Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis ALS CK-2127107 Reldesemtiv
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 458
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the effect of CK-2127107 (hereafter referred to as reldesemtiv) versus placebo on respiratory function and other measures of skeletal muscle function in patients with ALS.

Detailed description:
This was a double-blind, randomized, placebo-controlled, dose ranging study of reldesemtiv in patients with ALS. Eligible patients were randomized (1:1:1:1) to receive placebo or one of three doses of reldesemtiv (150, 300, or 450 mg twice daily) for 12 weeks. Randomization was stratified by riluzole concomitant use/non-use and edaravone concomitant use/non-use. Concomitant riluzole and edaravone were allowed as long as the riluzole dose had been stable for at least 30 days prior to screening and edaravone had been taken for 2 cycles prior to screening; these drugs could not be initiated during the study.

A total of 7 study visits were planned: screening, Day 1 (first dosing day), Weeks 2, 4, 8, and 12, and follow-up (4 weeks after the last dose of study drug). Study drug (placebo or reldesemtiv) was to be taken twice daily, approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.

Arms:
arm 1: Patients in this arm took 1 reldesemtiv 150 mg oral tablet and 2 matching placebo tablets every 12 hours for 12 weeks. arm 2: Patients in this arm took 2 reldesemtiv 150 mg oral tablets and 1 matching placebo tablet every 12 hours for 12 weeks. arm 3: Patients in this arm took 3 reldesemtiv 150 mg oral tablets every 12 hours for 12 weeks. arm 4: Patients in this arm took 3 placebo oral tablets every 12 hours for 12 weeks.

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

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
 
Protocol CY 5022 
CY 5022 Protocol Amendment 03: 18 Apr 2018 
1 
 
 
 
PROTOCOL CY 5022 
 
A PHASE 2, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, DOSE-RANGING, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF CK-2127107 IN PATIENTS WITH 
AMYOTROPHIC LATERAL SCLEROSIS (ALS)  
 
Product:  
 
 
 
CK-2127107 
 
EudraCT Number:  
2018-000586-37 
 
Sponsor:  
 
 
 
Cytokinetics Inc. 
 
 
 
 
 
 
 
280 East Grand Avenue 
South San Francisco, California 94080 
 
Original Protocol: 
 
6 March 2017 
Amendment 01:  
 
23 March 2017 
Amendment 01.1: 
16 June 2017 (CANADA) 
Amendment 02: 
31 August 2017 
Amendment 02.1: 
18 February 2018 (EUROPE) 
Amendment 03: 
18 April 2018 
 
 
CONFIDENTIAL  
DO NOT COPY OR REPRODUCE 
WITHOUT CONSENT OF CYTOKINETICS, INC. 
 
 
Sponsor (Medical Monitor) Signature:___________________________________________ 
 
Lead Investigator Signature:___________________________________________________ 


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TABLE OF CONTENTS 
STUDY IDENTIFICATION ...........................................................................................................8 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
1. 
INTRODUCTION ......................................................................................................13 
1.1. 
Background .................................................................................................................13 
1.2. 
Overview of CK-2127107 Nonclinical Studies ..........................................................13 
1.3. 
Overview of CK-2127107 Clinical Studies ................................................................14 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objective .......................................................................................................17 
2.1.1. 
Primary Efficacy Endpoint .........................................................................................17 
2.2. 
Secondary Objectives .................................................................................................17 
2.2.1. 
Secondary Endpoints ..................................................................................................17 
2.3. 
Exploratory Objectives ...............................................................................................17 
2.3.1. 
Exploratory Endpoints ................................................................................................18 
2.4. 
Pharmacokinetic / Pharmacodynamic Objective ........................................................18 
3. 
STUDY OVERVIEW .................................................................................................19 
3.1. 
Study Design ...............................................................................................................19 
3.2. 
Study Rationale ...........................................................................................................20 
3.3. 
Dose Rationale ............................................................................................................20 
4. 
STUDY POPULATION .............................................................................................22 
4.1. 
Inclusion Criteria ........................................................................................................22 
4.2. 
Exclusion Criteria .......................................................................................................23 
5. 
STUDY PROCEDURES ............................................................................................25 
5.1. 
Screening ....................................................................................................................25 
5.2. 
First Dosing Day (Day 1) ...........................................................................................25 
5.3. 
Week 2 Visit ...............................................................................................................26 
5.4. 
Week 4 Visit ...............................................................................................................27 
5.5. 
Week 8 Visit ...............................................................................................................28 
5.6. 
Week 12 Visit .............................................................................................................29 
5.7. 
Follow-Up Visit ..........................................................................................................29 
5.8. 
Early Termination Visit ..............................................................................................30 


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5.9. 
Visit Windows ............................................................................................................31 
5.10. 
Diet Control ................................................................................................................31 
5.11. 
Concomitant Medications ...........................................................................................32 
5.12. 
Pharmacokinetic Sampling .........................................................................................32 
5.13. 
Clinical Safety Assessments .......................................................................................32 
5.13.1. 
Clinical Laboratory Evaluations .................................................................................32 
5.13.2. 
12-Lead Electrocardiograms .......................................................................................32 
5.13.3. 
Vital Signs ..................................................................................................................33 
5.13.4. 
AE Assessments ..........................................................................................................33 
5.13.5. 
Physical Examinations ................................................................................................33 
5.13.6. 
Neurological Examinations ........................................................................................33 
5.13.7. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) ......................................33 
5.13.8. 
Falls Assessment .........................................................................................................33 
5.13.9. 
Ashworth Scale ...........................................................................................................33 
5.14. 
Clinical and Pharmacodynamic Outcome Measures ..................................................33 
5.14.1. 
Pulmonary Function Assessment ................................................................................33 
5.14.2. 
Hand-Held Dynamometry ..........................................................................................34 
5.14.3. 
ALSFRS-R ..................................................................................................................34 
5.14.4. 
Voice Recording .........................................................................................................34 
5.14.5. 
Fine Motor Assessments (Handwriting and Figure Tracing) .....................................34 
5.14.6. 
ALSAQ-5 ....................................................................................................................34 
5.14.7. 
Health Economic Outcomes Measures .......................................................................34 
5.15. 
Removal of Patients from Study Participation ...........................................................34 
5.16. 
Assessment of Safety ..................................................................................................36 
5.17. 
Study Drug Interruption ..............................................................................................36 
5.18. 
Study Discontinuation ................................................................................................36 
6. 
INVESTIGATIONAL PRODUCT ............................................................................37 
6.1. 
Description of Investigational Product .......................................................................37 
6.2. 
Dose Administration (CK-2127107 or Placebo) ........................................................37 
6.3. 
Dosing Diary ...............................................................................................................37 
6.4. 
Randomization Schedule and Removal of Blind ........................................................37 
6.5. 
Study Drug Accountability and Disposal ...................................................................38 
7. 
ADVERSE EVENTS..................................................................................................39 


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7.1. 
Definitions ..................................................................................................................39 
7.1.1. 
Adverse Event .............................................................................................................39 
7.1.2. 
Serious Adverse Event ................................................................................................40 
7.2. 
Collection of AEs/SAEs .............................................................................................41 
7.3. 
Recording and Reporting of AEs/SAEs .....................................................................41 
7.3.1. 
Recording and Reporting of AEs ................................................................................41 
7.3.2. 
Recording and Reporting of SAEs .............................................................................41 
7.4. 
Evaluating AEs and SAEs ..........................................................................................42 
7.4.1. 
Assessment of Severity ...............................................................................................42 
7.4.2. 
Assessment of Causality .............................................................................................42 
7.4.3. 
Assessment of Expectedness ......................................................................................43 
7.5. 
Follow-Up of AEs and SAEs ......................................................................................43 
7.6. 
Post-Study AEs/SAEs .................................................................................................44 
7.7. 
Pregnancy ...................................................................................................................44 
8. 
STATISTICAL METHODS .......................................................................................45 
8.1. 
General Considerations ...............................................................................................45 
8.1.1. 
General Approach .......................................................................................................45 
8.1.2. 
Sample Size and Randomization ................................................................................45 
8.2. 
Analysis Sets ...............................................................................................................45 
8.2.1. 
Full Analysis Set (FAS) ..............................................................................................45 
8.2.2. 
Safety Analysis Set (SAS) ..........................................................................................45 
8.2.3. 
Pharmacokinetics Analysis Set (PKS) ........................................................................45 
8.3. 
Endpoints ....................................................................................................................46 
8.3.1. 
Efficacy Endpoints ......................................................................................................46 
8.3.1.1. 
Primary Efficacy Endpoint .........................................................................................46 
8.3.1.2. 
Secondary Efficacy Endpoints ....................................................................................46 
8.3.1.3. 
Exploratory Efficacy Endpoints .................................................................................46 
8.3.2. 
Safety Endpoints .........................................................................................................46 
8.3.3. 
Pharmacokinetic Measurements .................................................................................47 
8.4. 
Statistical Analysis ......................................................................................................47 
8.4.1. 
Patient Disposition ......................................................................................................47 
8.4.2. 
Demographics and Other Baseline Characteristics .....................................................47 
8.4.3. 
Prior and Concomitant Medications ...........................................................................47 


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8.4.4. 
Efficacy Analysis ........................................................................................................47 
8.4.4.1. 
Primary Efficacy Analysis ..........................................................................................47 
8.4.4.2. 
Secondary Efficacy Analysis ......................................................................................47 
8.4.4.3. 
Exploratory Efficacy Analysis ....................................................................................48 
8.4.4.4. 
Multiplicity .................................................................................................................48 
8.4.5. 
Safety Analysis ...........................................................................................................48 
8.4.5.1. 
Study Drug Exposure ..................................................................................................48 
8.4.5.2. 
Adverse Event .............................................................................................................48 
8.4.5.3. 
Serious Adverse Event ................................................................................................48 
8.4.5.4. 
Clinical Laboratory Parameters ..................................................................................48 
8.4.5.5. 
Vital Signs ..................................................................................................................49 
8.4.5.6. 
ECGs ...........................................................................................................................49 
8.4.5.7. 
Physical and Neurological Examinations ...................................................................49 
8.4.5.8. 
Ashworth Score ..........................................................................................................49 
8.4.5.9. 
Falls Assessments .......................................................................................................49 
8.4.5.10. 
Beck Depression Inventory-Fast Screen .....................................................................49 
8.4.6. 
Exposure-Response Analysis......................................................................................49 
8.4.7. 
Pharmacokinetic Analysis ..........................................................................................49 
8.5. 
Interim Analysis ..........................................................................................................50 
8.6. 
Statistical Software .....................................................................................................50 
8.7. 
Changes in Statistical Methods ...................................................................................50 
9. 
ADMINISTRATIVE ASPECTS ................................................................................51 
9.1. 
Change in Protocol .....................................................................................................51 
9.2. 
Initiation Visit .............................................................................................................51 
9.3. 
Disclosure ...................................................................................................................51 
9.4. 
Monitoring ..................................................................................................................51 
9.5. 
Institutional Review Board/Research Ethics Board/Ethics Committee ......................51 
9.6. 
Informed Consent .......................................................................................................52 
9.7. 
Records .......................................................................................................................52 
9.8. 
Reference to Good Clinical Practices (GCP) ..............................................................52 
10. 
REFERENCES ...........................................................................................................53 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................54 


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APPENDIX B. MEDICATIONS AND FOODS THAT INHIBIT OR INDUCE 
CYP3A4 OR ARE OCT1/OCT2 SUBSTRATES ......................................................55 
APPENDIX C. LIVER SAFETY MONITORING AND ASSESSMENT.................................56 
APPENDIX D. CLINICAL LABORATORY EVALUATIONS ...............................................59 
 
 
 


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LIST OF TABLES 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups ..........................................19 
Table 2: 
Visit Windows ............................................................................................................31 
Table 3: 
Pharmacokinetic (PK) Samples ..................................................................................32 
Table 4: 
Study Drug ..................................................................................................................37 
Table 5: 
MedDRA Preferred Terms .........................................................................................43 
 
LIST OF FIGURES 
Figure 1: 
Patient Visit Diagram .................................................................................................20 
Figure 2: 
CY 5013: Increases in Force during Nerve Stimulation in Healthy 
Volunteers ...................................................................................................................21 
 
 


CONFIDENTIAL 
 
Protocol CY 5022 
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STUDY IDENTIFICATION 
Sponsor 
Cytokinetics, Inc. 
280 East Grand Avenue 
South San Francisco, California, 94080 
(650) 624-3000 (Main Telephone) 
(650) 624-3010 (Main Facsimile) 
 
Sponsor’s Study Contact 
Jacqueline Lee 
Director, Clinical Operations 
Cytokinetics, Inc. 
jlee@cytokinetics.com 
(650) 624-3017 (Office Telephone) 
(650) 291-5533 (Mobile Telephone) 
(650) 624-3225 (Office Facsimile) 
 
 Sponsor’s Medical Monitor  
Stacy Rudnicki, MD 
Senior Medical Director, Clinical Research, Neurology 
Cytokinetics, Inc. 
srudnicki@cytokinetics.com 
(650) 624-3269 (Office Telephone) 
(650) 515-2524 (Mobile Telephone) 
 
Lead Investigator 
Jeremy Shefner, MD, PhD 
Professor & Chair of Neurology 
Barrow Neurological Institute 
jeremy.shefner@dignityhealth.org 
(315) 378-8531 (Mobile Telephone) 
 
Study Site 
Multi-Center 
 
 
 


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Protocol CY 5022 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Cytokinetics. 
• Not to amend the protocol without agreement, prior review, and written approval 
from the Institutional Review Board (IRB)/Ethics Committee (EC) except where 
necessary to eliminate an immediate hazard to the patients. 
• That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in this protocol and any other information provided by the 
Sponsor including, but not limited to, the following: the current Investigator’s 
Brochure (IB) or equivalent document. 
• That I am aware of, and will comply with, “Good Clinical Practices” (GCP) and all 
applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed about 
the Cytokinetics investigational product(s) and of their study-related duties and 
functions as described in the protocol. 
• That I have been informed that certain regulatory authorities require the Sponsor to 
obtain and supply, as necessary, details about the Investigator’s ownership interest in 
the Sponsor or the investigational product, and more generally about his/her financial 
ties with the Sponsor. Cytokinetics will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
Hence I: 
• Agree to supply Cytokinetics with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent children); 
• Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study; and 
• Agree that Cytokinetics may disclose any information it has about such ownership 
interests and financial ties to regulatory authorities. 
 
 
Investigator Name: 
______________________________________________________ 
 
Investigator Signature: ________________________________  
Date: ________________  


CONFIDENTIAL 
 
Protocol CY 5022 
CY 5022 Protocol Amendment 03: 18 Apr 2018 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALSAQ-5 
ALS Assessment Questionnaire Short Form 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale - Revised 
ALT 
alanine aminotransferase (alanine transaminase) 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase (aspartate transaminase) 
AT 
aminotransferase 
AUC 
area under the plasma concentration-time curve 
BDI 
Beck Depression Inventory 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
clearance divided by fraction absorbed 
Cmax 
maximum observed plasma concentration 
Ctrough 
pre-dose plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HHD 
hand-held dynamometry 


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Abbreviation or Specialist Term 
Explanation 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
IV 
intravenous 
IWRS 
interactive web response system 
LFT 
liver function tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
OCT 
organic cation transporter 
PD  
pharmacodynamic(s) 
PK  
pharmacokinetic(s) 
PKS 
pharmacokinetics analysis set 
PT 
preferred term 
QTc 
corrected QT interval 
RAC 
Accumulation ratio 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAS 
safety analysis set 
SDD 
spray dried dispersion 
SOC 
system organ class 
SVC 
slow vital capacity 
t½  
apparent plasma terminal elimination half-life 
TBL 
total bilirubin 
TDD 
total daily dose 
TEAE 
treatment emergent adverse event 
tmax  
time where maximum concentration is reached 
TSH 
thyroid stimulating hormone 
UA  
urinalysis 
ULN 
upper limit of normal 


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Abbreviation or Specialist Term 
Explanation 
V/F 
volume of distribution divided by fraction absorbed 
WBC 
white blood cells 


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1. 
INTRODUCTION 
1.1. 
Background 
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 muscle weakness and/or fatigue. CK-2127107 selectively activates the fast skeletal muscle 
troponin complex by increasing its affinity for calcium. In intact rat skeletal muscle in vivo, 
CK-2127107 increases muscle force at sub-maximal nerve stimulation frequencies, increases 
muscle power, and decreases muscle fatigability. 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. It has similar potencies in muscle fibers from preclinical species and 
human fast skeletal muscle fibers. It is expected that CK-2127107 may provide benefit to 
patients with a wide variety of disorders characterized by muscle weakness and/or fatigue. 
ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle 
movement. In ALS, progressive death of motor neurons leads to denervation of skeletal muscles. 
Surviving motor units attempt to compensate for dying ones by innervating more muscle fibers 
(a process called sprouting) but are only partially successful (Kiernan, Vucic et al. 2011). Over 
time, progressive denervation and its consequent skeletal muscle atrophy lead to weakness, 
fatigue, and eventually complete paralysis and death, primarily from respiratory complications. 
No curative therapies for ALS exist. Rilutek® (riluzole, Sanofi-Aventis U.S. LLC) is the first 
medication approved for the treatment of ALS, and has a modest benefit on survival (Lacomblez, 
Bensimon et al. 1996). Two interventions that contribute greatly to the overall welfare and 
survival of ALS patients are the use of enteral feeding and ventilatory support. 
Radicava (edaravone) was recently approved to treat patients with ALS in the United States in 
May 2017. The efficacy of Radicava was demonstrated in a 6-month clinical trial conducted in 
Japan wherein 137 participants were randomized to receive edaravone or placebo. At Week 24, 
individuals receiving edaravone declined less on a clinical assessment of daily functioning 
compared to those receiving a placebo (Writing Group on behalf of the Edaravone (MCI-186) 
ALS 19 Study Group. 2017). 
To date, there are no available treatments that slow the decline of skeletal muscle function, and 
in particular, slow the decline of respiratory function. This clinical protocol is a double-blind, 
randomized, dose-ranging, placebo-controlled study to evaluate the efficacy, safety, and 
tolerability of CK-2127107 in patients with ALS. 
1.2. 
Overview of CK-2127107 Nonclinical Studies 
CK-2127107 was evaluated in a series of nonclinical safety studies in rat and monkey, including 
single- and repeat-dose (28 days and 13 weeks) toxicity studies, safety pharmacology studies, 
and a core battery of genotoxicity tests. CK-2127107 was formulated from a spray dried 
dispersion (SDD), which is a stabilized amorphous form of CK-2127107, to increase its 
absorption. 
The toxicology studies conducted in rat and monkey with CK-2127107 demonstrated an 
acceptable safety profile, and supported Phase 1 clinical trials in healthy volunteers. Based on in 
vitro metabolism studies, the monkey was selected as the non-rodent toxicology species since the 


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Protocol CY 5022 
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metabolism of CK-2127107 in monkeys was qualitatively comparable to that in humans, in 
particular with respect to the production of CK-2127106, an identified inactive metabolite of 
CK-2127107. In definitive 28-day and 13-week repeat-dose toxicity and toxicokinetic studies, 
the no observed adverse effect level for CK-2127107 was 600 mg/kg/day, the highest dose level 
evaluated, in both rats and monkeys. 
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 
studies of CK-2127107. 
The results of the bacterial reverse mutation, in vitro cytogenetic and in vivo rodent bone marrow 
micronucleus studies conducted with CK-2127107 indicated a lack of genotoxic hazard. 
CK-2127106 was equivocal in an in vitro cytogenetic assay conducted in human peripheral 
blood lymphocytes; in this assay, a statistically significant increase in the incidence of aberrant 
cells, compared to the vehicle control, was noted only at the highest CK-2127106 concentration 
evaluated (386 µg/mL) in the 21-hour regime. 
Additional information concerning the pharmacology, pharmacokinetics (PK), and toxicology of 
CK-2127107 is available in the Investigator’s Brochure (IB). 
1.3. 
Overview of CK-2127107 Clinical Studies 
Phase 1 Studies 
CK-2127107 has been evaluated in five Phase 1 studies. 
In a “first in human” study conducted in 35 healthy men (Study CY 5011), single oral doses of a 
SDD suspension (CK-2127107 ranging from 30 to 4000 mg were all well tolerated and no 
maximum tolerated dose was established. 
In Study CY 5012, multiple dose administration of the CK-2127107 SDD suspension at 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 PK profile to be described. 
A 4-way crossover, single dose PK/pharmacodynamic (PD) study (Study CY 5013) performed 
with placebo, 300 mg, 1000 mg and 3000 mg of the CK-2127107 SDD suspension demonstrated 
a dose- and concentration-dependent increase in the force-frequency relationship of the tibialis 
anterior muscle with transcutaneous electric stimulation of the deep fibular nerve. 
Another study in 25 healthy men (Study CY 5014) was conducted to evaluate the relative oral 
bioavailability of a suspension of the crystalline form of CK-2127107, CK-2127107 active 
pharmaceutical ingredient (API), to the CK-2127107 SDD suspension dosed at 300 and 
1000 mg. 
Lastly, in Study CY 5015, the PK 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. 
The food effect of the tablet was also evaluated in Study CY 5015. 
The terminal half-life (t½) of CK-2127107 was generally around 12 hours with a time to 
maximum concentration (tmax) of 2-3 hours. The increase in exposure was largely dose-
proportional although exposure was more variable at doses ≥3000 mg. There were no observed 
differences in PK parameters between young and elderly subjects but mean exposure was 


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slightly higher in women vs. men. A food effect was demonstrated with 2.6- and 1.6-fold 
increases in Cmax and AUC∞, respectively, following administration of the tablet formulation 
(500 mg as 2 x 250 mg tablets) with a high fat meal. 
Exposure (Cmax and AUC) to the inactive metabolite, CK-2127106, was higher after multiple 
doses of CK-2127107 compared to single doses. The geometric mean half-life of CK-2127106 
ranged from 25.4 to 39.3 hours. Maximum concentrations (Cmax) and area under the 
concentration-time curve (AUC) values increased somewhat greater than dose-proportionally 
following multiple dosing. 
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 (≥5%) AEs observed with 
CK-2127107 vs. placebo were dizziness, headache, nausea, and diarrhea. Dizziness, headache, 
and nausea 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 (one 
treated with placebo and three treated with CK-2127107 500 mg) had an AE of increased alanine 
aminotransferase (ALT)/hepatic enzymes; an additional three subjects (all treated with 
CK-2127107 500 mg) had at least one elevated liver enzyme during treatment with study drug 
that were not reported as an AE. Of these seven 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 organic cation 
transporter (OCT) 2, a mediator of renal tubular secretion of creatinine in the human kidney, 
with a half maximal inhibitory concentration (IC50) of 2.63 μM. 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; inhibition 
of renal tubular secretion has also been observed with other drugs, such as cimetidine 
(Ducharme, Smythe et al. 1993). It is noted that a similar increase in creatinine has been 
observed in toxicology studies of CK-2127107 in monkey. In the 13-week monkey toxicology 
study, creatinine values returned to baseline after completion of dosing and there were no 
abnormalities in kidney histopathology noted, providing further support that this finding is not a 
reflection of renal toxicity. 
Additional information on the Phase 1 clinical program can be found in the IB. 
Ongoing Studies 
There are 3 ongoing studies with CK-2127107. 
3318-CL-3001 (NCT03065959) is a Phase 1b, double-blind, randomized, placebo-controlled, 
2-period cross-over study of CK-2127107 of older healthy adults with limited mobility. Subjects 
are randomized (1:1) to placebo or 500 mg twice daily CK-2127107 for 14 days. The primary 
objective is to investigate the effect of CK-2127107 in tablet form on skeletal muscle fatigue 
assessed as change from baseline versus 14 days of treatment in sum of peak torque during 
isokinetic knee extensions. 
CY 5021 (NCT02644668) is a Phase 2, double-blind, randomized, placebo-controlled, multiple-
dose study of CK-2127107 in suspension form in two ascending dose cohorts of patients with 
spinal muscular atrophy ages 12 and older. The primary objective is to determine the potential 


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PD effects of CK-2127107 API suspension after multiple doses in patients with spinal muscular 
atrophy. 
3318-CL-3002 (NCT02662582) is a Phase 2, randomized, double blind placebo-controlled, two 
period crossover study in patients with chronic obstructive pulmonary disease. The dose of 
CK-2127107 will be 500 mg twice daily and each period will be 14 days. The primary objective 
is to assess the effect of CK-2127107 in tablet form on physical function in subjects with chronic 
obstructive pulmonary disease. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to assess the effect of CK-2127107 versus placebo on 
respiratory function in patients with ALS. 
2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Visit Week 12 in the percent 
predicted slow vital capacity (SVC). 
2.2. 
Secondary Objectives 
The secondary objectives of this study are:  
• To assess the effect of CK-2127107 versus placebo on measures of skeletal muscle 
function 
• To assess the effect of CK-2127107 versus placebo on global function 
• To evaluate the safety and tolerability of CK-2127107 administered orally to patients 
with ALS 
• To evaluate the exposure of CK-2127107 and its metabolites, when administered orally 
in tablet form to patients with ALS in the fed state 
2.2.1. 
Secondary Endpoints 
• Slope from baseline to Visit Week 12 in the mega-score of muscle strength measured 
by hand held dynamometry (HHD) and handgrip dynamometry  
• Change from baseline to Visit Week 12 in the ALS Functional Rating Scale – Revised 
(ALSFRS-R) 
• The incidence and severity of treatment-emergent adverse events (TEAEs) 
• Plasma concentrations of CK-2127107 at the sampled time points during the study 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are:  
• To assess the effect of CK-2127107 versus placebo on respiratory function self-
assessments made at home by the patient with help as needed by the caregiver 
• To assess the effect of CK-2127107 versus placebo on disease progression through 
measurement of speech production characteristics over time 
• To assess the effect of CK-2127107 versus placebo on disease progression through 
measurement of handwriting abilities over time 
• To assess the change from baseline to Visit Week 12 in quality of life (as measured by 
the ALS Assessment Questionnaire Short Form [ALSAQ-5]) and muscle strength in 
patients on CK-2127107 compared to placebo 


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• To assess the change in the slope of decline of measures of function in patients on 
CK-2127107 compared to placebo 
2.3.1. 
Exploratory Endpoints 
Endpoints assessed as a change from baseline include: 
• Change from baseline to Visit Week 12 in the percent predicted SVC measured at home  
• Change from baseline to Visit Week 12 in the components of voice analysis  
• Change from baseline to Visit Week 12 in the components of handwriting analysis  
• Percent changes from baseline in the strength of the muscle groups from baseline to 
Visit Week 12 that contribute to the Mega-score at Visit Week 12  
• Change from baseline to Visit Week 12 in the ALSAQ-5 
Endpoints assessed as a change in slope include:  
• Slope of change from baseline to Visit Week 12 in the percent predicted SVC 
• Slope of change from baseline to Visit Week 12 in the ALSFRS-R 
• Slope of change from baseline to Visit Week 12 in percent predicted SVC measured at 
home 
• Slope of change from baseline to Visit Week 12 in the components of voice analysis 
• Slope of change from baseline to Visit Week 12 in the components of handwriting 
analysis 
• Slope of change from baseline to Visit Week 12 in the ALSAQ-5 
2.4. 
Pharmacokinetic / Pharmacodynamic Objective 
The PK/PD objectives of this study are to characterize the PK of CK-2127107 following multiple 
doses in the fed state at three dose levels in ALS patients as well as to evaluate possible 
relationships between both dose and exposure of CK-2127107 and its PD effects following 
multiple oral doses in patients with ALS. 


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3. 
STUDY OVERVIEW 
3.1. 
Study Design 
This is a Phase 2, double-blind, randomized, placebo-controlled, dose ranging study of 
CK-2127107 in patients with ALS. 
Approximately 445 eligible ALS patients will be randomized (1:1:1:1) to receive the following 
doses of CK-2127107 or placebo: 
• 150 mg CK-2127107 twice a day for a 300 mg total daily dose (TDD) 
• 300 mg CK-2127107 twice a day for a 600 mg TDD 
• 450 mg CK-2127107 twice a day for a 900 mg TDD 
• Placebo twice daily 
Study medication should be taken twice daily, approximately 12 hours (± 2 hours) apart, and 
should be taken within the 2 hour period following a meal. 
An overview of the randomized treatment groups is provided in Table 1: 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups 
CK-2127107 
Placebo 
300 mg TDD 
1 tablet (150 mg) of 
CK-2127107 and 
2 placebo tablets twice 
daily for 12 weeks 
600 mg TDD 
2 tablets (150 mg) of 
CK-2127107 and 
1 placebo tablet twice 
daily for 12 weeks 
900 mg TDD 
3 tablets (150 mg) of 
CK-2127107 twice 
daily for 12 weeks 
3 placebo tablets twice 
daily for 12 weeks 
The screening and qualification period for the study will be no more than 14 days in duration. 
Once patients have completed screening and are considered eligible for the study, they will be 
randomized as described above and stratified by riluzole use/non-use and edaravone use/non-use. 
There will be a total of seven study visits for each patient: 
• Screening 
• First Dosing Day (Day 1) 
• Week 2 
• Week 4 
• Week 8 
• Week 12 
• Follow-Up Visit (4 weeks after last dose of study drug) 


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Figure 1: 
Patient Visit Diagram 
 
PD measures, vital signs, electrocardiograms (ECGs), and clinical laboratory evaluations will be 
performed at Screening and at specified times during the study. Patients will be evaluated at each 
study visit for signs and symptoms of intolerance to study drug. 
3.2. 
Study Rationale 
CK-2127107 is being investigated as a potential new therapy to slow the decline of skeletal 
muscle function, and in particular, slow the decline of respiratory function in patients with ALS. 
This is the first study being conducted in these patients with CK-2127107 and is designed to 
assess the effect of 12 weeks of its dosing on measures of muscle function in patients with ALS. 
The plasma concentration of CK-2127107 will be measured at selected time points during the 
course of dosing and the plasma concentrations obtained in this study may be used to conduct 
exposure-response analyses. A drug with a similar mechanism of action, tirasemtiv, is currently 
being investigated in a Phase 3 study in ALS (CY 4031, VITALITY-ALS) and in an open label 
extension study to CY 4031 (CY 4033, VIGOR-ALS). In a Phase 2b study (CY 4026, 
BENEFIT-ALS), patients on tirasemtiv had a reduction in the rate of decline in SVC compared 
to placebo. 
3.3. 
Dose Rationale 
CK-2127107 will be administered as 150 mg tablets, at doses of 300 mg/day, 600 mg/day, or 
900 mg/day TDD in the fed state as described above in Table 1. Based on initial population PK 
modeling of the Phase 1 study data, these three doses yield predicted mean Cmax values (%CV) 
ranging from approximately 1789 (44.1) to 5543 (35.9) ng/mL assuming exposures in ALS 
patients are similar to healthy volunteers. The doses selected in the current study should produce 
plasma concentrations that span the PD range observed in the healthy volunteer population in 
Study CY 5013.   


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In Study CY 5013, plasma concentrations were sampled at the time of nerve stimulation in order 
to understand the relationship between CK-2127107 plasma exposures and resulting changes 
from baseline force. Figure 2 shows that these plasma concentrations produce significant 
concentration-dependent increases in force at submaximal stimulation frequencies with the 
largest force increases at 10 Hz. 
Figure 2: 
CY 5013: Increases in Force during Nerve Stimulation in Healthy Volunteers 
 
Based on prior clinical experience, the doses selected for this study are expected to be well 
tolerated and potentially pharmacodynamically active. The information obtained in this study 
will guide the selection of doses for a potential Phase 3 clinical study of CK-2127107 in patients 
with ALS. 


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4. 
STUDY POPULATION 
Approximately 500 patients with ALS will be screened in order to enroll at least 445 patients 
with ALS who fulfill the eligibility criteria. 
4.1. 
Inclusion Criteria 
Patients who meet all the following criteria may be included in the study: 
1. Able to comprehend and willing to sign an Informed Consent Form (ICF) 
2. Males or females between the ages of 18 and 80 years of age, inclusive 
3. Diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-
supported probable, probable, or definite criteria for a diagnosis of ALS according to the 
World Federation of Neurology El Escorial criteria published in 2000 (Brooks, Miller et 
al. 2000) ≤ 24 months prior to screening 
4. Upright SVC ≥ 60% of predicted for age, height and sex at screening 
5. Able to swallow tablets 
6. A caregiver (if one is needed) 
7. Able to perform reproducible pulmonary function tests 
8. Pre-study clinical laboratory findings within the normal range or, if outside the normal 
range, deemed not clinically significant by the Investigator 
9. Male patients, who have not had a vasectomy and a confirmed zero sperm count, must 
agree after receiving the first dose of study drug until 10 weeks after the last dose to do 
either of the following: 
• use a condom during sexual intercourse with female partners who are of reproductive 
potential AND to have female partners use an additional effective means of 
contraception (e.g., diaphragm plus spermicide, or oral contraceptives) 
OR  
• abstain from sexual intercourse  
10. Female patients must be post-menopausal (≥ 1 year) OR sterilized, OR if of childbearing 
potential (i.e., females who have had their first period unless they are anatomically and 
physiologically incapable to become pregnant), must: 
• not be breastfeeding, 
• have a negative pregnancy test, 
• have no intention of becoming pregnant during the course of the study, AND do 
either of the following: 
− use contraceptive drugs or devices as detailed in item number 9 from Screening 
until 10 weeks after the last dose of study drug AND require male partners to use 
a condom during sexual intercourse 
OR 


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− abstain from heterosexual intercourse from Screening until 10 weeks after the last 
dose of study drug 
11. Patients must be either on riluzole for at least 30 days prior to screening or have not taken 
riluzole for at least 30 days prior to screening and not planning to start riluzole during the 
course of the study. 
12. Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at 
the time of screening or have not taken edaravone for at least 30 days prior to screening 
and not planning to start edaravone during the course of the study. Two cycles of dosing 
are defined as having completed Cycle 1 infusion, which is 14 consecutive days of 
intravenous (IV) edaravone followed by 14 days off edaravone, and Cycle 2, which is 10 
out of 14 days of IV edaravone. 
4.2. 
Exclusion Criteria 
Any of the following will exclude potential patients from the study: 
1. At the time of screening, any use of non-invasive ventilation, e.g. continuous positive 
airway pressure, noninvasive bi-level positive airway pressure or noninvasive volume 
ventilation, for any portion of the day, or mechanical ventilation via tracheostomy, or on 
any form of oxygen supplementation 
2. Neurological impairment due to a condition other than ALS  
3. Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal, 
musculoskeletal, or psychiatric illness that might interfere with the patient’s ability to 
comply with study procedures or that might confound the interpretation of clinical safety 
or efficacy data, including, but not limited to: 
a. A pulse <40 or >100 bpm; mean systolic blood pressure >180 mm Hg; mean diastolic 
blood pressure >100 mm Hg (based on measurements taken after rest for 3 minutes) 
that persist on 3 successive measurements taken at least 2 minutes apart. 
b. Clinically significant ECG abnormalities that require medical attention (i.e., persistent 
atrioventricular conduction block >first degree, or acute myocardial ischemic 
changes) 
c. New York Heart Association Class II or greater congestive heart failure 
d. Chronic obstructive pulmonary disease or asthma requiring daily use of 
bronchodilator medications 
e. Gastrointestinal disorder that is likely to impair absorption of study drug from the 
gastrointestinal tract  
f. ALT or aspartate aminotransferase (AST) greater than or equal to 3-times the upper 
limit of normal (ULN) or has total bilirubin (TBL) greater than or equal to 2-times the 
ULN at screening. These assessments may be repeated at the Investigator’s discretion 
(within the screening window). 
g. Poorly controlled or brittle diabetes mellitus 
h. Amputation of a limb 
i. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s 
ability to understand and/or comply with study procedures and provide informed 
consent 


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j. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of 
the cervix, or squamous cell carcinoma of the skin excised with clean margins) 
diagnosed and treated within the last five years 
k. Any other condition, impairment or social circumstance that, in the opinion of the 
Investigator, would render the patient not suitable to participate in the study 
l. Patient judged to be actively suicidal or a suicide risk by the Investigator 
m. Patient has estimated glomerular filtration rate (eGFR) less than 40 mL/min/1.73 m2 
calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
cystatin equation based on a cystatin C measurement at baseline 
4. Has taken any investigational study drug within 30 days or five half-lives of the prior 
agent, whichever is longer, prior to dosing 
5. Known to have received CK-2127107 or tirasemtiv in any previous clinical trial 
6. Has received or is considering receiving during the course of the study any form of stem 
cell therapy for the treatment of ALS 
7. Has received or is considering receiving during the course of the study any form of gene 
therapy for the treatment of ALS 
8. Has received or is considering obtaining during the course of the study a diaphragmatic 
pacing system 
9. History of substance abuse within the past 2 years 
10. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose of 
study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug 
11. Use of a medication that is an OCT1/OCT2 substrate within 7 days (see Appendix B)  


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5. 
STUDY PROCEDURES 
5.1. 
Screening 
A signed ICF will be obtained from each patient prior to performing any study-specific 
procedures. A copy of the ICF will be retained in the study file and a copy will be provided to 
the patient. 
The following screening procedures will be performed for all potential patients at a visit 
conducted within 14 days of study entry: 
1. Demographic data 
2. Medical history, including review of concomitant medications, tobacco and alcohol usage 
3. Review of inclusion/exclusion criteria 
4. Height, body weight, and calculation of body mass index (BMI) 
5. Routine physical examination 
6. Neurological examination 
7. 12-lead ECG 
8. Vital signs, including temperature, heart rate, blood pressure, and respiratory rate 
measured after the patient has been resting for at least 3 minutes 
9. Clinical laboratory evaluations, including complete blood count (CBC) and white blood 
cells (WBC) with differential, serum chemistries, cystatin C, urinalysis (UA), and thyroid 
stimulating hormone (TSH) 
10. Pregnancy test for all females of childbearing potential 
11. SVC 
12. Muscle strength measurements 
13. ALSFRS-R 
14. Voice recording 
15. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
16. Ashworth score 
17. ALSAQ-5 
18. Beck Depression Inventory-Fast Screen (BDI-Fast Screen) 
Once a patient is confirmed eligible to participate and before the first dose on Day 1, patients 
will be randomized to receive either CK-2127107 or placebo. 
5.2. 
First Dosing Day (Day 1) 
Prior to study drug dosing on Day 1, the following procedures will be performed: 


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1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
4. PK blood sample 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their first dose of study drug (CK-2127107 or placebo) within 2 hours of a 
meal. 
The following assessment will be performed after the first dose of study drug is given: 
16. PK blood sample at 1 hour post-dose 
Training will also be provided to the patient for the measurements patients will perform at home. 
•  For patients who have access to a mobile device, the application will be downloaded 
to the device and instructions provided as detailed in the study manual on recording 
voice. 
• All patients will be trained in performing SVC using a portable spirometer (if the 
device is suitable for use in that region) as detailed in the study manual. 
Home voice recordings and SVC testing will be performed by the patient weekly for the duration 
of the study following Day 1. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks. A dosing diary will be provided for patients to record the date and time of 
twice daily study drug administration. 
5.3. 
Week 2 Visit 
Prior to study drug dosing at the Week 2 Visit, the following procedures will be performed: 


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1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample  
4. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. Patients should be reminded to bring their unused study drug with them to the clinic and 
that they will be taking their dose of study drug while at the clinic. The following assessment 
will be performed after the dose of study drug is given: 
16. PK blood sample at 1 hour post-dose  
Patients will have already been given their supply of study drug (CK-2127107 or placebo) to 
take twice daily at home until their next clinic visit at Week 4. A dosing diary will be provided 
for patients to record the date and time of twice daily study drug administration. 
5.4. 
Week 4 Visit 
Prior to study drug dosing at the Week 4 Visit, the following procedures will be performed:  
1. 12-lead ECG 
2. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight and calculation of BMI 
4. PK blood sample 
5. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 


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6. SVC 
7. Muscle strength measurements 
8. ALSFRS-R 
9. Voice recording 
10. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
11. Ashworth score 
12. Falls assessment 
13. ALSAQ-5 
14. Record Health Economic Outcomes Measures 
15. AE/SAE evaluation and concomitant medication assessment (since last visit) 
16. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks at home until their next clinic visit at Week 8. A dosing diary will be provided 
for patients to record the date and time of twice daily study drug administration. 
5.5. 
Week 8 Visit 
Prior to study drug dosing at the Week 8 Visit, the following procedures will be performed: 
1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample 
4. SVC 
5. Muscle strength measurements 
6. ALSFRS-R 
7. Voice recording 
8. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
9. Ashworth score 
10. Falls assessment 
11. ALSAQ-5 
12. Record Health Economic Outcomes Measures 
13. AE/SAE evaluation and concomitant medication assessment (since last visit) 


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14. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks at home. A dosing diary will be provided for patients to record the date and 
time of twice daily study drug administration. 
5.6. 
Week 12 Visit 
Prior to the last dose of study drug at the Week 12 Visit, the following procedures will be 
performed:  
1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample 
4. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. The following assessment will be performed after the last dose of study drug is given: 
16. PK blood sample at 1 hour post-dose  
5.7. 
Follow-Up Visit  
The following procedures will be performed at a Follow-Up Visit 4 weeks after each patient’s 
final dose of study drug: 
1. 12-lead ECG 


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2. Vital signs including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight and calculation of BMI 
4. Abbreviated physical examination  
5. Neurological examination 
6. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C, UA, and TSH 
7. Pregnancy test for all females of childbearing potential 
8. SVC 
9. Muscle strength measurements 
10. ALSFRS-R 
11. Voice recording 
12. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
13. Ashworth score 
14. Falls assessment 
15. ALSAQ-5 
16. Record Health Economic Outcomes Measures 
17. AE/SAE evaluation and concomitant medication assessment (since last visit) 
18. BDI-Fast Screen 
5.8. 
Early Termination Visit 
If a patient decides to terminate early from the study, they should be seen in the clinic as soon as 
possible following discontinuation of study drug. The following procedures will be performed: 
1. 12-lead ECG 
2. Vital signs including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight 
4. Abbreviated physical examination  
5. Neurological examination 
6. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
7. SVC 
8. Muscle strength measurements 
9. ALSFRS-R 


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10. Voice recording 
11. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
12. Ashworth score 
13. Falls assessment 
14. ALSAQ-5 
15. Record Health Economic Outcomes Measures 
16. AE/SAE evaluation and concomitant medication assessment (since last visit) 
17. BDI-Fast Screen 
If a patient decides to terminate early from the study but does not wish to return to the clinic for 
an Early Termination Visit, they should be contacted by phone whenever possible and the 
following information should be collected: 
1. ALSFRS-R 
2. ALSAQ-5 
3. Record Health Economic Outcomes Measures 
4. Falls Assessment 
5. AE/SAE evaluation and concomitant medication assessment (since last visit) 
5.9. 
Visit Windows 
To aid in scheduling patient visits, the following study visit windows are considered acceptable 
(Table 2). If a patient visit must be scheduled outside the visit window, the Medical Monitor 
should be contacted. 
Table 2: 
Visit Windows 
Visit 
Visit Window 
Screening 
Up to 14 days prior to Day 1 visit (as per protocol) 
Day 1 
First day of randomized, double-blind dosing 
Week 2 (Day 15) 
± 2 days 
Week 4 (Day 29) 
± 2 days 
Week 8 (Day 57) 
± 4 days 
Week 12 (Day 85) 
± 4 days 
Follow-Up 
4 weeks after last dose of study drug ± 4 days 
5.10. 
Diet Control 
All doses of study drug should be taken within 2 hours following a meal. 
Subjects will abstain from consuming grapefruit and Seville oranges along with foods or 
beverages containing them from Day 1 through the Follow-Up visit. 


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5.11. 
Concomitant Medications 
All prescription drugs, over-the-counter medications, nutraceuticals and herbal remedies taken 
by the patient from the time of screening through the Follow-Up visit should be entered into the 
electronic case report form (eCRF). Medications that strongly inhibit the activity of CYP3A4 
should be avoided from 7 days before the start of dosing (Day 1) through the last day of dosing 
(End of Week 8). Medications that strongly induce the activity of CYP3A4 should be avoided 
from 14 days before the start of dosing (Day 1) through the last day of dosing (Week 12). Please 
refer to Appendix B  for strong inhibitors and inducers of CYP3A4. Medications that are 
OCT1/OCT2 substrates should be avoided from 7 days before the start of dosing or used with 
caution during the trial, as CK-2127107 may have the potential to inhibit OCT1 and OCT2-
mediated transport. Please refer to Appendix B  for OCT1/OCT2 substrates that should be 
avoided or used with caution. 
5.12. 
Pharmacokinetic Sampling 
Blood samples for analysis of CK-2127107, its metabolites, and riluzole will be collected from 
patients at the nominal time points listed in Table 3. 
Table 3: 
Pharmacokinetic (PK) Samples 
Day 
Sample Time Points 
Day 1 
Pre-dose and 1 (±15 min) hour post-dose  
Week 2 
Pre-dose and 1 (±15 min) hour post-dose 
Week 4 
Pre-dose 
Week 8 
Pre-dose 
Week 12 
Pre-dose and 1 (±15 min) hour post-dose 
If an indwelling catheter is used, saline flushes will be used. In some cases, sites may be unable 
to obtain the 6 hour timepoint at Week 2 or Week 12 for logistical reasons; these cases should be 
discussed with the medical monitor preferably ahead of time.  
After completion of bioanalysis, remaining plasma samples will be retained consistent with the 
Sponsor’s standard operating procedures. These samples will not be used for pharmacogenomic 
testing. 
5.13. 
Clinical Safety Assessments 
5.13.1. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be collected at Screening, Day 1, Week 2 visit, Week 4 visit, 
Week 12 visit, and at the Follow-Up Visit as described in Appendix D. 
5.13.2. 
12-Lead Electrocardiograms 
A 12-lead ECG, including ECG parameters of RR, PR, QRS, QT and QTc intervals as well as 
significant findings will be obtained at Screening, Week 4 visit, and at the Follow-Up Visit. 


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When 12-lead ECGs are scheduled at the same time as blood draws, the order of evaluation will 
be ECG, vital signs, and then blood draw. 
5.13.3. 
Vital Signs 
Heart rate, blood pressure, and respiratory rate (measured after the patient has been resting and 
seated for at least 3 minutes), will be obtained at every visit. Temperature will also be obtained at 
the Screening visit. Height is obtained only at the screening visit. Weight will be obtained at each 
visit; and BMI will be calculated at screening and subsequent visits. 
When vital signs are scheduled at the same time as blood draws, the order of evaluation will be 
ECG, vital signs, and then blood draw. 
5.13.4. 
AE Assessments 
Patients will be asked how they are feeling from the first administration of study drug through 
the Follow-Up visit (see Section 7.2). Patients will also be encouraged to voluntarily report any 
AEs they experience during the study. 
5.13.5. 
Physical Examinations 
A routine physical examination will be performed at Screening, and an abbreviated physical 
examination (consisting of an examination of general appearance, skin, lungs, cardiovascular and 
abdomen) will be performed at the Follow-Up Visit. 
5.13.6. 
Neurological Examinations 
A neurological examination will be administered at Screening and at the Follow-Up Visit as 
described in the Study Manual. 
5.13.7. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) 
The BDI-Fast Screen will be assessed at all study visits as described in the Study Manual. 
5.13.8. 
Falls Assessment 
Falls assessment will be performed at each study visit except Screening as described in the Study 
Manual. 
5.13.9. 
Ashworth Scale 
The Ashworth scale to assess spasticity will be performed at each study visit. Further description 
of the Ashworth Scale can be found in the Study Manual. 
5.14. 
Clinical and Pharmacodynamic Outcome Measures 
5.14.1. 
Pulmonary Function Assessment 
The pulmonary function assessment in this study will be SVC. Pulmonary function assessment 
will be performed at each study visit as described in the Study Manual. Patients will also perform 
home SVC assessments weekly through the course of the study following Day 1 (if the device is 
suitable for use in that region) as described in the Study Manual. 


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5.14.2. 
Hand-Held Dynamometry 
Muscle strength measurements of selected muscles will be performed using HHD and hand grip 
dynamometry at each study visit as described in the Study Manual. 
5.14.3. 
ALSFRS-R 
The ALSFRS-R will be performed at each study visit as described in the Study Manual. 
5.14.4. 
Voice Recording 
Voice recording will be performed at each study visit and for patients who have access to mobile 
devices weekly at home as described in the Study Manual. 
5.14.5. 
Fine Motor Assessments (Handwriting and Figure Tracing) 
The handwriting and figure tracing assessments will be done at each study visit (if the device is 
suitable for use in that region) as described in the Study Manual. 
5.14.6. 
ALSAQ-5 
The ALSAQ-5 will be performed at each study visit as described in the Study Manual. 
5.14.7. 
Health Economic Outcomes Measures 
During the course of the study, if the patient is prescribed and agrees to receive any of the 
following, it will be recorded including the date prescribed: 
• Non-invasive ventilation 
• Gastrostomy tube 
• Manual wheelchair 
• Power wheelchair 
• Augmentative and alternative communication 
5.15. 
Removal of Patients from Study Participation 
Patients will be informed that they are free to discontinue study drug or withdraw from the study 
at any time and for any reason. The Investigator may discontinue study drug or withdraw a 
patient from the study if, in the Investigator's opinion, it is not in the best interest of the patient to 
continue the study. Patients may discontinue study drug or withdraw from the study due to the 
following: 
a. A change in compliance with inclusion/exclusion criteria that is clinically relevant 
and/or affects patient safety, and/or study assessments/objectives, etc. 
b. Occurrence of intolerable AEs 
c. Changes in vital signs, ECGs, or clinical laboratory results that, in the opinion of the 
Investigator, pose a significant health risk 
d. Intake of non-permitted concomitant medication that might affect patient safety or 
study assessments/objectives, etc. 


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e. eGFR calculated using the CKD-EPI cystatin equation (Inker, Schmid et al. 2012) 
shows a >25% decline compared to baseline (defined as Day 1 or Screening if Day 1 
value is not available) as long as the decline is not related to dehydration or a 
superimposed reversible process such as infection or nausea. 
f. Changes in liver function tests (LFTs) as outlined in Appendix C   
g. Receiving any form of stem cell therapy for ALS either as part of a clinical trial or 
outside of a clinical trial 
h. Having a diaphragmatic pacing system implanted either as part of a clinical trial or 
outside of a clinical trial 
i. Initiating edaravone after screening. 
j. Initiating riluzole after screening. 
k. Initiating gene therapy for ALS either as part of a clinical trial or outside of a clinical 
trial after screening. 
Patients should be strongly encouraged to perform the early termination visit as soon as possible 
following last dose of study drug taken, and the Follow-Up Visit should be performed 28 days 
after last dose taken of study medication. In addition, they should be encouraged to return for all 
remaining study visits and assessments (with the exception of 12-lead ECG, clinical laboratory 
and PK sampling) for the duration of the study following study drug discontinuation. These 
remaining study visits should be performed according to the original study visit windows. 
Patients who decide to start or stop edaravone or riluzole after screening and before 
randomization, will no longer be eligible to be randomized and should not be followed 
subsequently. If a patient decides to start edaravone or riluzole after randomization, they will be 
terminated from taking study medication once that is known by the site. They should return to 
the clinic for their early drug termination visit as soon as possible following last dose of study 
drug taken and return 28 days after last dose taken for the Follow-Up Visit. They will not be 
followed thereafter. 
For patients who terminate early from the study and do not want to return to the clinic for the 
visits as described in the above paragraph, phone call visits should be performed to collect the 
information if the patient is willing (see Section 5.8). 
Notification of discontinuation will immediately be made to the Sponsor’s Medical Monitor. In 
case of withdrawal of study participation, efforts will be made to perform Early Termination 
(Section 5.8) and Follow-Up visit assessments (Section 5.7). The date the patient is withdrawn 
from the study and the reason for discontinuation will be recorded on the patient’s eCRF. All 
patients who prematurely discontinue from the study for AEs will be followed for up to 30 days, 
until the AE resolves, or until the unresolved AE is judged by the Investigator to have stabilized. 
The primary reason for a patient prematurely withdrawing from the study should be selected 
from the following categories and documented in the source documents: 
a. Patient Death 
b. Adverse Event:  One or more clinical or laboratory events which, in the medical 
judgment of the Investigator, are grounds for discontinuation even if the event does 
not appear to be related to study medication. The patient may withdraw because of an 
AE even if the Investigator does not feel that the event is grounds for discontinuation. 
c. Protocol Violation:  The patient’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements 


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d. Patient Withdrawal of Consent:  Patient desires to withdraw from further participation 
in the study and reason for doing so. 
e. Administrative/Other:  Any cause of premature termination from the study other than 
the above, such as illness of investigator, loss of study drug, or termination of study 
by the Sponsor. 
5.16. 
Assessment of Safety 
An independent Data Monitoring Committee (DMC) will periodically assess patient safety in an 
unblinded manner during the course of the study. No unblinded data will be accessible to site 
staff, the Sponsor, study monitors, and personnel of the electronic data capture vendors before 
the database is locked. The specific activities and responsibilities of the DMC are defined in the 
DMC Charter for CY 5022. 
Dosing of an individual will be stopped and not resumed if treatment-related AEs, changes in 
vital signs, ECGs, or clinical laboratory results are observed and these changes pose a significant 
health risk, in the opinion of either the Investigator or the Sponsor Medical Monitor. A blood 
sample for PK analysis should be collected at the time of the event or as close as possible to the 
time of the event. 
In the event of a confirmed, marked hepatic abnormality as defined in Appendix C  (Liver Safety 
Monitoring and Assessment), it is the Investigator’s responsibility to ensure contact with the 
Sponsor immediately (i.e., within 24 hours of awareness or at the earliest possible time point). 
Patients with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored. 
5.17. 
Study Drug Interruption 
Patients who do not take the total assigned daily dose of study drug due to conditions of 
hospitalization or other circumstances should be encouraged to return to treatment. The Medical 
Monitor should be contacted for a patient who has discontinued treatment for more than one 
week (prolonged study drug interruption). 
If study drug interruption for more than one week has occurred, the Investigator should evaluate 
the patient in clinic to ensure that it is safe for the patient to resume study drug dosing and 
consult with the Medical Monitor for the appropriate course of action. 
5.18. 
Study Discontinuation 
The study may be discontinued by the Sponsor for the following reasons: 
• Excessive rates of AEs  
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• A decision to cease or delay further development of the drug 


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Description of Investigational Product 
This is a double-blind, placebo-controlled study. As such, the site pharmacy staff, the 
Investigator, the patient, remaining study site clinical staff, and the Sponsor will be blinded to 
treatment assignment. 
CK-2127107 study drug is supplied as immediate release, white to off-white, modified capsule-
shaped tablets at a dose strength of 150 mg of CK-2127107 per tablet, which are to be stored 
under secure conditions at ≤25°C (77°F) with excursions allowed up to 30°C (86°F). 
Matching placebo tablets will be supplied and should also be stored at controlled room 
temperature under secure conditions. 
Active CK-2127107 tablets contain 150 mg of CK-2127107 plus excipients. Placebo tablets 
contain excipients only. 
Table 4: 
Study Drug 
Study Drug 
CK-2127107 
Placebo for CK-2127107  
Form 
Tablet 
Tablet 
Supplier 
Cytokinetics, Inc. 
Cytokinetics, Inc. 
Manufacturer 
Patheon, Inc. 
Patheon, Inc. 
CK-2127107 and matching placebo tablets will be supplied to the clinical site in blister strips 
inside labeled wallets. Patients will receive one or more wallets of study drug, CK-2127107 or 
matching placebo at the appropriate visit. Each wallet is sufficient for one week of dosing, plus 
overage. Double-blind wallets will be labeled with a unique random kit number. 
The study research coordinator or designated site staff will be responsible for patient 
randomizations, using an interactive web response system (IWRS). 
6.2. 
Dose Administration (CK-2127107 or Placebo)  
This study drug will be administered orally as tablets to patients with ALS. Doses (CK-2127107 
or placebo) for each of the treatment groups will be dispensed in accordance with the study 
randomization prior to the patient’s first dose. 
6.3. 
Dosing Diary  
A dosing diary will be maintained by the patient to record date and time of twice daily study 
drug administration. The dosing diary should be returned at each clinic visit. 
6.4. 
Randomization Schedule and Removal of Blind  
An IWRS will provide patient randomization assignments for this study. The site pharmacist or 
other qualified person responsible for randomizing patients will receive the appropriate kit 
numbers through the IWRS and provide it to the site staff who will be distributing study drug to 
the patient. RANDOMIZATION INFORMATION MAY BE MADE AVAILABLE TO THE 


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INVESTIGATOR ONLY IN THE EVENT OF A MEDICAL EMERGENCY OR AN AE THAT 
NECESSITATES IDENTIFICATION OF THE STUDY DRUG (CK-2127107 or placebo) FOR 
THE WELFARE OF THAT PATIENT. Except in a medical emergency, the Investigator (or 
designee) and study site clinical staff will remain blinded during the conduct of the study and 
until such time that all discrepancies in the clinical database are resolved (i.e., at the time of the 
database lock). The date/initials and reason for study blind removal by the Investigator and/or 
clinical staff will be documented. The Investigator will contact the Sponsor as soon as possible 
before or immediately following the emergency unblinding of any patient. 
6.5. 
Study Drug Accountability and Disposal   
The site pharmacist or other qualified person responsible for managing study drug supplies will 
maintain an accurate record of the receipt of the investigational study drug as shipped by the 
Sponsor (or designee), including the kit number and date received. One copy of this receipt will 
be returned to the Sponsor when the contents of the investigational study drug shipment have 
been verified. An accurate drug disposition record will be kept, specifying the study drug 
provided to each patient and the dates of dose administration. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
The patient should be instructed to return all unused study drug to the designated clinical site 
staff at each study visit. Study drug accountability is to be conducted by the designated study 
staff member with the patient at each study visit. The dosing diaries should also be referenced 
when completing drug accountability. 
All unused drug supplies will be returned to the Sponsor (or designee) or disposed of by the 
clinical research unit, per the Sponsor’s (or designee’s) instructions at the end of the study. 


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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
7.1.1. 
Adverse Event 
As defined by the International Conference on Harmonisation (ICH), an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered an investigational 
product, and which does not necessarily have to have a causal relationship with the 
investigational product. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the investigational product. 
Examples of an AE: 
• Conditions newly detected or diagnosed after the administration of the investigational 
product, including conditions that may have been present but undetected prior to the 
start of the study 
• Conditions known to have been present prior to the start of the study that increase in 
severity or frequency after the administration of the investigational product 
• Signs, symptoms, or the clinical sequelae of a suspected drug interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose (overdose per se 
should not be reported as an AE term) 
• Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other 
abnormal assessments (e.g., ECGs, vital signs, etc.) that are considered by the 
Investigator as a clinically significant change after the first dose of the investigational 
product. The Investigator will exercise his/her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is a 
clinically significant change after the first dose of the investigational product. 
Issues Not Considered AEs: 
• Medical or surgical procedures (e.g., appendectomy). The AE is the condition that 
leads to the procedure (e.g., appendicitis) if it qualifies according to the definition 
above. 
• Hospitalizations where an untoward medical occurrence did not occur. Examples 
include: 
− hospitalization for social reasons such as unavailability of a caregiver outside of 
the hospital due to living situation, OR 
− hospitalization for percutaneous endoscopic gastrostomy placement prior to 
signing the ICF 
• Fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not represent a clinically significant change after the first dose of 
the investigational product. 


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• Abnormal laboratory or test findings that are not assessed by the Investigator as a 
clinically significant change after the first dose of the investigational product. 
7.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that: 
a. Results in death 
NOTE: Death is selected as a seriousness criterion ONLY when the event is the cause 
of death. Death is an outcome and the event which led to the death should be the 
reported event term. 
b. Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the patient was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe, prolonged, 
or untreated. 
c. Requires hospitalization or prolongation of existing hospitalization  
NOTE: Hospitalization signifies that the subject has been admitted to the hospital as 
an in-patient for any length of time. Emergency room treatment does not qualify for 
this category, but may be appropriately included in category f (see below). If a 
complication prolongs the hospitalization or fulfills any other seriousness criterion or 
criteria, the complication will be considered an additional SAE. When in doubt as to 
whether ‘hospitalization’ occurred, consult the Medical Monitor. 
Hospitalization should not be considered an AE term in itself. It will be considered an 
outcome of an AE. For example, hospitalization for an elective treatment of a pre-
existing condition that did not worsen after the first dose of the investigational 
product will not be considered an AE. 
d. Results in disability/incapacity 
NOTE: The term disability means a substantial or permanent disruption of a person’s 
ability to conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) that may temporarily interfere with or prevent everyday life functions 
but do not constitute a substantial or permanent disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding if an event 
should be reported as serious. Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition may 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 


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of drug dependency or drug abuse. If in doubt as to whether or not an event qualifies 
as an “important medical event”, consult the Sponsor’s Medical Monitor. 
7.2. 
Collection of AEs/SAEs 
During each scheduled visit, ask about potential AEs or SAEs using the following standard 
questions: 
1. Have you had any medical problems since your last visit? 
2. Have you taken any new medications since your last visit? 
7.3. 
Recording and Reporting of AEs/SAEs 
7.3.1. 
Recording and Reporting of AEs 
Events occurring between the Screening Visit and just prior to the first dose of the 
investigational product on Day 1 should be recorded in the Medical History eCRF unless the 
event is related to a protocol-mandated procedure. If the event is deemed related to a protocol-
mandated procedure (e.g., hematoma at the puncture site) and deemed clinically significant by 
the Investigator, the event should be reported as an AE or an SAE (if applicable). 
AEs will be documented from the first administration of the investigational product through the 
Follow-Up Visit. The Investigator will review all documentation (e.g., hospital progress notes, 
laboratory and diagnostic reports) relevant to the event. A diagnosis will then be determined 
based on signs, symptoms, and/or other clinical information. The diagnosis and not the 
individual signs/symptoms should be reported as the AE term. 
ALS progression and signs/symptoms that are expected as part of ALS progression (see 
Section 7.4.3) will not be collected as AEs unless they meet seriousness criteria and should be 
recorded as SAEs. 
7.3.2. 
Recording and Reporting of SAEs 
If an AE meets any of the seriousness criteria (see Section 7.1.2), it must be reported using the 
SAE report form within 24 hours of the site’s knowledge. At a minimum, the following 
information should be included: 
• Patient number 
• Event term, including an onset date and stop date, if applicable, and a brief 
description 
• Seriousness criterion/criteria 
• Causality assessment in relation to the investigational product 
If all information regarding the SAE is not initially available, the site should still report the SAE 
within 24 hours of awareness/discovery. Additional information should be reported when it 
becomes available and no later than 24 hours after receipt of such information. 


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7.4. 
Evaluating AEs and SAEs 
7.4.1. 
Assessment of Severity 
The Investigator should assess the severity of each AE/SAE. The severity of AEs/SAEs will be 
assessed by assigning a Grade of 1, 2, 3, 4 or 5 according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, except for ALT, AST, 
and TBL levels as described in Appendix C. 
When an AE/SAE cannot be graded by CTCAE, the following severity grade may be used: 
• Grade 1 (Mild): Aware of sign or symptom, but easily tolerated and intervention is 
not indicated 
• Grade 2 (Moderate): Discomfort enough to cause interference with usual activity, 
local or non-invasive intervention is indicated 
• Grade 3 (Severe): Incapacitating with inability to work or do usual activity, not 
immediately life-threatening; hospitalization or prolongation of hospitalization may 
be indicated 
• Grade 4 (Life-Threatening): Refers to an event in which the patient was, in the view 
of the Investigator, at risk of death at the time of the event. (This category is not to be 
used for an event that hypothetically might have caused death if it were more 
severe.); urgent intervention is indicated 
• Grade 5 (Fatal): Death related to AE 
Severity should not be confused with seriousness. Severity is a category for rating the intensity 
of an event, and an event becomes serious when it meets one of the outcomes described in 
Section 7.1.2 “Serious Adverse Event”. 
7.4.2. 
Assessment of Causality 
The Investigator will assign causality to each SAE (related or unrelated). When assessing 
relationship to study drug, the Investigator will consider the following factors: 
• Temporal association between the administration of the investigational product and 
the event 
• Cessation of the AE following discontinuation of dosing 
• Recurrence of the AE with reintroduction of study drug, if performed 
• Similarity to known class effects 
• Alternative causes, such as:  
− Known effects of concomitant medications 
− Pre-existing risk factors 
− Concurrent illnesses 
The assessment of causality will be based on the information available, and may be changed 
upon receipt of additional information. 


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7.4.3. 
Assessment of Expectedness 
ALS is a progressive and uniformly fatal neurodegenerative disorder associated with relentlessly 
progressive loss of motor function, including appendicular, craniobulbar, and respiratory 
function due to the degeneration of the upper and lower motor neurons which control and 
innervate the voluntary skeletal muscles. The following events, in addition to death due to ALS 
progression, are anticipated to occur in the study population as signs/symptoms of ALS 
progression which may or may not lead to hospitalization. 
Table 5: 
MedDRA Preferred Terms 
MedDRA Preferred Terma 
MedDRA Preferred Terma 
Dysarthria 
Muscle spasticity 
Dysphagia 
Muscle weakness 
Dyspnoea 
Pneumonia aspiration 
Gait disturbance 
Respiratory failure 
Muscle contractions involuntary 
Weight decreased/Abnormal loss of weight 
Muscle spasms 
 
a MedDRA Version 19.1 
7.5. 
Follow-Up of AEs and SAEs 
After the initial recording of an AE/SAE, the Investigator should proactively follow the patient. 
Non-serious AEs that are still ongoing at the end of the study should be reviewed by the 
Investigator to determine if further follow up is required. The Investigator will document on the 
AE eCRF any/all ongoing non-serious AEs that will not be followed up further after the patient 
exits the study. If in doubt, the Investigator should consult the Medical Monitor. 
All SAEs should be followed until resolution, until the condition stabilizes, or until the patient is 
lost to follow-up. Once the seriousness criterion no longer applies to the SAE (e.g., patient was 
discharged), the corresponding AE eCRF page should be updated. All relevant additional 
information collected regarding an SAE, including laboratory test reports, consultation reports 
from other health care professionals, discharge summaries, or other information should be 
transmitted to Cytokinetics with the follow-up SAE report form within 24 hours of receipt or 
awareness. 
Cytokinetics may request the Investigator to perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
any AE/SAE. 
If a patient dies during participation in the study or during the follow-up period, the Investigator 
will provide Cytokinetics with a copy of any post-mortem findings, including an autopsy report 
if obtainable. 


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7.6. 
Post-Study AEs/SAEs 
A post-study AE/SAE is defined as any event that occurs outside of the AE detection period 
defined in Section 7.3.1. 
Investigators are not obligated to actively solicit AEs from former study participants. However, 
if the Investigator learns of an SAE that he/she considers reasonably related to the investigational 
product at any time after a patient has been terminated from the study, the Investigator will 
promptly notify Cytokinetics. 
7.7. 
Pregnancy 
Pregnancy is not an AE; however, information on pregnant female patients and partners of male 
patients will be collected if the pregnancy occurs after the patient receives the first dose of the 
investigational product until 10 weeks after the last dose. The pregnancy information and its 
outcome will be collected using the Pregnancy Report Form. If the pregnancy occurs in a partner 
of a male patient, the partner’s consent will be obtained before collecting information regarding 
the pregnancy and its outcome. 
If the pregnancy test (urine or serum) is positive, the pregnancy should be immediately reported 
to the Investigator and the Sponsor. Any female patient who becomes pregnant during the study 
is not eligible to continue the study and should complete the study procedures as soon as 
possible. 
If a partner of a male patient becomes pregnant during the study, the male patient may opt to 
continue his participation but must use barrier method (condom) to prevent fetal exposure. 
Accidental, therapeutic, or spontaneous abortions and congenital anomalies or birth defects will 
be reported as SAEs. 


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8. 
STATISTICAL METHODS 
8.1. 
General Considerations 
8.1.1. 
General Approach 
All pre-specified hypothesis tests will be 2-sided with a significance level of 0.05. Descriptive 
statistics for categorical variables will include frequency and percentage, and for continuous 
variables will include number of patients, mean, median, standard deviation, standard error, 
minimum and maximum. Baseline is defined as the last available measurement taken before the 
first dose of study medication unless otherwise specified. Missing data will not be imputed 
unless otherwise specified. 
8.1.2. 
Sample Size and Randomization 
Approximately 445 patients will be randomized to receive either one of the three CK-2127107 
doses (300 mg/day, 600 mg/day and 900 mg/day TDD) or matching placebo tablets in a ratio of 
1:1:1:1. Randomization will be stratified by riluzole use/non-use and edaravone use/non-use. The 
dropout rate at Visit Week 12 is estimated to be 10%, thus approximately 400 patients are 
expected to complete 12 weeks of double-blind treatment. The effect of CK-2127107 on the 
change from baseline to Week 12 in percent predicted SVC will be analyzed using a mixed 
model for repeated measures (MMRM) with the contrast (-5, -1, 3, 3) to reflect the assumed 
relationship for the placebo, 300 mg/day, 600 mg/day and 900 mg/day dose groups. The analysis 
is estimated to provide 90% power to detect 2.75, 5.5 and 5.5 percentage points advantage over 
placebo for the 300 mg/day, 600 mg/day and 900 mg/day CK-2127107 dose groups, 
respectively, in change from baseline of percent predicted SVC, at the end of the double-blind 
treatment (Visit Week 12). This calculation is based on a two-sided test with alpha set at 0.05 
and a common standard deviation of 14 percentage points. 
8.2. 
Analysis Sets 
8.2.1. 
Full Analysis Set (FAS) 
The FAS will consist of all randomized patients who receive at least one dose or portion of a 
dose of study drug and who have a baseline and at least one post-baseline efficacy assessment 
during the double-blind treatment. 
8.2.2. 
Safety Analysis Set (SAS) 
The SAS will consist of all randomized patients who receive at least one dose or portion of a 
dose of study drug. 
8.2.3. 
Pharmacokinetics Analysis Set (PKS) 
The PKS will consist of all randomized patients who have at least one evaluable plasma 
concentration of CK-2127107, provided they have no major protocol violations that could affect 
the PK of CK-2127107.  


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8.3. 
Endpoints 
8.3.1. 
Efficacy Endpoints 
8.3.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Visit Week 12 in the percent SVC. 
8.3.1.2. 
Secondary Efficacy Endpoints 
• Slope from baseline to Visit Week 12 in the mega-score of muscle strength measured 
by HHD and handgrip dynamometry  
• Change from baseline to Visit Week 12 in the ALSFRS-R 
8.3.1.3. 
Exploratory Efficacy Endpoints 
Change from Baseline Endpoints  
• Change from baseline to Visit Week 12 in the percent predicted SVC measured at 
home  
• Change from baseline to Visit Week 12 in the components of voice analysis  
• Change from baseline to Visit Week 12 in the components of handwriting analysis  
• Percent changes from baseline in the strength of the muscle groups from baseline to 
Visit Week 12 that contribute to the Mega-score at Visit Week 12 
• Change from baseline to Visit Week 12 in the ALSAQ-5 
Slope Endpoints:  
• Slope of change from baseline to Visit Week 12 in the percent predicted SVC 
• Slope of change from baseline to Visit Week 12 in the ALSFRS-R 
• Slope of change from baseline to Visit Week 12 in percent predicted SVC measured 
at home  
• Slope of change from baseline to Visit Week 12 in the components of voice analysis  
• Slope of change from baseline to Visit Week 12 in the components of handwriting 
analysis  
• Slope of change from baseline to Visit Week 12 in the ALSAQ-5 
8.3.2. 
Safety Endpoints 
The safety endpoints are listed in the following: 
• The incidence and severity of TEAEs 
• Clinically important changes in safety assessment results [including, as appropriate, 
vital signs, clinical laboratory tests, ECGs, Ashworth score, falls assessment, physical 
and neurological examinations, BDI-Fast Screen and suicidality assessment]. 


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8.3.3. 
Pharmacokinetic Measurements 
The plasma concentrations of CK-2127107 and possible metabolites will be measured at the 
sampled time points during the study. 
8.4. 
Statistical Analysis 
8.4.1. 
Patient Disposition 
The number and percentage of patients randomized, receiving any study drug, completing the 
study, prematurely discontinuing treatment and prematurely discontinuing from the study will be 
summarized by dose group, treatment and overall. Reasons of premature discontinuation will 
also be summarized. 
8.4.2. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized by dose group, 
treatment and overall using descriptive statistics. 
8.4.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be classified using the World Health Organization Drug 
dictionary, and summarized by drug class and preferred term (PT). 
8.4.4. 
Efficacy Analysis 
Efficacy analyses will be conducted for the FAS. 
8.4.4.1. 
Primary Efficacy Analysis 
The hypothesis for the primary efficacy analysis is that there is a positive treatment difference 
(CK-2127107 minus placebo) in change from baseline to Week 12 in the percent predicted SVC. 
The effect of CK-2127107 on the change from baseline to Week 12 in percent predicted SVC 
will be analyzed using a MMRM with the contrast (-5, -1, 3, 3) to reflect the assumed 
relationship for the placebo, 300 mg/day, 600 mg/day and 900 mg/day dose groups. The 
response variable in the model will be the change in the percent predicted SVC from baseline to 
each post-baseline visit. The model will include the terms of treatment, baseline value, pooled 
site, visit, randomization stratification factors of riluzole use/non-use and stratified edaravone 
use/non-use, as well as treatment-by-visit and baseline-by-visit interactions. An unstructured 
variance-covariance structure will be used to model the within-subject errors. 
8.4.4.2. 
Secondary Efficacy Analysis 
Slope from baseline in the mega-score of muscle strength will be analyzed using a MMRM. The 
response variable will be the change from baseline to each post-baseline visit. The model will 
include the terms of treatment, the baseline value, pooled site, time, randomization stratification 
factors of  riluzole use/non-use, and stratified edaravone use/non-use as well as treatment-by-
baseline and treatment-by-time interactions. A random slope effect will be assumed in the model. 
Change from baseline in the ALSFRS-R will be analyzed using the same method as for the 
primary efficacy analysis. 


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8.4.4.3. 
Exploratory Efficacy Analysis 
Exploration of the dose-response relationship will come from model-based analyses that will use 
various assumptions of an implicit dose-response relationship. In addition, placebo will be tested 
against each dose group of CK-2127107 for specified endpoints and the 600 mg/day and 
900 mg/day dose groups combined.  
8.4.4.4. 
Multiplicity 
The global null hypothesis for the primary and secondary efficacy endpoints will be tested in a 
pre-specified order using a closed testing procedure. This procedure will maintain the family-
wise error rate at two-sided significance level of 0.05 for all hypotheses tested in a confirmatory 
sense. Details of the procedures will be provided in the Statistical Analysis Plan. 
Hypotheses other than the primary and secondary efficacy endpoints will also be tested with a 
significance level of 0.05. However, no adjustments for multiple comparisons will be made for 
these tests. 
8.4.5. 
Safety Analysis 
Safety analyses will be conducted for the SAS. Safety data will be summarized by dose group, 
treatment and overall using descriptive statistics. 
8.4.5.1. 
Study Drug Exposure 
The amount of study drug received and duration of study drug exposure will be summarized. 
8.4.5.2. 
Adverse Event 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
tabulated by system organ class (SOC) and PT. Individual events (PT) within each SOC will be 
presented in order of descending frequency. 
An AE (or SAE) will be regarded as treatment emergent if it starts or worsens (e.g., increases in 
severity or frequency) during or after the first dose of study drug. TEAEs will be summarized by 
maximum severity, and by relationship to the study treatment. All AEs will be listed. 
8.4.5.3. 
Serious Adverse Event 
Treatment emergent SAEs will be summarized by maximum severity, and by relationship to the 
study treatment. All SAEs will be listed. 
8.4.5.4. 
Clinical Laboratory Parameters 
For each laboratory parameter, the number and percentage of subjects with alert values or values 
outside the normal range during the study will be tabulated. All laboratory evaluations identified 
as outside the normal range or as alerts by the central laboratory will be listed. The value and 
change from baseline in continuous laboratory parameters will be summarized at each scheduled 
visit where laboratory measurements are taken. 


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8.4.5.5. 
Vital Signs 
For each measurement of heart rate, blood pressure, respiratory rate, and BMI, the number and 
percentage of subjects with clinically relevant abnormalities during the study will be tabulated. 
All measurements identified as clinically relevant abnormalities will be listed. The value and 
change from baseline in heart rate, blood pressure, respiratory rate and BMI will be summarized 
at each scheduled visit where vital signs are taken. 
8.4.5.6. 
ECGs 
For each ECG measurement, the number and percentage of subjects with clinically relevant 
abnormalities during the study will be tabulated. ECG measurements identified as clinically 
relevant abnormalities will be listed. The value and change from baseline in ECG measurements 
will be summarized at each scheduled visit where measurements are taken. 
8.4.5.7. 
Physical and Neurological Examinations 
The number and percentage of subjects deemed by the investigators to have clinically significant 
abnormalities will be tabulated by type of exam at each scheduled visit where physical or 
neurological examinations are taken. All measurements identified as clinically relevant 
abnormalities will be listed. 
8.4.5.8. 
Ashworth Score 
Ashworth score will be determined bilaterally at the elbows and knees with the results 
summarized at each body location. 
8.4.5.9. 
Falls Assessments 
The number and percentage of subjects with falls will be tabulated at each scheduled visit where 
falls assessments are taken. Activities engaged at the time of the fall, physical symptoms 
experienced immediately preceding the fall, and if the fall resulted in injury will also be 
summarized. 
8.4.5.10. Beck Depression Inventory-Fast Screen 
The total score of the BDI-Fast Screen is determined by summing the scores from the 
7 questions, and can range from 0 to 21, with higher scores indicating greater depression 
severity. The value and change from baseline in the total score of the BDI-Fast Screen will be 
summarized at each scheduled visit where scores are taken. 
8.4.6. 
Exposure-Response Analysis 
The relationship of drug exposure with efficacy and safety endpoints of interest will be explored. 
Graphical and tabular presentations will be provided as appropriate. 
8.4.7. 
Pharmacokinetic Analysis 
PK analyses will be conducted using the PKS.  All of the PK samples collected, including those 
obtained at Hour 3 on Day 1 as well as Hour 3 and Hour 6 at Week 2 and Week 12 from patients 
enrolled prior to Amendment 03, will be used for PK analyses. PK parameters such as tmax, Cmax, 


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50  
 
Ctrough, AUC0-24, AUC∞, CL/F, V/F, t½ and RAC will be summarized by dose group using 
descriptive statistics as appropriate.  Nominal sample times will be presented in all statistical and 
graphical summaries.   
The observed plasma concentrations of CK-2127107 and its metabolites (if applicable) and 
riluzole at planned sampling time points will be summarized and listed. The potential for drug-
drug interaction between CK-2127107 given alone and in the presence of riluzole will also be 
assessed. 
The PK parameters with and without co-administration of riluzole will also be summarized. Box-
whiskers-plots of AUC and Cmax at Visit Week 12 with and without co-administration of riluzole 
will be presented. 
8.5. 
Interim Analysis  
After the last patient completes dosing, an interim analysis may be conducted by the Sponsor. 
8.6. 
Statistical Software 
Statistical analyses will be performed using SAS® version 9.4 or greater. 
8.7. 
Changes in Statistical Methods 
All changes in statistical methods that are described in the statistical analysis plan will be 
documented in the clinical study report. 


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9. 
ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. There will be no alterations in the protocol without the express written approval of 
the Sponsor, Investigator, and the Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) and regulatory authorities, as applicable. 
9.2. 
Initiation Visit 
Prior to the start of the clinical study at each site, the representative(s) of the Sponsor will meet 
with the Investigator(s) and appropriate clinical staff to familiarize the Investigator and clinical 
staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential. The Investigator agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts, etc.) by the Investigator(s) or their representative(s), shall require 
prior notification and review, within a reasonable time frame, by the Sponsor, and cannot be 
made in violation of the Sponsor’s confidentiality restrictions or to the detriment of the 
Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate site monitors who will be responsible for monitoring this clinical 
trial. The site monitor will monitor the study conduct, proper eCRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, the monitor will 
visit the study site at suitable intervals and be in frequent contact through verbal and written 
communication. It is essential that the site monitor have access to all documents (related to the 
study and the individual participants) at any time these are requested. In turn, the site monitor 
will adhere to all requirements for patient confidentiality as outlined in the ICF. The Investigator 
and other study personnel will be expected to cooperate with the site monitor, to be available 
during a portion of the monitoring visit to answer questions, and to provide any missing 
information. 
9.5. 
Institutional Review Board/Research Ethics Board/Ethics Committee  
In accordance with the US Code of Federal Regulations (CFR), 21 CFR 56, the protocol, subject 
recruitment advertisements (if applicable), and ICF will be submitted to the IRB/REB/EC for 
review and subsequent written approval by the IRB/REB/EC must be received before 
proceeding. The Sponsor will supply relevant material for the Investigator to submit to the IRB 
for the protocol’s review and approval. Verification of the IRB/REB/EC unconditional approval 
of the protocol and the written ICF statement will be transmitted to the Investigator. 


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The IRB/REB/EC will be informed by the Investigator of subsequent protocol amendments and 
of serious and unexpected AEs. Approval for protocol amendments will be transmitted in writing 
to the Investigator. If requested, the Investigator will permit audits by the IRB/REB/EC and 
regulatory inspections by providing direct access to source data/documents. 
The Investigator will provide the IRB/REB/EC with progress reports at appropriate intervals (not 
to exceed one year) and a Study Progress Report following the completion, termination, or 
discontinuation of the Investigator’s participation in the study. 
9.6. 
Informed Consent 
Before protocol-specific procedures are carried out, written informed consent for the study will 
be obtained from patients. The ICF generated by the Investigator (or designee) will be approved 
(along with the protocol) by the IRB/REB/EC and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The patients will be informed that participation is voluntary and that patients can 
withdraw from the study at any time. In accordance with 21 CFR 50, informed consent shall be 
documented by the use of a written ICF approved by the IRB/REB/EC and will be signed by the 
patient prior to protocol-specific procedures being performed. A copy of the signed consent, and 
the original will be maintained with the patient’s records. A copy of the IRB/REB/EC approved 
ICF must be sent to the Sponsor (or designee). 
9.7. 
Records 
The results from data collected during the study will be recorded in the patient’s eCRF. To 
maintain confidentiality, the patient will be identified only by a unique identification number. 
The completed eCRFs will be transferred to the Sponsor or designee. All source documents, 
records, and reports will be retained by the study site in accordance with 21 CFR 312.62(c). All 
primary data, or copies thereof (e.g., laboratory records, source documents, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the study site archives. 
9.8. 
Reference to Good Clinical Practices (GCP) 
The study procedures outlined in this protocol will be conducted in accordance with the CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), and Applications for FDA Approval to Market a New Drug (21 CFR 314), as 
appropriate. As such, these sections of U.S. Title 21 CFR, along with the applicable ICH 
Guidelines, are commonly known as Good Clinical Practices (GCP). 


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53  
 
10. 
REFERENCES 
Brooks, B. R., R. G. Miller, et al. (2000). "El Escorial revisited: revised criteria for the diagnosis 
of amyotrophic lateral sclerosis." Amyotroph Lateral Scler Other Motor Neuron Disord 
1(5): 293-299. 
CTCAE. "Common Terminology Criteria for Adverse Events (CTCAE) v4.0." from 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40. 
Ducharme, M. P., M. Smythe, et al. (1993). "Drug-induced alterations in serum creatinine 
concentrations." Ann Pharmacother 27(5): 622-633. 
FDA (2009). Guidance for Industry, Drug-induced liver injury: Premarketing clinical evaluation. 
D. Safety. 
Inker, L. A., C. H. Schmid, et al. (2012). "Estimating glomerular filtration rate from serum 
creatinine and cystatin C." N Engl J Med 367(1): 20-29. 
Kiernan, M., S. Vucic, et al. (2011). "Amyotrophic lateral sclerosis." Lancet 377(9769): 942-
955. 
Lacomblez, L., G. Bensimon, et al. (1996). "Dose-ranging study of riluzole in amyotrophic 
lateral sclerosis." The Lancet 347: 1425-1431. 
Temple, R. (2006). "Hy's law: predicting serious hepatotoxicity." Pharmacoepidemiol Drug Saf. 
15(4): 213-220. 
Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. (2017). "Safety and 
efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a 
randomised, double-blind, placebo-controlled trial." Lancet Neurol 16(7): 505-512. 
 
 


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APPENDIX A. SCHEDULE OF EVENTS 
Study Procedures 
Screening 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
FU Visit 
Informed Consent 
X 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Physical Exama 
X 
 
 
 
 
 
X 
Neurological Exam 
X 
 
 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
Weight & BMI 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
X 
 
 
X 
Vital Signs 
Xb 
X 
X 
X 
X 
X 
X 
Clinical Safety Labsc 
X 
X 
X 
X 
 
X 
X 
Pregnancy Testd 
X 
 
 
 
 
 
X 
PK Samplee 
 
X 
X 
X 
X 
X 
 
SVC 
X 
X 
X 
X 
X 
X 
X 
Muscle Strength 
X 
X 
X 
X 
X 
X 
X 
ALSFRS-R 
X 
X 
X 
X 
X 
X 
X 
Voice recording 
X 
X 
X 
X 
X 
X 
X 
Fine Motor Skillsf 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-5 
X 
X 
X 
X 
X 
X 
X 
Health Economic 
Outcomes Measurements 
 
X 
X 
X 
X 
X 
X 
Ashworth Scale 
X 
X 
X 
X 
X 
X 
X 
Falls Assessments 
 
X 
X 
X 
X 
X 
X 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
 
AE/SAE Evaluations 
 
X 
X 
X 
X 
X 
X 
BDI-Fast Screen 
X 
X 
X 
X 
X 
X 
X 
a Complete physical examination at Screening Visit, abbreviated physical examination at FU visit 
b Temperature only at Screening 
c TSH only at Screening and Follow-Up Visit 
d Serum pregnancy test only for females of childbearing potential 
e PK sampling on Day 1 visit, Week 2 visit, Week 4 visit, Week 8 visit, and Week 12 visit; refer to Table 3 in 
protocol  
f If the device is suitable for use in that region 
 
Schedule of Events for Home Testing 
SVC* 
To be done every Saturday (± 1 day) independent of day of first dose 
Voice recording 
To be done every Saturday (± 1 day) independent of day of first dose 
  
 
 
 
*if the device is suitable for use in that region 


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55  
 
APPENDIX B. 
MEDICATIONS AND FOODS THAT INHIBIT OR INDUCE CYP3A4 
OR ARE OCT1/OCT2 SUBSTRATES 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
Strong Inhibitors: (Avoid) 
Strong Inducers: (Avoid) 
indinavir 
avasimibe 
nelfinavir 
carbamazepine 
ritonavir 
phenobarbital 
clarithromycin 
phenytoin 
itraconazole 
St. John’s Wort 
nefazodone 
rifampin 
ketoconazole 
rifabutin 
grapefruit 
 
Seville oranges 
 
 
 
Moderate Inhibitors:  
Moderate Inducers: 
erythromycin 
bosentan 
diltiazem 
efavirenz 
verapamil 
etravirine 
suboxone 
modafinil 
 
nafcillin 
 
nevirapine 
 
 
Weak Inhibitors: 
Weak Inducers: 
cimetidine 
amprenavir 
 
aprepitant 
 
armodafinil 
 
echinacea 
 
pioglitazone 
 
prednisone 
 
rufinamide 
 
clobazam 
 
lesinurad 
 
OCT1 Substrates (Avoid) 
OCT2 Substrates (Avoid) 
oxaliplatin 
pindolol 
dofetilide 
varenicline 
 
pilsicainide 
 
 
OCT1 Substrates (Use with Caution) 
OCT2 Substrates (Use with Caution) 
aciclovir 
metformin 
ganciclovir 
 


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APPENDIX C. LIVER SAFETY MONITORING AND ASSESSMENT 
Any patient enrolled in a clinical study with active drug therapy who reveals an increase of 
serum aminotransferase (AT) to > 3 x ULN or bilirubin > 2 × ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, alkaline phosphatase [ALP], and TBL). 
Testing should be repeated within 48-72 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. 
Patients 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 as follows: 
 
 ALT or AST 
 
Total Bilirubin 
Moderate 
 > 3× ULN  
or 
> 2× ULN 
Severe 
 > 3× ULN 
and > 2× ULN 
In addition, the patient 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 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. Patients with confirmed abnormal LFTs should be followed as 
described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or less 
if abnormalities stabilize or the study drug has been discontinued and the patient 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 a SAE. The Sponsor 
should be contacted and informed of all patients 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 should be recorded as ‘adverse events’ on the AE 


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57  
 
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. Non-alcoholic steatohepatitis is seen in obese hyperlipoproteinemic, and/or 
diabetic patients and may be associated with fluctuating aminotransferase levels. The 
investigator should ensure that the medical history form captures any illness that pre-
dates study enrollment that may be relevant in assessing hepatic function. 
• Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. 
• Obtain a history of exposure to environmental chemical agents. 
• Based on the patient’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 international normalized ratio (INR), direct 
bilirubin 
• Consider gastroenterology or hepatology consultations 
Patient 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 patient may be 
discontinued from the study. The investigator may determine that it is not in the patient’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 
• 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 patient with moderate or severe hepatic laboratory tests is 
not possible, 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 10–50% mortality (or 
transplant) (Temple 2006; FDA 2009). 
The three “requirements” for Hy’s Law are:  
1. Patients with ALT or AST ≥ 3 × ULN compared to placebo, AND 
2. For patients with AT elevations (often much greater than 3 × ULN), elevation of serum 
TBL > 2 × ULN, without initial findings of cholestasis (elevated serum ALP), AND 


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3. No other reasons can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 


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59  
 
APPENDIX D. CLINICAL LABORATORY EVALUATIONS 
All Visits: 
TBL 
Urea nitrogen 
Globulin 
Magnesium 
Direct bilirubin 
Creatinine 
Triglycerides 
Cystatin C 
Indirect bilirubin 
Glucose 
Cholesterol 
UA 
ALP 
Uric acid 
Creatine kinase 
CBC with 
differential 
ALT 
Calcium 
Sodium 
AST 
Phosphorus 
Potassium 
eGFR (calculated 
by CKD-EPI 
Cystatin C 
equation) 
Gamma-glutamyl 
transferase 
Total protein 
Bicarbonate 
Lactate 
dehydrogenase 
Albumin 
Chloride 
Screening and Follow-Up only: 
TSH 
Serum Beta Human Chorionic Gonadotropin 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
VERSION: 1.0 
DATE OF PLAN: 14-DEC-2018 
 
 
STUDY DRUG: RELDESEMTIV (CK-2127107) 
 
PROTOCOL NUMBER: CY 5022 
 
STUDY TITLE: 
A PHASE 2, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, DOSE-RANGING, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND   
TOLERABILITY OF CK-2127107 IN PATIENTS WITH AMYOTROPHIC LATERAL 
SCLEROSIS (ALS)  
  
BASED ON: 
Protocol Amendment 03 dated April 18, 2018 
 
 
SPONSOR: 
Cytokinetics, Inc. 
280 East Grand Avenue, 
South San Francisco, CA 94080 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving of 
essential documents. 
 


Cytokinetics, Inc. 
 
Statistical Analysis Plan – Protocol CY 5022                                                   December 14, 2018 
 
Confidential and Proprietary 
 
2 
SIGNATURE PAGE 
This document has been reviewed and approved* by: 
 
Jenny Wei, Ph.D. 
Associate Director, Biostatistics, Cytokinetics, Inc. 
 
Lisa Meng, Ph.D. 
Senior Director, Biometrics, Cytokinetics, Inc. 
 
Bettina Cockroft, M.D., M.B.A 
Vice President, Clinical Research, Neurology, Cytokinetics, Inc. 
 
 
* See electronic signatures at the end of the document. 
 


Cytokinetics, Inc. 
 
Statistical Analysis Plan – Protocol CY 5022                                                   December 14, 2018 
 
Confidential and Proprietary 
 
3 
TECHNICAL SUMMARY REPORT (TSR) 
Name of Sponsor/Company 
Cytokinetics Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
No generic or trade name 
Page: 
 
Name of Active Ingredient: 
Reldesemtiv (CK-2127107) 
 
 
Title of Study: 
A PHASE 2, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, DOSE-RANGING, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF CK-
2127107 IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS) 
Investigators: 
Study Center(s):  
Studied period (years): 2017-
2018 
Phase of development: Phase 2 
Objectives: 
Primary:  
• 
To assess the effect of reldesemtiv versus placebo on respiratory function in patients with ALS. 
Secondary: 
• 
To assess the effect of reldesemtiv versus placebo on measures of skeletal muscle function 
• 
To assess the effect of reldesemtiv versus placebo on global function 
• 
To evaluate the safety and tolerability of reldesemtiv administered orally to patients with ALS 
• 
To evaluate the exposure of reldesemtiv and its metabolites, when administered orally in tablet 
form to patients with ALS in the fed state 
Methodology: 
This study is a Phase 2, double-blind, randomized, placebo-controlled, dose ranging study of reldesemtiv in 
patients with ALS.  Approximately 445 eligible ALS patients will be randomized (1:1:1:1) to receive the 
following doses of reldesemtiv or placebo: 
• 
150 mg reldesemtiv twice a day for a 300 mg total daily dose (TDD) 
• 
300 mg reldesemtiv twice a day for a 600 mg TDD 
• 
450 mg reldesemtiv twice a day for a 900 mg TDD 
• 
Placebo twice a day.  
Randomization will be stratified by riluzole and/or edaravone use (yes/no) at baseline. 
Number of Subjects (planned and analyzed):  
Approximately 445 eligible ALS patients will be enrolled and approximately 400 patients are expected to 
complete 12 weeks of double-blind treatment.  
Criteria for inclusion and exclusion: 
Inclusion criteria:  
1. Able to comprehend and willing to sign an Informed Consent Form (ICF)  
2. Males or females between the ages of 18 and 80 years of age, inclusive  


Cytokinetics, Inc. 
 
Statistical Analysis Plan – Protocol CY 5022                                                   December 14, 2018 
 
Confidential and Proprietary 
 
4 
3. Diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported 
probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation 
of Neurology El Escorial criteria published in 2000) ≤ 24 months prior to screening 
4. Upright Slow Vital Capacity (SVC) ≥ 60% of predicted for age, height and sex at screening 
5. Able to swallow tablets 
6. A caregiver (if one is needed) 
7. Able to perform reproducible pulmonary function tests 
8. Pre-study clinical laboratory findings within the normal range or, if outside the normal range, 
deemed not clinically significant by the Investigator 
11. Patients must be either on riluzole for at least 30 days prior to screening or have not taken 
riluzole for at least 30 days prior to screening and not planning to start riluzole during the course 
of the study.  
12. Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at the time 
of screening or have not taken edaravone for at least 30 days prior to screening and not planning 
to start edaravone during the course of the study. Two cycles of dosing are defined as having 
completed Cycle 1 infusion, which is 14 consecutive days of intravenous (IV) edaravone 
followed by 14 days off edaravone, and Cycle 2, which is 10 out of 14 days of IV edaravone. 
Exclusion criteria: 
1. At the time of screening, any use of non-invasive ventilation (NIV), eg, continuous positive airway 
pressure [CPAP], noninvasive bi-level positive airway pressure [NPPV] or noninvasive volume 
ventilation [NVV]for any portion of the day, or mechanical ventilation via tracheostomy, or on any 
form of oxygen supplementation 
2. Neurological impairment due to a condition other than ALS  
3. Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or 
psychiatric illness that might interfere with the patient’s ability to comply with study procedures or 
that might confound the interpretation of clinical safety or efficacy data, including, but not limited to: 
a. 
A pulse <40 or >100 bpm; mean systolic blood pressure >180 mm Hg; mean diastolic blood 
pressure >100 mm Hg (based on measurements taken after rest for 3 minutes) that persist on 3 
successive measurements taken at least 2 minutes apart 
b. Clinically significant ECG abnormalities that require medical attention (ie, persistent 
atrioventricular conduction block >first degree, or acute myocardial ischemic changes) 
c. 
New York Heart Association Class II or greater congestive heart failure 
d. Chronic obstructive pulmonary disease or asthma requiring daily use of bronchodilator 
medications 
e. 
Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal 
tract  
f. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3-
times the upper limit of normal (ULN) or has total bilirubin greater than or equal to 2-times the 
ULN at screening.  These assessments may be repeated at the Investigator’s discretion (within the 
screening window)   
g. Poorly controlled or brittle diabetes mellitus 
h. Amputation of a limb 
i. 
Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s ability to 
understand and/or comply with study procedures and provide informed consent 
j. 
Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, 
or squamous cell carcinoma of the skin excised with clean margins) diagnosed and treated within 
the last five years 
k. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, 
would render the patient not suitable to participate in the study 


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l. 
Patient judged to be actively suicidal or a suicide risk by the Investigator 
m. Patient has estimated glomerular filtration rate (eGFR) less than 40 mL/min/1.73 m2 calculated 
by the CKD-EPI cystatin equation based on a cystatin C measurement at baseline 
4. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, 
whichever is longer, prior to dosing 
5. Known to have received reldesemtiv or tirasemtiv in any previous clinical trial 
6. Has received or is considering receiving during the course of the study any form of stem cell therapy 
for the treatment of ALS 
7. Has received or is considering receiving during the course of the study any form of gene therapy for 
the treatment of ALS 
8. Has received or is considering obtaining during the course of the study a diaphragmatic pacing system 
9. History of substance abuse within the past 2 years 
10. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose of study drug 
or a strong CYP3A4 inducer within 14 days prior to first dose of study drug  
11. Use of a medication that is an OCT1/OCT2 substrate within 7 days prior to first dose of study 
drug(see Appendix B of study protocol) 
Test product, dose and mode of administration: 
Reldesemtiv study drug will be supplied as tablets at a dose strength of 150 mg of reldesemtiv per tablet, and 
administered orally twice a day for a daily dose of 300, 600 or 900 mg if patients are assigned to reldesemtiv 
dose groups. 
Duration of treatment: 
12 weeks. 
 
 


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Reference therapy, dose and mode of administration: 
 Placebo tablet will be provided and administered orally twice a day for 12 weeks. 
Criteria for evaluation; 
Primary Efficacy Endpoint: 
Change from baseline to Week 12 in percent predicted slow vital capacity (SVC) 
Secondary Efficacy Endpoint: 
• 
Slope from baseline to Week 12 in muscle strength mega score measured by hand held dynamometry 
and handgrip dynamometry 
• 
Change from baseline to Week 12 in ALS Functional Rating Scale – Revised (ALSFRS-R). 
Other Secondary Endpoints: 
• 
The incidence and severity of treatment-emergent adverse events (TEAEs) 
• 
Plasma concentrations of reldesemtiv at the sampled time points during the study 
Statistical methods: 
Unless otherwise specified, descriptive statistics for continuous data will be presented using the number of 
patients with data to be summarized (n), mean, standard deviation (SD), median, minimum (min) and 
maximum (max). Least square (LS) means, standard error (SE), and two-sided 95% confidence interval (CI) of 
LS means (where an applicable statistical model is used) will be presented. All categorical/qualitative data will 
be presented using frequency counts and percentages. Two-sided 95% CIs will be presented, where applicable. 
Change from baseline to Week 12 in percent predicted SVC will be analyzed using a MMRM with the contrast 
(-5, -1, 3, 3) to reflect the assumed relationship for the placebo, 300 mg/day, 600 mg/day and 900 mg/day dose 
groups. The response variable in the model will be the change in the percent predicted SVC from baseline to 
each post baseline visit. The model will include the terms of treatment, baseline value, pooled sites, visit, 
riluzole and edaravone use, as well as treatment-by-visit and baseline-by-visit interactions. An unstructured 
variance-covariance matrix will be used to model within-patient errors. 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................12 
1. 
INTRODUCTION ......................................................................................................13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................13 
2.1. 
Study Objectives .........................................................................................................13 
2.1.1. 
Primary Objective .......................................................................................................13 
2.1.2. 
Secondary Objectives .................................................................................................13 
2.1.3. 
Exploratory Objectives ...............................................................................................13 
2.1.4. 
Pharmacokinetic / Pharmacodynamic Objectives ......................................................14 
2.2. 
Study Endpoints ..........................................................................................................14 
2.2.1. 
Efficacy Endpoints ......................................................................................................14 
2.2.2. 
Primary Efficacy Endpoint .........................................................................................14 
2.2.3. 
Secondary Efficacy Endpoints ....................................................................................14 
2.2.4. 
Exploratory Efficacy Endpoints .................................................................................14 
2.2.5. 
Safety Endpoints .........................................................................................................15 
2.2.6. 
Pharmacokinetic Measurements .................................................................................15 
3. 
STUDY DESIGN .......................................................................................................15 
3.1. 
Summary of Study Design ..........................................................................................15 
3.2. 
Description of Study Drug ..........................................................................................16 
3.3. 
Sample Size Consideration .........................................................................................16 
3.3.1. 
Sample Size Justification ............................................................................................16 
3.4. 
Randomization ............................................................................................................17 
3.5. 
Clinical Assessments ..................................................................................................17 
4. 
PLANNED ANALYSES ............................................................................................17 
4.1. 
Safety Monitoring .......................................................................................................17 
4.2. 
Interim Analyses .........................................................................................................17 
4.3. 
Final Analyses ............................................................................................................17 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................18 
5.1. 
General Summary Table and Individual Patient Data Listing Considerations ...........18 
5.2. 
Data Management .......................................................................................................18 
5.3. 
Data Presentation Conventions ...................................................................................18 


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5.4. 
Analysis Sets ...............................................................................................................19 
5.4.1. 
Full Analysis Set .........................................................................................................19 
5.4.2. 
Safety Analysis Set .....................................................................................................19 
5.4.3. 
Pharmacokinetics Analysis Set ...................................................................................19 
5.4.4. 
Use of Analysis Sets in Different Analyses and Summary Level ..............................19 
5.5. 
Definitions ..................................................................................................................19 
5.5.1. 
Baseline Assessments .................................................................................................19 
5.5.2. 
Change from Baseline .................................................................................................19 
5.5.3. 
Study Day ...................................................................................................................20 
5.5.4. 
Analysis Visit Windows .............................................................................................20 
5.5.5. 
Determining “Analyzed Record” for Each Analysis Visit Window ..........................20 
5.5.6. 
Pooled Sites ................................................................................................................21 
5.5.7. 
Calculated Rate of Pre-Study Disease Progression ....................................................21 
5.5.8. 
Efficacy Assessments .................................................................................................21 
5.5.8.1. 
Percent Predicted Slow Vital Capacity .......................................................................21 
5.5.8.2. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised ..............................22 
5.5.8.3. 
Muscle Strength Mega Score ......................................................................................23 
5.5.8.4. 
Ashworth Score ..........................................................................................................23 
5.5.8.5. 
Components of Voice Analysis ..................................................................................23 
5.5.8.6. 
Components of Handwriting Analysis ........................................................................25 
5.5.8.7. 
ALS Assessment Questionnaire Short Form ..............................................................26 
5.5.9. 
Health Economic Outcome Measures ........................................................................27 
5.5.10. 
Safety and Related Data ..............................................................................................27 
5.5.10.1. 
Exposure and Compliance ..........................................................................................27 
5.5.10.2. 
Adverse Event .............................................................................................................27 
5.5.10.3. 
Clinically Relevant Abnormalities in Vital Signs, Weight, and ECG ........................28 
5.5.10.4. 
Prior and Concomitant Medications ...........................................................................28 
5.5.10.5. 
Beck Depression Inventory .........................................................................................28 
5.5.11. 
Pharmacokinetics Parameters .....................................................................................29 
5.5.12. 
Reldesemtiv Concentration Bin ..................................................................................30 
5.6. 
Handling of Missing Data ...........................................................................................30 
5.6.1. 
Missing Efficacy Endpoints ........................................................................................30 


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5.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................30 
5.6.3. 
Missing Dates of ALS Symptom Onset and Diagnosis ..............................................30 
5.6.4. 
Missing Onset and Stop Dates for Adverse Events ....................................................31 
6. 
STUDY POPULATION .............................................................................................31 
6.1. 
Patient Disposition ......................................................................................................31 
6.2. 
Screen Failures ............................................................................................................32 
6.3. 
Protocol Deviations ....................................................................................................32 
6.4. 
Demographic and Baseline Characteristics ................................................................32 
6.5. 
Listing of Patient Inclusion and Exclusion Criteria ....................................................32 
6.6. 
Medical History and Medical Conditions Present at Entry ........................................32 
6.7. 
Prior Medication History and Medications Present at Entry ......................................32 
6.8. 
Baseline Physical Examination ...................................................................................33 
6.9. 
Baseline Vital Signs ....................................................................................................33 
6.10. 
Baseline Laboratory Data ...........................................................................................33 
6.11. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................33 
7. 
EFFICACY .................................................................................................................33 
7.1. 
Testing Statistical Assumptions ..................................................................................33 
7.2. 
Statement of the Null and Alternate Hypotheses ........................................................33 
7.3. 
Subgroup Analyses .....................................................................................................34 
7.4. 
Multiple Comparisons and Multiplicity ......................................................................34 
7.5. 
Analysis of the Primary Efficacy Endpoints ..............................................................35 
7.5.1. 
Primary Efficacy Analysis ..........................................................................................35 
7.5.2. 
Sensitivity Analyses of the Primary Efficacy Results ................................................35 
7.6. 
Analysis of the Secondary Efficacy Endpoints ..........................................................36 
7.7. 
Analysis of the Exploratory Efficacy Endpoints ........................................................36 
7.8. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................37 
7.9. 
Exploratory Analyses ..................................................................................................37 
7.9.1. 
Joint Rank Test ...........................................................................................................37 
7.9.2. 
Time-To-Event Analysis for Muscle Strength ...........................................................38 
7.9.3. 
Evaluation of SVC Measured at Home Using SVC Measured in Clinic as the 
Standard ......................................................................................................................38 
7.9.3.1. 
Correlation Between at Home and in Clinic Assessments of SVC ............................38 


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7.9.3.2. 
Change from Baseline to Week 12 in Percent Predicted SVC Assessed at 
Home and in Clinic .....................................................................................................38 
7.9.3.3. 
Time to Event Analysis of Percent Predicted SVC Decline to Less Than 50% .........39 
7.9.3.4. 
Comparing Percent Predicted SVC Between Patients Who Used a Home 
Spirometer for SVC Assessments and Those who Never Used .................................39 
8. 
SAFETY AND TOLERABILITY ..............................................................................39 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............39 
8.1.1. 
Summaries of Adverse Event Incidence Rates for All Patients .................................39 
8.1.2. 
Summaries of Adverse Incidence Rates for Serious Adverse Events, Adverse 
Event Dropouts, and Death .........................................................................................40 
8.2. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................40 
8.3. 
Concomitant and Other Medications ..........................................................................40 
8.4. 
Routine Laboratory Data ............................................................................................41 
8.5. 
Vital Signs ..................................................................................................................41 
8.6. 
Electrocardiogram .......................................................................................................43 
8.7. 
Physical Examination .................................................................................................43 
8.8. 
Neurological Examinations ........................................................................................43 
8.9. 
Ashworth Score ..........................................................................................................44 
8.10. 
Beck Depression Inventory Fast Screen Version .......................................................44 
8.11. 
Fall Assessment ..........................................................................................................44 
8.12. 
Study Termination Status ...........................................................................................44 
9. 
PHARMACOKINETIC AND PHARMACOKINETIC 
/PHARMACODYNAMIC ANALYSES ....................................................................44 
9.1. 
Pharmacokinetic Analyses ..........................................................................................44 
9.2. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................45 
10. 
HEALTH ECONOMIC OUTCOMES ANALYSIS ..................................................46 
11. 
COMPUTER METHODS ..........................................................................................46 
12. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .....................................46 
13. 
STATISTICAL CODES .............................................................................................47 
14. 
REFERENCES ...........................................................................................................51 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................52 
APPENDIX B. ANALYSIS VISIT WINDOWS ........................................................................53 
APPENDIX C. REGIONAL SITE POOLING FOR FAS ..........................................................55 


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APPENDIX D. MSPLINE VALUE FOR CALCULATION OF PREDICTED SVC ...............57 
 
LIST OF TABLES 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups ..........................................15 
Table 2: 
Analysis Set and Summary Level ...............................................................................19 
Table 3: 
Dimensions and Items of ALSAQ-5 ...........................................................................26 
Table 4: 
Interpretation of Score Ranges for Dimensions on ALSAQ-5 ...................................27 
Table 5: 
Depression Level Classification by BDI Total Score .................................................29 
Table 6: 
Criteria of Potentially Clinically Significant (PCS) Vital Signs ................................42 
Table 7: 
Criteria of Abnormal and PCS ECG Values ...............................................................43 
 
LIST OF FIGURES 
Figure 1: 
Patient Visit Diagram .................................................................................................16 
 
 


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LIST OF ABBREVIATIONS 
The following abbreviations are used in this analysis plan. 
Abbreviation 
Term 
AE 
 
adverse event 
ALSAQ-5 
ALS Assessment Questionnaire Short Form 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale - Revised 
ALT 
alanine aminotransferase (alanine transaminase) 
AST  
aspartate aminotransferase (aspartate transaminase) 
AUC 
area under the plasma concentration-time curve 
BDI 
Beck Depression Inventory 
BMI 
body mass index 
CI 
confidence interval 
Cmax  
maximum observed plasma concentration 
Ctrough 
pre-dose plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
HHD 
hand-held dynamometry 
ICF 
 
informed consent form 
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
NCI 
National Cancer Institute 
PCS 
potentially clinically significant 
PD                    
pharmacodynamic 
PK 
 
pharmacokinetic 
PKS 
pharmacokinetics analysis set 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAS 
safety analysis set 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
SVC 
slow vital capacity 
TDD 
total daily dose 
TEAE 
treatment emergent adverse event 
tmax  
time where maximum concentration is reached 
ULN 
upper limit of normal 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a technical elaboration of the 
planned analyses and detailed data displays to be included in the Clinical Study Report (CSR) for 
CY 5022. 
This SAP was developed in accordance with ICH E9 guideline. All decisions regarding final 
analysis, as defined in this SAP document, will be made prior to the database lock (unblinding) 
of the study data. Further study information can be found in the protocol. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
 Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to assess the effect of reldesemtiv versus placebo on 
respiratory function in patients with amyotrophic lateral sclerosis (ALS). 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are:  
• To assess the effect of reldesemtiv versus placebo on measures of skeletal muscle 
function 
• To assess the effect of reldesemtiv versus placebo on global function 
• To evaluate the safety and tolerability of reldesemtiv administered orally to patients 
with ALS 
• To evaluate the exposure of reldesemtiv and its metabolites, when administered orally 
in tablet form to patients with ALS in the fed state 
2.1.3. 
Exploratory Objectives 
The exploratory objectives of this study are:  
• To assess the effect of reldesemtiv versus placebo on respiratory function self-
assessments made at home by patients with help as needed by caregivers 
• To assess the effect of reldesemtiv versus placebo on disease progression through 
measurement of speech production characteristics over time 
• To assess the effect of reldesemtiv versus placebo on disease progression through 
measurement of handwriting abilities over time 
• To assess the change from baseline to Visit Week 12 in quality of life (as measured 
by the ALS Assessment Questionnaire Short Form [ALSAQ-5]) and muscle strength 
in patients on reldesemtiv compared to placebo 


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• To assess the change in the slope of decline of measures of function in patients on 
reldesemtiv compared to placebo 
2.1.4. 
Pharmacokinetic / Pharmacodynamic Objectives 
The pharmacokinetic (PK) / pharmacodynamic (PD) objectives of this study are to characterize 
the pharmacokinetics of reldesemtiv following multiple doses in the fed state at three dose levels 
in ALS patients as well as to evaluate possible relationships between both dose and exposure of 
reldesemtiv and its pharmacodynamic effects following multiple oral doses in patients with ALS. 
2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
2.2.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Visit Week 12 in percent predicted 
slow vital capacity (SVC). 
2.2.3. 
Secondary Efficacy Endpoints 
• Slope from baseline to Visit Week 12 in the muscle strength mega score measured by 
hand held dynamometry (HHD) and handgrip dynamometry  
• Change from baseline to Visit Week 12 in the ALS Functional Rating Scale – 
Revised (ALSFRS-R) 
2.2.4. 
Exploratory Efficacy Endpoints 
Endpoints assessed as a change from baseline include: 
• Change from baseline to Visit Week 12 in the percent predicted SVC measured at 
home  
• Change from baseline to Visit Week 12 in the components of voice analysis  
• Change from baseline to Visit Week 12 in the components of handwriting analysis  
• Percent change in the strength of the muscle groups from baseline to Visit Week 12 
that contribute to the Mega score at Visit Week 12  
• Change from baseline to Visit Week 12 in the ALSAQ-5 
Endpoints assessed as a change in slope include:   
• Slope of change from baseline to Visit Week 12 in the percent predicted SVC 
• Slope of change from baseline to Visit Week 12 in the ALSFRS-R 
• Slope of change from baseline to Visit Week 12 in percent predicted SVC measured 
at home  
• Slope of change from baseline to Visit Week 12 in the components of voice analysis  


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• Slope of change from baseline to Visit Week 12 in the components of handwriting 
analysis  
• Slope of change from baseline to Visit Week 12 in the ALSAQ-5 
2.2.5. 
Safety Endpoints 
The safety endpoints are listed in the following: 
• Incidence and severity of treatment-emergent adverse events (TEAEs) 
• Clinically important changes in safety assessment results [including, as appropriate, 
vital signs, clinical laboratory tests, ECGs, Ashworth score, falls assessment, physical 
and neurological examinations, beck depression inventory and suicidality assessment] 
2.2.6. 
Pharmacokinetic Measurements 
• The plasma concentrations of reldesemtiv and possible metabolites will be measured 
at the sampled time points during the study. 
3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a Phase 2, double-blind, randomized, placebo-controlled, dose ranging study of 
reldesemtiv in patients with ALS. An overview of the randomized treatment groups is provided 
in Table 1: 
 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups 
CK-2127107 
Placebo 
300 mg TDD 
1 tablet (150 mg) of 
reldesemtiv and 2 
placebo tablets twice 
daily for 12 weeks 
600 mg TDD 
2 tablets (150 mg) of 
reldesemtiv and 1 
placebo tablet twice   
daily for 12 weeks 
900 mg TDD 
3 tablets (150 mg) of 
reldesemtiv twice 
daily for 12 weeks 
 
3 placebo tablets 
twice daily for 12 
weeks 
 
The screening and qualification period for the study will be no more than 14 days in duration.  
Once patients have completed screening and are considered eligible for the study, they will be 
randomized as described above and stratified by riluzole and edaravone use status.   
 


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Figure 1: 
Patient Visit Diagram 
 
 
PD measures, vital signs, ECGs, and clinical laboratory evaluations will be performed at 
Screening and at specified times during the study. Patients will be evaluated at each study visit 
for signs and symptoms of intolerance to study drug.   
3.2. 
Description of Study Drug 
Reldesemtiv 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 muscle weakness and/or fatigue. Reldesemtiv is supplied as immediate release, white to off-
white, modified capsule-shaped tablets. Active reldesemtiv tablets contain 150 mg of reldesemtiv 
per tablet plus excipients. Placebo tablets contain excipients only. Reldesemtiv and matching 
placebo tablets will be supplied to the clinical site in blister strips inside labeled wallets. Patients 
will receive one or more wallets of study drug, reldesemtiv or matching placebo at the 
appropriate visit. Each wallet is sufficient for one week of dosing, plus overage. Double-blind 
wallets will be labeled with a unique random kit number.   
3.3. 
Sample Size Consideration 
3.3.1. 
Sample Size Justification 
Approximately 445 patients will be randomized. The dropout rate at Visit Week 12 is estimated 
to be 10%, thus approximately 400 patients are expected to complete 12 weeks of double-blind 
treatment. The effect of reldesemtiv on the change from baseline to Week 12 in percent predicted 
SVC will be analyzed using a mixed model for repeated measures (MMRM) with the contrast (-
5, -1, 3, 3) to reflect the assumed relationship for the placebo, 300 mg/day, 600 mg/day and 900 
mg/day dose groups. The sample size is estimated to provide 90% power to detect 2.75, 5.5 and 
5.5 percentage points advantage over placebo in the change from baseline to Visit Week 12 of 


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percent predicted SVC for the 300 mg/day, 600 mg/day and 900 mg/day reldesemtiv dose 
groups, respectively. This calculation is based on a two-sided test with alpha set at 0.05 and a 
common standard deviation (SD) of 14 percentage points. 
3.4. 
Randomization 
Patients will be randomized to receive either one of the three reldesemtiv doses (300 mg/day, 
600 mg/day and 900 mg/day TDD) or matching placebo tablets in a ratio of 1:1:1:1. 
Randomization will be stratified by riluzole and edaravone use status at baseline.  
3.5. 
Clinical Assessments 
Clinical assessments of all visits are listed in Schedule of Events in Appendix A. 
4. 
PLANNED ANALYSES 
4.1. 
Safety Monitoring 
An independent data monitoring committee (DMC) will meet after approximately 30% of 
patients complete 2 weeks of dosing to review the accumulated safety data (potentially 
unblinded) for this trial. This committee will make a recommendation as to the continuation of 
this study based on safety data analysis reports provided at the meeting. The DMC will also 
provide recommendation(s) on the study conduct.   
The DMC will be informed of all initial suspected unexpected serious adverse reactions 
(SUSARs) within 15 days from the time Cytokinetics is first made aware of it. The DMC will 
further receive the final case versions of all SUSARs within 15 days after the case closure. DMC 
will also receive monthly summaries and listings of all serious adverse events and early 
termination of study treatment. 
The DMC may review additional data for safety monitoring purpose. The DMC or Cytokinetics 
can require an ad hoc DMC meeting at any time. No study activities will be suspended during the 
safety review.   
4.2. 
Interim Analyses 
Not applicable. 
4.3. 
Final Analyses 
The final analysis will be conducted after all patients have either completed all the scheduled 
study visits or have early terminated from the study. At that time, the database will be cleaned 
and locked and the study treatment will be unblinded. All endpoints will be analyzed based on 
the final data after the database is locked. 


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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
5.1. 
General Summary Table and Individual Patient Data Listing 
Considerations 
Summary tables will present descriptive statistics such as number of patients, mean, median, 
standard deviation, minimum and maximum for continuous variables, and number of patients 
and the percentage for categorical variables, by dose level in the planned analysis sets. For model 
based analysis, least square mean, difference of least square means among various dose levels, 
their standard errors and 95% confidence intervals, and two-sided p-values for the relative 
statistical inferences will be presented. For survival analyses, time to event will be summarized 
by median, 95% CI of median, and 1st and 3rd quartiles. Number and percentage will be 
presented for patients with events and patients whose data are censored. Hazard ratio between 
dose levels and the corresponding 95% CI and p-value will also be presented. 
Listings will include patient ID, demographics, dose level assigned and other relevant items, and 
sorted by treatment assignment, patient ID and date of assessment. 
5.2. 
Data Management 
Data will be entered into the clinical database with programmed edit checks and manual data 
review to insure integrity. Adverse events, Concomitant Medications and Medical History will 
be coded automatically by imbedded program in the clinical database with manual review of 
unique terms. Clinical safety laboratory, pharmacokinetic, handwriting, and voice recording data 
will be provided from external laboratory(s) or research organization(s) in the pre-specified 
format.  
5.3. 
Data Presentation Conventions 
The following conventions are applied to all data presentations and summaries. 
• For continuous variables, all mean and median values are formatted to one more 
decimal place than the measured value. Standard deviation values are formatted to 
two more decimal places than the measured value. Minimum and maximum values 
are presented with the same number of decimal places as the measured value. 
• For categorical variables, the number and percentage of responses are presented in the 
form XX (XX.X%) where the percentage is in the parentheses. 
• Date variables are formatted as DDMMMYYYY for presentation. Time is formatted 
in military time as HH:MM for presentation. 
• P-values, if applicable, will be presented to 4 decimal places. If the p-value is less 
than 0.0001 then it will be presented as <0.0001. If the rounded result is a value of 
1.000, it will be displayed as >0.9999. 
• Unless otherwise stated, any statistical tests performed will use 2-sided tests at the 5% 
significance level. 


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The table, figure and listing shells and table of contents provide the expected layout and titles of 
the produced outputs of tables, figures and listings. Only differences in the analysis methods or 
data handling will necessitate a SAP revision. 
5.4. 
Analysis Sets  
5.4.1. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized patients who received any amount of 
study drug and have a baseline and at least one post baseline efficacy assessment during the 
double-blind treatment. 
5.4.2. 
Safety Analysis Set 
The Safety Analysis Set (SAS) will consist of all randomized patients who received at least one 
dose or portion of a dose of study drug. 
5.4.3. 
Pharmacokinetics Analysis Set 
The Pharmacokinetics Analysis Set (PKS) will consist of all randomized patients who have at 
least one evaluable plasma concentration of reldesemtiv, provided they have no major protocol 
violations that could affect the PK results of reldesemtiv. 
5.4.4. 
Use of Analysis Sets in Different Analyses and Summary Level 
The analysis datasets to be used are described in Table 2. 
Table 2: 
Analysis Set and Summary Level 
Analyses 
Analysis Set 
Patients Disposition (Section 6.1) 
Randomized Patients, FAS 
Study Population (Section 6) except for Patients Disposition 
(Section 6.1) and Screen Failures (Section 6.2) 
SAS, FAS 
Efficacy Analyses (Section 7) 
FAS 
Safety and Tolerability (Section 8) 
SAS 
PK/PD Analyses (Section 9) 
PKS 
5.5. 
Definitions 
5.5.1. 
Baseline Assessments 
Baseline assessments are defined as the last non-missing measurement prior to administration of 
the first dose of study drug.  
5.5.2. 
Change from Baseline 
Change from baseline is calculated as (post baseline result – baseline result). 
Percent change from baseline is calculated as (change from baseline/baseline result) x 100%. 


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If either the baseline or the post baseline result is missing, the change from baseline and/or 
percentage change from baseline will be set to missing. 
5.5.3. 
Study Day 
If the date of interest occurs on or after the first dose date, then study day will be calculated as 
(date of interest – date of first dose) + 1. If the date of interest occurs prior to the first dose date, 
then study day will be calculated as (date of interest – date of first dose). There is no study day 0. 
5.5.4. 
Analysis Visit Windows 
Since study visits do not always take place exactly as scheduled in the protocol, it is necessary to 
assign the actual observation dates to visit windows for analysis purposes.  
For measurement taken prior to the first dose of study treatment, the visit window is defined as 
the interval of time prior to the first dose of study treatment. Measurements taken on or after the 
first dose of study treatment will be assigned to the next scheduled visit window.  
For data collected at a scheduled post baseline visit, the visit window is assigned based on the 
scheduled study day of the nominal visit as collected on the electronic case report form (eCRF).  
For unscheduled or early discontinuation post baseline visits, measurements taken on or after the 
first dose of study treatment will be assigned to a visit window using defined lower and upper 
bounds for each visit window. Measurements assigned in a visit window will have study day 
greater than or equal to the lower bound but no greater than the upper bound of the visit window. 
The lower bound and the upper bound for the visit windows are defined as the midpoints of the 
scheduled visits for all assessments (see Appendix B).  
Visits are identified as the nominal visits according to the eCRFs. Each visit will be identified 
with the visit descriptor (eg, “Week 12”). If a patient has two or more study visits in one visit 
window, one record will be flagged as the “analyzed record” for that visit window. 
5.5.5. 
Determining “Analyzed Record” for Each Analysis Visit Window 
Once visit windows are assigned, a patient’s individual visit window could potentially contain 
more than one visit. Records from all visits, including scheduled, unscheduled and early 
discontinuation visits could be flagged as the “analyzed record” within the visit window, 
although the records from scheduled visit will take priority.  
For measurement taken prior to the first dose of study treatment, in the event of multiple visits 
falling within the visit window, the following rule will be used to determine the “analyzed 
record”: 
• The record closest to, but prior to the first dose of study treatment should be selected 
as the baseline “analyzed record.” This could include scheduled visits and other 
screening visits. 
For post baseline visits, in the event of multiple visits falling within a visit window, the 
following rules will be used in sequence to determine the “analyzed record” for the visit window: 
• If a scheduled visit occurred during the visit window, then the measurement taken 
from the scheduled visit will be used. 


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• If no scheduled visit occurred during the visit window, the measurement taken closest 
to the scheduled day will be used as the “analyzed record.” 
• If no scheduled visit occurred during the visit window and there is a tie between visits 
in the number of days before and after the scheduled day, measurements from the 
later visit will be used as the “analyzed record.” 
For all analyses, only the “analyzed record” within each visit window will be summarized in a 
table. If there are other visit records within the visit window, they will only be included in data 
listings. In addition, composite scores (eg, ALSFRS-R total score or muscle strength mega score) 
will be calculated based on the “analyzed record.”  
5.5.6. 
Pooled Sites 
The “study site” will be used as a fixed effect in the efficacy analysis models. For analysis 
purpose, study sites that have few patients enrolled (eg, less than 10% of patients among all 
enrolled) may be pooled to ensure sufficient number of patients from each site and 
approximately equal number of patients among the sites. For study sites with few patients 
enrolled, the sites within a country will be pooled by geographic proximity into groups with 
appropriate number of patients in each group. If an entire country has less patients enrolled 
compared to other study sites, all sites within the country will be pooled into one group, and the 
group will further be pooled across countries as appropriate. See Appendix C for regional site 
pooling for FAS. 
5.5.7. 
Calculated Rate of Pre-Study Disease Progression 
Change in ALSFRS-R total score will be used to represent the status of ALS disease progression.   
The pre-study rate of disease progression evaluated at baseline will be calculated as the change 
in ALSFRS-R total score between the date of ALS symptom onset and the date at baseline.  
Assuming a patient has a ALSFRS-R total score of 48 at the time of ALS symptom onset, the 
rate of disease progression per month evaluated at baseline can be calculated as follows: (48 – 
ALSFRS-R total score at baseline) / months (30.25 days) since ALS symptom onset. 
5.5.8. 
Efficacy Assessments 
This section describes the efficacy assessments including how scores are calculated.   
5.5.8.1. 
Percent Predicted Slow Vital Capacity 
SVC is used to evaluate pulmonary status. It is the maximum volume of air that can be exhaled 
slowly after slow maximum inhalation. The percent predicted SVC presents the test result as a 
percent of the predicted values for patients based on sex, age, height, and race. It is calculated as: 
Percent Predicted SVC = (Trial SVC / Predicted SVC) x 100 (%) 
The predicted SVC is calculated using the Quanjer GLI-2012 Regression Equation (Quanjer 
2012) that factor the characteristics of sex, age, height and race into the prediction.  
For male,  
Predicted SVC = exp [ –11.2281 + 2.4135 x ln(Height)(cm) + 0.0865 x ln(Age)(yrs) 
– 0.1684 x AfrAm – 0.0405 x NEAsia – 0.1177 x SEAsia 


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– 0.0825 x Other + Mspline] 
For female,  
Predicted SVC = exp [ –10.403 + 2.2633 x ln(Height)(cm) + 0.0234 x ln(Age)(yrs)  
– 0.1555 x AfrAm – 0.0262 x NEAsia – 0.1516 x SEAsia  
– 0.0833 x Other + Mspline] 
where   
ln( ) = natural log transformation  
AfrAm = 1 if a patient is African American, otherwise = 0  
NEAsia = 1 if a patient is from North East Asia, otherwise = 0  
SEAsia = 1 if a patient is from South East Asia, otherwise = 0  
Other = 1 if a patient belongs to other ethnic group or has mixed ethnicity, otherwise = 0 
Mspline is determined by age and sex as shown in Appendix D. 
For each clinical visit, a patient’s SVC was evaluated in triplicate. The highest result among the 
evaluable measurements confirmed by the central read of an independent pulmonologist will be 
used for analysis (ie, measurements not confirmed as evaluable by the central read will be 
excluded from analysis). For SVCs measured at home, the highest result among the evaluable 
measurements collected during a day will be used for analysis, where ‘evaluable’ is defined as a 
measurement of SVC is not smaller than 0.5 times and not greater than 1.5 times of the highest 
evaluable SVC measured in clinic during the same week. 
The percent predicted SVC declines over time in patients with ALS. The change from baseline in 
percent predicted SVC will be calculated as the post baseline value minus the baseline value, so 
that a negative number for change from baseline indicates respiratory function decline relative to 
baseline, and a positive treatment difference (reldesemtiv minus placebo) favors reldesemtiv. 
5.5.8.2. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
The ALSFRS-R is a validated rating instrument for monitoring the progression of disability in 
patients with ALS (Cedarbaum 1999). The assessment is based on 12 clinical ratings that are 
categorized in four domains: bulbar (speech, salivation, swallowing), fine motor skills 
(handwriting, cutting food and handling utensils, dressing hygiene), gross motor skills (turning in 
bed and adjusting bedclothes, walking, climbing stairs) and respiratory function (dyspnea, 
orthopnea, respiratory insufficiency). Each clinical rating is assessed using an ordinal scale that 
ranges from 0 to 4, with a score of 4 representing normal function and lower scores indicating 
worse function. 
The ALSFRS-R total score is calculated as the sum of the 12 ratings. The score of each of the 
four domains (bulbar, fine motor skill, gross motor skill, and respiratory function) is calculated 
as the sum of the three ratings within each domain, and can range from 0 to 12. If a single rating 
is missing, the score of the corresponding domain and the ALSFRS-R total score will be set to 
missing. 


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The ALSFRS-R total scores can range from 0 to 48, with higher scores indicating less functional 
impairment. The score change from baseline will be calculated as the post baseline score minus 
the baseline score, so that a negative number for change from baseline indicates greater 
impairment relative to baseline. A positive treatment difference in the change from baseline 
(reldesemtiv minus placebo) favors reldesemtiv. 
5.5.8.3. 
Muscle Strength Mega Score 
Patients’ muscle strength was measured bilaterally using HHD and hand grip dynamometry. The 
HHD measures muscle strength of the six muscle groups: elbow flexion, wrist extension, first 
dorsal interosseous, knee extension, ankle dorsiflexion, and hip flexor. The hand grip 
dynamometry measures maximum hand grip strength. In each clinical visit, a patient’s muscle 
strength was evaluated in triplicate for those measured by HHD. The maximum result among the 
three measurements will be used for analysis.  
The muscle strength was recorded as 0 (pounds) on the eCRF for the following situations:  
• A patient was able to assume the correct position but unable to exert any force. 
• A patient was unable to assume the correct position, and the evaluator is able to 
determine the cause as muscle weakness or contracture. 
• A patient was too weak to perform the test. 
The muscle strength of each measured body location is transformed as a percent change from 
baseline using the equation: [(post baseline value – baseline value) / baseline value] x 100. The 
transformed muscle strength will be set to missing if the baseline value is zero. 
The mega score is a composite score that averages strength across muscle groups. It is calculated 
as the mean of the non-missing transformed muscle strength scores among the 14 measured body 
locations, including the six muscle groups measured bilaterally by the HHD, and the hand grip 
strength measured bilaterally by hand grip dynamometry.  
A greater muscle strength mega score indicates less muscle strength loss, and a positive 
treatment difference (reldesemtiv minus placebo) favors reldesemtiv. 
5.5.8.4. 
Ashworth Score 
Ashworth score measures resistance during passive soft-tissue stretching and is used as a simple 
measure of spasticity (Bohannon 1987). Ashworth score will be assessed for elbow and knee 
bilaterally in this study. For analysis purpose, the average of non-missing measurements from all 
assessed body location will be calculated as the Ashworth total score.   
5.5.8.5. 
Components of Voice Analysis 
To evaluate speech change associated with neuro-degeneration in patients with ALS, speech 
samples for voice analysis will be collected periodically using mobile app and analyzed using a 
computational model for speech production. The parameters of speech-based outcome can be 
classified in 3 domains (precision in speaking, vocal control, and speaking rate). Each parameter 
within the domains were summarized by Aural Analytics as follows: 
 
 


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Precision in Speaking 
• Articulation Entropy: An aggregated measure of how ‘typical’ speech sounds are.  
For example, the score for the word more is a combination of the typicality of 
pronunciation for ‘m’, ‘o’ and ‘r’. All articulation entropy raw values are negative.  
Normal speech has articulation entropy close to 0. Articulation Entropy is more 
negative in imprecise speech, as is typical in advanced ALS patients. 
• Vowel Space Area: A measure of how distinct vowel sounds are from each other.  
Typical speech has a large, positive vowel space area. Vowel Space Area decreases 
toward 0 as vowel sounds become less differentiated, as is typical in advanced ALS 
patients. 
• Low-Frequency Energy Distribution: A measure of how much speech sounds are 
‘nasalized’, sounding like ‘m’ or ‘n’. All values are negative; values closer to 0 are 
more nasalized, as often occurs in advanced ALS patients. 
• Low-Frequency/High Frequency Ratio: Another measure of how much speech 
sounds are ‘nasalized’, sounding like ‘m’ or ‘n’. All values are negative; values closer 
to 0 are more nasalized, as often occurs in advanced ALS patients. 
Vocal Control 
• Perceptual Loudness Decay: Measures how quickly the voice loses energy when 
holding out the sound ‘aaaaahhh.’ Normal voices lose energy slowly and have decay 
values that are near 0. Values can be positive or negative. Larger negative values are 
associated with an inability to sustain speech, as occurs in advanced ALS patients. 
• Flutter: A measure of involuntary movement (rapid tremor) in the vocal folds.  
Normal speech has 0 flutter. Greater than 0 flutter is associated with the type of vocal 
fold vibration that occurs in advanced ALS patients. 
• Phonatory Duration: Measures how long a patient can hold out the sound 
‘aaaaahhh.’ Longer, positive hold times are associated with normal voices; as the 
ability to hold out the vowel sound is lost, phonatory duration decreases toward 0. 
• Fundamental Frequency: A measure of voice pitch. Low fundamental frequency 
indicates low pitch. Fundamental frequency is always greater than 0. 
• Fundamental Frequency Variability: A measure of variability in voice pitch. 
Steadier voices have variability near 0; larger positive variability values indicate a 
more widely varying voice pitch. 
Speaking Rate 
• Articulation Rate: A measure of how quickly individual sounds in a word are 
spoken. Articulation rate is always greater than 0. Articulation rate closer to 0 
indicates slower speech and is associated with more advanced ALS patients. 
• Articulation Rate Variability: A measure of change in articulation rate over the 
course of a clinical session. Articulation rate variability can be positive or negative; 
more negative values indicate fatigue of muscles involved in speech. 


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• Speaking Rate: A measure of how quickly syllables in a word are spoken. Speaking 
rate is always greater than 0. Speaking rate closer to 0 indicates slower speech and is 
associated with more advanced ALS patients. 
• Speaking Rate Variability: A measure of change in speaking rate over the course of 
a clinical session. Speaking rate variability can be positive or negative; more negative 
values indicate fatigue of muscles involved in speech. 
• Pause Rate: A measure of how often patients need to pause for breath while 
speaking. Pause Rate is always greater than 0. A higher pause rate indicates that a 
speaker needs to pause for breath often, as is the case in advanced ALS patients. 
• Pause Rate Variability: A measure of control over respiration, derived from the 
change in pause rate over the course of a clinical session. Pause rate can be positive 
or negative; more positive values indicate loss of respiratory control. 
The speech-based outcome will be tracked within session and at each study visit over time. For 
each parameter, the longitudinal outcome collected at each study visit will first be normalized to 
adjust for background differences for individual patient, and be transformed as a percent change 
from baseline using the equation: [(post baseline value – baseline value) / baseline value] x 100. 
For a domain, the outcome for analysis will be the average of the percent changes from baseline 
from all parameters within the domain.    
5.5.8.6. 
Components of Handwriting Analysis 
Fine motor assessments, including handwriting and figure tracing, will be performed using a 
stylus and mobile app. The parameters used in the handwriting analysis can be classified into 2 
domains (fine motor precision and fine motor fatigue) and were summarized by Aural Analytics 
as follows:  
Fine Motor Precision 
• Tracing Error: Measure of deviation from traced line. All values are positive. Lines 
that closely match the trace will have low tracing error; lines that do not closely 
match the trace will have high tracing error. 
Fine Motor Fatigue 
• Average Pressure: Measure of pen pressure on writing surface. Pressure is always 
positive. The larger the value, the more pressure the user is applying to the surface of 
the iPad. 
• Average Pressure Decay: A measure of the decay in pressure over time. A negative 
value indicates reduced pressure over time; this means that the user is applying less 
and less pressure over the duration of the task. 
• Average Speed: Measure of pen speed over writing surface. Larger values indicate 
faster pen motion. 
• Average Speed Decay: A measure of the decay in speed over time. A negative value 
indicates greater reduction in speed over time; this means that the user is becoming 
slower and slower over the duration of the task. 


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• Average Acceleration: Measure of pen acceleration on the writing surface. Larger 
values indicate higher pen acceleration. 
• Average Acceleration Decay: A measure of the decay in acceleration over time. A 
negative value indicates greater reduction in acceleration over time. This means that 
the user’s acceleration is changing less and less over the duration of the task. 
• Average Tracking Jerk: A measure of change in the pen’s acceleration over the 
duration of the tasks. This captures ‘jerking’ behavior where the pen doesn’t glide 
smoothly across the tablet surface but rather exhibits ‘stop-go’ behavior. 
The fine motor assessments will be performed at all study visits. For analysis, the longitudinal 
data collected from each patient will be transformed as a percent change from baseline using the 
equation: [(post baseline value – baseline value) / baseline value] x 100. For a domain, the 
outcome for analysis will be the average of the percent changes from baseline from all 
parameters within the domain.    
5.5.8.7. 
ALS Assessment Questionnaire Short Form 
The ALSAQ-5 is a subjective health measure designed to assess the health-related quality of life 
in patients with ALS (Jenkinson 2001). It is a short form of ALSAQ derived from ALSAQ-40 
that includes 40 items evaluating 5 dimensions of health status that are affected by the disease: 
physical mobility (10 items), activities of daily living and independence (10 items), eating and 
drinking (3 items), communication (7 items), and emotional reactions (10 items). 
The ALSAQ-5 includes five selected items with one item representing each dimension. It 
produces results closely resembled those of the five dimension scores of the ALSAQ-40. The 
dimensions and the corresponding items for ALSAQ-5 are shown in Table 3. 
Patients are asked to select one of the five options according to the frequency of each event 
experienced during the last two weeks, and a score is assigned for each option: 0=never, 
1=rarely, 2=sometimes, 3=often, 4=always or cannot do at all. 
 
Table 3: 
Dimensions and Items of ALSAQ-5 
Dimension 
Item (Question) for ALSAQ-5 
physical mobility 
Q1: I have found it difficult to stand up. 
activities of daily living and 
independence 
Q2: I have had difficulty using my arms and hands. 
eating and drinking 
Q3: I have had difficulty eating solid food. 
communication 
Q4: I have felt that my speech has not been easy to understand. 
emotional functioning 
Q5: I have felt hopeless about the future. 
The score of item for each dimension is then transformed on a scale of 0 to 100 using the 
equation: (score of each dimension/4) x 100, with 0 indicating perfect health and 100 indicating 
worst possible health status. The interpretation of the score is shown in Table 4. 


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Table 4: 
Interpretation of Score Ranges for Dimensions on ALSAQ-5  
Score range 
Interpretation 
0 –19 
No problems  
20-39 
Problems rarely 
40-59 
Problems Sometimes  
60-79 
Problems Often  
80-100 
Problems always/ nearly always or unable to do at all  
Source: Jenkinson 2001 
The ALSAQ-5 total score is calculated as sum of the score from the 5 individual items, and the 
total score will be set to missing if any of the score among the 5 items is missing. 
5.5.9. 
Health Economic Outcome Measures 
If a patient is prescribed and agrees to receive any of the following during the course of the 
study, the date of prescription will be recorded: 
• Non-invasive ventilation  
• Gastrostomy tube  
• Manual wheelchair  
• Power wheelchair  
• Augmentative and alternative communication  
5.5.10. 
Safety and Related Data 
5.5.10.1. Exposure and Compliance 
Information of whether a patient received a scheduled dose will be recorded. 
5.5.10.2. Adverse Event  
AE Duration 
The duration (in days) of an adverse event (AE) is calculated as AE stop date - AE start date + 1. 
If the event is ongoing, the final database lock date will be used as the stop date in duration 
calculations. 
AE Severity 
The severity of an AE is based on the Common Terminology Criteria for Adverse Events 
(CTCAE) grades collected on the CRF: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 


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Grade 4 = Life threatening 
Grade 5 = Fatal 
For summary purposes, missing severity will be counted as severe. 
AE Relatedness 
All AEs classified as treatment related by the investigator on the CRF are considered treatment 
related. For summary purposes, missing relatedness will be counted as related. 
TEAE and Serious TEAE 
An AE or serious AE (SAE) will be regarded as treatment emergent if it starts or worsens (eg, 
increases in severity or frequency) during or after the first dose of study drug. 
Death 
Date and reason of death will be recorded and presented.  
5.5.10.3. Clinically Relevant Abnormalities in Vital Signs, Weight, and ECG 
The criteria used to identify clinically significant abnormalities in vital signs are given in Table 
6. The criteria used to identify clinically significant abnormalities in ECG are given in  Table 7. 
5.5.10.4. Prior and Concomitant Medications 
The prior and concomitant flags for medications other than study treatment will be derived.  
Medications with a stop date prior to the first dose of study drug will be considered prior 
medications. Medications with a stop date on or after the first dose of study drug will be 
considered concomitant medications. 
5.5.10.5. Beck Depression Inventory 
The Beck Depression Inventory (BDI®) ─ Fast Screen (BDI-FS) is a shortened version of the 
BDI-II that evaluates key symptoms of depression. It was developed to factor out co-occurring 
depression symptomatology that may be related to a medical condition (Steer 1999), and 
concentrate on factors of depression that relate solely to depression. The BDI-FS contains 7 self-
reported items that evaluate major depressive symptoms over the past 2 weeks, including 
sadness, pessimism, past failure, loss of pleasure, self-dislike, self-criticalness, and suicidal 
ideations (Beck 2000, Steer 1999). Individual scale items are scored on a 4-point continuum 
(0=least, 3=most), with a total summed score range of 0–21. Higher scores indicate greater 
depressive severity. Patient’s depression level will be classified using the BDI total score as 
shown in Table 5. The BDI total score will be set to missing if an answer to any of the 7 items is 
missing.  


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Table 5: 
Depression Level Classification by BDI Total Score 
Depression Level 
BDI Total Score 
Minimal Depression 
0 - 3 
Mild Depression 
4 - 6 
Moderate Depression 
7 - 9 
Severe Depression 
10 - 21 
 
5.5.11. 
Pharmacokinetics Parameters 
The PK parameters are defined as follows: 
Parameter 
Definition 
AUC0–t 
Area under the concentration-time curve from time zero to the last measurable 
concentration, also called AUClast. 
AUC0–τ 
Area under the concentration-time curve from time zero to time τ (eg, hours).  It is 
calculated by using the trapezoid rule if all concentrations are above quantitation limit 
before time τ, and by using extrapolation if concentration drops below quantitation 
limit before time τ. 
Cmax 
The maximum (or peak) concentration that a drug achieves in tested area after the 
drug has been administrated and prior to the administration of next dose. 
Ctrough 
The minimum concentration between dose time and dose time + τ (at 
Ttrough). 
tmax  
The time that Cmax was observed. 
The parameters Cmax, AUC and tmax will be derived using the following rules: 
• For calculation of Cmax, pre-dose value will not be included in the determinations.  
• Analyses will be based on actual sampling time converted to elapse time defined as 
time from dosing.  
• Any concentration below the lower limit of quantitation (LLOQ) will be reported as 
0.00 for summaries by each time point. 
• For AUC calculations, samples with values below the LLOQ prior to the first 
measurable concentration will be set to zero. Samples with below the LLOQ result 
after the first measurable concentration will be treated as missing and the calculation 
of AUC will proceed by fitting a trapezoid between the surrounding, non-missing 
values.   
• tmax will be calculated only for patients who have at least two samples collected after 
dosing.  


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At Weeks 2 and 12 PK samples will be collected at pre-dose, and 1, 3 and 6 hours post-dose.  
For AUC12 calculation, the pre-dose concentration will be used to approximate the concentration 
value at 12 hours. 
5.5.12. 
Reldesemtiv Concentration Bin 
The average Ctrough value from Weeks 2, 4, 8 and 12 as well as the average Cmax value from 
Weeks 2 and 12 will be calculated for each patient who received reldesemtiv, and the averaged 
Ctrough or Cmax values will then be used to assign patients to one of the reldesemtiv concentration 
bins that are classified by selected ranges of percentiles. For example, a set of the concentration 
bins can be defined using the quartiles of averaged Ctrough values as follows: 
• Bin A: averaged Ctrough ≤ Q1  
• Bin B: Q1 < averaged Ctrough ≤ Q2  
• Bin C: Q2 < averaged Ctrough ≤ Q3 
• Bin D: averaged Ctrough > Q3 
where Q1, Q2 and Q3 represent the 1st, 2nd and 3rd quartiles of the averaged Ctrough values, 
respectively. Approximately equal number of patients will be assigned to each reldesemtiv 
concentration bin. 
5.6. 
Handling of Missing Data 
5.6.1. 
Missing Efficacy Endpoints 
The efficacy analysis will be performed using mixed effect model as specified. The model will 
provide unbiased results without imputation assuming that the missing patterns are missing at 
random (MAR). If the percentage of missing values in the primary efficacy endpoint is > 20%, 
sensitivity analyses assuming different missing data pattern will be conducted.  Multiple 
imputation within the dose group of each missing data pattern will be performed using Markov 
chain Monte Carlo method.  
5.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Imputation of missing/partial dates will not be performed. The available year or year and month 
in a partial date will be used and will be compared to first dosing year, month and day to 
determine whether to include the medication in the medication history or as a concomitant 
medication. If the available data do not give sufficient information to classify the medication, the 
medication will be classified as concomitant medication. 
5.6.3. 
Missing Dates of ALS Symptom Onset and Diagnosis  
Imputation of missing/partial dates will not be performed. The available year or year and month 
in a partial date will be used to calculate the time from ALS symptom onset and the time from 
ALS diagnosis (in months). The following derivation rules will be used in sequence in the 
calculation: 
• If the duration in days can be derived based on the available date information, the 
duration in months will be calculated as 


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Duration in month = Duration in day / 30.4375  
• If the duration in months can be derived but not the duration in days, the derived 
duration in months will be used for data summary. 
• If the duration in years can be derived but not the duration in days and months, the 
duration in months will be calculated as 
Duration in month = Duration in year x 12 
5.6.4. 
Missing Onset and Stop Dates for Adverse Events 
For AEs with incomplete date information recorded in the eCRF, the imputation will follow the 
following algorithm: 
1. For missing AE onset Day and Time: 
• If an AE onset Day is missing and the Month of AE onset is known, then the first day 
of the month of AE onset will be imputed as the AE onset date. 
• If AE onset information is not available, then the first dosing date will be imputed as 
the AE onset date. 
2. For missing AE end Day and Time: 
• If the AE end Day is missing and the AE end Month is earlier or later than that of the 
Follow-Up Visit, then the last day of the AE end month will be the imputed as the AE 
end date. 
• If the AE end Day is missing and the AE end Month is the same as that of the Follow-
Up Visit, then the date of the Follow-Up Visit will be the imputed as the AE end date. 
• If no AE end information is available, then 
− For patients who discontinued early from study drug, the imputed AE end date 
will be on the later of the last dosing date + 28 days or the last visit or contact 
date. 
− For patients who completed the study, the imputed AE end date and time will be 
the date of the Follow-Up Visit. 
− If the stop date is missing and the event is ongoing, the event will be noted as 
ongoing” in the stop date column in data listings. 
6. 
STUDY POPULATION 
6.1. 
Patient Disposition 
Number of patients in each analysis set will be summarized. The number and percentage of 
patients who were randomized, who received at least one dose of study drug, who completed the 
study treatment, and who prematurely discontinued from the study treatment and/or from the 
study, will be presented by each dose level and overall, as well as by baseline riluzole and 


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edaravone use status. Reasons for premature discontinuation as recorded on the termination page 
of the eCRF will be summarized as well. 
All enrolled patients will be listed with their date of screening, date of last visit, dates of first and 
last dose, demographic information including age, sex, race, last contact date, and reasons for 
discontinuation from the study treatment and/or from the study. 
6.2. 
Screen Failures 
Number and percentage of screen failures will be summarized by reasons of screening failure. A 
listing will also be provided. 
6.3. 
Protocol Deviations 
Protocol deviation is any divergence from the protocol that impacts a patient's safety, rights, or 
welfare or materially reduces the quality or completeness of the data. Number and percentage of 
patients meeting any protocol deviation criteria will be summarized by type of deviation (major, 
minor), dose level and overall. A listing of protocol deviations will be provided.    
6.4. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics which include age, sex, race, ethnicity, height, weight, 
BMI, tobacco and alcohol use, etc. will be summarized overall, by dose level and by riluzole and 
edaravone use status at baseline. Patient listings will be provided. 
6.5. 
Listing of Patient Inclusion and Exclusion Criteria 
A listing of randomized patients who violate the inclusion and exclusion criteria will be 
provided. 
6.6. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized by dose level and overall for the safety population. The 
number and percentage of patients within each medical history item will be summarized by 
system organ class and preferred term. Patient listings with start date, stop date, system organ 
class, and preferred term will be provided. 
Medical history of ALS will be summarized by dose level and overall for the safety population.  
The number and percentage of patients with or without family history, onset site of ALS, and the 
descriptive statistics of time since first symptom onset and time since first diagnosis will be 
provided. Patient listing containing symptom onset date, and diagnosis date will be provided. 
6.7. 
Prior Medication History and Medications Present at Entry 
Prior medication history and medication present at entry will be coded using WHO Drug 
Dictionary Enhanced with Herbal, June 2015 to classify medications by therapeutic class (ATC 
Class 3) and preferred name.  If ATC Class 3 is not available, ATC Class 2 will be used in the 
summary. See Section 5.5.10.4 for the definition of prior medications.   


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6.8. 
Baseline Physical Examination 
Clinically significant physical examination findings will be summarized as medical history or 
AEs, as appropriate. 
6.9. 
Baseline Vital Signs 
Baseline vital signs such as heart rate, blood pressure, respiratory rate and BMI will be 
summarized and listed along with post baseline vital signs. 
6.10. 
Baseline Laboratory Data 
Baseline laboratory data of hematology, serum chemistry and urinalysis will be summarized and 
provided in the table along with post baseline laboratory data. The laboratory parameters to be 
included for analysis are given in appendices of the protocol. 
6.11. 
Baseline Primary and Secondary Efficacy Evaluations 
Baseline primary and secondary efficacy evaluation will be summarized and listed along with 
post baseline efficacy evaluation. 
7. 
EFFICACY  
Inferential statistical tests will be two-sided and will be performed at alpha levels of 0.05 to 
declare the significance of effects. 
7.1. 
Testing Statistical Assumptions  
Assumptions for statistical models will be evaluated graphically. If assumptions are substantially 
violated, additional analysis methods will be performed.   
7.2. 
Statement of the Null and Alternate Hypotheses 
The statistical null hypothesis is that there is no treatment difference between the two high dose 
groups combined and placebo group plus low dose group (ie, 600 mg/day and 900 mg/day dose 
groups combined vs. placebo and 300 mg/day dose groups combined) with the assumed dose-
response relationship in percent predicted SVC change from baseline to Week 12. The statistical 
alternative hypothesis is that there is a positive treatment difference (reldesemtiv minus placebo) 
in change from baseline to Week 12 in the percent predicted SVC.  
Suppose the means of the efficacy endpoint for the placebo, 300 mg/day, 600 mg/day and 900 
mg/day dose groups are µ placebo, µ 300 mg/day, µ 600 mg/day and µ 900 mg/day 300 mg/day, respectively. With 
the assumed dose-response relationship for the means among the placebo, 300 mg/day, 600 
mg/day and 900 mg/day dose groups, the null and alternative hypotheses can be expressed as 
follows:  
• H0:  - 5 x µ placebo – 1 x µ 300 mg/day + 3 x µ 600 mg/day + 3 x µ 900 mg/day = 0  
• HA: - 5 x µ placebo – 1 x µ 300 mg/day + 3 x µ 600 mg/day + 3 x µ 900 mg/day ≠ 0  


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7.3. 
Subgroup Analyses 
To examine the consistency of the observed treatment effect and to gain insight into the 
effectiveness of reldesemtiv in subpopulations, subgroup analyses will be performed. Analyses 
of the primary endpoint (percent predicted SVC change from baseline to Week 12) and the 
secondary endpoints (slope of muscle strength mega score through Week 12, and ALSFRS-R score 
change from baseline to Week 12) will be conducted for the following subgroups if the sample 
size in each category of a subgroup is sufficient for statistical modeling convergence and sound 
interpretation of analysis results: 
• Sex (male, female) 
• Age group (< 65, ≥ 65 years old) 
• Race (white, non-white) 
• BMI at baseline (< 25 kg/m2, ≥ 25 kg/m2) 
• Riluzole and edaravone use status at baseline (use both, use riluzole only, use 
edaravone only, use neither) 
• Percent predicted SVC at baseline (< 80%, ≥ 80%)  
• ALSFRS-R total score at baseline (< 38, ≥ 38) 
• ALSAQ-5 total score at baseline (< 150, ≥ 150) 
• Geographic region (North America, Europe, Australia) 
• Anatomic site of disease onset (limb, bulbar, cognitive, respiratory) 
• Time since ALS symptom onset (< 2 years, ≥ 2 years) 
• Time since ALS diagnosis (< 1 year, ≥ 1 year) 
• Time since ALS diagnosis (< 6 months, ≥ 6 months) 
• Pre-study rate of disease progression (1st tertile, 2nd tertile, and 3rd tertile)  
7.4. 
Multiple Comparisons and Multiplicity 
The null hypothesis for the primary and secondary efficacy endpoints will be tested in a 
prespecified order using a closed testing procedure. This procedure will maintain the family-wise 
error rate at two-sided significance level of 0.05 for all primary and secondary hypotheses tested 
in a confirmatory sense. 
Step 1. The null hypothesis H01 is that there is no treatment difference in the primary efficacy 
endpoint, percent predicted SVC change from baseline to Week 12, in the FAS. The 
hypothesis will be tested at the two-sided significance level of 0.05. If this hypothesis is 
rejected, testing will proceed to Step 2; otherwise testing will stop. 
Step 2. The null hypotheses H02 is that there is no treatment difference in the secondary 
efficacy endpoint, slope of muscle strength mega score through Week 12, in the FAS.  


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The hypotheses will be tested at the two-sided significance level of 0.05.  If this 
hypothesis is rejected, testing will proceed to Step 3; otherwise testing will stop. 
Step 3. The null hypotheses H03 is that there is no treatment difference in the secondary 
efficacy endpoint, ALSFRS-R total score change from baseline to Week 12, in the 
FAS. The hypotheses will be tested at the two-sided significance level of 0.05.    
No further hypothesis testing will be carried out in this closed testing procedure.  
7.5. 
Analysis of the Primary Efficacy Endpoints 
7.5.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint (change from baseline to Visit Week 12 in percent predicted 
SVC) will be analyzed for the FAS based on the percent predicted SVCs collected in clinic and 
were confirmed evaluable by the central read of an independent pulmonologist. A MMRM with 
the contrast (-5, -1, 3, 3) will be used for the analysis to reflect the assumed relationship for the 
placebo, 300 mg/day, 600 mg/day and 900 mg/day dose groups. The response variable will be 
the change from baseline to each post baseline visit up to Week 12. The model will include the 
following covariates: 
• Treatment (reldesemtiv 300 mg/day, 600 mg/day and 900 mg/day, and placebo) 
• Baseline (baseline value of the response variable) 
• Pooled site (Center)  
• Visit (scheduled, a categorical variable) 
• Riluzole and edaravone use status at baseline 
• Treatment-by-visit interaction 
• Baseline-by-visit interaction   
An unstructured variance-covariance structure will be used to model the within-subject errors. If 
a model fails to converge, other covariance matrix structures (eg, compound symmetry) may be 
used instead of the unstructured covariance matrix. Least square means and the corresponding 
standard errors, 95% CIs and p-values will be presented. 
7.5.2. 
Sensitivity Analyses of the Primary Efficacy Results 
Sensitivity analysis under the assumption of missing not at random (MNAR) will be conducted 
using control-based pattern imputation approach (Ratitch 2011) for the primary efficacy endpoint 
(change from baseline to Visit Week 12 in percent predicted SVC). A model for imputing 
missing observations of percent predicted SVC in both reldesemtiv and placebo groups will be 
constructed using the observed data in the placebo group. The sensitivity analysis will include all 
observed and the aforementioned imputed data in the analysis model for the primary efficacy 
endpoint.   


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7.6. 
Analysis of the Secondary Efficacy Endpoints 
Slope of muscle strength mega score over time through Week 12 will be analyzed for the FAS. 
The response variable will be muscle strength mega score at each post baseline visit up to Week 
12. The model will include the following covariates: 
• Treatment (reldesemtiv 300 mg/day, 600 mg/day and 900 mg/day, and placebo) 
• Pooled site (Center)  
• Time (time from the first dose, a continuous variable) 
• Riluzole and edaravone use status at baseline 
• Treatment-by-riluzole use status interaction   
• Treatment-by-edaravone use status interaction   
• Treatment-by-time interaction 
The time will be set as a random effect and the intercept will be set to zero. 
The Change from baseline to Visit Week 12 in ALSFRS-R will be analyzed using the same 
model as for the primary efficacy endpoint, except for the response variable.   
7.7. 
Analysis of the Exploratory Efficacy Endpoints 
Analyses for the exploratory endpoints specified in Section 2.2.4 will be performed for the FAS. 
The endpoints of change from baseline will be analyzed using the same model as described for 
the primary efficacy endpoint, except for the response variable. 
The endpoint of percent change from baseline or muscle strength mega score (calculated as 
percent change in muscle strength from baseline) will be analyzed using the same model as 
described for the primary efficacy endpoint, except that the terms “baseline” and “baseline-by-
visit interaction” will be excluded from the model.  
The endpoints of slope of the change from baseline will be analyzed using a MMRM. The 
response variable will be the change from baseline to each post baseline visit up to Week 12. The 
model will include the following covariates: 
• Treatment (reldesemtiv 300 mg/day, 600 mg/day and 900 mg/day, and placebo) 
• Baseline (baseline value of the response variable) 
• Pooled site (Center)  
• Time (time from the first dose, a continuous variable) 
• Riluzole and edaravone use status at baseline 
• Treatment-by-baseline   
• Treatment-by-time interaction 
The time will be set as a random effect and the intercept will be set to zero. 


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The endpoints of slope of percent change from baseline, including slope of percent change in 
parameters of handwriting and voice recording, will be analyzed using the same model as for the 
slope of muscle strength mega score over time described in Section 7.6. 
7.8. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses 
Reasons for excluding individual patients from the FAS will be summarized and listed. 
7.9. 
Exploratory Analyses  
7.9.1. 
Joint Rank Test 
Joint rank analyses using the combined assessment of function and survival (CAFS) (Berry 
2013) will be conducted to account for survival time in the analyses of change in the percent 
predicted SVC and ALSFRS-R total score at Week 12, individually.  
Each patient will be compared with all others in the analysis population in a pairwise manner on 
their survival status and the functional measurements, ie, changes from baseline in the percent 
predicted SVC or ALSFRS-R total score. A score of +1 or -1 will be assigned if one has better or 
worse outcome than the other, respectively. The following rule will be used: 
• Patients who died are ranked worse than those who survived. 
• Among patients who died, patients who died first are ranked worse. 
• For patients who discontinued treatment early but were alive, comparison is based on 
the last time-point measurements that are both available for the patients in pairs. A 
patient is ranked worse if the patient discontinued treatment early and did not have 
functional measurement collected before the discontinuation.  
• Among patients who completed, patients with greater decline from baseline in the 
functional measurement are ranked worse. 
• If it is not possible to assign either patient as having the better outcome, then the 
score assigned to the pair is 0. 
For each patient, the assigned scores from the pairwise comparisons with all others will first be 
summed, and all patients in the analysis population will be ranked according to their summated 
scores to create a rank score from 1 for the lowest summated score to N (total number of patients 
in the analysis population) for the highest summated score. If ties occur, each of the tied 
summated scores will be assigned the average of the ranks the tied summated scores would have 
if there were no ties. 
The rank scores will be analyzed using the generalized Gehan-Wilcoxon test. In addition, the 
rank scores will be analyzed using an ANCOVA model that adjusts for baseline variables 
(baseline functional measurement, time from symptom onset, site of disease onset and riluzole or 
edaravone use). The rank scores between the reldesemtiv and placebo groups will be compared, 
and the least square mean difference as well as the p-value will be presented. 


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7.9.2. 
Time-To-Event Analysis for Muscle Strength 
Time-to-event analysis will be performed for muscles that had a measurable muscle strength at 
baseline. The muscle strength measured by HHD will be analyzed using proportional hazard Cox 
regression model. The event is defined as muscle strength as measured by HHD equals 0 from 
any muscle in the evaluated muscle groups. For patients who had the event, the date of muscle 
strength reached 0 will be used as the event date. For patients who did not have the event, data 
will be censored at their last date of study visit. Kaplan-Meier method will be used to summarize 
the time to event, and median, 95% CIs of the median, Q1, Q3, and range will be provided. 
7.9.3. 
Evaluation of SVC Measured at Home Using SVC Measured in Clinic as the 
Standard 
In addition to performing SVC assessments in clinic, GoSpiro home spirometer was given to 
patients for collecting their SVC data weekly from home. However, the usage of the spirometer 
varies among patients due to different reasons (eg, patients forgot to take the assessments or had 
technical difficulties, etc.). Hence it is of interest to evaluate consistency of the SVCs measured 
at home vs. the SVCs measured in clinic. Also, there may be potential learning effect due to 
more frequent use of the spirometer that may resulting in higher SVC assessed later on. The 
analyses to be used for the evaluations are described in the following sections.  
7.9.3.1. 
Correlation Between at Home and in Clinic Assessments of SVC 
The test-retest reliability of SVC measured at home will be assessed using the measures in clinic 
as the standard for each patient. Each measure at home will be paired with a measure in the clinic 
within a seven-day of window. Correlation between at home and in clinic SVC assessments 
overall and by visit will be evaluated using Pearson correlation coefficient and paired t-test.  
7.9.3.2. 
Change from Baseline to Week 12 in Percent Predicted SVC Assessed at Home 
and in Clinic  
The SVC assessed at home and in clinic will be combined for a supportive analysis of change 
from baseline to Week 12 in percent predicted SVC. A MMRM will be used for the analysis.  
The response variable will be the change from baseline to each post baseline visit up to Week 12. 
The model will include the following covariates: 
• Treatment (reldesemtiv 300 mg/day, 600 mg/day and 900 mg/day, and placebo) 
• Location of SVC collection (at home or in clinic) 
• Baseline (baseline value of the response variable) 
• Pooled site 
• Time (time from the first dose, a continuous variable) 
• Riluzole and edaravone use status at baseline 
• Baseline-by-time interaction     
• Treatment-by-time interaction 


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An unstructured variance-covariance structure will be used to model the within-subject errors. If 
a model fails to converge, other covariance matrix structures (eg, compound symmetry) may be 
used instead of the unstructured covariance matrix. Least square means and the corresponding 
standard errors, 95% CIs and p-values will be presented. 
7.9.3.3. 
Time to Event Analysis of Percent Predicted SVC Decline to Less Than 50%  
To evaluate consistency of the SVCs measured at home vs. that measured in clinic, percent 
predicted SVC collected during clinic visits and at home will be analyzed using a proportional 
hazard Cox regression model. The event is defined as percent predicted SVC decline to less than 
50% during the 12 weeks of the study. For patients who had the event, the first date of SVC less 
than 50% will be used as the event date. For patients who did not have the event, data will be 
censored at their date of study visit or Week 12 visit, whichever is earlier. Kaplan-Meier method 
will be used to summarize the time to event for percent predicted SVC measured in clinic and at 
home, separately. The median of the time to event, 95% CIs of the median, Q1, Q3, and range 
will be provided. 
7.9.3.4. 
Comparing Percent Predicted SVC Between Patients Who Used a Home 
Spirometer for SVC Assessments and Those who Never Used 
To evaluate the potential learning effect of using a spirometer and its impact on the percent 
predicted SVC measured in clinic, the use of the spirometer will be added as a covariate in the 
MMRM for a supportive analysis of change from baseline to Week 12 in percent predicted SVC 
and be evaluated for if it’s a significant factor in predicting the outcome. The rates of decline (ie, 
slope) in percent predicted SVC assessed in clinic will also be compared between patients who 
performed SVC assessments using the home spirometer and those who did not use. In addition, 
since SVC will be assessed 3 times in each clinic visit, the variation among the 3 measurements 
collected at each visit will be compared between patients who used the home spirometer for SVC 
assessments and those who did not use. 
8. 
SAFETY AND TOLERABILITY 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
TEAEs and serious TEAE will be summarized. See Section 5.5.10.2 for the definitions of 
TEAEs and serious TEAEs.  
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify AEs by 
system organ class and preferred term. The severity of adverse events will be evaluated using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 4.0. Coding will be performed using version 20.0 of the MedDRA coding dictionary. 
8.1.1. 
Summaries of Adverse Event Incidence Rates for All Patients 
The number and percentage of patients with TEAEs will be summarized by system organ class, 
preferred term, dose level and overall, riluzole and edaravone use status at baseline, and will be 
further tabulated by CTCAE grade or relationship to study drug. For a patient with a particular 


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TEAE that were reported more than once within a particular system organ class or preferred 
term, the patient will be counted only once in that category using the most severe occurrence or 
closest relationship to the study drug. Listings of all AEs by patient will also be presented. 
8.1.2. 
Summaries of Adverse Incidence Rates for Serious Adverse Events, Adverse 
Event Dropouts, and Death 
SAEs and AEs leading to treatment discontinuation or death will also be summarized by system 
organ class, preferred term, dose level and overall, and riluzole and edaravone use status at 
baseline. Listings will be presented for patients who died and/or experienced serious AEs and for 
patients who discontinued due to TEAEs.   
8.2. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
The duration and exposure of study drug will be summarized by dose level and overall, and 
riluzole and edaravone use status at baseline for the safety analysis set. The duration will be 
calculated as the difference between the study day of the first dose and the last dose plus one 
day. The exposure will be calculated as the total dosage in mg. Patient listing with date, day and 
time of dose, actual/average daily dose, reason for incorrect dose and dose interruption will be 
presented. 
8.3. 
Concomitant and Other Medications 
Concomitant medications reported on the eCRF will be summarized for the safety analysis set.  
See Section 5.5.10.4 for the definition of concomitant medications. Medications with a start date 
that is 28 days after the last dose of the study drug will be excluded from the summary. The 
World Health Organization Drug dictionary will be used to classify medications by therapeutic 
class (ATC Class 3) and preferred name. If ATC Class 3 is not available, ATC Class 2 will be 
used in the summary. Coding will be performed using WHO Drug Dictionary Enhanced with 
Herbal Dictionary, B2, March 2017.   
The number and percentage of patients who received concomitant medication will be 
summarized by dose level, therapeutic class and preferred term (using ATC Class Level III). 
Multiple drug usage by a patient will be counted only once in each category. 
CYP3A4 strong inhibitors that should be avoided from 7 days before the start of dosing through 
the last day of dosing. CYP3A4 strong inducers that should be avoided from 14 days before the 
start of dosing through the last day of dosing. OCT1/OCT2 substrates that should be avoided 
from 7 days before the start of dosing or should be used with caution during the trial. Patients 
who take CYP3A4 strong inhibitors, CYP3A4 strong inducers, or OCT1/OCT2 substrates prior 
or during the study treatment will be listed. 
In addition, a listing of concomitant medication with start/stop date, days relative to the start of 
therapy, dose / unit / route / frequency, indication and purpose of all medications taken from 
screening through the end of study will be provided. 


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8.4. 
Routine Laboratory Data 
Clinical laboratory evaluations, including hematology, serum chemistry, and urinalysis as 
detailed in the protocol, will be collected at the Screening, Day 1, Week 2, Week 4, Week 12 and 
Follow-Up Visits. Descriptive statistics of assessment value and change from baseline of 
laboratory parameters will be presented at each assessment time point by dose level and overall.   
The number and percentage of patients who had normal or missing laboratory values at baseline 
and abnormal laboratory values post baseline will be presented by dose level and overall.  The 
lower limit of normal (LLN) and upper limit of normal (ULN) provided by the laboratories will 
be used as the criteria for abnormality. For each parameter, the denominator of the percentage 
will include patients with normal or missing assessments at baseline, and with at least one 
assessment post baseline. The numerator of the percentage will include patients who had at least 
one abnormal assessment post baseline among the patients that were counted in the denominator. 
Assessment collected at an unscheduled visit or the Follow-up Visit will also be included in the 
summary. 
Shift of clinical laboratory results in NCI-CTCAE grade from baseline grade to the maximum 
post baseline grade will be presented for selected laboratory parameters. Clinical laboratory 
values will be also listed. Values outside the Laboratory’s normal ranges and potentially 
clinically significant abnormal values will be flagged.   
Hy’s law (Temple 2006) will be used to evaluate drug induced liver injury (DILI); patients with 
ALT or AST elevations > 3 x ULN and total bilirubin elevations > 2 x ULN will be marked on a 
scatter plot.  Elevations of ALT or AST to 5 x, 10 x or 20 x ULN will also be plotted. 
Clinical laboratory results from patients with eGFR decline of 1) greater than 25%, 2) below 60, 
3) greater than 25% and below 60, and 4) greater than 25% or below 60 will be summarized and
listed. Time-to-event analysis will be performed for eGFR decline of greater than 25% using 
proportional hazard Cox regression model with the following model terms: riluzole and 
edaravone use status at baseline, age, sex, BMI and baseline eGRF values. Kaplan-Meier method 
will be used to summarize the time to eGFR decline of greater than 25% where the median of the 
time to event, 95% CIs of the median, Q1, Q3, and range will be provided. In addition, the 
correlation between eGFR level change from baseline and Ctrough of reldesemtiv and its 
metabolites will be examined. Similar method as described in Section 9.2 will be used for the 
analysis.    
8.5. 
Vital Signs 
Vital signs, which include blood pressure, heart rate and respiratory rate (measured after the 
patient has been resting for at least 3 minutes), height, weight and BMI will be obtained at the 
Screening, Day 1, Week 2, Week 4, Week 8, Week 12 and Follow-Up Visits. Descriptive 
statistics of absolute values and changes from baseline of vital sign parameters will be presented 
at each assessment time point by dose level and overall.   
The number and percentage of patients who had normal or missing values at baseline and 
Potentially Clinically Significant (PCS) values post baseline will be presented by dose level and 
overall. The PCS criteria are specified in Table 6. For each parameter, the denominator of the 
percentage will include patients with non-PCS or missing assessments at baseline, and with at 


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least one assessment post baseline. The numerator of the percentage will include patients who 
had at least one PCS assessment post baseline among the patients that were counted in the 
denominator. Assessment collected at an unscheduled visit or the Follow-up Visit will also be 
included in the summary. 
Oral temperature will be taken at Screening and will be presented in a listing. Individual vital 
signs will be listed with dose level, patient ID, and assessment time. Values outside the normal 
ranges will be flagged.  
Table 6: 
Criteria of Potentially Clinically Significant (PCS) Vital Signs 
Vital Sign Parameter 
Flag 
Criteria 
Systolic Blood Pressure (mmHg) 
High 
≥160 mmHg 
Low 
≤80 mmHg 
Diastolic Blood Pressure (mmHg) 
High 
≥100 mmHg 
Low 
≤ 50 mmHg 
Respiration Rate (Breaths per minute) 
High 
>18 bpm 
Low 
<8 bpm 
Pulse (bpm) 
High 
≥120 bpm 
Low 
≤50 bpm 
Weight (kg) 
Clinically 
Significant 
≥5% reduction from baseline 
Temperature (oC) 
High 
≥ 38 oC 
Low 
< 35 oC 


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8.6. 
Electrocardiogram 
A 12-lead ECG, including ECG parameters of RR, PR, QRS, and QT intervals as well as 
significant findings will be obtained at Screening, Week 4 and Follow-Up Visits. Descriptive 
statistics of absolute value and change from baseline of ECG parameters (PR interval, RR 
interval, QRS duration, QT interval, QTc interval [Bazett’s and Fridericia’s], Ventricular Heart 
Rate) will be presented at each assessment time point by dose level and overall.   
The number and percentage of patients who had normal or missing values at baseline and PCS 
values post baseline will be presented by dose level and overall. ECG parameters are regarded as 
PCS if the value meets the criterion shown in Table 7. For each parameter, the denominator of 
the percentage will include patients with non-PCS or missing assessments at baseline, and with 
at least one assessment post baseline. The numerator of the percentage will include patients who 
had at least one PCS assessment post baseline among the patients that were counted in the 
denominator. Assessment collected at an unscheduled visit or the Follow-up Visit will also be 
included in the summary. 
Twelve-lead ECG parameters (PR interval, QRS duration, QT interval, QTc interval [Bazett’s 
and Fridericia’s], Ventricular Heart Rate, and RR interval), will be listed with dose level, patient 
ID, visit and assessment date and time. PCS ECG values will be flagged. ECG findings and 
interpretations will be listed as well. 
      Table 7: Criteria of Abnormal and PCS ECG Values 
ECG Variable 
Units 
Upper Limit of Normal 
PCS 
High Values 
QRS Interval 
msec 
80 
≥120 
PR Interval 
msec 
200 
≥240 
QTcB Interval 
msec 
Males: 450 
Females: 460 
>500 
QTcF Interval 
msec 
Males: 450 
Females: 460 
>500 
QT Interval 
msec 
— 
> 500 
Ventricular Heart Rate 
bpm 
— 
>100 
8.7. 
Physical Examination 
A routine physical examination will be performed at Screening and Follow-Up Visits. Abnormal 
and clinically significant findings in physical examinations will be reported and summarized as 
Medical History or Adverse Events, as appropriate. 
8.8. 
Neurological Examinations 
A neurological examination will be administered at Screening and Follow-Up Visits.  
Neurological examination findings will be summarized for eye movements, facial sensations, 
motor function strength, sensory, reflexes, plantar response, cerebellar function / coordination by 


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visit, dose level and overall. Neurological examination findings shift from baseline visit to post- 
baseline visit will also be tabulated. 
Individual neurological examination findings will be listed for each test chronologically by 
patient ID, visit, and the actual assessment date and time.   
8.9. 
Ashworth Score 
Ashworth score will be assessed at all study visits. Summary statistics of the Ashworth total 
score at each study visit will be tabulated. A list will be provided with the actual assessment date 
and answers to all the questions. 
8.10. 
Beck Depression Inventory Fast Screen Version 
The BDI-FS will be assessed at all study visits. Summary statistics of the BDI total score will be 
provided for each assessment time point by dose level and overall. A list will be provided with 
the actual assessment date and answers to all questions. 
8.11. 
Fall Assessment 
The fall assessment will be conducted at all study visits except Screening. The number and 
percent of patients with one, two, three, four or more falls, with answers to the activities engaged 
at the time of fall, physical symptoms immediately preceding the fall, and whether resulting 
injury will be tabulated. A list will be provided with the actual assessment date, and answers to 
all questions. 
8.12. 
Study Termination Status 
Number and percentage of patients who completed or prematurely discontinued planned study 
dosing, and reasons of prematurely discontinuation will be tabulated. For patients who 
discontinued prematurely, the date and reason of premature discontinuation will be listed. 
9. 
PHARMACOKINETIC AND PHARMACOKINETIC 
/PHARMACODYNAMIC ANALYSES 
9.1. 
Pharmacokinetic Analyses 
PK analysis will be performed based on the PKS. All of the PK samples collected, including 
those obtained at Hours 0, 1, 3 on Day 1 as well as Hours 0, 1, 3 and 6 at Week 2 and Week 12 
from patients enrolled prior to Amendment 03, will be used for PK analyses. Descriptive 
statistics in terms of mean, SD, geometric mean, coefficient of variation (CV), geometric CV, 
median, and range will be provided for concentrations at all planned sampling time points. 
Geometric mean concentrations over time will be graphically displayed.   
For each patient enrolled prior to Amendment 03, the PK parameters tmax, Cmax and AUC12 at 
Week 2 and Week 12 will be calculated based on the plasma concentrations of reldesemtiv, its 
metabolites and riluzole using non-compartmental PK methods. The PK parameters tmax, Cmax on 
Day 1 for patients enrolled prior to Amendment 03, and Ctrough at Week 2 and Week 12 for all 


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patients will be calculated based on the plasma concentrations of reldesemtiv, its metabolites and 
riluzole. The PK parameters listed above will also be summarized by dose level.   
Dose proportionality will be examined using the power model approach based on Ctrough. The 
relationship between the PK parameter, Ctrough and dose can be described by the following power 
model: 
ln (Ctrough) = α + β x ln (dose) + ε 
where α and β are the intercept and slope of the modeling equation, and ε represents the error 
term. A tentative conclusion of dose-proportionality will be made if the 90% CI for the slope 
includes 1.   
The attainment of steady-state of reldesemtiv following multiple doses will be verified using a 
linear regression model for log-transformed trough concentrations on sample collection time by 
dose group.  Since the first post baseline PK sample is collected at Week 2, the trough 
concentrations starting from Week 2 and beyond will be included in the model.   If the 90% 
confidence interval (CI) of the slope from the model contains zero, steady state will be concluded 
as attained at no later than Week 2.  
Selected PK parameters (eg, AUC12, Cmax and Ctrough at Week 12) between patients who took 
reldesemtiv alone and those who took reldesemtiv plus edaravone will be compared. The natural 
log-transformed least square mean difference and the associated 90% CI will be calculated using 
a linear regression model that includes model terms of dose level, edaravone use status at 
baseline, and interaction of dose level by edaravone use status. An unstructured covariance 
matrix will be used for the model. Back-transformation will provide point estimates and 90% CIs 
for the geometric mean ratio that indicates the magnitude of drug interaction. Summaries of 
selected PK parameters will be presented graphically by dose level, as appropriate. 
9.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
PD analyses may be performed to explore the PK/PD relationship based on the PKS. PD 
measures will include, but not limited to, the following assessments: 
• Percent predicted SVC 
• Muscle strength mega score  
• ALSFRS-R 
• ALSAQ-5 
The change from baseline analyses will use the same model as for analysis of the primary 
efficacy endpoint, except that the model term ‘Treatment’ will be replaced by ‘Concentration’ (a 
continuous variable, plasma concentration of reldesemtiv) or “Concentration Bin” (a categorical 
variable that includes placebo group and approximately equal number of patients in each 
classified reldesemtiv concentration bin).      
 


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10. 
HEALTH ECONOMIC OUTCOMES ANALYSIS  
The prescription of non-invasive ventilation, gastrostomy tube, Manual wheelchair, power 
wheelchair, or augmentative and alternative communication will be analyzed. For patients who 
were prescribed and agree to receive the items above, the event will be set as 1, and the date of 
prescription will be used as the event date. For patients who were not prescribed or agreed to 
receive the items above, the event will be set as 0, and data will be censored at their last date of 
study visit. Time to event will be summarized by each dose group for patients with an event, and 
the differences of time to event between each reldesemtiv dose group vs. placebo will be tested 
using the log-rank test. In addition, the hazard ratios of each reldesemtiv dose group vs. placebo 
as well as the hazard for the assumed dose response trend (-5, -1, 3, 3) will be calculated using 
the proportional hazard Cox regression model.   
11. 
COMPUTER METHODS 
Statistical analyses will be performed using Version 9.4 (or newer) of SAS. SAS and all other 
SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc. in USA and other countries. 
12. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Not available.  


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13. 
STATISTICAL CODES 
The following code will be used as the prototype of the codes that will be used for the final analysis of the study. The final version of the 
statistical codes to be used will be determined prior to the database lock and will be documented in the specification document for the statistical 
report of the study.   
1. The SAS code to produce the estimates of the dose response relationship among treatment groups: 
For continuous variables: 
PROC MIXED data = work METHOD = REML; 
class <Patient> <Pooled Site> <Visit> <Treatment> <Riluzole Use> <Edaravone Use>; 
model <Continuous Variable> = <Pooled Site> <Visit> <Treatment> <Baseline Value> <Riluzole Use> <Edaravone Use>    
      <Interaction between Visit and Treatment> <Interaction between Visit and Baseline Value> / ddfm = kenwardroger; repeated 
<Visit> / subject = <Patient> type = un;  
lsmeans <Visit>*<Treatment> / pdiff cl; 
lsmestimate <Visit>*<Treatment> ‘300mg and 450mg - placebo at week 2’ [-1,1 1] [0,1 2] [0.5,1 3] [0.5,1 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘300mg and 450mg - placebo at week 4’ [-1,2 1] [0,2 2] [0.5,2 3] [0.5,2 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘300mg and 450mg - placebo at week 8’ [-1,3 1] [0,3 2] [0.5,3 3] [0.5,3 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘300mg and 450mg - placebo at week 12’ [-1,4 1] [0,4 2] [0.5,4 3] [0.5,4 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘Contrast at week 2’ [-0.83333,1 1] [-0.16666,1 2] [0.5,1 3] [0.5,1 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘Contrast at week 4’ [-0.83333,2 1] [-0.16666,2 2] [0.5,2 3] [0.5,2 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘Contrast at week 8’ [-0.83333,3 1] [-0.16666,3 2] [0.5,3 3] [0.5,3 4] / cl; 
lsmestimate <Visit>*<Treatment> ‘Contrast at week 12’ [-0.83333,4 1] [-0.16666,4 2] [0.5,4 3] [0.5,4 4] / cl; 
ods output LSMeans = lsm Diffs = diff LSMEstimates = lsmest;  
run; 
 
Note: Include outcome measurements collected at Weeks 2, 4, 8 and 12. For the endpoints of percent change from baseline (e.g., 
muscle strength mega score), the term “baseline value” and the interaction term <Interaction between Visit and Baseline Value> 
will be excluded from the model. 
 
 
 


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2. The SAS code to produce estimates of slope: 
 
PROC MIXED data = work METHOD = REML; 
class <Patient> <Pooled Site> <Treatment> <Riluzole Use> <Edaravone Use>; 
model <Continuous Variable> = <Pooled Site> < Days from First Dose> <Treatment> <Baseline Value> <Riluzole Use> 
      <Edaravone Use> <Interaction between Treatment and Day> <Interaction between Treatment and Baseline Value> / ddfm = 
kenwardroger noint;  
random <Day> / subject = <Patient>;  
 
estimate 'slope for placebo' <Day> 1 <Interaction between Day and Treatment> 1 0 0 0 / cl; 
estimate 'slope for 150mg'<Day> 1 <Interaction between Day and Treatment> 0 1 0 0 / cl; 
estimate 'slope for 300mg' <Day> 1 <Interaction between Day and Treatment> 0 0 1 0 / cl; 
estimate 'slope for 450mg' <Day> 1 <Interaction between Day and Treatment> 0 0 0 1 / cl; 
estimate 'slope for 300 & 450mg' <Day> 1 <Interaction between Day and Treatment> 0 0 0.5 0.5 / cl; 
estimate 'slope 150mg - placebo' <Interaction between Day and Treatment> -1 1 0 0 / cl; 
estimate 'slope for 300mg - placebo' <Interaction between Day and Treatment> -1 0 1 0 / cl; 
estimate 'slope for 450mg - placebo' <Interaction between Day and Treatment> -1 0 0 1 / cl; 
estimate 'slope for 300mg & 450mg combined - placebo' <Interaction between Day and Treatment> -1 0 0.5 0.5 / cl; 
estimate 'slope for contrast' <Interaction between Day and Treatment> -0.83333 -0.1666 0.5 0.5 / cl; 
 
ods output Estimates = est SolutionF = sf;  
run; 
 
• 
Note: The variable ‘Day’= days from the 1st dose. Include outcome measurements collected at baseline, Weeks 2, 4, 8, 12. 
For the endpoints of slope of percent change from baseline (e.g., slope of muscle strength mega score), the terms 
“baseline value” and “interaction between Treatment and Baseline” will be excluded from the model, and the interaction 
terms “Treatment-by-Riluzole use status” and “Treatment-by-Edaravone use status” will be added to the model.   
 
3. The SAS code to produce time to event analysis results among treatment groups: 
PROC LIFETEST data = work; 
time <Event Variable><Censor Variable(1)>;  
strata <Treatment>;  
ods output CensoredSummary=sum Quartiles=quart HomTests=test; 
run; 
 
PROC PHREG data = work; 
class <Pooled Site> <Riluzole Use> <Edaravone Use>; 
model <Event Variable> <Censor Variable(1)> = <Treatment> <Baseline Value>;  
strata <Pooled Site> <Riluzole Use> <Edaravone Use>; 
Contrast ‘150 mg - placebo’ <Treatment> -1 1 0 0 / Estimate=exp;  


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Contrast ‘300 mg - placebo’ <Treatment> -1 0 1 0 / Estimate=exp; 
Contrast ‘450 mg - placebo’ <Treatment> -1 0 0 1 / Estimate=exp; 
Contrast ‘300 and 450 mg - placebo’ <Treatment> -1 0 0.5 0.5 / Estimate=exp; 
Contrast ‘Contrast’ <Treatment> -0.83333 -0.1666 0.5 0.5 / Estimate=exp;  
ods output ContrastEstimate=est; 
run; 
 
 
 
 
Note: Include outcome measurements collected at baseline, Weeks 2, 4, 8, 12. For the endpoints of slope of percent change from 
baseline (e.g., slope of muscle strength mega score), the term “baseline value” will be excluded from the model. 
 
4. The SAS code to produce estimates of slope for concentration effect PK/PD analyses: 
Slope 1: 
PROC MIXED data = work METHOD = REML; 
class <Patient> <Pooled Site> <Riluzole Use> <Edaravone Use>; 
model <Efficacy Continuous Variable> = <Day> <Pooled Site> <Concentration> <Baseline Value> <Riluzole Use> <Edaravone Use> / 
       ddfm=kenwardroger s;  
random <Day> / subject = <Patient>;  
ods output SolutionF = sf;  
run; 
Slope 2: 
PROC MIXED data = work METHOD = REML; 
class <Patient> <Pooled Site> <Visit> <Riluzole Use> <Edaravone Use>; 
model <Continuous Variable> = <Pooled Site> <Visit> <Concentration> <Baseline Value> <Riluzole Use> <Edaravone Use> 
      <Interaction between Concentration and Visit> <Interaction between Concentration and Baseline Value>/ ddfm=kenwardroger 
s;  
estimate ‘slope of concentration at Week 2’ <Concentration> 1 <Interaction between Visit and Concentration> 1 0 0 0/ cl; 
estimate ‘slope of concentration at Week 4’ <Concentration> 1 <Interaction between Visit and Concentration> 0 1 0 0/ cl; 
estimate ‘slope of concentration at Week 8’ <Concentration> 1 <Interaction between Visit and Concentration> 0 0 1 0/ cl; 
estimate ‘slope of concentration at Week 12’<Concentration> 1 <Interaction between Visit and Concentration> 0 0 0 1/ cl; 
 
ods output SolutionF = sf estimates = est;  
run; 
 
Note: The variable ‘Day’= days from the 1st dose. Include outcome measurements collected at Weeks 2, 4, 8, 12. For the endpoints 
of percent change from baseline (e.g., muscle strength mega score), the terms “baseline value” and “Interaction between Visit 
and Baseline Value” will be excluded from the model. 
 
 


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5. The SAS code to produce the estimates of concentration bin effect PK/PD analyses: 
For continuous PD parameters: 
PROC MIXED data = work METHOD = REML; 
class <Patient> <Pooled Site> <Visit> <Riluzole Use> <Edaravone Use> <Concentration Bin>; 
model <Continuous Variable> = <Pooled Site> <Visit> <Concentration Bin> <Baseline Value> <Riluzole Use> <Edaravone Use> 
      <Interaction between Visit and Concentration Bin> <Interaction between Concentration Bin and Baseline Value> / 
ddfm=kenwardroger s;  
repeated <Visit> / subject = <Patient> type = un;  
lsmeans <Visit>*<Concentration Bin> / pdiff cl; 
ods output lsmeans = lsm diffs = diff;  
run; 
 
Note: For the endpoints of percent change from baseline (e.g., muscle strength mega score), the terms “baseline value” and 
“Interaction between Visit and Baseline Value” will be excluded from the model. 


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14. 
REFERENCES 
Beck, A. T., Steer, R. A. and Brown, G. K. (2000). "BDI-fast screen for medical patients 
manual." Psychological Corporation, San Antonio, TX. 
 
Berry, J. D., Miller, R., Moore, D. H., Cudkowicz, M. E., Van Den Berg, L. H., Kerr, D. A., et 
al. (2013). "The Combined Assessment of Function and Survival (CAFS): a new endpoint for 
ALS clinical trials." Amyotrophic lateral sclerosis and frontotemporal degeneration 14(3): 162-
168. 
 
Bohannon, R. W. and Smith, M. B. (1987). "Interrater Reliability of a Modified Ashworth Scale 
of Muscle Spasticity." Physical Therapy 67(2): 206-207. 
 
Cedarbaum, J. M., Stambler, N., Malta, E., Fuller, C., Hilt, D., Thurmond, B., et al. (1999). "The 
ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory 
function." Journal of the Neurological Sciences 169(1): 13-21. 
 
Jenkinson, C. and Fitzpatrick, R. (2001). "Reduced item set for the amyotrophic lateral sclerosis 
assessment questionnaire: development and validation of the ALSAQ-5." Journal of Neurology, 
Neurosurgery & Psychiatry 70(1): 70-73. 
 
Jenkinson, C., Fitzpatrick, R., Swash, M. and Levvy, G. (2001). "ALSAQ user manual: 
amyotrophic lateral sclerosis assessment questionnaire." Health Services Research Unit, 
University of Oxford, Oxford. 
 
Quanjer, P. H., Stanojevic, S., Cole, T. J., Baur, X., Hall, G. L., Culver, B. H., et al. (2012). 
"Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 
2012 equations." The European respiratory journal 40(6): 1324-1343. 
 
Ratitch, B. and O' Kelly, M. (2011). "Implementation of pattern-mixture models using standard 
SAS/STAT procedures." PharmaSUG, Paper-SP04. 
 
Steer, R. A., Cavalieri, T. A., Leonard, D. M. and Beck, A. T. (1999). "Use of the Beck 
Depression Inventory for Primary Care to screen for major depression disorders." General 
hospital psychiatry 21(2): 106-111. 
 
Temple, R. (2006). "Hy's law: predicting serious hepatotoxicity." Pharmacoepidemiology and 
drug safety 15(4): 241-243. 
 
 
 


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APPENDIX A. SCHEDULE OF EVENTS 
 
Study Procedures 
Screening 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
FU Visit 
Informed Consent 
X 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Physical Exama 
X 
 
 
 
 
 
X 
Neurological Exam 
X 
 
 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
Weight & BMI 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
X 
 
 
X 
Vital Signs 
Xb 
X 
X 
X 
X 
X 
X 
Clinical Safety Labsc 
X 
X 
X 
X 
 
X 
X 
Pregnancy Testd 
X 
 
 
 
 
 
X 
PK Samplee 
 
X 
X 
X 
X 
X 
 
SVC 
X 
X 
X 
X 
X 
X 
X 
Muscle Strength 
X 
X 
X 
X 
X 
X 
X 
ALSFRS-R 
X 
X 
X 
X 
X 
X 
X 
Voice recording 
X 
X 
X 
X 
X 
X 
X 
Fine Motor Skillsf 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-5 
X 
X 
X 
X 
X 
X 
X 
Health Economic 
Outcomes Measurements 
 
X 
X 
X 
X 
X 
X 
Ashworth Scale 
X 
X 
X 
X 
X 
X 
X 
Falls Assessments 
 
X 
X 
X 
X 
X 
X 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
 
AE/SAE Evaluations 
 
X 
X 
X 
X 
X 
X 
BDI-Fast Screen 
X 
X 
X 
X 
X 
X 
X 
a Complete physical examination at Screening Visit, abbreviated physical examination at FU visit 
b Temperature only at Screening 
b Oral temperature only at Screening 
c TSH only at Screening and Follow-Up Visit  
d Only for females of childbearing potential 
d Serum pregnancy test only for females of childbearing potential 
e PK sampling on Day 1 visit, Week 2 visit, Week 4 visit, Week 8 visit, and Week 12 visit; refer to Table 3 in the protocol 
f If the device is suitable for use in that region 
 
Schedule of Events for Home Testing 
SVC* 
To be done every Saturday independent of day of first dose 
Voice recording 
To be done every Saturday independent of day of first dose 
  
 
*if the device is suitable for use in that region


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APPENDIX B. ANALYSIS VISIT WINDOWS 
 
Analysis Visit Windows for SVC, Muscle Strength, ALSFRS-R, Voice Recording, Fine 
Motor Skills, ALSAQ-5, Vital Sign, Ashworth Scale and BDI-Fast Screen  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 2 
15 
2 
21 
Week 4 
29 
22 
42 
Week 8 
57 
43 
70 
Week 12 
85 
71 
98 
Follow-up 
113 
99 
> 99 
 
Analysis Visit Windows for 12-lead ECG  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Week 4 
29 
1 
70 
Follow-up 
113 
71 
>71 
 
Analysis Visit Windows for Clinical Safety Laboratories  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 2 
15 
2 
21 
Week 4 
29 
22 
56 
Week 12 
85 
57 
98 
Follow-up 
113 
99 
>99 
 
Analysis Visit Windows for PK Concentration  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Day 1 
1 
1 
1 
Week 2 
15 
2 
21 
Week 4 
29 
22 
42 
Week 8 
57 
43 
70 
Week 12 
85 
71 
>71 
 


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Analysis Visit Windows for Neurological Exam  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Follow-up 
113 
1 
>99 
 
Analysis Visit Windows for SVC Assessed at Home  
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Day 1 
1 
1 
1 
Week 1 
8 
2 
11 
Week 2 
15 
12 
18 
Week 3 
22 
19 
25 
Week 4 
29 
26 
32 
Week 5 
36 
33 
39 
Week 6 
43 
40 
46 
Week 7 
50 
47 
53 
Week 8 
57 
54 
60 
Week 9 
64 
61 
67 
Week 10 
71 
68 
74 
Week 11 
78 
75 
81 
Week 12 
85 
82 
88 
Week 13 
92 
89 
95 
Week 14 
99 
96 
102 
Week 15 
106 
103 
109 
Week 16 
113 
110 
>110 
 


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APPENDIX C. REGIONAL SITE POOLING FOR FAS 
Pooled Site 
Number 
Country 
State/Province 
Site Number 
Patient 
Count 
Sub-total of 
Patient Count 
1 
Australia 
New South Wales 
061078 
3 
20 
1 
Australia 
New South Wales 
061080 
3 
1 
Australia 
Queensland 
061079 
8 
1 
Australia 
South Australia 
061081 
2 
1 
Australia 
Western Australia 
061082 
4 
2 
Ireland 
Dublin 
353090 
4 
53 
2 
Netherlands 
Utrecht 
031089 
11 
2 
Spain 
Madrid 
034098 
38 
3 
Canada 
Alberta 
002065 
13 
49 
3 
Canada 
Alberta 
002068 
10 
3 
Canada 
Ontario 
002060 
15 
3 
Canada 
Ontario 
002070 
2 
3 
Canada 
Ontario 
002071 
7 
3 
Canada 
Saskatchewan 
002077 
2 
4 
Canada 
Quebec 
002061 
35 
52 
4 
Canada 
Quebec 
002063 
6 
4 
Canada 
Quebec 
002066 
11 
5 
United States 
Arizona 
001051 
10 
61 
5 
United States 
California 
001014 
8 
5 
United States 
California 
001016 
5 
5 
United States 
California 
001026 
5 
5 
United States 
California 
001054 
8 
5 
United States 
Colorado 
001019 
9 
5 
United States 
Oregon 
001013 
8 
5 
United States 
Oregon 
001050 
4 
5 
United States 
Washington 
001023 
4 
6 
United States 
Illinois 
001055 
6 
71 
6 
United States 
Indiana 
001043 
3 
6 
United States 
Iowa 
001030 
4 
6 
United States 
Kansas 
001003 
2 
6 
United States 
Michigan 
001036 
9 
6 
United States 
Michigan 
001046 
10 
6 
United States 
Minnesota 
001032 
3 
6 
United States 
Minnesota 
001059 
4 
6 
United States 
Missouri 
001005 
2 
6 
United States 
Missouri 
001033 
3 
6 
United States 
Nebraska 
001042 
4 


Cytokinetics, Inc. 
 
Statistical Analysis Plan – Protocol CY 5022                                                   December 14, 2018 
 
Confidential and Proprietary 
 
 56 
Pooled Site 
Number 
Country 
State/Province 
Site Number 
Patient 
Count 
Sub-total of 
Patient Count 
6 
United States 
Ohio 
001028 
7 
6 
United States 
Ohio 
001057 
10 
6 
United States 
Wisconsin 
001037 
4 
7 
United States 
District of Columbia 
001035 
2 
51 
7 
United States 
Maryland 
001008 
13 
7 
United States 
Pennsylvania 
001006 
11 
7 
United States 
Pennsylvania 
001015 
3 
7 
United States 
Tennessee 
001039 
9 
7 
United States 
Virginia 
001022 
3 
7 
United States 
Virginia 
001067 
8 
7 
United States 
West Virginia 
001004 
2 
8 
United States 
Connecticut 
001025 
10 
36 
8 
United States 
Massachusetts 
001045 
3 
8 
United States 
New York 
001001 
3 
8 
United States 
New York 
001017 
5 
8 
United States 
New York 
001027 
10 
8 
United States 
Vermont 
001056 
5 
9 
United States 
Florida 
001011 
9 
65 
9 
United States 
Florida 
001012 
9 
9 
United States 
Florida 
001066 
1 
9 
United States 
Florida 
001068 
4 
9 
United States 
Georgia 
001040 
1 
9 
United States 
North Carolina 
001010 
8 
9 
United States 
North Carolina 
001021 
10 
9 
United States 
North Carolina 
001047 
9 
9 
United States 
Texas 
001007 
2 
9 
United States 
Texas 
001020 
3 
9 
United States 
Texas 
001041 
9 


Cytokinetics, Inc. 
 
Statistical Analysis Plan – Protocol CY 5022                                                   December 14, 2018 
 
Confidential and Proprietary 
 
 57 
APPENDIX D. MSPLINE VALUE FOR CALCULATION OF PREDICTED 
SVC 
Table: Mspline Value 
 
 
 
Age (yrs) 
Male 
Female 
Age (yrs) 
Male 
Female 
18 
0.147849088 
0.135507529 
50 
-0.006647706 
0.028303776 
19 
0.160315109 
0.140628299 
51 
-0.014542406 
0.020206649 
20 
0.167159394 
0.143647414 
52 
-0.022604908 
0.011905392 
21 
0.169722148 
0.145330204 
53 
-0.030845244 
0.00339698 
22 
0.16923214 
0.146039097 
54 
-0.039274925 
-0.005323975 
23 
0.166543254 
0.145870185 
55 
-0.04790158 
-0.014258162 
24 
0.162315681 
0.144942845 
56 
-0.056735557 
-0.023411261 
25 
0.157092735 
0.143626724 
57 
-0.065782826 
-0.032797239 
26 
0.151293448 
0.142211366 
58 
-0.07504859 
-0.042417299 
27 
0.145106883 
0.140771596 
59 
-0.084531216 
-0.052260185 
28 
0.138681964 
0.13919976 
60 
-0.094214527 
-0.062313185 
29 
0.132266867 
0.137441293 
61 
-0.104078877 
-0.072556666 
30 
0.125876212 
0.135494281 
62 
-0.114093666 
-0.082975133 
31 
0.119459845 
0.133330256 
63 
-0.124218952 
-0.093558031 
32 
0.113049003 
0.130878076 
64 
-0.134413719 
-0.104301259 
33 
0.106735805 
0.12804587 
65 
-0.14465155 
-0.115203896 
34 
0.100550635 
0.124811373 
66 
-0.154914171 
-0.126261624 
35 
0.094499318 
0.121203564 
67 
-0.165181495 
-0.137466925 
36 
0.088531508 
0.117238065 
68 
-0.175439763 
-0.148808471 
37 
0.082567889 
0.112889589 
69 
-0.185681902 
-0.160268368 
38 
0.076537303 
0.108171834 
70 
-0.195901978 
-0.171827557 
39 
0.070402479 
0.103107309 
71 
-0.20609542 
-0.183468534 
40 
0.064129074 
0.097699941 
72 
-0.216260542 
-0.195173143 
41 
0.057677943 
0.091939589 
73 
-0.226393699 
-0.206921242 
42 
0.051046568 
0.085825419 
74 
-0.236485333 
-0.218692812 
43 
0.04427255 
0.079389589 
75 
-0.246523325 
-0.230468005 
44 
0.037387387 
0.07268763 
76 
-0.256496316 
-0.242227571 
45 
0.030394993 
0.06577409 
77 
-0.266395583 
-0.253951742 
46 
0.023277783 
0.058677615 
78 
-0.276212134 
-0.265621352 
47 
0.01602077 
0.051384134 
79 
-0.285939277 
-0.277219902 
48 
0.008623361 
0.043889005 
80 
-0.295573257 
-0.288731661 
49 
0.001072775 
0.036196648