A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Cytokinetics



Protocol CY 4031 
 
CONFIDENTIAL 
Version: 26 June 2017 
Page 2 
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) 
 
 Sponsor’s Medical Monitors 
Jinsy Andrews, MD, MSc 
Senior Director, Clinical Research & Development 
Head, Neuromuscular Therapeutics 
Cytokinetics, Inc. 
jandrews@cytokinetics.com 
(650) 243-1165 (Mobile Telephone) 
 
Stacy Rudnicki, MD 
Director, Clinical Research & Development 
Cytokinetics, Inc. 
srudnicki@cytokinetics.com 
(650) 515-2524 (Mobile Telephone) 
(650) 624-3225 (Office Facsimile) 
 
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-National 
 

Protocol CY 4031 
 
CONFIDENTIAL 
Version: 26 June 2017 
Page 3 
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), Research Ethics Board (REB), or 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 1 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: ________________ 
 

Protocol CY 4031 
 
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TABLE OF CONTENTS 
STUDY IDENTIFICATION ...........................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
1. 
INTRODUCTION ......................................................................................................13 
1.1. 
Background on Tirasemtiv .........................................................................................13 
1.2. 
Rationale for Tirasemtiv in the Potential Treatment of Amyotrophic Lateral 
Sclerosis ......................................................................................................................13 
1.3. 
Overview of Tirasemtiv Nonclinical Studies .............................................................14 
1.4. 
Overview of Tirasemtiv Clinical Studies ...................................................................15 
1.4.1. 
Phase 1 and Phase 2a Studies .....................................................................................15 
1.4.2. 
Phase 2b Clinical Trial in Patients with ALS (CY 4026; BENEFIT-ALS) ...............15 
2. 
STUDY OBJECTIVES ..............................................................................................28 
2.1. 
Primary Objective .......................................................................................................28 
2.1.1. 
Primary Endpoint ........................................................................................................28 
2.2. 
Secondary Objectives .................................................................................................28 
2.2.1. 
Secondary Endpoints ..................................................................................................28 
2.2.2. 
Tertiary Endpoints ......................................................................................................29 
3. 
STUDY OVERVIEW .................................................................................................31 
3.1. 
Estimated Study Duration ...........................................................................................34 
3.2. 
Tirasemtiv Dose Rationale .........................................................................................34 
3.3. 
Rationale for the Open-Label Lead-In Phase Prior to Randomization .......................36 
3.4. 
Riluzole Dose Adjustment Rationale ..........................................................................38 
3.5. 
Double-Blind, Placebo-Controlled, Tirasemtiv Withdrawal Phase Rationale ...........39 
4. 
STUDY POPULATION .............................................................................................41 
4.1. 
Inclusion Criteria ........................................................................................................41 
4.2. 
Exclusion Criteria .......................................................................................................41 
4.3. 
Additional Randomization Criterion ..........................................................................42 
5. 
STUDY PROCEDURES ............................................................................................43 
5.1. 
Screening ....................................................................................................................43 
5.2. 
Open-Label Phase .......................................................................................................43 
5.2.1. 
WEEK -2 VISIT .........................................................................................................43 
5.3. 
Double-Blind, Placebo-Controlled Phase ...................................................................44 

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5.3.1. 
DAY 1 VISIT .............................................................................................................45 
5.3.2. 
WEEK 2 VISIT ...........................................................................................................46 
5.3.3. 
WEEK 4 VISIT ...........................................................................................................47 
5.3.4. 
WEEK 8 VISIT ...........................................................................................................48 
5.3.5. 
WEEK 12 VISIT .........................................................................................................49 
5.3.6. 
WEEK 16 VISIT .........................................................................................................50 
5.3.7. 
WEEK 20 VISIT .........................................................................................................51 
5.3.8. 
WEEK 24 VISIT .........................................................................................................53 
5.3.9. 
WEEK 32 VISIT .........................................................................................................54 
5.3.10. 
WEEK 40 VISIT .........................................................................................................55 
5.4. 
Double-Blind, Placebo-Controlled, Tirasemtiv Withdrawal Phase ............................56 
5.4.1. 
WEEK 48 VISIT .........................................................................................................57 
5.4.2. 
WEEK 49 VISIT .........................................................................................................58 
5.4.3. 
WEEK 52 VISIT .........................................................................................................59 
5.5. 
FOLLOW-UP VISIT (Week 56) ................................................................................59 
5.6. 
Visit Windows ............................................................................................................60 
5.7. 
Timing of Doses .........................................................................................................61 
5.8. 
Concomitant Medications ...........................................................................................61 
5.9. 
PK Sample Collection .................................................................................................62 
5.10. 
Biomarker Sample Collection .....................................................................................63 
5.11. 
Clinical Safety Assessments .......................................................................................64 
5.11.1. 
Physical Examination .................................................................................................64 
5.11.2. 
Neurological Examination ..........................................................................................64 
5.11.3. 
Ashworth Score ..........................................................................................................64 
5.11.4. 
Clinical Laboratory Evaluations .................................................................................64 
5.11.5. 
12-Lead ECGs ............................................................................................................64 
5.11.6. 
Vital Signs ..................................................................................................................64 
5.11.7. 
Falls Assessment .........................................................................................................64 
5.11.8. 
Suicidality Assessment ...............................................................................................64 
5.12. 
Clinical and Pharmacodynamic Outcome Measures ..................................................65 
5.12.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R) .................................................65 
5.12.2. 
Respiratory Assessments ............................................................................................65 
5.12.3. 
Handgrip Strength .......................................................................................................65 

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5.12.4. 
Muscle Strength Measurements ..................................................................................65 
5.12.5. 
Quality of Life ............................................................................................................65 
5.12.6. 
Epworth Sleepiness Scale ...........................................................................................65 
5.12.7. 
Caregiver Burden Assessment ....................................................................................65 
5.13. 
Patient Discontinuation from Study Participation ......................................................65 
5.14. 
Study Discontinuation ................................................................................................66 
5.15. 
Safety Monitoring and Stopping Rules.......................................................................66 
5.16. 
Data Monitoring Committee .......................................................................................67 
6. 
INVESTIGATIONAL PRODUCT ............................................................................68 
6.1. 
Description of Investigational Product .......................................................................68 
6.1.1. 
Description of Riluzole or Placebo for Riluzole .........................................................68 
6.2. 
Dose Administration (Tirasemtiv or Placebo) ............................................................69 
6.3. 
Dose Adjustment Criteria ...........................................................................................69 
6.4. 
Treatment Interruption ................................................................................................69 
6.5. 
Randomization Schedule and Removal of Blind ........................................................69 
6.6. 
Daily Dosing Diary .....................................................................................................70 
6.7. 
Study Drug Handling and Disposal ............................................................................70 
6.8. 
Study Drug Accountability .........................................................................................70 
7. 
ADVERSE EVENTS AND SAFETY ASSESSMENTS ...........................................71 
7.1. 
Definitions ..................................................................................................................71 
7.1.1. 
Adverse Event .............................................................................................................71 
7.1.2. 
Serious Adverse Events ..............................................................................................72 
7.2. 
Adverse Event Severity ..............................................................................................73 
7.3. 
Assessment of Causality to Study Treatment .............................................................74 
7.4. 
Procedures for Eliciting and Recording Adverse Events ...........................................74 
7.4.1. 
Eliciting Adverse Events ............................................................................................74 
7.4.2. 
Recording of Adverse Events .....................................................................................74 
7.4.3. 
Adverse Event Term ...................................................................................................74 
7.4.4. 
Recording Serious Adverse Events ............................................................................75 
7.4.5. 
Pregnancy ...................................................................................................................75 
7.5. 
Reporting Period for Adverse Events .........................................................................75 
7.5.1. 
Follow-Up of Adverse Events ....................................................................................76 
7.6. 
Serious Adverse Events Require Immediate Reporting .............................................76 

Protocol CY 4031 
 
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8. 
STATISTICAL METHODS .......................................................................................77 
8.1. 
General Considerations ...............................................................................................77 
8.1.1. 
General Approach .......................................................................................................77 
8.1.2. 
Sample Size and Randomization ................................................................................77 
8.1.3. 
Data Monitoring Committee .......................................................................................78 
8.2. 
Analysis Sets ...............................................................................................................78 
8.2.1. 
Full Analysis Set (FAS) ..............................................................................................78 
8.2.2. 
Per Protocol Set (PPS) ................................................................................................78 
8.2.3. 
Safety Analysis Set (SAS) ..........................................................................................78 
8.2.4. 
Pharmacokinetic Evaluable Data Set (PKEDS) .........................................................78 
8.3. 
Efficacy Endpoints ......................................................................................................78 
8.3.1. 
Primary Endpoint ........................................................................................................78 
8.3.2. 
Secondary Endpoints ..................................................................................................79 
8.3.3. 
Tertiary Endpoints ......................................................................................................79 
8.3.4. 
Additional Endpoints ..................................................................................................81 
8.4. 
Statistical Analyses .....................................................................................................81 
8.4.1. 
Patient Disposition ......................................................................................................81 
8.4.2. 
Demographics and Other Baseline Characteristics .....................................................81 
8.4.3. 
Primary Efficacy Analysis ..........................................................................................81 
8.4.4. 
Supportive Efficacy Analyses .....................................................................................82 
8.4.5. 
Secondary and Tertiary Efficacy Analyses .................................................................82 
8.4.6. 
Other Supportive Efficacy Analyses ..........................................................................83 
8.4.7. 
Additional Efficacy Analyses .....................................................................................83 
8.4.8. 
Hypothesis Testing and Multiplicity ..........................................................................83 
8.4.9. 
Sensitivity Analysis ....................................................................................................83 
8.4.10. 
Subgroup Efficacy Analyses .......................................................................................84 
8.5. 
Safety Analysis ...........................................................................................................84 
8.5.1. 
Adverse Events ...........................................................................................................84 
8.5.2. 
Other Safety Assessments ...........................................................................................85 
8.5.3. 
Suicidality Assessments..............................................................................................85 
8.6. 
Study Drug Exposure ..................................................................................................85 
8.7. 
Concomitant Medication ............................................................................................85 
8.8. 
Pharmacokinetic Analysis ..........................................................................................86 

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8.9. 
Pharmacodynamic Analysis........................................................................................86 
8.10. 
Change in Statistical Methods ....................................................................................86 
9. 
ADMINISTRATIVE ASPECTS ................................................................................87 
9.1. 
Change in Protocol .....................................................................................................87 
9.2. 
Initiation Visit .............................................................................................................87 
9.3. 
Disclosure ...................................................................................................................87 
9.4. 
Monitoring ..................................................................................................................87 
9.5. 
Institutional Review Board / Ethics Committee / Research Ethics Board ..................87 
9.6. 
Informed Consent .......................................................................................................88 
9.7. 
Records .......................................................................................................................88 
9.8. 
Reference to Declaration of Helsinki/Basic Principles ..............................................88 
10. 
REFERENCES ...........................................................................................................89 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................90 
APPENDIX B. SUBSTRATES OF CYP2B6, 2C8, 2C9, AND 2C19 .......................................91 
APPENDIX C. SUBSTRATES, INHIBITORS AND INDUCERS OF CYP1A2 .....................92 
 
 
 
 

Protocol CY 4031 
 
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LIST OF TABLES 
Table 1: 
Exposure to Tirasemtiv at the NOAEL in Rat and Dog .............................................14 
Table 2: 
Estimated IC50, kinact, and KI Values for Tirasemtiv Time-Dependent 
Inhibition .....................................................................................................................15 
Table 3: 
Percent Predicted Slow Vital Capacity in BENEFIT-ALS ........................................17 
Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv ...........................20 
Table 5: 
Randomized Double-Blind Treatment Groups ...........................................................33 
Table 6: 
Randomized Double-Blind, Tirasemtiv Withdrawal Treatment .................................33 
Table 7: 
Distribution of Trough Tirasemtiv Concentration at Steady-State by Dose ...............35 
Table 8: 
Visit Windows ............................................................................................................61 
Table 9: 
Pharmacokinetic (PK) Samples ..................................................................................63 
Table 10: Biomarker Samples .....................................................................................................63 
Table 11: Study Drug ..................................................................................................................68 
Table 12: Riluzole and Placebo for Riluzole ..............................................................................69 
Table 13: Sample Size Re-estimation Depending on Common SD at Week 24 ........................78 
 
 
LIST OF FIGURES 
Figure 1: 
Changes from Baseline in Percent Predicted Slow Vital Capacity in 
BENEFIT-ALS ...........................................................................................................16 
Figure 2: 
Change from Baseline to Average after 8 and 12 Weeks in Percent Predicted 
Slow Vital Capacity ....................................................................................................18 
Figure 3: 
Study Design ...............................................................................................................31 
Figure 4: 
First and Second Randomization ................................................................................32 
Figure 5: 
Predicted Steady-State Pharmacokinetic Profiles for Tirasemtiv Target Dose 
Levels in CY 4031 ......................................................................................................35 
Figure 6: 
Incidence of Dizziness by Double-Blind Treatment Assignment and Day of 
Double-Blind Treatment in CY 4024 .........................................................................36 
Figure 7: 
Steady-State Plasma Riluzole Exposures with and without Steady-State 
Concomitant Tirasemtiv at Total Daily Doses from 250 mg to 500 mg in 
BENEFIT-ALS ...........................................................................................................38 
 
 
 

Protocol CY 4031 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Explanation  
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase (alanine transaminase) 
ALSAQ-5 
ALS Assessment Questionnaire Short Form 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
AM 
ante meridiem (morning) 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase (aspartate transaminase) 
AUCinf  
area under the concentration-time curve (extrapolated to infinity) 
AUC 
area under the plasma concentration-time curve (during dosing interval) 
BID 
twice a day 
BiPAP 
bilevel positive airway pressure 
BMI 
body mass index 
CBC 
Complete blood count (hematology clinical laboratory evaluations) 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CPAP 
continuous positive airway pressure 
CPK  
creatine phosphokinase 
Cmax 
maximum observed plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
pre-dose plasma concentration 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DPS 
diaphragm pacing system 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
full analysis set 
FDA 
Food and Drug Administration 

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Abbreviation 
Explanation  
GCP 
Good Clinical Practices 
GI 
gastrointestinal 
GLP 
Good Laboratory Practices 
HEK 
human embryonic kidney 
hERG 
human ether-à-go-go related gene 
HHD 
hand-held dynamometry 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
KI 
inactivation constant 
kinact  
maximum rate constant for inactivation 
LFT 
liver function tests 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
MTD  
maximum tolerated dose 
MVIC 
Maximum Voluntary Isometric Contraction 
MVV   
Maximum Voluntary Ventilation 
m2 
meters squared 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
NIPPV 
non-invasive positive pressure ventilation 
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
PD 
pharmacodynamic 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PKEDS 
pharmacokinetic evaluable data set 

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Abbreviation 
Explanation  
PM 
post meridiem (evening) 
PPS 
per protocol set 
QD 
once daily 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAS 
safety analysis set 
SD 
standard deviation 
SE 
standard error 
SNIP 
Sniff Nasal Inspiratory Pressure 
SVC 
slow vital capacity 
tmax 
time to maximum plasma concentration 
TDD 
total daily dose 
TEAE 
treatment-emergent adverse event 
TnC 
troponin C 
TSH 
thyroid stimulating hormone 
UA 
urinalysis 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 

Protocol CY 4031 
 
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1. 
INTRODUCTION 
1.1. 
Background on Tirasemtiv 
Tirasemtiv (formerly CK-2017357) is a novel small molecule activator of fast skeletal muscle 
troponin, intended to improve skeletal muscle function in disease states associated with muscular 
weakness or fatigue, including amyotrophic lateral sclerosis (ALS), without affecting the 
structure of muscle itself.  Tirasemtiv selectively binds to the fast skeletal muscle troponin 
complex and slows the rate of calcium release from troponin C (TnC).  This increases the affinity 
of TnC for calcium and thus sensitizes the sarcomere to calcium.  Tirasemtiv is selective for fast 
skeletal muscle troponin with little effect on slow skeletal muscle troponin and no effect on 
cardiac muscle troponin. By sensitizing the fast skeletal muscle troponin complex to calcium, 
tirasemtiv shifts the calcium-force relationship of muscle fibers leftward, amplifying the 
response of muscle to submaximal nerve stimulation and thereby increasing muscle force.  
Tirasemtiv decreases muscle fatigability in several preclinical models of exercise performance, 
presumably by reducing the energetic requirements of calcium cycling during muscle contraction 
(Russell, Hartman et al. 2012).  In a transgenic mouse model of ALS with functional deficits, 
single doses of tirasemtiv significantly increased submaximal isometric force, forelimb grip 
strength, grid hang time, and running performance on a rotating rod.  Additionally, diaphragm 
force and tidal volume were significantly higher (Hwee, Kennedy et al. 2014).  Acute and 
reversible clinical signs of intolerance were the dose-limiting toxicities in preclinical testing.  
The pharmacological profile of tirasemtiv is unique in that it is a direct and selective functional 
activator of fast skeletal muscle; as such, it could benefit patients with a wide variety of disorders 
characterized by muscle weakness or fatigue. 
In a Phase 2b study that enrolled 711 patients with ALS (CY 4026, also known as BENEFIT-
ALS), 12 weeks’ treatment with tirasemtiv was associated with statistically significant and 
potentially clinically meaningful reductions in the decline in slow vital capacity (SVC) versus 
placebo (see Section 1.4.2).  This observation is the basis for the current study, CY 4031.  
1.2. 
Rationale for Tirasemtiv in the Potential Treatment of Amyotrophic 
Lateral Sclerosis 
Amyotrophic lateral sclerosis, or 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 one of two 
medications approved for the treatment of ALS, and has a modest benefit on survival 
(Lacomblez, Bensimon et al. 1996). The other approved medication, Nuedexta®, has a specific 
effect on emotional lability, a symptom experienced by a minority of ALS patients.  Two 
interventions that contribute greatly to the overall welfare and survival of ALS patients are the 
use of enteral feeding and ventilatory support. 

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To date, there are no available treatments that can improve skeletal muscle function, and in 
particular respiratory function.  Because tirasemtiv has been demonstrated both to amplify 
skeletal muscle force production in response to diminished neuronal input and to delay the onset 
and reduce the magnitude of skeletal muscle fatigue during repeated or sustained efforts, it may 
be useful in the treatment of patients with ALS.  
1.3. 
Overview of Tirasemtiv Nonclinical Studies 
A brief summary of the nonclinical safety and pharmacokinetics (PK) of tirasemtiv is provided in 
this section.  Additional information concerning nonclinical assessments of the pharmacology, 
PK, and safety of tirasemtiv is available in the Investigator’s Brochure (IB). 
Tirasemtiv was evaluated in a series of Good Laboratory Practices (GLP) preclinical safety 
pharmacology and toxicology studies, including single- and repeat-dose toxicity studies 
performed in Sprague-Dawley rats up to 26 weeks and beagle dogs up to 39 weeks, teratology 
studies in rats and rabbits, single-dose phototoxicity studies in rats, and a core battery of 
genotoxicity tests.  
In rats, following administration of tirasemtiv for 26 weeks at dose levels of 0, 5, 15 and 
30 mg/kg/day, target organ effects were observed at levels of 15 and 30 mg/kg/day and consisted 
of fibrosis and/or atrophy of the mandibular salivary glands and hepatocellular hypertrophy of 
the liver.  The finding in the liver was fully recovered and the findings in the salivary glands 
were partially recovered at 30 mg/kg/day following the recovery period.  The no observed 
adverse effect level (NOAEL) in rats was considered to be 15 mg/kg/day in this study.  The 
exposures at the end of the study attained at the NOAEL are shown in Table 1 below. 
In dogs, administration of tirasemtiv for 39 weeks at dose levels of 0, 6, 20 and 50 mg/kg/day 
resulted in adverse but reversible clinical signs at 50 mg/kg/day, non-adverse effects on body 
weight at all dose levels, and a decrease in food consumption at the high dose.  Tirasemtiv 
caused partially reversible increases in aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) at 50 mg/kg/day, with a reversible increased total bilirubin in females at 
50 mg/kg/day and a reversible increase in creatine kinase and aldolase activities in individual 
males and females at 50 mg/kg/day.  The NOAEL in dogs was considered to be 20 mg/kg/day in 
this study.  The exposures at the end of the study attained at the NOAEL are shown in Table 1 
below. 
Table 1: 
Exposure to Tirasemtiv at the NOAEL in Rat and Dog 
 
26-Week Rat Toxicity Studies 
(NOAEL) 
39-Week Dog Toxicity Studies 
(NOAEL) 
M 
F 
M 
F 
Dose (mg/kg/day) 
15 
15 
20 
20 
Cmax (μg/mL) 
25.1 
46.5 
27.0 
20.9 
AUC (μg•h/mL) 
228.5 
589.0 
128.8 
80.6 
There was no evidence of genotoxicity in bacterial reverse mutation, human lymphocyte 
chromosomal aberration, or rat micronucleus assays.  There was no evidence of phototoxicity in 
single-dose studies in rat or of embryolethality, fetotoxicity, or teratogenicity in rats and rabbits.  
Tirasemtiv was observed to cause a reversible blockade of the hERG channel in human 

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embryonic kidney (HEK) cells in vitro at 250 μM, but was less than 50% inhibitory.  Findings in 
cardiovascular, central nervous system (CNS), and respiratory safety pharmacology studies of 
tirasemtiv were not considered adverse because of their mild severity and/or limited duration. 
The potential of tirasemtiv to inhibit cytochrome P450 (CYP) enzymes (CYP1A2, 2A6, 3A4, 
2B6, 2C8, 2C9, 2C19, 2D6, and 2E1) was studied in vitro in human liver microsomes at 
concentrations up to 100 - 200 µM.  Both direct and time-dependent inhibitions were assessed. 
Tirasemtiv did not inhibit CYP3A4, 2D6, 2A6, or 2E1 with half maximal inhibitory 
concentrations (IC50s) exceeding the highest concentrations tested.  Tirasemtiv was found to be a 
direct and time-dependent inhibitor of multiple CYP450 isoforms (CYP1A2, 2B6, 2C8, 2C9, and 
2C19).  Kinetic parameters for the time-dependent inhibition, including the time-dependent IC50 
(inhibitory constant following 20 or 30 minute pre-incubation with microsomes + NADPH), 
maximum rate constant for inactivation (kinact) and inactivation constant (KI), are shown in 
Table 2. 
Table 2: 
Estimated IC50, kinact, and KI Values for Tirasemtiv Time-Dependent 
Inhibition 
CYP Isoform 
Time-Dependent IC50 
(µM) 
kinact (min-1) 
KI (µM) 
CYP1A2 
5.5 
0.031 
1.9 
CYP2B6 
21 
0.035 
26 
CYP2C8 
80 
0.057 
46 
CYP2C9 
69 
0.021 
34 
CYP2C19 
4 
0.051 
11 
1.4. 
Overview of Tirasemtiv Clinical Studies 
1.4.1. 
Phase 1 and Phase 2a Studies 
Tirasemtiv has been evaluated in three completed Phase 1 clinical trials in healthy volunteers 
(CY 4011, CY 4012 and CY 4013).  Three Phase 2a clinical trials (CY 4021, CY 4024, and 
CY 4025) have been conducted in patients with ALS.  A Phase 2a clinical trial in patients with 
claudication secondary to peripheral artery disease (CY 4022) and a Phase 2a clinical trial in 
patients with myasthenia gravis (CY 4023) have also been completed.  The Phase 1 and Phase 2a 
clinical studies are summarized in Table 4.  Additional details are available in the IB. 
1.4.2. 
Phase 2b Clinical Trial in Patients with ALS (CY 4026; BENEFIT-ALS) 
CY 4026, also known as BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and 
Functional Improvement with Tirasemtiv in ALS), was a Phase 2b clinical trial in which 
711 patients with ALS were enrolled from 73 centers in North America and Western Europe into 
open-label treatment with tirasemtiv 125 mg twice a day.  Subsequently, patients who completed 
one week of open-label treatment were randomized 1:1 to double-blind treatment with either 
tirasemtiv (titrated at weekly intervals to each patient’s maximum tolerated dose ≤ 250 mg twice 
daily) or placebo for 12 weeks.  Clinical assessments were made at baseline (i.e., prior to 
treatment with open-label tirasemtiv), after 4, 8, and 12 weeks of double-blind treatment, and one 

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and four weeks after the last dose of double-blind study drug.  Safety and efficacy were assessed 
among the 295 patients randomized to placebo who received at least one dose of double-blind 
study drug and the 301 patients randomized to tirasemtiv who received at least one dose of 
double-blind study drug. 
The primary endpoint in BENEFIT-ALS, the mean change from baseline in the ALS Functional 
Rating Scale in its revised form (ALSFRS-R), was not statistically different between treatment 
groups. The least squares mean (LSM) changes from baseline were −2.40 in the placebo group 
and −2.98 in the tirasemtiv group. The LSM ± standard error (SE) difference between treatment 
groups (i.e., tirasemtiv response minus placebo response) was −0.58 ± 0.366 (95% confidence 
interval (CI): −1.30, 0.14; p = 0.114).  Although BENEFIT-ALS did not achieve its primary 
efficacy endpoint, two pre-specified secondary endpoints, both reflective of skeletal muscle 
function, were positively impacted.   
Treatment with tirasemtiv resulted in a statistically significant and potentially clinically 
meaningful reduction in the decline of vital capacity (measured as SVC) which assesses strength 
of the skeletal muscles responsible for breathing.  The percent predicted SVC declined -3.12 
percentage points (±0.90) from the baseline value over 12 weeks on tirasemtiv compared to a 
decline of -8.66 percentage points (±0.80) in the placebo group (p= <0.0001).  This pre-specified 
secondary efficacy endpoint declined less on tirasemtiv than on placebo at each assessment time 
point and this difference persisted throughout 28 days after discontinuation of double-blind 
treatment (Figure 1, Table 3).  Vital capacity has been shown to be an important predictor of 
disease progression and survival in prior clinical trials of patients with ALS.  
Figure 1: 
Changes from Baseline in Percent Predicted Slow Vital Capacity in 
BENEFIT-ALS 
 

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Table 3: 
Percent Predicted Slow Vital Capacity in BENEFIT-ALS 
Slow Vital Capacity 
Placebo 
(n = 210) 
Tirasemtiv 
(n = 178) 
All 
(N = 388) 
Baseline 
(prior to the one week Open-Label phase) 
(% Predicted, mean ± Standard Deviation 
[SD]) 
89.7 (17.2) 
85.7 (19.3) 
87.8 (18.3) 
Time Point during the Double-Blind 
Treatment 
Changes from Baseline  
(LSM ± SE) 
p-value 
Week 4 
-3.89 (0.62) 
-0.99 (0.68) 
0.001 
Week 8 
-5.81 (0.68) 
-2.85 (0.77) 
0.004 
Week 12 
-8.66 (0.80) 
-3.12 (0.90) 
<0.0001 
 
Slope of decline 
(Percentage Points per day) 
 
Baseline to Week 12 
-0.0905 
-0.0394 
0.0006 
 
Changes from Baseline  
(LSM ± SE) 
 
Week 13 (1 week after last DB dose) 
-8.03 (0.77) 
-3.75 (0.84) 
0.0002 
Week 16 (4 weeks after last DB dose) 
-10.30 (0.90) 
-5.39 (0.98) 
0.0002 
As shown in Figure 2, tirasemtiv reduced the decline in SVC compared to placebo regardless of 
age, gender, riluzole use, or body mass index (BMI).  Subgroups with the largest and most 
significant differences in SVC on tirasemtiv versus placebo (change from baseline to mean SVC 
after eight and 12 weeks of double-blind treatment) were: females (6.84%, p = 0.012); non-riluzole 
users (6.55%, p = 0.0005); and patients with baseline SVC ≥ median at baseline (6.02%, 
p < 0.0001).   

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Figure 2: 
Change from Baseline to Average after 8 and 12 Weeks in Percent Predicted 
Slow Vital Capacity  
 
The results of other secondary endpoints assessed in this trial were mixed.  The Muscle Strength 
Mega-Score, a measure of strength based on the percent change from baseline from several 
muscle groups in each patient, declined more slowly on tirasemtiv versus placebo (p = 0.016 for 
the difference in slope of decline); however, there were no differences at any time point that 
reached statistical significance.  The rate of decline for Sniff Nasal Inspiratory Pressure (SNIP) 
was not statistically significantly different between tirasemtiv and placebo (p = 0. 21); however, 
SNIP decreased statistically significantly more on tirasemtiv compared with placebo at four and 
12 weeks (p values at 4, 8, and 12 weeks were 0.012, 0.066, 0.050, respectively).  No differences 
in Maximum Voluntary Ventilation (MVV) and Hand Grip Fatigue were observed on tirasemtiv 
versus placebo.   
Serious adverse events (SAEs) during double-blind treatment were more frequent on tirasemtiv 
than on placebo (9.0% vs. 5.4%).  The most common SAE was respiratory failure, which 
occurred in one patient on tirasemtiv and three patients on placebo, while confusional state and 
delirium occurred in two patients on tirasemtiv and no patients on placebo.  Of patients receiving 
at least one dose of double-blind study drug, more patients on tirasemtiv withdrew from the trial 
following randomization than on placebo (97 vs. 26 patients, respectively).  Adverse events 
(AEs) more common on tirasemtiv than on placebo (> 10% difference) were dizziness (50.8% 
vs. 19.7%), fatigue (33.2% vs. 14.2%), and nausea (21.9% vs. 7.8%).   
Patients on tirasemtiv lost more weight than patients on placebo (change from baseline to 
Week 12: -1.70 kg vs. -0.79 kg; p = 0.006).  Weight loss was significantly greater in patients 

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with gastrointestinal (GI) AEs (e.g., nausea and decreased appetite) on either treatment.  
However, such AEs occurred more frequently on tirasemtiv than on placebo (43.5% vs. 25.8%).   
The statistically significant effect to reduce the decline in vital capacity observed in 
BENEFIT-ALS is a unique finding that has not been observed in any prior, sizable clinical trial 
in ALS patients.  Vital capacity is a quantitative measure of respiratory muscle function in ALS 
and has been shown to predict disease progression in prior clinical trials.  The significant results 
on SVC demonstrated in BENEFIT-ALS show that tirasemtiv has a biological effect.  The 
cardinal symptom of ALS that directly affects survival is weakness of the skeletal muscles 
necessary for respiration.  Therefore, the significant reduction in the decline in vital capacity 
seen in this trial over 12 weeks is clinically relevant to patients with ALS.  Furthermore, the 
difference in vital capacity (measured by SVC) between tirasemtiv and placebo was maintained 
four weeks after discontinuation of double-blind treatment.  This suggests that tirasemtiv may 
have a durable impact on this measure of respiratory function in patients with ALS.  These 
effects, if persistent over longer periods of time, suggest that tirasemtiv may reduce progressive 
respiratory decline in patients with ALS.  Consequently, the current Phase 3 protocol, CY 4031, 
has been developed with the objective to confirm and extend the potentially beneficial effects of 
tirasemtiv on SVC and muscle strength observed in BENEFIT-ALS. 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Healthy Male 
Volunteers 
Phase 1 
(CY 4011A) 
 
57 
• Double-blind, placebo-controlled; parallel 
dosing; tirasemtiv vs. placebo 
• Determine safety, tolerability and PK of 
increasing single doses 
• Determine maximum tolerated dose 
(MTD) and plasma concentration 
• Single doses up to 2500 mg administered 
– Solid active pharmaceutical ingredient in 
capsule: 20 mg to 1250 mg 
– Liquid suspension: 640 mg to 2500 mg 
• MTD determined to be 2000 mg; mean Cmax = 
29.24 µg/mL 
• Median Tmax 5.0 hr for both formulations 
• Terminal t1/2 averaged 12.2 and 11.5 hours for 
the solid and liquid formulation, respectively 
• Dose proportional increase in AUCinf over the 
dose range of 20 to 2500 mg 
• tirasemtiv was generally well tolerated; no 
SAEs 
07 May 2009 to     
17 Feb 2010 
 
Healthy Male 
Volunteers 
Phase 1 
(CY 4011B) 
12 
• Double-blind, randomized, placebo-
controlled 
• 4-period, cross-over; single doses of 250, 
500, 1000 mg and placebo in random 
order 
• Assess pharmacodynamic (PD) effects 
• Relate any effects observed to associated 
plasma concentrations 
 
• Statistically significant increases versus placebo 
in peak force generated by the tibialis anterior 
muscle during transcutaneous stimulation of the 
common peroneal nerve that were related to 
nerve stimulation frequency and to tirasemtiv 
dose and plasma concentration  
• Tirasemtiv was generally well tolerated; no 
SAEs 
 
07 Oct 2009 to      
21 Dec 2009 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Healthy Male 
Volunteers 
Phase 1 
(CY 4012) 
24 
• 
Double-blind, randomized, placebo-
controlled 
• 
Once daily dosing for 7 days 
• 
Two cohorts, parallel dosing: 
– tirasemtiv 250 mg vs. placebo 
– tirasemtiv 375 mg vs. placebo 
• 
After multiple doses to steady-state: 
– Assess safety and tolerability 
– Evaluate the PK profile 
 
• Dose proportional Cmax and AUC24hr 
• Modest (~70%) accumulation from single-dose 
to steady-state 
– Mean Cmax of 6.34 and 8.22 µg/mL after 
single doses of 250 mg and 375 mg, 
respectively 
– Mean Cmax of 9.13 and 13.39 µ/mL after 
dosing to steady-state with 250 mg QD 
and 375 mg QD, respectively 
• Mean t1/2 of 8.99 hr and 12.28 hr after dosing to 
steady-state with 250 mg QD and 375 mg QD, 
respectively 
• Systemic exposures were high; inter-subject 
variability was low  
• Tirasemtiv was generally well tolerated; no 
SAEs 
28 Oct 2009 to      
17 Dec 2009 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Healthy Male or 
Female Volunteers 
Phase 1 
(CY 4013) 
 
 
39 
• 
Open-label, drug-drug interaction (DDI) 
and food effect study (2 part study) 
Part A  
• 
steady-state administration of tirasemtiv 
on the PK of single doses of riluzole 
Part B 
• 
steady-state administration of tirasemtiv 
on the PK of single doses of a warfarin 
+ rosiglitazone cocktail 
• 
effect of food on a single dose of 
tirasemtiv 
• 
safety and tolerability of multiple doses 
of tirasemtiv 
Part A  
• 
Steady-state tirasemtiv (250 mg) raised the 
mean Cmax of riluzole approximately 
2.04-fold, mean AUCinf approximately 
3.77-fold compared with riluzole alone 
• 
Mean t1/2 of riluzole increased from 7.52 
hours to 14.72 hours in the presence of 
steady-state tirasemtiv 
• 
Co-administration of tirasemtiv reduced the 
inter-subject variability of riluzole Cmax and 
clearance 
Part B 
• 
Analysis of PK data from Part B of the 
study indicated that the AUCinf for 
rosiglitazone and both S-warfarin and R-
warfarin increased approximately 2-fold in 
the presence of steady-state plasma 
tirasemtiv achieved by daily dosing at a 
dosage of 250 mg once daily 
• 
Food had no effect on tmax, or AUC  
• 
Administration of a high-fat meal increased 
the Cmax of tirasemtiv by approximately 55%  
15 Mar 2011 to      
27 Jun 2011 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with ALS  
Phase 2a 
(CY 4021) 
67 
• Double-blind, randomized, placebo-
controlled 
• 3-period, crossover study 
• Single doses of tirasemtiv (250 mg, 500 
mg) and placebo 
• 
Single doses of tirasemtiv were safe and 
generally well tolerated 
• 
Dizziness, which was generally mild, was 
the most frequently reported and most 
clearly dose-related adverse event 
• 
Both patients and investigators perceived a 
dose- and concentration-dependent 
improvement in the patients’ overall status 
at 6 hours after dosing  
• 
Statistically significant improvement in 
Maximum Voluntary Ventilation (MVV) at 
6 and 24 hours after a single 500 mg dose; 
Sniff Nasal Inspiratory Pressure (SNIP) also 
trended to increase  
• 
Trend to increase in sub-maximum grip 
strength endurance 
• 
Small but statistically significant increases 
in Maximum Voluntary Isometric 
Contraction (MVIC) strength of some but 
not all muscles studied 
29 Mar 2010 to       
2 Nov 2010 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with 
Claudication  
Phase 2a 
(CY 4022) 
61 
• Double-blind, randomized, placebo-
controlled  
• 3-period cross-over study 
• Single doses of tirasemtiv (375 mg, 750 
mg) and placebo; the protocol was 
amended to reduce the 750 mg dose to 500 
mg 
• Single doses of 375mg and 500 mg were safe 
and generally well tolerated 
• Two patients experienced SAEs including 
severe dizziness, prompting a protocol 
amendment to reduce the 750 mg dose to 
500 mg   
• Statistically significant and dose-related 
increases in total calf muscle work assessed by 
heel raise testing 
• Statistically significant and dose-related 
decreases in 6 minute walk distance, possibly 
due to AEs such as dizziness that interfered 
with performance of the test 
 
28 May 2010 to     
31 Mar 2011 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with ALS  
Phase 2a 
(CY 4024) 
49 
• Double-blind, randomized, placebo-
controlled study to evaluate the safety and 
tolerability of 14 days dosing of tirasemtiv 
without and with the concomitant 
administration of riluzole 
• 14 days of once daily oral dosing with 
tirasemtiv or placebo 
• Four parallel treatment groups 
– Placebo 
– tirasemtiv 125 mg 
– tirasemtiv 250 mg 
– tirasemtiv 375 mg 
• Part A (no riluzole): 7-day washout of 
riluzole followed by 14 days of tirasemtiv 
or placebo 
• Part B: All patients took riluzole 50 mg 
once daily for 7 days before and during the 
14 days of double-blind, once daily 
tirasemtiv or placebo 
• 49 patients treated 
– Placebo: 6 Part A, 7 Part B  
– tirasemtiv 125 mg: 6 Part A, 6 Part B 
– tirasemtiv 250 mg: 6 Part A, 6 Part B 
– tirasemtiv 375 mg: 6 Part A, 6 Part B 
• Tirasemtiv appeared to be safe and well 
tolerated at once daily doses of 125 mg, 250 
mg, and 375 mg daily for 14 days 
• Plasma concentrations of tirasemtiv were 
unaffected by co-administration with riluzole, 
while plasma concentrations of riluzole 
approximately doubled during co-
administration with tirasemtiv 
• AEs and clinical outcome measures during 
treatment with tirasemtiv appeared similar with 
or without co-administration of riluzole 50 mg 
daily 
• The most frequently reported adverse event 
was dizziness. Most episodes were mild in 
intensity and began and resolved early after 
initiation of treatment and during continued 
dosing 
• Encouraging trends to increase the ALS 
Functional Rating Scale-Revised score and 
MVV were observed in patients treated with 
tirasemtiv 
Part A:                   
20 Jun 2011 to      
10 Nov 2011 
Part B:                   
05 Oct 2011 to      
02 Mar 2012  
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with ALS  
Phase 2a 
(CY 4025) 
27 
• Double-blind, randomized, placebo-
controlled study to evaluate the safety and 
tolerability of 21 days dosing of tirasemtiv 
administered according to a twice-daily, 
dose titration regimen with the 
concomitant administration of riluzole 
• 21 days of twice daily oral dosing with 
tirasemtiv or placebo 
• Two parallel treatment groups 
– Placebo dose titration  
− 
Week 1: 1 tablet twice daily 
− 
Week 2: 1 tablet in the 
morning and 2 tablets in the 
evening 
− 
Week 3: 2 tablets twice daily 
– Tirasemtiv dose titration 
− 
Week 1: 125 mg twice daily 
− 
Week 2: 125 mg in the 
morning and 250 mg in the 
evening 
− 
Week 3: 250 mg twice daily 
• All patients took riluzole 50 mg once daily 
for 7 days before and during the 21 days of 
double-blind, twice-daily dose titration 
with tirasemtiv or placebo 
• 27 patients treated  
– Placebo titration: 6 
– tirasemtiv titration: 21 
• Tirasemtiv administered in the twice-daily, 
dose titration regimen studied appeared to be 
safe and well tolerated 
• 14 of 21 patients randomized to tirasemtiv were 
titrated to tirasemtiv 250 mg twice daily and 
completed the study at that dose level 
• Dizziness was the most frequent adverse event, 
reported by 12 of 21 patients on tirasemtiv 
– Mild in 10 patients, moderate in 2 patients 
– Resolved during continued dosing in 6 
patients 
• Encouraging trends to increase the ALS 
Functional Rating Scale-Revised score and 
MVV were observed in patients treated with 
tirasemtiv 
18 Nov 2011 to     
16 Mar 2012 
 

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Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv (Continued) 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with 
Myasthenia Gravis  
Phase 2a 
(CY 4023) 
32 
• Double-blind, randomized, placebo-
controlled 
• 3-period cross-over study 
• Single doses of tirasemtiv (250 mg, 500 
mg) and placebo 
 
• 
Single doses of tirasemtiv were safe and 
generally well tolerated 
• 
Dizziness, which was generally mild, was 
the most commonly reported adverse event 
• 
There were no premature terminations and 
no SAEs reported 
• 
Quantitative Myasthenia Gravis (QMG) 
score decreased in a dose-related fashion 
• 
Forced Vital Capacity (FVC) increased 
versus placebo at 6 hours after dosing  
 
29 Dec 2010 to       
10 Oct 2012 
 

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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective is to assess the effect of tirasemtiv versus placebo on respiratory function 
in patients with ALS.   
2.1.1. 
Primary Endpoint 
The primary endpoint is the change from baseline to Week 24 of the double-blind, placebo-
controlled phase in percent predicted SVC. 
2.2. 
Secondary Objectives 
Secondary objectives include: 
• Evaluation of alternative methods to assess the effect of tirasemtiv versus placebo on 
percent predicted SVC in patients with ALS 
• Assessment of the effect of tirasemtiv versus placebo on other clinical measures related 
to the progressive decline in respiratory function in patients with ALS 
• Assessment of the effect of tirasemtiv versus placebo on measures of skeletal muscle 
function in patients with ALS 
2.2.1. 
Secondary Endpoints 
The following secondary endpoints will be analyzed in a closed testing procedure if the primary 
efficacy analysis is met as defined in Section 8.4.3. 
• Change from baseline in the ALSFRS-R score of the three respiratory items of the 
ALSFRS-R (i.e., the sum of items 10, 11 and 12) at the end of 48 weeks of double-blind, 
placebo-controlled treatment 
• Slope of mega-score of muscle strength during the 48 weeks of double-blind, placebo-
controlled treatment  
• Time to the first occurrence of a decline from baseline in percent predicted SVC ≥20 
percentage points or the onset of respiratory insufficiency or death at the end of the 48 
weeks of double-blind, placebo-controlled treatment 
• Time to the first occurrence of a decline in SVC to ≤50% predicted or the onset of 
respiratory insufficiency or death at the end of the 48 weeks of double-blind, placebo-
controlled treatment 
• Change from baseline in the ALSFRS-R total score to the end of 48 weeks of the double-
blind, placebo-controlled treatment 
• Time to the first use of mechanical ventilatory assistance or death during all 48 weeks of 
double-blind, placebo-controlled treatment 
 

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2.2.2. 
Tertiary Endpoints 
Tertiary endpoints are presented grouped by their similarities to one another.  The prospectively 
defined tertiary endpoints listed below will be the subject of descriptive, exploratory analyses as 
defined in the Statistical Analysis Plan.  Additional tertiary endpoints of interest may be added to 
the Statistical Analysis Plan. 
1. “Time to Event” analyses including: 
a. Time to the first occurrence of a decline in SVC to ≤ 50% predicted or the onset of 
respiratory insufficiency (defined as tracheostomy or the use of non-invasive 
ventilation for ≥ 22 hours per day for ≥ 10 consecutive days) or death during the first 
24 weeks of double-blind, placebo-controlled treatment 
b. Time to the first occurrence of a decline from baseline in percent predicted SVC 
≥ 10 percentage points or the onset of respiratory insufficiency or death during the 
first 24 weeks of double-blind, placebo-controlled treatment 
c. Time to the first occurrence of a decline from baseline in percent predicted SVC 
≥ 20 percentage points or the onset of respiratory insufficiency or death during the 
first 24 weeks of double-blind, placebo-controlled treatment 
d. Time to the first occurrence of a decline in the respiratory components of the 
ALSFRS-R (i.e., items 10, 11, and 12) or death during the first 24 weeks of double-
blind, placebo-controlled treatment 
e. Time to the first occurrence of a decline in either of the ALSFRS-R items 11 or 12 or 
death during the first 24 weeks and during all 48 weeks of double-blind, placebo-
controlled treatment 
f. Time to the first occurrence of a decline in either of the ALSFRS-R item 12 or death 
during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled 
treatment 
g. Time to the first occurrence of the first use of mechanical ventilatory assistance or 
death during the first 24 weeks of double-blind, placebo-controlled treatment 
In addition, each of the first three composite endpoints listed above will be analyzed with 
“first use of mechanical ventilatory assistance” in place of “respiratory insufficiency”.  
2. “Responder analyses” including: 
a. Proportion of patients with no decline from baseline in percent predicted SVC, free 
from respiratory insufficiency and alive during the first 24 weeks and during all 
48 weeks of double-blind, placebo-controlled treatment 
b. Proportion of patients with a decline from baseline ≤ 6 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 
c. Proportion of patients with a decline from baseline ≤ 10 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 
d. Proportion of patients with a decline from baseline ≤ 20 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 

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3. Change from baseline to 24 weeks of double-blind, placebo-controlled treatment in the 
following measures: 
a. ALSFRS-R total score 
b. ALSFRS-R score of the three respiratory subdomains of the ALSFRS-R 
(i.e., items 10, 11, and 12) 
c. Muscle strength as determined by the mega-score of: 
• Elbow flexion (bilateral) 
• Wrist extension (bilateral) 
• Knee extension (bilateral) 
• Ankle dorsiflexion (bilateral) 
• Handgrip strength (bilateral) 
d. SNIP 
4. Slopes of the changes from baseline in percent predicted SVC, ALSFRS-R, mega-score 
of muscle strength, and SNIP: 
a. From baseline to 24 weeks of the randomized, double-blind, placebo-controlled phase  
b. From baseline to 48 weeks of the randomized, double-blind, placebo-controlled phase 
(excluding mega-score of muscle strength) 
c. From the end of 24 weeks of the randomized, double-blind, placebo-controlled phase 
to the end of the double-blind, randomized, placebo-controlled phase at 48 weeks 
5. Changes in percent predicted SVC, muscle strength mega-score, and SNIP from baseline 
to the end of Week 48 of the double-blind, placebo-controlled phase. 
6. Change in percent predicted SVC from baseline to the end of Week 12 of the double-
blind, placebo-controlled phase. 

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3. 
STUDY OVERVIEW 
CY 4031 is a multi-national, double-blind, randomized, placebo-controlled, stratified, parallel 
group study with the selective fast skeletal muscle troponin activator, tirasemtiv, in patients with 
ALS who can complete two weeks of treatment with open-label tirasemtiv (125 mg twice daily).  
Both patients who are currently taking riluzole and those who are not will be enrolled in the 
study.  Patients taking riluzole who are randomized to tirasemtiv will have their riluzole dose 
decreased to 50 mg/day (half the approved dose) in a double-blind fashion, since previous 
studies have demonstrated that administration of tirasemtiv approximately doubles the exposure 
to concomitant riluzole. 
The study includes three phases (Figure 3); an open-label phase, a double-blind, placebo-
controlled phase, and a double-blind, placebo-controlled tirasemtiv withdrawal phase. 
Following completion of two weeks of treatment with open-label tirasemtiv, patients will be 
randomized 3:2:2:2 to placebo and three different dose levels of tirasemtiv.   
Approximately 600 patients are expected to be enrolled in the open-label phase.  Approximately 
477 of the patients enrolled onto open-label treatment are expected to be randomized in the 
double-blind, placebo-controlled phase. 
Figure 3: 
Study Design 
 
Screening 
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, they will be enrolled to 
receive open-label tirasemtiv for two weeks. 
Open-Label Phase 
Week -2 is the first study visit after screening.  At Week -2, patients will report to the study site 
to begin the open-label phase, which will last 14 days.  During the open-label phase, patients will 
take 1 tablet (125 mg) of tirasemtiv twice daily.  Patients will be contacted by phone after seven 
days and return to the study site after 14 days of open-label treatment. 

Protocol CY 4031 
 
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Double-Blind, Placebo-Controlled Phase 
Day 1 is the beginning of the double-blind, placebo-controlled phase, which will last 
approximately 48 weeks.  Patients who have demonstrated adequate tolerance of tirasemtiv 
during the open-label phase will be randomized to one of four study groups (Figure 4) prior to 
the Day 1 procedures.  Patients in Groups 2, 3, and 4 will receive double-blind tirasemtiv for the 
next 48 weeks and patients in Group 1 will receive matching placebo tablets in lieu of tirasemtiv 
(Table 5).   
During the double-blind, placebo-controlled phase, additional study visits will take place at the 
end of Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, 
and Week 48. 
Patients will not escalate their dose if signs of intolerability are present.  Patients who do not 
tolerate a dose escalation due to symptoms believed to be due to treatment with study drug will 
be returned to a previously tolerated dose level.  Decisions regarding dose escalation and de-
escalation will be made and executed in a manner that does not compromise blinding either to 
treatment or to dose level. 
Figure 4: 
First and Second Randomization 
 

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Table 5: 
Randomized Double-Blind Treatment Groups 
Group 1 
(Placebo) 
Group 2 
(target 250 mg/day of 
tirasemtiv) 
Group 3 
(target 375 mg/day of 
tirasemtiv) 
Group 4 
(target 500 mg/day of 
tirasemtiv) 
Weeks 1 through 48 
2 placebo tablets twice 
daily to end of Week 48 
Weeks 1 through 48 
1 tablet (125 mg) of 
tirasemtiv and 1 tablet of 
matching placebo in AM 
and 1 tablet of tirasemtiv 
(125 mg) and 1 tablet of 
matching placebo in PM 
Weeks 1 and 2 
1 tablet (125 mg) of 
tirasemtiv and 1 tablet of 
matching placebo in AM 
and 1 tablet of tirasemtiv 
(125 mg) and 1 tablet of 
matching placebo in PM 
Weeks 3 through 48 
1 tablet (125 mg) of 
tirasemtiv and 1 tablet of 
matching placebo in AM 
and 2 tablets of tirasemtiv 
(250 mg) in PM 
Weeks 1 and 2 
1 tablet (125 mg) of 
tirasemtiv and 1 tablet of 
matching placebo in AM 
and 1 tablet of tirasemtiv 
(125 mg) and 1 tablet of 
matching placebo in PM 
Weeks 3 and 4 
1 tablet (125 mg) of 
tirasemtiv and 1 tablet of 
matching placebo in AM 
and 2 tablets of tirasemtiv 
(250 mg) in PM 
Weeks 5 through 48 
2 tablets (250 mg) of 
tirasemtiv in AM and 
2 tablets of tirasemtiv 
(250 mg) in PM 
Riluzole Users Only 
Group 1 
(Placebo) 
Groups 2-4 
(Active Treatment Groups) 
Riluzole tablets 
50 mg riluzole (personal 
supply) in the morning 
plus blinded riluzole 
50 mg in the evening 
Riluzole tablets 
50 mg riluzole (personal supply) in the morning plus blinded riluzole placebo in the 
evening 
Double-Blind, Placebo-Controlled Tirasemtiv Withdrawal Phase 
Upon completion of the double-blind, placebo-controlled phase, patients will be randomized a 
second time (Figure 4) to placebo or to continue their current active dose level of treatment in an 
allocation ratio of 1:1 for the next four weeks as part of the double-blind, placebo-controlled 
tirasemtiv withdrawal phase (Table 6).  Both the first and second randomizations will be 
stratified by riluzole use/non-use.  
Table 6: 
Randomized Double-Blind, Tirasemtiv Withdrawal Treatment 
Group 1 
(maintained on tirasemtiv) 
Group 2 
(withdrawn to placebo) 
Weeks 49 through 52 
Maintained on the tirasemtiv dose taken during the 
double-blind, placebo-controlled phase 
Weeks 49 through 52 
Withdrawn to or maintain placebo dose in AM and PM 
During the double-blind, placebo-controlled, tirasemtiv withdrawal phase, additional study visits 
will take place at the end of Week 49 and Week 52. 

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A final follow-up visit will occur four weeks after completion of the double-blind, placebo-
controlled tirasemtiv withdrawal phase at Week 56. 
Riluzole 
Patients who were not taking riluzole prior to study entry will be encouraged not to take riluzole 
until they complete study drug dosing.  Patients who were not taking riluzole at study entry but who 
later decide to start riluzole during the dosing phase of the study will not be allowed to continue 
taking study drug. When patients are taking tirasemtiv during the study, their dose of riluzole will 
be reduced to 50 mg once daily in the morning as described in Section 5.8. 
3.1. 
Estimated Study Duration 
Individual patient participation will take place as follows: 
Screening 
2 Weeks 
Open-Label Phase 
2 Weeks 
Double-Blind, Placebo-Controlled  
48 Weeks 
Double-Blind, Placebo-Controlled, Tirasemtiv Withdrawal 
4 Weeks 
Follow Up 
4 Weeks 
Total 60 Weeks 
3.2. 
Tirasemtiv Dose Rationale 
In the Phase 2b study of tirasemtiv in patients with ALS, BENEFIT-ALS, following a one week 
open-label run-in period at 250 mg/day, patients were titrated using weekly dose increases to 
their maximum tolerated dose (MTD), up to 500 mg/day.  Flexible dosing was allowed to 
maximize tolerability.  Patients tended to drop out after titration from 250 mg/day to 375 mg/day 
and from 375 mg/day to 500 mg/day, suggesting that a longer titration schedule may improve 
tolerability.  Among patients on tirasemtiv who completed the study, approximately half were on 
500 mg/day, and the remainder was divided generally equally between 375 mg/day and 
250 mg/day.  Analyses of the change from baseline in percent predicted SVC on tirasemtiv 
versus placebo by MTD and tirasemtiv exposure suggested that doses lower than 500 mg/day 
may still meaningfully reduce the decline from baseline in SVC in patients with ALS. 
Given the data from BENEFIT-ALS, we propose to evaluate further the relationship of specific 
tirasemtiv doses to the intended effect to reduce the decline in respiratory function as measured 
by SVC while also attempting to improve the tolerability of tirasemtiv with a more gradual dose 
titration schedule.  Thus, this study has been designed to test three separate target tirasemtiv 
doses (250 mg/day, 375 mg/day, and 500 mg/day), using a more gradual dose titration schedule 
than was employed in BENEFIT-ALS.  Patients who discontinue drug treatment will be expected 
to stay in the trial and complete all scheduled assessments.    
Figure 5 shows the range of tirasemtiv concentrations associated with the steady-state PK 
profiles predicted to occur in CY 4031 based on data from BENEFIT-ALS and the tirasemtiv 
population PK model.  The solid lines represent the predicted average concentration-versus-time 

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profile and the upper and lower dashed lines represent the concentration-versus-time profiles at 
the 95th and 5th percentiles.   
Table 7 provides the distribution of AM and PM trough tirasemtiv concentrations by dose level 
at steady-state.  
Figure 5: 
Predicted Steady-State Pharmacokinetic Profiles for Tirasemtiv Target Dose 
Levels in CY 4031  
 
The black lines are for 125 mg BID, the blue lines are for 125 mg AM/ 250 mg PM, and the red 
lines are for 250 mg BID, respectively. 
 
Table 7: 
Distribution of Trough Tirasemtiv Concentration at Steady-State by Dose 
Parameters 
125 mg BID 
125 mg AM and 
250 mg PM 
250 mg BID 
Trough prior to evening dose 
(µg/mL, median [5-95 percentile]) 
5.4 [ 2.8 - 9.7 ] 
7.1 [ 3.4 - 13 ] 
9.9 [ 5 - 17.5 ] 
Trough prior to morning dose 
(µg/mL, median [5-95 percentile]) 
5.4 [ 2.8 - 9.7 ] 
8.2 [ 4.3 - 14.3 ] 
9.9 [ 5 - 17.6 ] 
Trough prior to evening dose 
% of patients below 5/6/7/8 µg /ml 
39.8/60.3/75.9/86 
18/32.4/47.6/61.7 
4.9/9.9/18/27.8 
Trough prior to evening dose 
% of patients above 13/14/15/16 µg /ml 
0.4/0.3/0.2/0.2 
5/2.8/1.8/1.2 
22.2/16.4/12.1/9.2 
0
5
10
15
20
0
5
10
15
20
25
Time (hour)
Concentration (ug/mL)
Steady state

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3.3. 
Rationale for the Open-Label Lead-In Phase Prior to Randomization 
The open-label treatment phase for all patients prior to randomization to double-blind active 
tirasemtiv versus placebo has been incorporated into the design of CY 4031 in order to diminish 
the potential for the occurrence of dizziness and other AEs known to occur during treatment with 
tirasemtiv to unmask the double-blind treatment assignment.  Open-label treatment at study onset 
also will serve to eliminate those patients unable to tolerate a dose of 125 mg of tirasemtiv twice 
daily prior to randomization and inclusion in the intent to treat cohort. 
Treatment with tirasemtiv has been associated with a dose-related increase in reports of dizziness 
in both healthy volunteers and patients with ALS.  The dizziness is most often mild and usually 
resolves with continued dosing.  For example, the Phase 2a study, CY 4024, 49 patients with 
ALS received two weeks’ treatment with once daily doses of placebo (n = 13) or tirasemtiv at 
125 mg, 250 mg, or 375 mg (n = 12 for each group).  Dizziness was not reported on placebo in 
CY 4024 but occurred in 25%, 42%, and 50% of patients receiving tirasemtiv at 125 mg, 
250 mg, and 375 mg once daily, respectively.  As shown below in Figure 6, among patients who 
reported dizziness, the symptom usually began early after the initiation of treatment and had 
mostly resolved by the second week. 
Figure 6: 
Incidence of Dizziness by Double-Blind Treatment Assignment and Day of 
Double-Blind Treatment in CY 4024  
 
In another Phase 2a study, CY 4025, 21 patients with ALS were randomized to receive double-
blind tirasemtiv administered as 125 mg twice daily for one week, followed by 125 mg in the 
morning and 250 mg in the evening during the second week, and 250 mg twice daily during the 
third and final week of treatment.  Another six patients were randomized to a dummy dose 
titration with matching double-blind placebo.  None of the patients who received placebo in 
CY 4025 reported dizziness, while dizziness was reported by 12 of the 21 patients (57%) 
randomized to dose titration with active tirasemtiv.  Once again, among the 12 patients who 
reported dizziness, the symptom usually began early after the initiation of treatment.  In 10 of 
these 21 patients (48%), dizziness began during the first week of tirasemtiv treatment at 

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125 mg BID.  Of the 11 patients who did not experience dizziness during that first week of 
treatment, only two experienced its first onset during the second week, after up-titration to 
125 mg in the morning and 250 mg in the evening, and no patients in CY 4025 first experienced 
dizziness after titration to the highest dose of 250 mg twice daily.  Furthermore, in four of the 
12 patients who reported dizziness at any time during CY 4025, the symptom resolved during 
continued administration of tirasemtiv, including up-titration to 250 mg twice daily and 
successful completion of the study in three patients. 
In summary, in CY 4024 and CY 4025, roughly half the ALS patients treated with tirasemtiv at 
daily doses of 250 mg and above reported dizziness, which generally began within the first few 
days of initiating treatment.  In many of these patients, however, dizziness tended to resolve with 
continued dosing, usually within a few days of its first occurrence. 
Due to concerns that the occurrence of dizziness and other AEs could contribute to the effective 
unblinding of patients in BENEFIT-ALS, all patients received one week of open-label treatment 
with tirasemtiv 125 mg BID prior to randomization to double-blind active tirasemtiv versus 
placebo in an effort to diminish this potential for such unmasking of the double-blind treatment 
assignment.  Roughly half the patients enrolled were expected to experience dizziness during 
open-label treatment with tirasemtiv 125 mg BID; however, if dizziness resolved after 
randomization to double-blind therapy, it could have been due to spontaneous resolution of the 
symptom despite continued treatment with active tirasemtiv (as described above) or due to 
withdrawal of active tirasemtiv and initiation of double-blind placebo. 
During BENEFIT-ALS, 291 of the 711 patients enrolled into the open-label portion of the study 
had at least one treatment-emergent adverse event (TEAE) of dizziness.  In these patients, the 
mean ± standard deviation (SD) time to onset of the first episode of dizziness was 1.1 ± 
1.45 days (with a range of 0 to 10.4 days) and the mean ± SD duration of the first episode of 
dizziness was 14.7 ± 23.97 days (with a range of 0 to 121.4 days).  Among these 291 patients, 
222 went on to be randomized to placebo or tirasemtiv.  Among the 111 of these 222 patients 
randomized to placebo, the mean ± SD duration of the first episode of dizziness that began 
during the open-label treatment was 14.2 ± 25.47 days (with a range of 0 to 121.4 days).  Among 
the 111 of these 222 patients randomized to tirasemtiv, the mean ± SD duration of the first 
episode of dizziness that began during the open-label treatment was 20.0 ± 27.70 days (with a 
range of 0 to 113.6 days).  There is sufficient similarity between these durations and their ranges 
to suggest that the week of open-label treatment with tirasemtiv prior to randomization was 
generally effective in preventing dizziness on tirasemtiv from unmasking the double-blind 
treatment assignment of an individual patient.  Consequently, an open-label phase prior to 
randomization has been retained in the design of the current study, CY 4031. 
Another purpose of open-label treatment with tirasemtiv prior to randomization is to prevent 
randomization of patients who do not tolerate the starting dose of 125 mg BID.  In BENEFIT-
ALS, 16% of patients withdrew from open-label treatment prior to randomization; however, 
4.7% of patients randomized to tirasemtiv withdrew during the first week of double-blind 
treatment (compared to 1.7% of patients randomized to placebo), even though the tirasemtiv 
dose during that first week was identical to the open-label tirasemtiv dose regimen of 
125 mg BID.  Consequently, the duration of the open-label phase in CY 4031 has been increased 
to two weeks. 

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3.4. 
Riluzole Dose Adjustment Rationale 
Tirasemtiv is a mechanism-based inhibitor of the drug metabolizing enzyme CYP1A2, the major 
pathway of elimination for riluzole; consequently, when tirasemtiv is administered 
concomitantly with riluzole, plasma riluzole concentrations are increased relative to when 
riluzole is administered in the absence of tirasemtiv.  Consequently, in BENEFIT-ALS, patients 
taking riluzole who were randomized to double-blind tirasemtiv had their riluzole dose decreased 
from 50 mg twice daily to 50 mg once daily in a double-blind manner as will be done in the 
current study, CY 4031 (described in Section 5.8 Concomitant Medications). 
With the riluzole dose adjustment employed in BENEFIT-ALS, the analysis depicted in 
Figure 7, below, showed that during treatment with tirasemtiv over the dose range to be studied 
in CY 4031 (i.e., 125 mg twice daily to 250 mg twice daily), steady-state plasma riluzole 
concentrations at trough were not increased, while plasma riluzole concentrations at one and 
three hours after dosing were increased by somewhat less than 2-fold, and riluzole AUC24h 
values were increased approximately 1.5-fold relative to when riluzole was dosed in the absence 
of tirasemtiv.  Importantly, these steady-state riluzole exposures did not vary significantly with 
the total daily dose (TDD) of tirasemtiv over the range from 250 mg to 500 mg.   
Figure 7: 
Steady-State Plasma Riluzole Exposures with and without Steady-State 
Concomitant Tirasemtiv at Total Daily Doses from 250 mg to 500 mg in 
BENEFIT-ALS 
 
The riluzole dose reduction employed in patients randomized to treatment with double-blind 
tirasemtiv in BENEFIT-ALS did not completely adjust for the effect of tirasemtiv to increase 
plasma riluzole concentrations when the two drugs were administered concomitantly.  As shown 
above, patients randomized to tirasemtiv experienced somewhat higher riluzole exposures than 
patients randomized to placebo, despite the dose reduction.  Nevertheless, the riluzole dose 

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adjustment employed in BENEFIT-ALS will be implemented again in the current study, 
CY 4031, for the following reasons: 
1. Because riluzole is supplied only as 50 mg tablets, it is the only practicable dose 
adjustment for patients randomized to double-blind tirasemtiv that preserves trough riluzole 
levels in the ranges observed in patients taking riluzole and double-blind placebo in 
BENEFIT-ALS.  Given the demonstrated benefits of riluzole in the treatment of patients 
with ALS, it is important to err on the side of over-exposure rather than under-exposure. 
2. There were no differences in safety or tolerability observed between patients taking riluzole 
and those not taking riluzole in BENEFIT-ALS.  Differences in AE rates between the 
tirasemtiv and placebo treatment groups were generally similar between patients taking 
riluzole and those not taking riluzole; furthermore, liver function tests (LFT) were similar 
in patients taking riluzole and those not taking riluzole. 
Accordingly, patients who enter CY 4031 taking riluzole will take half of the standard riluzole 
dose (i.e., 50 mg once daily) during the open-label phase and half of the standard riluzole dose 
(i.e., 50 mg once daily) during the treatment phases when they are randomized to receive double-
blind tirasemtiv.  Patients who enter CY 4031 taking riluzole and who are randomized to receive 
double-blind placebo will continue to receive the standard dose of 50 mg twice daily.  As noted 
elsewhere in this protocol (see Section 5.8), the evening riluzole dose will be supplied by the 
study site during the placebo-controlled phases of the study in a double-blind fashion (active 
versus placebo riluzole) to preserve blinding of the randomization to tirasemtiv versus placebo.  
In addition, because riluzole exposure is frequently associated with elevations of LFT, LFT will 
be obtained after initiation of study drug and during dose escalation in CY 4031. 
3.5. 
Double-Blind, Placebo-Controlled, Tirasemtiv Withdrawal Phase 
Rationale 
The double-blind, placebo-controlled, tirasemtiv withdrawal phase has been incorporated into the 
design of CY 4031 in order to evaluate the possibility of a “rebound effect” after 48 weeks of 
treatment with tirasemtiv; i.e., increasing symptoms or loss of function after discontinuation of 
treatment to a point worse than if the patient had not received tirasemtiv.  This will be evaluated 
by comparing measures in those patients randomized to tirasemtiv for the 48 weeks of double-
blind, placebo-controlled treatment but who were then randomized to placebo for the double-
blind, placebo-controlled, tirasemtiv withdrawal phase to those randomized to placebo 
throughout the trial during clinic visits scheduled at Week 49 and Week 52.  At Week 49, 
clearance of tirasemtiv should have essentially just completed among those patients who had 
received 48 weeks of tirasemtiv, which is when rebound effects might be expected to be at their 
most prominent, should they occur.  The visit at Week 52 will allow assessment of the duration 
of such rebound effects (if any), or may document their resolution (again, should any such 
rebound effects be observed). 
Of note, there was no evidence for rebound worsening of symptoms or function after 
discontinuation of tirasemtiv following 12 weeks of treatment in the Phase 2b study, BENEFIT-
ALS.  The assessment for rebound effects in CY 4031, however, will occur after 48 weeks of 
treatment with active tirasemtiv.  The substantially longer duration of tirasemtiv treatment in 

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CY 4031 versus BENEFIT-ALS supports the inclusion of an assessment of rebound effects in 
CY 4031. 

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4. 
STUDY POPULATION 
Approximately 600 patients who fulfill the eligibility criteria will be enrolled in the study and 
approximately 477 are expected to be randomized in the double-blind, placebo-controlled phase. 
4.1. 
Inclusion Criteria 
1. Able to comprehend and willing to sign an Informed Consent Form (ICF) 
2. Male or female 18 years of age or older 
3. A 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) ≤ 24 months prior to screening 
4. Upright SVC ≥ 70 % of predicted for age, height and sex 
5. Able to swallow tablets without crushing, and in the opinion of the Investigator, is 
expected to continue to be able to do so during the trial 
6. A caregiver if one is needed 
7. Clinical laboratory findings within the normal range or, if outside the normal range, 
deemed not clinically significant by the Investigator 
8. Male patients must agree for the duration of the study and 10 weeks after the end of the 
study to use a condom during sexual intercourse with female partners who are of 
childbearing potential (i.e., following menarche until post-menopausal if not anatomically 
and physiologically incapable of becoming pregnant) and to have female partners use an 
additional effective means of contraception (e.g., diaphragm plus spermicide, or oral 
contraceptives) or the male patient must agree to abstain from sexual intercourse during 
and for 10 weeks after the end of the study, unless the male patient has had a vasectomy 
and confirmed sperm count is zero 
9. Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of childbearing 
potential, not be breastfeeding, have a negative pregnancy test, have no intention to 
become pregnant during the course of the study, and use effective contraceptive drugs or 
devices while requiring male partner to use a condom for the duration of the study and for 
10 weeks after the end of the study 
10. Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 days 
prior to screening or have not taken riluzole for at least 30 days prior to screening and are 
willing not to begin riluzole use until they complete study drug dosing 
4.2. 
Exclusion Criteria 
1. At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, 
e.g. continuous positive airway pressure [CPAP] or bi-level positive airway pressure 
[BiPAP]) for any portion of the day, or mechanical ventilation via tracheostomy, or on 
any form of oxygen supplementation 
2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS 
placement during the course of the study 

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3. BMI of 20.0 kg/m2 or lower 
4. Unwilling or unable to discontinue tizanidine and theophylline-containing medications 
during study participation 
5. Serum chloride outside the normal reference range 
6. Neurological impairment due to a condition other than ALS, including history of 
transient ischemic attack within the past year  
7. 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. Poorly controlled hypertension 
b. NYHA Class II or greater congestive heart failure 
c. Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator 
medications 
d. GI disorder that might impair absorption of study drug  
e. History of significant liver disease defined by bilirubin > 2 times the upper limit of 
normal (ULN) or ALT or AST > 3 times the ULN on repeat testing   
f. Poorly controlled diabetes mellitus 
g. History of vertigo within three months of study entry 
h. History of syncope without an explainable or treated cause 
i. History of untreated intracranial aneurysm or poorly controlled seizure disorder  
j. Amputation of a limb 
k. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s 
ability to give informed consent and to understand and/or comply with study 
procedures  
l. 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 two years 
m. 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 
n. Patient judged to be actively suicidal or a suicide risk by the Investigator 
8. Has taken any investigational study drug within 30 days or five half-lives of the prior 
agent, whichever is greater, prior to dosing 
9. Prior participation in any form of stem cell therapy for the treatment of ALS 
10. Previously received tirasemtiv in any previous clinical trial 
4.3. 
Additional Randomization Criterion 
Patients must tolerate two weeks of open-label treatment with tirasemtiv 125 mg twice daily to 
be eligible for randomization.  

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5. 
STUDY PROCEDURES 
5.1. 
Screening 
A signed ICF will be obtained prior to any screening procedures and before any study specific 
assessments are initiated.  
The following screening procedures will be performed for all potential patients at a visit 
conducted within 14 days of start of the open-label phase of the study: 
1. Informed consent documentation 
2. Inclusion/exclusion criteria evaluation 
3. Demographic data collection 
4. Medical history collection (includes smoking history) 
5. Clinical safety laboratory evaluations including a serum chemistry panel, complete blood 
count (CBC), urinalysis (UA), creatine phosphokinase (CPK), and thyroid stimulating 
hormone (TSH) 
6. Serum pregnancy test for females of child bearing potential 
7. Vital signs measurements (sitting for at least three minutes) including blood pressure, 
pulse, respiration rate and temperature 
8. 12-lead electrocardiogram (ECG) 
9. Routine physical examination, including height and weight 
10. Neurological examination 
11. ALSFRS-R 
12. Respiratory assessment 
13. Concomitant medication assessment 
14. Ashworth score 
15. Suicidality assessment  
Confirmation of eligibility for enrollment into the open-label phase must occur prior to the 
Week -2 visit. 
5.2. 
Open-Label Phase 
5.2.1. 
WEEK -2 VISIT 
Week -2 is the first study visit after screening and the start of the open-label phase.  Patients will 
report to the study site for the Week -2 visit which may occur at any time up to, but not after 
14 days following the Screening Visit.  Patients will be instructed to bring their own riluzole 
supply to the study visit and not to take their morning dose of riluzole (for patients on riluzole) 
prior to arrival at the study site.   

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The following procedures will then be performed: 
1. PK blood sampling 
2. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK 
3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight  
4. Respiratory assessment 
5. Handgrip strength (bilateral) 
6. Muscle strength measurements 
7. ALSFRS-R 
8. ALS Assessment Questionnaire Short Form (ALSAQ-5) 
9. Epworth Sleepiness Scale 
10. Falls assessment 
11. Caregiver Burden assessment 
12. AE evaluation and concomitant medication assessment (since last visit) 
13. Suicidality assessment  
Once the assessments are completed at the Week -2 visit, patients will receive their first morning 
dose of open-label study drug (125 mg of tirasemtiv).  Patients currently taking riluzole also will 
take 50 mg riluzole from their personal supply. 
Patients will be given an adequate supply of open-label study drug (tirasemtiv) to take twice 
daily for 14 days at home until their next clinic visit (Day 1 Visit).  A diary will be provided for 
patients to record the date and time of twice daily study drug administration and riluzole 
administration (if on riluzole).  Patients on riluzole will be reminded to take 50 mg riluzole from 
their personal supply at the same time as their morning dose of study drug and not to take their 
evening dose of riluzole during the open-label phase.  Patients will be contacted by phone after 
seven days of open-label tirasemtiv and will return to the study site after 14 days of open-label 
treatment for the Day 1 visit.  
5.3. 
Double-Blind, Placebo-Controlled Phase 
The double-blind, placebo-controlled phase will last approximately 48 weeks.  Patients who have 
demonstrated adequate tolerance of tirasemtiv during the open-label phase will be randomized to 
tirasemtiv versus placebo prior to the Day 1 procedures.  Randomization should occur following 
completion of the open-label phase and prior to Day 1 visit procedures.  Randomization must not 
occur until the patient has been contacted by study site personnel at the end of the open-label 
phase and the Investigator is confident that the patient has tolerated the open-label phase such 
that, if any adverse symptoms that the patient experienced during open-label treatment were to 
continue throughout the double-blind portion of the study with the same severity, those 
symptoms would be sufficiently mild that they would not likely prevent the patient from 

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completing the study.  The patient, caregiver, and the Investigator will all be blinded to the 
patient’s treatment group assignment.   
5.3.1. 
 DAY 1 VISIT  
Day 1 marks the beginning of the double-blind, placebo-controlled phase.  During the first two 
weeks of the double-blind, placebo-controlled phase, all patients will take a TDD of 250 mg of 
tirasemtiv or placebo for 14 days.   
Patients will be instructed to bring their own riluzole supply to the study visit and not to take 
their morning dose of study drug or riluzole (for patients on riluzole) prior to arrival at the study 
site. 
The following assessments will be performed prior to administration of riluzole and study drug 
while in the clinic: 
1. PK blood sampling 
2. Biomarker sample 
3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. Respiratory assessment   
5. ALSFRS-R 
6. Falls assessment 
7. AE evaluation and concomitant medication assessment (since last visit) 
8. Suicidality assessment  
Once all pre-dose procedures have been performed at the Day 1 visit, patients will take their 
morning dose of assigned study drug (125 mg of tirasemtiv or placebo).  For patients taking 
riluzole, 50 mg riluzole from their personal supply should also be taken with the morning dose of 
study drug. 
Patients will begin double-blind dosing as follows for the next two weeks. 
Patients randomized to receive double-blind tirasemtiv:  
• Patients randomized to the TDD of 250 mg, 375 mg or 500 mg of tirasemtiv will 
begin dosing with 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in 
the morning and 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in 
the evening for two weeks 
Patients randomized to receive double-blind placebo will begin dosing with 2 placebo tablets 
in the morning and 2 placebo tablets in the evening for two weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for two weeks at home until their next clinic visit (Week 2 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 

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will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   
5.3.2. 
WEEK 2 VISIT  
Patients will return approximately two weeks later to the study site for the Week 2 visit.  Patients 
will be instructed to bring their own riluzole supply to the study visit and not to take their 
morning dose of study drug or riluzole (for patients on riluzole) prior to arrival at the study site. 
The following assessments will be performed prior to administration of riluzole and study drug 
while in the clinic: 
1. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
2. Falls assessment 
3. AE evaluation and concomitant medication assessment (since last visit) 
4. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 2 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 
Patients will continue study drug dosing as follows for the next two weeks. 
Patients randomized to receive double-blind tirasemtiv:  
• For patients randomized to the TDD of 250 mg of tirasemtiv, patients will continue 
dosing with 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the 
morning and 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the 
evening for two weeks 
• For patients randomized to the TDD of 375 mg or 500 mg of tirasemtiv, patients will 
begin dosing with 1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in 
the morning and 2 tablets (250 mg) of tirasemtiv in the evening for two weeks  
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for two weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for two weeks at home until their next clinic visit (Week 4 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   

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5.3.3. 
WEEK 4 VISIT   
Patients will return approximately two weeks later to the study site for the Week 4 visit and 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 
visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site. 
The following assessments will be performed prior to administration of riluzole and study drug 
while in the clinic: 
1. PK blood sampling 
2. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK  
3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. Respiratory assessment  
5. Handgrip strength (bilateral)  
6. Muscle strength measurements   
7. ALSFRS-R 
8. Ashworth score 
9. Falls assessment 
10. AE evaluation and concomitant medication assessment (since last visit) 
11. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 4 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug.    
Patients will continue study drug dosing as follows for the next four weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
four weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for four weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will begin dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for four weeks   

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Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for four weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home until their next clinic visit (Week 8 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   
5.3.4. 
WEEK 8 VISIT  
Patients will return approximately four weeks later to the study site for the Week 8 visit and 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 
visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site. 
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. PK blood sampling 
2. Biomarker sample  
3. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK  
4. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
5. 12-lead ECG 
6. Respiratory assessment  
7. Handgrip strength (bilateral)  
8. Muscle strength measurements  
9. ALSFRS-R 
10. Ashworth score  
11. Falls assessment 
12. AE evaluation and concomitant medication assessment (since last visit) 
13. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 8 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 
Patients will continue study drug dosing as follows for the next four weeks. 

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Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
four weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for four weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for four weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for four weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home until their next clinic visit (Week 12 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   
5.3.5. 
WEEK 12 VISIT  
Patients will return approximately four weeks later to the study site for the Week 12 visit and 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 
visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site. 
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
2. Respiratory assessment  
3. Handgrip strength (bilateral)  
4. Muscle strength measurements  
5. ALSFRS-R 
6. ALSAQ-5 
7. Epworth Sleepiness Scale 
8. Ashworth score  

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9. Falls assessment 
10. AE evaluation and concomitant medication assessment (since last visit) 
11. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 12 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 
Patients will continue study drug dosing as follows for the next four weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
four weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for four weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for four weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for four weeks.   
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home until their next clinic visit (Week 16 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   
5.3.6. 
WEEK 16 VISIT  
Patients will return approximately four weeks later to the study site for the Week 16 visit and 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 
visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site.   
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. PK blood sampling 
2. Biomarker sample  

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3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. Respiratory assessment  
5. Handgrip strength (bilateral)  
6. Muscle strength measurements  
7. ALSFRS-R 
8. Falls assessment 
9. AE evaluation and concomitant medication assessment (since last visit) 
10. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 16 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 
Patients will continue study drug dosing as follows for the next four weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
four weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for four weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for four weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for four weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home until their next clinic visit (Week 20 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.   
5.3.7. 
WEEK 20 VISIT  
Patients will return approximately four weeks later to the study site for the Week 20 visit and to 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 

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visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site.   
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
2. Respiratory assessment  
3. Handgrip strength (bilateral)  
4. Muscle strength measurements 
5. ALSFRS-R 
6. Falls assessment 
7. AE evaluation and concomitant medication assessment (since last visit) 
8. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 20 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 
Patients will continue study drug dosing as follows for the next four weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
four weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for four weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for four weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for four weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home until their next clinic visit (Week 24 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 

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morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study visit.  
5.3.8. 
WEEK 24 VISIT  
The end of Week 24 marks the halfway point in the double-blind, placebo-controlled phase.   
Patients will return approximately four weeks later to the study site for the Week 24 visit and to 
continue with dosing.  Patients will be instructed to bring their own riluzole supply to the study 
visit and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site.   
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic:  
1. PK blood sampling 
2. Biomarker sample 
3. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK 
4. Serum pregnancy test for females of child bearing potential 
5. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
6. 12-lead ECG 
7. Respiratory assessment  
8. Handgrip strength (bilateral)  
9. Muscle strength measurements 
10. Routine physical examination 
11. Neurological examination 
12. ALSFRS-R 
13. ALSAQ-5 
14. Epworth Sleepiness Scale 
15. Ashworth score 
16. Falls assessment 
17. Caregiver burden assessment 
18. AE evaluation and concomitant medication assessment (since last visit) 
19. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 24 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug. 

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Patients will continue study drug dosing as follows for the next eight weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
eight weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for eight weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for eight weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for eight weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for eight weeks at home until their next clinic visit (Week 32 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study visit.   
5.3.9. 
WEEK 32 VISIT   
Patients will return approximately eight weeks later to the study site for the Week 32 visit.  
Patients will be instructed to bring their own riluzole supply to the study visit and not to take 
their morning dose of study drug or riluzole (for patients on riluzole) prior to arrival at the study 
site. 
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. PK blood sampling 
2. Biomarker sample  
3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. Respiratory assessment  
5. Handgrip strength (bilateral)  
6. Muscle strength measurements 
7. ALSFRS-R  

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8. Falls assessment 
9. AE evaluation and concomitant medication assessment (since last visit) 
10. Suicidality assessment 
Once all pre-dose procedures have been performed at the Week 32 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug.   
Patients will continue study drug dosing as follows for the next eight weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
eight weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for eight weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for eight weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for eight weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for eight weeks at home until their next clinic visit (Week 40 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.  
5.3.10. 
WEEK 40 VISIT   
Patients will return approximately eight weeks later to the study site for the Week 40 visit.  
Patients will be instructed to bring their own riluzole supply to the study visit and not to take 
their morning dose of study drug or riluzole (for patients on riluzole) prior to arrival at the study 
site. 
The following assessments will be performed prior to administration of morning dose of riluzole 
and study drug while in the clinic: 
1. PK blood sampling 
2. Biomarker sample  

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3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. Respiratory assessment  
5. Handgrip strength (bilateral)  
6. Muscle strength measurements 
7. ALSFRS-R  
8. Falls assessment 
9. AE evaluation and concomitant medication assessment (since last visit) 
10. Suicidality assessment 
Once all pre-dose procedures have been performed at the Week 40 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug.   
Patients will continue study drug dosing as follows for the next eight weeks. 
Patients randomized to receive double-blind tirasemtiv: 
• Patients randomized to the TDD of 250 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the evening for 
eight weeks 
• Patients randomized to the TDD of 375 mg of tirasemtiv will continue dosing with 
1 tablet (125 mg) of tirasemtiv and 1 tablet of matching placebo in the morning and 
2 tablets (250 mg) of tirasemtiv in the evening for eight weeks 
• Patients randomized to the TDD of 500 mg of tirasemtiv will continue dosing with 
2 tablets (250 mg) of tirasemtiv in the morning and 2 tablets (250 mg) of tirasemtiv in 
the evening for eight weeks   
Patients randomized to receive double-blind placebo will continue dosing with 2 placebo 
tablets in the morning and 2 placebo tablets in the evening for eight weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for eight weeks at home until their next clinic visit (Week 48 visit).  Patients taking riluzole 
will also be given a supply of double-blind riluzole or placebo riluzole to take as the evening 
riluzole dose at home.  A diary will be provided for patients to record the date and time of twice 
daily study drug administration and riluzole administration (if on riluzole).  Patients on riluzole 
will be reminded to take 50 mg riluzole from their personal supply at the same time as their 
morning dose of study drug and riluzole from the provided supply of double-blind riluzole 
(active or placebo) at the same time as their evening dose of study drug.  
5.4. 
Double-Blind, Placebo-Controlled, Tirasemtiv Withdrawal Phase 
The double-blind, placebo-controlled, tirasemtiv withdrawal phase will last approximately four 
weeks.  Upon completion of the double-blind, placebo-controlled phase, patients will be 

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randomized to continue active dosing or to withdraw from active treatment and receive placebo 
for the next four weeks.   
Randomization should occur following completion of the double-blind, placebo-controlled phase 
and prior to Week 48 visit procedures.  
5.4.1. 
 WEEK 48 VISIT 
The Week 48 visit marks the beginning of the double-blind, placebo-controlled, tirasemtiv 
withdrawal phase.  Patients will be instructed to bring their own riluzole supply to the study visit 
and not to take their morning dose of study drug or riluzole (for patients on riluzole) prior to 
arrival at the study site.   
The following assessments will be performed prior to administration of the morning dose of 
riluzole and study drug while in the clinic: 
1. PK blood sampling 
2. Biomarker sample  
3. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK  
4. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
5. 12-lead ECG 
6. Respiratory assessment  
7. Handgrip strength (bilateral)  
8. Muscle strength measurements  
9. Routine physical examination 
10. Neurological examination 
11. ALSFRS-R 
12. ALSAQ-5 
13. Epworth Sleepiness Scale 
14. Ashworth score   
15. Falls assessment 
16. Caregiver burden assessment 
17. AE evaluation and concomitant medication assessment (since last visit) 
18. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 48 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug.  

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Patients will continue study drug dosing for the next four weeks based on the second 
randomization as follows (refer to Figure 4): 
• Patients previously on double-blind tirasemtiv and randomized to double-blind 
tirasemtiv will maintain the tirasemtiv dose previously taken during the double-blind, 
placebo-controlled phase for the next four weeks. 
• Patients previously on double-blind tirasemtiv and randomized to double-blind 
placebo will begin dosing with 2 placebo tablets in the morning and 2 placebo tablets 
in the evening for the next four weeks. 
• Patients previously on double-blind placebo will be randomized to continue to 
receive double-blind placebo with 2 placebo tablets in the morning and 2 placebo 
tablets in the evening for the next four weeks. 
Patients will be given an adequate supply of study drug (tirasemtiv or placebo) to take twice 
daily for four weeks at home.  Patients taking riluzole will also be given a supply of double-blind 
riluzole or placebo riluzole to take as the evening riluzole dose at home.  A diary will be 
provided for patients to record the date and time of twice daily study drug administration and 
riluzole administration (if on riluzole).  Patients on riluzole will be reminded to take 50 mg 
riluzole from their personal supply at the same time as their morning dose of study drug and 
riluzole from the provided supply of double-blind riluzole (active or placebo) at the same time as 
their evening dose of study drug.  
Patients will be reminded that even though they will receive a four week supply of study drug at 
this visit, they will need to return for a study visit (Week 49) following one week of treatment in 
the double-blind, placebo-controlled, tirasemtiv withdrawal phase.   
5.4.2. 
WEEK 49 VISIT 
Patients will return approximately one week later to the study site for the Week 49 visit.  Patients 
will be instructed to bring their own riluzole supply to the study visit and not to take their 
morning dose of study drug or riluzole (for patients on riluzole) prior to arrival at the study site.   
The following assessments will be performed prior to administration of the morning dose of 
riluzole and study drug while in the clinic: 
1. PK blood sampling  
2. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
3. Respiratory assessment  
4. Handgrip strength (bilateral)  
5. Muscle strength measurements  
6. ALSFRS-R 
7. Falls assessment 
8. AE evaluation and concomitant medication assessment (since last visit) 

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9. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 49 visit, patients will take their 
morning dose of assigned study drug.  For patients taking riluzole, 50 mg riluzole from their 
personal supply should also be taken with the morning dose of study drug.  
Patients will continue study drug dosing as described in the Week 48 visit for the remaining three 
weeks of the double-blind, placebo-controlled, tirasemtiv withdrawal phase.  Patients should be 
reminded to continue to record the date and time of twice daily study drug administration and 
riluzole administration (if on riluzole) in their patient diary.  Patients on riluzole will be 
reminded to take 50 mg riluzole from their personal supply at the same time as their morning 
dose of study drug and riluzole from the provided supply of double-blind riluzole (active or 
placebo) at the same time as their evening dose of study assignment.   
5.4.3. 
 WEEK 52 VISIT  
Patients will return approximately three weeks later to the study site for the Week 52 visit.  
Patients will be instructed not to take their morning dose of study drug or riluzole (for patients on 
riluzole) prior to arrival at the study site.  
The following assessments will be performed while in the clinic:   
1. PK blood sampling 
2. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK 
3. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
4. 12-lead ECG 
5. Respiratory assessment 
6. Maximum handgrip (bilateral) 
7. Muscle strength measurements 
8. ALSFRS-R   
9. Falls assessment 
10. AE evaluation and concomitant medication assessment (since last visit) 
11. Suicidality assessment 
The Week 52 visit represents the end of dosing.  Patients on riluzole will resume taking their 
prescribed 50 mg riluzole dose from their personal supply starting the evening of the Week 52 
visit, and their prescribed 50 mg riluzole twice daily starting the day after the Week 52 visit. 
5.5. 
FOLLOW-UP VISIT (Week 56)  
Patients will return to the study site approximately four weeks following the last dose of study 
drug taken during the double-blind, placebo-controlled, tirasemtiv withdrawal phase, and the 
following final assessments will be performed:   

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1. Clinical Safety laboratory evaluations including serum chemistry panel, CBC, UA, and 
CPK  
2. Vital signs measurements (including blood pressure, pulse, respiration rate after sitting 
for at least three minutes, and temperature) as well as body weight (if the patient has lost 
≥ 5% of body weight since baseline, the Investigator will be alerted) 
3. 12-lead ECG 
4. Respiratory assessment 
5. Maximum handgrip (bilateral) 
6. Muscle strength measurements 
7. Routine physical examination   
8. Neurological examination 
9. ALSFRS-R 
10. ALSAQ-5 
11. Epworth Sleepiness Scale 
12. Ashworth score 
13. Falls assessment 
14. Caregiver burden assessment 
15. AE evaluation and concomitant medication assessment (since last visit) 
16. Suicidality assessment  
Upon collection of the assessments listed above, patients will have completed their participation 
in the study. 
5.6. 
Visit Windows 
To aid in scheduling patient visits, the following study visit windows are considered acceptable 
(Table 8).  If a patient visit must be scheduled outside the visit window, the Medical Monitor 
should be contacted. 

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Table 8: 
Visit Windows 
Visit 
Visit Window 
Week -4 
Screening up to 14 days prior to Week -2 Visit (as per protocol) 
Week -2  
14 days prior to Day 1 Visit, + 2 days 
Day 1 
First day of randomized, double-blind dosing 
Week 2 
+/- 2 days 
Week 4 
+/- 2 days 
Week 8 
+/- 4 days 
Week 12 
+/- 4 days 
Week 16 
+/- 4 days 
Week 20 
+/- 4 days 
Week 24 
+/- 4 days 
Week 32 
+/- 7 days 
Week 40 
+/- 7 days 
Week 48 
+/- 7 days 
Week 49 
+/- 1 day 
Week 52 
+/- 3 days 
Week 56 
Follow-Up 4 weeks after last dose, +/- 3 days 
5.7. 
Timing of Doses 
Study drug (tirasemtiv or placebo) should be taken in the morning at home (except on study visit 
days where it should be taken in the clinic) and in the evening, approximately 12 hours apart.  
Tirasemtiv should be taken ≥ 2 hours after a meal or 1 hour prior to a meal.  For patients taking 
riluzole, tirasemtiv may be taken at the same time as riluzole. 
5.8. 
Concomitant Medications 
All prescription drugs, over-the-counter medications, nutriceuticals and herbal remedies taken by 
the patient from the time of the screening visit through the follow-up visit should be entered into 
the electronic case report form (eCRF). 
Patients who were intolerant to riluzole or chose not to take riluzole prior to study entry, will be 
encouraged not to take riluzole until they complete study drug dosing.  Patients who were not 
taking riluzole at study entry but who later decide to start riluzole during the dosing phase of the 
study will not be allowed to continue taking study drug.  When patients are taking tirasemtiv during 
the study, their dose of riluzole will be reduced to 50 mg once daily in the morning as described 
below. 
In order to preserve the blind with respect to assignment to tirasemtiv versus placebo, patients 
taking riluzole will take 50 mg riluzole from their personal supply in the morning and during the 
placebo-controlled phases of the study (double-blind, placebo-controlled phase and the double-
blind, placebo-controlled tirasemtiv withdrawal phase), a blinded (active or placebo) riluzole 

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tablet (supplied by the study site) in the evening.  Patients will resume taking their prescribed 
50 mg riluzole twice daily from their personal supply starting at Week 52. 
Thus, patients taking riluzole prior to study entry will have their riluzole adjusted, as follows: 
• During the open-label phase, patients will take 50 mg riluzole from their personal 
supply in the morning and will not take an evening riluzole dose.  
• During the double-blind, placebo-controlled phase (Day 1 – Week 48), patients will 
take their morning dose of riluzole (50 mg once daily) and will take a blinded (active 
or placebo) riluzole tablet (supplied by the study site) in the evening. 
• During the double-blind, placebo-controlled, tirasemtiv withdrawal phase (Week 48 – 
Week 52), patients will take their morning dose of riluzole (50 mg once daily) and 
will take a blinded (active or placebo) riluzole tablet (supplied by the study site) in 
the evening. 
• Patients will resume taking their prescribed 50 mg riluzole twice daily from their 
personal supply starting at Week 52. 
Tirasemtiv inhibits multiple CYP450 isoforms (1A2, 2B6, 2C8, 2C9, and 2C19).  Consequently, 
exposure to drugs primarily metabolized by these isoforms may be increased when these drugs 
are given in conjunction with tirasemtiv.  Therefore, close attention should be paid to potential 
AEs related to their administration.  For example, blood pressure should be closely monitored for 
hypertensive patients taking angiotensin II receptor blockers metabolized by CYP 2C9, such as 
losartan and irbesartan.  Diabetic patients taking oral anti-diabetic agents metabolized by 
CYP 2C8 or 2C9, including glyburide, glibencilamide, glipizide, glimepride and tolbutamide, 
should be cautioned to be aware of signs and symptoms of hypoglycemia, and serum glucose 
should be monitored as clinically appropriate.  Finally, caution should be exercised in the 
initiation of warfarin (also metabolized by CYP 2C9) if required during the study for the 
treatment of thromboses or thromboembolic events, with careful monitoring of prothrombin 
times and/or international normalized ratio (INR).  A list of currently approved drugs 
metabolized by CYP 2B6, 2C8, 2C9, and 2C19 may be found in Appendix B. 
Patients must refrain from taking theophylline or tizanidine, which are primarily metabolized by 
CYP 1A2 (see Section 1.3), during their participation in the study.  Additionally, patients should 
be advised to avoid or use caution when taking medications or ingesting other substances that are 
metabolized by CYP 1A2, such as fluvoxamine, because their metabolism is inhibited by 
tirasemtiv, so co-administration with tirasemtiv will increase exposure to these compounds. 
Other medications that inhibit or induce the activity of CYP 1A2 may increase or decrease, 
respectively, exposure to riluzole which is metabolized by CYP 1A2.  Consequently, these drugs 
should be avoided by patients taking riluzole.  A list of currently approved drugs that interact 
with CYP 1A2 is found in Appendix C. 
5.9. 
PK Sample Collection  
Blood samples for PK analysis of tirasemtiv, and its acid metabolite, CK-2018595, and riluzole 
(if the patient is taking riluzole) will be collected at the time points listed in Table 9.   The 
morning study drug and riluzole dose should be taken at the site on these days.  Patients will be 

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instructed NOT to take their morning dose of study drug or their dose of riluzole until after the 
pre-dose PK blood draw.   
Table 9: 
Pharmacokinetic (PK) Samples 
Visit 
Sample Time Points 
Week -2  
Pre-AM dose 
Day 1 
Pre-AM dose 
Week 4 
Pre-AM dose 
Week 8 
Pre-AM dose 
Week 16 
Pre-AM dose 
Week 24 
Pre-AM dose 
Week 32 
Pre-AM dose 
Week 40 
Pre-AM dose 
Week 48 
Pre-AM dose 
Week 49 
Pre-AM dose 
Week 52 
Pre-AM dose 
PK plasma samples remaining after completion of bioanalysis may also be used for exploratory 
analysis of tirasemtiv metabolites.  These samples will NOT be used for pharmacogenomic or 
other testing. 
5.10. 
Biomarker Sample Collection  
Biomarkers are objective measures or indicators of normal biological processes, pathological 
processes or pharmacological responses to a therapeutic intervention.  Biomarker development 
may be useful in developing markers to identify disease subtypes, to guide therapy, or predict 
disease severity.  Where authorized by the applicable IRB/EC/REB approved informed consent, 
blood samples for biomarker development will be collected at the time points shown in Table 10.   
 Table 10: 
Biomarker Samples 
Visit 
Sample Time Points 
Day 1 
Pre-AM dose 
Week 8 
Pre-AM dose 
Week 16 
Pre-AM dose 
Week 24 
Pre-AM dose 
Week 32 
Pre-AM dose 
Week 40 
Pre-AM dose 
Week 48 
Pre-AM dose 
Plasma samples will be stored for future biomarker analyses and will NOT be used for 
pharmacogenomic testing. 

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5.11. 
Clinical Safety Assessments 
5.11.1. 
Physical Examination 
A routine physical exam will be performed at Screening, Week 24, Week 48, and the Follow-Up 
Visit.   
5.11.2. 
Neurological Examination 
The neurological exam will be administered as described in the study manual and will include an 
assessment of cranial nerve function (including extra-ocular movements), motor strength, and 
sensory function. 
A neurological exam will be performed at Screening, Week 24, Week 48, and the Follow-Up 
Visit.  
5.11.3. 
Ashworth Score 
The Ashworth Score will be assessed as described in the study manual at Screening, Week 4, 
Week 8, Week 12, Week 24, Week 48 and the Follow-Up Visit. 
5.11.4. 
Clinical Laboratory Evaluations 
Clinical safety laboratory evaluations (serum chemistry panel, CBC, UA, and CPK) will be 
collected at Screening, Week -2, Week 4, Week 8, Week 24, Week 48, Week 52, and the Follow-
Up Visit.  A TSH will be collected only at the Screening visit and a serum pregnancy test for 
females of child bearing potential will be collected at Screening and the Week 24 visit.   
5.11.5. 
12-Lead ECGs 
A 12-lead ECG will be obtained at Screening, Week 8, Week 24, Week 48, Week 52, and the 
Follow-Up Visit. 
5.11.6. 
Vital Signs 
Vital signs measurements (including blood pressure, pulse, respiration rate after sitting for at 
least three minutes, and temperature) as well as body weight will be recorded at all study visits. 
5.11.7. 
Falls Assessment 
A fall is defined as a sudden, unintentional change in position causing an individual to land at a 
lower level on an object, the floor, the ground, or other surface.  For the purposes of this study, 
the definition of a fall does not include stumbles or trips from which the patient rights 
him/herself without landing lower than his/her previous position (Tinetti, Baker et al. 2004).  A 
falls assessment will be performed at each clinic visit, starting at Week -2 through the final 
Follow-Up Visit.   
5.11.8. 
Suicidality Assessment 
The suicidality assessment will be assessed as described in the study manual at all study visits. 

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5.12. 
Clinical and Pharmacodynamic Outcome Measures 
5.12.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R)  
The ALSFRS-R will be administered as described in the study manual at all study visits except 
Week 2.  When a patient does not present in person for a scheduled visit, every attempt should be 
made to obtain the ALSFRS-R score by telephone as described in the study manual. 
5.12.2. 
Respiratory Assessments 
The respiratory assessments in this study include SVC and SNIP.  They will be performed as 
described in the study manual at every study visit except Week 2.  
5.12.3. 
Handgrip Strength  
Maximum handgrip strength will be measured bilaterally as described in the study manual at 
every study visit except Screening, Day 1, and Week 2.   
5.12.4. 
Muscle Strength Measurements 
Muscle strength measurements (elbow flexion, wrist extension, knee extension, and ankle 
dorsiflexion) will be performed using the Hand Held Dynamometer (HHD), as described in the 
study manual at every study visit except Screening, Day 1, and Week 2.   
5.12.5. 
Quality of Life  
The ALS Assessment Questionnaire Short Form (ALSAQ-5) will be used to assess the patient’s 
overall sense of well-being as described in the study manual at Week -2, Week 12, Week 24, 
Week 48, and the Follow-Up Visit. 
5.12.6. 
Epworth Sleepiness Scale 
The Epworth Sleepiness Scale will be assessed as described in the study manual at Week -2, 
Week 12, Week 24, Week 48 and the Follow-Up Visit. 
5.12.7. 
Caregiver Burden Assessment 
Caregiver burden will be assessed as described in the study manual at Week -2, Week 24, 
Week 48, and the Follow-Up Visit. 
5.13. 
Patient Discontinuation from Study Participation 
Patients will be informed that they are free to withdraw from the study at any time and for any 
reason.  The Investigator may remove a patient from the study at any time if, in the Investigator's 
opinion, it is not in the best interest of either the patient or the study for the patient to continue in 
the study.  For those patients who will not return to the study center for further study scheduled 
assessments as described below, the Follow-Up Visit (Week 56) study assessments should be 
performed and recorded.  Notification of discontinuation will immediately be made to the 
Sponsor’s Medical Monitor. 
In all cases, patients who were randomized and discontinue study drug should be strongly 
encouraged to perform all remaining study visits and assessments for the duration of the study 

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and most importantly the assessments at 24 weeks rather than withdraw from the study.  Unless 
patients withdraw their consent for further contact, those patients who are unable to attend 
scheduled study visits, should be contacted on a monthly basis to obtain vital status and 
respiratory status (i.e., use of non-invasive ventilation or permanent mechanical ventilation) 
through 48 weeks.   
The date the patient is withdrawn from study drug treatment or study participation and the 
reason(s) for discontinuation will be recorded on the patient’s eCRF.  See Section 7.5.1 
regarding follow-up of AEs (both non-serious and serious) continuing at the time of study 
discontinuation.   
5.14. 
Study Discontinuation 
An Investigator may discontinue the participation of his/her study site, or the entire study may be 
discontinued at the discretion of the Sponsor, based on the occurrence of the following: 
• AEs  
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of patients 
• cancellation of drug development 
5.15. 
Safety Monitoring and Stopping Rules 
Individual AEs meeting any of the following criteria will be reviewed by the head of Drug Safety 
and the Sponsor’s Medical Monitor in a blinded manner on a periodic basis: 
1. SAEs thought by the Sponsor or the Investigator to be related to study drug 
administration  
2. Withdrawals due to AEs (both serious and non-serious) 
3. Grade 3 or 4 (according to Common Terminology Criteria for Adverse Events [CTCAE 
version 4.0], see Section 7.2) non-serious AEs thought by the Sponsor to be related to 
study drug administration 
4. Any death thought by the sponsor or the investigator to be related to study drug will 
result in stopping all randomization in order to perform a review.   
This review may result in:  
• Discontinuation of the study 
• Discontinuation of enrollment at the affected and higher dose levels 
• Modification to study conduct, or 
• No change to the conduct of the study (if AEs are determined to have been unrelated 
to study drug administration) 

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5.16. 
Data Monitoring Committee 
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 (EDC) vendors 
before the database is locked.  
The specific activities and responsibilities of the DMC are defined in the DMC Charter for 
CY 4031. Based on the totality of available data, the DMC will make an overall recommendation 
to the Sponsor whether to continue the study according to the protocol or whether to make any 
changes in study conduct to protect the safety and welfare of the patients participating in the 
study.  

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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, and remaining study site clinical staff will be blinded to treatment 
assignment. 
CK-2017357 (tirasemtiv) study drug is supplied as immediate release, white, modified oval 
tablets at a dose strength of 125 mg of tirasemtiv per tablet, which are to be stored under secure 
conditions at controlled room temperature (20-25°C; 68-77°F) with temporary excursions 
allowed between 15-30°C; 59-86°F.  Matching placebo tablets will be supplied and should also 
be stored at controlled room temperature under secure conditions.  Active CK-2017357 tablets 
contain 125 mg of tirasemtiv plus excipients.  Placebo tablets contain excipients only.   
Table 11: 
Study Drug 
Study Drug 
CK-2017357 
Placebo for CK-2017357  
Form 
Tablet 
Tablet 
Supplier 
Cytokinetics, Inc. 
Cytokinetics, Inc. 
Manufacturer 
Patheon, Inc. 
Patheon, Inc. 
CK-2017357 (tirasemtiv) and matching placebo tablets will be supplied to the clinical site in 
blister strips inside labeled wallets.  During the open-label phase of the study, patients will 
receive a bottle containing 40 tablets of tirasemtiv, sufficient for two weeks of dosing plus 
overage.  Open-label bottles will be labeled with a lot number.  During the double-blind 
randomized phases of the study, patients will receive one or more wallets containing 72 tablets of 
study drug (tirasemtiv or matching placebo) at each visit.  Each wallet is sufficient for two weeks 
of dosing, plus overage.  Double-blind wallets will be labeled with a unique random kit number.   
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.  The study research coordinator or designated site staff will be responsible for 
patient randomizations, using an IWRS.  In addition, an accurate drug disposition record will be 
kept, specifying the kit number 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. 
All unused drug supplies will be returned to the Sponsor (or designee) or disposed of by the 
study site, per the Sponsor’s (or designee’s) instructions at the end of the study. 
6.1.1. 
Description of Riluzole or Placebo for Riluzole  
This is a double-blind, placebo-controlled study.  As such, the site pharmacy staff, the 
Investigator, the patient, and remaining study site clinical staff will be blinded to riluzole or 
placebo treatment. 

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Riluzole and matching placebo will be supplied as white, capsule shaped tablets.  One riluzole 
tablet will contain 50 mg riluzole plus excipients.  Placebo tablets for riluzole will contain 
excipients only.  Riluzole and matching placebo tablets are to be stored under secure conditions 
at controlled room temperature (20-25°C; 68-77°F) with temporary excursions allowed between 
(15-30°C; 59-86°F).   
Table 12: 
Riluzole and Placebo for Riluzole 
Study Drug 
Riluzole 
Placebo for Riluzole   
Form 
Tablet 
Tablet 
Supplier 
Cytokinetics, Inc. 
Cytokinetics, Inc. 
Manufacturer 
Almac Clinical Services, LLC 
Almac Clinical Services, LLC 
Riluzole and placebo for riluzole will be supplied to the clinical site in blister strips inside 
labeled wallets.  Patients will receive one or more wallets, containing 18 riluzole or placebo for 
riluzole tablets at each visit.  Each wallet is sufficient for two weeks of dosing, plus overage.  
Double-blind wallets will be labeled with a unique random kit number.  
6.2. 
Dose Administration (Tirasemtiv or Placebo) 
This study drug will be administered orally as tablets to patients with ALS.  Doses (tirasemtiv 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. 
Dose Adjustment Criteria 
Patients who do not tolerate a dose escalation due to symptoms believed to be due to treatment 
with study drug may be returned to a previously tolerated dose level at the discretion of the 
Investigator.  No upward dose adjustments will be allowed subsequent to a dose reduction. 
6.4. 
Treatment 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. Specific instructions regarding treatment interruption are provided in the study manual. 
6.5. 
Randomization Schedule and Removal of Blind 
There are two separate randomizations in this study; one prior to the start of the double-blind, 
placebo-controlled phase, and one prior to the start of the double-blind, placebo-controlled, 
tirasemtiv withdrawal phase for all patients.  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 INVESTIGATOR ONLY IN THE 
EVENT OF A MEDICAL EMERGENCY OR AN AE THAT NECESSITATES 
IDENTIFICATION OF THE STUDY DRUG (tirasemtiv or placebo) FOR THE WELFARE OF 

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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. 
6.6. 
Daily Dosing Diary 
A dosing diary will be maintained by the patient to record date and time of twice daily study 
drug administration plus twice daily riluzole (if taking riluzole).  The dosing diary should be 
returned at each clinic visit. 
6.7. 
Study Drug Handling 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.  The study research coordinator or designated study staff will be responsible for 
patient randomization, using an IWRS.  In addition, an accurate drug disposition record will be 
kept, specifying the kit number 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. 
All unused drug supplies will be returned to the Sponsor (or designee) or disposed of by the 
study site, per the Sponsor’s (or designee’s) instructions at the end of the study. 
6.8. 
Study Drug Accountability 
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.     

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7. 
ADVERSE EVENTS AND SAFETY ASSESSMENTS 
NOTE: the term “adverse event (AE)” includes both non-serious and serious AEs unless 
otherwise specified. 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication and measurements of 
protocol-specific physical examination findings and laboratory tests. 
7.1. 
Definitions  
7.1.1. 
Adverse Event 
As defined by the International Council on Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   
Consider the following information when determining whether or not to record a test result, 
medical condition or other incident on the AE eCRF: 
• From the time of informed consent to first administration of study drug (Week -2 
visit), only study protocol-related AEs should be recorded 
• New symptoms or diagnoses reported/found between the time of signing of informed 
consent and the first administration of study drug will be recorded as medical history 
on the medical history eCRF 
• Conditions newly detected or diagnosed after administration of study drug, including 
conditions that may have been present but undetected prior to the start of the study 
should be recorded 
• All AEs (regardless of relationship to study drug) should be recorded from first 
administration of study drug (Week -2 visit) through the end of the safety reporting 
period (see Section 7.5, Reporting Period for AEs and SAEs)    
• In general, an abnormal laboratory value should not be recorded as an AE unless it is 
assessed by the Investigator as clinically significant (e.g., associated with clinical 
signs or symptoms, requires intervention, results in a SAE, or results in study 
termination or interruption/discontinuation of study treatment).  When recording an 
AE resulting from a laboratory abnormality, the resulting medical condition rather 
than the abnormality itself should be recorded (e.g., record “thrombocytopenia” rather 
than “low platelets”) 
• Conditions known to have been present prior to the start of the study that increase in 
severity or frequency after administration of study drug should be recorded 
• Signs, symptoms, or the clinical sequelae of a suspected drug interaction should be 
recorded 

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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication (overdose per se should not be 
reported as an AE) 
• New and/or exacerbated symptoms of ALS should be recorded 
Issues Not Considered AEs 
• Medical or surgical procedures (e.g., endoscopy, appendectomy); rather, record the 
medical condition that led to a procedure (e.g., appendicitis) 
• Situations where an untoward medical occurrence did not occur (e.g., social, 
diagnostic, or convenience admissions to a hospital) 
• 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 
study drug 
• Abnormal laboratory or test findings that are not assessed by the Investigator as a 
clinically significant change after the first dose of study drug 
7.1.2. 
Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 
Death 
AE resulted in death 
Life threatening The AE placed the patient at immediate risk of death. It does not refer to an 
event that hypothetically might have caused death if it were more severe, 
prolonged, or untreated. 
Hospitalization 
The AE required or prolonged an existing inpatient hospitalization.  
Hospitalizations for elective medical or surgical procedures or treatments 
planned before the signing of informed consent in the study or routine 
check-ups are not SAEs by this criterion.  Admission to palliative unit or 
hospice care facility is not considered to be a hospitalization. When in doubt 
as to whether ‘hospitalization’ occurred, consult the Medical Monitor. 
Disability/ 
Incapacity 
Resulted in a persistent or significant incapacity or substantial disruption of 
the patient’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 
disruption. 
Congenital 
Anomaly/Birth 
Defect 
An adverse outcome in a child or fetus of a patient exposed to the molecule 
or study treatment regimen before conception or during pregnancy. 

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Important 
Medical Event 
The AE did not meet any of the above criteria, but could have jeopardized 
the patient and might have required medical or surgical intervention to 
prevent one of the outcomes listed above.  Examples of such events are 
invasive cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization.  The development of drug dependency or drug abuse would 
also be examples of important medical events.  If in doubt as to whether or 
not an event qualifies as a “medically significant event”, consult the 
Sponsor’s Medical Monitor. 
7.2. 
Adverse Event Severity 
The severity of AEs will be assessed using the National Cancer Institute (NCI) CTCAE, 
version 4.0 as defined below: 
• Grade 1 (Mild) – Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• Grade 2 (Moderate) – Moderate; minimal, local or non-invasive intervention 
indicated; limiting age-appropriate activities of daily living 
• Grade 3 (Severe) – Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living  
• Grade 4 (Life-Threatening) – Life-threatening consequences; urgent intervention 
indicated  
• Grade 5 (Fatal) – Death due to AE 
Notes:  
• AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the 
Sponsor for defining regulatory reporting obligations (see definition for Serious AE) 
• Note that “life-threatening” in the criteria for “serious” has a more immediate 
definition than the CTCAE definition of “life-threatening”.  Thus, an AE may be 
CTCAE Grade 4 in severity and still not meet the SAE definition of “life-
threatening”. 

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7.3. 
Assessment of Causality to Study Treatment 
The relationship of each AE to each study treatment [tirasemtiv] and [riluzole] should be 
evaluated by the Investigator using the following criteria: 
Related 
There is evidence to suggest a causal relationship between the drug and the AE, 
such as an event that is uncommon and known to be strongly associated with 
drug exposure (e.g. angioedema, hepatic injury, Stevens-Johnson Syndrome) an 
event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the population exposed to the drug (e.g. tendon rupture) 
Unrelated 
Another cause of the AE is more plausible (e.g., due to underlying disease or 
occurs commonly in the study population), or a temporal sequence cannot be 
established with the onset of the AE and administration of the study treatment, or 
a causal relationship is considered biologically implausible 
The assessment of causality will be based on the information available, and may be changed 
upon receipt of additional information. 
7.4. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study site personnel will report all AEs and SAEs whether elicited during 
patient questioning, discovered during physical examination, laboratory testing and/or other 
methods by recording them on the eCRF and/or SAE Form, as appropriate. 
7.4.1. 
Eliciting Adverse Events 
Use of an open-ended or non-directed method of questioning should be used at each study visit 
to elicit the reporting of AEs. 
7.4.2. 
Recording of Adverse Events 
When an AE occurs, the Investigator will review all documentation (e.g., hospital progress notes, 
laboratory and diagnostic reports) relevant to the event.   
The following information should be recorded on the AE eCRF: 
• Description including onset and resolution dates 
• Whether serious criteria was met 
• Severity 
• Relationship to study treatment 
• Outcome 
7.4.3. 
Adverse Event Term 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
signs/symptoms.  Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 

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standard medical textbooks.  If any aspect of the sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
7.4.4. 
Recording Serious Adverse Events 
Record SAE terms on both the AE eCRF and an SAE Report Form.  The following should be 
considered when recording SAEs: 
• Death is an outcome.  Record the event that resulted in death on both the SAE Form 
and AE eCRF 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself.  Capture the procedure in the narrative description as part of the action taken in 
response to the illness 
7.4.5. 
Pregnancy  
Complete a Pregnancy Report Form and fax or email the completed form to the Sponsor’s (or 
designee) Drug Safety Department within 24 hours of becoming aware of a pregnancy.  
Pregnancy, per se, will not be considered an AE in this study.  However, a urine or serum 
pregnancy test should be performed if any female patient or partner of a male patient suspects 
that she has become pregnant during the time of signing of informed consent to within 10 weeks 
after the end of the study.  If the test is positive, the pregnancy should be immediately reported to 
the Investigator and Sponsor.  Any patient who becomes pregnant during the study is not eligible 
to continue in the study and should complete any end of study procedures at that time. 
Complete pregnancy information, including the outcome of the pregnancy, should be collected in 
the source documents on the female patient or partner of a male patient (if she is willing).  In the 
absence of complications, follow-up after delivery will be no longer than eight weeks.  Abortion, 
whether accidental, therapeutic, or spontaneous, should be reported as an SAE.  Congenital 
anomalies or birth defects should also be reported as defined by the ‘serious’ criterion (see 
definitions Section 7.1.2). 
Any SAE occurring as a result of a post-study pregnancy and considered reasonably related to 
the investigational product by the Investigator should be reported to the Sponsor. 
7.5. 
Reporting Period for Adverse Events 
The safety reporting period for all AEs is from the first administration of study drug (Week -2 
visit) through 28 days after the patient’s last dose of study drug (Follow-Up Visit).  However, all 
study protocol-related AEs are to be collected from the time of informed consent.  All SAEs that 
occur after the safety reporting period and are considered study drug-related in the opinion of the 
Investigator should also be reported to the Sponsor.  
All SAEs should be followed until significant changes return to baseline, until the condition 
stabilizes, or is no longer considered clinically significant by the Investigator, or until the patient 
dies, withdraws consent, or study closure.  All non-serious AEs will be followed through the 
safety reporting period.  Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure. 

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7.5.1. 
Follow-Up of Adverse Events 
After the initial recording of an AE, the Investigator should proactively follow the patient.  Any 
non-serious AEs that are still on-going at the end of the study should be reviewed to determine if 
further follow-up is required.  The Investigator will document on the AE eCRF any/all on-going 
non-serious AEs that will not be followed further (and the reason why) after the patient exits the 
study.  If in doubt, the Investigator should consult the Sponsor’s Medical Monitor.   
The Sponsor may request that the Investigator 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.   
7.6. 
Serious Adverse Events Require Immediate Reporting 
Within 24 hours of the study site’s knowledge of an SAE, Investigators are to report the event to 
the Sponsor, regardless of relationship of the event to the study drug. 
For initial SAE reports, available details of the event are to be recorded on an SAE Report Form.  
At a minimum, the following should be included: 
• Patient number 
• Date of event onset 
• Seriousness criterion or criteria 
• Description of the event 
• Study treatment 
• Causality assessment 
If not all information regarding an SAE is initially available, the site should not wait to receive 
additional information before reporting the event to the Sponsor within 24 hours.   

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8. 
STATISTICAL METHODS 
8.1. 
General Considerations 
8.1.1. 
General Approach 
Summary statistics for continuous variables will include numbers of patients, means, medians, 
standard deviations, standard errors, minima, and maxima.  For categorical variables, frequencies 
and percentages will be given.  For time to event variables, the number of patients at risk, 
number of events, the median and 95% confidence intervals (CI) of the median, and quartiles 
will be provided by Kaplan Meier method.  Assumptions for statistical models will be evaluated.  
If assumptions are substantially violated, alternative analysis methods will be considered.  
Missing data will not be imputed unless specified.  Baseline is defined as the last available 
measurement taken before the first dose of study medication received in the open-label phase 
unless otherwise specified.  Analyses will be conducted by study phase including open-label 
phase, first 24-week double blind placebo-controlled phase, 48-week double blind placebo-
controlled phase, randomized withdrawal phase, and follow-up period. 
8.1.2. 
Sample Size and Randomization 
Approximately 600 patients will be enrolled in the study.  Following the open-label phase, 
approximately 477 patients will be randomized to placebo and three different target dose levels 
of tirasemtiv in an allocation ratio of 3:2:2:2 for the double-blind, placebo-controlled treatment 
phase.  The dropout rates at 24 weeks are estimated to be 16% for placebo and 25% for all 
tirasemtiv target dose groups combined. With a two-tailed alpha error of 0.05, approximately 
360 patients are expected to complete 24 weeks of double-blind treatment, which is estimated to 
provide 90% power to detect a treatment difference from placebo in percent predicted SVC 
change from baseline to the end of the first 24 week double-blind, placebo-controlled phase of 
6 percentage points for all tirasemtiv target dose groups pooled with a common standard 
deviation (SD) of 17 percentage points. 
After patients complete the 48 weeks of the double-blind, placebo-controlled treatment, patients 
will be randomized to placebo or to continue their current active dose level of treatment in an 
allocation ratio of 1:1. Patients who are on placebo will be re-randomized only to placebo at the 
end of Week 48.  Both randomizations will be stratified by riluzole use/non-use. 
The common SD about the primary endpoint (the change from baseline to 24 weeks of the 
double-blind, placebo-controlled phase) will be monitored in a blinded manner.  When one-half 
of the planned completed study patients have been followed for 24 weeks, the common SD of the 
primary endpoint will be calculated on aggregate data with no separation of results by treatment 
group. If this common SD during the study appears to be larger than 17 percentage points, the 
sample size will be re-estimated with the updated common SD to maintain the intended study 
statistical power for the primary analysis using Table 13 .  At this time, the Sponsor may 
consider increasing the sample size. For example, if the common SD is larger than 17 and equal 
to or less than 18, then consideration will be given to increasing the sample size from 360 
evaluable patients at Week 24 (approximately 477 randomized patients) to 421 evaluable patients 
at Week 24 (approximately 540 randomized patients). 

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Table 13: 
Sample Size Re-estimation Depending on Common SD at Week 24 
Common SD at Week 24 
>17-18 
>18-19 
>19-20 
Total Number of Randomized Patients  
540 
594 
666 
Total Number of Evaluable Patients at Week 24 
421 
463 
519 
8.1.3. 
Data Monitoring Committee 
An independent DMC (see Section 5.16) will periodically assess patient safety in an unblinded 
manner during the course of the study. The independent DMC will be provided unblinded data 
by an independent unblinded statistician from an independent biostatistical group.  The DMC 
activities are described in the DMC charter.  
8.2. 
Analysis Sets 
8.2.1. 
Full Analysis Set (FAS) 
The FAS will consist of all randomized patients who received at least one dose of study 
medication during randomized double-blind, placebo-controlled treatment, and had at least one 
post-randomization efficacy assessment.  The FAS will be analyzed as randomized. 
8.2.2. 
Per Protocol Set (PPS) 
The PPS will consist of all FAS patients who complete a minimum of 20 weeks of double-blind, 
placebo-controlled treatment, have at least one post-baseline efficacy assessment during 
treatment with double-blind study drug, and have no major protocol violations. 
8.2.3. 
Safety Analysis Set (SAS) 
The SAS will consist of all patients who receive any study medication, including patients in the 
open-label phase. 
8.2.4. 
Pharmacokinetic Evaluable Data Set (PKEDS) 
The PKEDS will consist of all randomized patients with at least one evaluable PK concentration, 
provided they have no major protocol violations that could affect the PK of tirasemtiv or riluzole. 
8.3. 
Efficacy Endpoints 
8.3.1. 
Primary Endpoint 
The primary endpoint is the change from baseline to Week 24 of the double-blind, placebo-
controlled phase in percent predicted SVC.  The primary analysis will be conducted using all 
observed data during the randomized, double-blind, placebo-controlled phase without any 
missing data imputations and will be based on the FAS.  To minimize the potential for missing 
data, patients who wish to discontinue study drug will be encouraged to continue study 
assessments and at minimum present for the 24 week assessments. 

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8.3.2. 
Secondary Endpoints 
The following secondary endpoints will be analyzed in a closed testing procedure if the primary 
efficacy analysis is met as defined in Section 8.4.3. 
• Change from baseline in the ALSFRS-R score of the three respiratory items of the 
ALSFRS-R (i.e., the sum of items 10, 11 and 12) at the end of 48 weeks of double-blind, 
placebo-controlled treatment 
• Slope of mega-score of muscle strength during the 48 weeks of double-blind, placebo-
controlled treatment  
• Time to the first occurrence of a decline from baseline in percent predicted SVC ≥20 
percentage points or the onset of respiratory insufficiency or death at the end of the 48 
weeks of double-blind, placebo-controlled treatment 
• Time to the first occurrence of a decline in SVC to ≤50% predicted or the onset of 
respiratory insufficiency or death at the end of the 48 weeks of double-blind, placebo-
controlled treatment 
• Change from baseline in the ALSFRS-R total score to the end of 48 weeks of the double-
blind, placebo-controlled treatment  
• Time to the first use of mechanical ventilatory assistance or death during all 48 weeks of 
double-blind, placebo-controlled treatment 
8.3.3. 
Tertiary Endpoints 
Tertiary endpoints are presented grouped by their similarities to one another.  The prospectively 
defined tertiary endpoints listed below will be the subject of descriptive, exploratory analyses as 
defined in the Statistical Analysis Plan.  Additional tertiary endpoints of interest may be added to 
the Statistical Analysis Plan. 
1. “Time to Event” analyses including: 
a. Time to the first occurrence of a decline in SVC to ≤ 50% predicted or the onset of 
respiratory insufficiency (defined as tracheostomy or the use of non-invasive 
ventilation for ≥ 22 hours per day for ≥ 10 consecutive days) or death during the first 
24 weeks of double-blind, placebo-controlled treatment 
b. Time to the first occurrence of a decline from baseline in percent predicted SVC 
≥ 10 percentage points or the onset of respiratory insufficiency or death during the 
first 24 weeks of double-blind, placebo-controlled treatment 
c. Time to the first occurrence of a decline from baseline in percent predicted SVC 
≥ 20 percentage points or the onset of respiratory insufficiency or death during the 
first 24 weeks of double-blind, placebo-controlled treatment 
d. Time to the first occurrence of a decline in the respiratory components of the 
ALSFRS-R (i.e., items 10, 11, and 12) or death during the first 24 weeks of double-
blind, placebo-controlled treatment 
e. Time to the first occurrence of a decline in either of the ALSFRS-R items 11 or 12 or 
death during the first 24 weeks and during all 48 weeks of double-blind, placebo-
controlled treatment 

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f. Time to the first occurrence of a decline in either of the ALSFRS-R item 12 or death 
during the first 24 weeks and during all 48 weeks of double-blind, placebo-controlled 
treatment 
g. Time to the first occurrence of the first use of mechanical ventilatory assistance or 
death during the first 24 weeks of double-blind, placebo-controlled treatment 
In addition, each of the first three composite endpoints listed above will be analyzed with “first 
use of mechanical ventilatory assistance” in place of “respiratory insufficiency”.  
2. “Responder analyses” including: 
a. Proportion of patients with no decline from baseline in percent predicted SVC, free 
from respiratory insufficiency and alive during the first 24 weeks and during all 
48 weeks of double-blind, placebo-controlled treatment 
b. Proportion of patients with a decline from baseline ≤ 6 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 
c. Proportion of patients with a decline from baseline ≤ 10 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 
d. Proportion of patients with a decline from baseline ≤ 20 percentage points in percent 
predicted SVC, free from respiratory insufficiency and alive during the first 24 weeks 
and during all 48 weeks of double-blind, placebo-controlled treatment 
3. Change from baseline to 24 weeks of double-blind, placebo-controlled treatment in the 
following measures: 
a. ALSFRS-R total score 
b. ALSFRS-R score of the three respiratory subdomains of the ALSFRS-R 
(i.e., items 10, 11, and 12) 
c. Muscle strength as determined by the mega-score of: 
• Elbow flexion (bilateral) 
• Wrist extension (bilateral) 
• Knee extension (bilateral) 
• Ankle dorsiflexion (bilateral) 
• Handgrip strength (bilateral) 
d. SNIP 
4. Slopes of the changes from baseline in percent predicted SVC, ALSFRS-R, mega-score 
of muscle strength, and SNIP: 
a. From baseline to 24 weeks of the randomized, double-blind, placebo-controlled phase  
b. From baseline to 48 weeks of the randomized, double-blind, placebo-controlled phase 
(excluding mega-score of muscle strength) 
c. From the end of 24 weeks of the randomized, double-blind, placebo-controlled phase 
to the end of the double-blind, randomized, placebo-controlled phase at 48 weeks 

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5. Change in percent predicted SVC, muscle strength mega-score, and SNIP from baseline 
to the end of Week 48 of the double-blind, placebo-controlled phase. 
6. Change in percent predicted SVC from baseline to the end of Week 12 of the double-
blind, placebo-controlled phase. 
8.3.4. 
Additional Endpoints 
1. ALSAQ-5 change from baseline to the end of Week 24 
2. Epworth Sleepiness Scale change from baseline to the end of Week 24   
3. Caregiver burden change from baseline to the end of Week 24 
4. ALSAQ-5 change from baseline to the end of Week 48 
5. Epworth Sleepiness Scale change from baseline to the end of Week 48  
6. Caregiver burden change from baseline to the end of Week 48 
8.4. 
Statistical Analyses 
8.4.1. 
Patient Disposition 
The number of patients who are enrolled and receive open-label treatment but are not 
randomized will be presented.  The number of patients who are randomized, who receive any 
double-blind study medication, who complete the study, and who prematurely discontinue from 
the study will be presented by treatment group and target dose level overall and for each phase 
separately.  Reasons for premature discontinuation as recorded on the termination page of the 
eCRF will be summarized by treatment group and target dose level overall and for each phase 
separately. 
8.4.2. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized by treatment group 
and target dose level overall and by phase separately.  To assess the comparability of treatment 
groups, demographic and baseline characteristics will be compared between the pooled active 
treatment dose levels and placebo for the FAS using Cochran-Mantel-Haenszel tests for binary 
categorical variables, van Elteren tests for ordinal categorical measures, or analysis of variance 
(ANOVA) for continuous variables, stratified by riluzole use/non-use and pooled site. 
A demographic or baseline disease characteristic found to have a statistically significant (2-sided 
p-value ≤ 0.050) imbalance between the two treatment groups will be adjusted in supportive 
analyses of the primary efficacy endpoint.  
8.4.3. 
Primary Efficacy Analysis 
The primary analysis is to test the global null hypothesis that there is no treatment difference in 
the change from baseline in percent predicted SVC at Week 24 between patients in the FAS 
randomized to placebo and those randomized to tirasemtiv (pooled three target dose levels) 
during the placebo-controlled double-blind treatment.  The analysis will be performed using a 
repeated-measures mixed model which will include terms of treatment, baseline, pooled center, 
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visit with an unstructured covariance matrix, using all observed data during the 24-week, double-
blind, placebo-controlled phase without any missing data imputations.  The treatment variable 
will be introduced to the mixed model with 4 categories including placebo and the three target 
dose levels.  The difference in the primary endpoint of the overall tirasemtiv effect relative to 
placebo will be calculated in an estimate statement.   
The sites will be pooled by country and then by criteria to be determined if there are more than 
40 patients enrolled in one country.  The detailed algorithm will be determined and submitted to 
the regulatory authorities after the enrollment completes and before the database lock for 
Week 24 placebo-controlled phase.  
8.4.4. 
Supportive Efficacy Analyses  
As a key supportive analysis, the primary efficacy endpoint will be analyzed for the FAS using 
rank transformation repeated measures analysis of covariance (ANCOVA) including the same 
terms in the primary efficacy analysis.  Ranks will be applied to all observed changes from 
baseline (regardless of visits) for continuous variables in the model in case large variance 
heterogeneity or inflation of variance from extreme outliers is observed.  Based on the extent of 
outliers in the blinded data review when all patients complete the treatment at Week 24 before 
database lock, the rank-based analysis (or a more rigorous randomized-based version for within 
visit rankings) will be conducted.   
As supportive analyses, the primary efficacy endpoint will be analyzed for the FAS and the PPS 
using the same method as the primary efficacy analysis, including terms of unbalanced baseline 
characteristics and the treatment-by-factor interactions. 
8.4.5. 
Secondary and Tertiary Efficacy Analyses 
All analyses will be performed with the methods below for all secondary or tertiary endpoints for 
the first 24-week double-blind placebo-controlled phase and the 48-week double-blind placebo-
controlled phase separately.  For endpoints related to skeletal muscle function, the interaction of 
treatment-by-riluzole will also be included in the models.  
Secondary or tertiary endpoints of change from baseline parameters will be analyzed using the 
same method as the primary efficacy analysis.  
For binary variables, the proportion of patients with an event will be provided.  Odds ratios and 
their 95% CIs as well as p-values will be calculated using conditional logistic regression for 
treatment difference between tirasemtiv and placebo, stratified for pooled site with terms of 
baseline, treatment, and riluzole use/non-use in the model.  
For time to event variables, a proportional hazards Cox regression model will be used to estimate 
the hazards ratio and its 95% CI between the two treatment groups, including treatment and 
covariates of baseline SVC value, pooled site, and riluzole use/non-use.  
Slope endpoints will be analyzed using a mixed model which will include treatment, the baseline 
value, pooled site, time, and riluzole use/non-use as well as interaction terms of treatment-by-
baseline, treatment-by-time, assuming random slope effect. Slope endpoints will be compared 
between the patients randomized to all tirasemtiv target dose levels during the double-blind, 
placebo-controlled phase and the patients who were randomized to placebo during the double-

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blind, placebo-controlled phase for the first 24-week double-blind placebo-controlled phase and 
the 48-week double-blind placebo-controlled phase separately. 
8.4.6. 
Other Supportive Efficacy Analyses  
The potential for a rebound effect following withdrawal of tirasemtiv (i.e., acute worsening of 
function to a degree significantly worse than the decrement over time associated with placebo 
treatment) will be assessed by comparing the change from baseline to 49 weeks and from 
baseline to 52 weeks for all primary, secondary, and tertiary change from baseline endpoints on 
tirasemtiv (48 weeks of double-blind placebo-controlled phase)/placebo (4 weeks of randomized 
withdrawal phase) versus placebo (48 weeks of double-blind placebo-controlled phase)/placebo 
(4 weeks of randomized withdrawal phase) for the randomized withdrawal phase. The 95% CIs 
will be calculated for the difference in LSM between the placebo/placebo group and the 
tirasemtiv/placebo group.  
8.4.7. 
Additional Efficacy Analyses 
Additional efficacy analyses based on the change from baseline of additional efficacy endpoints 
will be analyzed using the same method as described for the primary efficacy analysis in the 
FAS.  
8.4.8. 
Hypothesis Testing and Multiplicity 
The 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.  The methodology of the closed testing procedure is fully described in the statistical 
analysis plan.  
Comparisons of dose groups for the primary and secondary endpoints will be considered 
exploratory and used to supportively confirm which driving dose(s) that has the effect on these 
endpoints versus placebo.   
8.4.9. 
Sensitivity Analysis 
Several sensitivity analyses will be conducted.  First, the primary efficacy analysis will be 
repeated using multiple imputations with the Markov chain Monte Carlo method to impute 
missing data points for the actual change from baseline in percent predicted SVC.  After the 
multiple imputations under a missing at random paradigm, imputed values subsequent to death 
will be set to 50% worse than the values produced from the multiple imputations.  The sensitivity 
analysis for the base case will use the change from baseline of all observed and the 
aforementioned imputed data in the primary analysis model.  Two additional sensitivity analyses 
will be conducted using the invocations of such multiple imputations with 5% and 10% 
pessimism for the imputed missing values at each visit for the active treatment group.  When 
imputed data no longer have compatibility with parametric assumptions, ANCOVA based on 
ranks subsequent to imputations will be used.  Second, the primary efficacy analysis will be 
repeated in all randomized patients in the first 24 weeks of placebo-controlled phase. 

Protocol CY 4031 
 
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8.4.10. 
Subgroup Efficacy Analyses 
Analyses of the primary efficacy endpoint and the secondary endpoints evaluating the change 
from baseline in the ALSFRS-R score of the three respiratory items of the ALSFRS-R at the end 
of 48 weeks of double-blind, placebo-controlled treatment and the slope of mega-score of muscle 
strength during the 48 weeks of double-blind, placebo-controlled treatment phase will be 
conducted in subgroups based on the medians of percent predicted SVC, body weight, and BMI 
at baseline, riluzole use/non-use, baseline ALSFRS-R, time since first symptom, time since 
diagnosis of ALS, by randomized target dose level, by actual maintenance dose established 
during the double-blind placebo-controlled phase, sex, age group (<65, > 65 years old), race, 
geographic region (i.e., Europe versus North America), anatomic site of disease onset (bulbar 
versus limb), and other subgroups as may be specified in the SAP, in the FAS.  The reduced 
sample size within each subgroup will reduce the power of the statistical tests, so significant 
treatment effects within each subgroup are not expected. 
8.5. 
Safety Analysis 
Safety analyses will be based on the SAS overall and by the phases of the study (i.e., open-label 
phase; the first 24 weeks of the double-blind, placebo-controlled phase; all 48 weeks of the 
double-blind, placebo-controlled phase; the double-blind, placebo-controlled tirasemtiv 
withdrawal phase; and until the end of the follow-up period as well as subgroup analyses by 
riluzole use/non-use. 
8.5.1. 
Adverse Events 
A TEAE is an AE with an onset after initiation of study drug dosing, or an AE present at 
initiation of study drug dosing that worsens in severity after initiation of study drug dosing.  AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Terms and grouped by System Organ Class.  The version of the MedDRA dictionary will be 
noted in the report.  AEs will be classified according to CTCAE grade.  
TEAEs will be assigned to the open-label phase treatment, to the randomized target dose level, 
or to the dose level administered immediately prior to the onset of the TEAE during the double-
blind treatment.  TEAEs that begin during the open-label phase but continue without an increase 
in severity after randomization into the double-blind, placebo-controlled, treatment phase will be 
assigned to the randomized, double-blind treatment only if they persist without an increase in 
severity beyond 96 hours after the first dose of double-blind, placebo-controlled study 
medication.  In BENEFIT-ALS, this convention minimized the assignment to double-blind 
placebo of those TEAEs that began during treatment with open-label tirasemtiv but resolved 
shortly after the initiation of treatment with double-blind placebo while appropriately assigning 
to double-blind tirasemtiv those TEAEs that began during treatment with open-label tirasemtiv 
that continued past the initiation of treatment with double-blind tirasemtiv. 
If a TEAE continues after a change in dose level without an increase in intensity, it will be 
assigned only to the dose level at which it initiated.  If a TEAE continues and worsens in 
intensity after a change in dose level, it will be assigned both to the dose level at which it 
initiated and to the dose level at which it worsened.  If a TEAE resolves during continued 
treatment at the same dose level at which it initiated but then recurs following a change in dose 

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level, it will be assigned both to the dose level at which it initiated and resolved and again at the 
dose level at which it re-initiated.   
The number and percentage of patients with TEAEs will be summarized by system organ class, 
preferred term, dose level, and treatment overall and by phase.  The number and percentage of 
patients reporting TEAEs will be tabulated by system organ class, preferred term, dose level, 
treatment, and severity overall and by phase.  On patient-based AE tables, for a specific TEAE, 
the patient will be counted only once under the most severe grade if the TEAE is reported more 
than once per patient per dose level and treatment.  The above AE summaries will also be 
performed by riluzole use and non-use.  Additionally, the number and percentage of patients with 
TEAEs will be summarized for the open-label phase, by system organ class, preferred term, 
comparing patients who later received active tirasemtiv to those who received placebo during the 
randomized double-blind treatment.  Further tabulation by severity for the open-label phase will 
also be provided.  Similar TEAE summaries will be provided for the double-blind, placebo-
controlled phase and the tirasemtiv withdrawal phase as well.  The above TEAE summaries will 
be repeated by randomized treatment and dose level. 
Only TEAEs occurring from the first dose through 28 days after the last dose of study drug will 
be summarized.  All AEs will be included in patient listings. 
8.5.2. 
Other Safety Assessments 
The death incidence density will be provided by treatment group, adjusting for patients’ actual 
treatment duration.  The ratio of death incidence density and 95% CI in tirasemtiv relative to 
placebo will be calculated using Poisson regression.  Weight change from baseline will be 
evaluated by using the same method as the primary analysis.  Clinical laboratory data, vital signs, 
ECGs, neurological exams, physical exams, and falls assessments will be descriptively 
summarized by dose level and treatment overall and by phase. 
8.5.3. 
Suicidality Assessments 
Suicidality ideation and its intensity will be summarized descriptively by treatment and dose 
level overall and by phase.  
8.6. 
Study Drug Exposure 
Study drug exposure will be summarized.  The distribution of exposure by randomized dose 
level will be tabulated overall and by phase. 
8.7. 
Concomitant Medication 
Concomitant medications taken between seven days prior to the first dose of study drug 
throughout 28 days after the last dose of study drug will be summarized and classified by drug 
class and preferred name by treatment, dose levels overall and for each study phase, using the 
World Health Organization (WHO) Drug dictionary in the most current version when the study 
enrollment starts.  The version of the WHO Drug dictionary will be noted in the clinical study 
report. 

Protocol CY 4031 
 
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8.8. 
Pharmacokinetic Analysis 
PK analysis will be based on the PKEDS.  Descriptive statistics (arithmetic mean, SD, median, 
minimal, maximum, geometric mean, and coefficient of variation) will be presented for the 
concentration of  tirasemtiv, its metabolites, and for riluzole by treatment group and study visit.   
8.9. 
Pharmacodynamic Analysis  
Pharmacodynamic (PD) analysis may be performed to explore the relationship between 
tirasemtiv exposure and efficacy and safety endpoints.   
8.10. 
Change in Statistical Methods 
All changes in statistical methods that are described in the statistical analysis plan will be 
documented in the clinical study report. 

Protocol CY 4031 
 
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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 
Principal Investigator (PI). 
There will be no alterations in the protocol without the express written approval of the Sponsor, 
Investigator, and the IRB/EC/REB (see Form FDA 1572). 
9.2. 
Initiation Visit 
Prior to the start of the clinical study, 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 / Ethics Committee / Research Ethics 
Board 
In accordance with the US Code of Federal Regulations, 21 CFR 56, the protocol, advertisement 
(if applicable), and ICF will be submitted to the IRB/EC/REB for review and subsequent written 
approval by the IRB/EC/REB must be received before proceeding.  The Sponsor will supply 
relevant material for the Investigator to submit to the IRB/EC/REB for the protocol’s review and 

Protocol CY 4031 
 
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approval.  Verification of the IRB/EC/REB unconditional approval of the protocol and the 
written ICF statement will be transmitted to the Investigator. 
The IRB/EC/REB 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/EC/REB 
and regulatory inspections by providing direct access to source data/documents. 
The Investigator will provide the IRB/EC/REB 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 
Written informed consent for the study will be obtained from all patients before protocol-specific 
procedures are carried out.  The ICF generated by the Investigator (or designee) will be approved 
(along with the protocol) by the IRB/EC/REB 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 they 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/EC/REB and will be signed by the 
patient prior to protocol-specific procedures being performed.  The patient will be given a copy 
of the signed consent, and the original will be maintained with the patient’s records.  A copy of 
the IRB/EC/REB-approved site-specific 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 patients will be identified only by numbers. 
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 Declaration of Helsinki/Basic Principles 
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), which are consistent with 
the Declaration of Helsinki, 1996. 

Protocol CY 4031 
 
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Page 89 
10. 
REFERENCES 
Hwee, D., A. Kennedy, et al. (2014) "Fast Skeletal Muscle Troponin Activator tirasemtiv 
Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse 
Model." PLoS One DOI: 10.1371/journal.pone.0096921. 
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. 
Russell, A., J. Hartman, et al. (2012). "Activation of fast skeletal muscle troponin as a potential 
therapeutic approach for treating neuromuscular diseases." Nat Med 18(3): 452-455. 
Tinetti, M., D. Baker, et al. (2004). The Victorian Quality Council Guidelines for Minimising the 
Risk of Falls &Fall-related Injuries. Reducing the risk of falls among older adults in the 
community, Peacable Kingdom Press. 
 

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APPENDIX A. SCHEDULE OF EVENTS 
Procedure 
Screening 
Open-
Label 
Phase 
Double-Blind, Placebo Controlled Phase 
Double-Blind, 
Placebo-Controlled, 
Tirasemtiv 
Withdrawal Phase 
Follow- 
Up 
Week -4 Week -2 
Day 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 Week 24 Week 32 Week 40 Week 48 Week 49 Week 52 Week 56 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc/Exc Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Ashworth Score 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Safety Labs3 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Serum Pregnancy4 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PK Sample 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Biomarker Sample 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
ALSFRS-R 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Handgrip Strength 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Respiratory Assessment 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Muscle Strength 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-5 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Epworth Sleepiness Scale 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Suicidality Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Caregiver Burden 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Falls Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Riluzole Dosing5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Phone Contact 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Includes smoking history 
2 Weight obtained at each visit  
3 TSH only at screening visit 
4 Serum pregnancy test only for females of child bearing potential 
5 Riluzole dosing if applicable for patients currently taking riluzole 
6 Phone contact with patient after 7 days of open-label tirasemtiv 

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APPENDIX B. SUBSTRATES OF CYP2B6, 2C8, 2C9, AND 2C19 
2B6 
2C8 
2C9 
2C19 
artemisinin 
amodiaquine 
NSAIDs: 
PPIs: 
bupropion 
cerivastatin 
diclofenac 
esomeprazole 
cyclophosphamide 
paclitaxel 
ibuprofen 
lansoprazole 
efavirenz 
repaglinide 
lornoxicam 
omeprazole 
ifosphamide 
sorafenib 
meloxicam 
pantoprazole 
ketamine 
torsemide 
S-naproxen→Nor 
Anti-epileptics: 
meperidine 
piroxicam 
diazepam→Nor 
methadone 
suprofen 
phenytoin(O) 
nevirapine 
Oral Hypoglycemic 
S-mephenytoin 
propafol 
tolbutamide 
phenobarbitone 
selegiline 
glipizide 
Other: 
sorafenib 
Angiotensin II Blockers: 
amitriptyline 
losartan 
carisoprodol 
irbesartan 
citalopram 
Sulfonylureas: 
chloramphenicol 
glyburide 
clomipramine 
glibenclamide 
clopidogrel 
glipizide 
cyclophosphamide 
glimepiride 
hexobarbital 
tolbutamide 
imipramine N-DeME 
Other: 
indomethacin 
amitriptyline 
labetalol 
celecoxib 
R-mephobarbital 
fluoxetine 
moclobemide 
fluvastatin 
nelfinavir 
glyburide 
nilutamide 
nateglinide 
primidone 
phenytoin-4-OH 
progesterone 
rosiglitazone 
proguanil 
tamoxifen 
propranolol 
torsemide 
teniposide 
valproic acid 
R-warfarin→8-OH 
S-warfarin 
voriconazole 
zakirlukast 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 

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APPENDIX C. SUBSTRATES, INHIBITORS AND INDUCERS OF CYP1A2 
Substrates 
Inhibitors 
Inducers 
amitriptyline 
fluvoxamine*** 
broccoli 
caffeine 
ciprofloxacin*** 
brussel sprouts 
clomipramine 
cimetidine* 
carbanazepine 
clozapine 
amiodarone 
char-grilled meat 
cyclobenzaprine 
efavirenz 
insulin 
duloxetine 
fluoroquinolones 
methylcholanthrene 
estradiol 
fluvoxamine 
modafinil 
fluvoxamine 
furafylline 
nafcillin 
haloperidol 
interferon 
beta-naphthoflavone 
imipramine N-DeMe 
methoxsalen 
omeprazole 
mexiletine 
mibefradil 
rifampin 
nabumetone 
ticlopidine 
tobacco 
naproxen 
olanzapine 
ondansetron 
phenacetin1 
acetaminophen→NAPQI 
propranolol 
riluzole 
ropivacaine 
tacrine 
theophylline 
tizanidine 
triamterene 
verapamil 
(R)warfarin 
zileuton 
zolmitriptan 
 
***strong inhibitor, *weak inhibitor 
http://medicine.iupui.edu/clinpharm/ddis/main-table/