
16. Subject giving a history of asthma, allergic rhinitis or atopy shall be evaluated by the 
investigator to determine whether the subject’s predominant diagnosis is COPD rather 
than asthma.
17. Subject has neurological conditions or neuromuscular diseases that are causing impaired 
muscle function or mobility.
18. Subject has a current diagnosis of schizophrenia, other psychotic disorders or bipolar 
disorder.
19. Subject in the active phase of pulmonary rehabilitation or had completed pulmonary 
rehabilitation or exercise training within the 13 weeks prior to screening.
20. Subject has severe and/or uncontrolled medical conditions that could interfere with the 
study (e.g., severe neurological deficit after stroke, developed diabetic peripheral 
neuropathy, respiratory diseases requiring daytime supplemental oxygen, infection, 
gastrointestinal disorder, uncontrolled pain or any other non-stable illness) as judged by 
the medical investigator.
21. Subject has a known history of positive test for hepatitis B surface antigen (HBsAg) or 
hepatitis C antibody or history of a positive test for human immunodeficiency virus 
(HIV) infection.
22. Subject has a history of alcoholism or drug/chemical substance abuse within 2 years 
prior to screening.
23. Subject has used any medications known to affect physical function or muscle mass 
including androgen supplements, anti-androgens (such as luteinizing hormone-releasing 
hormone [LHRH] agonists), anti-estrogen (tamoxifen, etc.), recombinant human growth 
hormone (rhGH), oral beta adrenergic agonists, megestrol acetate, dronabinol, or other 
drugs which, in the opinion of the investigator, might influence physical function or 
muscle mass within 6 weeks prior to screening.


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24. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 28 days or 5 half-lives whichever is longer, prior to the 
initiation of screening.
25. Subject has any other condition that in the opinion of the investigator precludes the 
subject’s participation in the trial.
Waivers to the Exclusion Criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug(s)
CK-2127107 study drug will be supplied in a blinded form by Astellas as CK-2127107-C 
250 mg tablets, film-coated.  The tablets are white oral tablets.
4.1.2
Comparative Drug(s)
Placebo for CK-2127107-C tablets will be supplied by Astellas in a blinded form to match 
the active tablets.
4.1.3
Rescue Drug(s)
In the event of a bronchospasm, albuterol is allowed to be self-administered by the subject,
except for testing days (visits 4, 6, 7 and 9). Subjects requiring rescue albuterol on testing 
days (beyond the dose administered with spirometry) before completing all assessments will 
return to the clinic as soon as possible to repeat the entire study day.
NOTE:  During the scheduled spirometry assessments the subjects will receive 2 puffs of 
albuterol in the laboratory 10 to 15 minutes prior to the spirometry assessment on each study 
day.  Requirement of additional “rescue” doses would indicate that that the subject’s disease 
is not stable.
The allowable dose and mode of administration for albuterol is 180 μg (2 puffs):  inhaled by 
mouth every 4 to 6 hours; not to exceed 12 inhalations/24 hours.
4.2
Packaging and Labeling
All study drugs used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas or Sponsor’s designee in accordance with Astellas 
or Sponsor’s designee standard operating procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and applicable local laws/regulations.
Each bottle, containing 30 tablets of CK-2127107 or matching placebo, will bear a label 
conforming to regulatory guidelines, GMP and local laws and regulations which identifies 
the contents as investigational drug.


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CK-2127107 and matching placebo should be stored in the original bottle at United States 
Pharmacopeia controlled room temperature, 20°C to 25°C (68°F to 77°F) with excursions 
permitted from 15°C to 30°C (59°F to 86°F).
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and that such deliveries are 
recorded, that study drug is handled and stored according to labeled storage conditions, that 
study drug with appropriate expiry/retest is only dispensed to study subjects in accordance 
with the protocol, and that any unused study drug is returned to the Sponsor.
Drug inventory and accountability records for the study drugs will be kept by the investigator
or designee.  Study drug accountability throughout the study must be documented and 
reconciled. The following guidelines are therefore pertinent:
●
The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs.
●
A study drug inventory will be maintained by the investigator or designee. The 
inventory will include details of material received and a clear record of when they were 
dispensed and to which subject.
●
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration.
4.4
Blinding
4.4.1
Blinding Method
This is a double blind study. Subjects will receive CK-2127107 or matching placebo in a 
double-blind fashion such that the investigator, Sponsor’s study management team, clinical 
staff and the subjects will not know which agent is being administered.  The randomization 
number will be assigned based on information obtained from the Interactive Response 
Technology (IRT).
4.4.2
Confirmation of the Indistinguishability of the Study Drugs
The appearance, size and color of the CK-2127107-C 250 mg tablets, film coated are the 
same as the matching placebo.


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4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The randomization list and study drug blind will be maintained by the IRT system.  A 
separate instruction manual will be provided to the investigator and staff on use of the IRT 
for randomization and generation of randomization number.
4.4.4
Breaking the Treatment Code for Emergency
In the event of a medical emergency requiring knowledge of a subject’s treatment assignment, 
only the investigator or other persons designated as subinvestigators are authorized to receive 
a subject’s treatment assignment after approval by the Astellas Medical Monitor or Astellas 
Pharmacovigilance (PSP) physician. For immediate access to treatment code assignments, 
the IRT system provides a 24-hour telephone Global Help Desk service to assist users 
365 days a year. In the event of a problem accessing the IRT system or completing a 
transaction, the IRT Help Desk will provide assistance.
If the blind is broken, the time, date, subject number, and reason for breaking the blind must 
be documented.  Subjects and other study personnel will not be made aware of unblinding 
unless a medical emergency necessitates such disclosure. The subject numbers of unblinded 
subjects will be reported to the Sponsor before database lock.
4.4.5
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a suspected 
unexpected serious adverse reaction (SUSAR), in order to determine if the individual case or 
a group of cases requires expedited regulatory reporting. Individual Emergency Codes will be 
provided to the limited staff who are responsible to break the codes for all SUSAR cases for 
reporting purposes.
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject. The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file. They must only be requested by the investigator 
or other persons designated as subinvestigators. No subjects or other study personnel will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure.
Unblinding of the study drug should only be considered for subject safety or when critical 
therapeutic decisions are contingent upon knowing the blinded study drug assignment.  Any 
unblinding by the investigational staff must be reported immediately to the Sponsor and must 
include an explanation of why the study drug was unblinded.  If possible, the Sponsor should 
be contacted prior to unblinding of the study drug.


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4.5
Assignment and Allocation
Randomization will be performed via IRT. Prior to the initiation of the study treatment, the 
site staff will contact the IRT in order to determine the randomly assigned treatment 
sequence. Specific procedures for randomization through the IRT are contained in the study 
procedures manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Subjects will be screened up to 28 days prior to randomization. Informed consent/
authorization will be obtained prior to randomization and before any study-related procedures 
are performed.
Subjects will be randomly assigned to 1 of 2 treatment sequences and will receive 
CK-2127107 as two 250 mg tablets (500 mg twice a daily [1000 mg daily total]) or 2 tablets 
twice daily of matching placebo during the 2 treatment periods. Doses are to be taken in the 
morning and evening within 2 hours after a meal (approximately 12 hours apart).  Each 
treatment period consists of 14 days.  Each medication period is separated by a 14-day 
washout period.
The time of daily study drug dosing is to be recorded in the paper diary. Subjects will take 
study drugs as follows: once a day after dinner at day 1, twice a day within 2 hours after 
breakfast and dinner between day 2 and day 13 and once a day within 2 hours after breakfast 
at day 14.  At day 14, in order to collect the trough pharmacokinetic sample, the subject is to 
wait and take the morning dose at the site after pharmacokinetic sample collection has been 
performed.
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
No increase or reduction of CK-21271070 will be allowed for an individual subject.
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication Therapy)
Concomitant Medication/Food Restrictions or Requirements:
Change in medication (including non-COPD agents and dietary aids/food supplements) will 
not be allowed within 2 weeks prior to screening.
No systemic corticosteroid administration (except for topical or inhaled corticosteroids) is 
allowed within 6 weeks prior to screening. 
The following concomitant medications and treatments are prohibited as described:
●
Systemic corticosteroids 
●
Strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, grapefruit juice, Seville 
oranges) [see Appendix 12.1]


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●
CYP3A4 inducers (e.g., barbiturates, rifampin, St. John’s wort) [see Appendix 12.1]
●
Cannabis/tetrahydrocannabinol (THC)-based medication
●
Skeletal muscle relaxants
●
OCT1/OCT2 substrates:  oxaliplatin, pindolol, varencicline, pilisicainide and dofetilide
●
Any medications known to affect physical function or muscle mass including androgen 
supplements, anti-androgens (such as LHRH agonists), anti-estrogen (tamoxifen, etc.), 
rhGH, oral beta adrenergic agonists, megestrol acetate, dronabinol, or other drugs which, 
in the opinion of the investigator, might influence physical function or muscle mass
[Appendix 12.1].
Caution is recommended for concomitant administration of the OCT1 substrates (e.g., 
aciclovir, ganciclovir) and OCT1/2 substrates (e.g., in particular metformin [antidiabetic], 
dofetilide, pindolol) as CK-2127107 may have the potential to inhibit OCT1 and OCT2-
mediated transport [Appendix 12.2].
In case non-permitted treatment is necessary, withdrawal of the subject from the study should 
be considered by the authorized medical personnel.
The following will be allowed during the study: 
●
Chronic medications including COPD and non-COPD agents and dietary aids/food 
supplements are permitted, but change in the dose regimen or dosage, or starting any 
new medication is not allowed after the screening evaluations. The subject should be in 
a stable state, including prescribed medications throughout the study. 
●
Albuterol (180 μg) is to be administered by inhalation 10 to 15 minutes prior to 
spirometry assessment on each study day.
All concomitant medication usage will be noted and recorded during each study visit.
A list of excluded concomitant medication is provided in [Appendix 12.1].
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. Compliance will be verified by the accounting of study drug as recorded by the 
subject via paper diary. Compliance of the study drug will be monitored by the accounting of 
unused medication returned by the subject at visits. When study drug is administered at the 
research facility, it will be administered under the supervision of study personnel.
Treatment compliance should be monitored closely, and deviation in treatment compliance, 
such as receiving the wrong treatment or dose, should be reported to the Sponsor; the 
appropriate documents should be submitted and, if applicable, reported to the IRB/IEC.


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5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic and baseline characteristics will be collected during screening for all subjects 
according to the Schedule of Assessments [Table 1] and will include date of birth, sex, race 
and ethnicity, height, body weight, smoking history and alcohol use. Vital signs such as 
heart rate, blood pressure, body temperature as well as resting ECG are measured during 
screening.  Heart rate and ECG will also be recorded simultaneously during all IET and 
CWR exercise tests.  Blood pressure will be taken by auscultation during exercise tests 
periodically (approximately every 2 min) and recorded in the electronic exercise test record.
At screening a full pulmonary function test that includes force expiratory flows, lung 
volumes (including total lung capacity [TLC], IC and residual volume [RV]) and diffusing 
capacity will be performed.  This will characterize the subject’s lung function and disease for 
entry into the study. MIP and MEP are measured following the resting spirometry test prior 
to the exercise test (visits 4, 6, 7 and EOT only). During the remainder of the trial, only the 
spirometry (FEV, FVC) and MIP/MEP will be measured. Spirometry (FEV1, FEV1/FVC, 
etc.) will be performed according to ATS guidelines [Miller et al, 2005].
5.2.2
Medical History
Site personnel will collect and record information regarding the subject’s medical history at 
screening and any updated information will be recorded on study day 1 of each treatment 
period.
Medical history will include: subject diagnosis for clinical diagnosis of moderate to severe 
COPD, with a postbronchodilator FEV1/FVC < 70% and 30% ≤FEV1 < 80% predicted at 
screening. Medical records will be reviewed whenever possible. In cases where the 
investigator decides that COPD is the predominant diagnosis (and that the subject is to be 
included), his/her reasoning shall be explained in a note to the subject’s study file.
Additionally, the following information will be obtained: BMI, grade on the mMRC Dyspnea 
Scale at screening and smoking history.
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease
Subjects must have clinical diagnosis of moderate to severe COPD, with a postbronchodilator 
FEV1/FVC < 70% and 30% ≤ FEV1 < 80% predicted at screening; general stable health with 
no change in medication (including non-COPD agents) and no exacerbations or hospitalization 
within 6 weeks prior to screening; and grade of ≥ 2 on the mMRC Dyspnea Scale 
[Appendix 12.8] at screening.
5.3
Efficacy | Exploratory | Pharmacokinetics Assessment
5.3.1
Efficacy Assessment
Refer to the Study Procedure Manual for details regarding the individual assessments for 
testing subject endurance. The efficacy assessments will be performed per the Schedule of 
Assessments [Table 1].


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5.3.1.1 IET and CWR
Subjects will perform IET and a CWR exercise test on a cycle ergometer. IET will be 
performed at screening visit 1 and characterizes the subject and determines the WR to use for 
CWR exercise test.  The IET will be performed only once and characterizes the subject’s 
aerobic capacity (VO2 peak), lactate threshold, ventilatory efficiency (VE/VCO2 nadir) and 
peak WR.  The IET will not be repeated. At screening visit 2, the CWR test will be 
completed at least 24 hours after the IET.  Additionally the CWR test will be performed at 
treatment period 1 (visits 4 and 6) and treatment period 2 (visits 7 and 9). 
In this protocol, a Vmax breath-by-breath metabolic measurement system with integrated 
12-lead ECG and cycle ergometer will be used. All variables are recorded breath-by-breath 
in the cardiopulmonary exercise testing system. Blood pressure, IC, as well as Borg CR10 
score ratings of dyspnea and leg discomfort, are recorded at isotime and peak during the 
CWR test.  Blood pressure is measured manually by auscultation. These values are manually 
entered into the electronic Vmax record of in the metabolic system during the test.
The ergometer is computer controlled by the metabolic system and delivers the desired WR 
profile (IET or CWR). The ECG is monitored continuously; heart rate is derived beat-by-
beat from the ECG.  A 12-lead configuration for the initial IET will be used, so that a full 
diagnostic recording can be made. In CWR tests, a 3-lead configuration will be used. The 
ECG is stored in the integrated software program, which facilitates analyses such as 
arrhythmias and ST segment changes.  A test’s ECG can be stored in full (the full beat-by-
beat record) or a summary form.  Heart rate is recorded to the breath-by-breath record in the 
Vmax breath-by-breath metabolic measurement system. Generally, the subject will have 
about 5 minutes of recovery recorded (i.e., with mouthpiece in place and ECG being 
recorded).
The selection of the work rate for the initial testing has to be individualized to the subject’s 
exercise tolerance [Casaburi R, 2005]. Establishing a period baseline duration for all subjects 
(normalized to within the 4 to 8 minute limit) allows for the correct interpretation of the 
change in post-treatment intervention exercise duration among different individuals’ ERS 
Statement [Puente-Maestu et al, 2016].
CWR time to intolerance (endurance time) is assessed by a stopwatch.  This is verified from 
the electronic record of the power output on the cycle ergometer.
5.3.1.2 EMG
EMG will be performed at treatment period 1 (visits 4 and 6) and treatment period 2 (visits 7 
and 9).  Surface accessory muscle EMG activity will be measured during the exercise test.  
Surface electrodes are applied during the set-up for the exercise test; their application takes 
10 minutes. The continuous time course of the EMG from each electrode is recorded for 
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5.3.1.3 Borg CR10 
Borg CR10 will be conducted during screening (visit 2).  Additionally Borg CR10 will be 
performed at treatment period 1 (visits 4 and 6) and treatment period 2 (visits 7 and 9).
The 10-item Borg Scale [Borg et al, 1982] is a simple method of rating perceived exertion 
(RPE) and collects information on perceived exertion in an individual's rating of exercise 
intensity [Appendix 12.9].  The Borg CR10 will be administered and scored by the 
investigator or delegated research staff. Subjects will be asked to use this scale to rate the 
intensity of their breathing and leg discomfort before, during, and after exercise.
5.3.1.4 Physical Activity
Physical activity will be measured by an online 12-item PRO questionnaire (7-day recall
[C-PPAC]) which has to be completed at the site. Physical activity is assessed by questions 
targeted at the amount of physical activity and perceived difficulty during physical activity.
The European Union Innovative Medicines Initiative PROactive project [Gimeno-Santos et 
al, 2015] conducted qualitative research and drafted a conceptual framework to set out the 
concept of physical activity from patients’ experiences and to provide the necessary basis to 
generate an item pool for 2 PROs, 1 with a daily recall period and 1 with a 7-day recall 
period (daily and clinical visit versions, respectively) to measure the experience of physical
activity in patients with COPD.
5.3.1.5 Spirometry
Spirometry will be performed at screening visit 1, treatment period 1 (visits 4 and 6), 
treatment period 2 (visits 7 and 9) and FUV (visit 10).  Spirometry measures the volume of 
air exhaled at specific time points during a forceful and complete exhalation after a maximal 
inhalation (i.e., the total exhaled volume, known as FVC, the volume exhaled in the first 
second, known as FEV1, and their ratio [FEV1/FVC] are measured). Spirometry will be 
performed according to ATS guidelines. Resting spirometry is measured before exercise but 
after inhalation of albuterol.  It is measured at approximately the same time of day, at the 
same duration after the subject’s morning dose of normal bronchodilator medications.  This
is also to confirm whether the drug affects pulmonary function in subjects.  Also, a marked 
variation (especially a worsening) would be a sign that the subject is not in a stable state or 
may be suffering an exacerbation.
5.3.2
Exploratory Assessment
5.3.2.1 MIP and MEP
Respiratory muscle strength tests, MIP and MEP will be performed at treatment period 1 (visits 
4 and 6) and treatment period 2 (visits 7 and 9).  MIP is the maximum negative pressure that 
can be generated from 1 inspiratory effort starting from functional residual capacity (FRC) or 
RV.  In this study, the test will be performed from a maximal exhalation to RV.  MEP 
measures the maximum positive pressure that can be generated from 1 expiratory effort starting 
from TLC.  Unlike inspiratory muscles, expiratory muscles (abdominal and thoracic muscles) 
reach their optimal force–length relationship at large pulmonary volumes. MIP reflects the 


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strength of the diaphragm and other inspiratory muscles, while the MEP reflects the strength of 
the abdominal muscles and other expiratory muscles as well as lung and chest wall elastic 
rebound.
5.3.2.2 SGRQ-C
The SGRQ-C [Jones PW et al, 1991; Jones PW et al, 1992; Merguro M et al, 2007] will be 
performed at treatment period 1 (visits 4 and 6) and treatment period 2 (visits 7 and 9). The 
SGRQ-C was developed from the SGRQ which was designed to measure health impairment 
in patients with asthma and COPD. The SGRQ-C was developed using COPD data only, and 
this version is shorter with 40 items (14 questions) compared to the original 50 items.  The 
questionnaire is designed for supervised self-administration, site staff will be available to 
ensure the subject completes the questionnaire. The questionnaire will be administered 
electronically. The SGRQ-C will be scored by Astellas using an excel-based scoring system 
provided by St. George’s University of London.  
5.3.2.3 SF-36
The SF-36 will be performed at treatment period 1 (visits 4 and 6) and treatment period 2 
(visits 7 and 9). The questionnaire will be self administered by subject electronically at the 
site.  SF-36 was designed for use in clinical practice and research, health policy evaluations 
and general population surveys.  
The SF-36 is a QoL instrument designed to assess generic health concepts relevant across 
age, disease, and treatment groups. It is aimed at both adults and adolescents aged 18 years 
and older. It has been used in a range of diseases (non-disease specific).
The SF-36 consists of 8 domains of health status: Physical functioning (10 items), 
Role-physical (4 items), Bodily pain (2 items), General health (5 items), Vitality (4 items), 
Social functioning (2 items), Role emotional (3 items) and Mental health (5 items).  Two 
component scores, the Physical Component Summary and the Mental Component Summary 
can also be calculated. 
For both the SF-36 domain scores and summary scores, higher scores indicate better health 
status. The SF-36 has a recall period of the ‘past 4 weeks’.
The SF-36 will be scored by quality metrics.
5.3.2.4 SPPB
SPPB will be performed at treatment period 1 (visits 4 and 6) and treatment period 2 (visits 7 
and 9).  SPPB is a simple test to measure lower extremity function using tasks that mimic 
daily activities; static balance, gait speed and getting in/out of a chair.
The SPPB score is based on timed measures of standing balance, walking speed and ability to 
rise from a chair.  For the balance test, subjects will be asked to maintain their feet in side-
by-side, semi-tandem (heel of 1 foot beside the big toe of the other foot) and tandem (heel of 
1 foot in front and touching the other foot) positions for 10 seconds each. Walking speed 
will be assessed by asking subjects to walk at their usual pace over a 4-meter course. Two 


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walk times will be recorded, and the faster of the 2 will be used to compute the walking test 
score. For the chair test, subjects will be asked to stand up from a sitting position with their 
arms folded across the chest. If subjects are able to perform this task, they will be asked to 
stand up and sit down 5 times as quickly as possible, and the time to perform the test will be 
recorded.  Each of the 3 performance measures will be assigned a score ranging from 0 to 4, 
with 4 indicating the highest level of performance and 0 the inability to complete the test.  A 
summary score (range 0 to 12) will be subsequently calculated by adding the 3 scores.  For 
the test of balance, subjects will be assigned the following scores: 1 if they could only hold a 
side-by-side standing position for 10 seconds; 2 if they could hold a semi-tandem position for 
10 seconds, but were unable to hold a full-tandem position for more than 2 seconds; 3 if they 
could stand in a full-tandem position for 3 to 9 seconds; and 4 if they could stand in a full-
tandem position for 10 seconds [Guralnik et al, 1994].
5.3.3
Pharmacokinetics Assessment
Blood samples to assess the pharmacokinetics of CK-2127107 and possible metabolite(s) (if 
applicable) are to be predose collected on day 1 of treatment period 2, day 14 and end of 
treatment (EOT) and 6 hours postdose on day 14 and EOT.
5.4
Safety Assessment
The safety assessments include the following and will be performed per the Schedule of 
Assessments [Table 1]:
1.
AEs/SAEs are to be assessed at every visit.
2.
A 12-lead ECG will be performed at screening and at visits 4, 6, 7, 9 and 10.
3.
The following clinical laboratory tests will be collected at screening and visits 4, 5, 6, 7, 
8, 9 and 10:
o
Serum chemistry
o
Hematology (excluding visits 5 and 8)
o
Urinalysis (excluding visits 5 and 8)
4.
A standard urine drug screen and alcohol screen will be performed at screening and day 1 
of each treatment period.
5.4.1
Vital Signs
Vital signs include blood pressure, heart rate and body temperature.
5.4.2
Adverse Events
See [Section 5.5] for information regarding AE collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin
See [Appendix 12.3] for detailed information on liver abnormalities, monitoring and 
assessment, if the AE for a subject enrolled in a study and receiving study drug is accompanied 
by increases in liver function tests (LFTs; e.g., AST, ALT, bilirubin, etc.) or is suspected to be 
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Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.
5.4.2.2 Adverse Events of Possible Renal Origin
See [Appendix 12.4] for details.  Subjects shall be discontinued from the study drug should 
their serum creatinine demonstrate an increase of 1.5 to 2.0 times above baseline (CTCAE 
grade 1) in concordance with an increase in serum cystatin C levels.  
5.4.3
Laboratory Assessments
[Appendix 12.6] lists the laboratory tests that will be performed during the conduct of the 
study.  See the Schedule of Assessments [Table 1] for study visit collection dates. 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/subinvestigator who is a qualified physician.
5.4.4
Physical Examination
A full physical examination will be performed at screening visit 1 and follow-up visit 10. Body 
systems to be evaluated include general appearance, skin, lymphatic, head and neck, ears, nose 
and throat, chest and lungs, cardiovascular, abdomen, extremities, musculoskeletal, and 
neuromuscular. At the visits 4, 6, 7, and 9, a symptom-directed physical exam will be 
performed.  
Any clinically relevant abnormality at screening will be recorded as medical history. Any 
clinically relevant change from baseline to visit 10/FUV will be recorded as an AE in the 
eCRF. Documentation that an exam has occurred needs to be reflected in the site source 
documents. 
Screening physical examination is to be conducted in person by a physician. Remaining 
physical examinations can be symptom-directed and delegated to a Nurse Practitioner or 
Physician Assistant (if the study physician is unavailable) and signed off by the study 
physician.  
5.4.5
Electrocardiogram (ECG)
A standard 12-lead ECG will be conducted at screening and on visits 4, 6, 7, 9 and 10.  
Specific attention will be given to the ST segment at screening to assess eligibility for this 
study. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs) and transmitted 
electronically for central reading.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can 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. 


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Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the electronic case report form (eCRF) 
accordingly.  
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical examination) should be defined as 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 investigator.
5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death).
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, should also 
usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)


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●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject exposure to 
the Sponsor medicinal product [e.g., name confusion])
All of the events of interest noted above should be recorded on the eCRF.  Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ on the SAE worksheet. 
The Sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per this classification as “always serious,” 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration which makes a causal 
relationship improbable, and/or in which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on re-administration 
(rechallenge) or withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:
●
Mild: 
No disruption of normal daily activities
●
Moderate:
Affect normal daily activities
●
Severe: 
Inability to perform daily activities
5.5.5
Reporting of Serious Adverse Events (SAEs)
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
signed informed consent form (ICF) and will continue to 30 days after last dose of study 
drug. In the case of an SAE, the investigator must contact the Sponsor by telephone, email or 
fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 


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24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel.  Please email 
or fax the SAE Worksheet to:
Astellas Pharma Global Development – United States
Pharmacovigilance
Fax number: 1-888-396-3750
North America Alternate Fax: 1-847-317-1241
International Fax Number:  +44-800-471-5263
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel).
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
International Study Number (ISN)/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies (i.e., FDA) as necessary, and will inform the investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 
IRB/IEC within timelines set by regional regulations (i.e., EU, (e)CTD, FDA).  Documentation 
of the submission to and receipt by the IRB/IEC of expedited safety reports should be retained 
by the site.
The Sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SAEs which require submission per local requirements of the IRB/IEC 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
Investigators and study personnel may contact the Sponsor's Medical Monitor/Expert for any 
other problem related to the safety, welfare, or rights of the subject.
For Suspected Unexpected Serious Adverse Reactions (SUSAR) from a blinded trial, 
unblinded CIOMS-I report will be submitted to the authorities and IRB/IEC where required.


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5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor. 
Please refer to [Appendix 12.3] for detailed instructions on Drug-Induced Liver Injury (DILI).
5.5.7
Monitoring of Common Serious Adverse Events
For this protocol, there is no list of common SAEs anticipated for the study population for the 
purposes of IND safety reporting [Appendix 12.5].
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 10 weeks from the discontinuation of dosing, the investigator should report 
the information to the Sponsor as if it is an SAE.  The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated conception date, pregnancy 
result and neonatal data etc., should be included in this information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure 
for SAEs.  Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant should be 
evaluated at the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the Sponsor as an SAE.


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5.5.9
Emergency Procedures and Management of Overdose
No cases of overdosing have occurred thus far.  In case of accidental overdose, 
symptom-directed supportive care is advised. It is not known whether CK-2127107 is 
dialyzable, and no antidote for CK-2127107 currently exists. The Medical Monitor/Expert 
should be contacted as applicable.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study properly, 
the Sponsor will inform all investigators involved in the clinical study as well as the regulatory 
authorities. Investigators should inform the IRB/IEC of such information when needed.
5.6
Study Drug Concentration
Blood samples for pharmacokinetics of CK-2127107 and possible metabolite(s) (if 
applicable) will be collected from every subject.
A single pharmacokinetic sample will be collected at each of the following time points [Table 3].
Table 3
Pharmacokinetic Timepoints
Time window
Time point
-14 hours
Prior to evening dose at day 1 of treatment period 2
-15 min
Prior to morning dose (trough) at day 14 of both treatment period 1 and 2
±15 min
Approximately 6 hours post-morning dose at day 14 of both treatment period 1 and 2
Details on sampling, processing, storage and shipment procedures will be provided in a 
separate central laboratory manual. Bioanalysis of CK-2127107 and possible metabolite(s) 
(if applicable) will be performed using a validated liquid chromatography with tandem mass 
spectrometry method.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis)
A pharmacogenetic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics and toxicity/safety issues. A PGx 
sample is to be collected 1 time prior to first dose at day 1 of treatment period 1 [see Table 1] a 
4 mL sample of whole blood for possible retrospective PGx analysis will be collected using a 
vacutainer tube containing EDTA. After collection, gently invert the blood sample 8 to 
10 times. The blood collection tube may either be stored upright at 4°C for up to 5 days prior 
to shipment or stored frozen at -20°C or below at the site for extended storage. Samples will 
be shipped to a Sponsor-designated banking contract research organization (CRO).
Labels should uniquely identify each sample and contain at least:
●
Protocol number (3318-CL-3002),
●
Subject number;
●
Purpose and biological matrix (i.e., “biobanking”, “whole blood”)


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Subject participation in the pharmacogenomics sample collection is optional, subjects 
choosing to participate will be required to sign a separate ICF. 
Details on sample collection, labeling, storage and shipment procedures will be provided in 
the central laboratory manual.
See [Appendix 12.7] for further details on the banking procedures.
5.7.2
Exploratory Biomarker Analysis Using Metabolomics and Proteomics
Plasma samples remaining after the completion of bioanalysis of CK-2127107 and possible 
metabolite(s) (if applicable) may be used for an optional exploratory biomarker analysis 
using metabolomics and proteomics for subjects who sign a separate ICF. The purpose of the 
exploratory analysis is to evaluate the correlation between CK-2127107 drug response and 
proteomic and/or metabolome profile.  
5.8
Total Amount of Blood
A total volume of approximately 216 mL of blood per subject will be collected for laboratory 
evaluations:
●
A total volume of approximately 106 mL of blood will be collected for laboratory 
evaluations.
●
Approximately 75 mL will be collected for safety laboratory evaluation (serum pregnancy 
test draws are included in this total).
●
Approximately 30 mL will be collected for CK-21271017 pharmacokinetic evaluation.
●
Approximately 4 mL will be collected for pharmacogenetics testing (optional).
The maximum volume of blood collected at a single visit is approximately 25 mL of blood.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or the study for any reason and 
at any time without giving a reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the subject from study treatment and to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it.
If a subject withdraws from active participation in the study (i.e., randomized and receiving 
study drug), the subject should be asked to complete the early discontinuation (ED) visit and 
return 7 days after ED visit for a FUV to assess safety and to return study drug that was 
provided.
This FUV should take place 7 days after the most recent study visit (ED) and follow the 
assessments as specified in the Schedule of Assessments [Table 1].  Study site personnel 
must document all assessments in the site’s source documents.


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If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
A subject should be considered for discontinuation, if:
1. The subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject,
2. The subject withdraws consent for further treatment,
3. A liver abnormality occurs [see Appendix 12.3],
4. A renal abnormality occurs [Appendix 12.4],
5. The subject is noncompliant with the protocol based on the investigator or medical 
monitor assessment,
6. The subject experiences an AE, clinical laboratory abnormality, intercurrent illness or 
significant worsening of intercurrent illness which, in the opinion of the Investigator, 
indicates that continued participation in the clinical study is not in the best interest of the 
subject.
The Sponsor or delegated CRO should be consulted for all cases mentioned above.
A clear and concise reason for discontinuation should be recorded in the eCRF.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US. A 
statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized 
before the database soft lock at the latest. Any changes from the analyses planned in SAP 
will be justified in the clinical study report (CSR).
Prior to Database Lock, a Final Review of Data and TLFs Meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 


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documented.  A meeting to determine analysis set classifications may also be held prior to 
database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median, and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
A sample size of 40 subjects will provide 84% power to detect a difference of 60 seconds in 
CWR duration from period baseline for CK-2127107 versus placebo with a 1-sided alpha 
error of 0.05, assuming the standard deviation for change from period baseline is 
100 seconds.  In order to maintain the statistical power of 80%, approximately 36 subjects 
would need to complete period 1.  Should the discontinuation rate in the first treatment 
period exceed 10% (approximately 5 subjects), additional subjects will need to be recruited
to account for the discontinued subjects.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock except 
Pharmacokinetic Analysis Set (PKAS).  The allocation of subjects to PKAS will be 
determined after database hard lock. 
7.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug and have at least 1 baseline measurement and 1 post baseline 
measurement within a period. Subjects will be included in the treatment arm based on actual 
treatment received.  This will be the primary analysis set for efficacy analyses.
7.2.2
Safety Analysis Set
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least 1 dose of study drug.  Subjects will be included 
in the treatment arm based on actual treatment received.
7.2.3
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least 
1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling is 
known.
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment sequence 
group for the FAS, SAF and PKAS.  Descriptive statistics will include number of subjects, 
mean, standard deviation, minimum, Q1, median, Q3 and maximum for continuous endpoints, 
and frequency and percentage for categorical endpoints. 


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7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS.  The interpretation of results from statistical 
tests will be based on the FAS.  
7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The primary endpoint is the difference in change from period baseline in CWR endurance time
at the end of each period. The primary analysis for the change from period baseline in CWR 
endurance time will be a mixed effect model with subject as a random effect and treatment and 
period as fixed effects. A mixed effect model is a standard model for a crossover study. It 
improves efficiency by taking in to account both within-subject and between-subject variances. 
Two-sided 90% confidence interval will be provided based on this model.  In addition, 
statistical tests will be performed based on the model. The hypothesis for comparisons is given 
as follows:
H0: The change from baseline at the end of period for CK-2127107 and placebo are the 
same
H1: The change from baseline at the end of period for CK-2127107 and placebo are not 
the same
Comparisons will be performed at a 2-sided 0.10 significance level.  The primary analysis 
will use the FAS.
7.4.1.2 Sensitivity Analysis
The same analysis of the primary endpoint as described in [Section 7.4.1.1] will be conducted 
with a model that adds carry-over as a fixed effect to the primary analysis model.
7.4.1.3 Subgroup Analysis
The analysis of the primary variable will be repeated separately by gender and age group. 
Other subgroup analyses might be added to the SAP.
7.4.2
Analysis of Secondary Endpoints 
Analysis of secondary endpoints will be performed based on similar model with the primary 
endpoint. The analysis set will be the FAS.
7.4.3
Analysis of Exploratory Endpoints 
Analysis will be performed based on similar model with the primary endpoint. The analysis 
set will be the FAS. 
7.5
Analysis of Safety
Safety analysis will be performed using the SAF.


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7.5.1
Adverse Events 
AEs will be coded using MedDRA.  The number and percentage of AEs, SAEs, AEs leading 
to discontinuation, and AEs related to study drug will be summarized by system organ class, 
preferred term and treatment.  The number and percentage of AEs by severity will also be 
summarized. All AEs will be listed.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from period baseline by treatment and time point. Shifts relative to 
normal ranges from baseline to each time point during treatment period in laboratory tests 
will also be tabulated.  Laboratory data will be displayed in listings.
7.5.3
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from period 
baseline by treatment and time point.  Vital signs data will be displayed in listings.
7.5.4
ECGs
The number and percentage of subjects with normal and abnormal results as assessed by 
12-lead central ECG will be tabulated by treatment and time point.  Number and percentage 
of subjects with 12-lead ECG abnormalities will be summarized by treatment group and time 
point.  The 12-lead ECG results will be displayed in data listings.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (e.g., number of subjects, mean, standard deviation, minimum, median, 
maximum, coefficient of variation and geometric mean) will be provided for pharmacokinetic 
parameter (day 14 Ctrough and C6h and day 1 [only for treatment period 2] predose plasma 
concentration) of CK-2127107 and possible metabolite(s) (if applicable).
7.7
Protocol Deviations and Other Analyses
7.7.1
Protocol Deviations
Protocol deviations as defined in [Section 8.1.6] will be summarized for all randomized 
subjects by treatment sequence and total as well as by site. A data listing will be provided by 
site and subjects.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment,
PD5 – Plasma samples were not drawn.


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7.7.2
Other Analyses
Exploratory biomarker analysis evaluating the correlation between proteomic and/or 
metabolomic profiles and CK-2127107 drug response will be specified in a separate analysis 
plan.  Any results will be summarized in a report separate from the CSR.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Missing efficacy data will not be imputed.
See the SAP for details of the definitions for visit time windows to be used for analyses by 
visit.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an electronic data capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within 10 days after the subject visit. 
The investigator or site designee is responsible to ensure that all data in the eCRFs and queries 
are accurate and complete and that all entries are verifiable with source documents. These 
documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that there 
are no inconsistencies between them.
Laboratory tests are performed at a central laboratory. Laboratory data will be transferred 
electronically to the Sponsor or designee at predefined intervals during the study.  The 
laboratory will provide the Sponsor or designee with a complete and clean copy of the data. 
ECG results are performed at a central ECG reading facility.  Central ECG read data will be 
transferred electronically to the Sponsor or designee at predefined intervals during the study.  
The central ECG laboratory will provide the Sponsor or designee with a complete and clean 
copy of the data.
For screen failures, the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.


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ePRO:
Subject diaries and questionnaires will be completed by the subject on an electronic device 
(ePRO).  The information completed by the subject on the electronic device will be 
automatically uploaded into a central website. The investigator or site designee should review 
the diaries and questionnaire data on the website for confirmation of transmittal while the 
subject is at the site.  The diary and questionnaire data will be transferred electronically to the 
Sponsor or designee at predefined intervals during the study.  The vendor, ERT, will provide 
Sponsor or designee with a complete and clean copy of the data.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and to 
substantiate the integrity of study data collected.  Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated ICFs
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data (as specified in the protocol)
●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Test assessment printouts: CWR, IET, MIP,MEP, SPPB and physical activity
●
Site created source document for spirometry
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable) 
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/subinvestigator are accurate and complete and that they are verifiable with study-
related records such as source documents. The Sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring. They will monitor the study in accordance with 
planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The investigator and the site must accept monitoring and auditing by the Sponsor or delegated 
CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. In these 


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instances, they must provide all study-related records, such as source documents [refer to
Section 8.1.2] when they are requested by the Sponsor monitors and auditors, the IRB/IEC, or 
regulatory authorities.  The confidentiality of the subject's identities shall be well protected 
consistent with local and national regulations when the source documents are subject to direct 
access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management. All study specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA and 
WHO Drug Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who:
●
Entered into the study even though they did not satisfy entry criteria
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose
●
Received excluded concomitant treatment
●
Plasma samples were not drawn
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / or 
efficacy of the subject to determine subject continuation in the study.
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the trial master file.  


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NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as applicable.
8.1.7
End of Trial in All Participating Countries
The end of study in all participating countries is defined as the last subject’s last visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
The clinical study may begin after acquisition of a written approval from IRB/IEC.
GCP requires that the clinical protocol, any protocol amendments, the IB, the ICF and all other 
forms of subject information related to the study (e.g., advertisements used to recruit subjects) 
and any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  IEC/IRB 
approval of the protocol, informed consent and subject information and/or advertising, as 
relevant, will be obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to both 
responsible Ethics Committees and regulatory agencies, as required.  During the conduct of the 
study, the investigator should promptly provide written reports (e.g., ICH Expedited Reports 
and any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects. Written documentation of 
the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies after last subject out  or termination of the 
study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that have 
their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior to 
any study-related screening procedures being performed on the subject, the informed consent 


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statement will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements.  A copy of the signed ICF will be given to the subject and the 
original will be placed in the subject’s medical record.  An entry must also be made in the 
subject’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF.  A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record.  An entry must be made in the subject’s records documenting the re-
consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited.  Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the Sponsor.  
However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.


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The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., HIPAA).
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
Sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the Sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she has 
an obligation to provide the Sponsor with all data obtained during the study.
Publication of the study results is discussed in the clinical study agreement.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., subject identification code list, source data, 
electronic data sources, and Investigator's File) and relevant correspondence.  These 
documents are to be kept on file for the appropriate term determined by local regulation (for 
US sites, 2 years after approval of the NDA or discontinuation of the IND).  The Sponsor will 
notify the site/investigator if the NDA/MAA/J-NDA is approved or if the 
IND/IMPD/CHIKEN TODOKE is discontinued.  The investigator agrees to obtain the 
Sponsor's agreement prior to disposal, moving, or transferring of any study-related records. 
The Sponsor will archive and retain all documents pertaining to the study according to local 
regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. Data will be entered on the eCRFs supplied for 
each subject.
The investigator and Sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments.  
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).  
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 


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which affects subject safety or the evaluation of safety, and/or efficacy or pharmacokinetics.
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations.
If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File. 
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study.  The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory
documents, eCRFs and source documents. Direct access to these documents will be required 
by the auditors.


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10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s)
Not applicable.
10.2
Other Study Organization
Not applicable.


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11
REFERENCES 
Agarwal R. Creatinine clearance with cimetidine for measurement of GFR. Lancet. 
1993;341(8838):188.
Aguilaniu B. Impact of bronchodilator therapy on exercise tolerance in COPD. Int J Chron Obstruct 
Pulmon Dis. 2010;5:57-71.
Borel B, Provencher S, Saey D, Maltais F. Responsiveness of various exercise-testing protocols to 
therapeutic interventions in COPD. Pulm Med. 2013;2013:410748.
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377-81.
Casaburi R. Factors determining constant work rate exercise tolerance in COPD and their role in 
dictating the minimal clinically important difference in response to interventions. COPD. 
2005;2:131-6.
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory capacity and 
hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest. 
2003;124:1743–8.
Ducharme MP, Smythe M, Strohs G. Drug-induced alterations in serum creatinine concentrations. Ann 
Pharmacother. 1993;27(5):622-33.
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity reduces hospital 
admission and mortality in chronic obstructive pulmonary disease: a population based cohort
study. Thorax. 2006;61:772-8.
Gimeno-Santos E, Raste Y, Demeyer H, Louvaris Z, de Jong C, Rabinovich RA, et al. The PROactive 
instruments to measure physical activity in patients with chronic obstructive pulmonary disease. 
ERJ Express. 2015 Jun 11;1-13. doi:10.1183/09031936.00183014. Available from: 
http://www.proactivecopd.com/.
Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical 
performance battery assessing lower extremity function: association with self-reported disability 
and prediction of mortality and nursing home admission. J Gerontol. 1994;49:M85-94.
Hilbrands LB, Wetzels JF, Koene RA. Creatinine clearance with cimetidine for measurement of GFR. 
Lancet. 1993;341(8838):187-8.
Jones PW, Quirk FH, Baveystock CM. The St. George’s Respiratory Questionnaire. Respir Med. 
1991;85(Suppl B):25-31.
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for 
chronic airflow limitation - the St George’s Respiratory Questionnaire. Am Rev Respir Dis. 
1992;145:1321-7.
Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigarè R, et al. An official American 
Thoracic Society/European Respiratory Society Statement: update on limb muscle dysfunction in 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189:e15-62.


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Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an improved, COPD –
specific version of the St. George Respiratory Questionnaire. Chest. 2007;132:456-63.
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of 
spirometry. Eur Respir J. 2005;26:319-38.
O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to 
exercise in chronic obstructive pulmonary disease. Eur Respir J. 2004;24:86–94.
Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in 
chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir 
Crit Care Med. 2003;167;544-9.
Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda A, Isumi T. The effects of oxitropium bromide on 
exercise performance in patients with stable chronic obstructive pulmonary disease. A 
comparison of three different exercise tests. Am J Respir Crit Care Med. 2000;161:1897-1901.
Palange P, Valli G, Onorati P, Antonucci R, Paoletti P, Rosato A, et al. Effect of heliox on lung 
dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl 
Physiol. 2004;97:1637-42.
Payne RB. Creatinine clearance with cimetidine for measurement of GFR. Lancet. 1993;341(8838):187.
Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, et al. Use of exercise 
testing in the evaluation of interventional efficacy: An Official ERS Statement. Eur Respir J.
2016;47:429-60.  doi:10.1183/13993003.00745-2015.
Ribeiro F, Thériault M-E, Debigaré R, Maltais F. Should all patients with COPD be exercise trained? J 
Appl Physiol. 2013;114:1300-8.
Schutzer KM, Svensson MK, Zetterstrand S, Eriksson UG, Wahlander K. Reversible elevations of 
serum creatinine levels but no effect on glomerular filtration during treatment with the direct 
thrombin inhibitor AZD0837. Eur J Clin Pharmacol. 2010;66(9):903-10.
Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, et al. Safety, tolerability and 
pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph 
Lateral Scler. 2012;13:430-8.
van Acker BA, Koomen GC, Koopman MG, de Waart DR, Arisz L. Creatinine clearance with 
cimetidine for measurement of GFR. Lancet. 1993;341(8852):1089-90.
Waschki B, Kirsten A, Holz O, Müller KC, Meyer T, Watz H, et al. Physical activity is the strongest 
predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest. 
2011;140:331-42.
World Health Organization (WHO). Burden of COPD [Internet]. [cited 2015 Oct 14]. Available from: 
http://www.who.int/respiratory/copd/burden/en/.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications/Foods
CYP3A4
Strong Inhibitors
CYP3A4 Inducers
OCT1 Substrates
OCT2 Substrates
Indinavir
Carbamazepine
Oxaliplatin
Pindolol
Nelfinavir
Efavirenz
Dofetilide
Varenicline
Ritonavir
Nevirapine
Pilsicainide
Clarithromycin
Phenobarbital
Itraconazole
Phenytoin
Ketoconazole
Pioglitazone
Nefazodone
Rifabutin
Grapefruit juice
Rifampin
Seville oranges
St. John’s Wort
Troglitazone


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12.2
List of Concomitant Medication to be Used With Caution
OCT1 Substrates
OCT1/2 Substrates
Aciclovir
Metformin
Ganciclovir


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12.3
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN, or bilirubin > 2 × ULN, should undergo 
detailed testing for liver enzymes (including at least ALT, AST, ALP, and TBL).  Testing 
should be repeated within 48 to 72 hours of notification of the test results. For studies for 
which a central laboratory is used, alerts will be generated by the central laboratory regarding 
moderate and severe liver abnormality to inform the investigator, study monitor and study 
team.  Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 × ULN
or
> 2 × ULN
Severe*
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks  
●
ALT or AST > 3 × ULN and International Normalized Ratio (INR) > 1.5 (if INR testing 
is applicable/evaluated).
●
ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal LFTs, other than as described above, may 
qualify as moderate or severe abnormalities and require additional monitoring and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests.  The site should complete the liver abnormality 
case report form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document.  Subjects with confirmed abnormal LFTs should be 
followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly 
or less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as an SAE.  


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The Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases is to be recorded as ‘adverse events’ on the AE page of the eCRF.
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted.  Nonalcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic, and/or diabetic subjects and may 
be associated with fluctuating aminotransferase levels.  The investigator should ensure 
that the medical history form captures any illness that predates study enrollment that may 
be relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets.  Medications, including dose, are to be entered on the concomitant 
medication page of the eCRF.  Information on alcohol, other substance use and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history,  other testing may be appropriate including: 

Acute viral hepatitis (A,B, C, D, E or other infectious agents) 

Ultrasound or other imaging to assess biliary tract disease

Other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study.  The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment.  Discontinuation of treatment should be considered 
if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks 
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (if INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study drug should be discontinued.
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality 


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(or transplant).  The 2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
than 3 × the ULN (“2 × ULN elevations are too common in treated and untreated subjects to 
be discriminating”). 2) Cases of increased bilirubin (at least 2 x ULN) with concurrent 
transaminase elevations at least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated ALP) or Gilbert’s syndrome [Temple, 2006].
References
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241-3.


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12.4
Renal Safety Monitoring 
As noted in previous clinical studies with CK-2127107 have laboratory values for creatinine 
increased in a dose and concentration dependent fashion. The elevated values appear to 
slowly return toward normal and no associated symptoms or AEs were reported. It is 
possible that CK-2127107 or 1 of its metabolites may interfere with either the creatinine 
assay [Ducharme et al, 1993] or may inhibit the renal tubular secretion of creatinine, as has 
been reported with other drugs including cimetidine [Agarwal, 1993; Hilbrands et al, 1993; 
Payne, 1993; van Acker et al, 1993; Schutzer et al, 2010].  The inhibition of renal tubular 
OCT2 by CK-2127107 could also be a potential factor of increases in serum creatinine.
Subjects shall be discontinued from the study drug should their serum creatinine demonstrate 
an increase of 1.5 to 2.0 times above baseline (CTCAE grade 1) due to study druga in 
concordance with an increase in serum cystatin C levels.
References:
Agarwal R. Creatinine clearance with cimetidine for measurement of GFR. Lancet. 
1993;341(8838):188.
Ducharme MP, Smythe M, Strohs G. Drug-induced alterations in serum creatinine concentrations. 
Ann Pharmacother. 1993;27(5):622-33.
Hilbrands LB, Wetzels JF, Koene RA. Creatinine clearance with cimetidine for measurement of GFR. 
Lancet. 1993;341(8838):187-8.
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03. NCI, NIH, 
DHHS. NIH Publication #09-5410. June 14, 2010.
Payne RB. Creatinine clearance with cimetidine for measurement of GFR. Lancet. 
1993;341(8838):187.
Schutzer KM, Svensson MK, Zetterstrand S, Eriksson UG, Wahlander K. Reversible elevations of 
serum creatinine levels but no effect on glomerular filtration during treatment with the direct 
thrombin inhibitor AZD0837. Eur J Clin Pharmacol. 2010;66(9):903-10.
van Acker BA, Koomen GC, Koopman MG, de Waart DR, Arisz L. Creatinine clearance with 
cimetidine for measurement of GFR. Lancet. 1993;341(8852):1089-90.
                                                
a Patients should be evaluated first for potential other reasons of elevated serum creatinine and cystatin C levels 
(i.e., dehydration, concomitant medication or any underlying pathology that could explain the increase in renal 
markers).


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12.5
Common Serious Adverse Events
For this protocol, there is no list of common SAEs anticipated for the study population for the 
purposes of IND safety reporting.


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12.6
Clinical Laboratory Tests
Visit
Type
Analyte
Screening, Day 1, Day 6a, 
Day 14, EOT/ED, Follow-up
Biochemistry
Sodium
Potassium
Calcium
Chloride
Glucose
Creatinine
ALP
AST
ALT
GGT
TBL
Total protein
Albumin
BUN
Cholesterol
LDH
Magnesium
Phosphorus
Total CPK
Triglycerides
Uric acid
Cystatin C
Screening, Day 1, Day 14, 
EOT/ED, Follow-up
Urinalysis
Protein
Glucose
pH
Blood
Bilirubin
Ketones
Leukocytes
Nitrite
Urobilinogen
Specific Gravity
Screening, Day 1, Day 14, 
EOT/ED, Follow-up
Hematology
Hematocrit
Hemoglobin
MCH
MCV
MPV
Platelet count
Red blood cell distribution width
Red blood cell count
WBC count
WBC differential
Table continued on next page


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Visit
Type
Analyte
Screening, Day 1
Drug screening 
(Urine)
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Marijuana/Cannabinoids (THC)
Methadone
Opiates
Phencyclidine
Screening, Day1
Alcohol screening
Alcohol
Screening, EOT/ED, Follow-up
Pregnancy test
β-HCG
Screening
Serology
HBsAg
HCV antibody
HIV antibody
β-HCG: β-human chorionic gonadotropin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: 
aspartate aminotransferase; BUN: blood urea nitrogen; CPK: creatine phosphokinase; EOT: end of treatment; 
ED: early discontinuation; GGT: γ-glutamyl transferase; HBsAg: hepatitis B surface antigen; HCV: hepatitis C 
virus; HIV: human immunodeficiency virus; LDH: lactate dehydrogenase; MCH: mean corpuscular 
hemoglobin; MCV: mean corpuscular volume; MPV: mean platelet volume; TBL: total bilirubin; THC: 
tetrahydrocannabinol; WBC: white blood cell
a.
Serum samples for monitoring creatinine, BUN, cystatin C and liver enzymes (renal and liver safety 
assessments) will be collected on day 6.


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12.7
Retrospective PGx Substudy
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject.  Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood.  As many diseases may be influenced by 1 or more genetic variations, PGx 
research may identify which genes are involved in determining the way a subject may or may 
not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory.  The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx substudy.  
As part of this substudy, subjects must provide written consent prior to providing any blood 
samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this substudy will provide one 4-mL tube of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique subject number 
(first code).  Samples will be shipped frozen to a designated banking CRO either directly 
from site or via a central laboratory as directed by Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety. 
DISPOSAL OF PGx SAMPLES / DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed.  The results of any PGx analysis conducted on a sample prior to its withdrawal 
will be retained at Astellas indefinitely.


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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.


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12.8
mMRC Scale
The mMRC scale is a modification of the scale originally defined in 1959 by Fletcher et al as 
the first clinical scale for the determination of dyspnea.  It is a 5-point scale based on the 
sensation of breath difficulty experienced by the subject during daily life activities:
Grade
Description
0
I only get breathless with strenuous exercise.
1
I get short of breath when hurrying on the level or walking up a slight hill.
2
I walk slower than people of the same age on the level because of breathlessness, or 
I have to stop for breath when walking at my own pace on the level.
3
I stop for breath after walking about 100 meters or after a few minutes on the level.
4
I am too breathless to leave the house or I am breathless when dressing or 
undressing.
References
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, 
management, and prevention of chronic obstructive pulmonary disease (Updated 2015) 
[Internet]. [cited 2015 Oct 22].  Available from: http://www.goldcopd.org/.


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12.9
Borg CR10 
Rating of Perceived Exertion
Description
0
Complete rest
1
Very, very easy
2 
Easy
3
Moderate
4
Somewhat Hard
5
Hard
6
7
Very Hard
8
9
10
Extremely Hard (almost maximal)
---
Exhaustion
---: maximal
References
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5):377-81.


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13
ATTACHMENT 1:  NON-SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
1.
Remove Accelerometer Test and Leg Extension Strength Test
DESCRIPTION OF CHANGE:
Remove accelerometer test and leg extensor strength test from the exploratory objectives 
and endpoints.
RATIONALE:
To streamline assessments, exploratory endpoints that would not significantly contribute to 
the validity of the primary endpoint are removed.
2.
Increase Number of Study Sites
DESCRIPTION OF CHANGE: 
Revise the number of study sites to “approximately 4”.
RATIONALE:
The number of sites is amended to allow approximately 2 additional sites to participate in 
the study.
3.
Clarify Number of Subjects Randomized in the Study
DESCRIPTION OF CHANGE:
Specify that approximately 40 subjects “are planned to be randomized,” rather than “will 
be randomized.”
RATIONALE:
This change is made to allow for recruitment of additional subjects if the discontinuation 
rate in the first treatment period exceeds 5 subjects, in order to maintain the statistical 
power of 80%.
4.
Specify Assessment of Physical Activity
DESCRIPTION OF CHANGE:
Add language to specify that physical activity will be assessed using an online 12-item 
patient reported outcome (PRO) questionnaire (7-day recall clinical visit version of PRO 
active physical activity in COPD [C-PPAC]) due to the removal of the accelerometer.
RATIONALE:
The accelerometer test is removed from the protocol as specified in non-substantial change 
No. 1, therefore additional detail regarding continued use of the online 12-item PRO
questionnaire is added for clarification.


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5.
Update Physical Examination
DESCRIPTION OF CHANGE:
Revise Section 5.4.4. (Physical Examination) to state that a full physical examination will 
be performed at screening and visit 10, while a symptom-directed physical examination 
will be performed at the remaining visits 4, 6, 7, and 9.
RATIONALE:
This wording is updated to clarify at which visits the full physical examination is required 
and which visits will allow a symptom-directed exam, based on the discretion of the study 
physician.  Language is added to specify that a study physician (MD or DO) will be able to 
delegate this task to a nurse practitioner and/or physician assistant per institutional policy. 
6.
Revise Definition of Full Analysis Set
DESCRIPTION OF CHANGE:
Revise the definition of Full Analysis Set (FAS) to state that subjects will be included in 
this treatment arm based on actual treatment received.
RATIONALE:
The purpose of the study is to understand the action of the study drug; therefore, it is more 
meaningful to include subjects in the FAS based on treatment received.
7.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol) and update the List of Abbreviations, Flow Chart, and Schedule 
of Assessments.  
RATIONALE:
These changes are made to provide clarifications to the protocol and to ensure complete 
understanding of study procedures.


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II. Amendment Summary of Changes:
IV Synopsis, Study Objective(s) and 2 Study Objective(s), Design and Endpoints
2.1 Study Objectives
WAS:
Secondary Objectives
●
To assess cardiopulmonary and neuromuscular effects of CK-2127107 relative to 
placebo on:
o The change from period baseline in oxygen uptake (VO2), ventilation (VE), 
ventilatory equivalent for carbon dioxide (VE/VCO2) and other breath-by-breath 
cardiometabolic variables, inspiratory capacity (IC) and perceived exertion for 
dyspnea and leg discomfort (Borg CR10), at isotime and peak during CWR test
o Activation of accessory respiratory muscles (by electromyogram [EMG]) at isotime* 
and peak exercise during CWR test
●
To assess the effect of CK-2127107 on resting spirometry relative to placebo
●
To assess the safety and tolerability of CK-2127107
●
To assess the pharmacokinetics of CK-2127107
Exploratory Objectives
●
To explore the effects of CK-2127107 relative to placebo on:
o Patient reported outcomes (PROs) and physical activity assessed by an 
accelerometer
o Physical performance via a short physical performance battery (SPPB) and leg 
muscle strength via a leg extensor strength test (1 repetition maximum [1RM])
o Respiratory muscle strength by maximal inspiratory pressure (MIP) and maximal 
expiratory pressure (MEP)
*Isotime is the shortest duration of all of the CWR tests performed before and after 
treatment, not including screening.
IS AMENDED TO:
Secondary Objectives
●
To assess cardiopulmonary and neuromuscular effects of CK-2127107 relative to 
placebo on:
o The change from period baseline in oxygen uptake (VO2), ventilation (VE), 
ventilatory equivalent for carbon dioxide (VE/VCO2) and other breath-by-breath 
cardiometabolic variables, inspiratory capacity (IC) and perceived exertion for 
dyspnea and leg discomfort (Borg CR10), at isotime* and peak during CWR test
o Activation of accessory respiratory muscles (by electromyogram [EMG]) at isotime* 
and peak exercise during CWR test
●
To assess the effect of CK-2127107 on resting spirometry relative to placebo
●
To assess the safety and tolerability of CK-2127107
●
To assess the pharmacokinetics of CK-2127107
*Isotime is the shortest duration of all of the CWR tests performed before and after 


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treatment, not including screening.
Exploratory Objectives
●
To explore the effects of CK-2127107 relative to placebo on:
o Patient reported outcomes (PROs) and physical activity assessed by an 
accelerometer
o Physical performance via a short physical performance battery (SPPB) and leg 
muscle strength via a leg extensor strength test (1 repetition maximum [1RM])
o Respiratory muscle strength by maximal inspiratory pressure (MIP) and maximal 
expiratory pressure (MEP)
*Isotime is the shortest duration of all of the CWR tests performed before and after 
treatment, not including screening.
IV Synopsis, Number of Subjects to be Enrolled/Randomized
WAS:
Approximately 40 subjects will be randomized.
IS AMENDED TO:
Approximately 40 subjects are planned to will be randomized.
IV Synopsis, Planned Total Number of Study Centers and Location(s) and 3 Study 
Population
3.1 Selection of Study Population
WAS:
Approximately 40 subjects will be randomized to 1 of 2 treatment sequences in a crossover 
fashion.  Enrollment for this study will be at 1 to 2 sites in the United States and possibly 
Canada or the United Kingdom.
IS AMENDED TO:
Approximately 40 subjects are planned to will be randomized to 1 of 2 treatment sequences 
in a crossover fashion.  Enrollment for this study will be at 1 to 2 approximately 4 sites in 
the United States and possibly Canada or the United Kingdom.
IV Synopsis, Study Design Overview and 2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
WAS:
After the CWR test, subjects receive an accelerometer, physical activity will be monitored at 
home for 1 week using an accelerometer combined with a PRO during the screening period 
(between visit 2 and day -1). 
The CWR test will be completed at visit 2 at least 24 hours after the IET. The CWR exercise 
test will be performed at 80% peak WR (rounded to the nearest 5 watts). This screening test 
is used to confirm the correct WR selection for the rest of the study and to familiarize the 


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subject with the testing procedure.  Subjects are expected to tolerate this WR for durations in 
the range of 4 to 8 minutes. Establishing a WR that will achieve this specific duration is 
critical if constant work rate testing is deemed to detect treatment effects in interventional 
studies [Casaburi R, 2005; Puente-Maestu et al, 2016]. In the event that the tolerable 
duration is outside this range, a second CWR is performed within the next 5 days at ± 5 watts 
to determine whether this adjusted WR will result in an endurance time in the desired range.  
If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be 
classified as a screen failure and no additional assessments completed. Once the WR is 
established that leads to intolerance in 4 to 8 minutes, all subsequent tests use the WR that 
led to intolerance. No additional WR adjustments can be made once the WR intolerance 
level is set. 
At visit 3 subjects will return the accelerometer to the clinical unit and a weekly PRO 
assessment will be completed at the end of the 7-day activity monitoring using a 7-day recall 
online 12-item questionnaire. If the subject is not compliant, or for some unforeseen reason 
the accelerometer does not record correctly, the physical activity monitoring may be repeated 
in the screening period. Visit 3 will be considered optional if the subject successfully 
completes the CWR at visit 2.  Those subjects could also return the accelerometer and 
complete the weekly PRO assessment (C-PPAC) at visit 4.
On day 1 (visit 4) at baseline, all subjects will complete postbronchodilator spirometry, 
respiratory muscle strength tests (MIP and MEP), a resting ECG, CWR test (including 
breath-by-breath cardiometabolic measurements and respiratory muscle EMG), quality of life 
(QoL) assessments (St. George’s respiratory questionnaire for COPD patients [SGRQ-C] and 
short form-36 [SF-36]), a SPPB and a leg extensor strength test (1RM) to establish period 
baseline measurements, and will be randomly assigned to 1 of 2 treatment sequences in a 1:1 
ratio.
To achieve steady-state exposure to CK-2127107, subjects will receive CK-2127107 
(500 mg) or matching placebo twice daily for 14 days, except on day 1 and day 14.  On day 
1, subjects will take active or placebo drug once in the evening, and on day 14, subjects will 
take active or placebo drug once in the morning. Subjects will receive an accelerometer at 
visit 5, and physical activity will be monitored using the accelerometer and a combined PRO 
during the second week (days 7 to 13). At visit 5, subjects will also have renal and liver 
safety assessments.
IS AMENDED TO:
After the CWR test, subjects receive an accelerometer, physical activity will be monitored at 
home for 1 week using an accelerometer combined with a PRO during the screening period 
(between visit 2 and day 1). 
The CWR test will be completed at visit 2 at least 24 hours after the IET. The CWR exercise 
test will be performed at 80% peak WR (rounded to the nearest 5 watts). This screening test 
is used to confirm the correct WR selection for the rest of the study and to familiarize the 
subject with the testing procedure.  Subjects are expected to tolerate this WR for durations in 
the range of 4 to 8 minutes. Establishing a WR that will achieve this specific duration is 
critical if constant work rate testing is deemed to detect treatment effects in interventional 
studies [Casaburi R, 2005; Puente-Maestu et al, 2016]. In the event that the tolerable 
duration is outside this range, a second CWR is performed within the next 5 days at ± 5 watts 


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to determine whether this adjusted WR will result in an endurance time in the desired range.  
If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be 
classified as a screen failure and no additional assessments completed. Once the WR is 
established that leads to intolerance in 4 to 8 minutes, all subsequent tests use the WR that 
led to intolerance. No additional WR adjustments can be made once the WR intolerance 
level is set. 
At visit 3 subjects will return the accelerometer to the clinical unit and a weekly PRO 
assessment will be completed at the end of the 7 day activity monitoring using a 7 day recall 
online 12 item questionnaire.  If the subject is not compliant, or for some unforeseen reason 
the accelerometer does not record correctly, the physical activity monitoring may be repeated 
in the screening period.  Visit 3 will be considered optional if the subject successfully 
completes the CWR at visit 2.  Those subjects could also return the accelerometer and 
complete the weekly PRO assessment (C PPAC) at visit 4.
On day 1 (visit 4) at baseline, all subjects will complete postbronchodilator spirometry, 
respiratory muscle strength tests (MIP and MEP), a resting ECG, CWR test (including 
breath-by-breath cardiometabolic measurements and respiratory muscle EMG), quality of life 
(QoL) assessments (St. George’s respiratory questionnaire for COPD patients [SGRQ-C] and 
short form-36 [SF-36]), physical activity assessments (7-day recall 12-item 
questionnaire), and a SPPB and a leg extensor strength test (1RM) to establish period 
baseline measurements, and will be randomly assigned to 1 of 2 treatment sequences in a 1:1 
ratio.
To achieve steady-state exposure to CK-2127107, subjects will receive CK-2127107 
(500 mg) or matching placebo twice daily for 14 days, except on day 1 and day 14.  On day 
1, subjects will take active or placebo drug once in the evening, and on day 14, subjects will 
take active or placebo drug once in the morning. Subjects will receive an accelerometer at 
visit 5, and physical activity will be monitored using the accelerometer and a combined PRO 
during the second week (days 7 to 13).  At visit 5, subjects will also have renal and liver 
safety assessments.
IV Synopsis, Inclusion/Exclusion Criteria and 3 Study Population
3.2 Inclusion Criteria
WAS:
5.    Subject is able to complete technically acceptable respiratory muscle strength tests, 
spirometry, muscle strength test, physical performance test and exercise tests.
6.    Subject is willing to wear an accelerometer during waking hours in assigned periods 
during the study.
IS AMENDED TO:
5.    Subject is able to complete technically acceptable respiratory muscle strength tests, 
spirometry, muscle strength test, physical performance test and exercise tests.
6.    Subject is willing to wear an accelerometer during waking hours in assigned periods 
during the study. This criterion has been deleted.


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IV Synopsis, Endpoints for Evaluation and 2 Study Objective(s), Design and Endpoints
2.3.3 Exploratory Endpoints
WAS:
The exploratory endpoints are as follows:
●
Change from period baseline in QoL outcomes (SGRQ-C, SF-36) relative to placebo
●
Change from baseline in physical activity using the PROactive approach (DynaPort®©
accelerometer and combined PRO). This will be assessed during only the first treatment 
period. Therefore, this will represent the response to placebo for half the subjects and 
the response to the study drug for the other half of subjects.
●
Change from period baseline in physical performance tests battery score (SPPB) relative 
to placebo
●
Change from period baseline in leg muscle strength relative to placebo (as assessed by 
the maximal weight a subject can lift with 1 repetition [1RM])
●
Change from period baseline in MIP and MEP relative to placebo. This test is 
performed before exercise testing and is part of the resting assessment.
IS AMENDED TO:
The exploratory endpoints are as follows:
●
Change from period baseline in QoL outcomes (SGRQ-C, SF-36) relative to placebo
●
Change from baseline in physical activity using a 7-day recall online 12-item 
questionnaire. the PROactive approach (DynaPort®© accelerometer and combined 
PRO).  This will be assessed during only the first treatment period.  Therefore, this will 
represent the response to placebo for half the subjects and the response to the study drug 
for the other half of subjects.
●
Change from period baseline in physical performance tests battery score (SPPB) relative 
to placebo
●
Change from period baseline in leg muscle strength relative to placebo (as assessed by 
the maximal weight a subject can lift with 1 repetition [1RM])
●
Change from period baseline in MIP and MEP relative to placebo. This test is 
performed before exercise testing and is part of the resting assessment.
V Flow Chart and Schedule of Assessments
Table 1 Schedule of Assessments
WAS:
Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 
2
Follow-
up
Baseline 
for 
physical 
activity
Day
-
28 
to 
-9
-
27 
to 
-8
-26 to -1a
-19
to -
1
1
6
7 
to 
13
14
14 days
1
6 EOTb/
ED
7 days 
after 
EOT/ED
Window 
-
-
-
-
-
+3
-
+3
+7
-
+3
+3
+7
Visit Number
1
2
-
3c
4
5
-
6
-
7
8
9
10
Informed consent
X
Inclusion/Exclusion 
X
Medical history
X
X
X


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Demographics
X
Drug and alcohol 
screend
X
X
X
Randomization
X
Dispense/Collect 
study drug
X
X
X
X
Administration of 
study druge 
Physical 
examination
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Serum chemistries
X
X
Xg
X
X
Xg
X
X
Serology
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy 
test
X
X
X
Spirometryh
X
X
X
X
X
X
Respiratory muscle 
strength tests (MIP, 
MEP)
X
X
X
X
12-lead ECG
X
X
X
X
X
X
CWR exercise test
Xi
X
X
X
X
QoL outcomes 
(SGRQ-C, SF-36)
X
X
X
X
Physical 
performance test 
(SPPB)
X
X
X
X
Leg extensor 
strength test (1RM) 
X
X
X
X
IET
X
Supply acclerometer
Xj
X
Physical activity 
monitoring
(Accelerometer and 
PRO)k
Return 
accelerometer and 
complete PRO
X
X
X
Blood sampling for 
pharmacokineticsl
Predose6h
Predose
Predose 
6h
Optional blood 
sampling for 
pharmacogenomicsm
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
assessment
X
X
X
X
X
X
X
X
X
X
X
CWR: constant work rate; ECG: electrocardiogram; ED: early discontinuation; EOT: end of treatment; IET: 
incremental exercise test; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; PRO: patient 
reported outcome; 1RM: 1 repetition maximum; SF-36: Short Form-36; SGRQ-C: St. George’s Respiratory 
Questionnaire for COPD; SPPB: short physical performance battery
a.
Physical activity will be monitored at home for 7 days (1 week) and may occur between days -26 to -1.  If 
the subject was not compliant or for some unforeseen reason the accelerometer did not record correctly, the 
physical activity monitoring and the assessment of a weekly PRO (7-day recall) may be repeated in the 
screening period.
b.
EOT: day 14 of treatment period 2
c.
Visit 3 will be considered optional if the subject successfully completes the CWR at visit 2.  Subjects who 
do not attend visit 3 will resume their visit schedule with visit 4.


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d.
A standard urine screen for drugs of abuse (e.g., cannabinoids, cocaine and amphetamines) and 
benzodiazepines, and blood, urine, or breathalyzer alcohol screen will be performed by a central laboratory.
e.
The time of daily study drug dosing is to be recorded in the paper diary.  Subjects will take study drugs as 
follows: once a day after dinner at day 1, twice a day within 2 hours after breakfast and dinner between day 
2 and day 13 and once a day within 2 hours after breakfast at day 14.  In order to collect the trough 
pharmacokinetic sample on day 14, the subject is to wait and take the morning dose at the site after 
pharmacokinetic sample collection has been performed.
f.
Vital signs include blood pressure, heart rate and body temperature.
g.
Specifically for the monitoring of creatinine, blood urea nitrogen (BUN), cystatin C and liver enzymes 
(renal and liver safety assessments) at visits 5 and 8.
h.
At screening visit, subjects perform spirometry both pre and postbronchodilator, but only 
postbronchodilator thereafter: Subjects will receive 2 puffs of albuterol in the laboratory 10 to 15 minutes 
prior to the spirometry assessment on each study day.
i.
At screening CWR will be completed at least 24 hours after IET at visit 2 and may be retested within the 
next 5 days at the investigator’s discretion (within the visit window) if target exercise duration is not 
obtained. If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be 
classified as a screen failure and no additional assessments completed.  All exercise tests (IET and CWR) 
will record heart rate and ECG simultaneously with breath-by-breath gas exchange and ventilatory 
variables during all exercise performance.  Borg CR10 is performed with CWR at all of the time points 
shown in the schedule.  The Electromyogram (EMG) is also performed with the CWR, but only at visits 4, 
6, 7 and 9/EOT.
j.
An accelerometer may be supplied to subjects after visit 2 due to the subject’s availability between days -
26 to -8.
k.
Physical activity will be monitored for 7 continuous days during the screening period (baseline for physical 
activity), and treatment period 1 (endpoints). Subject will be given an accelerometer to wear during 
waking hours to monitor physical activity for 1 week.  A weekly physical activity assessment (clinical visit 
version of PROactive physical activity in COPD [C-PPAC]) will be completed at the end of the 7-day 
activity monitoring using an accelerometer and a 7-day recall online 12-item questionnaire at the site.
l.
Blood samples for pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable) will be 
collected from EVERY subject.  A single pharmacokinetic sample will be collected at each of the 
following time points: prior to evening dose at day 1 of treatment period 2, prior to morning dose (trough)
and then approximately 6 hours postmorning dose at day 14 of both treatment period 1 and 2.
m.
Sample to be collected 1 time prior to first dose at day 1 of treatment period 1.
IS AMENDED TO:
Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 
2
Follow-
up
Baseline 
for 
physical 
activity
Day
-
28 
to 
-9
-
27 
to 
-8
26 to 1a
-19
to -
1
1
6
7 
to 
13
14
14 days
1
6 EOTba/
ED
7 days 
after 
EOT/ED
Window 
-
-
-
-
-
+3
-
+3
+7
-
+3
+3
+7
Visit Number
1
2
3cb
4
5
6
-
7
8
9
10
Informed consent
X
Inclusion/Exclusion 
X
Medical history
X
X
X
Demographics
X
Drug and alcohol 
screendc
X
X
X
Randomization
X
Dispense/Collect 
X
X
X
X


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study drug
Administration of 
study druged
Physical 
examinatione
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Serum chemistries
X
X
Xg
X
X
Xg
X
X
Serology
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy test
X
X
X
Spirometryh
X
X
X
X
X
X
Respiratory muscle 
strength tests (MIP, 
MEP)
X
X
X
X
12-lead ECG
X
X
X
X
X
X
CWR exercise test
Xi
X
X
X
X
QoL outcomes 
(SGRQ-C, SF-36)
X
X
X
X
Physical 
performance test 
(SPPB)
X
X
X
X
Leg extensor strength 
test (1RM) 
X
X
X
X
IET
X
Supply acclerometer
Xj
X
Physical activity 
monitoring
(Accelerometer and 
PRO)k
Return accelerometer 
and complete PRO
(C-PPAC)
X
X
X
Blood sampling for 
pharmacokineticslj
Predose
6h
Predose
Predose 
6h
Optional blood 
sampling for 
pharmacogenomicsmk
X
Concomitant 
medication
X
X
X
X
Xl
X
X
X
X
Xl
X
X
Adverse events 
assessment
X
X
X
X
Xl
X
X
X
X
Xl
X
X
C-PPAC: clinical visit version of PRO active physical activity in COPD; CWR: constant work rate; ECG: 
electrocardiogram; ED: early discontinuation; EOT: end of treatment; IET: incremental exercise test; MEP: 
maximal expiratory pressure; MIP: maximal inspiratory pressure; PRO: patient reported outcome; 1RM: 1 
repetition maximum; SF-36: Short Form-36; SGRQ-C: St. George’s Respiratory Questionnaire for COPD; 
SPPB: short physical performance battery
a.
Physical activity will be monitored at home for 7 days (1 week) and may occur between days 26 to 1.  If 
the subject was not compliant or for some unforeseen reason the accelerometer did not record correctly, the 
physical activity monitoring and the assessment of a weekly PRO (7 day recall) may be repeated in the 
screening period.
ba.  EOT: day 14 of treatment period 2.
cb.  Visit 3 will be considered optional if the subject successfully completes the CWR at visit 2.  Subjects who 
do not attend visit 3 will resume their visit schedule with visit 4.
dc.  A standard urine screen for drugs of abuse (e.g., cannabinoids, cocaine and amphetamines) and 
benzodiazepines, and blood, urine, or breathalyzer alcohol screen will be performed by a central laboratory.
ed.  The time of daily study drug dosing is to be recorded in the paper diary.  Subjects will take study drugs as 
follows: once a day after dinner at day 1, twice a day within 2 hours after breakfast and dinner between day 


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2 and day 13 and once a day within 2 hours after breakfast at day 14.  In order to collect the trough 
pharmacokinetic sample on day 14, the subject is to wait and take the morning dose at the site after 
pharmacokinetic sample collection has been performed.
e.
A full physical examination will be performed at screening visit 1 and follow-up visit 10. Body 
systems to be evaluated include general appearance, skin, lymphatic, head and neck, ears, nose and 
throat, chest and lungs, cardiovascular, abdomen, extremities, musculoskeletal, and neuromuscular. 
At visits 4, 6, 7, and 9, a symptom-directed physical exam will be performed.
f.   Vital signs include blood pressure, heart rate and body temperature.
g.   Specifically for the monitoring of creatinine, blood urea nitrogen (BUN), cystatin C and liver enzymes 
(renal and liver safety assessments) at visits 5 and 8.
h.   At screening visit, subjects perform spirometry both pre and postbronchodilator, but only 
postbronchodilator thereafter: Subjects will receive 2 puffs of albuterol in the laboratory 10 to 15 minutes 
prior to the spirometry assessment on each study day.
i.    At screening CWR will be completed at least 24 hours after IET at visit 2 and may be retested within the 
next 5 days at the investigator’s discretion (within the visit window) if target exercise duration is not 
obtained. If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be 
classified as a screen failure and no additional assessments completed.  All exercise tests (IET and CWR) 
will record heart rate and ECG simultaneously with breath-by-breath gas exchange and ventilatory 
variables during all exercise performance.  Borg CR10 is performed with CWR at all of the time points 
shown in the schedule.  The Electromyogram (EMG) is also performed with the CWR, but only at visits 4, 
6, 7 and 9/EOT.
j.    An accelerometer may be supplied to subjects after visit 2 due to the subject’s availability between days 26 
to 8.
k.    Physical activity will be monitored for 7 continuous days during the screening period (baseline for physical 
activity), and treatment period 1 (endpoints).  Subject will be given an accelerometer to wear during 
waking hours to monitor physical activity for 1 week.  A weekly physical activity assessment (clinical visit 
version of PROactive physical activity in COPD [C PPAC]) will be completed at the end of the 7 day 
activity monitoring using an accelerometer and a 7 day recall online 12 item questionnaire at the site.
lj.   Blood samples for pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable) will be 
collected from EVERY subject.  A single pharmacokinetic sample will be collected at each of the 
following time points: prior to evening dose at day 1 of treatment period 2, prior to morning dose (trough)
and then approximately 6 hours postmorning dose at day 14 of both treatment period 1 and 2.
mk.  Sample to be collected 1 time prior to first dose at day 1 of treatment period 1.
l.    If a subject experiences an AE or change in concomitant medications during days 7 to 13, they should 
call the study site to inform them of this change.
5 Treatments and Evaluation
5.3.1.4 Physical Activity
WAS:
At screening (visit 2) and  treatment period 1 (visit 5) the subject will receive an 
accelerometer to be worn for 7 days between visit 2 and day-1 and days 7 to 13.  Physical 
activity will be measured by wearing an accelerometer (movement intensity, different body 
positions, steps) for 7 days followed by an online 12 item PRO questionnaire (7 day recall [C 
PPAC]) which has to be completed at the site.  Physical activity is assessed by questions 
targeted at the amount of physical activity and perceived difficulty during physical activity.
The European Union Innovative Medicines Initiative PROactive project [Gimeno-Santos et 
al, 2015] conducted qualitative research and drafted a conceptual framework to set out the 
concept of physical activity from patients’ experience and to provide the necessary basis to 


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generate an item pool for 2 PROs, 1 with a daily recall period and 1 with a 7-day recall 
period (daily and clinical visit versions, respectively) to measure the experience of physical 
activity in patients with COPD.
Accelerometer: the DynaPort system (McRoberts BV [The Hague, The Netherlands]) 
requires that the monitor be initially programed with an activation time/date by physically 
attaching it to a computer with the DynaPort software.  Monitors will stay attached to the 
charging station until they are administered to the subject to ensure a full 7 days of recording 
and instruct the subjects carefully how to wear the monitor and set it to “activated mode”.  
Subjects are required to return to the clinic at the day 6 of treatment period 1 to be fitted with 
the physical activity monitor.
IS AMENDED TO:
At screening (visit 2) and  treatment period 1 (visit 5) the subject will receive an 
accelerometer to be worn for 7 days between visit 2 and day 1 and days 7 to 13.  Physical 
activity will be measured by wearing an accelerometer (movement intensity, different body 
positions, steps) for 7 days followed by an online 12 item PRO questionnaire (7 day recall [C 
PPAC]) which has to be completed at the site.  Physical activity is assessed by questions 
targeted at the amount of physical activity and perceived difficulty during physical activity.
The European Union Innovative Medicines Initiative PROactive project [Gimeno-Santos et 
al, 2015] conducted qualitative research and drafted a conceptual framework to set out the 
concept of physical activity from patients’ experience and to provide the necessary basis to 
generate an item pool for 2 PROs, 1 with a daily recall period and 1 with a 7-day recall 
period (daily and clinical visit versions, respectively) to measure the experience of physical 
activity in patients with COPD.
Accelerometer: the DynaPort system (McRoberts BV [The Hague, The Netherlands]) 
requires that the monitor be initially programed with an activation time/date by physically 
attaching it to a computer with the DynaPort software.  Monitors will stay attached to the 
charging station until they are administered to the subject to ensure a full 7 days of recording 
and instruct the subjects carefully how to wear the monitor and set it to “activated mode”.  
Subjects are required to return to the clinic at the day 6 of treatment period 1 to be fitted with 
the physical activity monitor.
5 Treatments and Evaluation
5.3.2.5 IRM
DELETED
5.3.2.5 1RM
The leg extensor strength test, 1RM will be performed at treatment period 1 (visits 4 and 6) 
and treatment period 2 (visits 7 and 9).  1RM is a measure of the maximal weight a subject 
can lift with 1 repetition.  1RM is the heaviest weight a subject can lift once with seated leg 
press, which largely reflects activation of the quadriceps muscles, hamstrings and gluteus 
maximus.


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Version 3.1 Incorporating Non-Substantial Amendment 1
5 Treatments and Evaluation
5.4.4 Physical Examination
WAS:
A physical examination will be performed at the screening and at the visits 4, 6, 7, 8, 9 and 
10.  Body systems to be evaluated include general appearance, skin, lymphatic, head and 
neck, ears, nose and throat, chest and lungs, cardiovascular, abdomen, extremities, 
musculoskeletal and neuromuscular.
Only the date of the physical examination will be recorded in the eCRF.  Any clinically 
relevant abnormality at screening will be recorded as Medical History.  Any clinically 
relevant change from baseline to visit 9/EOT will be recorded as an AE in the eCRF.
IS AMENDED TO:
A full physical examination will be performed at screening visit 1 and follow-up visit 10. 
Body systems to be evaluated include general appearance, skin, lymphatic, head and 
neck, ears, nose and throat, chest and lungs, cardiovascular, abdomen, extremities, 
musculoskeletal, and neuromuscular. At the visits 4, 6, 7, and 9, a symptom-directed 
physical exam will be performed.  
Only the date of the physical examination will be recorded in the eCRF. Any clinically 
relevant abnormality at screening will be recorded as medical history. Any clinically relevant 
change from baseline to visit 9/EOT 10/FUV will be recorded as an AE in the eCRF.
Documentation that an exam has occurred needs to be reflected in the site source 
documents. 
Screening physical examination is to be conducted in person by a physician. Remaining 
physical examinations can be symptom directed and delegated to a Nurse Practitioner 
or Physician Assistant (if the study physician is unavailable) and signed off by the study 
physician.  A physical examination will be performed at the screening and at the visits 4, 6, 
7, 8, 9 and 10.  Body systems to be evaluated include general appearance, skin, lymphatic, 
head and neck, ears, nose and throat, chest and lungs, cardiovascular, abdomen, extremities, 
musculoskeletal and neuromuscular.
Only the date of the physical examination will be recorded in the eCRF.  Any clinically 
relevant abnormality at screening will be recorded as Medical History.  Any clinically 
relevant change from baseline to visit 9/EOT will be recorded as an AE in the eCRF.
5 Treatments and Evaluation
5.8 Total Amount of Blood
WAS:
●
Approximately 5 mL will be collected for pharmacogenetics testing (optional).
IS AMENDED TO:
●
Approximately 45 mL will be collected for pharmacogenetics testing (optional).


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Version 3.1 Incorporating Non-Substantial Amendment 1
7 Statistical Methodology
7.1 Sample Size
WAS:
A sample size of 40 subjects will provide 84% power to detect a difference of 60 seconds in 
CWR duration from period baseline for CK-2127107 versus placebo with a 1-sided alpha 
error of 0.05, assuming the standard deviation for change from period baseline is
100 seconds.  In order to maintain the statistical power of 80%, approximately 36 subjects 
would need to complete period 1.  Should the discontinuation rate in the first treatment 
period exceed 10%, additional subjects will need to be recruited.
IS AMENDED TO:
A sample size of 40 subjects will provide 84% power to detect a difference of 60 seconds in 
CWR duration from period baseline for CK-2127107 versus placebo with a 1-sided alpha 
error of 0.05, assuming the standard deviation for change from period baseline is 
100 seconds.  In order to maintain the statistical power of 80%, approximately 36 subjects 
would need to complete period 1.  Should the discontinuation rate in the first treatment
period exceed 10% (approximately 5 subjects), additional subjects will need to be recruited
to account for the discontinued subjects.
7 Statistical Methodology
7.2.1 Full Analysis Set (FAS)
WAS:
7.2.1
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug and have at least 1 baseline measurement and 1 post baseline 
measurement within a period.  Subjects will be included in the treatment arm based on 
randomization regardless of actual treatment received.  This will be the primary analysis set 
for efficacy analyses.
IS AMENDED TO:
7.2.1
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug and have at least 1 baseline measurement and 1 post baseline 
measurement within a period.  Subjects will be included in the treatment arm based on 
randomization regardless of actual treatment received.  This will be the primary analysis set 
for efficacy analyses.


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Version 3.1 Incorporating Non-Substantial Amendment 1
III.  Non-Substantial Amendment Rationale:
Rationale for Non-Substantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety 
or scientific value of the clinical study.


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Version 3.1 Incorporating Non-Substantial Amendment 1
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Two 
Period, Crossover Study to Assess the Effect of CK-2127107 on 
Physical Function in Subjects with Chronic Obstructive 
Pulmonary Disease
ISN/Protocol 3318-CL-3002
ClinicalTrials.gov Identifier: NCT02662582
Date of SAP v2: 19 Jul 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
ISN/Protocol 3318-CL-3002
19-Jul-2018
Astellas
Page 1 of 60
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 19-Jul-2018
A Phase 2a, Randomized, Double-blind, Placebo-controlled,
Two Period, Crossover Study to Assess the Effect of CK-2127107
on Physical Function in Subjects with Chronic Obstructive 
Pulmonary Disease
ISN: 3318-CL-3002
IND number: 127,897
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way 
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
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19-Jul-2018
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Page 2 of 60
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 7
2
FLOW CHART AND VISIT SCHEDULE···················································· 8
3
STUDY OBJECTIVE(S) AND DESIGN······················································12
3.1
Study Objectives ··············································································12
3.1.1
Primary Objective ·······································································12
3.1.2
Secondary Objectives···································································12
3.1.3
Exploratory Objectives ·································································12
3.2
Study Design···················································································12
3.3
Randomization·················································································13
4
SAMPLE SIZE·····················································································13
5
ANALYSIS SETS ·················································································13
5.1
Full Analysis Set (FAS) ······································································14
5.2
Safety Analysis Set (SAF) ···································································14
5.3
Pharmacokinetic Analysis Set (PKAS)·····················································14
6
ANALYSIS VARIABLES ·······································································14
6.1
Efficacy Endpoints············································································14
6.1.1
Primary Efficacy Endpoints····························································16
6.1.2
Secondary Efficacy Endpoints·························································16
6.1.3
Exploratory Efficacy Endpoints ·······················································18
6.2
Safety Variables···············································································22
6.2.1
Adverse Events ··········································································22
6.2.2
Clinical Laboratory Variables··························································22
6.2.3
Vital Signs················································································23
6.2.4
Electrocardiograms (ECGs)····························································23
6.3
Pharmacokinetic Variables···································································23
6.4
Other Variables················································································23
7
STATISTICAL METHODOLOGY ···························································25
7.1
General Considerations·······································································25
7.2
Study Population ··············································································26
7.2.1
Disposition of Subjects ·································································26
7.2.2
Protocol Deviations ·····································································27
7.2.3
Demographic and Other Baseline Characteristics ···································27


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7.2.4
Previous and Concomitant Medications ··············································31
7.3
Study Drugs····················································································31
7.3.1
Exposure··················································································31
7.3.2
Treatment Compliance··································································32
7.3.3
Exposure Rate············································································32
7.4
Analysis of Efficacy ··········································································32
7.4.1
Overview of Efficacy Analyses························································32
7.4.2
Analysis of Primary Endpoint ·························································34
7.4.3
Analysis of Secondary Endpoints ·····················································35
7.4.4
Analysis of Exploratory Endpoints····················································36
7.5
Analysis of Safety·············································································36
7.5.1
Adverse Events ··········································································37
7.5.2
Clinical Laboratory Evaluation ························································38
7.5.3
Vital Signs················································································40
7.5.4
Electrocardiograms (ECGs)····························································41
7.5.5
Pregnancies···············································································41
7.6
Analysis of PK·················································································41
7.6.1
Plasma Concentrations··································································41
7.6.2
Statistical Analysis ······································································41
7.6.3
Concentration-Response Relationship Analysis ·····································41
7.7
Subgroups of Interest ·········································································41
7.8
Other Analyses ················································································42
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················42
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········42
7.10.1
Missing Data ·············································································42
7.10.2
Outliers ···················································································43
7.10.3
Values BLOQ············································································43
7.10.4
Visit Windows ···········································································43
8
DOCUMENT REVISION HISTORY ·························································46
9
REFERENCES ····················································································55
10
APPENDICES ·····················································································56
10.1
Appendix 1: Predictive Equations···························································56
10.2
Appendix 2: Key Contributors and Approvers ············································59


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
ISN/Protocol 3318-CL-3002
19-Jul-2018
Astellas
Page 4 of 60
I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of Abbreviations
1RM
1 repetition maximum
AE
adverse event
AEE
Average Energy Expenditure
ALP
alkaline phosphatase
ALT
alanine aminotransferase
API
active pharmaceutical ingredient
AST
aspartate aminotransferase
ATS
American Thoracic Society
Bf
Breathing Frequency
BMI
body mass index
BMR
Basal Metabolic Rate
C-PPAC
clinical visit version of PROactive physical activity in COPD
Ca2+
Calcium
COPD
chronic obstructive pulmonary disease
CRO
contract research organization
CWR
constant work rate
CYP
cytochrome P450
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture
EMG
electromyogram
EOT
end of treatment
ERS
European Respiratory Society
FAS
full analysis set
FEV1
forced expiratory volume in 1 second
FUV
follow-up visit
FVC
forced vital capacity
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GMP
Good Manufacturing Practice
IC
inspiratory capacity
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IET
incremental exercise test
INR
international normalized ratio


Sponsor: Astellas Pharma Inc.
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Page 5 of 60
Abbreviations
Description of Abbreviations
IRB
institutional review board
IRT
Interactive Response Technology
IRV
Inspiratory reserve volume
LA-CRF
liver abnormality case report form
LFT
liver function tests
LHRH
luteinizing hormone-releasing hormone
MedDRA
Medical Dictionary for Regulatory Activities
MEP
maximal expiratory pressure
MI
Movement Intensity
MIP
maximal inspiratory pressure
mMRC
Modified Medical Research Council
NOAEL
no observed adverse effect level
OCT
organic cation transporter
PAL
Physical Activity Level
PAR
Physical Activity Ratio
PETCO2
End-tidal PCO2
PETO2
End-tidal PO2
PKAS
pharmacokinetic analysis set
PPS
per protocol set
PRO
patient reported outcome
QoL
quality of life
RER
Respiratory exchange ratio
RPE
rating perceived exertion
RV
residual volume
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
Standard deviation
SE
Standard Error
SF-36
Short Form-36
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SOP
standard operating procedure
SPPB
short physical performance battery
SPO2
Arterial oxygen saturation from pulse oximetry
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TEE
Total Energy Expenditure
TLC
total lung capacity
ULN
upper limit of normal
VCO2
Carbon dioxide output


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
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19-Jul-2018
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Abbreviations
Description of Abbreviations
VE
Minute ventilation
VE/VCO2
ventilator equivalent for carbon dioxide
VMU
Vector Magnitude Unit
VO2
oxygen uptake
VT
Tidal volume
WHO
World Health Organization
WHO-DD
World Health Organization – Drug Dictionary
WR
work rate
List of Key Terms
Terms
Definition of terms
Sequence
Enrolled subject will be randomly assigned to 1 of 2 treatment sequences. 
Sequence 1: subject will receive CK-2127107 in treatment period 1 and then 
receive Placebo in treatment period 2
Sequence 2: subject will receive Placebo in treatment period 1 and then 
receive CK-2127107 in treatment period 2
Treatment period
This study is two period crossover design. Period 1 and Period 2 are the first 
and second period respectively in the crossover design.
Period baseline
Baseline in each period


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to database hard lock. For operational efficiency an 
earlier time is usually targeted and wherever possible, the SAP should be developed in 
parallel with protocol finalization. The SAP should be developed and approved before First 
Subject In (FSI). If needed, revisions to the approved SAP may be made prior to database 
hard lock. Revisions will be version controlled.
This statistical analysis is coordinated by the responsible biostatistician of GD-US. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock except Pharmacokinetic Analysis Set (PKAS). For PKAS, analysis set 
classification may be held after database hard lock.




Sponsor: Astellas Pharma Inc.
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Table 1
Schedule of Assessments
Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 2
Follow-up
Day
-28 to -9
-27 to -8
-19 to -1
1
6
14
14 days
1
6
EOTa/
ED
7 days after 
EOT/ED
Window 
-
-
-
-
+3
+3
+7
-
+3
+3
+7
Visit Number
1
2
3b
4
5
6
-
7
8
9
10
Informed consent
X
Inclusion/Exclusion 
X
Medical history
X
X
X
Demographics
X
Drug and alcohol screenc
X
X
X
Randomization
X
Dispense/Collect study drug
X
X
X
X
Administration of study 
drugd
Physical examinatione
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Serum chemistries
X
X
Xg
X
X
Xf
X
X
Serology
X
Urinalysis
X
X
X
X
X
X
Serum pregnancy test
X
X
X
Spirometryh
X
X
X
X
X
X
Respiratory muscle strength 
tests (MIP, MEP)
X
X
X
X
12-lead ECG
X
X
X
X
X
X
CWR exercise test
Xi
X
X
X
X
QoL outcomes 
(SGRQ-C, SF-36)
X
X
X
X
Physical performance test 
(SPPB)
X
X
X
X
IET
X
Table continued on the next page


Sponsor: Astellas Pharma Inc.
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Assessments
Screening
Treatment 
Period 1 
Washout
Treatment Period 2
Follow-up
Day
-28 to -9
-27 to -8
-19 to -1
1
6
14
14 days
1
6
EOTa/
ED
7 days after 
EOT/ED
Window 
-
-
-
-
+3
+3
+7
-
+3
+3
+7
Visit Number
1
2
3b
4
5
6
-
7
8
9
10
PRO (C-PPAC)
X
X
Blood sampling for 
pharmacokineticsj
Predose 6h
Predose
Predose 6h
Optional blood sampling 
for pharmacogenomicsk
X
Concomitant medication
X
X
X
X
X
Xl
X
X
Xl
X
X
Adverse events assessment
X
X
X
X
X
Xl
X
X
Xl
X
X
C-PPAC: clinical visit version of PROactive physical activity in COPD; CWR: constant work rate; ECG: electrocardiogram; ED: early discontinuation; EOT: end of treatment; IET: 
incremental exercise test; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; PRO: patient reported outcome; SF-36: Short Form-36; SGRQ-C: St. George’s 
Respiratory Questionnaire for COPD; SPPB: short physical performance battery
a. EOT: day 14 of treatment period 2.
b. Visit 3 will be considered optional if the subject successfully completes the CWR at visit 2.  Subjects who do not attend visit 3 will resume their visit schedule with visit 4.
c. A standard urine screen for drugs of abuse (e.g., cannabinoids, cocaine and amphetamines) and benzodiazepines, and blood, urine, or breathalyzer alcohol screen will be performed 
by a central laboratory.
d. The time of daily study drug dosing is to be recorded in the paper diary.  Subjects will take study drugs as follows: once a day after dinner at day 1, twice a day within 2 hours after 
breakfast and dinner between day 2 and day 13 and once a day within 2 hours after breakfast at day 14.  In order to collect the trough pharmacokinetic sample on day 14, the subject 
is to wait and take the morning dose at the site after pharmacokinetic sample collection has been performed.
e. A full physical examination will be performed at screening visit 1 and follow-up visit 10. Body systems to be evaluated include general appearance, skin, lymphatic, head and neck, 
ears, nose and throat, chest and lungs, cardiovascular, abdomen, extremities, musculoskeletal, and neuromuscular. At visits 4, 6, 7, and 9, a symptom-directed physical exam will be 
performed.
f.
Vital signs include blood pressure, heart rate and body temperature.
g. Specifically for the monitoring of creatinine, blood urea nitrogen (BUN), cystatin C and liver enzymes (renal and liver safety assessments) at visits 5 and 8.
h. At screening visit, subjects perform spirometry both pre and postbronchodilator, but only postbronchodilator thereafter: Subjects will receive 2 puffs of albuterol in the laboratory 
10 to 15 minutes prior to the spirometry assessment on each study day.
Footnotes are continued on the next page


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i.
At screening CWR will be completed at least 24 hours after IET at visit 2 and may be retested within the next 5 days at the investigator’s discretion (within the visit window) if 
target exercise duration is not obtained. If this cannot be achieved with 2 adjustments (a total of 3 CWR tests), the subject will be classified as a screen failure and no additional 
assessments completed.  All exercise tests (IET and CWR) will record heart rate and ECG simultaneously with breath-by-breath gas exchange and ventilatory variables during all 
exercise performance.  Borg CR10 is performed with CWR at all of the time points shown in the schedule.  The Electromyogram (EMG) is also performed with the CWR, but only 
at visits 4, 6, 7 and 9/EOT.
j.
Blood samples for pharmacokinetics of CK-2127107 and possible metabolite(s) (if applicable) will be collected from EVERY subject.  A single pharmacokinetic sample will be 
collected at each of the following time points: prior to evening dose at day 1 of treatment period 2, prior to morning dose (trough) and then approximately 6 hours postmorning dose
at day 14 of both treatment period 1 and 2.
k. Sample to be collected 1 time prior to first dose at day 1 of treatment period 1.
l.
If a subject experiences an AE or change in concomitant medications during days 7 to 13 or washout, they should call the study site to inform them of this change.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objectives
3.1.1
Primary Objective
To assess the effect of CK-2127107 relative to placebo on cycle ergometer exercise tolerance, 
assessed as change from period baseline in CWR endurance time, utilizing a breath-by-breath 
metabolic measurement system with integrated electrocardiogram (ECG). The time to 
intolerance is assessed by a stopwatch and verified from electronic recordings of the cycle 
ergometer.
3.1.2
Secondary Objectives
●
To assess cardiopulmonary and neuromuscular effects of CK-2127107 relative to 
placebo on:
o The change from period baseline in oxygen uptake (VO2), ventilation (VE), 
ventilatory equivalent for carbon dioxide (VE/VCO2) and other breath-by-breath 
cardiometabolic variables, inspiratory capacity (IC) and perceived exertion for 
dyspnea and leg discomfort (Borg CR10), at iso time and peak during CWR test
o Activation of accessory respiratory muscles (by electromyogram [EMG]) at isotime* 
and peak exercise during CWR test
●
To assess the effect of CK-2127107 on resting spirometry relative to placebo
●
To assess the safety and tolerability of CK-2127107
●
To assess the pharmacokinetics of CK-2127107
3.1.3
Exploratory Objectives
●
To explore the effects of CK-2127107 relative to placebo on:
○Patient reported outcomes (PROs) and physical activity assessed by an accelerometer
○Physical performance via a short physical performance battery (SPPB) and leg 
muscle strength via a leg extensor strength test (1 repetition maximum [1RM])
○Respiratory muscle strength by maximal inspiratory pressure (MIP) and maximal 
expiratory pressure (MEP)
*Isotime is the shortest duration of all of the CWR tests performed before and after 
treatment, not including screening.
3.2
Study Design
This is a phase 2a, randomized, double-blind, placebo-controlled, two period, crossover study 
to assess the potential effects on physical function and safety of CK-2127107 in subjects with 
COPD.  Approximately 40 subjects will be randomly assigned to 1 of 2 treatment sequences
and will receive both CK-2127107 and matching placebo over 2 treatment periods as per the 
following schedule [Table 2].  If the discontinuation rate in the first treatment period exceeds 
10%, additional subjects will be recruited to ensure a total of at least 36 subjects completing 
the study.


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Table 2
Treatment Sequence
Sequence
Treatment Period 1
Treatment Period 2
1
CK-2127107
Placebo
2
Placebo
CK-2127107
Each treatment period consists of 14 days dosing of CK-2127107 or matching placebo. Each 
medication period is separated by a 14-day washout period. The total study duration 
including screening period and follow-up visit (FUV) for an individual subject will be 
approximately 12 weeks (see Flow Chart [Figure 1] and Schedule of Assessments [Table 1]).
3.3
Randomization
All subject numbers will be assigned using the interactive response technology (IRT) starting 
at screening. All subjects will have a unique, ten-digit subject number. The first five digits of 
this number will be the Investigator’s research number. The second five digits assigned will 
represent the subject’s accession number. This will be the number that identifies a subject 
during the course of the study.
All Baseline procedures will be performed prior to Randomization. Only subjects who meet 
all inclusion criteria and exhibit none of the exclusion criteria will be randomly assigned to
one of 2 treatment sequences in a 1:1 ratio and will receive CK-2127107 as two 250 mg 
tablets (500 mg twice a daily [1000 mg daily total]) or 2 tablets twice daily of matching
placebo during the 2 treatment periods.
Randomization will be performed via IRT. If a subject is assigned a subject number, but does 
not receive study drug, the subject number will not be used again.
The randomization schedules that determine subject treatment will be computer-generated by 
a designated Contract Research Organization (CRO) before the beginning of the study.
Specific procedures for randomization through the IRT are contained in the study-specific 
IRT manual.
4
SAMPLE SIZE
A sample size of 40 subjects will provide 84% power to detect a difference of 60 seconds in 
CWR duration from period baseline for CK-2127107 versus placebo with a 1-sided alpha 
error of 0.05, assuming the standard deviation for change from period baseline is 
100 seconds. In order to maintain the statistical power of 80%, approximately 36 subjects 
would need to complete period 1. Should the discontinuation rate in the first treatment period 
exceed 10% (approximately 5 subjects), additional subjects will need to be recruited to 
account for the discontinued subjects.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.


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Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock except 
Pharmacokinetic Analysis Set (PKAS). The allocation of subjects to PKAS will be 
determined after database hard lock.
5.1
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least 1 dose of study drug and have at least 1 baseline measurement and 1 post baseline 
measurement in either treatment period for CWR endurance time. Subjects will be included 
in the treatment arm based on actual treatment received. This will be the primary analysis set 
for efficacy analyses.
5.2
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least 1 dose of study medication. Subjects will be 
included in the treatment arm based on actual treatment received.
5.3
Pharmacokinetic Analysis Set (PKAS)
The PKAS consists of the administered population for which at least one quantifiable plasma 
trough concentration or concentration at 6 hours is available for CK-2127107 or CK-2127106 
and for whom the time of dosing on the day of sampling is known.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
The following table provides definitions for the efficacy parameters.
Parameter
Definition
Constant Work Rate (CWR) 
Endurance Time
The CWR defines how long it takes until the subject 
reaches symptom limitations while simultaneously being 
monitored and is called “CWR time to intolerance” which 
determines the “CWR endurance time”.
Inspiratory Capacity (IC)
The volume of air that can be inspired after a normal 
expiration; it is the sum of the tidal volume (VT) and 
the inspiratory reserve volume.
Minute ventilation (VE)
Volume of gas exhaled from the lungs in 1 minute.
Oxygen uptake (VO2)
Volume of O2 extracted from inspired air in a given period 
of time.
Carbon dioxide output (VCO2)
Volume of CO2 exhaled from the body per unit of time.
Ventilatory equivalent for 
carbon dioxide (VE/VCO2)
Ratio of VE to VCO2. It is a dimensionless quantity. This 
ratio indicates how many liters of air exhaled breathed to 
eliminate 1 liter of CO2.


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End-tidal PO2 (PETO2)
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.
End-tidal PCO2 (PETCO2)
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.
Tidal volume (VT)
Volume of gas exhaled in each respiratory cycle. Tidal 
volume is typically measured as an average value 
over several respiratory cycles and expressed in liters.
Ventilatory reserve (VE/MVV)
Expresses the rate if expired ventilation to the 
capacity. Ventilatory capacity is estimated from the 
maximum voluntary ventilation (MVV), and in this suited 
is calculated from 40 times the forced expiratory volume 
in 1 second (FEV1). The ratio of VE/MVV is expressed as 
a percentage.
Arterial oxygen saturation from 
pulse oximetry (SPO2)
Noninvasive estimation of arterial hemoglobin oxygen 
saturation, using a device that utilizes the combined 
principles of spectrophotometry and pulse 
plethysmography.
Breathing frequency (Bf)
The number of breaths (an entire inspiratory and 
expiratory respiratory cycle) per minute.
For efficacy variables, the following predicted parameter results are entered in eCRF. 
Appendix 1 provides the predictive equations that are used to calculate the results for these 
parameters. These results are applicable for healthy subjects and only going to be used to 
derive the percent of predicted parameters for the subjects in this study. Derivation details for 
percent of predicted parameters that will be used for analysis are presented in Section 6.1.2
and Section 7.2.3.1
Predicted FEV1 (L)
Predicted FVC (L)
Predicted FRC (L)
Predicted SVC (L)
Predicted IC (L)
Predicted TLC (L)
Predicted VA (L)
Predicted DLCO (L)
Predicted VO2max (L/min)


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6.1.1
Primary Efficacy Endpoints
The primary endpoint is the change from period baseline in CWR endurance time relative to 
placebo.  
For change from baseline in CWR endurance time, a positive change indicates an 
improvement from baseline (i.e., a favorable outcome).
CWR endurance time will be performed during screening and on day 1 and day 14 during 
each of the 2 treatment periods or at early discontinuation (ED) [Table 1].
6.1.2
Secondary Efficacy Endpoints
The secondary endpoints are as follows:
●
Change from period baseline in VO2, VE, VE/VCO2, IC, as well as other cardiometabolic 
variables and perceived exertion for dyspnea and leg discomfort (Borg CR10) at 
isotime* and peak during CWR as compared to placebo
Other cardiometabolic variables:
○
PETO2
○
PETCO2
○
VT
○
Bf
○
VE/MVV
VE/MVV (%) = (VE/MVV) x 100 where MVV = FEV1 x 40
○
HR
○
SBP
○
DBP
○
SPO2
○
IRV
IRV (L) = VT (L) – IC (L)
○
RER  
RER = VCO2 (L/min) / VO2 (L/min)
○
Dyspnea (Borg CR10)
○
Leg Effort (Borg CR10)
●
Change from period baseline in activation of accessory respiratory muscles (by EMG) at 
isotime* and peak exercise during CWR
●
Change in resting spirometry compared to placebo
For change from baseline in spirometry parameters, a positive change indicates an 
improvement from baseline (i.e., a favorable outcome).
Pre-Exercise Parameters:
●
FEV1 (L)
●
FVC (L)
●
FEV1 percent predicted (%) 
FEV1 percent predicted (%) = (FEV1 (L) / FEV1 predicted (L)) x 100


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In the numerator, FEV1 (L) is the result from pre-exercise spirometry at each visit. In 
the denominator, FEV1 predicted (L) result is from Screening Pulmonary Function
CRF.
●
FVC percent predicted (%)
FVC percent predicted (%) = (FVC (L) / FVC predicted (L)) x 100
In the numerator, FVC (L) result is from pre-exercise spirometry at each visit. In the 
denominator, FVC predicted (L) result is from Screening Pulmonary Function CRF.
Follow-up Parameters:
●
Post-Bronchodilator measured FEV1 (L) 
●
Post-Bronchodilator measured FVC (L)
●
Post-Bronchodilator FEV1 percent predicted (%) 
Post-Bronchodilator FEV1 percent predicted (%) = (Post-Bronchodilator FEV1 (L) / 
FEV1 predicted (L)) x 100
In the numerator, Post-Bronchodilator FEV1 (L) result is from Follow-up Spirometry 
CRF. In the denominator, FEV1 predicted (L) result is from Follow-up Spirometry 
CRF.
●
Post-Bronchodilator FVC percent predicted (%)
Post-Bronchodilator FVC percent predicted (%) = (Post-Bronchodilator FVC (L) / 
FVC predicted (L)) x 100
In the numerator, Post-Bronchodilator FVC (L) result is from Follow-up Spirometry 
CRF. In the denominator, FVC predicted (L) result is from Follow-up Spirometry 
CRF.
*Isotime is the shortest duration of all of the CWR tests performed before and after treatment, 
not including screening.
These endpoints relate to the isotime physiologic measurements that underpin the increase in 
exercise tolerance and represent an integrated examination of cardiopulmonary measurements. 
The analysis of variables that are recorded breath-by-breath (e.g., VO2, VE, VE/VCO2) are 
facilitated by averaging data over 20 second intervals within the metabolic cart system 
(recorded by the Vmax breath-by-breath metabolic measurement system). Surface accessory 
muscle EMG activity is recorded throughout the exercise and analyzed over the same time 
intervals as the breath-by-breath data.  IC is recorded every 2 minutes during exercise; its 
measurement requires the subject to produce a maximum inspiration (from end-inspiration) on 
command every 2 minutes during the exercise test.  This allows the determination of whether 
IC is reduced during exercise as a consequence of dynamic hyperinflation, which is common 
during exercise in COPD.  The exercise system software stores this maneuver and facilitates 
post-test examination of each maneuver to assess quality. Therefore IC assessment of dynamic 
hyperinflation is obtained with 2-minute resolution.
Resting spirometry is measured before exercise but after inhalation of albuterol. It is 
measured at approximately the same time of day, at the same duration after the subjects’ 
morning dose of normal bronchodilator medications. Subjects will receive 2 puffs of 
albuterol in the lab 10 to 15 minutes prior to the spirometry assessment on each study day.


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6.1.3
Exploratory Efficacy Endpoints
The exploratory endpoints are as follows:
●
Change from period baseline in QoL outcomes (SGRQ-C, SF-36) relative to placebo
●
Change from baseline in physical activity using the PROactive approach (DynaPort®©
accelerometer and combined PRO). This will be assessed during only the first treatment 
period. Therefore, this will represent the response to placebo for half the subjects and the 
response to the study drug for the other half of subjects.
Physical Activity Monitoring
Physical activity will be measured by wearing the accelerometer during waking hours 
(movement intensity, different body positions, steps) for 7 days. From the accelerometer, 
the following daily parameters will be reported for various positions or combination of 
the positions: lying, sitting, walking, stair walking, cycling, standing, shuffling, cycling, 
overall worn and not worn.
●
Maximum wearing time 
●
Average wearing time
●
Median wearing time
●
Total wearing time
●
Number of transitions from one position to another position
●
Number of periods
This is the number of periods of each activity.
●
Average movement intensity (MI)
MI is derived from the acceleration signals. MI gives an indication of the power of 
movements.
●
Vector magnitude unit (VMU)
VMU is comparable with the MI and gives an indication of the power of the 
movements. The VMU is only based on the movements captured by the medial-lateral 
axis of the sensor.
●
Active Energy Expenditure (AEE)
This is total activity related energy expenditure from each position.
●
Total Energy Expenditure (TEE)
This is sum of AEE, Basal metabolic rate (BMR) and diet induced thermogenesis. 
Diet induced thermogenesis is the amount of energy utilized for digestion, absorption 
and transportation of nutrients.
●
Physical Activity Ratio (PAR)


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This is the ratio of energy expenditure during a specific physical activity i.e., 
TEE/BMR or also called as Metabolic equivalent of task (MET). The PAR of all 
activities of a whole day is called the Physical Activity Level (PAL). A chair- or bed-
bound lifestyle corresponds to an average PAL value of 1.2, while a lifestyle of 
strenuous work or highly active leisure corresponds to a PAL value of 2.0 to 2.4.
Also the following daily parameters will be reported:
●
Number of steps
●
BMR spent during wearing time
BMR is the minimum amount of energy that a body requires when lying in 
physiological and mental rest.
●
MET minutes (number of MET minutes above or equal to 3 METs)
This is summation of all periods with a MET value >=3 multiplied by the duration of 
the periods in minutes.
For the daily parameters: average MI, VMU, AEE, TEE and number of steps, if daily 
total wearing time is less than 8 hours then that daily parameter value will be not valid i.e., 
set to missing in the calculation of the following weekly parameters. Also for the 
applicable weekly parameters, weighted mean is calculated as Sum(weight x daily 
parameter result)/sum(weight) where weight is the total wearing time. Using the daily 
parameter results, the following weekly parameters will be derived for each subject as 
follows:
●
Mean total wearing time on valid days
Arithmetic mean of non-missing daily total wearing time collected on valid days 
within time window per visit windows defined in Section 7.10.4.2 Table 5. If the total 
wearing time is missing on all of the days during the time window, then the mean 
total wearing time for that time point will be set to missing.
●
Mean total wearing time on all days
Arithmetic mean of non-missing daily total wearing time collected within time 
window per visit windows defined in Section 7.10.4.2 Table 5. If the total wearing 
time is missing on all of the days during the time window, then the mean total 
wearing time for that time point will be set to missing.
●
Mean average MI during total wearing time
Weighted mean of non-missing daily average MI collected on valid days within time 
window per visit windows defined in Section 7.10.4.2 Table 5. If the average MI is 
missing on all of the days during the time window, then the mean average MI for that 
time point will be set to missing.


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●
Median VMU/min during total wearing time
Median of non-missing daily VMU/min collected on valid days within time window 
per visit windows defined in Section 7.10.4.2 Table 5  If the VMU/min is missing on 
all of the days during the time window, then the median VMU/min for that time point 
will be set to missing.
●
Median VMU group during total wearing time
o
0: median VMU/min < 60
o
1: median VMU/min ≥ 60  to ≤ 130
o
2: median VMU/min > 130 to ≤ 210
o
3: median VMU/min > 210 to ≤ 370
o
4: median VMU/min > 370
●
Mean AEE during total wearing time
Weighted mean of non-missing daily AEE collected on valid days within time 
window per visit windows defined in Section 7.10.4.2 Table 5. If the AEE is missing 
on all of the days during the time window, then the mean AEE for that time point will 
be set to missing.
●
Mean TEE during total wearing time
Weighted mean of non-missing daily TEE collected on valid days within time 
window per visit windows defined in Section 7.10.4.2 Table 5. If the TEE is missing 
on all of the days during the time window, then the mean TEE for that time point will 
be set to missing.
●
Median number of steps during total wearing time
Median of non-missing daily number of steps collected on valid days within time 
window per visit windows defined in Section 7.10.4.2 Table 5. If the number of steps 
is missing on all of the days during the time window, then the median number of steps 
for that time point will be set to missing.
●
Median steps score group during total wearing time
o
0: median number of steps < 1500
o
1: median number of steps ≥ 1500  to ≤ 2500
o
2: median number of steps > 2500 to ≤ 4500
o
3: median number of steps > 4500 to ≤ 6500
o
4: median number of steps > 6500


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C-PPAC questionnaire
The following items will be derived:
●
Difficulty Score
Q1 (about walking) score + Q2 (about chores outside the house) score + median 
weekly steps score group + median weekly VMU score group from the physical 
activity data.
If the response is missing for any of the individual questions involved in this 
derivation then the score will be set to missing.
●
Amount Score
Sum of remaining questions Q3 to Q12 scores.
If the response is missing for any of the individual questions involved in this 
derivation then the score will be set to missing.
●
Total Score
Difficulty score + amount score.
If the score is missing for the difficulty or amount then the total score will be set to 
missing.
●
Change from period baseline in physical performance tests battery score (SPPB) relative 
to placebo
●
Change from period baseline in leg muscle strength relative to placebo (as assessed by 
the maximal weight a subject can lift with one repetition [1RM])
●
Change from period baseline in MIP and MEP relative to placebo. This test is performed 
before exercise testing and is part of the resting assessment.
●
Change from period baseline in VO2, VE, VE/VCO2, IC, as well as other cardiometabolic 
variables and perceived exertion for dyspnea and leg discomfort (Borg CR10) at rest 
during CWR as compared to placebo
Other cardiometabolic variables: 
○
PETO2
○
PETCO2
○
VT
○
Bf
○
VE/MVV
VE/MVV (%) = (VE/MVV) x 100 where MVV = FEV1 x 40
○
HR
○
SBP
○
DBP
○
SPO2
○
IRV
IRV (L) = VT (L) – IC (L)
○
RER  
RER = VCO2 (L/min) / VO2 (L/min)
○
Dyspnea (Borg CR10)
○
Leg Effort (Borg CR10)
●
Change from period baseline in activation of accessory respiratory muscles (by EMG) at 
rest during CWR


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6.2
Safety Variables
6.2.1
Adverse Events
Treatment-emergent adverse events (TEAEs) will be defined as any adverse event that started 
or worsened in severity after first dose of study drug up to 14 days after the last dose of 
study drug. If the adverse event occurs on Day 1 and the onset check box is marked “Onset 
after first dose of study drug” or the onset check box is left blank, then the adverse event will 
be considered treatment emergent. If the adverse event occurs on Day 1 and the onset check 
box is marked “Onset before first dose of study drug”, then the adverse event will not be 
considered treatment emergent.
TEAEs will be summarized by treatment group. TEAEs at treatment period 1 will be defined 
as TEAE which occurs after first dose of study drug at treatment period 1 up to first dose of 
study drug at treatment period 2. If a subject discontinues in treatment period 1, TEAEs at 
treatment period 1 will be defined as TEAE which occurs after first dose of study drug at 
treatment period 1 up to 14 days after the last dose of study drug. TEAEs at treatment period 
2 will be defined as TEAE which occurs after first dose of study drug at treatment period 2 
up to 14 days after the last dose of study drug. 
Drug-related TEAE will be defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
TEAE variables are frequency, severity, seriousness, relationship to study drug, and count.
Imputed date for the AE onset date may be used to determine a TEAE (Section 7.10.1.3).
6.2.2
Clinical Laboratory Variables
Clinical laboratory variables are raw values (i.e., values at each scheduled visit) and changes 
from period baseline for hematology and urinalysis parameters at Day 14. Biochemistries 
will be summarized as the change from period baseline at Day 6 and at Day 14.
Liver function tests including alanine transaminase (ALT), aspartate transaminase (AST), 
total bilirubin and alkaline phosphatase (ALP) will be assessed at Screening, Baseline and 
Day 14. The following groups will be defined, as flags on a subject level, during the 
treatment period, based on the maximum value during study period, according to the Upper 
Limit of Normal (ULN):
●
ALT > 3× ULN, > 5× ULN, > 10× ULN, and > 20× ULN
●
AST > 3× ULN, > 5× ULN, > 10× ULN, and > 20× ULN
●
ALT or AST > 3× ULN
●
Total Bilirubin > 2× ULN
●
ALP > 1.5× ULN
●
ALT and/or AST > 3× ULN and Total Bilirubin > 2× ULN


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For the ALT and/or AST > 3× ULN and Total Bilirubin > 2× ULN criteria, the subject’s 
ALT and/or AST and Total Bilirubin values must be measured within the same sample to be 
counted.
The maximum value during the study period, defined as the maximum value of all 
post-Baseline assessments, will be derived for liver function tests.
6.2.3
Vital Signs
Vital signs variables are raw values for and changes from Baseline in temperature, pulse rate, 
systolic blood pressure and diastolic blood pressure at Day 14.
6.2.4
Electrocardiograms (ECGs)
The 12-lead ECG scheduled assessments will be made at Screening, Baseline and Day 14. 
The results will be recorded as normal or abnormal. ECG variables are raw values 
(categorical) at each scheduled visit and changes from Baseline (shift from Baseline) at 
Day 14.
6.3
Pharmacokinetic Variables
Pharmacokinetics of CK-2127107 and CK-2127106:
○
Day 1 (only treatment period 2): predose plasma concentration
○
Day 14 (of both treatment period 1 and 2): Ctrough and C6h
6.4
Other Variables
Other variables include the following variables:
●
Duration of exposure 
For each subject at each period, duration of exposure (defined as length of time on 
2 weeks of treatment period) will be calculated in days, using the following formula:
Duration of exposure in each period = Date of last dose of study drug up to 
Week 2/EOT – Date of first dose of study drug +1, 
where the date of first dose of study drug and the date of last dose of study drug up to 
Week 2/EOT are defined as the first study drug dosing date and the last study drug 
dosing date.
Total duration of exposure in this study will be calculated as below:
Total duration of exposure = Duration of exposure of period 1 + Duration of exposure 
of period 2.
Total duration will be calculated for only period 1 if subjects discontinue before 
period 2.


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●
Treatment compliance 
Subjects will be instructed to take tablet two times per day. Treatment compliances 
based on number of tablets will be calculated as follows:
Treatment compliance in each period (%) with tablets = 100 × (total number of tablets 
actually taken during 2 weeks of treatment period / total number of tablets planned to 
receive during 2 weeks of treatment period),
where 
○
Total number of tablets planned to receive during 2 weeks in each treatment 
period = 4 × duration of exposure – 4 (if more than one day of dosing) - 2 (if only 
one day of dosing). Duration of exposure will be calculated as described above. 
○
Total number of tablets actually taken during 2 weeks in each treatment period = 
total number of tablets dispensed during 2 weeks in each treatment period  – total 
number of tablets returned during 2 weeks in each treatment period, where 

Total number of tablets dispensed during 2 weeks in each treatment period 
will be calculated as the sum of tablets contained in the kits dispensed prior to 
Week 2/EOT Visit (i.e., excluding the kits dispensed at Week 2/EOT Visit), 

Total number of tablets returned during 2 weeks in each treatment period will 
be calculated as the sum of tablets returned in the kits dispensed prior to 
Week 2/EOT Visit,

Total number of tables dispensed and returned during 2 weeks in each
treatment period will be obtained from the IRT Accountability.
●
Exposure rate
Exposure rate based on number of tablets will be calculated as follows:
Total number of tablets taken during 2 weeks in each treatment period
[(Last visit date – First visit date +1) x 4] -4
x100
Total number of tablets calculation is provided in previous bullet for treatment 
compliance.
First visit date:
Period 1: Visit 4 CRF visit date
Period 2: Visit 7 CRF visit date
Last visit date:
Period 1: Last CRF visit date on or prior to CRF Visit 6 date or CRF Visit 
9/EOT date if the subject is discontinued in period 1
Period 2: Last CRF visit date on or prior to CRF Visit 9 date
●
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date 
of first dose of study drug. 


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Concomitant medication is defined as medication with at least one dose taken between 
the date of first dose of study drug and the date of last dose of study up to EOT. 
Imputed dates for the medication start date and stop date may be used to determine 
whether a medication is a previous or a concomitant medication (Section 7.10.1.4).
7
STATISTICAL METHODOLOGY
7.1
General Considerations
Efficacy, safety, PD and other variables will be summarized by treatment group, by treatment 
group and visit (schedule of assessments is provided in Table 1), or in combination as 
appropriate. Summaries will be provided as follows:
●
For continuous variables: number of subjects (n), mean, standard deviation (SD), 
median, minimum, and maximum. 
●
For continuous PK plasma concentration: n, geometric mean, SD, median, minimum,
maximum, and coefficient of variation. Geometric mean will be obtained by 
exponentiating the mean of log of the values; additional information will be provided 
in the TLF Specs document for the study. 
●
For categorical variables: number and percentages of subjects. 
Statistical hypothesis testing will be performed only if specified in this SAP. If statistical 
testing is performed, then treatment groups will be compared (CK-2127107 versus placebo)
using two-sided tests at the 0.10 significance level. No multiplicity adjustments will be made.
All data, including observed and derived data, will be presented in subject data listings.
All data processing, summaries, and analyses will be performed using SAS® Version 9.3 or 
higher. 
Definitions and Calculations:
Period baseline will be defined as the last non-missing measurement prior to the first dose of 
study drug in each period. That is, Baseline are the visit 4 and visit 7 in Figure 1 [Section 2] 
for period 1 and period 2, respectively if the value at each visit is not missing; if the value at 
each visit is missing, then the Baseline will be considered a missing value.
EOT Value
For the physical activity data collected using accelerometer, the available post-baseline 
measurements within the visit window as defined in Section 7.10.4.2 will be used to derive 
the EOT value.
For other efficacy data, the last available post-baseline measurement within the treatment 
period as defined by the visit window in Section 7.10.4.2 will be used as the EOT value.
Change from baseline to post-baseline will be calculated as: post-baseline value – baseline 
value.


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Percent change from baseline to post-baseline will be calculated as: 100 × (change / 
baseline). 
Handling of baseline value of 0 in analysis involving percent change is discussed in the TLF 
Specs for this study.
For follow-up visit, if a subject has at least one dose of study drug in period 2, then baseline 
result from period 2 will be used to calculate change from baseline and percent change from 
baseline. If a subject discontinues after at least one dose of study drug in period 1, period 1 
baseline result will be used to calculate change from baseline and percent change from 
baseline.
Treatment Period or Follow-up Period
Treatment Period
Treatment period for efficacy variables is defined as any assessment after the first dose day 
(Day 1) of study drug through last dose day of study drug in each period + 3 days. Treatment 
period for safety variables is defined as any assessment after the first dose day (Day 1) of 
study drug through last dose day of study drug in each period + 6 days.
Follow-up Period for Safety Data
Follow-up period for safety variables is defined as any assessment ≥ last dose day of study 
drug in last period + 7 days.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number of subjects screened (i.e., with informed consent), number of subjects 
rescreened (i.e., with informed consent), number and percentage of subjects screen-
failed, the primary reasons for screen failure (percentage will be based on number of 
subjects screen-failed), and randomized (overall only). For rescreened subjects, the 
results from the subject’s new ID will be used.
●
Number and percentage of subjects randomized in each analysis set, by sequence and 
overall.
●
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation for randomized subjects and SAF, by sequence 
and overall.
●
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation for randomized subjects, by sequence and overall.
●
Number and percentage of subjects for each protocol version by treatment sequence 
and ‘Total’ over all treatment sequences for randomized subjects, as well as, number 
and percentage of subjects for each protocol version for screen failures and total 
number of subjects including screen failures. For rescreened subjects, the results from 
the subject’s new ID will be used.


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7.2.2
Protocol Deviations
Protocol deviations, as defined in the study protocol (Section 8.1.6 [Protocol Deviations]), 
will be assessed for all randomized subjects. Number and percentage of subjects meeting any 
protocol deviation criteria will be summarized for each criterion and overall criteria, by 
sequence and overall. Subjects deviating from a criterion more than once will be counted 
once for the corresponding criterion. Any subjects who have more than one protocol 
deviation will be counted once in the overall summary. A data listing will be provided by 
subject.   
Protocol deviation criteria will be uniquely identified in the summary table and listing. The 
unique identifiers will be as follows:
PD1 – Entered into the study even though they did not satisfy entry criteria 
PD2 – Developed withdrawal criteria during the study and was not withdrawn
PD3 – Received wrong treatment or incorrect dose
PD4 – Received excluded concomitant treatment
PD5 – Plasma samples were not drawn
7.2.3
Demographic and Other Baseline Characteristics
The following demographic variables will be summarized by sequence and overall for all 
randomized subjects, SAF and FAS:
●
Sex (Male, Female) 
●
Age (years) at Screening, calculated  as: (date of Screening visit – date of birth + 1) / 
365.25, truncated to whole numbers 
●
Age group (< 65 years, 65 – 75 years, > 75 years) 
●
EudraCT Age Category (Adults (18 – 64 years) , 65 – 84 years)
●
Race (White, Black or African-American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other pacific islander, Other). 
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Weight (kg) at Screening
●
Height (cm) at Screening 
●
Body mass index (BMI) (kg / m2) at Screening, calculated as weight / [(height / 
100)2], where weight is measured in kg and height is measured in cm.
●
FEV1 at Screening
○
pre-Bronchodilator measured (L)
○
post-Bronchodilator measured (L)
○
pre-Bronchodilator percent predicted (%) = (Pre-Bronchodilator measured (L)
/ Predicted (L)) x 100
In the numerator, Pre-Bronchodilator measured (L) is from Screening 
Pulmonary Function CRF. In the denominator, predicted (L) result is from 
Screening Pulmonary Function CRF.


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○
post-Bronchodilator percent predicted (%) = (Post-Bronchodilator measured 
(L) / Predicted (L)) x 100
In the numerator, Post-Bronchodilator measured (L) is from Screening 
Pulmonary Function CRF. In the denominator, predicted (L) result is from 
Screening Pulmonary Function CRF.
○FVC at Screening
○
pre-Bronchodilator measured (L)
○
post-Bronchodilator measured (L)
○
pre-Bronchodilator percent predicted (%) = (Pre-Bronchodilator measured 
(L) / Predicted (L)) x 100
In the numerator, Pre-Bronchodilator measured (L) is from Screening 
Pulmonary Function CRF. In the denominator, predicted (L) result is from 
Screening Pulmonary Function CRF.
○
post-Bronchodilator percent predicted (%) = (Post-Bronchodilator measured 
(L) / Predicted (L)) x 100
In the numerator, Post-Bronchodilator measured (L) is from Screening 
Pulmonary Function CRF. In the denominator, predicted (L) result is from 
Screening Pulmonary Function CRF.
●
Pre-Bronchodilator measured FEV1/FVC ratio (%) at Screening
Pre-Bronchodilator measured FEV1/FVC ratio (%) at Screening = 
(Pre-Bronchodilator measured FEV1 (L) at Screening / Pre-Bronchodilator measured 
FVC (L) at Screening) x 100
●
Post-Bronchodilator measured FEV1/FVC ratio (%) at Screening
Post-Bronchodilator measured FEV1/FVC ratio (%) at Screening = 
(Post-Bronchodilator measured FEV1 (L) at Screening / Post-Bronchodilator 
measured FVC (L) at Screening) x 100
●
FRC measured (L) at Screening
●
FRC percent predicted (%) at Screening
FRC percent predicted (%) at Screening = (FRC measured (L) at Screening / FRC 
predicted (L) at Screening) x 100
●
SVC measured (L) at Screening
●
SVC percent predicted (%) at Screening
SVC percent predicted (%) at Screening = (SVC measured (L) at Screening / SVC 
predicted (L) at Screening) x 100
●
TLC measured (L) at Screening 
●
TLC percent predicted (%) at Screening
TLC percent predicted (%) at Screening = (TLC measured (L) at Screening / TLC 
predicted (L) at Screening) x 100
●
IC measured (L) at Screening
●
IC percent predicted (%) at Screening
IC percent predicted (%) at Screening =(IC measured (L) at Screening / IC predicted 
(L) at Screening) x 100
●
VA measured (L) at Screening


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●
VA percent predicted (%) at Screening
VA percent predicted (%) at Screening = (VA measured (L) at Screening / VA 
predicted (L) at Screening) x 100
●
DLCO measured (mL/min/mmHg)
●
DLCO percent predicted (%) at Screening
DLCO percent predicted (%) at Screening =  (DLCO measured (mL/min/mmHg) at 
Screening / DLCO predicted (mL/min/mmHg) at Screening) x 100
●
IET Ramp rate (watt/min) at Screening (Exercise protocol)
●
IET Ramp duration (min) at Screening (Exercise protocol)
●
CWR work rate (watt) at Screening (Exercise protocol)
●
CWR duration (min) at Screening (Exercise protocol)
●
IET Peak parameters at Screening (IET Physiology Parameters)
○
IET WR (watt)
○
IET VO2 (mL/min/kg)
IET VO2 (mL/min/kg) = (IET VO2 (L/min) at Screening x 1000) / Weight (kg) 
at Screening
○
IET VCO2 (L/min) 
○
IET PETO2 (mmHg)
○
IET PETCO2 (mmHg)
○
IET VT (L)
○
IET Bf (breaths/min)
○
IET VE (L/min)
○
IET IC (L)
○
IET HR (beats/min)
○
IET SYSBP (mmHg)
○
IET DIABP (mmHg)
○
IET SPO2 (%)
○
IET Borg (Dyspnea)
○
IET Borg (Leg Effort)
The above results are from Screening Procedures – IET Physiology CRF. From 
this CRF, results from Peak will be used.
In addition the following parameters will be derived:
○
IET VE/MVV (%) Peak at Screening
IET VE/MVV (%) = (VE (L/min) x 100) / (FEV1 (L) at Screening (Pre-
exercise spirometry) x 40)
In the numerator, VE (L/min) result is from Screening Procedures – IET
Physiology CRF. VE result from Peak will be used as VE (L/min). In the 
denominator, FEV1 (L) at Screening result is from pre-exercise spirometry 
Screening Procedures – IET CRF.
○
IET IRV measured (L) Peak at Screening
IET IRV measured (L) at Screening = IET VT (L) at Screening – IET IC (L) at 
Screening


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VT (L) and IET IC (L) results are from Screening Procedures – IET
Physiology CRF. VT result from Peak and IC result from Peak will be used.
○
IET RER Peak at Screening
IET RER = IET VCO2 (L/min) at Screening / IET VO2 (L/min) at Screening
In the numerator, VCO2 (L/min) result is from Screening Procedures – IET
Physiology CRF. VCO2 result from Peak will be used as VCO2 (L/min). In the 
denominator, VO2 (L/min) result is from Screening Procedures – IET
Physiology CRF. VO2 result from Peak will be used as VO2 (L/min).
○
IET VO2 percent predicted (%) Peak at Screening
IET VO2 percent predicted (%) = (VO2 measured (L/min) / VO2max predicted 
(L/min)) x 100
In the numerator, VO2 measured (L/min) result is from Screening Procedures 
– IET Physiology CRF. VO2 result from Peak will be used as VO2 measured 
(L/min). In the denominator, VO2max predicted (L/min) result is from 
Screening Procedures – IET CRF.
●
IET Rest parameters at Screening (IET Physiology Parameters)
○
IET WR (watt)
○
IET VO2 (mL/min/kg)
IET VO2 (mL/min/kg) = (IET VO2 (L/min) at Screening x 1000) / Weight (kg) 
at Screening
○
IET VCO2 (L/min) 
○
IET PETO2 (mmHg)
○
IET PETCO2 (mmHg)
○
IET VT (L)
○
IET Bf (breaths/min)
○
IET VE (L/min)
○
IET IC (L)
○
IET HR (beats/min)
○
IET SYSBP (mmHg)
○
IET DIABP (mmHg)
○
IET SPO2 (%)
○
IET Borg (Dyspnea)
○
IET Borg (Leg Effort)
These results are from Screening Procedures – IET Physiology CRF. From this 
CRF, results from Rest will be used.
●
IET LT parameters at Screening (IET Physiology Parameters)
○
IET WR (watt)
○
IET VO2 (mL/min/kg)
IET VO2 (mL/min/kg) = (IET VO2 (L/min) at Screening x 1000) / Weight (kg) 
at Screening
○
IET VCO2 (L/min) 
○
IET PETO2 (mmHg)
○
IET PETCO2 (mmHg)


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○
IET VT (L)
○
IET Bf (breaths/min)
○
IET VE (L/min)
○
IET IC (L)
○
IET HR (beats/min)
○
IET SYSBP (mmHg)
○
IET DIABP (mmHg)
○
IET SPO2 (%)
○
IET Borg (Dyspnea)
○
IET Borg (Leg Effort)
These results are from Screening Procedures – IET Physiology CRF. From this 
CRF, results from LT will be used.
●
IET FEV1 (L) at Screening (Pre-exercise spirometry)
●
IET FVC (L) at Screening (Pre-exercise spirometry)
●
IET FEV1/FVC ratio (%) at Screening (Pre-exercise spirometry)
Number and percentage of subjects randomized in each country will be presented by 
sequence and overall for all randomized subjects. 
7.2.3.1 Medical History 
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, by sequence and overall for the SAF.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with World Health Organization – Drug Dictionary 
(WHO-DD), and will be summarized using number and percentage of subjects by therapeutic 
subgroup (ATC 2nd level), chemical subgroup (ATC 4th level) and preferred WHO name by 
sequence and overall for the SAF.  
Concomitant medication will be summarized similarly. Subjects taking the same medication 
multiple times will be counted once per medication. A medication which can be classified 
into several chemical and/or therapeutic subgroups is presented in all chemical and 
therapeutic subgroups. 
7.3
Study Drugs
Duration of exposure and treatment compliance will be summarized for each treatment by 
sequence and overall for the SAF and FAS.
7.3.1
Exposure
Duration of exposure will be summarized as below:
●
As a continuous variable: number of subjects exposed, mean duration of exposure, 
SD, median, minimum and maximum.
●
As a categorical variable: number and percentage of subjects in each of the following 
duration categories:


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o
0 day
o
1 to 13 days
o
14 days
o
>14 days
7.3.2
Treatment Compliance
Treatment compliance will be summarized in two ways:
●
As a continuous variable: mean compliance and other descriptive statistics.
●
As a categorical variable: number and percentage of subjects in each of the following 
compliance categories:
o
< 50%
o
50%  - < 75% 
o
75%  - < 90%
o
90% - ≤ 100%
o
> 100%
7.3.3
Exposure Rate
Exposure rate will be summarized in two ways:
●
As a continuous variable: descriptive statistics will be presented.
●
As a categorical variable: number and percentage of subjects in each of the following 
exposure rate categories:
o
< 50%,
o
≥ 50%  to < 75%,
o
≥ 75%  to < 90%, 
o
≥ 90% to ≤ 100%, and
o
>100%.
7.4
Analysis of Efficacy 
7.4.1
Overview of Efficacy Analyses
Efficacy analysis will be conducted on the FAS.  The interpretation of results from statistical 
tests will be based on the FAS. Table 3 summarizes the analyses of the primary, secondary 
and exploratory efficacy variables. The table footnotes provide explanatory information and 
details. Handling of missing data is addressed in Section 7.10.1, if applicable.


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Table 3
Overview of Planned Efficacy Analyses
Analysis Variable /Analysis Type
Analysis Method
Primary Efficacy Variable: Change from period baseline in CWR endurance time at the end of each period
1.1
Primary Analysis:
Mixed effect model: subject as a random effect; 
treatment and period as fixed effects
1.1.1
Exploratory data (physical activity weekly 
parameters and C-PPAC parameters) Primary 
Analysis
Analysis of Covariance (ANCOVA) model:
baseline as covariate; treatment as a fixed effect
1.2
Secondary Analyses:
1.2.1
Baseline, Post-baseline and change from baseline
by each treatment and sequence
Descriptive statistics
1.3
Sensitivity Analyses:
1.3.1
Carry-over effect is a covariate
Mixed effect model: subject as a random effect; 
treatment, period and carry-over as fixed effects
1.4
Subgroup Analyses: 
1.4.1
   Gender
Descriptive statistics: Repeat 1.2.2 by each 
subgroup
1.4.2
   Race
1.4.3
   Age Group
Secondary Efficacy Variables:
-
Change from period baseline in Physiological parameters (VO2, VCO2, VE/VCO2, PETO2, PETCO2, 
VT, Bf, VE, IC, VE/MVV, HR, SBP/DBP, SPO2, IRV, RER) at isotime
-
Change from period baseline in peak physiological parameters
-
Change from period baseline in change from rest to peak value of IC
-
Change from period baseline in Borg CR10 at isotime and peak for dyspnea and leg effort
-
Change from period baseline in activation of accessory respiratory muscles by EMG at isotime
-
Change from period baseline in peak activation of accessory respiratory muscles by EMG
-
Change from period baseline in spirometry (resting FEV1/FVC, resting FEV1, resting FEV1
percent predicted, resting FVC and resting FVC percent predicted)
X.1
Same as primary analysis in primary endpoint
Mixed effect model: subject as a random effect; 
treatment and period as fixed effects
X.2.2
Baseline, Post-baseline and change from baseline 
by each period and sequence
Descriptive statistics
X.3.1
Carry-over effect is a covariate
Mixed effect model: subject as a random effect; 
treatment, period and carry-over as fixed effects
Table continued on next page


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Exploratory Efficacy Variables:
-
Change from period baseline in SGRQ-C (Total score and each domain score), SF-36 (Total score 
and each domain score), SPPB, 1RM, MIP and MEP
-
Change from period baseline in resting physiological parameters
-
Change from period baseline in Borg CR10 at rest for dyspnea and leg effort
-
Change from period baseline in resting activation of accessory respiratory muscles by EMG
X.1
Same as primary analysis in primary endpoint
Mixed effect model: subject as a random effect; 
treatment and period as fixed effects
X.2.2
Baseline, Post-baseline and change from baseline 
by each period and sequence
Descriptive statistics
X.3.1
Carry-over effects a covariate
Mixed effect model: subject as a random effect; 
treatment, period and carry-over as fixed effects
Exploratory Efficacy Variables: Change from period baseline in PROactive (physical activity weekly 
parameters and C-PPAC parameters)
X.1.1
Analysis of Covariance (ANCOVA) with baseline 
as covariate
ANCOVA model: baseline as covariate; 
treatment as a fixed effect for physical activity 
weekly continuous parameters excluding mean 
total wearing time parameters
X.2.2
Baseline, Post-baseline and change from baseline
Descriptive statistics
Analysis Results Presentation
The following statistics will be provided in tables summarizing results from analysis.
Mixed effect model or ANCOVA tables of results:
●
n, mean and standard error (SE) for each treatment group
●
Difference in LS means (CK-2127107 vs. placebo) and SE
●
Two-sided 90% CI for treatment difference
●
Two-sided p-value for each fixed effect
●
Two-sided p-value for treatment difference 
Descriptive tables of results:
n, mean, SD, median, minimum, and maximum for each period and sequence
7.4.2
Analysis of Primary Endpoint
The primary endpoint is the difference in change from period baseline in CWR endurance time
at the end of each period.
7.4.2.1 Primary Analysis
An overview of the planned analyses of the primary variable is provided in Table 3  The 
primary analysis for the change from period baseline in CWR endurance time will be a mixed 
effect model with subject as a random effect and treatment and period as fixed effects. A 
mixed effect model is a standard model for a crossover trial. It improves efficiency by taking in 
to account both within-subject and between-subject variances. Compound symmetry will be 
used as a covariance structure. Restricted maximum likelihood will be used to estimate the 


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model parameters. Two-sided 90% confidence interval will be provided based on this model.  
In addition, statistical tests will be performed based on the model. The hypothesis for 
comparisons is given as follows:
H0: The change from baseline at the end of period for CK-2127107 and placebo are the 
same
H1: The change from baseline at the end of period for CK-2127107 and placebo are not 
the same
Comparisons will be performed at a two-sided 0.10 significance level. The primary analysis 
will use the FAS. In a mixed effect model analysis, the subject who has at least either one of 
the change from period baseline from period 1 and period 2 will be included in the analysis.
7.4.2.2 Secondary Analysis
Period baseline, period post-baseline and change from period baseline for the primary 
endpoint by period and sequence will be summarized as descriptive statistics. 
7.4.2.3 Sensitivity Analysis
The same analysis of the primary endpoint as described in [Section 7.4.2.1] will be conducted 
with a model that adds carry-over as a fixed effect to the primary analysis model.
7.4.2.4 Subgroup Analysis
Period baseline, period post-baseline and change from period baseline for the primary 
endpoint by each period and sequence will be summarized separately by gender, race and age 
group. 
7.4.3
Analysis of Secondary Endpoints 
An overview of the planned analyses of the secondary endpoints is provided in Table 3 The 
analyses for the primary endpoint [Section 7.4.2.1, 7.4.2.2 and 7.4.2.3] will be repeated for 
change from period baseline in each secondary endpoint, and period baseline, period 
post-baseline and change from period baseline for all secondary endpoints by period and 
sequence will be summarized as descriptive statistics:
●
Physiological parameters (VO2, VCO2, VE/VCO2, PETO2, PETCO2, VT, Bf, VE, IC, 
VE/MVV, HR, SBP/DBP, SPO2, IRV, RER) at isotime
●
Peak physiological parameters
●
Change from rest to peak value of IC
●
Borg CR10 at isotime
○
Dyspnea 
○
Leg Effort
●
Borg CR10 at peak
○
Dyspnea 
○
Leg Effort
●
Activation of accessory respiratory muscles by EMG at isotime
●
Peak activation of accessory respiratory muscles by EMG


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●
Spirometry (resting FEV1/FVC, resting FEV1, resting FEV1 percent predicted, resting 
FVC and resting FVC percent predicted)
7.4.4
Analysis of Exploratory Endpoints 
An overview of the planned analyses of the exploratory endpoints is provided in Table 3. The 
analyses for the primary endpoint [Section 7.4.2.1, 7.4.2.3 and 7.4.2.4] will be repeated for 
each exploratory endpoint, and period baseline, period post-baseline and change from period 
baseline for all secondary endpoints by period and sequence will be summarized as 
descriptive statistics:
●
Change from period baseline in physiological parameters (VO2, VCO2, VE/VCO2, 
PETO2, PETCO2, VT, Bf, VE, IC, VE/MVV, HR, SBP/DBP, SPO2, IRV, RER) at rest
●
Change from period baseline in Borg CR10 at rest
○
Dyspnea 
○
Leg Effort
●
Change from period baseline in SGRQ-C total score and each domain score
●
Change from period baseline in SF-36 total score and each domain score
●
Change from period baseline in activation of accessory respiratory muscles (by EMG) 
at rest during CWR
●
Change from baseline in PROactive
An overview of the planned analyses of the exploratory endpoints is provided in 
Table 3  For the weekly continuous physical activity parameters excluding mean total 
wearing time parameters, change from baseline result at week 2 will be analyzed 
using an ANCOVA with baseline as a covariate and treatment as a fixed effect. 
Weekly derived parameters median steps score group and median VMU group, 
baseline value, postbaseline value will be summarized using number and percentage 
of subjects by treatment. For the weekly derived parameters mean total wearing time 
on valid days, mean total wearing time of all days, mean average MI, median VMU,  
mean AEE, mean TEE and median number of steps, baseline value, postbaseline 
value and change from baseline to each specified postbaseline time point will be 
summarized using descriptive statistics.
For the C-PPAC parameters difficulty, amount and total scores, baseline value, 
postbaseline value and change from baseline to each specified postbaseline time point
will be summarized using descriptive statistics.
●
Change from period baseline in SPPB
●
Change from period baseline in 1RM
●
Change from period baseline in MIP
●
Change from period baseline in MEP
7.5
Analysis of Safety
All safety variables will be presented using descriptive statistics by treatment group and total 
for SAF, unless specified otherwise. No statistical hypothesis testing will be performed.


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7.5.1
Adverse Events
Summaries and listings of serious adverse events (SAEs) and Serious TEAEs include SAEs 
upgraded by the sponsor based on review of the Sponsor’s list of Always Serious terms if any 
upgrade was done. 
The coding dictionary for this study will be Medical Dictionary for Regulatory Activities 
(MedDRA). It will be used to summarize AEs by SOC and PT. 
In the subject count, subjects reporting more than one AE for a given MedDRA PT will be 
counted only once for that term. Subjects reporting more than one occurrence of the same AE 
within a SOC will be counted only once for the SOC total. Subjects reporting more than one 
AE will be counted only once in the overall AE total.
An overview table will summarize the following details: 
●
Number of the following TEAE variables:
○
TEAEs
○
Drug related TEAEs (defined as any TEAE with possible, probable or missing
relationship to study drug as assessed by the investigator)
○
Serious TEAEs
○
Drug related serious TEAEs
○
TEAEs leading to death
○
Drug related TEAEs leading to death
○
TEAEs leading to permanent discontinuation of study drug
○
Drug related TEAEs leading to permanent discontinuation of study drug
●
Number and percentage of subjects with the following TEAE variables:
o
TEAEs
o
Drug related TEAEs
o
Deaths
o
Serious TEAEs
o
Drug related serious TEAEs
○
TEAEs leading to death
○
Drug related TEAEs leading to death
o
TEAEs leading to permanent discontinuation of study drug
o
Drug related TEAEs leading to permanent discontinuation of study drug
●
Number of deaths reported after the first study drug administration.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. Summaries will be provided for:
●
TEAEs
●
Drug related TEAEs 
●
Serious TEAEs 
●
Drug related serious TEAEs
●
TEAEs leading to permanent treatment discontinuation of study drug
●
Drug related TEAEs leading to permanent treatment discontinuation of study drug


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●
TEAEs excluding serious adverse events that equal or exceed a threshold of 5.0% in 
any treatment group
●
Common TEAEs (≥ 5.0% in any treatment group)
●
TEAEs by severity 
If a subjects has multiple TEAEs with the same SOC and PT, but with differing 
severity, then the subject will be counted only once with the worst severity, however, 
if any of the severity values are missing then the subject will be counted only once 
with missing severity. 
TEAE with missing severity will be displayed with a missing category. 
●
Drug related TEAEs by severity
●
TEAEs by relationship to study drug
If a subjects has multiple TEAEs with the same SOC and PT, but with differing 
relationship, then the subject will be counted once with the highest degree of 
relationship, however, if any of the relationship values are missing, then the subject 
will be counted only once with missing relationship.  
TEAE with missing relationship to study drug missing will be counted as drug related.
The number of TEAEs, as classified by SOC and PT will be summarized for each treatment 
group. Summaries will be provided for:
●
Serious TEAEs
●
Drug related serious TEAEs
●
TEAEs excluding serious adverse events that equal or exceed a threshold of 5.0% in 
any treatment group 
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized for each treatment group. 
7.5.2
Clinical Laboratory Evaluation
Raw values at each scheduled laboratory measurement visit, changes from Baseline at each 
post-baseline scheduled visit, and shifts from Baseline will be summarized for each 
laboratory parameter (as appropriate) in International System of Units (SI) using descriptive 
statistics. It will be summarized 1) by treatment group, and 2) by sequence and treatment 
group. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. The number and percentage of subjects 
below and above reference range will be summarized for each treatment group at each visit.
For hematology and biochemistry variables, shift relative to normal ranges from Baseline to 
each scheduled post-Baseline laboratory measurement. 
Number and percentage of subjects with positive and negative results in qualitative urinalysis 
variables will be presented for each treatment group at each visit. 


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All laboratory measurements, including the derived outcomes (changing from Baseline and 
flagging of abnormal value with high and low) will be presented in listing. 
7.5.2.1 Liver Enzymes and Total Bilirubin
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s maximum value during the study 
period will be used, which is defined in Section 6.2.2
Parameter
Criteria
ALT
> 3×ULN
> 5×ULN
> 10×ULN
> 20×ULN
AST
> 3×ULN
> 5×ULN
> 10×ULN
> 20×ULN
ALT or AST
> 3×ULN
Total Bilirubin
> 2×ULN
ALP
> 1.5×ULN
ALT or AST and Total Bilirubin*
(ALT and/or AST > 3×ULN) and Total 
Bilirubin > 2×ULN
The denominator will be the number of subjects who had at least one non-missing post-baseline value 
in each period.
*Combination of values measured within same sample (i.e., sample collected on the same day)
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the study period will be presented by treatment group.
The following data will be presented graphically: 
●
Scatter plot of individual subject maximum postbaseline relative to ULN values for ALT 
or AST and TBL during the study period with ALT or AST values on x-axis and total 
bilirubin values on y-axis [Senior, 2014]. Here maximum postbaseline relative to ULN
values for ALT or AST for each subject = maximum of (maximum relative to ULN 
postbaseline value for ALT, maximum relative to ULN postbaseline value for AST), and
●
Line plot of individual subject relative to ULN values for liver enzymes and total 
bilirubin and list of adverse events for selected subjects experiencing potentially 
clinically significant criteria of postbaseline ALT > 3xULN or AST > 3xULN or TBL > 
2xULN during the study period.
A listing will be presented for liver enzymes and total bilirubin results for subjects 
experiencing potentially clinically significant criteria of postbaseline ALT > 3xULN or AST 
> 3xULN or TBL > 2xULN during the study period.


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7.5.2.2 Serum Creatinine and Cystatin C
The following potentially clinically significant criteria in Serum Creatinine and Cystatin C 
tests and their combination are defined. The subject’s maximum value among all postbaseline 
results in each period will be used.
Parameter
Criteria
Serum Creatinine
>=1.5 to <=2 x baseline
>=1.5 to <=2 x baseline and abnormal
>2 x baseline
>2 x baseline and abnormal
Cystatin C
>=1.5 to <=2 x baseline
>=1.5 to <=2 x baseline and abnormal
>2 x baseline
>2 x baseline and abnormal
Serum Creatinine or Cystatin C
Serum Creatinine >=1.5 to <=2 x baseline or Cystatin C  
>=1.5 to <=2 x baseline
(Serum Creatinine >=1.5 to <=2 x baseline and abnormal) 
or (Cystatin C  >=1.5 to <=2 x baseline and abnormal)
Serum Creatinine and Cystatin C(*)
Serum Creatinine >=1.5 to <=2 x baseline and Cystatin C  
>=1.5 to <=2 x baseline
Serum Creatinine >=1.5 to <=2 x baseline and abnormal
Serum Creatinine and Cystatin C  >=1.5 to <=2 x 
baseline and abnormal cystatin C
The denominator will be the number of subjects who had a non-missing baseline value and at least 
one post-baseline value in each period.
Abnormal: below LLN or above ULN for the post baseline result in each period.
(*) Combination of values measured from the samples collected on the same day.
The number and percentage of subjects with potentially clinically significant values in Serum 
Creatinine and Cystatin C tests during the study period will be presented by treatment. 
A scatter plot of maximum postbaseline relative to baseline value for serum creatinine and
cystatin C during the study period with serum creatinine values on x-axis and cystatin C 
values on y-axis. 
A listing will be presented for serum creatinine, Cystatin C and BUN results for subjects 
experiencing the above potentially clinically significant criteria for any postbaseline result. 
7.5.3
Vital Signs
Vital signs values at each scheduled visit and changes from Baseline at scheduled 
post-Baseline visit will be summarized by 1) treatment group and 2) by sequence and 
treatment group.


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7.5.4
Electrocardiograms (ECGs)
Raw values (categorical) and changes from Baseline (shift from Baseline) will be 
summarized, and the summaries will include number and percentage of subjects with normal
and abnormal 12-lead ECG findings. It will be summarized 1) by treatment group, and 2) by 
sequence and treatment group. If there is more than one result reported at each time point, 
worst case i.e., abnormal will be used.
Number and percentage of patients with 12-lead ECG abnormalities will be summarized by 
treatment group and time point. If a subject has more than one abnormality at a given time 
point that corresponded to a single interpretation then the subject will be counted once for 
each abnormality. Also at a given time point, if a subject has the same abnormality 
reported more than once, then the subject will be counted only once for that abnormality.
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.
7.6
Analysis of PK
7.6.1
Plasma Concentrations
Descriptive statistics (i.e., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation, geometric mean and geometric cv) will be provided for plasma 
concentrations (day 14 Ctrough and C6h and day 1 (only for period 2) pre-dose plasma 
concentration) of CK-2127107 and CK-2127106.
7.6.2
Statistical Analysis
An exploration of covariates of day 14 Ctrough, including sex, age, and body weight will be 
investigated.  If applicable, population pharmacokinetic analysis will be further employed to 
explore covariates and such analysis will be performed by pharmacokinetic modeling and 
simulation group. The population analysis will be reported separately.
7.6.3
Concentration-Response Relationship Analysis
Potential relationship between day 14 Ctrough of CK-2127107 or CK-2127106 and 
efficacy/safety measures (primary/secondary/exploratory efficacy endpoints) will be explored
and such analysis will be performed by pharmacokinetic modeling and simulation group.  If 
applicable, exposures derived from the population analysis will be also utilized for the 
exploration exposure- efficacy measures relationships.  This will be reported separately.
7.7
Subgroups of Interest 
Primary efficacy endpoint will be summarized by the treatment group for the following 
subgroups and categories of interest. 
Additional information is provided in Section 7.4.2.4


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Subgroup
Subgroup Category
Sex
Female
Male
Race
White
Black or African-American
Asian
American Indian or Alaska Native
Native Hawaiian or other pacific islander
Other
Age group
< 65 years
≥ 65 years
7.8
Other Analyses
No specific other analyses will be performed in this study.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No interim analysis will be performed in this study.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.10.1
Missing Data
7.10.1.1 Handling of Missing Efficacy Data 
Unless otherwise specified, no missing data will be imputed for any descriptive statistics 
summaries of efficacy variables. All observed data in subject who has missing value or 
discontinues during the study will be used for a mixed effect model analysis.
7.10.1.2 Handling of Missing Safety Data 
Unless otherwise specified, no missing data will be imputed in any summaries or analyses of 
the safety variables defined in Section 6.2 and of other variables defined in Section 6.4.
7.10.1.3 Handling of Missing Diagnosis/Onset Date
Missing diagnosis/onset date will be imputed as follows. If only the day of the month is 
missing (e.g., MAR/2016), then the first day of the month will be used (01/MAR/2016), and 
if both day and month are missing (e.g., 2016), then the first day of January will be used 
(01/JAN/2016). If an onset date is missing completely, the imputed onset date will be the 
latest of the following non-missing dates:
●
First dose date of study drug in period 1
●
Randomization date + 1 day


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7.10.1.4 Handling of Missing Start and Stop Dates of Previous and Concomitant 
Medications
For Previous and Concomitant Medications, a missing or incomplete start and stop dates will 
be imputed according to the following conventions:
If start date is missing or partial:
●
if day is missing, use the first day of the month under consideration
●
if month is missing, use January
●
if year is missing, use year of the informed consent date
●
if entire date is missing, use informed consent date
If stop date is missing or partial and medication is not ongoing:
●
if month is missing, use December
●
if day is missing, use the last day of the month under consideration
●
if year or the entire date is missing, set to December 31st, 2099
If the imputed start date is after the stop date, then the imputed start date will be one day 
prior to the stop date.
Medication that ended or ongoing after the first dose date of study drug is counted as both 
previous medication as well as concomitant medication.
If the medication is ongoing, the stop date will remain missing.
7.10.2
Outliers
All values will be included in the analyses.
7.10.3
Values BLOQ
CK-2127107, CK-2127106 and metabolite (if applicable) plasma concentrations below limit 
of quantification (BLOQ) will be set to 0 for calculating descriptive statistics. For plasma 
concentrations, in cases where more than half of the individual data in a group are BLOQ, 
SD, coefficient of variation and geometric coefficient of variation will not be calculated. If 
one or more values are BLOQ, the geometric mean will not be calculated.
For laboratory safety quantitative variables, values recorded as “<X” or “<=X” or “>Y” or 
“>=Y” will be imputed by “X” and “Y” respectively for descriptive statistics. This will be 
documented in a footnote to all summary tables and all output where such a replacement was 
performed.
7.10.4
Visit Windows
The number of study days relative to the first dose date of study drug (Study Day), is 
calculated as: 
●
Study Day = Date of assessment – Date of first dose of study drug +1, when the date 
of assessment is on or after the date of first dose of study drug
●
Study Day = Date of assessment – Date of first dose of study drug, when the date of 
assessment is before the date of first dose of study drug.


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The day of the first dose of study drug is defined as Study Day 1, while the day before the 
date of first dose of study drug (i.e., Randomization visit) is defined as Study Day -1 (there is 
no Study Day 0). 
7.10.4.1 Post Dosing Efficacy Observations
For efficacy variables, observations will not contribute to the efficacy analyses if the 
patient’s last dose of study drug is as follows:
In each period, any days which are > 3 days after the last dose of study drug will not be 
included in the analysis related to on-treatment time points and the EOT time point. This 
needs to be done before implementing the visit windows in Section 7.10.4.2.
7.10.4.2 Algorithm for Computing Baseline and Post-Baseline in each period from 
Efficacy Variables
Baseline is defined as the last non-missing measurement prior to the first dose of study drug 
in each period. That is, Baseline are the visit 4 and visit 7 in Figure 1 [Section 2] for period 1 
and period 2, respectively if the value at each visit is not missing; if the value at each visit is 
missing, then the Baseline will be considered a missing value. 
EOT is defined as the last non-missing assessment in each period from the date of first dose 
of study drug + 1 through the date of last dose of study drug +3 days. 
Table 4
Time Windows for Analyses of Efficacy Variables
Treatment Period 
Time Point
Target Visit Day
(Study Day)
Time Window 
(Study Day Range)
Screening (IET)
–28 to –9
Period 1
Baseline
1
-3 to 1
Day 14
14
11 - 17
Period 2
Baseline
1
-3 to 1
Day 14
14
11 - 17
Follow-up*
last dose day+7
>= last dose day+4 to <= last dose day +14
* Follow-up visit is created for spirometry data only.
Table 5
Time Windows for Physical Activity (accelerometer) Data
Treatment 
Period 
Analysis Time 
Point
Visit Window 
(Study Day Range)
Baseline
-26 to -1 where data from (last reported day -7) to last reported day will be 
used
Period 1
Week 2
7 to 14
EOT
2 to 14 where post-baseline data from (last reported day -7) to last 
reported day will be used
Multiple assessments: For analysis, if a subject has more than one visit with a measurement 
included within a time window, the assessment closest to the target day will be used. If 


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multiple assessments exist in the same time window, the latest one will be picked. If more 
than one assessment is included on the same day, then the last assessment regarding the time 
on that day will be used in the analysis. If the time of assessment is not available, the worst 
assessment will be used (if applicable), otherwise the average will be used.
7.10.4.3 Post Dosing Safety and PD Observations
For safety and PD variables, observed days for the variables will not contribute to the 
analyses if the patient’s last dose of study drug is as follows:
Any days which are > 6 days after the last dose of study drug will not be included in the 
analysis related to on-treatment time points and the EOT time point. This needs to be done 
before implementing the visit windows in Section 7.10.4.4
7.10.4.4 Safety and PD Analyses
For safety laboratory tests, vital signs, ECG and PD variables:
Baseline is defined as the last non-missing measurement prior to the first dose of study drug 
in each period. That is, Baseline are the visit 4 and visit 7 in Figure 1 [Section 2] for period 1 
and period 2, respectively if the value at each visit is not missing; if the randomization visit 
value at period 1 is missing, then the Screening value (if applicable) will be used as the 
baseline value. If both the Screening and Randomization visit values are missing, the 
Baseline will be considered a missing value in the period 1.
Scheduled visits will use the visit window outlined in Table 6
Table 6
Visit Windows for Safety Laboratory Tests (Hematology and Urinalysis), 
Vital Signs, ECG and PD Variables
Treatment Period
Scheduled Visit 
Target Visit Day
(Study Day)
Time Window 
(Study Day Range)
Period 1
Baseline
1
≤ 1
Post-baseline
14
2 - 20
Period 2
Baseline
1
–7 - 1
Post-baseline
14
2 - 20
Follow-up
last dose day+7
>= last dose day+7
Table 7
Visit Windows for Safety Laboratory Tests (Biochemistries)
Treatment Period
Scheduled Visit 
Target Visit Day
(Study Day)
Time Window 
(Study Day Range)
Period 1
Baseline
1
≤ 1
Post-baseline 1
6
2 – 9
Post-baseline 2
14
10 – 20
Period 2
Baseline
1
–7 - 1
Post-baseline 1
6
2 – 9
Post-baseline 2
14
10 - 20
Follow-up
last dose day+7
>= last dose day+7


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Unscheduled visits: If a subject has an unscheduled visit, then the unscheduled assessment 
will be mapped to an analysis visit according to the visit window specified in Table 6.
Multiple assessments: For analysis, if a subject has more than one visit with a measurement 
included within a time window, the assessment closest to the target day will be used. If 
multiple assessments exist in the same time window, the latest one will be picked. If more 
than one assessment is included on the same day, then the last assessment regarding the time 
on that day will be used in the analysis. If the time of assessment is not available, the worst 
assessment will be used (if applicable), otherwise the average will be used.
For the PK plasma concentration data, any data days which are > 6 days after the last dose of 
study drug in each period will not be included in the analysis related to on-treatment visits. 
For the plasma concentrations, nominal visits will be used as analysis visits. 
For the visit 7 predose timepoint, if the actual time relative to dosing is after dosing, then the 
timepoint will be excluded from the descriptive statistics. For the visit 9/EOT/ED predose 
timepoint, if the actual time relative to dosing is after dosing or more than 4 hours prior to 
dosing, then the timepoint will be excluded from the descriptive statistics. For the 6 hours
timepoint, if the actual time relative to dosing is more than +/- 2 hours from the planned time 
of 6 hours, then the timepoint will be excluded from the descriptive statistics. 
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for 
change
1.0
25-Jan-2016
NA
Document finalized
2.0
13-Jun-2018
I. LIST OF ABBREVIATIONS AND 
KEY TERMS
Added abbreviations for physical activity 
parameters, efficacy parameters and 
removed abbreviation for SDD.
Due to the updates made 
to the SAP.
2.0
16-May-2018
2 Flow Chart and Visit Schedule are 
updated
Due to protocol version 
3.1.
2.0
16-May-2018
1 Introduction and 5 Analysis Sets
Updated wording about the allocation of 
subjects to PKAS.
Due to protocol version 
3.0.
2.0
16-May-2018
3.1.2 Secondary Objectives
The secondary objective about CWR 
parameters is updated.
Due to protocol version 
3.1.
2.0
16-May-2018
3.2 Study Design
Study design details are updated.
Due to protocol version 
3.1 and additional details 
are available in the 
protocol.
2.0
16-May-2018
4 Sample Size
Sample size details are updated about 
discontinuation rate.
Due to protocol version 
3.1.


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Version
Date
Changes
Comment/rationale for 
change
2.0
16-May-2018
5.1 Full Analysis Set (FAS)
The FAS definition in the SAP is updated 
to provide the variable name for the FAS.
Updated the word ‘period’ as ‘treatment 
period’.
Due to protocol version 
3.0.
Protocol Section 7.2.1 
definition for FAS did not 
list the variable needed for 
the analysis set.
Wording update is due to 
typographical error.
2.0
16-May-2018
5.2 Per Protocol Set (PPS)
PPS is removed.
Due to protocol version 
3.0.
2.0
16-May-2018
5.3 Pharmacokinetic Analysis Set 
(PKAS)
PKAS definition is updated as follows: The 
pharmacokinetic analysis set (PKAS) 
consists of the administered population for 
which at least one quantifiable plasma 
trough concentration or concentration at 6 
hours is available for CK-2127107 or CK-
2127106 and for whom the time of dosing 
on the day of sampling is known.
Quantifiable concentration 
and time of dosing is 
needed to determine the 
PKAS hence the 
definition for PKAS is 
updated.
2.0
13-Jun-2018
6.1 Efficacy Endpoints
Definitions for efficacy variables are added.
Derivation details for percent of predicted 
parameters that are used for the analysis are 
added.
7.4.3 Analysis of Secondary Endpoints 
Added list of derived parameters for 
percent of predicted FEV1 and FVC.
6.1.1 Primary Efficacy Endpoints
Definition of CWR duration is moved 
under Section 6 Efficacy Endpoints.
For CWR duration, a sentence about 
direction of improvement is added.
To provide definitions of 
efficacy variables and 
derivation details for 
percent of predicted 
parameters using 
predicted results.
To interpret the results for 
change from baseline
CWR duration and to 
provide all definitions in 
one section.
2.0
13-Jun-2018
6.1.2 Secondary Efficacy Endpoints
List of variables for other cardiometaboloic 
variables are added.
Derivation details for MVV, IRV, RER and 
VE/MVV are added.
Wording for ‘Accessory muscle EMG 
activity’ is updated as ‘Surface accessory 
muscle EMG activity’.
For endpoint Change in resting spirometry 
compared to placebo, details about the 
For clarification.
Wording update is due to 
protocol version 3.0.
To list and provide the 


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Version
Date
Changes
Comment/rationale for 
change
parameters are added. 
derivation details of 
spirometry parameters.
2.0
05-Jul-2018
6.1.3 Exploratory Efficacy Endpoints
Details about physical activity parameters 
and C-PPAC questionnaire parameters are 
added.
Added endpoints for CWR physiology at 
Rest (cardiometabolic variables), Borg 
CR10 at rest and EMG at Rest.
For clarification.
To provide summaries and 
analyses for these 
endpoints.
2.0
16-May-2018
6.2.1 Adverse Events
TEAE definition for day 1 is updated as 
follows: If the adverse event occurs on 
Day 1 and the onset check box is marked 
“Onset after first dose of study drug” or the 
onset check box is left blank, then the 
adverse event will be considered treatment 
emergent. If the adverse event occurs on 
Day 1 and the onset check box is marked 
“Onset before first dose of study drug”, 
then the adverse event will not be 
considered treatment emergent.
Time is not collected on 
the CRF page. Instead a 
check box is available for 
adverse events that occurs 
on day 1 to indicate Onset 
of a AE after first dose of 
study drug. 
2.0
16-May-2018
6.2.1 Adverse Events
Added the following for TEAE treatment 
period 1 in second paragraph:
If a subject discontinues in treatment period 
1, TEAEs at treatment period 1 will be 
defined as TEAE which occurs after first 
dose of study drug at treatment period 1 up 
to 14 days after the last dose of study drug.
Additional details are 
added to associate TEAE 
with a period in the 
situation of a subject 
discontinue the study in 
period 1.
2.0
16-May-2018
6.2.1 Adverse Events
Removed the imputation details of AEs
with missing onset dates (partial or full date 
is missing) and added a sentence 
referencing to Section 7.10.1.3.
Details about imputation 
are provided in section 
7.10.1.3 and added a 
sentence referencing to 
this section.
2.0
16-May-2018
6.2.3 Vital Signs
Parameter respiration is removed.
Not collected in the study.
2.0
16-May-2018
6.2.4 Electrocardiograms (ECGs)
ECG summary details are updated as 
follows:
The 12-lead ECG scheduled assessments 
will be made at Screening, Baseline and 
Day 14. The results will be recorded as 
From central reading, 
results are reported either 
normal or abnormal. 


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Version
Date
Changes
Comment/rationale for 
change
normal or abnormal. ECG variables are 
raw values (categorical) at each scheduled 
visit and changes from Baseline (shift from 
Baseline) at Day 14.
2.0
16-May-2018
6.4 Other Variables
Exposure rate is added and a corresponding 
section (Section 7.3.3) for the summary is 
added.
To provide exposure rate 
results using first and last 
CRF visit dates in the 
denominator.
2.0
16-May-2018
6.4 Other Variables
For treatment compliance, updated the 
formula for total number of tablets planned 
to receive as follows: 
Total number of tablets planned to receive 
during 2 weeks in each treatment period = 4 
× duration of exposure - 4.
Total treatment compliance (%) with 
tablets is removed.
For Previous and concomitant medication, 
removed the imputation details about 
previous or concomitant determination 
with missing start or end dates (partial 
or full date is missing) and added a 
sentence referencing to 
Section 7.10.1.4.
Tablet strength is 250 mg 
hence a subject needs to 
take a total of 4 tablets 
each day. Treatment 
compliance for each 
treatment is useful in a 
crossover study so total 
treatment compliance (%) 
with tablets is removed. 
Details about imputation 
of the start and end dates 
are provided in Section 
7.10.1.4 hence removed 
the paragraph and added a 
sentence referencing to 
this section.
2.0
16-May-2018
7.1 General Considerations
SAS procedure names for summaries of 
continuous or categorical variables are 
removed.
No need to list the SAS 
procedures in the SAP.
2.0
16-May-2018
7.1 General Considerations
EOT definition is updated.
Was:
Week 2/EOT will be defined as the last 
non-missing assessment in each period 
from the date of first dose of study drug 
through 1 day after the date of last dose of 
study drug up to Week 2/EOT. That is, 
post-baseline are the visit 6 and visit 8 in 
Figure 1 [Section 2] for period 1 and period 
2, respectively if the value at each visit is 
not missing.
Updated as:
EOT Value
For the physical activity data collected
using accelerometer, the available post-
baseline measurements within the visit 
For clarification.


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Version
Date
Changes
Comment/rationale for 
change
window as defined in Section 7.10.4.2 will 
be used to derive the EOT value.
For other efficacy data, the last available 
post-baseline measurement within the 
treatment period as defined by the visit 
window in Section 7.10.4.2 will be used as 
the EOT value.
2.0
16-May-2018
7.1 General Considerations
Treatment period and follow-up period 
definitions are added.
Details about calculating change from 
baseline for follow-up visit are added.
For clarification.
2.0
16-May-2018
7.2.1 Disposition of Subjects
Updated bullet points about rescreened 
patients. Treatment discontinuation will be 
presented for SAF as well.
A summary is added for number and 
percentage of subjects for each protocol 
version.
To explain how to handle 
the results from 
rescreened subjects. To 
provide treatment 
discontinuation summary 
for SAF.
To provide a summary for 
number and percentage of 
subjects for each protocol 
version.
2.0
13-Jun-2018
7.2.3 Demographic and Other Baseline 
Characteristics
Additional screening parameters for 
spirometry and IET are added.
To provide summary of 
additional parameters for 
spirometry and IET.
2.0
16-May-2018
7.3 Study Drugs
Sentence about exposure and treatment 
compliance is revised.
Was:
Duration of exposure and treatment 
compliance will be summarized by 
sequence and overall for the SAF and FAS. 
It will be also repeated by sequence and 
treatment.
Updated as:
Duration of exposure and treatment 
compliance will be summarized for each 
treatment by sequence and overall for the 
SAF and FAS. 
For clarification.


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Version
Date
Changes
Comment/rationale for 
change
2.0
17-Jul-2018
7.4.1 Overview of Efficacy Analyses
Table 3: Details about exploratory efficacy 
data (physical activity and C-PPAC 
questionnaire) are added. For secondary 
efficacy variables missing parameters RER, 
IRV, VE/VCO2 and VT are added. For Borg 
CR10 details about the parameters are 
added. 
Endpoints CWR physiology at Rest, Borg 
CR10 at rest and EMG at rest are moved 
from secondary endpoints to exploratory 
endpoints.
Label ‘Mixed effect model tables of results’ 
is updated as ‘Mixed effect model or 
ANCOVA tables of results’. 
For descriptive statistics, median, 
minimum, and maximum are added.
Due to the updates in 
Sections 6.1.2 and 6.1.3.
To provide the additional 
statistics that will help 
understand the distribution
of the data.
2.0
16-May-2018
7.4.3 Analysis of Secondary Endpoints
For physiological parameters missing 
parameters IRV, RER, VE/VCO2 and VT
are added. For Borg CR10 details about the 
parameters are added. For EMG, removed 
endpoints about rest and maximum.
Due to the updates in 
Section 6.1.2.
For EMG, the endpoints at 
rest is exploratory 
endpoint and the endpoint 
about maximum is 
redundant hence removed.
2.0
05-Jul-2018
7.4.4 Analysis of Exploratory Endpoints
For Change from baseline in PROactive, 
details about analysis of the PROactive 
parameters and C-PPAC questionnaire are 
added.
Added the endpoint about EMG at rest
For Borg CR10 at rest and physiological 
parameters at rest, details about the 
parameters are added.
Due to the updates in 
Section 6.1.3.
2.0
16-May-2018
7.5.1 Adverse Events
The following details are added for the 
overview of TEAEs:
TEAEs leading to death
Drug related TEAEs leading to death
The following details are added for number 
and percentage of subjects with TEAEs:
TEAEs leading to death
To provide summary for 
these variables.


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Version
Date
Changes
Comment/rationale for 
change
Drug related TEAEs leading to death
AE summary for number of deaths reported 
after the first study drug administration.
2.0
16-May-2018
7.5.1 Adverse Events
For TEAEs and drug-related TEAEs by 
severity removed NCI CTCAE Grade.
NCI CTCAE grading is 
not used in this study.
2.0
16-May-2018
7.5.2 Clinical Laboratory Evaluation
Removed the following sentence and 
moved to Section 7.5.2.1 Liver Enzymes 
and Total Bilirubin.
A listing will be presented for liver 
enzymes and total bilirubin results for 
subjects experiencing potentially clinically 
significant criteria of postbaseline ALT > 
3xULN or AST > 3xULN or TBL > 
2xULN during the study period. 
For clarification.
2.0
16-May-2018
Section 7.5.2.1 Liver Enzymes and Total 
Bilirubin
Details about denominator are added.
Added the following plots:
Scatter plot of individual subject maximum
postbaseline relative to ULN values for 
ALT or AST and TBL during the study 
period with ALT or AST values on x-axis 
and total bilirubin values on y-axis, and
Individual display of liver enzymes and 
total bilirubin for selected subjects 
experiencing potentially clinically 
significant criteria of postbaseline ALT > 
3xULN or AST > 3xULN or TBL > 
2xULN during the study period.
For clarification and to 
provide plots for liver 
enzymes and total 
bilirubin.
2.0
16-May-2018
Created a new section ‘Section 7.5.2.2 
Serum creatinine and Cystatin C’.
Removed the following sentence from
Section 7.5.2.1 Liver Enzymes and Total 
Bilirubin:
The number and percentage of subjects 
with potentially clinically significant values 
in Serum Creatinine, BUN and Cystatin C 
tests during the study period will be 
presented by treatment group.
To provide details about 
potentially clinically 
significant criteria and 
plots for Serum creatinine 
and Cystatin C.
2.0
16-May-2018
7.5.4 Electrocardiograms (ECGs)
Updated this section as follows:
Raw values (categorical) and changes from 
Baseline (shift from Baseline) will be 
Due to protocol version 
3.0.


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Version
Date
Changes
Comment/rationale for 
change
summarized, and the summaries will 
include number and percentage of subjects 
with normal and abnormal 12-lead ECG 
findings. It will be summarized 1) by 
treatment group, and 2) by sequence and 
treatment group. If there is more than one 
result reported at each time point, worst 
case i.e., abnormal will be used.
Number and percentage of patients with 12-
lead ECG abnormalities will be 
summarized by treatment group and time 
point. If a subject has more than one 
abnormality at a given time point that 
corresponded to a single interpretation then 
the subject will be counted once for each 
abnormality. Also at a given time point, if a 
subject has the same abnormality 
reported more than once, then the subject 
will be counted only once for that 
abnormality.
2.0
16-May-2018
7.6.2 Statistical Analysis and 7.6.3
Concentration-Response Relationship 
Analysis
Added a sentence that analysis will be 
performed by pharmacokinetic modeling 
and simulation group.
To provide the details of 
the function that will 
perform these analyses.
2.0
16-May-2018
7.10.1.3 Handling of Missing 
Diagnosis/Onset Date
Imputation details for missing AE onset 
date are added.
To provide the imputation 
details of AE onset date so 
that TEAE determination 
can be made.
2.0
16-May-2018
A new section for ‘7.10.1.4 Handling of 
Missing Start and Stop Dates of Previous 
and Concomitant Medications’ is added.
To provide imputation 
details of missing start and 
stop dates of previous and 
concomitant medications.
2.0
16-May-2018
A new section for ‘7.10.3 Values BLOQ’ 
is added and subsequent sections are 
renumbered.
To provide imputation 
details of results BLOQ or 
recorded as <X, <=X, >Y 
or >= Y.
2.0
16-May-2018
A new section for ‘7.10.4.1 Post Dosing 
Efficacy Observations’ is added.
To provide details about 
handling the efficacy data 
collected after last dose of 
study drug.
2.0
16-May-2018
7.10.4.2 Algorithm for Computing 
Baseline and Post-Baseline in each 
period from Efficacy Variables
Baseline, Week 2, EOT definitions are 
For baseline, efficacy 
results from study -3 to -1 
are not expected to be 
different from day 1.


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Version
Date
Changes
Comment/rationale for 
change
updated.
In Table 4, Target visit details are added. 
Also follow-up visit window details for 
spirometry are added.
Table is added to provide visit windows for 
physical activity data.
Details about handling multiple 
assessments are added.
For Week 2, Efficacy 
results from study day 11 
to 13 are not expected to 
be different from day 14 
to 17.
EOT definition is updated 
so that it is consistent 
treatment period window.
For clarification.
2.0
16-May-2018
A new section for ‘7.10.4.3 Post Dosing 
Safety and PD Observations’ is added.
To provide details about 
handling the safety and 
PD data collected after 
last dose of study drug.
2.0
16-May-2018
7.10.4.4 Safety and PD Analyses
In Tables 5 and 6, follow-up visit window 
details are updated.
Tables is added to provide visit windows 
for physical activity data.
Details about handling multiple 
assessments are updated.
Visit window details for PK concentrations 
data are updated.
Follow-up visit window 
details are updated so that 
it is consistent with 
follow-up period window.
For clarification.
To clarify that nominal 
visits will be used as 
analysis visits and 
additional details for the 
timepoint windows are 
added.
2.0
16-May-2018
10.2 Appendix 2: Key Contributors and 
Approvers
Primary Author and Contributors and 
Reviewers detailed are updated for SAP 
author, global statistical lead and clinical
study manager.
Due to changes to team 
members.


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9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Jones, B. and Kenward, M. G. (2014). Design and Analysis of Cross-Over Trials, Third Edition. CRC 
Press.
Mehrotra, D. V. (2014). A recommended analysis for 2 x 2 crossover trials with baseline 
measurements. Pharmaceutical Statistics, 13, 376-387.


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10
APPENDICES
10.1
Appendix 1: Predictive Equations
Spirometry (Male Adults 20 years; Female Adults 18 years)
Units: Height = cm; Age = years
FEV1 (L) – NHANES/Hankinson
Equation
Source
Caucasian Male
0.5536-0.01303*Age-
0.000172*Age2+0.0001498*Height2
Hankinson et al. Am J 
Respir Crit Care Med
159:179-187, 1999.
Caucasian Female
0.4333-0.00361*Age-
0.000194*Age2+0.00011496*Height2
African-American Male
0.3411-0.02309*Age+0.00013194*Height2
African-American Female
0.3433-0.01293*Age-
0.000097*Age2+0.00010846*Height2
Mexican-American Male
0.6306-0.02928*Age+0.00015104*Height2
Mexican-American Female
0.4529-0.01178*Age-
0.000113*Age2+0.00012154*Height2
Asian-American Male
(Caucasian Male FEV1)*0.94
Korotzer et al., Am J 
Respir Crit Care Med
161:1101–1108, 2000.
Asian-American Female
(Caucasian Male FEV1)*0.93
FVC (L) – NHANES/Hankinson
Equation
Source
Caucasian Male
-0.1933+0.00064*Age-
0.000269*Age2+0.00018642*Height2
Hankinson et al. Am J 
Respir Crit Care Med
159:179-187, 1999.
Caucasian Female
-0.3560+0.01870*Age-
0.000382*Age2+0.00014815*Height2
African-American Male
-0.1517-0.01821*Age+0.00016643*Height2
African-American Female
-0.3039+0.00536*Age-
0.000265*Age2+0.00013606*Height2
Mexican-American Male
0.2376-0.00891*Age-
0.000182*Age2+0.00017823*Height2
Mexican-American Female
0.1210+0.00307*Age-
0.000237*Age2+0.00014246*Height2
Asian-American Male
(Caucasian Male FEV1)*0.89
Korotzer et al., Am J 
Respir Crit Care Med
161:1101–1108, 2000.
Asian-American Female
(Caucasian Male FEV1)*0.94


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Lung Volumes (adults 18-70 yrs)
Units: Height = cm; Age = years
FRC (L) – ERS/ECSC/Quanjer
Equation
Source
Male
2.34*(Height/100)+(0.009*Age)-1.09
Quanjer et al., Eur Respir J 6 
(suppl 16):5-40, 1993.
Female
2.24*(Height/100)+(0.001*Age)-1.00
African-American 
race adjustment 
Both male and female = (Predicted_FRC)*0.88
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
Asian race 
adjustment
Male = (Predicted_FRC)*0.96
Female = (Predicted_FRC)*0.94
Korotzer et al., Am J Respir Crit 
Care Med 161:1101–1108, 2000.
Hispanic race 
adjustment
No adjustment
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
SVC (L) – ERS/ECSC/Quanjer
Equation
Source
Male
5.76*(Height/100)-(0.026*Age)-4.34
Quanjer et al., Eur Respir J 6 
(suppl 16):5-40, 1993.
Female
4.43*(Height/100)-(0.026*Age)-2.89
African-American 
race adjustment 
Both male and female = (Predicted_TLC)*0.88
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
Asian race 
adjustment
Male = (Predicted_TLC)*0.89
Female = (Predicted_TLC)*0.94
Korotzer et al., Am J Respir Crit 
Care Med 161:1101–1108, 2000.
Hispanic race 
adjustment
No adjustment
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
TLC (L) – ERS/ECSC/Quanjer
Equation
Source
Male
7.99*(Height/100)-7.08
Quanjer et al., Eur Respir J 6 
(suppl 16):5-40, 1993.
Female
6.60*(Height/100)-5.79
African-American 
race adjustment 
Both male and female = (Predicted_TLC)*0.88
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
Asian race 
adjustment
Male = (Predicted_TLC)*0.96
Female = (Predicted_TLC)*0.94
Korotzer et al., Am J Respir Crit 
Care Med 161:1101–1108, 2000.
Hispanic race 
adjustment
No adjustment
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
IC (L) – ERS/ECSC/Quanjer
Equation
Source
Male
IC = Predicted TLC – Predicted RV
RV= 1.31*(Height/100)+(0.022*Age)-1.23
Quanjer et al., Eur Respir J 6 
(suppl 16):5-40, 1993.
Female
IC = Predicted TLC – Predicted RV
1.81*(Height/100)+(0.016*Age)-2.00
African-American 
race adjustment 
Both male and female = (Predicted_TLC)*0.88
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.
Asian race 
adjustment
Male = (Predicted_TLC)*0.96
Female = (Predicted_TLC)*0.94
Korotzer et al., Am J Respir Crit 
Care Med 161:1101–1108, 2000.
Hispanic race 
adjustment
No adjustment
Pellegrino et al., Eur Respir J 26: 
948-968, 2005.


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Diffusing Capacity (adult, nonsmokers, single breath DLCO method)
Units: Height = cm; Age = years
DLCO (ml/mmHg/min, STPD) – Miller, Single Breath
Equation
Source
Male
12.9113+(0.4180*2.54*Height)-(0.2290*Age)
Miller et al., Am Rev Respir Dis
127:270-27, 1983.
Female
2.2382+(0.4068*2.54*Height)-(0.111*Age)
DLco/TLC (L) – Miller, Single Breath
Equation
Source
Male
These equations assume VA = TLC 
10.0882-(0.0570*2.54*Height)-(0.0309*Age)
Miller et al., Am Rev Respir Dis
127:270-27, 1983.
Female
These equations assume VA = TLC 
8.3297-(0.0460*2.54*Height)-(0.0157*Age)
Cycle Ergometry Aerobic Capacity (Adults)
Units: Weight = kg; Height = cm Age = years; 
VO2peak (L/min) – Hansen/Wasserman
Equation
Source
Male
Ideal weight = (0.79*Height)-60.7
Where actual weight equals or exceeds ideal weight:
VO2peak = (0.0337*Height)-(0.000165*Age*Height-
1.963)+0.006*(actualweight-idealweight)
Where actual weight is less than ideal weight:
VO2peak = (0.0337*Height)-(0.000165*Age*Height-
1.963)+0.014*(actualweight-idealweight)
Wasserman et al. 
Principles of Exercise 
Testing and 
interpretation 5th Edn. 
Lippincott Williams and 
Wilkins, 2012. Pp 158.
Female
Ideal weight = (0.65*Height)-42.8
VO2peak = (0.001*Height)*(14.783-0.11*Age)+0.006*
(actualweight-idealweight)


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10.2
Appendix 2: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author
Data Science
Contributors and Reviewers
Data Science
Medical Science
Clinical Science
Japan/Asia Clinical 
Development II
PPD
PPD
PPD
PPD
PPD