Conditions: Amyotrophic Lateral Sclerosis (ALS)
Keywords: Amyotrophic Lateral Sclerosis ALS tirasemtiv
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 280
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the long-term safety and tolerability of tirasemtiv in patients with ALS who had completed the double-blind placebo-controlled study of tirasemtiv in ALS (CY 4031).

Detailed description:
Enrolled participants will begin dosing of tirasemtiv 125 mg twice daily (250 mg/day) for a period of 4 weeks and will titrate to their tolerated dose, the maximum dose being 250 mg twice daily (500 mg/day). This study will also compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 with those who completed treatment with placebo in CY 4031 during continued treatment of both groups with tirasemtiv during CY 4033, compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 during that study with their clinical course during continued treatment with tirasemtiv during CY 4033, and compare the clinical course of patients who completed treatment with placebo in CY 4031 during that study with their clinical course during treatment with tirasemtiv during CY 4033.

Arms:
arm 1: The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033. arm 2: The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033.

Interventions: intervention 1: tirasemtiv
Intervention descriptions: intervention 1: Oral

Protocol document:
Prot_000.pdf: 
Protocol CY 4033 
CONFIDENTIAL 
PROTOCOL CY 4033 
A Phase 3, Open-Label Extension Study of Tirasemtiv for Patients with Amyotrophic Lateral 
Sclerosis (ALS) Who Completed VITALITY -ALS (CY 4031) 
Product Number: 
CK-2017357 
Product Name: 
tirasemtiv 
EudraCT Number: 
2016-002629-13 
Sponsor: 
Cytokinetics, Inc. 
280 East Grand A venue 
South San Francisco, California 94080 
Original Protocol: 
13 July 2016 
Lead Investigator Signature: ~-~- L 
Version: 13 July 2016 
CONFIDENTIAL 
Do Not Copy or Reproduce 
Without Consent of Cytokinetics, Inc. 
Page 1 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
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 Monitor 
Stacy Rudnicki, MD 
Director, Clinical Research & Development 
Cytokinetics, Inc. 
srudnicki@cytokinetics.com 
(650) 515-2524 (Mobile Telephone) 
(650) 624-3269 (Office 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 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
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 
(tirasemtiv), 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 (tirasemtiv) 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 (tirasemtiv), 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 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 4 
TABLE OF CONTENTS 
STUDY IDENTIFICATION ...........................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Background on Tirasemtiv ..........................................................................................11 
1.2. 
Rationale for Tirasemtiv in the Potential Treatment of Amyotrophic Lateral 
Sclerosis ......................................................................................................................11 
1.3. 
Overview of Tirasemtiv Nonclinical Studies ..............................................................12 
1.4. 
Overview of Tirasemtiv Clinical Studies ....................................................................13 
1.4.1. 
Phase 1 and Phase 2a Studies .....................................................................................13 
1.4.2. 
Phase 2b Clinical Trial in Patients with ALS (CY 4026; BENEFIT-ALS) ...............13 
1.4.3. 
Phase 3 Clinical Trial in Patients with ALS (CY 4031; VITALITY-ALS) ...............17 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.1.1. 
Primary Endpoint ........................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
2.2.1. 
Secondary Endpoints ..................................................................................................29 
3. 
STUDY OVERVIEW .................................................................................................31 
3.1. 
Tirasemtiv Dose Rationale in the Open Label Extension Study .................................32 
3.2. 
Riluzole Dose Adjustment Rationale ..........................................................................32 
4. 
STUDY POPULATION .............................................................................................33 
4.1. 
Inclusion Criteria ........................................................................................................33 
4.2. 
Exclusion Criteria .......................................................................................................33 
5. 
STUDY PROCEDURES ............................................................................................35 
5.1. 
Day 1 Clinic Visit .......................................................................................................35 
5.2. 
Week 2 Phone Call .....................................................................................................36 
5.3. 
Week 4 Clinic Visit ....................................................................................................36 
5.4. 
Week 6 Phone Call .....................................................................................................36 
5.5. 
Week 8 Clinic Visit ....................................................................................................36 
5.6. 
Week 10 Phone Call ...................................................................................................37 
5.7. 
Week 12 Clinic Visit ..................................................................................................37 
5.8. 
Week 24 Clinic Visit ..................................................................................................38 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
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5.9. 
Week 36 Clinic Visit ..................................................................................................38 
5.10. 
Week 48 Clinic Visit ..................................................................................................39 
5.11. 
Ongoing Clinic Visits Every 12 Weeks ......................................................................39 
5.12. 
Tirasemtiv Discontinuation Visit ................................................................................40 
5.13. 
28 Day Safety Follow-Up Visit ..................................................................................41 
5.14. 
Visit Windows ............................................................................................................41 
5.15. 
Timing of Doses .........................................................................................................42 
5.16. 
Concomitant Medications ...........................................................................................42 
5.17. 
PK Sample Collection .................................................................................................43 
5.18. 
Clinical Safety Assessments .......................................................................................43 
5.18.1. 
Clinical Laboratory Evaluations .................................................................................43 
5.18.2. 
Vital Signs ..................................................................................................................43 
5.18.3. 
Suicidality Assessment ...............................................................................................44 
5.19. 
Clinical and Pharmacodynamic Outcome Measures ..................................................44 
5.19.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R) .................................................44 
5.19.2. 
Slow Vital Capacity (SVC) ........................................................................................44 
5.20. 
Patient Discontinuation from Study Participation ......................................................44 
5.21. 
Study Discontinuation ................................................................................................44 
5.22. 
Safety Monitoring and Stopping Rules.......................................................................45 
6. 
INVESTIGATIONAL PRODUCT ............................................................................46 
6.1. 
Description of Investigational Product .......................................................................46 
6.2. 
Dose Administration of Tirasemtiv ............................................................................46 
6.3. 
Dose Adjustment Criteria ...........................................................................................46 
6.4. 
Treatment Interruption ................................................................................................47 
6.5. 
Daily Dosing Diary .....................................................................................................47 
6.6. 
Tirasemtiv Handling and Disposal ..............................................................................47 
6.7. 
Tirasemtiv Accountability ..........................................................................................47 
7. 
ADVERSE EVENTS AND SAFETY ASSESSMENTS ...........................................48 
7.1. 
Definitions ..................................................................................................................48 
7.1.1. 
Adverse Event .............................................................................................................48 
7.1.2. 
Serious Adverse Events ..............................................................................................49 
7.2. 
Adverse Event Severity ..............................................................................................50 
7.3. 
Assessment of Causality to Tirasemtiv .......................................................................51 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 6 
7.4. 
Procedures for Eliciting and Recording Adverse Events ...........................................51 
7.4.1. 
Eliciting Adverse Events ............................................................................................51 
7.4.2. 
Recording of Adverse Events .....................................................................................51 
7.4.3. 
Adverse Event Term ...................................................................................................51 
7.4.4. 
Recording Serious Adverse Events ............................................................................52 
7.4.5. 
Pregnancy ...................................................................................................................52 
7.5. 
Reporting Period for Adverse Events .........................................................................52 
7.5.1. 
Follow-Up of Adverse Events ....................................................................................53 
7.6. 
Serious Adverse Events Require Immediate Reporting .............................................53 
8. 
STATISTICAL METHODS .......................................................................................54 
8.1. 
General Considerations ...............................................................................................54 
8.1.1. 
General Approach .......................................................................................................54 
8.1.2. 
Sample Size ................................................................................................................54 
8.2. 
Analysis Sets ...............................................................................................................54 
8.2.1. 
Safety Analysis Set (SAS) ..........................................................................................54 
8.2.2. 
Efficacy Analysis Set (EAS) ......................................................................................55 
8.2.3. 
Pharmacokinetic Set (PKS) ........................................................................................55 
8.3. 
Study Endpoints ..........................................................................................................55 
8.3.1. 
Primary Endpoint ........................................................................................................55 
8.3.2. 
Secondary Endpoints ..................................................................................................55 
8.3.2.1. 
Time-to-Event Endpoints ............................................................................................55 
8.3.2.2. 
Change from Baseline Endpoints ...............................................................................55 
8.3.2.3. 
Slope Endpoints ..........................................................................................................55 
8.4. 
Statistical Analyses .....................................................................................................56 
8.4.1. 
Patient Disposition ......................................................................................................56 
8.4.2. 
Demographics and Other Baseline Characteristics .....................................................56 
8.4.3. 
Efficacy Analyses .......................................................................................................56 
8.4.3.1. 
Change from Baseline Endpoints ...............................................................................56 
8.4.3.2. 
Time-to-Event Endpoints ............................................................................................56 
8.4.4. 
Hypothesis Testing and Multiplicity ..........................................................................57 
8.4.5. 
Sensitivity Analysis ....................................................................................................57 
8.4.6. 
Subgroup Efficacy Analyses .......................................................................................57 
8.5. 
Safety Analysis ...........................................................................................................57 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 7 
8.5.1. 
Adverse Events ...........................................................................................................57 
8.5.2. 
Other Safety Assessments ...........................................................................................58 
8.5.3. 
Suicidality Assessments..............................................................................................58 
8.6. 
Study Drug Exposure ..................................................................................................58 
8.7. 
Concomitant Medication ............................................................................................58 
8.8. 
Pharmacokinetic Analysis ..........................................................................................59 
8.9. 
Pharmacodynamic Analysis........................................................................................59 
8.10. 
Change in Statistical Methods ....................................................................................59 
9. 
ADMINISTRATIVE ASPECTS ................................................................................60 
9.1. 
Change in Protocol .....................................................................................................60 
9.2. 
Initiation Visit .............................................................................................................60 
9.3. 
Disclosure ...................................................................................................................60 
9.4. 
Monitoring ..................................................................................................................60 
9.5. 
Institutional Review Board / Ethics Committee / Research Ethics Board ..................60 
9.6. 
Informed Consent .......................................................................................................61 
9.7. 
Records .......................................................................................................................61 
9.8. 
Reference to Good Clinical Practices (GCP) ..............................................................61 
10. 
REFERENCES ...........................................................................................................62 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................63 
APPENDIX B. SUBSTRATES OF CYP2B6, 2C8, 2C9, AND 2C19 .......................................64 
APPENDIX C. SUBSTRATES, INHIBITORS AND INDUCERS OF CYP1A2 .....................65 
 
 
 
 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
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LIST OF TABLES 
Table 1: 
Exposure to Tirasemtiv at the NOAEL in Rat and Dog .............................................12 
Table 2: 
Estimated IC50, kinact, and KI Values for Tirasemtiv Time-Dependent 
Inhibition .....................................................................................................................13 
Table 3: 
Percent Predicted Slow Vital Capacity in BENEFIT-ALS ........................................15 
Table 4: 
Completed Phase 1 and Phase 2a Clinical Studies with Tirasemtiv ...........................18 
Table 5: 
Completed Phase 2b Clinical Studies with Tirasemtiv ...............................................26 
Table 6: 
Ongoing Phase 3 Clinical Study with Tirasemtiv .......................................................28 
Table 7: 
Study Dosing Plan ......................................................................................................31 
Table 8: 
Visit Windows ............................................................................................................42 
Table 9: 
Pharmacokinetic (PK) Samples ..................................................................................43 
Table 10: Tirasemtiv Investigational Product .............................................................................46 
 
 
LIST OF FIGURES 
Figure 1: 
Changes from Baseline in Percent Predicted Slow Vital Capacity in 
BENEFIT-ALS ...........................................................................................................14 
Figure 2: 
Change from Baseline to Average after 8 and 12 Weeks in Percent Predicted 
Slow Vital Capacity ....................................................................................................16 
Figure 3: 
Study Visit Diagram ...................................................................................................31 
 
 
 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase (alanine transaminase) 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
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 
BMI 
body mass index 
CBC 
Complete blood count (hematology clinical laboratory evaluations) 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CPK  
creatine phosphokinase 
Cmax 
maximum observed plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DPS 
diaphragm pacing system 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
hERG 
human ether-à-go-go related gene 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 


Protocol CY 4033 
 
CONFIDENTIAL 
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Page 10 
Abbreviation 
Definition 
IRB 
Institutional Review Board 
KI 
inactivation constant 
kinact  
maximum rate constant for inactivation 
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 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
NOAEL 
no observed adverse effect level 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PKS 
pharmacokinetic 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 
SOP 
standard operating procedure 
SVC 
slow vital capacity 
tmax 
time to maximum plasma concentration 
TEAE 
treatment-emergent adverse event 
TnC 
troponin C 
TSH 
thyroid stimulating hormone 
UA 
Urinalysis 
WHO 
World Health Organization 


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CONFIDENTIAL 
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Page 11 
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 led to CY 4031, also known as VITALITY-ALS, 
a Phase 3 double-blind placebo-controlled study of tirasemtiv administered for 52 weeks with a 
projected enrollment of 600 patients.  The current study, CY 4033, is the open label extension for 
those patients who complete participation on study drug in the CY 4031 (VITALITY-ALS) 
study.   
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.   


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No curative therapies for ALS exist.  Rilutek® (riluzole, Sanofi-Aventis U.S. LLC) is the only 
medication approved for the treatment of ALS, and has a modest benefit on survival (Lacomblez, 
Bensimon et al. 1996).  Two interventions that contribute greatly to the overall welfare and 
survival of ALS patients are the use of enteral feeding and ventilatory support. 
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) nonclinical 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 increase in 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 Study 
39-Week Dog Toxicity Study 
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 


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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.  
There was little effect of tirasemtiv on the human ether-à-go-go related gene (hERG) channel 
(inhibition of 19.5% at 250 µM).  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 each half maximal inhibitory 
concentration (IC50) 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) 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 


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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 1 
and 4 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 CY 4026, 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 CY 4026 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 through 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 8 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).   


Protocol CY 4033 
 
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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 4 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 


Protocol CY 4033 
 
CONFIDENTIAL 
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Page 17 
with gastrointestinal 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 CY 4026 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 CY 4026 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.  
1.4.3. 
Phase 3 Clinical Trial in Patients with ALS (CY 4031; VITALITY-ALS) 
CY 4031, also known as VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and 
Assessments of Longitudindal Indices after Treatment for a Year in ALS), is an ongoing Phase 3 
clinical trial enrolling patients with ALS from about 80 centers in North America and Western 
Europe.   
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 are enrolled in the study.  
Patients taking riluzole randomized to tirasemtiv have had their riluzole dose decreased to 50 
mg/day (half the approved dose) in a double-blind fashion, since previous studies demonstrated 
that administration of tirasemtiv approximately doubles the exposure to concomitant riluzole. 
CY 4031 includes three phases; 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 are 
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. 
An independent Data Monitoring Committee (DMC) has periodically assessed patient safety in 
an unblinded manner during the course of the study and there have been no changes to study 
conduct.   
Study CY 4031 began enrollment in September 2015 and is currently ongoing.  Additional 
information about the study can be found at www.clinicaltrials.gov.


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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 
 


Protocol CY 4033 
 
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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 
 


Protocol CY 4033 
 
CONFIDENTIAL 
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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 
 


Protocol CY 4033 
 
CONFIDENTIAL 
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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 
 


Protocol CY 4033 
 
CONFIDENTIAL 
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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  
 


Protocol CY 4033 
 
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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 
 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 25 
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 
 
 
 


Protocol CY 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 26 
Table 5: 
Completed Phase 2b Clinical Studies with Tirasemtiv 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with ALS 
BENEFIT-ALS 
Phase 2b,  
(CY 4026) 
 
711 
• Double-blind, randomized (1:1), placebo-
controlled study to evaluate the safety and 
tolerability of 12 weeks of 250-500 mg 
tirasemtiv administered according to a twice 
daily dose titration regimen 
– Open-label period: following screening 
and confirmation of eligibility, patients 
are enrolled in the study and receive 125 
mg tirasemtiv twice daily for 1 week 
– Dose-titration period: patients 
randomized to tirasemtiv or placebo and 
are titrated to their MTD with a target 
dose of 250 mg BID over 3 weeks 
– MTD period: patients maintained at their 
MTD for 9 weeks 
• Patients randomized to tirasemtiv who were 
taking riluzole had a blinded dose reduction 
to 50 mg once daily 
• Primary objective: assess effect of 
tirasemtiv on ALSFRS-R total score 
• Secondary objectives: alternate assessments 
of effect on change from baseline in 
ALFRS-R and effect on respiratory function 
and other measures of skeletal muscle 
function 
 
The efficacy assessments showed: 
• Tirasemtiv had no impact on changes from 
baseline in ALSFRS-R total score compared 
with placebo 
• Compared with placebo, treatment with 
tirasemtiv showed a statistically significant 
reduction in the decline in SVC, no impact on 
MVV, and a mixed effect on SNIP, with no 
effect on the rate of decline, but a statistically 
significantly greater decrease at the end of 
Weeks 4 and 12 
• Treatment with tirasemtiv had no effect on 
handgrip fatigue and a mixed effect on muscle 
strength mega-score, with a significantly slower 
rate of decline, but no statistical difference at 
any measured time point 
The safety and tolerability assessments obtained 
during the study showed:  
• A greater proportion of patients treated with 
tirasemtiv had AEs and AEs leading to 
discontinuation from the study than patients 
treated with placebo 
• Commonly reported AEs with tirasemtiv 
treatment were dizziness, fatigue, and nausea; all 
were reported more frequently with tirasemtiv 
than placebo  
23 Oct 2012 to       
21 Mar 2014 


Protocol CY 4033 
 
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Page 27 
Table 5: 
Completed Phase 2b Clinical Studies with Tirasemtiv (Continued) 
 
 
 
• Patients treated with tirasemtiv experienced 
dizziness sooner than patients treated with 
placebo, and the duration of the dizziness 
episode was longer with tirasemtiv than placebo  
• Patients treated with tirasemtiv lost more weight 
than those treated with placebo; weight loss 
appeared to be associated with gastrointestinal 
AEs 
• Laboratory parameters, vital signs, and ECG 
intervals were stable over the course of the study 
 
 
 
 


Protocol CY 4033 
 
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Page 28 
Table 6: 
Ongoing Phase 3 Clinical Study with Tirasemtiv 
Population 
Phase 
(Study #) 
N 
Trial Design 
Results 
Start/End 
Start = First screened  
End = Last visit 
Patients with ALS 
VITALITY-ALS 
Phase 3 
(CY 4031) 
600 
• 
Multi-national, double-blind, randomized, 
placebo-controlled, stratified, parallel 
group, study with tirasemtiv treatment up 
to 52 weeks in ALS 
• 
Only those patients who tolerated two 
weeks of open-label tirasemtiv (125 mg 
BID), are randomized to the blinded phase 
• 
Patients randomized 3:2:2:2 to placebo and 
three total daily dose levels of tirasemtiv 
(250, 375 and 500 mg) for 48 weeks with 
gradual dose titration over the first 6 weeks 
• 
Following the 48 weeks, patients on 
tirasemtiv are re-randomized 1:1 to either 
their same dose of tirasemtiv or to placebo 
for the next 4 weeks (to Week 52). Patients 
originally randomized to placebo will 
continue to receive placebo 
• 
After completion of study drug, there is a 
final follow-up visit at Week 56 
Study Ongoing 
28 Aug 2015 
Ongoing 


Protocol CY 4033 
 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective is to assess the long-term safety and tolerability of tirasemtiv, in patients 
with ALS.   
2.1.1. 
Primary Endpoint 
The primary endpoint is the incidence of adverse events (AEs) in the patient population.  
2.2. 
Secondary Objectives 
The secondary objectives are: 
• To compare the clinical course of patients who completed treatment with tirasemtiv in 
CY 4031 with those who completed treatment with placebo in CY 4031 during 
continued treatment of both groups with tirasemtiv during CY 4033 
• To compare the clinical course of patients who completed treatment with tirasemtiv in 
CY 4031 during that study with their clinical course during continued treatment with 
tirasemtiv during CY 4033 
• To compare the clinical course of patients who completed treatment with placebo in 
CY 4031 during that study with their clinical course during treatment with tirasemtiv 
during CY 4033 
2.2.1. 
Secondary Endpoints 
The secondary endpoints are: 
• Time to first use of assisted ventilation or death 
• Time to the first occurrence of respiratory insufficiency (defined as tracheostomy or 
the use of non-invasive ventilation for ≥22 hours per day for ≥10 consecutive days) or 
death 
• Time to death 
• Decline in percent predicted SVC from baseline 
• Decline in ALSFRS-R score from baseline 
• Slope of the change from baseline in percent predicted SVC 
• Slope of the change from baseline in ALSFRS-R 
The time to event endpoints will be assessed from the start of CY 4031 and from the start of 
CY 4033 to the end of CY 4033. The change from baseline endpoints will be assessed from the 
start of CY 4031 and from the start of CY 4033 to Week 24 and Week 48 of CY 4033. The slope 
of change endpoints will be assessed during the first 24 weeks and first 48 weeks of either CY 
4031 or CY 4033. 


Protocol CY 4033 
 
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See Section 8.3.2.1 for detailed descriptions of the secondary endpoint measures and their 
analyses.   


Protocol CY 4033 
 
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3. 
STUDY OVERVIEW 
CY 4033 is an open-label extension study with the selective fast skeletal muscle troponin 
activator, tirasemtiv, in patients with ALS who finished double-blind study drug and completed 
participation (through Week 56) in the CY 4031 study (VITALITY-ALS).  Approximately 
350 patients from the sites that participated in CY 4031 study are expected to be enrolled in the 
open-label extension study, CY 4033. 
Following enrollment, patients will begin dosing of tirasemtiv 125 mg twice daily (250 mg/day) 
for a period of 4 weeks and will titrate to their tolerated dose, the maximum dose being 250 mg 
twice daily (500 mg/day) (Table 7).  The Principal Investigator (PI), or designee with 
prescriptive authority in their local jurisdiction, may decide to up-titrate, maintain dose, or down-
titrate the patient to the previously tolerated dose of tirasemtiv.  Please see Section 6.3 for further 
guidance on dose adjustment. 
Table 7: 
Study Dosing Plan 
Initial Dose 
(Day 1 Clinic Visit) 
Planned Up-Titration  
(Week 4 Clinic Visit) 
Planned Up-Titration  
(Week 6 Phone Call) 
250 mg tirasemtiv total daily dose 
First dose: 1 tablet (125 mg) of 
tirasemtiv  
Second dose: 1 tablet (125 mg) of 
tirasemtiv  
(approximately 12 hours apart) 
375 mg tirasemtiv total daily dose 
First dose: 1 tablet (125 mg) of 
tirasemtiv  
Second dose: 2 tablets (250 mg) 
of tirasemtiv  
(approximately 12 hours apart) 
500 mg tirasemtiv total daily dose 
First dose: 2 tablets (250 mg) of 
tirasemtiv 
Second dose: 2 tablets (250 mg) 
of tirasemtiv 
(approximately 12 hours apart) 
  
Patient clinic visits will occur at Day 1, Week 4, Week 8, Week 12, Week 24, Week 36, 
Week 48, and every 12 weeks thereafter.  Patients will be contacted by phone to assess their 
tolerability at Week 2, Week 6, and Week 10. If a patient decides to discontinue tirasemtiv, the 
patient will come into the clinic for the Tirasemtiv Discontinuation Visit and the 28 Day Safety 
Follow-up Visit if the patient is able; otherwise the patient will be contacted by phone for these 
visits (Table 3). 
 
Figure 3: 
Study Visit Diagram 
 


Protocol CY 4033 
 
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3.1. 
Tirasemtiv Dose Rationale in the Open Label Extension Study 
In the Phase 3 study of tirasemtiv in patients with ALS, CY 4031 (VITALITY-ALS), following a 
2 week open-label run-in period at 250 mg/day, patients were randomized 3:2:2:2 to placebo and 
three different maximum dose levels of tirasemtiv, 250 mg/day (125 mg twice daily), 
375 mg/day (125 mg in the morning and 250 mg in the evening), and 500 mg/day (250 mg twice 
daily). 
In CY 4031, for patients randomized to 500 mg/day, the initiation and titration of dosing was 
done as follows: 
• Open label treatment for 2 weeks at 250 mg/day (125 mg twice daily) 
• Following randomization, treatment for another 2 weeks at 250 mg/day (125 mg 
twice daily) 
• If well tolerated, up-titration to 375 mg/day (125 mg in the morning and 250 mg in 
the evening) for 2 weeks 
• If well tolerated, up-titration to the final dose of 500 mg/day (250 mg twice daily) 
In this open label extension study, the maximum dose level for all patients will be 500 mg/day.  
Initiation and titration of dosing will follow the same schedule employed in CY 4031 as follows: 
• Treatment for 4 weeks at 250 mg/day (125 mg twice daily) 
• If well tolerated, up-titration to 375 mg/day (125 mg in the morning and 250 mg in 
the evening) for 2 weeks 
• If well tolerated, up-titration to the final dose of 500 mg/day (250 mg twice daily) 
It is important to note that 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.   
To date, the DMC has not asked for any change in the study conduct of CY 4031, thus the 500 
mg/day dose is being employed in this study as it may maximize efficacy and will maximize the 
evaluation of the safety and tolerability of tirasemtiv. 
3.2. 
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.  In CY 4031, 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.   
In the current study, CY 4033, all patients will be taking tirasemtiv.  Thus, patients also taking 
riluzole will be advised to skip their evening dose of riluzole.  Patients who take riluzole will use 
their own supply of riluzole (described in Section 5.16, Concomitant Medications). 
 


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4. 
STUDY POPULATION 
Approximately 350 patients who fulfill the eligibility criteria will be enrolled in the study. 
4.1. 
Inclusion Criteria 
1. Able to comprehend and willing to sign an Informed Consent Form (ICF). If verbal 
consent is given, a Legal Designee of the patient must sign the ICF form 
2. Completed participation on study drug and the Follow-Up Visit in the CY 4031 study 
3. Male patients, who have not had a vasectomy AND confirmed zero sperm count, must 
agree for the duration of their participation in the study to either: 
a. 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 a 
highly effective means of contraception (see below): 
OR 
b. Abstain from sexual intercourse during participation in the study. 
4. Female patients who are not post-menopausal (≥ 1 year) or sterilized, must: 
a. Not be breastfeeding 
b. Have a negative pregnancy test 
c. Have no intention to become pregnant during participation in the study, 
AND  
d. Practice sexual abstinence, defined as refraining from intercourse during the duration 
of the study OR if male partners are not vasectomized with a confirmed zero sperm 
count, require use of a condom AND use of a highly effective contraceptive measure, 
for the duration of the study such as: 
− Combined (estrogen and progestogen containing) oral, intravaginal, or 
transdermal hormonal contraception associated with inhibition of ovulation 
− Progestogen-only oral, injectable, or implantable hormonal contraception 
associated with inhibition of ovulation 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS) 
− Bilateral tubal occlusion 
4.2. 
Exclusion Criteria 
1. Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during 
the course of the study 
2. Has taken any investigational study drug (other than tirasemtiv) prior to dosing, within 30 
days or five half-lives of the prior agent, whichever is greater 


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3. Use of tizanidine and theophylline-containing medications during study participation 
4. Participation or planning to participate in another clinical trial involving stem cell therapy 
for the treatment of ALS or another investigational drug  
 


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5. 
STUDY PROCEDURES 
5.1. 
Day 1 Clinic Visit  
The Day 1 Clinic Visit for CY 4033 may be the same day as the Follow-Up Visit (Week 56) for 
the CY 4031 (VITALITY-ALS) study. A signed ICF for the CY 4033 study must be obtained 
prior to any study procedures for the Follow-Up Visit (Week 56) for CY 4031 and before 
CY 4033 study specific assessments are initiated. In the event that a patient is unable to 
physically sign an ICF but is able to provide verbal consent, a Legal Designee of the patient can 
sign on the patient’s behalf.  
The following are done as part of the Follow-Up Visit for CY 4031 and this data will be included 
as part of the Day 1 Clinic Visit for CY 4033. These procedures do not need to be repeated as 
part of the Day 1 Clinic Visit for CY 4033.  Patients who elect to take riluzole, should be 
instructed to take only half of their dose of riluzole during their participation in CY 4033:  
1. Clinical safety laboratory evaluations including a serum chemistry panel, complete blood 
count (CBC), urinalysis, creatine phosphokinase (CPK) * Please note that Safety Lab 
results are not prohibitory to the start of dosing. 
2. Vital signs including weight 
3. Slow Vital Capacity (SVC) 
4. ALSFRS-R 
5. Physical examination 
6. Adverse Event Evaluation 
7. Concomitant medication assessment  
8. Suicidality assessment  
In addition, these assessments are mandatory prior to administration of tirasemtiv in CY 4033: 
1. Informed consent documentation 
2. Inclusion/exclusion criteria evaluation 
3. Demographic data collection 
4. Serum pregnancy test for females of child bearing potential 
Once all pre-dose procedures have been performed at the Day 1 Clinic Visit for CY 4033, 
patients may receive open label tirasemtiv.  
Patients will be instructed to take tirasemtiv twice daily, approximately 12 hours apart. A diary 
will be provided for patients to record the date and time of twice daily tirasemtiv administration. 
Patients will be given an adequate supply of tirasemtiv to take twice daily for four weeks at 
home until their next clinic visit (Week 4 Clinic Visit).   


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5.2. 
Week 2 Phone Call  
Patients will be contacted by site staff approximately two weeks later for the Week 2 Phone Call 
to assess tolerability, adverse events, and any changes to concomitant medications.   
Patients will continue tirasemtiv dosing until the Week 4 Clinic Visit. 
5.3. 
Week 4 Clinic Visit 
Patients will return to the study site for the Week 4 Clinic Visit. Patients will be instructed not to 
take their dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
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. SVC   
4. ALSFRS-R 
5. AE evaluation 
6. Concomitant medication assessment since last visit 
7. Suicidality assessment  
If patients are tolerating tirasemtiv, they may be up-titrated to 375 mg/day; if not, patients should 
be maintained at their current dose level.  
Once all pre-dose procedures have been performed at the Week 4 Clinic Visit, patients may take 
their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration. Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 4 weeks at home until their next clinic visit, Week 8 Clinic Visit. 
5.4. 
Week 6 Phone Call  
Patients will be contacted by PI or designee with prescriptive authority in their local jurisdiction, 
approximately 2 weeks later for the Week 6 Phone Call to assess tolerability, adverse events, and 
any changes to concomitant medications.  The PI or designee with prescriptive authority in their 
local jurisdiction will assess if it is appropriate to up-titrate patients.  Patients will either continue 
at their current dose of tirasemtiv or, if previously up-titrated at the Week 4 Clinic Visit and 
continue to tolerate tirasemtiv, patients will be up titrated to 500 mg/day.  
Patients will continue tirasemtiv dosing as advised until the Week 8 Clinic Visit. 
5.5. 
Week 8 Clinic Visit 
Patients will return to the study site for the Week 8 Clinic Visit. Patients will be instructed not to 
take their dose of tirasemtiv prior to arrival at the study site. 


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The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
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. SVC  
4. ALSFRS-R 
5. AE evaluation  
6. Concomitant medication assessment since last visit 
7. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 8 Clinic Visit, patients may take 
their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration.  Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 4 weeks at home until their next clinic visit, Week 12 Clinic Visit.   
5.6. 
Week 10 Phone Call 
Patients will be contacted by site staff approximately 2 weeks later for the Week 10 Phone Call 
to assess tolerability, adverse events, and any changes to concomitant medications.   
Patients will continue tirasemtiv dosing until the Week 12 Clinic Visit. 
5.7. 
Week 12 Clinic Visit 
Patients will return to the study site for the Week 12 Clinic Visit. Patients will be instructed not 
to take their dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
2. PK sampling 
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. SVC   
5. ALSFRS-R 
6. AE evaluation  
7. Concomitant medication assessment since last visit 
8. Suicidality assessment  


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Once all pre-dose procedures have been performed at the Week 12 Clinic Visit, patients may 
take their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration. Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 12 weeks at home until their next clinic visit, Week 24 Clinic Visit.   
5.8. 
Week 24 Clinic Visit 
Patients will return to the study site for the Week 24 Clinic Visit. Patients will be instructed not 
to take their dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
2. Serum pregnancy test for females of child bearing potential 
3. PK sampling 
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. SVC   
6. ALSFRS-R 
7. AE evaluation  
8. Concomitant medication assessment since last visit 
9. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 24 Clinic Visit, patients may 
take their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration. Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 12 weeks at home until their next clinic visit, Week 36 Clinic Visit.   
5.9. 
Week 36 Clinic Visit 
Patients will return to the study site for the Week 36 Clinic Visit. Patients will be instructed not 
to take their dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
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. SVC   


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4. ALSFRS-R 
5. AE evaluation  
6. Concomitant medication assessment since last visit 
7. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 36 Clinic Visit, patients may 
take their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration. Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 12 weeks at home until their next clinic visit, Week 48 Clinic Visit.   
5.10. 
Week 48 Clinic Visit 
Patients will return to the study site for the Week 48 Clinic Visit. Patients will be instructed not 
to take their dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 
2. Serum pregnancy test for females of child bearing potential 
3. PK sampling 
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. SVC   
6. ALSFRS-R 
7. AE evaluation  
8. Concomitant medication assessment since last visit 
9. Suicidality assessment  
Once all pre-dose procedures have been performed at the Week 48 Clinic Visit, patients may 
take their dose of tirasemtiv. Patients will be instructed to continue to take tirasemtiv twice daily, 
approximately 12 hours apart. A diary will be provided for patients to record the date and time of 
twice daily tirasemtiv administration. Patients will be given an adequate supply of tirasemtiv to 
take twice daily for 12 weeks at home until their next clinic visit.   
5.11. 
Ongoing Clinic Visits Every 12 Weeks 
Patients will return to the study site every 12 weeks. Patients will be instructed not to take their 
dose of tirasemtiv prior to arrival at the study site. 
The following assessments will be performed prior to administration of tirasemtiv while in the 
clinic: 
1. Clinical Safety Labs 


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2. Serum pregnancy test for females of child bearing potential (every 24 weeks) 
3. PK sampling (every 24 weeks) 
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. SVC 
6. ALSFRS-R 
7. AE evaluation  
8. Concomitant medication assessment since last visit 
9. Suicidality assessment  
Once all pre-dose procedures have been performed at the Ongoing Clinic Visit Every 12 Weeks, 
patients may take their dose of tirasemtiv. Patients will be instructed to continue to take 
tirasemtiv twice daily, approximately 12 hours apart. A diary will be provided for patients to 
record the date and time of twice daily tirasemtiv administration. Patients will be given an 
adequate supply of tirasemtiv to take twice daily for 12 weeks at home until their next clinic 
visit.   
5.12. 
Tirasemtiv Discontinuation Visit 
Patients will be advised to immediately contact their clinical site if they would like to 
discontinue tirasemtiv use. Patients will be requested to come into the clinic as soon as possible 
or to have a phone visit if transport is not possible. If a patient is able to come in for a clinic visit, 
the following assessments will be conducted: 
1. Clinical Safety Labs 
2. Serum pregnancy test for females of child bearing potential 
3. PK Sampling  
4. Vital Signs 
5. SVC 
6. ALSFRS-R 
7. AE evaluation 
8. Concomitant medication assessment since last visit 
9. Inquire about use of non-invasive ventilation, if so collect how many hours a day 
10. Inquire if patient has had a tracheostomy 
11. Assessment of Suicidality 
If a patient is unable to come in for a clinic visit, the following assessments will be conducted 
via a phone call: 
1. Survival status 


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2. ALSFRS-R 
3. AE evaluation 
4. Concomitant medication assessment since last visit 
5. Inquire about use of non-invasive ventilation, if so collect how many hours a day 
6. Inquire if patient has had a tracheostomy  
7. Assessment of Suicidality 
5.13. 
28 Day Safety Follow-Up Visit 
Patients who are able to return to the clinic for the 28 Day Safety Follow-Up Visit in person will 
undergo the following assessments: 
1. Clinical Safety Labs 
2. Vital Signs 
3. SVC 
4. ALSFRS-R 
5. AE evaluation  
6. Concomitant medication assessment since last visit 
7. Inquire about use of non-invasive ventilation, if so collect how many hours a day 
8. Inquire if patient has had a tracheostomy 
9. Assessment of Suicidality 
If a patient is unable to come in for a clinic visit, the following assessments will be conducted 
via a phone call: 
1. Survival status 
2. ALSFRS-R 
3. AE evaluation 
4. Concomitant medication assessment since last visit 
5. Inquire about use of non-invasive ventilation, if so collect how many hours a day 
6. Inquire if patient has had a tracheostomy  
7. Assessment of Suicidality 
5.14. 
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. Please note that the Week 6 Phone Call needs to be conducted by the PI or 
designee with prescriptive authority in their local jurisdiction. 


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Table 8: 
Visit Windows 
Visit 
Visit Window 
Day 1 Clinic 
Week 56 of CY 4031/First day of Dosing CY 4033 
Week 2 Call 
2 Weeks after the Day 1 Visit ± 2 days 
Week 4 Clinic 
4 Weeks after the Day 1 Visit ± 2 days 
Week 6 Call 
6 Weeks after the Day 1 Visit ± 2 days 
Week 8 Clinic 
8 Weeks after the Day 1 Visit ± 2 days 
Week 10 Call 
10 Weeks after the Day 1 Visit ± 2 days 
Week 12 Clinic 
12 Weeks after the Day 1 Visit ± 2 days 
Week 24 Clinic 
24 Weeks after the Day 1 Visit ± 7 days 
Week 36 Clinic 
36 Weeks after the Day 1 Visit± 7 days 
Week 48 Clinic 
48 Weeks after the Day 1 Visit ± 7 days 
Ongoing 12 Week Clinic Visits 
Ongoing every 12 weeks since last visit ± 7 days 
Tirasemtiv Discontinuation Visit 
To occur as soon as possible after patient Discontinues Tirasemtiv use 
28 Day Safety Follow-up Visit 
28 days after the Tirasemtiv Discontinuation date +5 days 
5.15. 
Timing of Doses 
Tirasemtiv should be taken twice daily (except on clinic visit days where it should be taken in the 
clinic), approximately 12 hours apart.  Tirasemtiv should be taken ≥ 2 hours after a meal or 1 
hour prior to a meal. 
5.16. 
Concomitant Medications 
All prescription drugs, over-the-counter medications, nutriceuticals and herbal remedies taken by 
the patient from the time of the Day 1 visit through the 28 Day Safety Follow-up visit should be 
entered into the electronic case report form (eCRF). 
Patients who are currently taking riluzole at study entry should reduce their dose to 50 mg once 
daily while taking tirasemtiv in the open-label extension study. Patients who choose to take 
riluzole will use their personal supply. For patients taking riluzole, tirasemtiv may be taken at the 
same time as riluzole. 
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 


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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. 
5.17. 
PK Sample Collection  
Blood samples for PK analysis of tirasemtiv, and its acid metabolite, CK-2018595 will be 
collected at the time points listed in Table 9. For each clinic visit, patients will be instructed 
NOT to take their next dose of tirasemtiv until after the pre-dose PK blood draw.  
Table 9: 
Pharmacokinetic (PK) Samples 
Visit 
Sample Time Points 
Week 12 
Pre-dose 
Week 24 
Pre-dose 
Week 48 
Pre-dose 
Every 24 Weeks Ongoing 
Pre-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. 
5.18. 
Clinical Safety Assessments 
5.18.1. 
Clinical Laboratory Evaluations 
Clinical safety laboratory evaluations (serum chemistry panel, CBC, UA, and CPK) will be 
collected at Day 1, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, and every 12 
weeks thereafter, including at the Tirasemtiv Discontinuation and 28 Day Follow-up Visits when 
possible.  TSH will be collected every year after Day 1 in CY 4033. A serum pregnancy test for 
females of child bearing potential will be collected at the Day 1 Clinic Visit, the Week 24 Clinic 
Visit, every 24 weeks thereafter and at the Tirasemtiv Discontinuation Visit.  
5.18.2. 
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 clinic visits. 


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5.18.3. 
Suicidality Assessment 
The suicidality assessment (Beck Depression Inventory-Fast Screen) will be assessed as 
described in the study manual for all clinic visits, including the Tirasemtiv Discontinuation Visit, 
and the 28 Day Safety Follow-Up Visit. 
5.19. 
Clinical and Pharmacodynamic Outcome Measures 
5.19.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R)  
The ALSFRS-R will be administered as described in the study manual for the following visits; 
Day 1, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, ongoing every 12 weeks, 
Tirasemtiv Discontinuation Visit, and the 28 Day Safety Follow-Up Visit.  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. 
5.19.2. 
Slow Vital Capacity (SVC) 
SVC will be performed as described in the study manual at every study clinic visit; Day 1, Week 
4, Week 8, Week 12, Week 24, Week 48, every 12 weeks ongoing, and if the patient returns to 
the Clinic for the Tirasemtiv Discontinuation Visit. 
5.20. 
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 the patient to continue in the study. For those patients who 
will not return to the study center for further study scheduled assessments, the Tirasemtiv 
Discontinuation Visit and 28 Day Safety Follow-Up Visit study assessments should be 
performed via phone whenever possible and documented. Notification of discontinuation will 
immediately be made to the Sponsor’s Medical Monitor. 
In all cases, for patients who discontinue tirasemtiv, the Investigator should discuss with the 
patient the option of continuing in the study to allow for once every 12 weeks telephone calls to 
assess vital status, NIV use, and/or ALSFRS-R rather than withdrawal from the study.  The level 
of follow up that is agreed to by the patient (eg, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical records) 
should be documented by the Investigator. 
The date the patient is withdrawn from tirasemtiv 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.   
5.21. 
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 


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• Cancellation of the development of tirasemtiv for the potential treatment of ALS 
• Commercial availability of tirasemtiv in a given patient’s jurisdiction 
• When fewer than 20% of patients who began open-label treatment with tirasemtiv in 
CY 4033 remain active in CY 4033 (*When [or if] this situation occurs, those 
patients who remain on treatment with tirasemtiv in CY 4033 will continue to receive 
tirasemtiv under circumstances compliant with the laws and regulations of their local 
jurisdictions; however, they will no longer be participants in the CY 4033 protocol) 
5.22. 
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, or designee, in a blinded manner on a periodic basis: 
1. SAEs thought by the Sponsor or the Investigator to be related to tirasemtiv 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 
tirasemtiv administration 
4. Any death thought by the sponsor or the Principal Investigator (PI) to be related to 
tirasemtiv will result in stopping all enrollment in order to perform a review.   
5. This review may result in any of the following:  
• Discontinuation of the study 
• Discontinuation of enrollment at the affected and higher dose levels 
• Modification to study conduct 
• No change to the conduct of the study (if AEs are determined to have been unrelated 
to tirasemtiv administration) 


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Description of Investigational Product 
CK-2017357 (tirasemtiv) investigational product 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, as specified in the Investigator’s Brochure.  CK-2017357 tablets contain 
125 mg of tirasemtiv plus excipients.   
Table 10: 
Tirasemtiv Investigational Product 
Study Drug 
CK-2017357 
Form 
Tablet 
Supplier 
Cytokinetics, Inc. 
Manufacturer 
Patheon, Inc. 
CK-2017357 (tirasemtiv) tablets will be supplied to the clinical site in induction sealed 60 cc 
white HDPE bottles containing 60 tablets per bottle.  Bottles will be labeled with a lot number.   
The site pharmacist or other qualified person responsible for managing investigational product 
supplies will maintain an accurate record of the receipt of tirasemtiv as shipped by the Sponsor 
(or designee).  One copy of this receipt will be returned to the Sponsor when the contents of the 
tirasemtiv shipment have been verified.  In addition, an accurate drug disposition record will be 
kept, specifying the lot 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. 
6.2. 
Dose Administration of Tirasemtiv 
Tirasemtiv will be administered orally as tablets (125 mg per tablet) to patients with ALS.  Doses 
of tirasemtiv will be dispensed in accordance with the study dosing plan (Table 7). 
In this open label extension study with tirasemtiv, the maximum dose level for all patients will 
be 500 mg/day.  Initiation and titration of dosing will use the following schedule: 
• Treatment for 4 weeks at 250 mg/day (125 mg twice daily) 
• If tolerated, up-titration to 375 mg/day (125 mg first dose and 250 mg second dose) 
for 2 weeks 
• If tolerated, up-titration to the final dose of 500 mg/day (250 mg twice daily) 
6.3. 
Dose Adjustment Criteria 
Patients who do not tolerate a dose escalation due to symptoms believed to be due to treatment 
with tirasemtiv may be returned to a previously tolerated dose at the discretion of the 
Investigator, or designee with prescriptive authority in their local jurisdiction.  No upward dose 
adjustments will be allowed subsequent to a dose reduction.  


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6.4. 
Treatment Interruption 
Patients who interrupt treatment with tirasemtiv 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 tirasemtiv for more than one week. Specific 
instructions regarding tirasemtiv interruption are provided in the study manual. 
6.5. 
Daily Dosing Diary 
A dosing diary will be maintained by the patient to record date and time of twice daily tirasemtiv 
administration.  The dosing diary should be collected at each clinic visit. 
6.6. 
Tirasemtiv Handling and Disposal 
The site pharmacist, or other qualified person responsible for managing investigational product 
supplies, will maintain an accurate record of the receipt of tirasemtiv 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 content of the investigational drug shipment has been verified. 
At the completion of the study, the original tirasemtiv accountability record will be available for 
review by the Sponsor upon request. 
All unused tirasemtiv supplies will be returned to the Sponsor (or designee) for destruction per 
facility standard operating procedure (SOP) or disposed of by the study site per site specific 
SOPs. 
6.7. 
Tirasemtiv Accountability 
The patient should be instructed to return all unused tirasemtiv to the designated clinical site staff 
at each study visit.  Tirasemtiv accountability is to be conducted by the designated study staff 
member with the patient at each study clinic visit.  The dosing diaries should also be referenced 
when completing drug accountability. 


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7. 
ADVERSE EVENTS AND SAFETY ASSESSMENTS 
7.1. 
Definitions  
7.1.1. 
Adverse Event 
An adverse event (AE) is defined as 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 clinically 
significant test result, medical condition or other incident on the AE eCRF: 
• From the time of informed consent to first administration of tirasemtiv record only 
AEs which are related to a study protocol-mandated procedure 
• 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 CY 4033 medical history eCRF 
• Conditions newly detected or diagnosed after the first administration of tirasemtiv on 
the CY 4033 study, including conditions that may have been present but undetected 
prior to the start of the study should be recorded as AEs 
• All AEs (regardless of relationship to study drug) should be recorded from first 
administration of tirasemtiv through the end of the safety reporting period (see 
Section 7.5, Reporting Period for Adverse Events)    
• An abnormal lab test result 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)   
• Conditions listed on the medical history eCRF 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 as AEs 
• Signs, symptoms, or the clinical sequela/sequelae of a suspected drug interaction 
should be recorded as AEs 
• Signs, symptoms, or the clinical sequela/sequelae of a suspected overdose of either 
tirasemtiv or a concurrent medication (overdose per se should not be reported as an 
AE) should be recorded as AEs 
• New and/or exacerbated symptoms of ALS (i.e., those not listed on the medical 
history eCRF) should be recorded as AEs 
Issues Not Considered AEs 
• Medical or surgical procedures (e.g., endoscopy, appendectomy); planned prior to the 
patient enrolling into the study 


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• Situations where the patient is hospitalized but 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 diagnostic test findings after the first dose of tirasemtiv that 
are assessed by the Investigator as not clinically significant change from baseline 
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 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 Sponsor’s Medical Monitor, or 
designee. 
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 or 
permanent disruption. 
Congenital 
Anomaly/Birth 
Defect 
An adverse outcome in a child or fetus of a patient exposed to tirasemtiv 
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 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, or 
designee. 
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 in Section 7.1.2) 
• Note that “life-threatening” in the criteria for “seriousness” 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 Tirasemtiv 
The relationship of each AE to tirasemtiv 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) or 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 between 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 Report 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 seriousness criteria was met 
• Severity 
• Relationship to tirasemtiv 
• 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 
standard medical textbooks.  If any aspect of the sign or symptom does not fit into a classic 


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pattern of the diagnosis, report the individual symptom as a separate AE.  Medical or surgical 
procedures (e.g., endoscopy, appendectomy) should not be reported as an AE term.  The AE term 
should be the medical condition that led to the procedure (e.g., appendicitis instead of 
appendectomy). 
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 and should not be used as an SAE term.  The cause of death 
should be the only event that has the outcome of death 
• The surgical or diagnostic procedure should not be recorded as the SAE term. The 
condition which led to the procedure requiring hospitalization should be the reported 
term.  Capture the procedure in the description of events as part of the action taken in 
response to the illness/condition. 
• The onset date of an SAE is when the AE met any one of the defined serious criteria 
• The resolution date for an SAE with a fatal outcome is the date of death. 
7.4.5. 
Pregnancy  
Complete a Pregnancy Report Form and fax or email the completed form to the fax number or 
email address on the form 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 from the first administration of tirasemtiv 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 female patient who becomes pregnant during the study is not eligible to continue 
in the study and should complete the end of study procedures at that time.   Any male patient 
whose partner becomes pregnant may continue with the study but will prevent further fetal 
exposure by using a condom during sexual intercourse. 
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 the partner 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 tirasemtiv 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 tirasemtiv through 
28 days after the patient’s last dose of tirasemtiv.  However, all AEs associated with a protocol-
mandated procedure are to be collected from the time of informed consent.  All SAEs that occur 


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after the safety reporting period and are considered tirasemtiv-related in the opinion of the 
Investigator should also be reported to the Sponsor.  
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 rationale) 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.   
All SAEs should be followed until significant changes return to baseline, the condition stabilizes, 
is no longer considered clinically significant by the Investigator, or 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. 
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 tirasemtiv. 
For initial SAE reports, available details of the event are to be recorded on an SAE Report Form.  
At a minimum, the following must be included: 
• Patient number 
• Date of event onset 
• Seriousness criterion or criteria 
• Description of the event 
• Dose of tirasemtiv  
• 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 endpoints will include numbers of patients, means, medians, 
standard deviations, standard errors, minima, and maxima. For categorical endpoints, frequencies 
and percentages will be given. For time-to-event endpoints, 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.  
Two baseline values will be used in this study. One is the CY 4033 baseline value which will be 
the assessment at the Follow-Up Visit (Week 56) in CY 4031 that is also the Day 1 Clinic Visit 
for CY 4033. The other is the CY 4031 baseline which is the last available assessment prior to 
the open-label lead-in phase in the CY 4031 study. 
Analyses will compare the effect of tirasemtiv on endpoints between the group of patients who 
previously received tirasemtiv at the first randomization in CY 4031 (the early-start treatment 
group) and the delayed-start treatment group (patients who previously received placebo at the 
first randomization in CY 4031 and started tirasemtiv during CY 4033).  Analyses will also be 
conducted to compare the effect of tirasemtiv in CY 4031 and CY 4033 within the delayed-start 
treatment group and the early-start treatment group separately. If data permits, the above 
comparisons will be performed by the maintenance total daily dose determined by the clinical 
review. 
8.1.2. 
Sample Size  
Approximately 350 patients from the sites that participated in the CY 4031 study are expected to 
be enrolled in the CY 4033 study. All patients will begin dosing with 125 mg of tirasemtiv twice 
daily for a period of 4 weeks and titrate to the patient’s tolerable dose level (250 mg, 375 mg or 
500 mg per day). At any point in time, patients who cannot tolerate the current dose level may 
return to their previously tolerated dose level. 
8.2. 
Analysis Sets 
8.2.1. 
Safety Analysis Set (SAS) 
The SAS will consist of all patients who are enrolled and receive at least one dose of tirasemtiv 
in the CY 4033 study. 


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8.2.2. 
Efficacy Analysis Set (EAS) 
The EAS will consist of all patients who are enrolled in the CY 4033 study and receive at least 
one dose of tirasemtiv, and have at least one efficacy outcome assessment during the CY 4033 
study. 
8.2.3. 
Pharmacokinetic Set (PKS) 
The PKS will consist of all patients with at least one evaluable PK concentration, provided they 
have no major protocol violations that could affect the PK of tirasemtiv. 
8.3. 
Study Endpoints 
8.3.1. 
Primary Endpoint 
The incidence of adverse events (AEs) in the patient population during the CY 4033 study. 
8.3.2. 
Secondary Endpoints 
8.3.2.1. 
Time-to-Event Endpoints 
There will be two time frames: 1) from the baseline in CY 4031 to the end of the CY 4033 study; 
2) from the CY 4033 baseline to the end of CY 4033 study. 
1. Time to first use of assisted ventilation or death 
2. Time to the first occurrence of respiratory insufficiency (defined as tracheostomy or the 
use of non-invasive ventilation for ≥22 hours per day for ≥10 consecutive days) or death  
3. Time to death  
8.3.2.2. 
Change from Baseline Endpoints 
1. Decline in percent predicted SVC from CY 4031 baseline to Week 24 and to Week 48 of 
CY 4033  
2. Decline in percent predicted SVC from CY 4033 baseline to Week 24 and to Week 48 of 
CY 4033  
3. Decline in ALSFRS-R score from CY 4031 baseline to Week 24 and to Week 48 of 
CY 4033 
4. Decline in ALSFRS-R score from CY 4033 baseline to Week 24 and to Week 48 of 
CY 4033 
8.3.2.3. 
Slope Endpoints 
1. Slopes of the changes from baseline in percent predicted SVC and ALSFRS-R score 
during the first 24 weeks and the first 48 weeks of either CY 4031 or CY 4033 


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8.4. 
Statistical Analyses 
8.4.1. 
Patient Disposition 
The total number of patients who will receive tirasemtiv, number of patients who complete and 
discontinue from the study treatment by every 12 weeks interval will be presented overall and by 
the early-start and delayed-start treatment groups as well as the maintenance dose level, as 
determined according to the clinical review. 
8.4.2. 
Demographics and Other Baseline Characteristics 
Patient demographic (i.e., age, gender, race, and ethnicity) and other baseline characteristics will 
be summarized overall and by the early-start and the delayed-start treatment groups, as well as 
the maintenance dose level and overall using descriptive statistics for the SAS and EAS 
separately. 
8.4.3. 
Efficacy Analyses 
8.4.3.1. 
Change from Baseline Endpoints 
Analyses for change from baseline endpoints will be performed with the methods below based 
on the EAS.  
The change from baseline endpoints will be summarized descriptively by the early-start and the 
delayed-start treatment groups, maintenance dose level and overall at each clinical visit in the 
CY 4033 study. The change from baseline at each clinic visit will be analysed using Mixed-
Effect Model Repeated Measures (MMRM) model-based method which will include the early-
start and the delayed-start treatment group, CY 4031 baseline value, visit, riluzole use/non-use as 
well as interaction terms of the early-start and the delayed-start treatment group-by-baseline, the 
early-start and the delayed-start treatment group-by-visit with an unstructured covariance matrix. 
The least-squares mean of the difference of the early-start and the delayed-start treatment groups, 
standard error of the difference, and 95% CI of the difference will be presented.    
Slope endpoints will be analyzed using a mixed model which will include the early-start and the 
delayed-start treatment group, CY 4031 baseline value, time, riluzole use/non-use as well as 
interaction terms of the early-start and the delayed-start treatment group-by-baseline, early and 
delayed start treatment group-by-time, assuming random slope effect. The estimated slope and 
the slope difference as well as their standard errors will be presented.   
8.4.3.2. 
Time-to-Event Endpoints 
Analyses for time-to-event endpoints will be performed with the methods below based on the 
SAS. The patients will be censored to their last contact date if there is no event during the trial.  
The multiple time to events will be analyzed using approaches in (Saville, Herring et al. 2010), 
Wei–Lin–Weissfeld method (WLW).  
A proportional hazards Cox regression model including treatment group, riluzole use/non-use, 
and SVC percent predicted baseline will be used to estimate the hazards ratio and its 95% CI 
between the early-start treatment group and the delay-start treatment group with delay-start 


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treatment group as reference. The tirasemtiv treatment effect will be tested using the likelihood 
ratio test. 
8.4.4. 
Hypothesis Testing and Multiplicity 
No formal hypothesis test will be conducted in this study. Comparisons between the delayed-
start treatment group and the early-start treatment group will be presented using the nominal p-
values at the two-sided 5% significance level. 
To address multiple comparisons in the study, Hochberg and Holm p-values will be provided for 
the key secondary analyses that will be pre-specified in the statistical analysis plan. 
8.4.5. 
Sensitivity Analysis 
Sensitivity analysis will be conducted in this study taking into account the extent of missing data 
as well as censoring algorithm for the time-to-event endpoints. 
8.4.6. 
Subgroup Efficacy Analyses 
Analyses of the efficacy endpoints in subgroups may be conducted when data permit. Subgroups 
based on gender, age group (<65, > 65 years old), geographic region (North America vs. Europe) 
etc. might be considered when data permit. 
8.5. 
Safety Analysis 
All safety data collected on or after the date that tirasemtiv was first dispensed in the CY 4033 
study up to the date of last dose of tirasemtiv plus 28 days in the CY 4033 study will be 
summarized overall, by the early-start and the delayed-start treatment groups and by 
maintenance dose level (250 mg, 375 mg, and 500 mg) received separately. 
8.5.1. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is an AE with an onset after initiation of study drug 
dosing in CY 4033, 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 maintenance dose level, or to the total daily dose level 
administered immediately prior to the onset of the TEAE during the CY 4033 treatment.  
If a TEAE continues after a change in total daily dose level without an increase in intensity, it 
will be assigned only to the total daily 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 total daily dose 
level at which it initiated and to the total daily dose level at which it worsened.  If a TEAE 
resolves during continued treatment at the same total daily dose level at which it initiated but 
then recurs following a change in total daily dose level, it will be assigned both to the total daily 
dose level at which it initiated and resolved and again at the total daily dose level at which it re-
initiated.   


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TEAEs will be listed and summarized by the early-start and the delayed-start treatment groups 
and maintenance dose level as well as total daily dose level administered immediately prior to 
the onset of the AE.  Only TEAEs occurring through 28 days after the last dose of study drug 
will be summarized.  All AEs will be included in patient listings. 
The number and percentage of patients reporting TEAEs will be summarized by system organ 
class, preferred term, the early and delayed start treatment groups and overall. The number and 
percentage of subjects reporting TEAEs will be tabulated by system organ class, preferred term, 
severity and by the early and delayed start treatment groups and overall.  On subject-based AE 
tables, for a specific TEAE, the subject will be counted only once under the most severe grade if 
the TEAE is reported more than once per subject per the early and delayed-start treatment group 
and preferred term.  The above AE summaries will also be performed by riluzole use and non-
use if appropriate.  The above TEAE summaries will be repeated by the maintenance dose level, 
total daily dose level administered immediately prior to the AE onset and overall separately. 
The prevalence of adverse events will also be summarized by the early-start and delayed-start 
treatment groups and maintenance dose level. The treatment associated with an AE in this 
summary will be the total daily dose level the patient was receiving when the AE began as well 
as any total daily dose level the patient received while the AE continued. 
8.5.2. 
Other Safety Assessments 
The death incidence will be summarized descriptively by the early-start and the delayed-start 
treatment groups, maintenance dose level and overall. Weight change from baseline will be 
analyzed by using the same method. Clinical laboratory data, vital signs, ECGs, neurological 
exams, physical exams, and falls assessments will be descriptively summarized by the early-start 
and the delayed-start treatment groups, maintenance dose level and overall separately. The death 
incidence density will be provided by the early-start and the delayed-start treatment groups, 
adjusting for patients’ actual treatment duration from the open-label lead-in dose of CY 4031to 
the end of the CY 4033 study.  The ratio of death incidence density and 95% CI in the early-start 
treatment group relative to the delayed-start treatment group will be calculated using Poisson 
regression. 
8.5.3. 
Suicidality Assessments 
Suicidality assessment will be summarized descriptively by the early-start and the delayed-start 
treatment groups and maintenance dose level overall.  
8.6. 
Study Drug Exposure 
Descriptive statistics will be provided by the early-start and the delayed-start treatment groups, 
maintenance dose level of tirasemtiv, the total exposure and the duration of tirasemtiv treatment. 
8.7. 
Concomitant Medication 
Concomitant medications taken between the first dose of study drug of CY 4033 throughout 28 
days after the last dose of study drug will be summarized and classified by drug class and 
preferred name by the early-start and the delayed-start treatment groups, maintenance dose level, 
and overall, using the World Health Organization (WHO) Drug dictionary in the most current 


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version when the study enrollment starts.  The version of the WHO Drug dictionary will be noted 
in the clinical study. 
8.8. 
Pharmacokinetic Analysis 
PK analysis will be based on the PKS. Descriptive statistics (arithmetic mean, SD, median, 
minimal, maximum, geometric mean, and coefficient of variation) will be presented for pre-dose 
PK concentration and tirasemtiv metabolites overall and by the early-start and the delayed-start 
treatment groups, maintenance dose level and study visit. The trough concentration will be 
modeled as a function of body weight over time, including covariates that are deemed to be 
related to the population PK.    
8.9. 
Pharmacodynamic Analysis  
Pharmacodynamic (PD) analysis may be performed to graphically explore the relationship 
between tirasemtiv concentration and efficacy and safety endpoints.  Additional analysis to 
describe the PK/PD relationship may also be performed, if deemed feasible.  
Statistical analyses will be performed using SAS® version 9.4 or greater. 
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 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 60 
9. 
ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the Lead 
Investigator.  
There will be no alterations in the protocol without the express written approval of the Sponsor, 
Investigator, the IRB/EC/REB, and regulatory authorities, as applicable. 
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 4033 
 
CONFIDENTIAL 
Version: 13 July 2016 
Page 61 
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 this study will be obtained from all patients before 
protocol-specific Day 1 procedures are carried out.  If a patient is physically unable to sign 
consent, a Legal Designee of the patient may sign ICF on their behalf if verbal consent is given 
by the patient. 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, or their Legal Designee, prior to protocol-specific procedures being performed.  The 
patient will be given a copy of the signed ICF 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 Good Clinical Practices (GCP) 
The study procedures outlined in this protocol will be conducted in accordance with the CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), and Applications for FDA Approval to Market a New Drug (21 CFR 314), as 
appropriate.  As such, these sections of U.S. Title 21 CFR, along with the applicable ICH 
Guidelines, are commonly known as Good Clinical Practices (GCP). 


Protocol CY 4033 
 
CONFIDENTIAL 
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Page 62 
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. 
Saville, B. R., A. H. Herring, et al. (2010). A Robust Method for comparing Two Treatments in a 
Confirmatory Clinical Trial via Multivariate Time-to-event Methods that jointly 
incorporate information from longitudinal and Time-to-event Data. Stat Med. Author 
Manuscript: 29(21): 75-85. 
 


Protocol CY 4033 
 
CONFIDENTIAL 
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Page 63 
APPENDIX A. SCHEDULE OF EVENTS 
Procedures 
Day 1 
Clinic 
Week 2 
Call 
Week 4 
Clinic 
Week 63 
PI/Sub-I 
Call 
Week 8 
Clinic 
Week 10 
Call 
Week 12 
Clinic 
Week 24 
Clinic 
 
Week 36 
Clinic 
Week 48 
Clinic 
Every 12 
Weeks 
Ongoing 
Clinic 
Tirasemtiv 
Disc Clinic 
Visit 
Tirasemtiv 
Disc Phone 
Call 
28 Day 
Safety 
Follow-up 
Clinic Visit 
28 Day 
Safety 
Follow-up 
Phone Call 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc/Exc Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Safety Labs1 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum Pregnancy Test2 
X 
 
 
 
 
 
 
X 
 
X 
 
X2 
 
 
 
PK Sample4 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
SVC 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
ALSFRS-R 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality Assessment 
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 
Tirasemtiv Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
1 TSH every year after Day 1 Clinic Visit 
2 Serum pregnancy test only for females of child bearing potential at Day 1 Clinic Visit, every 24 weeks thereafter, and at the Tirasemtiv Discontinuation Visit  
3 Phone contact with patient by PI or designee with prescriptive authority in their local jurisdiction  
4 PK Sample to be collected every 24 weeks after the Week 48 Clinic Visit as well as Tirasemtiv Discontinuation and 28 Day Safety Follow-Up Visits 
 


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CONFIDENTIAL 
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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/ 

SAP_001.pdf: 
 
Statistical Analysis Plan - Protocol CY 4033 
 
Version 1.0 dated 24 October 2017 
 
 
1 
 
 
CONFIDENTIAL 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NUMBER: 
CY 4033 
 
STUDY TITLE: 
A Phase 3, Open-Label Extension Study of Tirasemtiv for Patients with Amyotrophic Lateral 
Sclerosis (ALS) who Completed VITALITY-ALS (CY 4031)        
 
STUDY DRUG: 
Tirasemtiv 
 
VERSION: 1.0 
 
DATE OF PLAN: 
24 October 2017 
 
BASED ON: 
Protocol Dated on 13 July 2016 
 
 
SPONSOR: 
Cytokinetics, Inc.  
280 East Grand Avenue, 
South San Francisco, CA 94080 
Tel No.  650 624 3000 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 


 
Statistical Analysis Plan - Protocol CY 4033 
 
Version 1.0 dated 24 October 2017 
 
 
2 
 
 
CONFIDENTIAL 
SIGNATURE PAGE 
 
* This document has been reviewed and approved by: 
 
Long Ma, Ph.D. 
Senior Biostatistician, Biometrics 
Cytokinetics, Inc. 
 
 
 
 
 
 
 
Lisa Meng, Ph.D. 
Senior Director, Biometrics 
Cytokinetics, Inc. 
 
 
 
 
 
 
 
Bettina Cockroft, M.D., Ph.D. 
Vice President, Clinical Research 
Cytokinetics, Inc. 
 
 
 
 
 
 
 
 
*See electronic signatures at the end of the document. 
 


 
Statistical Analysis Plan - Protocol CY 4033 
 
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CONFIDENTIAL 
TECHNICAL SUMMARY REPORT (TSR) 
 
Name of Sponsor/Company 
Cytokinetics, Inc.  
Individual Study Table 
Referring to Part of the 
Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
Tirasemtiv 
Page: 
 
Name of Active Ingredient: 
CK-2017357 
 
 
Title of Study: 
A Phase 3, Open-Label Extension Study of Tirasemtiv for Patients with Amyotrophic Lateral Sclerosis (ALS) 
who Completed VITALITY-ALS (CY 4031)   
Investigators: 
Study Center(s):  
Studied Period (years): up to 6 years   
Phase of Development: Phase 3 - Open Label Extension 
Objectives: 
Primary:  
The primary objective is to assess the long-term safety and tolerability of tirasemtiv, in patients with 
Amyotrophic Lateral Sclerosis (ALS). 
Secondary:  
1. To compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 with 
those who completed treatment with placebo in CY 4031 during continued treatment of both groups with 
tirasemtiv during CY 4033. 
2. To compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 during 
that study with their clinical course during continued treatment with tirasemtiv during CY 4033. 
3. To compare the clinical course of patients who completed treatment with placebo in CY 4031 during 
that study with their clinical course during treatment with tirasemtiv during CY 4033. 
Methodology: 
CY 4033 is an open-label extension study of tirasemtiv in patients with ALS who completed participation 
(through Week 56) in CY 4031 (VITALITY-ALS).  Following enrollment, patients will begin dosing with 
tirasemtiv 125 mg twice daily (250 mg/day) for 4 weeks and will titrate to their maximum tolerated dose with an 
increase to 375 mg/day at Week 4 and (if 375 mg/day is tolerated) to 500 mg/day at Week 6, the maximum dose 
being 250 mg twice daily (500 mg/day). Patients can down-titrate to a tolerated dose of tirasemtiv at any time. 
Clinic visits will occur at Day 1, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Slow vital capacity 
(SVC), the ALS Functional Rating Scale (as revised; i.e., the ALSFRS-R), laboratory evaluations, vital signs, 
adverse events, and other related assessments will be conducted at each clinic visit. 


 
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Number of Patients (Planned and Analyzed): 
Approximately 350 patients who completed CY 4031 through the Follow-up Visit are expected to be enrolled in 
this open-label extension study. 
Diagnosis and Main Criteria for Inclusion and Exclusion: 
Inclusion criteria: 
1. Able to comprehend and willing to sign an Informed Consent Form. 
2. Completed participation on study drug and the Follow-up Visit in CY 4031 study 
Exclusion criteria: 
1. Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during the course of 
the study. 
2. Has taken any investigational study drug (other than tirasemtiv) prior to dosing, within 30 days or five 
half-lives of the prior agent, whichever is greater. 
3. Use of tizanidine and theophylline-containing medications during study participation. 
4. Participation or planning to participate in another clinical trial involving stem cell therapy for the 
treatment of ALS or another investigational drug 
Test Product, Dose and Mode of Administration: 
CK-2017357 (tirasemtiv) investigational product is supplied as immediate release, white, modified oval tablets 
containing 125 mg of tirasemtiv which are to be stored under secure conditions at 15-30°C; 59-86°F. Tirasemtiv 
tablets will be supplied to the clinical site in induction sealed 60 cc white high-density polyethylene bottles 
containing 60 tablets per bottle. Bottles will be labeled with a lot number. 
In this open label extension study with tirasemtiv, the maximum dose level for all patients will be 500 mg/day. 
Initiation and titration of dosing will use the following schedule: 
• 
Treatment for 4 weeks at 250 mg/day (125 mg twice daily) 
• 
If tolerated, up-titration to 375 mg/day (125 mg in the morning and 250 mg in the evening) for 2 
weeks 
• 
If tolerated, up-titration to the final dose of 500 mg/day (250 mg twice daily) 
Duration of Treatment: 
Clinic visits will occur at Day 1, Weeks 4, 8, and 12, and every 12 weeks thereafter.  
Reference Therapy, Dose and Mode of Administration: 
Not applicable. 


 
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Criteria for Evaluation: 
Safety Endpoints: 
The long-term safety and tolerability of tirasemtiv will be assessed by the incidence of adverse events (AEs). 
Additional safety evaluations will include clinical laboratory results, vital signs, and suicidality assessments. 
Efficacy Endpoints: 
• 
Time to first use of assisted ventilation or death 
• 
Time to the first occurrence of respiratory insufficiency (defined as tracheostomy or the use of non-
invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive days) or death 
• 
Time to death  
• 
Change in percent predicted SVC from baseline  
• 
Change in ALSFRS-R score from baseline  
• 
Slope of changes from baseline in percent predicted SVC  
• 
Slope of changes from baseline in ALSFRS-R  
The time-to-event endpoints will be assessed from the baseline of CY 4031 and from the baseline of CY 4033 to 
the end of CY 4033. The change-from-baseline endpoints will be assessed from baseline of CY 4031 and from 
baseline of CY 4033 to Week 24 and Week 48 of CY 4033. The slope of change from baseline endpoints will be 
assessed during the first 24 weeks and first 48 weeks of either CY 4031 or CY 4033. 
Statistical Methods: 
Patients who received tirasemtiv at the first randomization in CY 4031 and who therefore continue to receive 
tirasemtiv during CY 4033 will be considered the “early start” treatment group. Patients who received placebo at 
the first randomization in CY 4031 and who therefore initiate tirasemtiv during CY 4033 will be considered the 
“delayed start” treatment group. Summary statistics (by treatment group and overall) for continuous endpoints 
will include numbers of patients, means, medians, standard deviations, minima, and maxima. For categorical 
endpoints, frequencies and percentages will be given. For time-to-event endpoints, the number of patients at risk, 
number of events, the median and Greenwood’s 95% confidence intervals (CI) of the median, and quartiles will 
be provided by Kaplan-Meier method. 
The number and percentage of patients reporting treatment-emergent adverse events (TEAEs) will be 
summarized by system organ class and preferred term for the early and delayed start treatment groups and overall. 
In addition, the number and percentage of patients reporting TEAEs will be tabulated by system organ class, 
preferred term, and severity for the early and delayed start treatment groups and overall. 
The change from baseline at each clinic visit will be analyzed using Mixed-Effect Model Repeated Measures 
(MMRM) model-based method which will include treatment group, baseline value, visit, pooled site, and riluzole 
use/non-use during the double-blind, placebo-controlled phase in CY 4031 as well as interaction terms for 
treatment group-by-baseline and treatment group-by-visit for efficacy endpoints. The least-squares mean of the 
difference between the treatment groups, standard error of the difference, and 95% CI of the difference will be 
presented.  
Slope endpoints will be analyzed using a mixed model which will include treatment group, baseline value, pooled 
site, time from baseline, riluzole use/non-use in the double-blind, placebo-controlled phase in CY 4031 as well as 
interaction terms for treatment group-by-baseline, and treatment group-by-time, assuming random slope effect. 
The estimated slope and the slope difference as well as their standard errors will be presented. 
 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................11 
1. 
INTRODUCTION ......................................................................................................13 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................14 
2.1. 
Study Objectives .........................................................................................................14 
2.1.1. 
Primary Objective .......................................................................................................14 
2.1.2. 
Secondary Objectives .................................................................................................14 
2.2. 
Study Endpoints ..........................................................................................................14 
2.2.1. 
Safety Endpoints .........................................................................................................14 
2.2.2. 
Efficacy Endpoints ......................................................................................................14 
2.2.3. 
Additional Time-to-Event Endpoints .........................................................................15 
2.2.4. 
Additional Change-from-Baseline and Slope Endpoints ............................................16 
3. 
STUDY DESIGN .......................................................................................................17 
3.1. 
Summary of Study Design ..........................................................................................17 
3.2. 
Definition of Study Drugs ..........................................................................................17 
3.3. 
Sample Size Considerations .......................................................................................17 
3.4. 
Clinical Assessments ..................................................................................................17 
4. 
PLANNED ANALYSES ............................................................................................18 
4.1. 
Interim Analyses .........................................................................................................18 
4.2. 
Final Analysis .............................................................................................................18 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................19 
5.1. 
General Summary Table and Individual Patient Data Listing Considerations ...........19 
5.2. 
Data Management .......................................................................................................19 
5.3. 
Data Presentation Conventions ...................................................................................19 
5.3.1. 
Data Handling for Pharmacokinetics Data .................................................................20 
5.4. 
Analysis Populations ..................................................................................................20 
5.4.1. 
Screen Failures ............................................................................................................20 
5.4.2. 
Safety Analysis Set .....................................................................................................20 
5.4.3. 
Full Analysis Set .........................................................................................................20 
5.4.4. 
Efficacy Analysis Set ..................................................................................................20 
5.4.5. 
Pharmacokinetic Analysis Set ....................................................................................20 


 
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5.4.6. 
Pharmacodynamic Analysis Set .................................................................................20 
5.5. 
Baseline Definition .....................................................................................................21 
5.5.1. 
Baseline for Efficacy Endpoints .................................................................................21 
5.5.2. 
Baseline for Safety Endpoints ....................................................................................21 
5.6. 
Derived and Transformed Data ..................................................................................21 
5.6.1. 
Time Point and Durations ...........................................................................................21 
5.6.2. 
Time-to-Events Endpoints ..........................................................................................22 
5.6.3. 
ALS Functional Rating Scale-Revised .......................................................................22 
5.6.4. 
Respiratory Function ..................................................................................................22 
5.6.5. 
Change from Baseline .................................................................................................22 
5.6.6. 
Analysis Visit Windows .............................................................................................22 
5.6.7. 
Multiple Assessments within Visit Windows .............................................................23 
5.7. 
Handling of Missing Data ...........................................................................................23 
5.7.1. 
Missing Efficacy Endpoints ........................................................................................23 
5.7.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................23 
5.7.3. 
Missing Start and Stop Dates for Adverse Events ......................................................23 
6. 
STUDY POPULATION .............................................................................................25 
6.1. 
Patients Disposition ....................................................................................................25 
6.2. 
Protocol Deviations ....................................................................................................25 
6.3. 
Demographic and Baseline Characteristics ................................................................25 
6.3.1. 
Demographics and Baseline Characteristics ...............................................................25 
6.3.2. 
Other Baseline Characteristics ....................................................................................26 
6.4. 
Listing of Patient Inclusion and Exclusion Criteria ....................................................26 
6.5. 
Medical Conditions Present at Entry ..........................................................................26 
6.6. 
Prior Medication History and Medications Present at Entry ......................................26 
6.7. 
Baseline Physical Examination ...................................................................................26 
6.8. 
Baseline Vital Signs ....................................................................................................26 
6.9. 
Baseline Laboratory Data ...........................................................................................26 
6.10. 
Baseline Efficacy Evaluations ....................................................................................26 
7. 
EFFICACY .................................................................................................................27 
7.1. 
General Considerations ...............................................................................................27 
7.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................29 


 
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7.3. 
Subgroup Analyses .....................................................................................................29 
7.4. 
Multiple Comparisons and Multiplicity......................................................................29 
7.5. 
Analysis of Change from Baseline Endpoints ............................................................29 
7.5.1. 
Change-from-Baseline to Week 24 and to Week 48 in CY 4033...............................29 
7.5.2. 
Slope of Changes-from-Baseline ................................................................................30 
7.5.3. 
Sensitivity Analyses of the Change from Baseline.....................................................31 
7.6. 
Analysis of the Time-to-Event Endpoints ..................................................................31 
7.7. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................32 
8. 
SAFETY AND TOLERABILITY ..............................................................................33 
8.1. 
Overall Summary of Tolerability ................................................................................33 
8.2. 
Adverse Event Preferred Term and System Organ Class Summary Tables ...............33 
8.2.1. 
Summaries of Adverse Event Incidence Rates for All Patients .................................34 
8.2.2. 
Missing and Partial AE Onset Dates ..........................................................................34 
8.2.3. 
Summaries of Adverse Event Incidence Rates for Serious Adverse Events, 
Adverse Event Dropouts, and Deaths .........................................................................34 
8.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication .......................................................................34 
8.3.1. 
Total Duration of Exposure of Tirasemtiv ..................................................................34 
8.3.2. 
Average Daily Dose ....................................................................................................35 
8.3.3. 
Maintenance Dose Level ............................................................................................36 
8.4. 
Concomitant and Other Medications ..........................................................................36 
8.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........37 
8.5. 
Routine Laboratory Data ............................................................................................37 
8.6. 
Vital Signs ..................................................................................................................38 
8.7. 
Suicidality Assessment ...............................................................................................39 
8.8. 
Physical Examination .................................................................................................39 
8.9. 
Study Termination Status ...........................................................................................39 
9. 
PHARMACOKINETIC/ PHARMACODYNAMIC ANALYSIS .............................40 
9.1. 
Pharmacokinetic Analysis ..........................................................................................40 
9.2. 
Pharmacodynamic Analysis/ Pharmacokinetic Analysis ............................................40 
10. 
STATISTICAL CODES .............................................................................................41 
11. 
REFERENCES ...........................................................................................................44 


 
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APPENDIX 1. SCHEDULE OF EVENTS .................................................................................45 
 
 


 
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LIST OF TABLES 
Table 1: 
Study Dosing Plan ......................................................................................................17 
Table 2: 
Analysis Visit Windows in CY 4033 (Days) ..............................................................23 
Table 3: 
CY 4033 Analysis Set and Efficacy Endpoints ..........................................................28 
Table 4: 
Criteria for Clinically Significant Vital Signs ............................................................39 
Table 5: 
Depression Level Classification by BDI Total Score .................................................39 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALS  
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
ATC 
anatomical therapeutic chemical 
BDI 
Beck depression inventory  
BLQ 
below the lower limit of quantitation 
CI 
confidence interval 
eCRF 
electronic case report form 
CSR  
clinical study report 
EAS  
efficacy analysis set  
EDC 
electronic data capture  
FAS 
full analysis set 
ID 
identification 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MMRM 
mixed-effect model repeated measures 
NIV 
non-invasive ventilation 
NCI-CTCAE 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
PCS  
potential clinical significance 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PT 
preferred term  
Q1 
first quartile 
Q3 
third quartile 
SD 
standard deviation 
SAE 
serious adverse event 
SAS 
safety analysis set 
SAP  
statistical analysis plan 


 
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Abbreviation 
Term 
SOC 
system organ class  
SVC  
slow vital capacity  
TEAEs 
treatment-emergent adverse events  
TFL 
tables, figures and listings 
WHO 
World Health Organization 
 


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures and listings (TFL) in the clinical study report (CSR) for 
CY 4033 study. This SAP is based on the study protocol dated on 13 July, 2016. The SAP will 
be finalized before database finalization for CY 4031. Any changes made after the finalization of 
the SAP will be documented in an amended version of the SAP and will be tracked in the 
revision history. 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective is to assess the long-term safety and tolerability of tirasemtiv, in patients 
with Amyotrophic Lateral Sclerosis (ALS). 
2.1.2. 
Secondary Objectives 
The secondary objectives are: 
• To compare the clinical course of patients who completed treatment with tirasemtiv in 
CY 4031 with those who completed treatment with placebo in CY 4031 during 
continued treatment of both groups with tirasemtiv during CY 4033 
• To compare the clinical course of patients who completed treatment with tirasemtiv in 
CY 4031 during that study with their clinical course during continued treatment with 
tirasemtiv during CY 4033 
• To compare the clinical course of patients who completed treatment with placebo in 
CY 4031 during that study with their clinical course during treatment with tirasemtiv 
during CY 4033 
2.2. 
Study Endpoints 
2.2.1. 
Safety Endpoints 
The long-term safety and tolerability of tirasemtiv will be assessed primarily through the 
incidence of adverse events (AEs) during the study. Additional safety evaluations will include 
clinical laboratory results, vital signs, and suicidality assessments. 
2.2.2. 
Efficacy Endpoints 
There will be two analysis sets for the efficacy endpoints: 
1. The analyses for the efficacy endpoints with the reference baseline in CY 4031 will be 
based on the population of all patients in the Full Analysis Set (FAS) in CY 4031.  
2. The analyses for the efficacy endpoints with the reference baseline in CY 4033 will be 
based on the Efficacy Analysis Set (EAS) defined in Section 5.4.4. The analyses for 
selected efficacy endpoints from baseline in CY 4031 based on EAS will be conducted as 
well. 
2.2.2.1. 
Time-to-Event Endpoints 
There will be two analysis timeframes for time-to-event endpoints: 1) From baseline in CY 4031 
to the end of CY 4033; 2) From baseline in CY 4033 to the end of CY 4033. 
Time-to-event endpoints include the following: 


 
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1. Time to the first use of assisted ventilation or death. Assisted ventilation is defined as 
invasive (tracheostomy) or non-invasive ventilation (NIV) for at least 2 hours over a 24-
hour period for at least 5 consecutive days. 
2. Time to the first occurrence of respiratory insufficiency (defined as tracheostomy or the 
use of non-invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive days) or death 
3. Time to death 
2.2.2.2. 
Change-from-Baseline Endpoints 
Change-from-baseline endpoints will be presented descriptively only if one third of patients 
remain in either of the delayed start or early start treatment groups in CY 4033 at the time points 
indicated below. 
Change-from-baseline endpoints: 
1. Change in percent predicted slow vital capacity (SVC) (Knudson, Lebowitz et al. 1983) 
from baseline in CY 4031 to Week 24 and to Week 48 of CY 4033 
2. Change in percent predicted SVC from baseline in CY 4033 by visit in CY 4033 
3. Change in ALS Functional Rating Scale-Revised (ALSFRS-R) (Cedarbaum, Stambler et 
al. 1999) total score from baseline in CY 4031 to Week 24 and to Week 48 of CY 4033 
4. Change in ALSFRS-R total score from baseline in CY 4033 by visit in CY 4033 
2.2.2.3. 
Slope Endpoints 
Slopes of changes from baseline in percent predicted SVC and in ALSFRS-R total score during 
the first 24 and first 48 weeks of CY 4033 include the following: 
1. Slopes of changes from CY 4031 baseline in percent predicted SVC to Week 24 and to 
Week 48 in CY 4033 
2. Slopes of changes from CY 4033 baseline in percent predicted SVC to Week 24 and to 
Week 48 in CY 4033 
3. Slopes of changes from CY 4031 baseline in ALSFRS-R total score to Week 24 and to 
Week 48 in CY 4033 
4. Slopes of changes from CY 4033 baseline in ALSFRS-R total score to Week 24 and to 
Week 48 in CY 4033 
2.2.3. 
Additional Time-to-Event Endpoints 
The following time-to-event endpoints will be analyzed using the two timeframes defined in 
Section 2.2.2.1: 
1. Time to the first occurrence of a decline from baseline in percent predicted SVC ≥ 20 
percentage points or the onset of respiratory insufficiency (defined as tracheostomy or the 
first day of the use of non-invasive ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days) or death 


 
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2. Time to the first occurrence of a decline from baseline in percent predicted SVC ≥ 20 
percentage points or the first use of mechanical ventilatory assistance or death. 
Mechanical ventilatory assistance is defined as invasive or non-invasive ventilation for at 
least 2 hours over a 24-hour period for at least 5 consecutive days 
3. Time to the first occurrence of a decline from baseline in SVC to ≤ 50 percent predicted 
or the onset of respiratory insufficiency (defined as tracheostomy or the first day of the 
use of non-invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive days) or death 
4. Time to the first occurrence of a decline from baseline in SVC to ≤ 50 percent predicted 
or first use of mechanical ventilatory assistance or death.  
5. Time to the initiation of regular use of non-invasive ventilation or death. The regular use 
of non-invasive ventilation is defined as non-invasive ventilation use for at least 2 hours 
over a 24-hour period for at least 5 consecutive days. 
6. Time to the first occurrence of a two-point or greater drop in the composite of the 
respiratory components of the ALSFRS-R (i.e., items 10, 11, and 12) from baseline or 
death. 
2.2.4. 
Additional Change-from-Baseline and Slope Endpoints 
1. Change from CY 4031 baseline in the respiratory sub-score of the ALSFRS-R (i.e., the 
sum of scores for items 10, 11, and 12) to Week 24 and to Week 48 in CY 4033 
2. Change from CY 4033 baseline in the respiratory sub-score of the ALSFRS-R (i.e., the 
sum of scores for items 10, 11, and 12) by visit in CY 4033 
3. Slopes of changes from CY 4031 baseline in the respiratory sub-score of the ALSFRS-R 
(i.e., the sum of scores for items 10, 11, and 12) to Week 24 and to Week 48 in CY 4033 
4. Slopes of changes from CY 4033 baseline in the respiratory sub-score of the ALSFRS-R 
(i.e., the sum of scores for items 10, 11, and 12) to Week 24 and to Week 48 in CY 4033 


 
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
CY 4033 is a multi-national, open-label extension treatment study with the selective fast skeletal 
muscle troponin activator, tirasemtiv, in patients with ALS who completed participation (through 
Week 56) in the VITALITY-ALS (CY 4031) study. Following enrollment, patients will begin 
dosing with tirasemtiv 125 mg twice daily (250 mg/day) for 4 weeks and will titrate to their 
maximum tolerated dose with an increase to 375 mg/day at Week 4 and (if 375 mg/day is 
tolerated) to 500 mg/day at Week 6, the maximum dose being 250 mg twice daily (500 mg/day). 
Patients who do not tolerate a higher dose after up-titration may return to a previously tolerated 
dose at any time. No upward dose adjustments are allowed after a dose reduction. 
Table 1: 
Study Dosing Plan 
Initial Dose 
(Day 1 Clinic Visit) 
Planned Up-Titration 
(Week 4 Clinic Visit) 
Planned Up-Titration 
(Week 6 Phone Call) 
250 mg tirasemtiv total daily dose 
First dose: 1 tablet (125 mg) of 
tirasemtiv 
Second dose: 1 tablet (125 mg) of 
tirasemtiv 
(approximately 12 hours apart) 
375 mg tirasemtiv total daily dose 
First dose: 1 tablet (125 mg) of 
tirasemtiv 
Second dose: 2 tablets (250 mg) of 
tirasemtiv 
(approximately 12 hours apart) 
500 mg tirasemtiv total daily dose 
First dose: 2 tablets (250 mg) of 
tirasemtiv 
Second dose: 2 tablets (250 mg) of 
tirasemtiv 
(approximately 12 hours apart) 
Clinic visits will occur at Day 1, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, and 
every 12 weeks thereafter. Patients will be contacted by phone to assess their tolerance of 
tirasemtiv at Week 2, Week 6, and Week 10. If a patient discontinues tirasemtiv, the patient will 
come to the clinic for the Tirasemtiv Discontinuation Visit and the 28 Day Safety Follow-up 
Visit if the patient is able; otherwise the patient will be contacted by phone for these visits. Slow 
vital capacity (SVC), the ALS Functional Rating Scale (as revised; i.e., the ALSFRS-R), 
laboratory evaluations, vital signs, adverse events, and other related assessments will be 
conducted at each clinic visit. 
3.2. 
Definition of Study Drugs 
The investigational product or study drug in CY 4033 is CK-2017357 (tirasemtiv). 
3.3. 
Sample Size Considerations 
Approximately 350 patients who completed CY 4031 through the Follow-up Visit are expected to be 
enrolled in this open-label extension study, CY 4033.  
3.4. 
Clinical Assessments 
Clinical safety assessments, including clinical laboratory evaluations, vital signs and suicidality 
assessment (Beck Depression Inventory-Fast Screen) (Beck, Steer et al. 1996), and efficacy 
assessments, including ALSFRS-R and SVC, are listed in Schedule of Events (Appendix 1). 


 
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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
CY 4033 is an open-label extension study of tirasemtiv in patients with ALS who completed 
CY 4031. After database lock and unblinding of study CY 4031, an interim analysis of CY 4033 
will be performed. 
Additional interim analyses also may be conducted after all patients reach study time point 
milestones. Possible milestones include (but are not limited to): Week 24, Week 48, and Week 
96. Trigger criterion for these potential milestones will be based upon emerging safety and 
tolerability data from the CY 4033 study. A description of any interim analyses conducted while 
the study is ongoing will be specified in separate statistical analysis plan(s). Each interim 
analysis plan will provide the details of data cut-off, including data cutoff date, data extraction 
date, data cleaning and extraction specifications. 
4.2. 
Final Analysis 
The final analysis of the data will be performed after all patients discontinue study participation 
and final database lock.  


 
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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
5.1. 
General Summary Table and Individual Patient Data Listing 
Considerations 
Analysis results will be presented using descriptive statistics by early start (the group of patients 
who received tirasemtiv at the first randomization in CY 4031) and delayed start (the group of 
patients who received placebo at the first randomization in CY 4031 and began tirasemtiv during 
CY 4033) treatment groups and overall in summary tables in the safety and efficacy analysis 
sets. For continuous variables, the number of patients, mean, standard deviation (SD), median, 
minimum and maximum will be presented; for categorical variables, the number and percentage 
of patients in each category will be presented; time-to-event endpoints will be summarized using 
Kaplan-Meier method (Kaplan and Meier 1958) (first quartile (Q1), third quartile (Q3), median, 
and corresponding Greenwood’s 95% confidence intervals (CIs) (Kalbfleisch and Prentice 
2011). For model-based analysis, least-squares mean, difference of least-squares means between 
the early start and delayed start treatment groups, their standard errors and 95% CIs, and 2-sided 
p-values for the relative statistical inferences will be presented. The above comparisons will be 
performed by the maintenance dose level defined in Section 8.3.3.  
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.  
Data will be presented in by-patient listings for all patients unless otherwise specified. All by-
patient listings will be sorted by treatment group, patient ID and visit and will include 
demographics (age at baseline of CY 4033 and sex), maintenance dose level, in ascending order. 
5.2. 
Data Management 
Data will be entered into an electronic data capture (EDC) system with programmed edit checks 
to insure integrity. Any missing data and potential data issues will be queried to the participating 
clinical sites. Laboratory tests will be conducted by a central laboratory with results entered into 
database managed by the central laboratory. 
5.3. 
Data Presentation Conventions 
The following conventions are applied to all data presentations and summaries. 
• For continuous variables, all mean and median values are formatted to one more 
decimal place than the measured value. Standard deviation values are formatted to 
two more decimal places than the measured value. Minimum and maximum values 
are presented with the same number of decimal places as the measured value. 
• For categorical variables, the number and percentage of responses are presented in the 
form XX (XX.X%). 
• P-values, if applicable, will be presented to 4 decimal places. If the p-value is less 
than 0.0001 then it will be presented as < 0.0001. If the rounded result is a value of 
1.000, it will be displayed as > 0.9999. 


 
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5.3.1. 
Data Handling for Pharmacokinetics Data 
Natural logarithm transformation will be used for the analysis of plasma/blood concentrations. 
Plasma concentration values that are below the lower limit of quantitation (BLQ) will be 
presented as “BLQ” in the concentration data listing.  
5.4. 
Analysis Populations  
Analysis populations define the patients to be included in an analysis. Analysis sets and their 
definitions are provided in this section. For each analysis set, the number and percentage of 
patients eligible for inclusion, as well as the number and percentage of patients who were 
excluded and the reasons for their exclusion, will be provided by early start and delayed start 
treatment groups. 
5.4.1. 
Screen Failures 
Not applicable. Patients who signed the Informed Consent Form but did not receive the study 
medication will be listed and excluded from analysis. 
5.4.2. 
Safety Analysis Set 
The Safety Analysis Set (SAS) will consist of all patients who were enrolled and received at least 
one dose of tirasemtiv in CY 4033. 
5.4.3. 
Full Analysis Set 
The Full Analysis Set will consist of all randomized patients who received at least one dose of 
study medication during the randomized double-blind, placebo-controlled phase and had at least 
one post-randomization efficacy assessment in CY 4031, regardless of whether or not they 
continued into CY 4033. 
5.4.4. 
Efficacy Analysis Set 
The Efficacy Analysis Set will consist of all patients who completed CY 4031, were enrolled in 
CY 4033, received at least 1 dose of tirasemtiv, and had at least one post-baseline efficacy 
outcome assessment during CY 4033. If there is a gap of more than 60 days between the Week 
56 Follow-up Visit in CY 4031 and Day 1 in CY 4033, and the patient does not have a Day 1 
assessment in CY 4033, then the patient will be excluded in the efficacy analysis set. 
5.4.5. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set includes all patients who were received at least 1 dose of 
tirasemtiv and have at least 1 measurable post-dose concentration value for tirasemtiv, provided 
they have no major protocol violations that could affect the PK of tirasemtiv in CY 4033. 
5.4.6. 
Pharmacodynamic Analysis Set 
The Pharmacodynamic (PD) Analysis Set includes all patients who received at least 1 dose of 
tirasemtiv and have at least 1 measurable post-dose tirasemtiv plasma concentration and at least 
one measurable post-baseline assessment of at least one the PD endpoints in CY 4033. 


 
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5.5. 
Baseline Definition 
5.5.1. 
Baseline for Efficacy Endpoints  
Two baseline values will be used for change-from-baseline endpoints:  
• The CY 4033 baseline value refers to the assessment at the Day 1 in CY 4033. If the 
assessment at the Day 1 in CY 4033 is not available, and no more than 60 days have 
elapsed since the assessment at the Follow-up Visit (Week 56) in CY 4031, the 
assessment at the Follow-up Visit (Week 56) in CY 4031 will be the baseline in 
CY 4033. 
• The CY 4031 baseline refers to the last available assessment prior to the first dose of 
the open-label lead-in phase in CY 4031. 
Two reference dates will be used for time-to-event endpoints: 
• The date of first dose of study drug in the double-blind, placebo-controlled phase of 
CY 4031 
• The date of first dose of study drug in CY 4033  
5.5.2. 
Baseline for Safety Endpoints  
Baseline for clinical laboratory assessments, suicidality assessment and vital signs are defined as 
the last non-missing assessment prior to the first dose of study drug in CY 4033. 
5.6. 
Derived and Transformed Data 
5.6.1. 
Time Point and Durations 
1. Two timeframes for time-to-event endpoints will be used in this study: 
Time-to-event days relative to reference date = event date – reference date + 1 
The reference date is the date of first dose of study drug in double-blind, placebo-
controlled phase in CY 4031 or the date of first dose of tirasemtiv in CY 4033. 
2. Days to AE onset: 
Days to AE onset = onset date – first dose date in CY 4033 + 1 
Days to AE onset = onset date – first dose date in CY 4033 (if onset is before the date of 
first dose of CY 4033)  
3. Days of change-from-baseline 
Days from CY 4031 baseline = post-baseline assessment date – assessment date at 
CY 4031 baseline + 1 
Days from CY 4033 baseline = post-baseline assessment date – assessment date at 
CY 4033 baseline + 1 


 
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5.6.2. 
Time-to-Events Endpoints 
Patients will be censored at the end of study if the patient does not experience an event prior to 
date of the last study contact. 
5.6.3. 
ALS Functional Rating Scale-Revised 
The ALS Functional Rating Scale-Revised (ALSFRS-R) assessments will be conducted on 
Screening, Open-label Lead-in phase, Double-Blind, Placebo Controlled Phase, Double-Blind, 
Placebo-Controlled, tirasemtiv Withdrawal Phase and Week 56 Follow up in CY 4031, and on 
Day 1, Week 4, Week 8, Week 12 and every 12 weeks thereafter and at the 28-day Follow-up 
Clinical Visit in CY 4033. The ALSFRS-R total score is the sum of the scores of the 12 
individual questions from all domains. Subtotal scores will also be calculated for each domain:  
• Bulbar domain: (1) speech, (2) salivation, (3) swallowing 
• Fine motor domain: (4) handwriting, (5) cutting food and handling utensils, (6) 
dressing hygiene  
• Gross motor domain: (7) turning in bed and adjusting bedclothes, (8) walking, (9) 
climbing stairs  
• Respiratory domain: (10) dyspnea, (11) orthopnea, (12) respiratory insufficiency  
The total score of ALSFRS-R cannot be calculated if the answer to any of the 12 individual 
questions is missing. Subtotal score will be assigned to missing if any question in the domain is 
missing. 
5.6.4. 
Respiratory Function 
Respiratory function will be analyzed by percent predicted SVC. The respiratory function 
assessments are conducted on Screening, Open-label Lead-in phase, Double-Blind, Placebo 
Controlled Phase, Double-Blind, Placebo-Controlled, tirasemtiv Withdrawal Phase and Week 56 
Follow up in CY 4031, and on Day 1, Week 4, Week 8, Week 12 and every 12 weeks thereafter 
at the 28-day Follow-up Clinical Visit in CY 4033. SVC is collected at each clinical visit. The 
highest result from trials 1, 2, and 3 for SVC, measured in liters at each clinical visit as recorded 
on the eCRFs, and the calculated percent predicted SVC will be used for analysis.  
5.6.5. 
Change from Baseline 
Baseline for efficacy endpoints are defined in the Section 5.5.  
Change from baseline = post-baseline assessment value – baseline value 
5.6.6. 
Analysis Visit Windows 
Nominal visits in CY 4033 will be used for all analyses. Nominal visits in CY 4031 will be used 
in the comparisons of clinical course of patients in CY 4031 and CY 4033. Please see the section 
of Analysis Visit Windows for the definition of nominal visits in the SAP for CY 4031. 
Unscheduled visits in CY 4033 will be assigned to the closest nominal visit if data at the nominal 
visit is not available. The lower limit and upper limit of each nominal visit is listed in Table 2 
below. 


 
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Table 2: 
Analysis Visit Windows in CY 4033 (Days) 
Nominal Visit 
Nominal Day 
Lower Limit 
Upper Limit 
Day 1 
1 
1 
1 
Week 4 
29 
2 
42 
Week 8 
57 
43 
70 
Week 12 
85 
71 
126 
Week 12*n 
12*n*7+1 
12*(n-0.5)*7+1 
12*(n+0.5)*7 
- 
Day displayed for these nominal visits is calculated relative to Day 1 dosing in CY 4033 
- 
n: start from 2 
5.6.7. 
Multiple Assessments within Visit Windows 
If multiple non-missing numeric observations exist in an analysis window or with same nominal 
visit name, records closest to the nominal day will be chosen if a single value is needed. The later 
measurement will be used if there are ties. 
5.7. 
Handling of Missing Data 
5.7.1. 
Missing Efficacy Endpoints 
The handling of missing efficacy endpoints is described in Section 7.5.3. 
5.7.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
No imputation of missing/partial dates will be performed. The available year or year and month 
in a partial date will be used and will be compared to first dosing year, month and day to 
determine whether to include the medication in the medication history or as a concomitant 
medication. If the available data do not give sufficient information to classify the medication, the 
medication will be classified as a concomitant medication. 
5.7.3. 
Missing Start and Stop Dates for Adverse Events 
For AEs with incomplete date information recorded in the eCRF, date/time imputation will 
follow the algorithm below: 
1. For missing AE onset dates and times: 
• If the AE onset date is missing and the month of AE onset is after the month of the 
first dosing date, then the first day of the month of AE onset will be the imputed date 
of AE onset. 
• If the AE onset date is missing and the month of AE onset is the same as the month of 
the first dosing date in CY 4033 and the AE onset is after the first dosing date, then 
the first dosing date in CY 4033 will be the imputed AE onset date. 
• If no AE onset information is available and the AE was not reported in CY 4031, then 
the first dosing date in CY 4033 will be the imputed AE onset date. 


 
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• If the AE which was carryover from CY 4031 is without AE onset information, then 
the AE onset date will follow the imputation rules defined in Section 8.2 of CY 4031 
SAP. 
2. For missing AE end dates and times: 
• If the AE end date is missing and the AE end month is earlier than that of the Follow-
up Visit, then the last day of the AE end month will be the imputed as the AE end 
date. 
• If the AE end date is missing and the AE end month is the same as that of the Follow-
up Visit, then the date of the Follow-up Visit will be the imputed as the AE end date. 
• If no AE end information is available, then AE end date will not be imputed. 
 


 
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6. 
STUDY POPULATION 
6.1. 
Patients Disposition 
Patient disposition will be presented for the SAS. The number and percentage of patients who 
completed CY 4031, and who did not receive any study drug, who received at least one dose of 
study drug, who discontinued from treatment, and who discontinued from the study will be 
presented by early start and delayed start treatment group and overall in CY 4033. 
Reasons for dose discontinuation as recorded on the End of Dosing page, and reasons for the 
study discontinuation as recorded on the End of Study page of the eCRF will be summarized as 
well. 
A listing of patient disposition will be provided for the SAS. The listing will include the 
following: date of Week 56 Follow-up in CY 4031, dates of first and last dose in CY 4033, dates 
of final follow-up visit/last study contact, date of death, duration of tirasemtiv in CY 4031 and 
CY 4033 and in CY 4033 alone, demographic information (including age on CY 4033 Day 1), 
dose received at the time of tirasemtiv discontinuation, and reason for study discontinuation in 
CY 4033. The listing will be sorted by patient ID number in ascending order. 
6.2. 
Protocol Deviations 
A protocol deviation is any divergence from the protocol that impacts a patient's safety, or 
welfare or materially reduces the quality or completeness of the data. 
The number and percentage of patients meeting any of the following protocol deviation criteria 
will be summarized by type of deviation, by the early start and delayed start treatment groups, 
and overall: 
1. Patient was enrolled even though they did not satisfy inclusion and exclusion criteria; 
2. Patient developed withdrawal criteria during the study but was not withdrawn; 
3. Patient received the incorrect dose of tirasemtiv; 
4. Patient took more than 50 mg riluzole while taking tirasemtiv; 
5. Patient received an excluded concomitant treatment.  
A listing will be provided by patient ID in ascending order. 
6.3. 
Demographic and Baseline Characteristics 
6.3.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by the early start and delayed start 
treatment groups and overall as well as by the maintenance dose level for the SAS. Summaries 
will also will be provided for the EAS if the number of patients in the SAS is 10% more than the 
number of patients in the EAS. Patient demographic and baseline characteristics will include the 
following: age at Day 1 in CY 4033, gender, race, height (in cm), body weight in (kg) and body 
mass index (BMI, in kg/m2). 
A listing will be provided by patient ID in ascending order. 


 
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6.3.2. 
Other Baseline Characteristics 
Other baseline characteristics include ALSFRS-R total and individual domain scores, and 
percent predicted SVC baselines in CY 4031 and in CY 4033. These baseline characteristics will 
be summarized by early start and delayed start treatment groups and overall using descriptive 
statistics (n, mean, SD, median, minimum, and maximum) for continuous variables and using the 
frequency counts and percentages of patients for categorical variables for the SAS. Summaries 
will also be provided for the EAS if the number of patients in the SAS is 10% more than the 
number of patients in the EAS.  
6.4. 
Listing of Patient Inclusion and Exclusion Criteria 
A listing of patients who do not meet inclusion and/or exclusion criteria will be provided by 
patient ID in ascending order. 
6.5. 
Medical Conditions Present at Entry 
Adverse events that are ongoing at the time of enrollment in Study CY 4033 are being collected 
using a Prior Adverse Events eCRF page and will be summarized as Adverse Events in 
CY 4033.  
6.6. 
Prior Medication History and Medications Present at Entry 
Medications started during the CY 4031 study and without stopping dates or after the first dose 
of study drug in CY 4033, or started during CY 4033 will be summarized as Concomitant 
Medications in CY 4033 (Section 8.4). 
6.7. 
Baseline Physical Examination 
Physical examination will be conducted at Day 1 visit in CY 4033 only. 
6.8. 
Baseline Vital Signs 
Baseline vital signs in CY 4033 will be the assessments at Day 1 in CY 4033. Baseline vital 
signs will be summarized and provided in the tables and listings along with post-baseline vital 
signs in Section 8.6. 
6.9. 
Baseline Laboratory Data 
Baseline laboratory data including hematology, serum chemistry, and urinalysis in CY 4033 will 
be the assessments at Day 1 in CY 4033. The baseline laboratory data in CY 4033 will be 
summarized and provided in the tables and listings along with post-baseline laboratory data 
Section 8.5. 
6.10. 
Baseline Efficacy Evaluations 
The baseline efficacy endpoints including percent predicted SVC and ALSFRS-R baseline 
values in CY 4031 and in CY 4033 defined in Section 5.5.1 will be summarized and presented in 
the tables and listings along with post-baseline efficacy assessments. 


 
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7. 
EFFICACY  
7.1. 
General Considerations 
Efficacy analysis will be based on the EAS unless otherwise specified.  
Two efficacy baseline values for change-from-baseline endpoints defined in Section 5.5.1 will be 
used in this study. Two timeframes defined in Section 2.2.2.1 will be used for time-to-event 
endpoints. 
Analyses will compare the effect of tirasemtiv on endpoints between the early start and the 
delayed start treatment groups. Analyses will also be conducted to compare the effect of 
tirasemtiv within the delayed start treatment group and the early start treatment group, 
separately. The efficacy endpoints and related analysis sets are listed in Table 3. 
Assumptions for statistical models will be graphically evaluated. If assumptions are substantially 
violated, alternative analysis methods will be considered. Missing data will not be imputed 
unless specified.  
 


 
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Table 3: 
CY 4033 Analysis Set and Efficacy Endpoints 
Analysis 
Population 
Baseline 
Data Included in the 
Analysis 
Efficacy Endpoints 
Subgroup 
Analysis 
Full 
Analysis Set 
CY 4031 
Including all 
CY 4031 data (i.e., 
including data from 
patients who did and 
who did not progress 
into CY 4033) and 
CY 4033 data 
Change from CY 4031 baseline to Week 24 and Week 48 of CY 4033 
in percent predicted SVC, ALSFRS-R total score, and ALSFRS-R 
respiratory domain score 
No 
Slope of change from CY 4031 baseline to Week 24 and to Week 48 
of CY 4033 in percent predicted SVC, ALSFRS-R total score and 
respiratory domain score in the analysis comparing the slope change 
during treatment in the double-blind, placebo-controlled phase in 
CY 4031 with slope change during treatment with tirasemtiv in the 
first 48 weeks in CY 4033 
No 
Time-to-event endpoints 
No 
Efficacy 
Analysis Set 
CY 4033 
Including CY 4033  
data only 
Change from CY 4033 baseline to Week 24 and to Week 48 of 
CY 4033 in percent predicted SVC, ALSFRS-R total score and 
respiratory domain score 
Yes 
Slope of change from CY 4033 baseline to Week 24 and to Week 48 
of CY 4033 in percent predicted of SVC, ALSFRS-R total score and 
respiratory domain score 
No 
Time-to-event endpoints 
No 
Efficacy 
Analysis Set 
CY 4031 
Including CY 4031 
data only from those 
patients who 
completed CY 4031 
and progressed into 
CY 4033  
and CY 4033 data 
Change from CY 4031 baseline to Week 24 and Week 48 of CY 4033 
in percent predicted SVC, ALSFRS-R total score and respiratory 
domain score 
No 
 
Slope of change from CY 4031 baseline to Week 24 and to Week 48 
of CY 4033 in percent predicted SVC, ALSFRS-R total score and 
respiratory domain score in the analysis comparing the slope change 
during treatment in the double-blind, placebo-controlled phase in 
CY 4031 with slope change during treatment with tirasemtiv in the 
first 48 weeks in CY 4033 
No 


 
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7.2. 
Testing Statistical Assumptions Including Comparability at Baseline 
Not applicable. 
7.3. 
Subgroup Analyses 
Analyses of the efficacy endpoints including change from baseline in percent predicted SVC and in 
ALSFRS-R total score in subgroups may be conducted on EAS with CY 4033 baseline descriptively. 
No statistical test will be conducted. 
Subgroup factors are: 
1. Riluzole Use/Non-Use at the enrollment in CY 4033 
2. Gender (Male vs. Female)  
3. Age group at Day 1 in CY 4033 (<65, ≥ 65 years old) 
4. Geographic region (North America vs. Europe)   
5. Time from ALS symptom onset to CY 4031 baseline (< median vs. ≥ median) 
TEAEs will be summarized overall in the following subgroups: 
1. Gender (Male vs. Female) 
2. Age group at Day 1 in CY 4033 (< 65, ≥ 65 years old) 
3. Riluzole Use/Non-Use at the enrollment in CY 4033 
To graphically display treatment effect changes across subsets, arithmetic mean differences by 
subgroup level will be produced. 
7.4. 
Multiple Comparisons and Multiplicity 
No adjustment will be made for multiple comparisons. 
7.5. 
Analysis of Change from Baseline Endpoints 
7.5.1. 
Change-from-Baseline to Week 24 and to Week 48 in CY 4033 
Analyses for the endpoints starting from CY 4031 baseline will be performed on FAS; analyses 
for the endpoints starting from CY 4033 baseline will be performed on EAS; analyses for the 
endpoints of change from CY 4031 baseline to Week 48 in CY 4033 will be performed on EAS 
as well. Please see the analyses of endpoints with related analysis sets in Table 3. 
Endpoints of change-from-baseline include change-from-baseline in percent predicted SVC, in 
ALSFRS-R total score and in ALSFRS-R respiratory sub-score. Descriptive statistics will be 
provided by visit and by early start and delayed start treatment groups and overall.  
The difference in the change from either CY 4031 baseline or CY 4033 baseline at Week 24 or at 
Week 48 in CY 4033 between patients in the early start and the delayed start treatment 
(referenced as “treatment” in the model statement below) with tirasemtiv during the open-label 
extension phase will be evaluated using a repeated-measures mixed model using the restricted 
maximum likelihood method (Henderson 1984).  


 
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The model will include terms for treatment group, percent predicted SVC (or ALSFRS-R) at 
baseline, visit, pooled site, and CY 4031 baseline riluzole use/non-use as well as interaction 
terms of treatment-by-percent predicted SVC (or ALSFRS-R) at baseline, treatment-by-visit with 
an unstructured covariance matrix. If the model fails to converge, other covariance matrix 
structures (e.g., Toeplitz or compound symmetry) may be used instead of the unstructured 
covariance matrix. In this case, Akaike's information criterion (proportional to maximized log 
likelihood – number of parameters) will be used to guide the choice of covariance structure. The 
least-squares mean of the difference between the early start and the delayed start treatment 
groups, standard error of the difference, and 95% CIs of the difference will be presented. The 
treatment effect will be calculated in an estimate statement. The CY 4031 and CY 4033 baselines 
will be included as a covariate in the different mixed models. For the analyses of change from 
CY 4031 baseline, data collected from CY 4031 double-blind phase are also included in the 
model. Section 10 provides sample SAS code for this analysis. 
The analyses will be performed on FAS and EAS separately. Treatment group differences will 
not be estimated if less than one third of the patients have data at Weeks 36 or 48 in CY 4033 in 
either of the treatment groups and descriptive statistics will be presented. Caution should be used 
when interpreting estimates when there is extensive missing data. Joint-rank tests or other rank-
based analyses may be explored as appropriate. Variable of pooled site will be removed if the 
model cannot converge in the subgroup analyses. 
Least-squares mean (±SE) plots of change-from-baseline at each visit will be provided.  
7.5.2. 
Slope of Changes-from-Baseline  
7.5.2.1. 
The Comparison of Slopes of Changes between the Treatment Groups in 
CY 4033 
Endpoints of slope of changes from baseline include slopes of changes from baseline in percent 
predicted SVC, in ALSFRS-R total score and in ALSFRS-R respiratory sub-score. Slope of 
changes from baseline during the first 24 weeks and during the first 48 weeks in CY 4033 will be 
analyzed using a mixed model which will include early start and delayed start treatment group, 
baseline value, pooled site, time from baseline, riluzole use/non-use in double-blinded, placebo-
controlled phase in CY 4031 as well as interaction terms of early start and delayed start treatment 
group-by-baseline, early start and delayed start treatment group-by-time, assuming random slope 
effect. The estimated slope and the slope difference as well as their standard errors will be 
presented. 
Days of change from baseline of the assessments in CY 4033 will be calculated based on the 
definitions in Section 5.6.1. 
The comparisons of slopes of changes from baseline in each parameter are conducted: 
1. Slope comparisons of the early start treatment and the delayed start treatment with 
respect to the estimated rate of change from CY 4031 baseline during the first 24 weeks 
and during the first 48 weeks in CY 4033 
2. Slope comparisons of the early start treatment and the delayed start treatment with 
respect to the estimated rate of change from CY 4033 baseline during the first 24 weeks 
and during the first 48 weeks in CY 4033 


 
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Scatter plots with regression line fit to the change from baseline either in CY 4031 or in CY 4033 
to Week 24 and to Week 48 in CY 4033 will be provided. 
7.5.2.2. 
The Comparison of Slopes of Changes from CY 4031 Baseline During the 
Treatment Course 
The comparison of slopes of changes from CY 4031 baseline during the treatment course will be 
based on the FAS. A piecewise linear mixed regression model will be used to compare the slope of 
changes from baseline in CY 4031 to Week 48 in CY 4031 and the slope of changes from baseline in 
CY 4031 during the first 48 weeks in CY 4033 in the early start and delayed start treatment groups, 
separately. The model will include the terms of percent predicted SVC (or ALSFRS-R) at baseline 
value in CY 4031, time from baseline in CY 4031, time from baseline in CY 4033 for the 
assessments in CY 4033, pooled site, riluzole use/non-use in double-blinded, placebo-controlled 
phase in CY 4031, assuming random intercept, time from CY 4031 baseline, and time from CY 4033 
baseline. The estimated slopes with standard error, difference of slopes between the treatment in 
double-blind, placebo-controlled phase in CY 4031 and the treatment in the first 48 weeks in 
CY 4033 in the early start and delayed start treatment groups with standard error and p-value will be 
presented.  
Piecewise regression (Ryan, Porth et al. 2002) line plots of changes from baseline in CY 4031 to 
Week 48 in CY 4031 and the changes from baseline in CY 4031 to Week 48 in CY 4033 during 
CY 4033 by treatment group will be provided. 
A by-patient listing with demographics, CY 4031 baseline, CY 4033 baseline, clinical visit, 
assessment date and time, measurement and change from baseline at clinical visits will be 
presented by patient ID in ascending order and clinical visit date in chronological order within 
patient. 
7.5.3. 
Sensitivity Analyses of the Change from Baseline 
If the percentage of missing values of percent predicted SVC is ≥ 20% at the end of the first 48 
weeks in CY 4033, multiple imputation will be used to impute the missing assessments. 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.  
No imputation will be conducted for the missing values of ALSFRS-R. 
Subgroup analysis will not be conducted for sensitivity analyses. 
7.6. 
Analysis of the Time-to-Event Endpoints 
Analyses for time-to-event endpoints starting from CY 4031 baseline will be performed on FAS; 
analyses for time-to-event endpoints starting from CY 4033 baseline will be performed on EAS.  
Time-to-event endpoints will be summarized using Kaplan-Meier method. A plot of the Kaplan-
Meier curves will be provided by early start and delayed start treatment group. Medians, ranges, 
Q1 and Q3, and corresponding Greenwood’s 95% CIs on the treatment estimates will be 
presented. Patients will be censored at the end of study if the patient does not experience an 
event prior to date of the last study contact. Log-rank tests (Peto and Peto 1972) will be 
performed. Cox regression analysis (Cox 1992) will be performed with the fixed factors of early 
start and delayed start treatment, riluzole use/non-use in double-blinded, placebo-controlled 


 
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phase in CY 4031, and percent predicted SVC at baseline, stratifying by pooled site to estimate 
the hazard ratio and its 95% CI between the early start and the delay start treatment groups with 
delay start treatment group as reference. The early tirasemtiv start treatment effect will be tested 
using the likelihood ratio test. 
The time-to-event endpoints will be calculated based on the definitions in Section 5.6.1. 
Subgroup analysis will not be conducted for time-to-event endpoints. 
7.7. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses 
Not Applicable.  


 
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8. 
SAFETY AND TOLERABILITY 
Analysis of safety and tolerability data will be based on the SAS and will include the time period 
which extends from the first dose of study medication in Study CY 4033 until the end of the 
Follow-up period unless otherwise specified. Results will be summarized by early start and 
delayed start treatment groups and overall. 
The analysis of safety and tolerability data includes summaries of tolerability, adverse event 
preferred terms by system organ class, drug exposure (duration of treatment), dosing 
information, concomitant medications, clinical laboratory results, vital signs, suicidality 
assessment, and reasons of early termination from the treatment. Tables summarizing the adverse 
events reported by patients who died, experienced non-fatal serious adverse events (SAE), or 
prematurely discontinued the study due to adverse event (AEs) will be prepared. Summaries of 
potentially clinically notable laboratory results and vital sign abnormalities will be presented. 
Data listings will be provided to support the summaries of deaths, SAEs, AEs, and laboratory 
and vital sign abnormalities and will be sorted first by patient then by event preferred term or 
parameter. 
In general, inferential statistical tests are not performed for adverse event incidence rates unless 
specified.  
8.1. 
Overall Summary of Tolerability 
The overall summary of tolerability table will present data by early start and delayed start 
treatment groups and overall for all treated patients separately. Entries in this table are the 
number of: 
1. Patients treated and days of drug exposure. 
2. Patients with treatment emergent adverse events. 
3. Patients with serious treatment emergent adverse events. 
4. Patients requiring a dose reduction due to adverse events. 
5. Patients discontinuing treatment due to adverse events. 
6. Deaths. 
8.2. 
Adverse Event Preferred Term and System Organ Class Summary 
Tables 
A treatment-emergent adverse event (TEAE) is an AE with an onset after initiation of study drug 
dosing in CY 4033, or an AE present at initiation of study drug dosing in CY 4033 that worsens 
in severity after initiation of study drug dosing. 
TEAEs will be assigned to the total daily dose level administered immediately prior to the onset 
of the TEAE during the CY 4033 treatment.  
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify Adverse 
Events by system organ class (SOC) and preferred term (PT). Coding will be performed using 
version 18.0 of the MedDRA coding dictionary. The severity of adverse events will be evaluated 


 
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using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 4.0.  
TEAEs will be listed and summarized by the early start and delayed start treatment groups and 
maintenance dose level as well as total daily dose level administered immediately prior to the 
onset of the AE. Only TEAEs occurring through 28 days after the last dose of study drug will be 
summarized. All AEs will be included in patient listings. 
8.2.1. 
Summaries of Adverse Event Incidence Rates for All Patients 
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to NCI-CTCAE 
Version 4.0. The severity grade of events for which the investigator did not record severity will 
be categorized as “missing” for tabular summaries and data listings. The missing category will 
be listed last in summary presentation. 
The relationship of the event to tirasemtiv and the relationship of the event to riluzole will be 
collected using the AE eCRF page as follows:   
1. AE relationship to tirasemtiv: unrelated, related 
2. AE relationship to riluzole: unrelated, related 
If the relationship to tirasemtiv is missing, it will be imputed as related to tirasemtiv in the 
summaries; however, by-patient data listings will show the relationship as missing.  
A by-patient listing will include: age, gender dose of tirasemtiv at the onset of the event, time on 
treatment at the onset of the event, AE onset and resolution dates and times, SAE designation, 
classification by system organ class and preferred term, the event severity and relationship to 
study medication, action taken, and outcome sorted by onset date/time and SOC/PT ascendingly. 
8.2.2. 
Missing and Partial AE Onset Dates 
The handling of missing and partial AE onset dates are described in the Section 5.7.3 above. 
Imputed dates will be flagged in the individual patient listings. 
8.2.3. 
Summaries of Adverse Event Incidence Rates for Serious Adverse Events, 
Adverse Event Dropouts, and Deaths 
SAEs and AEs leading to treatment discontinuation or death will also be summarized by system 
organ class, preferred term, early start and delayed start treatment groups, the total daily dose 
level administered immediately prior to the onset of the TEAE, and overall. Listings will be 
presented, for patients who died and/or experienced serious AEs and for patients who 
discontinued due to TEAEs. 
8.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication 
8.3.1. 
Total Duration of Exposure of Tirasemtiv 
The total duration of exposure to tirasemtiv will be summarized by early start and delayed start 
treatment groups and overall for the safety population, regardless of any temporary interruptions 
in study drug administration, and will be expressed in days using up to 1 decimal place.  


 
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Duration of exposure to tirasemtiv in CY 4033 = Last tirasemtiv dose date in CY 4033 - First 
tirasemtiv dose date in CY 4033 + 1 
Duration of exposure to tirasemtiv in CY 4031 and CY 4033 combined for patients randomized to 
placebo in CY 4031: 
Duration of exposure to tirasemtiv in CY 4031 and CY 4033 = 
 
Last lead-in tirasemtiv dose date in CY 4031 – First lead-in tirasemtiv dose date in 
CY 4031 +1 + Duration of exposure to tirasemtiv in CY 4033  
Duration of exposure to tirasemtiv in Studies CY 4031 and CY 4033 combined for patients 
randomized to tirasemtiv in Study CY 4031: 
 
Last tirasemtiv dose date in CY 4031 – First lead-in dose date in CY 4031 +1 + Duration 
of exposure to study drug in CY 4033 
When the date of the last tirasemtiv dose is missing or partial, the following rule will be used to 
impute the last dose date: 
• If the last dose date is partial, then: last dose date will be imputed with the earliest of 
the last date of the month (if month and year are available) or the last month of the 
year (if only year is available), or the date of death. 
The total duration of exposure to tirasemtiv will be summarized using descriptive statistics 
(number of patients, mean, SD, median, minimum, and maximum) and using the number (i.e., 
cumulative counts) and percentage of patients exposed through the following time periods for 
each period in CY 4031 and CY 4033, respectively: 
In CY 4031: 
 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 
56  
In CY 4033: 
Week 12, Week 24, Week 36, Week 48 and every 12 weeks thereafter.  
The number of patients who have down titration or interruption, will be summarized by actual 
dose level at each clinical visits and phone call in CY 4033. 
8.3.2. 
Average Daily Dose 
The total number of tirasemtiv tablets received and average daily dose (mg) in CY 4031 and 
CY 4033 will be summarized using descriptive statistics (n, mean, SD, median, minimum, and 
maximum) by early start and delayed start treatment groups.  
The total number of tirasemtiv tablets received for patients in CY 4031 and CY 4033 combined 
will be the sum of the number of tablets collected from first lead-in tirasemtiv dose date in 
CY 4031 to the last tirasemtiv dose date in CY 4033. 
The total number of tirasemtiv tablets received for patients in CY 4033 will be the sum of the 
number of tablets collected from Day 1 to the last tirasemtiv dose date in CY 4033.  


 
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The total amount of tirasemtiv administered (mg) = total number of tablets administered * 125 mg 
The average daily dose (mg) will be calculated using the following formula: 
Average Daily Dose (mg) = 𝑇𝑇otal amount of study drug administered (mg)
Duration of exposure to study drug
 
The maximum daily dose of a patient in CY 4031 and CY 4033 combined is the maximum daily 
dose from first lead-in tirasemtiv dose date in CY 4031 to the last tirasemtiv dose date in 
CY 4033. The maximum daily dose of a patient in CY 4033 is the maximum daily dose from 
Day 1 to the last date of tirasemtiv of the patient in CY 4033.  
Final daily dose is the last daily dose administered prior to the study termination in CY 4033. 
A separate by-patient listing with the total duration of exposure of tirasemtiv, the total amount of 
tirasemtiv administered (mg), the average daily dose (mg), maximum daily dose (mg), tirasemtiv 
accountability will be provided by patient ID (in ascending order) and visit (in chronological 
order). 
8.3.3. 
Maintenance Dose Level 
The maintenance dose level is defined as the scheduled daily dose level at Week 12 in CY 4033. 
If the patient discontinued the study drug prior to Week 12, the nominal dose level which is close 
to the average daily dose will be assigned as the maintenance dose.  
Week 12 Dose: patients will be assigned to maintenance dose level based on the dose prescribed 
at their Week 12 visit:   
a. 250 mg/day group 
b. 375 mg/day group 
c. 500 mg/day group 
Patients will be assigned to maintenance dose level based on their average dose level defined in 
Section 8.3.2:  
a. 250 mg/day group  
(0 mg / day ≤ Average dose level < 312.5 mg/day) 
b. 375 mg/day group  
(312.5 mg/day ≤ Average dose level < 437.5 mg/day) 
c. 500 mg/day group  
(Average dose level ≥ 437.5 mg/day) 
8.4. 
Concomitant and Other Medications 
Medications other than the study drug reported on the eCRF will be summarized as concomitant 
medications for the safety population. Medications with an end date that is 7 days or more prior 
to the first dose of the study drug, or medications with a start date that is 28 days after the last 
dose of the study drug in CY 4033, will be excluded from the summary. Medications with a start 
date in CY 4031 and without an end date after the first dose of the study drug in CY 4033, will 
be included in the summary. The World Health Organization Drug dictionary will be used to 
classify medications by therapeutic class (ATC Class Level III) and preferred term name. If ATC 
Class Level III is not available, ATC Class Level II will be used in the summary. Coding will be 
performed using WHO Drug Dictionary Enhanced Herbal format B2 Mar 2015.    


 
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The number and percentage of patients who receive concomitant medication will be summarized 
by early start and delayed start treatment groups, therapeutic class and preferred term (using 
ATC Class Level III) and overall. Multiple drug usage by a patient will be counted only once in 
each category. 
In addition, a by-patient listing with start/stop date, days relative to the start of therapy in 
CY 4033, dose / unit / route / frequency, indication and purpose of all medications taken from 
Day 1 in CY 4033 or from the first dose in double-blind, placebo-controlled phase in CY 4031 
through the end of study will be provided. 
8.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Please see the Section 5.7.2 for the imputation of missing/partial dates of concomitant 
medication. 
Imputed dates will be flagged in the individual patient listings. 
8.5. 
Routine Laboratory Data 
Clinical laboratory evaluations, including hematology, serum chemistry, and urinalysis as 
detailed in the protocol, will be collected at Day 1, Week 4, Week 8, Week 12 and every 12 
weeks thereafter, discontinuation clinical visit and at the Follow-up Visit. Descriptive statistics 
for laboratory assessment values and their changes from baseline will be presented at each 
assessment time point by early start and delayed start treatment, maintenance dose level and 
overall. Baseline is defined as the last non-missing assessment value prior to the first dose of 
study drug in CY 4033. In the case of multiple values in an analysis window defined in Section 
5.6.6, data will be selected for analysis as described in Section 5.6.7. 
The number and percentage of patients with abnormal laboratory values will be presented by 
early start and delayed start treatment groups, maintenance dose level and overall. The lower 
limit of normal and upper limit of normal provided by the laboratories will be the criteria used to 
determine abnormal laboratory values. The number and percentage of patients with potentially 
clinically significant (PCS) abnormal laboratory values will be presented by early start and 
delayed start treatment groups and overall. Severe PCS abnormal laboratory values are defined 
as Grade 3 laboratory abnormalities according to NCI-CTCAE Version 4.0. 
In calculating percentages of patients with abnormal laboratory values for each parameter, the 
denominator is the number of dosed patients with a normal or missing baseline assessment and 
with at least one post-baseline assessment (patients with an abnormal baseline laboratory value 
will be excluded from the denominator for that parameter); the numerator is the number of dosed 
patients with a normal or missing baseline assessment and at least one abnormal post-baseline 
assessment (including unscheduled assessments, and assessments at the Follow-up Visit) at the 
treatment group and overall. 
The boxplots will be presented for selected laboratory quantitative tests over time in CY 4033. 
A shift table will be provided in the form of shifts from baseline NCI-CTCAE grade to the 
maximum grade post baseline by early start and delayed start treatment groups, laboratory tests. 
Shifts for the last available on-drug assessments and at the follow-up visit also will be included. 
Only laboratory tests with available NCI-CTCAE toxicity grade reference ranges will be 
included.  


 
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A by-patient listing of clinical laboratory (hematology, serum chemistry, urinalysis, and other) 
with demographic, visit, the actual assessment date and time, relative day, type of visit, 
laboratory test, lab test units, lab test results, and the lower and upper limits of normal sorted by 
patient ID and chronologically by visit, the actual assessment date and time will be presented. 
Values outside the Laboratory’s normal ranges will be flagged. Unscheduled laboratory values 
also will be noted. 
The association between concentration of tirasemtiv and the change from baseline in selected 
laboratory tests may be explored. 
8.6. 
Vital Signs 
Vital signs, which include heart rate, respiration rate, blood pressure measured at rest (i.e. after 
the patient sits or has been supine for at least 3 minutes), and weight (kg) will be obtained at Day 
1, Week 4, Week 8, Week 12 visits and every 12 weeks visits thereafter, at the discontinuation 
clinical visit and at the 28 Day Safety Follow-up Visit. Height (cm) will be collect at Screening 
visit of CY 4031. Weight (kg) will be obtained at each clinic visit starting from the Screening 
through the Follow-up Visit in CY 4033. 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) of observed values and 
changes from CY 4033 baseline of vital sign parameters will be presented at each assessment 
time point and by early start and delayed start treatment groups and overall. Repeat and multiple 
measurements will be processed analogously with the method described in the clinical laboratory 
data in Section 8.5. 
The number and percentage of patients with PCS vital signs, using the criteria specified in 
Table 4, will be presented by the early start and delayed start treatment groups and overall. For 
each parameter, the denominator is the number of patients with non-PCS or non-missing baseline 
assessment and with at least one post baseline assessment; and the numerator is the number of 
patients with non-PCS or non-missing baseline assessment and with at least one post baseline 
PCS value including repeated and unscheduled measurements (subset of the denominator). 
Assessment at Follow-up Visit will also be included in the summary. 
Descriptive statistics of weight and weight loss from CY 4031 baseline and from CY 4033 
baseline will be presented by visit and by early start and delayed start treatment groups. Scatter 
plots with regression line fit to the weight loss from baseline either in CY 4031 or in CY 4033 
will be presented. 
A by-patient listing of individual vital signs with demographic, visit, the actual assessment date 
and time, relative day, type of visit, and vital sign values with units sorted by patient ID and 
chronologically by visit, the actual assessment date and time will be presented. PCS vital signs 
will be flagged. Unscheduled vital sign values also will be noted. Table 4 below lists the criteria 
for clinically significant values outside of normal range of vital signs. 
 
 


 
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Table 4: 
Criteria for Clinically Significant Vital Signs 
Vital Sign Parameter 
Flag 
PCS Criteria 
Systolic Blood Pressure (mmHg) 
High 
≥160 mmHg 
Low 
≤80 mmHg 
Diastolic Blood Pressure (mmHg) 
High 
≥100 mmHg 
Low 
≤ 50 mmHg 
Respiration Rate (Breaths per minute) 
High 
>18 breaths per minute  
Low 
<8 breaths per minute  
Pulse (beats per minute) 
High 
≥120 bpm 
Low 
≤50 bpm 
Weight (kg) 
Clinically 
Significant 
≥5% reduction from baseline 
8.7. 
Suicidality Assessment 
The suicidality assessment (Beck Depression Inventory (BDI) Fast Screen) will be collected at 
the Day 1, Week 4, Week 8, Week 12 clinical visits and every 12 weeks thereafter, Tirasemtiv 
Discontinuation Clinic Visit, Tirasemtiv Discontinuation Phone Call, and at the 28 Day Safety 
Follow-up Clinic Visit/Phone Call in CY 4033. 
The BDI total score is the sum of the scores of the seven individual questions, where each 
question is scored from 0 to 3. The total score of the BDI cannot be calculated if answer to any 
of the seven individual questions is missing. 
Total BDI scores at each assessment will be classified as shown in Table 5.  
Table 5: 
Depression Level Classification by BDI Total Score 
Depression Level 
BDI Total Score 
Minimal Depression 
0 - 3 
Mild Depression 
4 - 6 
Moderate Depression 
7 - 9 
Severe Depression 
10 - 21 
A by-patient listing of individual BDI score with demographic, visit week, actual assessment 
date, relative day, and total score with depression classification sorted by early start and delayed 
start treatment groups, and chronologically by visit week, the actual assessment date will be 
presented. The worst values of the total score and an individual question, Suicidal Thoughts, for 
each patient will be flagged. 
8.8. 
Physical Examination 
Physical examination will not be listed.  
8.9. 
Study Termination Status 
Number and percentage of patients who complete and prematurely discontinue planned study 
dosing with reasons for premature discontinuation will be included in the disposition table. 


 
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9. 
PHARMACOKINETIC/ PHARMACODYNAMIC ANALYSIS 
9.1. 
Pharmacokinetic Analysis 
Pharmacokinetics (PK) analyses will be based on the PK analysis set. Concentration data for 
tirasemtiv will be summarized by early start and delayed start treatment groups by nominal 
sampling time using descriptive statistics (arithmetic mean, SD, median, minimum, maximum, 
geometric mean, and coefficient of variation). All concentrations below the lower limit of 
quantification (LLOQ) will be set to zero for purposes of calculating descriptive statistics.  
The trough concentration will be modeled as a function of body weight over time using a 
repeated measurement mixed model, including early start and delayed start treatment group, 
clinical visit, gender and age group (<65 and ≥65 years old) as covariates. 
The concentration will be taken as the natural log-transformation before using the analysis in the 
models and the back-transformation (geometric mean ratio) and back-transformed 90% CI will 
be reported. 
A by-patient listing with demographic, treatment group, visit week, study drug administration 
date and time, sample collection data and time, relative day, and PK time point, PK 
concentration and LLOQ of tirasemtiv sorted by early start and delayed start treatment groups, 
patient ID and chronologically by visit week, the actual assessment date and time will be 
presented. 
Concentrations of riluzole will not be analyzed in this study. 
9.2. 
Pharmacodynamic Analysis/ Pharmacokinetic Analysis 
Pharmacodynamic (PD) analyses will be performed to graphically explore the relationship 
between trough tirasemtiv concentration and efficacy and safety endpoints by early start and 
delayed start treatment groups based on the PD Analysis Set.  
Changes from baseline in PD measurements will be paired with coincidentally measured trough 
plasma concentrations of tirasemtiv. Only the concentration measurements collected within the 
time window around the nominal time as per the analysis specifications will be included in the 
analyses based on concentration. For all these parameters, baseline is defined as the last non-
missing assessment, including unscheduled assessments, made prior to the initial dose at Day 1 
in CY 4033. The PD assessments will include: 
− SVC 
− ALSFRS-R total score and respiratory sub-score  
− Weight loss 


 
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10. 
STATISTICAL CODES 
The following code will be used as the prototype of the codes that will be used for the final 
analysis of the study. The final version of the statistical codes to be used will be determined and 
will be documented in the specification document for the statistical report of the study. 
1. SAS code for the final analysis for the efficacy endpoint at Week 24 and Week 48 
proc mixed data=work; 
class <subject> <riluzole use> <pooled site> <dose level> <treatment> <visit>; 
model chg=<base>  <riluzole use> <visit> <pooled site> <treatment> <treatment>*<base> 
<treatment>*<visit> /solution ddfm=kr ; 
repeated <visit>/subject=<subject> type=un; 
lsmestimate <treatment>*<visit> 
'Early-start vs. Delayed-start at Week 24' [-1,1 4] [1,2 4]/ e cl elsm; 
 
ods output LSMEstimates=lsme ; 
run; 
Variable VISIT has four categories with Day 1 coded as 1 and Week 24 coded as 4.  
Analysis at Week 48 will use a similar model where the level for VISIT is 6 for Week 48.  
'Early-start vs. Delayed-start at Week 48' [-1,1 6] [1,2 6]/e cl elsm; 
 
2. SAS code for slope analysis between treatment group during CY 4033 
PROC MIXED data=work method=REML; 
class <Subject> <treatment> <pooled site> <riluzole use>; 
model <chg> = <base> <treatment> <pooled site> <days from base> <riluzole use> 
<treatment>*<base>  <treatment>*<days from base>/ 
ddfm=kr noint; 
Random <days from base> / type=un subject=<Subject>; 
Estimate 'Slope Diff between pooled early-start vs. delayed-start' <treatment>*<days 
from base>  1 -1/e cl; 
run; 
Change from baseline at baseline time point (change=0) is included in the input dataset and no 
intercept is fit to the model. 
 
3. SAS code for slope analysis during the clinical course of treatment 
proc mixed data=work method=REML; 
    class  <subject> <pooled site> <riluzole use>;   
    model chg=<base> <riluzole use> <pooled site> <days from CY 4031 base> <days from 
CY 4033 base> <base> * <days from CY 4031 base>    /s ddfm=kr; 
 
    random intercept <days from CY 4031 base> <days from 4033 base> / sub=<subject> 
type=un g gcorr;    
     
estimate 'Slope in CY 4031: Placebo '    <days from CY 4031 base 1 <day from 
CY 4033 base > 0 /e cl; 
estimate 'Slope in CY 4033: Placebo '    <days from CY 4031 base 1 <day from 
CY 4033 base > 1 /e cl; 
estimate 'Slope Difference between in CY 4033/CY 4031: Placebo '    <days from 
CY 4031 base 0 <day from CY 4033 base > 1 /e cl; 
run; 
 
Coding: <days from CY 4031 base> is the days from CY 4031 baseline time point (change=0)  


 
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 <days from CY 4033 base> is the days from CY 4031 baseline time point of the 
assessments in CY 4033 only. If the assessments in CY 4031, the values will be assigned to 0. 
 
4. The SAS code for proportional hazard Cox regression model for time to onset endpoints is as 
follows. 
PROC phreg data=work; 
class <treatment>(ref=first) <pooled site> <Riluzole use>; 
model <response>*censor (<censor list>)=<SVC base> <treatment> <riluzole use>; 
hazardratio <treatment>; 
strata <pooled site>; 
Run; 
 
5. The SAS code for multiple imputations is as follows. 
Step 1: Impute the missing data 
PROC mi data=work seed=13113 nimpute=50 out=miwork; 
mcmc chain=multiple; 
var <day 1> <week 4> <week 8> <week 12> <week 24> <week 36> <week 48>; 
by <treatment>; 
run; 
Step 2: Analyze the complete data 
PROC MIXED data=miwork METHOD=REML; 
class <Subject> <Treatment> <Visit> <pooled site> <Riluzole use>; 
model <chg> = <Baseline> <Baseline>*<Visit> <Treatment> <Visit> <pooled site> 
<Riluzole use> <Treatment>*<Visit>/ 
ddfm=kr solution covb; 
repeated <Visit> / SUBJECT=<Subject> Type=UN; 
lsmestimate <treatment>*<visit> 'Early-Start vs. Delayed-start at Week 24' 
 
[-1,1 4] [1,2 4] 
/e cl elsm; 
ods output LSMEstimates=est; 
By _imputation_; 
run; 
Step 3: Combine the results of the analysis of imputations. 
PROC Mianalyze data=est; 
Modeleffects estimate; 
Stderr stderr; 
Run; 
 
6. The normality assumptions for the ANCOVA analysis will be assessed by residual illustration. 
The outpred=outpred option in in the model statement in the above MIXED model stores 
residuals which are used to test the assumption of normality. Examination of residuals can be 
done using the following codes. 
PROC UNIVARIATE DATA=OUTPRED NORMAL PLOT; 
VAR RESID; 
QQPLOT RESID; 
RUN; 
 
PROC PLOT DATA=TEMP; 


 
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PLOT RESID*PRED; 
RUN; 
 
7. The SAS code for Kaplan-Meier method is as follows: 
PROC LIFETEST data=AE; 
time <Var_time>*dizziness(0); 
strata <treatment>; 
run; 
where Var_time is either time to the first onset of dizziness or duration of the first dizziness 
under each treatment/dose level (total daily dose). 
 
8. The following SAS code will be used in evaluation of the associations between observed 
concentration and the time to the onset of dizziness: 
PROC PHREG data=work; 
model <time_to_event>*<censor>(0) = PK parameter of interest /rl; 
id patient; 
Run; 
 
9. The SAS code to evaluate concentration effect expressed in terms of slope estimated from 
ANCOVA models is as follows: 
PROC MIXED data=work METHOD=REML; 
Class <Subject> <Riluzole use> <pooled site> <visit>; 
Model <chg> = <Baseline> <pooled site> <concentration> /ddfm=kr; 
Repeated <visit> /type=UN subject=<Subject>; 
run; 


 
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11. 
REFERENCES 
Beck, A. T., R. A. Steer, et al. (1996). "Beck depression inventory-II." San Antonio 78(2): 490-
498. 
Cedarbaum, J. M., N. Stambler, et al. (1999). "The ALSFRS-R: a revised ALS functional rating 
scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase 
III)." J Neurol Sci 169(1-2): 13-21. 
Cox, D. R. (1992). Regression models and life-tables. Breakthroughs in statistics, Springer: 527-
541. 
Henderson, C. (1984). "Applications of linear models in animal breeding (University of Guelph, 
Guelph, ON, Canada)." 
Kalbfleisch, J. D. and R. L. Prentice (2011). The statistical analysis of failure time data, John 
Wiley & Sons. 
Kaplan, E. L. and P. Meier (1958). "Nonparametric estimation from incomplete observations." 
Journal of the American statistical association 53(282): 457-481. 
Knudson, R. J., M. D. Lebowitz, et al. (1983). "Changes in the normal maximal expiratory flow-
volume curve with growth and aging." Am Rev Respir Dis 127(6): 725-734. 
Peto, R. and J. Peto (1972). "Asymptotically efficient rank invariant test procedures." Journal of 
the Royal Statistical Society. Series A (General): 185-207. 
Ryan, S. E., L. S. Porth, et al. (2002). "Defining phases of bedload transport using piecewise 
regression." Earth Surface Processes and Landforms 27: 971-990. 
 


Statistical Analysis Plan - Protocol CY 4033 
                                                                             Version 1.0 dated 24 October 2017 
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APPENDIX 1. SCHEDULE OF EVENTS 
Procedures 
Day 1 
Clinic 
Week 2 
Call 
Week 4 
Clinic 
Week 63 
PI/Sub-I 
Call 
Week 8 
Clinic 
Week 10 
Call 
Week 12 
Clinic 
Week 24 
Clinic 
 
Week 36 
Clinic 
Week 48 
Clinic 
Every 12 
Weeks 
Ongoing 
Clinic 
Tirasemtiv 
Disc Clinic 
Visit 
Tirasemtiv 
Disc Phone 
Call 
28 Day 
Safety 
Follow-up 
Clinic Visit 
28 Day 
Safety 
Follow-up 
Phone Call 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc/Exc Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical Safety Labs1 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum Pregnancy Test2 
X 
 
 
 
 
 
 
X 
 
X 
 
X2 
 
 
 
PK Sample4 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
SVC 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
ALSFRS-R 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality Assessment 
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 
Tirasemtiv Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
1 TSH every year after Day 1 Clinic Visit 
2 Serum pregnancy test only for females of child bearing potential at Day 1 Clinic Visit, every 24 weeks thereafter, and at the Tirasemtiv Discontinuation Visit  
3 Phone contact with patient by PI or designee with prescriptive authority in their local jurisdiction  
4 PK Sample to be collected every 24 weeks after the Week 48 Clinic Visit as well as Tirasemtiv Discontinuation and 28 Day Safety Follow-Up Visits 
 
  
 
 
 
 
 
 
 
  
 
 
 


Signature Manifest
Document Number: PRD-0009
Revision: 00
Title: CY 4033 - Statistical Analysis Plan (A Phase 3, Open-Label Extension Study of Tirasemtiv for
Patients with Amyotrophic Lateral Sclerosis (ALS) who Completed VITALITY-ALS (CY 4031))
Effective Date: 09 Nov 2017
All dates and times are in Pacific Time.
CY 4033 SAP
 
1: Electronic Approvals
Name/Signature
Title
Date
Meaning/Reason
Long Ma (LMA)
Sr. Biostatistician
09 Nov 2017, 10:05:40 AM
Approved
Lisa (Lixin) Meng (LMENG)
Sr. Director, Biometrics
09 Nov 2017, 10:29:28 AM
Approved
Bettina Cockroft
(BCOCKROFT)
VP, Clinical Research, Neuro
09 Nov 2017, 10:57:35 AM
Approved