A Phase 3, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Cytokinetics

PROTOCOL CY 5031 
A PHASE 3, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE THE EFFICACY AND 
SAFETY OF RELDESEMTIV IN PATIENTS WITH AMYOTROPHIC 
LATERAL SCLEROSIS (ALS) 
 
Trial Name: 
COURAGE-ALS 
Protocol Version and Date: 
Amendment 5: 24 February 2023 
Previous Version(s): 
01 February 2023 
08 March 2022 
20 January 2022 
08 February 2021 
19 August 2020 
Product: 
CK-2127107 
Product Name: 
Reldesemtiv 
Regulatory Authority 
Identifier Number(s): 
IND 134567 
EudraCT Number 2020-004040-29 
Sponsor: 
Cytokinetics, Inc. 
350 Oyster Point Blvd 
South San Francisco, CA 94080, USA 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without documented approval from Cytokinetics, Inc. 
 
 

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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CY 5031 
Protocol Title: 
A Phase 3, Multi-Center, Double-Blind, Randomized, Placebo-
Controlled Trial to Evaluate the Efficacy and Safety of 
Reldesemtiv in Patients with Amyotrophic Lateral Sclerosis 
(ALS) 
Protocol Version and Date: 
Amendment 5: 24 February 2023 
 
Principal Investigator Commitment 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the International Conference on Harmonisation (ICH) 
E6(R2) Good Clinical Practice (GCP) guidelines, as well as with any and all applicable federal, 
state and/or local laws and regulations, and agree to conduct this study in accordance with the 
protocol referenced herein. 
 
Investigator Name: 
 
Date:  
Investigator Signature: 
 
 
 
 

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PROTOCOL APPROVAL PAGE 
 
Protocol Number: 
CY 5031 
Protocol Title: 
A Phase 3, Multi-Center, Double-Blind, Randomized, Placebo-
Controlled Trial to Evaluate the Efficacy and Safety of 
Reldesemtiv in Patients with Amyotrophic Lateral Sclerosis 
(ALS) 
Protocol Version and Date: 
Amendment 5: 24 February 2023 
Sponsor: 
Cytokinetics, Inc. 
350 Oyster Point Blvd 
South San Francisco, CA 94080 
 
 
 
 
 
 
 
 
Stacy Rudnicki, MD 
Vice President, Clinical Research, Neurology 
 
Date: 
 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
PROTOCOL APPROVAL PAGE ...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................16 
1.3. 
Schedule of Activities .................................................................................................17 
1.4. 
Key Contacts ...............................................................................................................19 
2. 
INTRODUCTION ......................................................................................................20 
2.1. 
Study Rationale ...........................................................................................................20 
2.2. 
Background .................................................................................................................20 
2.2.1. 
Amyotrophic Lateral Sclerosis ...................................................................................20 
2.2.2. 
Reldesemtiv ................................................................................................................21 
2.3. 
Benefit/Risk Assessment ............................................................................................21 
2.3.1. 
Risk Assessment .........................................................................................................21 
2.3.1.1. 
Mitigation Strategy .....................................................................................................22 
2.3.2. 
Benefit Assessment .....................................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY DESIGN .......................................................................................................25 
4.1. 
Overall Design ............................................................................................................25 
4.2. 
Scientific Rationale for Study Design ........................................................................26 
4.3. 
Justification for Dose ..................................................................................................29 
4.4. 
End of Study Definition ..............................................................................................29 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
5.2. 
Exclusion Criteria .......................................................................................................32 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.4. 
Screen Failures ............................................................................................................33 
5.4.1. 
Rescreening .................................................................................................................33 

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6. 
INVESTIGATIONAL PRODUCT ............................................................................35 
6.1. 
Study Drug Administered ...........................................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Drug Compliance .............................................................................................36 
6.5. 
Concomitant Therapy .................................................................................................37 
6.6. 
Dose Modification ......................................................................................................38 
6.7. 
Access to Investigational Product after the End of the Study ....................................38 
7. 
TEMPORARY INTERRUPTION OF STUDY DRUG, 
DISCONTINUATION OF STUDY DRUG, AND PATIENT CONSENT 
WITHDRAWAL ........................................................................................................39 
7.1. 
Temporary Study Drug Interruption ...........................................................................39 
7.2. 
Permanent Discontinuation of Study Drug .................................................................39 
7.2.1. 
Management of Patients after Permanent Discontinuation of Study Drug .................40 
7.3. 
Renal Function Monitoring and Study Drug Management ........................................41 
7.4. 
Liver Function Monitoring and Study Drug Management .........................................42 
7.5. 
Discontinuation from Study Procedures .....................................................................45 
7.6. 
Patient Consent Withdrawal .......................................................................................45 
7.7. 
Lost to Follow Up .......................................................................................................45 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................47 
8.1. 
Efficacy Assessments .................................................................................................48 
8.1.1. 
ALSFRS-R ..................................................................................................................48 
8.1.2. 
Pulmonary Function Assessment ................................................................................48 
8.1.3. 
Hand Grip Strength .....................................................................................................48 
8.1.4. 
Muscle Strength ..........................................................................................................49 
8.1.5. 
Health Economic Outcomes Measures .......................................................................49 
8.1.6. 
Quality of Life ............................................................................................................49 
8.1.7. 
Structured Patient Interviews ......................................................................................49 
8.1.8. 
Hospitalizations ..........................................................................................................49 
8.2. 
Safety Assessments .....................................................................................................50 
8.2.1. 
Physical Examinations ................................................................................................50 
8.2.2. 
Vital Signs ..................................................................................................................50 
8.2.3. 
Electrocardiograms .....................................................................................................50 

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8.2.4. 
Neurological Examinations ........................................................................................51 
8.2.5. 
Laboratory Assessments .............................................................................................51 
8.2.6. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) ......................................51 
8.3. 
Adverse Events and Serious Adverse Events .............................................................51 
8.3.1. 
Adverse Events ...........................................................................................................51 
8.3.1.1. 
Definition of Adverse Event .......................................................................................51 
8.3.1.2. 
Definition of Serious Adverse Event ..........................................................................52 
8.3.1.3. 
Severity of Adverse Events ........................................................................................53 
8.3.1.4. 
Relationship to Study Drug ........................................................................................53 
8.3.1.5. 
Relationship to Study Procedures ...............................................................................54 
8.3.1.6. 
Reporting of AEs ........................................................................................................54 
8.3.1.7. 
Reporting Procedures for SAEs ..................................................................................54 
8.3.1.8. 
Follow-up of AEs and SAEs .......................................................................................55 
8.3.1.9. 
Regulatory Reporting ..................................................................................................55 
8.3.1.10. 
Pregnancy and Breastfeeding .....................................................................................56 
8.4. 
Treatment of Overdose ...............................................................................................57 
8.5. 
Pharmacokinetics ........................................................................................................57 
8.6. 
Genetics ......................................................................................................................58 
8.7. 
Biomarkers ..................................................................................................................58 
8.8. 
Immunogenicity Assessments ....................................................................................59 
8.9. 
Sample Storage ...........................................................................................................59 
9. 
STATISTICAL CONSIDERATIONS .......................................................................60 
9.1. 
Statistical Hypotheses .................................................................................................60 
9.2. 
Sample Size Determination ........................................................................................60 
9.3. 
Populations for Analyses ............................................................................................60 
9.4. 
Statistical Analyses .....................................................................................................61 
9.4.1. 
General Considerations ...............................................................................................61 
9.4.1.1. 
Multiplicity Adjustment..............................................................................................61 
9.4.1.2. 
Timing of Final Analyses ...........................................................................................61 
9.4.2. 
Primary Endpoint ........................................................................................................62 
9.4.3. 
Secondary Endpoint(s) ................................................................................................62 
9.4.4. 
Exploratory Endpoint(s) .............................................................................................63 
9.4.5. 
Safety Analysis ...........................................................................................................64 

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9.4.5.1. 
Adverse Events ...........................................................................................................64 
9.4.5.2. 
Serious Adverse Events ..............................................................................................65 
9.4.6. 
Pharmacokinetic Endpoints ........................................................................................65 
9.4.7. 
Patient Disposition ......................................................................................................65 
9.4.8. 
Demographics and Other Baseline Characteristics .....................................................65 
9.4.9. 
Investigational Product Exposure ...............................................................................65 
9.4.10. 
Concomitant Medications ...........................................................................................65 
9.4.11. 
Clinical Laboratory Parameters ..................................................................................65 
9.4.12. 
Vital Signs ..................................................................................................................65 
9.4.13. 
Electrocardiogram .......................................................................................................66 
9.5. 
Interim Analyses .........................................................................................................66 
9.6. 
Data Monitoring Committee .......................................................................................67 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................68 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................68 
10.1.2. 
Financial Disclosure ...................................................................................................68 
10.1.3. 
Informed Consent Process ..........................................................................................68 
10.1.4. 
Data Protection ...........................................................................................................69 
10.1.5. 
Committees Structure .................................................................................................69 
10.1.6. 
Data Quality Assurance ..............................................................................................70 
10.1.7. 
Source Documents ......................................................................................................70 
10.1.8. 
Study and Site Start and Closure ................................................................................70 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................72 
10.3. 
Appendix 3: Contraceptive Guidance .........................................................................73 
10.4. 
Appendix 4: Common Medications and Foods that Inhibit or Induce 
CYP3A4 or are OCT1/OCT2 Substrates ....................................................................75 
10.5. 
Appendix 5: Abbreviations .........................................................................................76 
11. 
REFERENCES ...........................................................................................................80 

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LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................23 
Table 2: 
Study Drug ..................................................................................................................35 
Table 3: 
CY 5031 Visit Windows .............................................................................................47 
Table 4: 
Signs and Symptoms Commonly Associated with ALS ............................................54 
Table 5: 
Summary of PK Time Points ......................................................................................58 
Table 6: 
PK Sub-Study Time Points .........................................................................................58 
Table 7: 
Biomarker Samples .....................................................................................................58 
Table 8: 
Analysis Sets ...............................................................................................................60 
Table 9: 
Protocol-Required Safety Laboratory Assessments ...................................................72 
LIST OF FIGURES 
Figure 1:  Study Schema .............................................................................................................16 
Figure 2: 
CY 5022 Primary Endpoint – SVC Change from Baseline to Week 12 ....................27 
Figure 3: 
CY 5022 – ALSFRS-R Change from Baseline Over Time (All Active vs 
Placebo) ......................................................................................................................28 
Figure 4: 
CY 5022 – Subgroup Analyses of ALSFRS-R Total Scores .....................................28 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Investigational Product(s) (IP): Reldesemtiv 
Name of Active Ingredient(s): CK-2127107 
Protocol Title: A Phase 3, Multi-Center, Double-blind, Randomized, Placebo-Controlled Trial to 
Evaluate the Efficacy and Safety of Reldesemtiv in Patients with Amyotrophic Lateral Sclerosis (ALS) 
Protocol Number: CY 5031 
Protocol Name: COURAGE-ALS 
Phase of Development: Phase 3 
Rationale: 
Reldesemtiv, a fast skeletal muscle troponin activator (FSTA), is being investigated as a potential 
therapy to slow the decline of skeletal muscle function in patients with ALS. This pivotal trial with 
reldesemtiv is being conducted in ALS patients and is designed to assess the effect of reldesemtiv on 
functional outcomes during treatment up to 48 weeks. The first trial with reldesemtiv in ALS patients 
(FORTITUDE-ALS [CY 5022]) after 12 weeks of dosing, showed that patients on all doses of 
reldesemtiv tended to decline less than patients on placebo for slow vital capacity (SVC) and ALS 
Functional Rating Scale-Revised (ALSFRS-R), with larger and clinically meaningful differences 
emerging over time. The results support progression in a further clinical trial with a longer dosing 
duration. 
Objectives and Endpoints: 
Objectives 
Endpoint(s) 
Primary 
• To assess the effect of reldesemtiv versus 
placebo on functional outcomes in ALS  
• Change from baseline to Week 24 in ALSFRS-R 
total score 
Secondary 
• To assess the effect of reldesemtiv versus 
placebo on combined functional and survival 
outcomes in ALS 
• To assess the effect of reldesemtiv versus 
placebo on ventilatory function  
• To assess the effect of reldesemtiv versus 
placebo on quality of life  
• To assess the effect of reldesemtiv versus 
placebo on handgrip strength 
• Combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted 
ventilation (use of non-invasive or invasive 
ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days), and survival time up to 
Week 24 
• Change from baseline to Week 24 in the percent 
predicted FVC 
• Change from baseline to Week 24 in the 
ALSAQ-40 total score 
• Change from baseline to Week 24 in handgrip 
strength (average of both hands) 

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Exploratory 
• To assess the effect of reldesemtiv versus 
placebo on the progression of ALS 
 
 
 
 
 
• Time to the patient being prescribed and patient 
agrees to it, time to first receipt, time to first use, 
time to daily use, time to dependence and number 
used of any of the following durable medical 
equipment items (manual wheelchair, power 
wheelchair, augmentative and alternative 
communication device, non-invasive ventilation 
(NIV) and/or gastrostomy tube) from 
randomization to the end of the 24-week double-
blind, placebo-controlled period and to the end 
of Week 48. Time to dependence on invasive 
ventilation will also be recorded. 
• Change from baseline to Week 24 in the four 
subdomain scores of the ALSFRS-R 
• Time spent in each MiToS stage and number of 
patients to transition stages from baseline to 
Week 24  
• Change from baseline to Week 48 in ALSFRS-R 
total score 
• Change from baseline to Week 48 in forced vital 
capacity (FVC) 
• Combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted 
ventilation (use of non-invasive or invasive 
ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days), and survival time up to 
Week 48 
• Change from baseline to Week 24 in the mega-
score of muscle strength measured by hand-held 
dynamometry (HHD) in bilateral first dorsal 
interosseous muscles, abductor pollicus brevis 
muscles, and abductor digiti minimi muscles 
• Change from baseline to Week 24 and Week 48 
in the EQ-5D-5L 
• Change from baseline to Week 24 and Week 48 
in the EQ-Visual Analogue Scale (VAS) 
• Time to event for first hospitalization to Week 24 
and Week 48 
Safety 
• To assess the safety and tolerability of 
reldesemtiv compared to placebo 
• Patient incidence of adverse events and serious 
adverse events 

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Overall Design: 
This is a Phase 3, double-blind, randomized, placebo-controlled trial of reldesemtiv in patients aged 18 
to 80 with ALS. 
The screening and qualification period for the trial will be no more than 21 days in duration. 
Approximately 555 eligible ALS patients will be randomized (2:1) to receive the following dose of 
reldesemtiv or placebo (stratified by riluzole use/non-use and edaravone use/non-use) for the first 
24 weeks (double-blind, placebo-controlled period): 
• 
300 mg reldesemtiv twice a day for a 600 mg total daily dose (TDD) 
• 
Placebo twice daily 
At the end of the 24-week double-blind, placebo-controlled period, patients will transition to the active 
drug period, where all patients will receive the following dose of reldesemtiv for the next 24 weeks: 
• 
300 mg reldesemtiv twice a day for a 600 mg TDD for patients who were not down titrated 
during the 24 weeks of blinded dosing 
• 
150 mg reldesemtiv twice a day for a 300 mg TDD for patients who were down titrated for 
any reason during the 24 weeks of blinded dosing 
For the entire 48 weeks of dosing, patients and sites shall remain blinded to the randomized treatment 
assignment patients received during the first 24 weeks. 
Study drug should be taken twice daily, morning and afternoon (at least 8 hours apart) and should be 
taken either with food or within a 2-hour period following food. 
Study Visits: 
There will be up to eight clinic visits and nine remote assessment visits (with most requiring an 
accompanying phone or video call) as follows: 
• 
Screening: clinic visit/lab 
• 
Day 1 (start of dosing): clinic visit/lab 
• 
End of Week 2: remote - lab only 
• 
End of Week 4: clinic visit/lab  
• 
End of Week 8: remote visit/lab 
• 
End of Week 12: clinic visit/lab 
• 
End of Week 16: remote visit/lab 
• 
End of Week 20: remote visit/lab 
• 
End of Week 24 (last dose of double-blind dosing): clinic visit/lab 
• 
End of Week 26: remote - lab only 
• 
End of Week 28: remote visit/lab 
• 
End of Week 32: remote visit/lab 
• 
End of Week 36: clinic visit/lab 
• 
End of Week 40: remote visit/lab 
• 
End of Week 44: remote visit/lab 
• 
End of Week 48 (last dose of active drug dosing): clinic visit/lab 
• 
Follow-Up (4 weeks after last dose of study drug): clinic visit/lab 

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For patients who complete Week 48 and want to enter the open label extension (OLE), they will not 
have the follow-up visit; instead they will enter the OLE on the same day as their Week 48 visit. If the 
patient does not want to enter the OLE, or if the OLE has not yet been approved at the site, the follow-
up visit will take place as above. 
Since we plan to conduct the trial in different regions of the world, including Europe, Canada, Australia 
and the US, standard of care regarding ALS for the local region, as determined by the physician in 
discussion with the patient, should be followed.  
Study Center(s): 
Patients will be enrolled from approximately 85 clinical trial sites, in US, Canada, Europe and 
Australia. 
Number of Patients: 
Approximately 740 patients will be screened in order to randomize/enroll approximately 555 patients, 
such that approximately 444 evaluable patients complete the 24-week of double-blind period of the 
trial. 
Key Eligibility Criteria:  
A full listing of eligibility criteria can be found in Section 5. Patients are eligible to be included in the 
trial only if all criteria are met. 
Key Inclusion Criteria  
• 
Males or Females between the ages of 18 and 80 years of age, inclusive 
• 
Diagnosis of familial or sporadic ALS (defined as meeting the laboratory-supported probable, 
probable, or definite criteria for ALS according to the World Federation of Neurology El Escorial 
criteria published in 2000 [Brooks 2000]). Patients who meet the possible criteria are eligible if 
they have lower motor neuron findings; those who have purely upper motor neuron findings are 
ineligible. 
• 
First symptom of ALS ≤ 24 months prior to screening. The qualifying first symptoms of ALS are 
limited to manifestations of weakness in extremity, bulbar, or respiratory muscles. Cramps, 
fasciculations, or fatigue should not be taken in isolation as a first symptom of ALS. 
• 
ALSFRS-R total score ≤ 44 at screening. Patients with a total score of 45 or higher may be 
rescreened 60±7 days following the original screening date and be deemed eligible if their 
ALSFRS-R total score is ≤ 44 or if their score is 2 or more points less than at initial screening. 
Such patients must continue to meet all other inclusion/exclusion criteria at the time of rescreening. 
• 
Upright FVC ≥ 65.0% of predicted for age, height, sex and ethnicity at screening according to 
Global Lung Initiative equation 
• 
Able to perform reproducible pulmonary function tests defined as being able to perform FVC at 
screening with variability of the 2 highest raw values of less than 10% with a maximum of 5 trials 
permitted. Screening FVC results must be reviewed and approved by the central review process 
prior to randomization. 
• 
Must be either on riluzole for ≥ 30 days prior to screening or have not taken it for at least 30 days 
prior to screening  

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• 
Must have completed at least 2 cycles of edaravone at the time of screening or have not received it 
for at least 30 days prior to screening  
• 
Able to swallow whole tablets at the time of screening 
• 
Clinical laboratory findings within the normal range, or if outside the normal range, not deemed 
clinically significant by the Investigator, except as specifically indicated as laboratory exclusion  
• 
Must be either on the combination product (brand name only) of sodium phenylbutyrate and 
taurursodiol (also known as TUDCA, ursodoxicoltaurine or Tauroursodeoxycholic acid) for 
≥51 days or have not received it for at least 30 days prior to screening 
Key Exclusion Criteria  
• 
eGFRCr and eGFRCysC < 45.0 mL/min/1.73 m2 at screening 
• 
Urine protein/creatinine ratio > 1 mg/mg (113 mg/mmol) at screening 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3-times the upper limit of 
normal (ULN)  
• 
Total bilirubin (TBL), direct or indirect bilirubin above the ULN. 
• 
Cognitive impairment, related to ALS or otherwise that impairs the patient’s ability to understand 
and/or comply with study procedures and provide informed consent 
• 
Other medically significant neurological conditions that could interfere with the assessment of ALS 
symptoms, signs or progression. 
• 
Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal, 
musculoskeletal, or psychiatric illness that might interfere with the patient’s ability to comply with 
study procedures or that might confound the interpretation of clinical safety or efficacy data 
• 
Has a tracheostomy  
Investigational Product: 
Reldesemtiv will be administered as 150 mg tablets, at a dose of 300 mg twice a day for a 600 mg TDD 
and matching placebo. 
Reldesemtiv and matching placebo tablets will be supplied to the clinical site in bottles. Patients will 
receive one or more bottles of study drug (reldesemtiv or matching placebo) at each clinic visit. 
The study research coordinator or designated site staff will be responsible for patient randomizations, 
using an interactive web response system (IWRS). 
Patients must interrupt study drug for certain specified laboratory abnormalities . Hepatic related 
interruptions are permanent discontinuations. For renal related laboratory abnormalities, the 
interruption continues until the laboratory value in question has returned to the threshold specified in 
the protocol for re-initiation of treatment. Patients may then resume dosing at 1 table twice a day 
thereafter (150 mg twice daily). Patients also may be down-titrated to 1 tablet twice a day by the 
Investigator in the case of adverse events felt to be related to study drug. Once patients have been 
down-titrated to one tablet twice daily for any reason, their dose may not be returned to two tablets 
twice daily. 
 

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Data Monitoring Committee:  
An independent Data Monitoring Committee (DMC) will periodically assess patient safety in an 
unblinded manner during the course of the trial. 
Interim Analyses: 
Twelve (12) weeks after approximately one-third or more of the planned sample size is randomized, 
the first interim analysis may be triggered. Its purpose is to determine if there is a lack of effect of 
reldesemtiv on the ALSFRS-R in CY 5031, a finding that would be inconsistent with the prior 
observed effect on the change from baseline at 12 weeks in ALSFRS-R total score in the Phase 2 trial, 
CY 5022. At this interim analysis, the DMC will receive unblinded efficacy data from the independent, 
third-party biostatistical group supporting them and assess the effect of reldesemtiv on the change from 
baseline to Week 12 in the ALSFRS-R total score. At this interim assessment, if the treatment 
difference for change from baseline to Week 12 in ALSFRS-R total score has a one-sided p-value 
larger than or equal to 0.5 (ie, the estimated treatment difference of the change from baseline at 
Week 12 in ALSFRS-R total score is favoring placebo), the DMC may recommend stopping the trial 
due to futility. This futility analysis based on the data of change from baseline to Week 12 in ALSFRS-
R will not have any alpha spending in the final analysis of the trial. The Sponsor will monitor the 
blinded aggregate standard deviation of the change from baseline to Week 12 in ALSFRS-R total score 
periodically and possibly adjust the specified p-value before this interim analysis is conducted. 
Twenty-four (24) weeks after at least one-third or more of the planned sample size is randomized, the 
second interim analysis will be triggered. The goal of the second interim analysis is to evaluate whether 
the proposed Phase 3 trial has adequate power to achieve a statistically significant effect on the primary 
endpoint in the final primary analysis, given the planned enrollment, or if continuing the trial is futile. 
At this interim analysis, the DMC will receive unblinded efficacy data from the independent, third-
party biostatistical group supporting them and assess the effect of reldesemtiv on the primary endpoint. 
In terms of futility, the DMC may recommend stopping the trial if the conditional power (CP) is less 
than 0.10 for the primary endpoint. 
If the CP of the primary endpoint is within a pre-specified promising zone from 0.40 to 0.90, the DMC 
may recommend increasing the sample size by 150 patients unless there is any safety concern or other 
concerns that preclude this recommendation. This interim analysis will spend a 2-sided alpha of 0.0001 
for the primary endpoint and all individual secondary endpoints. The DMC is also expected to 
recommend stopping this trial due to superiority if a two-sided p-value is ≤ alpha of 0.0001 for the 
primary endpoint as well as all individual secondary endpoints. Therefore, the significance level of 
2-sided alpha of 0.0499 would be used for the final primary analysis for the primary endpoint to control 
familywise error rate at overall alpha of 0.05. 
Statistical Methods:  
Sample Size Justification: 
With a 2:1 randomization ratio to reldesemtiv and placebo groups, respectively, a sample size of 
approximately 555 patients is required to achieve at least 90% power to detect at least a 1.8 point 
treatment difference between reldesemtiv and placebo in the change from baseline to Week 24 in 
ALSFRS-R total score. This calculation is based on a two-sample t-test with two-sided alpha at 
0.05 level and a common standard deviation (SD) of 5.5 points, accounting for missing data and early 
treatment terminations. 

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Statistical Methods: 
Unless specified otherwise, efficacy analyses will be performed on the full analysis set (FAS), which 
includes all randomized subjects who receive at least one dose of randomized study drug and have a 
baseline and at least one post-baseline efficacy assessments or have survival status recorded, by 
randomized treatment group. 
The analysis for the primary endpoint is to test the global null hypothesis that there is no treatment 
difference in the change from baseline to Week 24 in ALSFRS-R total score between patients 
randomized to placebo and those randomized to reldesemtiv during the double-blind, placebo-
controlled period in the FAS. The FAS consists of all randomized patients who receive any amount of 
study drug and who have a baseline and at least one post baseline efficacy assessment during the first 
24-week double-blind placebo-controlled period. 
The primary analysis will be conducted using a Mixed Model for Repeated Measures (MMRM) with a 
restricted maximum likelihood method (SAS® PROC MIXED default). At randomization, patients will 
be stratified by riluzole use/non-use and edaravone use/non-use and the primary model will include 
terms of treatment group, baseline ALSFRS-R value, visit, baseline riluzole use, and baseline 
edaravone use as well as the interaction terms of baseline-by-visit and treatment group-by-visit. An 
unstructured variance-covariance matrix will be used in the model. Prior to applying the MMRM, 
missing data will be imputed using the multiple imputation procedure (Rubin 1987) for the primary 
analysis, and the estimates from each imputed dataset will be combined into one set of overall 
estimates using the SAS® PROC MIANALYZE procedure. . The extent of missing data and the 
pattern of missing data reasons will be tabulated. Imputation details will be pre-specified in the SAP. 
Least square means (LSM), LSM difference and the corresponding standard errors, 95% confidence 
intervals (CI) and p-values will be presented. 
Multiplicity will be addressed using closed testing procedure. The testing sequence below the first 
secondary endpoint will be provided in the statistical analysis plan (SAP). 
Safety data will be analyzed descriptively in the safety analysis set, including patients who take at least 
one dose of study drug. All AE terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Primary system organ class (SOC) and preferred term (PT) of the Treatment 
Emergent Adverse Events (TEAEs) will be tabulated by the early-start and delayed-start treatment 
groups and period (placebo-controlled period and active drug period). TEAEs will also be summarized 
by severity and relationship to study drug. AEs that led to early discontinuation from treatment or trial 
will be summarized. 
General and additional analysis methods will be detailed in the SAP. 

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1.2. 
Schema 
Figure 1:  
Study Schema 
 
 
 

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1.3. 
Schedule of Activities 
 
 
 
Double-Blind, Placebo-Controlled Period 
Active Drug Period 
 
Scree
-ning 
Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 48  
(or ED) 
FU 
In Clinic 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
Remote Visit and/or Lab 
Draw 
 
 
X1 
 
X 
 
X 
X 
 
X1 
X 
X 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight & BMI 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
Concomitant Med Review  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Neurological Exam  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Vital Signs 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
AE/SAE Evaluation 
X2 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X7 
Clinical Safety Labs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (WOCBP 
only)  
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Sample4 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X5 
 
 
 
 
Biomarker sample6 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Genetic Sample (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
ALSFRS-R 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
FVC (Clinic) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 

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Double-Blind, Placebo-Controlled Period 
Active Drug Period 
 
Scree
-ning 
Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
26 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 48  
(or ED) 
FU 
In Clinic 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
Remote Visit and/or Lab 
Draw 
 
 
X1 
 
X 
 
X 
X 
 
X1 
X 
X 
 
X 
X 
 
 
FVC (Home)8 ** 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Health Economics Outcomes 
Measure (DME Use) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-40 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
Grip Strength 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
HHD 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
EQ-5D-5L and EQ VAS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
BDI-FS 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
ED=Early discontinuation; AE=adverse event; ECG=electrocardiogram; BMI=body mass index; PK=pharmacokinetics; SAE=serious adverse event; WOCBP=women of 
childbearing potential, FVC=forced vital capacity; FU=Follow-Up; ALSFRS-R=Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; BDI-FS=Beck 
Depression Inventory-Fast Screen; ALSAQ-40=Amyotrophic Lateral Sclerosis Assessment Questionnaire; DME=Durable Medical Equipment;  
HHD=Hand-Held Dynamometry; EQ-5D-5L=EuroQol-5D-5L; EQ VAS=EuroQol Visual Analog Scale 
*Drug dosing will not occur at the ED visit 
**Dosing should take place prior to the telemedicine contact on the dosing day such that the FVC is performed approximately 2 hours after taking the dose 
1=Remote visit lab draw only (no phone call) at Week 2 and Week 26; all other remote visits include video call and home lab draw 
2= During the interval between the time of signing the informed consent form and immediately before the first dose of study drug, serious adverse events considered by 
the investigator to be related to study protocol-mandated procedure should be collected in the AE CRF. All other medical conditions should be collected as medical 
history prior to the first dose of study drug. 
3=Clinical safety labs to include: 
Chemistry: sodium, potassium gamma-glutamyl transferase, chloride, calcium, magnesium, phosphorus, urea nitrogen, creatinine, eGFRCr (calculated using CKD-EPI 
creatinine equation), Total protein, cholesterol, bicarbonate, total bilirubin, direct bilirubin, indirect bilirubin, CK, ALP, LDH, AST (SGOT), ALT (SGPT), Cystatin C, 
eGFRCysC (calculated by CKD-EPI cystatin C equation), uric acid, albumin, triglycerides, glucose 
Hematology: hemoglobin, hematocrit, RBC, RDW, MCV, MCH, MCHC, WBC, platelets 
Urinalysis: specific gravity, pH, blood, protein, glucose, bilirubin, UPCR and microscopy 
TSH at screening; bHCG as applicable for WOCBP, FSH as required to determine menopausal status at Screening per Appendix 3 (Section 10.3) 
4=PK sample at Week 4, Week, 12, and Week 24 at pre-dose and 2-4 hrs post-dose 
5=PK samples at Week 36 for Sub-Study at pre-dose and at 0.5, 1, 2, 3, 4 and 6 hrs post-dose 
6=Biomarker samples at Day 1 pre-dose and Week 24 pre-dose 
7=Additional testing to be conducted if AEs of special interest are not resolved at the 4-week FU visit 
8= Refer to Section 8.1.2 for details of timing of home spirometry relative to FVC performed at in-clinic visits

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1.4. 
Key Contacts 
Sponsor’s Study Contact: 
Jacqueline Lee 
Senior Director, Clinical Operations 
Email:  CY5031ClinicalOperations@cytokinetics.com 
Phone:  +1 (650) 624-3017 
Cell:  
+1 (650) 291-5533 
Sponsor’s Medical Monitor: 
Tyrell Simkins, DO, PhD 
Associate Medical Director 
Email:  CY5031MedicalMonitor@cytokinetics.com 
Phone:  +1 (650) 624-3269 
Cell:  
+1 (517) 303-4010 
Serious Adverse Event Reporting: Drug Safety 
Email:  CY5031DrugSafety@cytokinetics.com 
Fax:  
+1 (650) 243-4199 
Lead Investigator: 
Jeremy Shefner, MD, PhD 
Professor & Chair of Neurology 
Barrow Neurological Institute 
Email:  jeremy.shefner@dignityhealth.org 
Cell:  +1 (315) 378-8531 
 

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2. 
INTRODUCTION 
This trial of reldesemtiv is being conducted in patients with amyotrophic lateral sclerosis (ALS). 
2.1. 
Study Rationale 
Reldesemtiv, a fast skeletal muscle troponin activator (FSTA), is being investigated as a 
potential therapy to slow the decline of skeletal muscle function in patients with ALS. This 
pivotal trial with reldesemtiv is being conducted in ALS patients and is designed to assess the 
effect of reldesemtiv on functional outcomes during treatment up to 48 weeks. The first trial with 
reldesemtiv in ALS patients (FORTITUDE-ALS [CY 5022]) after 12 weeks of dosing, showed 
that patients on all doses of reldesemtiv tended to decline less than patients on placebo for slow 
vital capacity (SVC) and ALS Functional Rating Scale-Revised (ALSFRS-R), with larger and 
clinically meaningful differences emerging over time. The results support progression in a 
further clinical trial with a longer treatment duration. 
2.2. 
Background 
2.2.1. 
Amyotrophic Lateral Sclerosis 
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 2011). Over time, 
progressive denervation and its consequent skeletal muscle atrophy lead to weakness, fatigue, 
and eventually complete paralysis and death, primarily from respiratory complications. 
No curative therapies for ALS exist. Rilutek® (riluzole) is the first drug approved for the 
treatment of ALS in 1995 and 1996 in the US and EU, respectively, and has a modest benefit on 
survival (Lacomblez 1996). While non-invasive ventilation (NIV) use has been demonstrated to 
provide a survival benefit in ALS patients, a third of ALS patients may be non-compliant, and 
non-compliance may be even higher in those with bulbar involvement and frontotemporal 
dysfunction (Bourke 2006; Kleopa 1999). Improvements in the ventilation machines have likely 
led to improved tolerability in more recent years, however, NIV may still be under-utilized 
(Lechtzin 2018). While patients may undergo gastrostomy tube placement with disease 
progression, it is less clear if the use of enteral feeding prolongs survival with studies showing 
inconsistent results (Forbes 2004; Burkhardt 2017). 
As of July 2020, Radicava® (edaravone) was approved to treat patients with ALS in in Japan, 
South Korea, United States (US), Canada, Switzerland and China. The efficacy of edaravone was 
demonstrated in a 6-month clinical trial conducted in Japan wherein 137 participants were 
randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone 
declined less on a clinical assessment of daily functioning (ALSFRS-R) compared to those 
receiving placebo (Abe 2017). Oral Radicava® (edaravone) was approved for ALS in the US 
based upon bioequivalence data. (Shimizu 2021). 
The combination product of sodium phenylbutyrate and taurursodiol (also known as TUDCA, 
ursodoxicoltaurine or Tauroursodeoxycholic acid) was approved in Canada and the US on the basis 
of a 6-month clinical trial conducted in the US involving 137 participants randomized to 2 to 1 to 

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either active drug or placebo. The primary endpoint was rate of change in the ALSFRS-R; the 
decline was -1.24 points per month in the active arm and -1.66 points per month in the placebo 
arm (p = 0.033) (Paganoni 2020). 
To date, there are no available treatments that slow the decline of skeletal muscle strength or 
slow the decline of respiratory function. This clinical protocol is a double-blind, randomized, 
dose-ranging, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of 
reldesemtiv in patients with ALS. 
2.2.2. 
Reldesemtiv 
Reldesemtiv is a small molecule activator of the fast skeletal muscle troponin complex, a 
sarcomere-directed therapy intended to improve skeletal muscle function in conditions associated 
with muscle weakness and/or fatigue. Reldesemtiv selectively activates the fast skeletal muscle 
troponin complex by increasing its affinity for calcium. In intact rat skeletal muscle in vivo, 
reldesemtiv increases muscle force at sub-maximal nerve stimulation frequencies, increases 
muscle power, and decreases muscle fatigability. Reldesemtiv is selective for the troponin 
complex in fast skeletal muscle and does not activate the slow skeletal troponin complex or the 
cardiac troponin complex. It has similar potencies in muscle fibers from preclinical species and 
human fast skeletal muscle fibers. It is expected that reldesemtiv may provide benefit to patients 
with a wide variety of disorders characterized by muscle weakness and/or fatigue. 
Please refer to the Investigator’s Brochure (IB) for detailed information on the nonclinical and 
clinical studies of reldesemtiv. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
In CY 5022, treatment emergent adverse events (TEAEs) reported more frequently for the 
reldesemtiv groups than for the placebo group (with a difference in patient incidence of > 5%) 
were cystatin C increased, GFR decreased, and fatigue. TEAEs that appeared to increase in 
frequency with increasing dose included fatigue, nausea, cystatin C increased, GFR decreased, 
alanine aminotransferase (ALT) increased, and aspartate aminotransferase (AST) increased. 
Serum cystatin C was obtained in CY 5022 and used to determine the estimated glomerular 
filtration rate (eGFRCysC) as it was previously recognized that exposure to reldesemtiv resulted in 
a rise in creatinine; this was attributed to Organic Cation Transporter 2 (OCT2) inhibition. There 
was a dose dependent decline in eGFRCysC from baseline in CY 5022 and therefore the rise in 
creatinine observed in prior studies could not be ascribed solely to OCT2 inhibition. Mean eGFR 
declined to an essentially stable level by 2 weeks of active treatment and tended to recover after 
4 weeks off drug. Decline in eGFRCysC was the most common reason for early termination of 
study drug due to AEs, occurring in 7/457 (1.5%) participants. No patients had significant 
sequalae related to the decline in eGFRCysC such as requiring dialysis or developing 
hyperkalemia. 
Elevations in ALT or AST greater than 3×upper limit of normal (ULN) occurred in 25 patients; 
24 (7.0%) were assigned reldesemtiv and 1 (0.9%) assigned placebo. Overall, the transaminase 
elevations appeared to be transient, dose dependent, mild to moderate, and not associated with 
increase in bilirubin or any clinical manifestations. 

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A total of 6 patients (none of whom had concurrent elevations in ALT or AST > 5×ULN), all on 
reldesemtiv and 5 in the 450 mg bid group, had a postbaseline total bilirubin value > 2×ULN. All 
elevations were observed within approximately 1 month of starting reldesemtiv dosing and 
resolved or were normalizing at last contact. 
2.3.1.1. 
Mitigation Strategy 
For both the renal and hepatic findings in CY 5022, the frequency was highest in those patients 
on the highest dose of reldesemtiv (450 mg twice a day); thus, the highest dose that will be used 
in the current trial is reldesemtiv 300 mg twice a day and a careful monitoring of renal function 
and liver enzymes will be implemented during the trial. 
Renal Safety  
For renal safety, the mitigation strategy includes specific inclusion and exclusion criteria to 
reduce the risk of a drop in eGFR below a clinically meaningful threshold, renal function 
monitoring (at least monthly, more frequently at dose initiation) and detailed study drug dose 
management with the potential for a dosing interruption and down-titration of dose, as described 
in Section 7.3. 
Key Relevant Exclusion Criteria: 
• eGFRCr and eGFRCysC less than 45.0 mL/min/1.73m2  
• Urine protein/creatinine ratio greater than 1 mg/mg 
Hepatic Safety  
For hepatic safety, the mitigation strategy includes specific inclusion and exclusion criteria, liver 
function monitoring (at least monthly, more frequently at dose initiation) and detailed study drug 
management as described in Section 7.4. 
Key Relevant Exclusion Criteria: 
• Total, indirect, or direct bilirubin values greater than the ULN 
• ALT or AST greater than or equal to 3×ULN  
• History of Gilbert’s Disease, Dubin-Johnson syndrome, or Rotor syndrome 
2.3.2. 
Benefit Assessment 
Given that patients in this trial will be symptomatic and progressing on their existing background 
therapy, reldesemtiv may afford those randomized to reldesemtiv an opportunity to slow the 
decline in their function. For details regarding potential benefits of reldesemtiv in ALS, please 
see Section 4.2 which provides the results of the Phase 2 trial (CY 5022) of reldesemtiv in 
patients with ALS. 
Patient contributions to the performance of this trial may yield a new therapeutic modality for the 
treatment of their disease. 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 1: 
Study Objectives and Endpoints 
Objectives 
Endpoint(s) 
Primary 
• To assess the effect of reldesemtiv versus 
placebo on functional outcomes in ALS 
• Change from baseline to Week 24 in ALSFRS-
R total score 
Secondary 
• To assess the effect of reldesemtiv 
versus placebo on combined functional 
and survival outcomes in ALS 
• To assess the effect of reldesemtiv 
versus placebo on ventilatory function  
• To assess the effect of reldesemtiv 
versus placebo on quality of life  
• To assess the effect of reldesemtiv 
versus placebo on handgrip strength 
• Combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted 
ventilation (use of non-invasive or invasive 
ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days), and survival time up to 
Week 24 
• Change from baseline to Week 24 in the percent 
predicted forced vital capacity (FVC) 
• Change from baseline to Week 24 in the 
Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-40) total score 
• Change from baseline to Week 24 in handgrip 
strength (average of both hands) 
Exploratory 
• To assess the effect of reldesemtiv 
versus placebo on the progression of 
ALS 
 
 
 
 
 
• Time to the patient being prescribed and patient 
agrees to it, time to first receipt, time to first 
use, time to daily use and time to dependence 
and number used of any of the following 
durable medical equipment items (manual 
wheelchair, power wheelchair, speech 
generating device, NIV and/or gastrostomy 
tube) from randomization to the end of the 
24-week double-blind, placebo-controlled 
period and to the end of Week 48. Time to 
dependence on invasive ventilation will also be 
recorded. 
• Change from baseline to Week 24 in the four 
subdomain scores of the ALSFRS-R 
• Time spent in each MiToS stage and number of 
patients to transition stages from baseline to 
Week 24  

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Objectives 
Endpoint(s) 
• Change from baseline to Week 48 in ALSFRS-
R total score 
• Change from baseline to Week 48 in FVC 
• Combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted 
ventilation (use of non-invasive or invasive 
ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days), and survival time up to 
Week 48 
• Change from baseline to Week 24 in the mega-
score of muscle strength measured by hand held 
dynamometry (HHD) in bilateral first dorsal 
interosseous muscles, abductor pollicus brevis 
muscles, and abductor digiti minimi muscles 
• Change from baseline to Week 24 and Week 48 
in the EQ-5D-5L 
• Change from baseline to Week 24 and Week 48 
in the EuroQol Visual Analog Scale (EQ-VAS) 
• Time to event for first hospitalization to 
Week 24 and Week 48 
Safety 
• To assess the safety and tolerability of 
reldesemtiv compared to placebo 
• Patient incidence of adverse events and serious 
adverse events 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, double-blind, randomized, placebo-controlled trial of reldesemtiv in patients 
aged 18 to 80 with ALS. 
The screening and qualification period for the trial will be no more than 21 days in duration. 
Approximately 555 eligible ALS patients will be randomized (2:1) to receive the following dose 
of reldesemtiv or placebo (stratified by riluzole use/non-use and edaravone use/non-use) for the 
first 24 weeks (double-blind, placebo-controlled period): 
• 300 mg reldesemtiv twice a day for a 600 mg total daily dose (TDD) 
• Placebo twice daily 
At the end of the 24 week double-blind, placebo-controlled period, patients will transition to the 
active drug period, where all patients will receive the following dose of reldesemtiv for the next 
24 weeks: 
• 300 mg reldesemtiv twice a day for a 600 mg TDD for patients who were not down 
titrated during the 24 weeks of blinded dosing 
• 150 mg reldesemtiv twice a day for a 300 mg TDD for patients who were down 
titrated for any reason during the 24 weeks of blinded dosing 
For patients being seen in the morning of the Week 24 visit: 
• 
Following the pre-dose PK, the last dose of double-blind study drug will be taken 
from the bottle received at the prior drug dispensation visit 
• 
The patient will take their second dose of the day (which will be unblinded 
reldesemtiv) at home from the new bottle dispensed at the Week 24 visit 
approximately 8 hours after the first dose 
If a patient is being seen in the afternoon for the Week 24 visit and taking their second dose of 
the day in the clinic: 
• 
Following the pre-dose PK, the last dose of blinded study drug will be taken from 
the bottle received at the prior drug dispensation visit and they will take no further 
doses that day 
• 
The following morning, the patient will start taking unblinded study drug 
(reldesemtiv) from the new bottle dispensed at Week 24. 
For the entire 48 weeks of dosing, patients and sites shall remain blinded to the randomized 
treatment assignment the patients received during the first 24 weeks. 
Study drug should be taken twice daily, morning and afternoon (at least 8 hours apart) and 
should be taken within a 2-hour period following food. 
Study Visits: 
There will be up to eight clinic visits and nine remote assessment visits (with most requiring an 
accompanying phone/video call) as follows: 
• Screening: clinic visit/lab 

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• Day 1 (start of dosing): clinic visit/lab 
• End of Week 2: remote visit (lab only) 
• End of Week 4: clinic visit/lab 
• End of Week 8: remote visit/lab 
• End of Week 12: clinic visit/lab 
• End of Week 16: remote visit/lab 
• End of Week 20: remote visit/lab 
• End of Week 24 (last dose of double-blind dosing): clinic visit/lab 
• End of Week 26: remote (lab only) 
• End of Week 28: remote visit/lab 
• End of Week 32: remote visit/lab 
• End of Week 36: clinic visit/lab 
• End of Week 40: remote visit/lab 
• End of Week 44: remote visit/lab 
• End of Week 48 (last dose of active drug dosing): clinic visit/lab 
• Follow-Up (4 weeks after last dose of study drug): clinic visit/lab 
For patients who complete Week 48 and want to enter the open label extension (OLE), they will 
not have the follow-up visit; instead they will enter the OLE on the same day as their Week 48 
visit. If the patient does not want to enter the OLE, or if the OLE has not yet been approved at 
the site, the follow-up visit will take place as above. 
Remote Visits 
Remote visits are defined as any of the following contacts with the patient: home (or other 
location outside of the clinic) phlebotomy draw, telephone calls, telemedicine, and video contact. 
Patients will be provided a device to enable telemedicine contact for the remote visits. Screening 
and Day 1 visits must occur in-clinic; in addition, it is strongly encouraged that Week 24 and 
Week 48 visits take place in the clinic. Week 48 must take place in clinic if the patient is 
enrolling in the OLE study at the Week 48 visit. In-clinic visits can be converted to remote visits 
in the event the clinic is closed to patient care, or if the investigator believes the health of the 
patient would be best served by replacing the in-clinic visit with a remote one. The medical 
monitor must be contacted in advance of converting an in-clinic visit to a remote visit. 
Standard of Care for ALS 
Since we plan to conduct the trial in different regions of the world, including Europe, Canada, 
Australia and the US, standard of care regarding ALS for the local region as determined by the 
physician in discussion with the patient should be followed. Standard of care may include, but is 
not limited to, therapies for the treatment of ALS that have been approved in the respective 
regions where the trial is conducted. 
4.2. 
Scientific Rationale for Study Design 
CY 5031 is a Phase 3 clinical trial intended to evaluate the safety and efficacy of reldesemtiv for 
the treatment of patients with ALS, based on the results of a Phase 2 clinical trial, CY 5022. In 

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CY 5022, 458 patients with ALS were randomized 1:1:1:1 to 12 weeks of treatment with placebo 
versus reldesemtiv at 150 mg, 300 mg, or 450 mg twice daily. The primary efficacy analysis of 
the weighted dose response of change from baseline to 12 weeks in slow vital capacity (SVC, 
analyzed using a Mixed Model for Repeated Measures (MMRM) with multiple contrasts) was 
not statistically significant (p = 0.11); however, the decline in SVC was less than on placebo in 
all three reldesemtiv treatment groups (Figure 2). 
Figure 2: 
CY 5022 Primary Endpoint – SVC Change from Baseline to Week 12 
 
In a post-hoc analysis, the change from baseline to 12 weeks in the ALSFRS-R total score for all 
three reldesemtiv dose groups pooled versus placebo did achieve nominal statistical significance 
(LS mean difference = 0.9 points favoring reldesemtiv, p = 0.01; Figure 3). In addition, when the 
CY 5022 population was divided into tertiles based on the calculated rates of pre-study ALS 
progression, the apparent benefit of reldesemtiv in the three active treatment groups pooled 
versus placebo was particularly evident among the two faster progressing tertiles relative to the 
slowest progressing tertile (Figure 4). This replicates earlier observations that a reduction in 
measures of ALS disease progression by an intervention is less easily demonstrated among 
patients whose ALS was progressing relatively slowly prior to enrollment. 

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Figure 3: 
CY 5022 – ALSFRS-R Change from Baseline Over Time (All Active vs 
Placebo) 
 
Figure 4: 
CY 5022 – Subgroup Analyses of ALSFRS-R Total Scores 
 
*Pre-study rate of disease progression: 48 minus baseline ALSFRS-R total score divided by symptom duration in months 
Subsequent examination of the data from CY 5022 revealed that most (but not all) patients in the 
slowest progressing tertile had ALS symptoms for > 24 months and/or an ALSFRS-R total score 
at baseline > 44. Consistent with the above observations, the apparent effect of reldesemtiv to 
decrease the decline in the ALSFRS-R total score from baseline to 12 weeks versus placebo was 
substantially more evident in the group of patients in CY 5022 with ALS symptoms for 
≤ 24 months and an ALSFRS-R total score at baseline ≤ 44. Consequently, in CY 5031, patients 
with ALS symptoms for > 24 months are excluded as are patients with an ALSFRS-R total score 
at screening > 44 (with certain exceptions as set forth in Section 5.1). 

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A placebo control and double-blinded approach are employed in this trial to avoid bias in data 
collection, including the safety assessments and pharmacodynamics (PD) measures that comprise 
the primary and secondary endpoints. 
4.3. 
Justification for Dose 
The principle for dose selection is to ensure the potential benefits outweigh the risks of treatment 
with reldesemtiv, based on data from the dose ranging trial of CY 5022. In the Full Analysis Set 
(FAS), all three reldesemtiv dose levels appeared to be pharmacodynamically active. The totality 
of data in CY 5022 suggested that the three reldesemtiv dose levels had similar effects on 
ALSFRS-R and SVC; however, the more complete experience in the reldesemtiv clinical 
development program (as well as the clinical experience with tirasemtiv, another fast skeletal 
muscle troponin activator with a mechanism of action identical to that of reldesemtiv) indicates 
that higher exposures are associated with greater increases relative to placebo in skeletal muscle 
force production. Consequently, there is a rationale for using the highest dose of reldesemtiv that 
is safe and well tolerated in CY 5031. 
The 450 mg dose level was associated with a higher rate of AEs related to nausea, decline in 
eGFR, elevations in ALT and AST and early terminations (compared to the 300 mg and 150 mg 
dose levels) in CY 5022. The dose selected for CY 5031 is 300 mg bid based on better 
tolerability compared to 450 mg bid with relatively similar efficacy between the two doses. A 
down titration to one tablet bid (for those assigned reldesemtiv, the dose would then be 150 mg 
bid) may be implemented for patients who experience an adverse event (AE) that is believed to 
be study drug related. See Section 6.6 for details regarding dose modification. Since elevations in 
transaminases and declines in eGFRCysC were dose related, by resuming drug at a lower dose for 
the remainder of the trial, the reoccurrence of the lab abnormality is expected to be less likely to 
occur. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last patient in the trial. 

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5. 
STUDY POPULATION 
Before patients begin any study-specific activities/procedures, Cytokinetics requires a copy of 
the site’s institutional review board/independent ethics committee (IRB/IEC) approval of the 
protocol, informed consent form (ICF), and all other patient information and/or recruitment 
material, if applicable. A signed ICF must be obtained from each patient before commencement 
of any study-specific activities/procedures. 
A patient is considered entered into the trial after signing the informed consent. After confirming 
the patient has met all eligibility criteria, randomization will then occur before the first dose on 
Day 1 is administered. The site is to document the informed consent signature and randomization 
date in the patient’s medical record and in/on the case report form (CRF). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exceptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the trial only if all the following criteria apply: 
101. Able to comprehend and willing to sign an ICF and willing to comply with all study 
procedures and restrictions for the duration specified in the Schedule of Activities 
(SoA; Section 1.3). If patient is able to comprehend and is willing to sign the ICF, but 
cannot physically sign the ICF, an impartial witness must sign the ICF form. 
102. Males and females between 18 and 80 years of age, inclusive, at screening. 
103. Diagnosis of familial or sporadic ALS (defined as meeting the laboratory-supported 
probable, probable, or definite criteria for ALS according to the World Federation of 
Neurology El Escorial criteria published in 2000 [Brooks 2000]). Patients who meet 
the possible criteria are eligible if they have lower motor neurone findings; those who 
have purely upper motor neurone findings are ineligible. 
104. First symptom of ALS ≤ 24 months prior to screening. The qualifying first symptoms 
of ALS are limited to manifestations of weakness in extremity, bulbar, or respiratory 
muscles. Cramps, fasciculations, or fatigue should not be taken in isolation as a first 
symptom of ALS. 
105. ALSFRS-R total score ≤ 44 at screening. Patients with a total score of 45 or higher may 
be rescreened 60±7 days following the original screening date and be deemed eligible if 
their ALSFRS-R total score is ≤ 44 or if their score is 2 or more points less than at 
initial screening. Such patients must continue to meet all other inclusion/exclusion 
criteria at the time of rescreening. 
106. Upright FVC ≥ 65.0% of predicted for age, height, sex and ethnicity at screening 
according to Global Lung Initiative equation (Quanjer 2012). 
107. Able to perform reproducible pulmonary function tests defined as being able to perform 
FVC at screening with variability of the 2 highest raw values of less than 10% with a 
maximum of 5 trials permitted. Screening FVC results must be reviewed and approved 
by the central review process prior to randomization. 

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108. Must be either on riluzole for ≥ 30 days prior to screening or not have taken it for at 
least 30 days prior to screening  
109. Must have completed at least 2 cycles of edaravone at the time of screening or not have 
received it for at least 30 days prior to screening  
110. Clinical laboratory findings within the normal range, or if outside the normal range, not 
deemed clinically significant by the Investigator, except as specifically indicated as 
laboratory exclusion in Section 5.2. 
111. Able to swallow whole tablets.at the time of screening 
112. Male patients, who have not had a vasectomy with medical assessment of surgical 
success, or a confirmed sperm count of zero, are eligible to participate if they agree to 
the following during the trial and for at least 10 weeks after the last dose of study drug: 
a. Refrain from donating sperm 
Plus when their female partner is of childbearing potential must either:  
b. Be abstinent from heterosexual intercourse and agree to remain abstinent  
OR 
Must agree to use a male condom AND have his female partner use a highly 
effective method of contraception during the study (as described in Appendix 3 
[Section 10.3]) , and also for at least 4 weeks after the last dose of study drug. 
113. A female patient is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
a. Is not a woman of childbearing potential (WOCBP; as described in Appendix 3 
[Section 10.3]) 
OR 
Is a WOCBP and using a highly effective method of contraceptive during the study 
(as described in Appendix 3 [Section 10.3]) and also for at least 4 weeks after the 
last dose of study drug, and her male partner must agree to use a male condom 
during the trial and for at least 4 weeks after the last dose of study drug. 
b. A WOCBP must have a negative pregnancy test (urine or serum as required by 
local regulations) within 3 days before the first dose of study drug. 
Note: The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a woman with 
an early undetected pregnancy. 
Contraceptive use by men or WOCBPs should be consistent with the guidance in 
Appendix 3 (Section 10.3) and local regulations regarding the methods of 
contraception for those participating in clinical studies. 
114. Able to complete all screening procedures. 
115. Must be either on the combination product (brand name only) of sodium phenylbutyrate 
and taurursodiol (also known as TUDCA, ursodoxicoltaurine or Tauroursodeoxycholic 

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acid) for ≥ 51 days prior to screening or not have taken it for at least 30 days prior to 
screening  
5.2. 
Exclusion Criteria 
Patients will be excluded from the trial if any of the following criteria apply: 
201. Other medically significant neurological conditions that could interfere with the 
assessment of ALS symptoms, signs or progression. 
202. Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal, 
musculoskeletal, or psychiatric illness that might interfere with the patient’s ability to 
comply with study procedures or that might confound the interpretation of clinical 
safety or efficacy data, including, but not limited to: 
a. Poorly controlled systemic hypertension 
b.Clinically significant electrocardiogram (ECG) abnormalities that require medical 
attention (ie, persistent atrioventricular conduction block >first degree, or acute 
myocardial ischemic changes) 
c. New York Heart Association Class II or greater congestive heart failure 
d.Chronic obstructive pulmonary disease  
e. Gastrointestinal disorder that is likely to impair absorption of study drug from the 
gastrointestinal tract  
f. eGFRCr and eGFRCysC < 45.0 mL/min/1.73 m2 at screening 
g.ALT or AST ≥ 3×ULN at screening 
h.Urine protein creatinine ratio > 1 mg/mg (113 mg/mmol) at screening 
i. Total bilirubin (TBL), direct or indirect bilirubin above the ULN. 
j. History of Gilbert’s Disease, Dubin-Johnson syndrome, or Rotor syndrome 
k.Poorly controlled or brittle diabetes mellitus 
l. Amputation of a limb 
m. Cognitive impairment, related to ALS or otherwise that impairs the patient’s ability 
to understand and/or comply with study procedures and provide informed consent 
n.Cancer currently being treated (other than basal cell carcinoma, carcinoma in situ of 
the cervix, or squamous cell carcinoma of the skin excised with clean margins) or a 
history of cancer with an expected survival of less than 5 years. Breast cancer 
survivors with an expected survival of ≥ 5 years who are on long-term endocrine 
therapy are eligible. 
o.Any other condition, impairment or social circumstance that, in the opinion of the 
Investigator, would render the patient not suitable to participate in the trial 
p.Patient judged to be actively suicidal or a suicide risk by the Investigator 
203. Known to have received reldesemtiv or tirasemtiv in any previous clinical trial 
204. Has received or is considering receiving during the course of the trial any form of gene 
therapy (including antisense therapy) for the treatment of ALS 
205. Has received or is considering receiving during the course of the study any form of 
stem cell therapy for the treatment of ALS 
206. Has received or is considering obtaining during the course of the trial a diaphragmatic 
pacing system 

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207. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose 
of study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study 
drug 
208. Use of a medication that is an OCT1/OCT2 substrate within 7 days prior to first dose of 
study drug per Appendix 4 (Section 10.4) 
209. Currently participating in another trial, managed access program, open label extension, 
early access program, or through the right to try act is receiving an investigational drug 
or received an investigational drug or device within 30 days (or 5 half-lives for drugs, 
whichever is longer) prior to screening. Patients also cannot be taking outside of a 
clinical trial certain investigational drugs (which includes drugs, supplements, and 
nutraceuticals) within 30 days of screening (or 5 half-lives for drugs, whichever is 
longer) that are currently being studied or have been studied for the treatment of ALS. 
A full listing of excluded agents can be found in the Study Manual. 
210. Has a tracheostomy 
211. Known to have hypersensitivity to study drug, placebo or excipients 
5.3. 
Lifestyle Considerations 
Not applicable. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demographics, reason for screen failure, eligibility criteria, and any serious 
adverse events (SAEs) related to study-related procedures. 
The screening eligibility period is 21 days as defined in Section 4.1. An individual who does not 
meet the criteria for participation in this trial is referred to as a screen failure. 
5.4.1. 
Rescreening 
Patients may be rescreened one time after initial screening for any of the following reasons:  
• ALSFRS-R value at original screening > 44. To be eligible, a patient’s ALSFRS-R total 
score at rescreening must be ≤ 44 OR there is a drop in the score of 2 or more points 
compared to their original screening score. Rescreening for this reason must be done 
60 days (±7 days) after initial screening 
• Not on stable edaravone or riluzole doses at original screening. To be eligible, if taking 
riluzole, must be on riluzole for 30 days prior to rescreening or not taking it for 30 days 
prior to rescreening; if taking edaravone, must have completed at least 2 cycles of 
edaravone at the time of rescreening or not received it for at least 30 days prior to 
rescreening. If taking the combination product (brand name only) of sodium 
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have taken it for at least 30 days prior to rescreening. Rescreening may occur once the 
necessary time interval has passed. 
• Poorly controlled systemic hypertension at original screening. Rescreening may occur 
once the hypertension is adequately controlled 
• Received an investigational device or drug or a prohibited drug as described in 
Section 5.2, Item 209, within 30 days (or less than 5 half-lives, whichever is longer), at 
original screening. Rescreening may occur once the necessary time interval has passed. 
• Was outside the screening window for their original Day 1 visit. Rescreening may occur 
once scheduling permits both rescreen and Day 1 visits to occur within the 21-day 
window 
Patients must re-sign an informed consent before they are rescreened. At rescreening, they must 
meet all inclusion/exclusion criteria at the time of rescreening and have all elements of the 
screening visit performed again to be eligible. Patients may only rescreen once. 
If an element of the screening visit could not be performed for logistical reasons (eg, trained 
evaluator was out sick, lab kits or outcome measure device was unavailable) the patient can 
return within the screening eligibility period to complete the visit. 
Retesting for abnormal lab work within the original screening period may also be performed if 
there is reason to believe the repeat labs may improve and not be clinically significant and the 
patient is otherwise eligible to participate. Patients cannot be retested for abnormal bilirubin 
laboratory results. Patients who are retested for abnormal laboratory results during the original 
screening eligibility period do not need to re-sign an informed consent. 
No waivers will be granted regarding inclusion/exclusion criteria. 

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6. 
INVESTIGATIONAL PRODUCT 
This section describes any study drug: investigational product (IP) (ie, reldesemtiv) or placebo 
intended to be administered to a trial patient according to the protocol. 
6.1. 
Study Drug Administered 
Table 2: 
Study Drug 
Arm Name 
Active 
Placebo 
IP/Product Name 
Reldesemtiv 
Placebo 
Type  
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
150 mg 
Matching placebo 
Dosage Level(s) 
2 tablets twice a day for 600 mg 
TDD 
2 matching placebo tablets twice a 
day  
Route of 
Administration 
Oral or via gastrostomy tube 
Oral or via gastrostomy tube 
Use 
Experimental 
Placebo 
IMP  
IMP 
IMP 
Sourcing 
Patheon, Inc. 
Toronto Regional Operations (TRO) 
2100 Syntex Court 
Mississauga, Ontario L5N 7K9 
Canada 
Patheon, Inc. 
Toronto Regional Operations (TRO) 
2100 Syntex Court 
Mississauga, Ontario L5N 7K9 
Canada 
Packaging and 
Labeling 
IP will be provided in bottles. Each 
bottle will be labeled as required per 
country requirement 
Placebo will be provided in bottles. 
Each bottle will be labeled as 
required per country requirement 
Excipients in Active 
and Placebo tablets  
 
Microcrystalline cellulose       Lactose monohydrate  
Croscarmellose sodium           Providone  
Sodium lauryl sulfate              Magnesium stearate  
IMP = investigational medicinal product; NIMP = non-investigational medicinal product 
6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and resolved 
before use of the IP. 
Only patients randomized in the trial may receive study drug and only authorized site staff may 
supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. Study drug may be 
shipped to patients by the site to avoid drug interruption. 

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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, chain of custody, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drug are provided in 
the Pharmacy Manual. 
IP should be stored at or below 25°C. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All patients will be centrally assigned to randomized study drug using an Interactive Web 
Response System (IWRS). Before the trial is initiated, the log in information & directions for the 
IWRS will be provided to each site. 
Study drug will be dispensed at the study visits summarized in the SoA (Section 1.3). Returned 
study drug should not be re-dispensed to the patients. 
The IWRS will be programmed with blind-breaking instructions and the unblinding procedure is 
documented in the IWRS User Manual. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a patient’s treatment assignment is warranted. 
Patient safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact Cytokinetics prior to unblinding a patient’s treatment assignment unless this could delay 
emergency treatment of the patient. If a patient’s treatment assignment is unblinded, Cytokinetics 
must be notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF, as applicable. 
An unblinded physician (unmasked to renal labs but blinded to treatment assignments) who is 
not on the study team may direct a study drug interruption and a down-titration of patients based 
upon review of unmasked renal function laboratory values that meet the prespecified criteria 
(Section 6.6 and Section 7.3). In order to preserve blinding of site staff and the study operation 
team, a small number of placebo patients will be selected for dummy down-titration during the 
study by the unblinded Clinical Research Organization (CRO) physician and will undergo repeat 
laboratory testing similar to what could be directed for patients receiving active treatment with 
laboratory abnormalities. The blinded down-titration selection criteria and records will be 
documented by the unblinded physician and the unblinded statistician separately. In order to 
maintain the blind, placebo patients who had a dummy down-titration during the double-blind 
dosing period will take 150 mg bid of reldesemtiv during the active drug period. 
The randomization treatment assignments for individual patients will remain blinded to site staff 
and patients until the entire study is completed and the database is locked. 
6.4. 
Study Drug Compliance 
When patients are dosed at the site, the route, the date and time of the dose administered in the 
clinic will be recorded in the source documents and recorded in the CRF. 
When patients self-administer study drug at home, compliance with study drug will be assessed 
at each visit. Compliance will be assessed by counting returned tablets during the in-clinic visits, 

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through documentation in the patient’s dosing diary, the source documents and the CRF. 
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF. 
All study drug should be taken either with food or within 2 hours following eating food. Water 
may be consumed ad libitum. 
• During the study, patients who lose the ability to swallow tablets can continue in the 
study taking crushed tablets. The crushed tablet dose can be administered either as: 
Crushed tablets in approximately 30 mL (2 tablespoons) of applesauce (or a vehicle 
of similar consistency) administered orally, followed by up to 250 ml (one cup) of 
water 
• Crushed tablets suspended in approximately 3 tablespoons of water administered through 
a PEG tube, preceded and followed by 118 mL (1/2 cup) of water to flush the tube 
A record of the number of study drug tablets dispensed to and taken by each patient must be 
maintained and reconciled with study drug and compliance records. Study drug dosing start and 
stop dates, including dates for dosing delays and/or dose reductions, and date of route change, 
will also be recorded in the CRF. 
6.5. 
Concomitant Therapy 
Any medication, including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements, that the patient is receiving at the time of enrollment or receives during the trial 
must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose, frequency and route of administration 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Patients may continue to take prescription medications and non-prescription medications which 
in the opinion of the investigator and the Medical Monitor, will not interfere with the trial. 
During the trial, medications and doses should remain stable whenever appropriate. However, 
investigators may prescribe or adjust any concomitant medication or treatment deemed necessary 
to provide adequate supportive care. 
Prior use of riluzole, edaravone and the combination product (brand name only) of sodium 
phenylbutyrate and taurursodiol, even if stopped prior to screening, will be recorded along with 
the reason why it was stopped (patient choice, adverse event, cost). Patients should neither stop 
nor start edaravone, riluzole or the combination product of sodium phenylbutyrate and 
taurursodiol following randomization. However, it is recognized that changes in medications 
may occur including those due to the development of adverse events potentially related to these 
medications or changes in insurance coverage. Patients who start or stop edaravone, riluzole and 
the combination product (brand name only) of sodium phenylbutyrate and taurursodiol following 
randomization will be permitted to continue in the trial. 
 

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Drug-Drug Interactions 
Medications that strongly inhibit the activity of CYP3A4 should be avoided from 7 days before 
the start of dosing (Day 1) through the last day of dosing (Week 48). Medications that strongly 
induced the activity of CYP3A4 should be avoided from 14 days before the start of dosing 
(Day 1) through the last day of dosing (Week 48). Please refer to Appendix 4 (Section 10.4) for 
the most common strong inhibitors and inducers of CYP3A4. Medications that are OCT1/OCT2 
substrates should be avoided from 7 days before the start of dosing or used with caution during 
the trial, as reldesemtiv may have the potential to inhibit OCT1 and OCT2-mediated transport. 
Please refer to Appendix 4 (Section 10.4) for the most common OCT1/OCT2 substrates that 
should be avoided or used with caution. 
6.6. 
Dose Modification 
Any dose interruption, as described in Section 7.1 must be documented in the CRF and include 
the reason for stopping, the stop date, and the restart date. For study drug dose management in 
relation to renal or hepatic abnormal laboratory values, see Section 7.3 and Section 7.4. 
Following a dose interruption for adverse events other than those related to renal labs, if the 
adverse event is thought to be potentially related to study drug, the investigator may restart the 
study drug when symptom(s) have resolved or have substantially improved, and there are no 
safety concerns before resuming the study drug. If the patient has been off study drug for more 
than 7 days, the investigator may choose to see the patient in the clinic or via telemedicine prior 
to resuming study drug. While investigators are encouraged to resume dosing at 2 tablets twice a 
day, down-titration of the dose to 1 tablet twice a day is an option. If the patient resumed the 
study drug at 2 tablets twice a day and has recurrence of the AE, the investigator once again 
should have the patient temporarily interrupt dosing until the symptom(s) have resolved or have 
substantially improved, and there are no safety concerns before resuming the study drug. If the 
study drug is resumed, the patient should be down-titrated to 1 tablet twice a day. 
Once down-titration occurs for any reason, no subsequent up-titration to the prior dose should 
occur. 
6.7. 
Access to Investigational Product after the End of the Study 
Assuming continuing development of reldesemtiv in ALS, Cytokinetics has put in place an open 
label extension study for patients who complete dosing through Week 48 in CY 5031. 
Participation in the open label extension study is at the discretion of the patient and not a 
condition of participation in CY 5031. 

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7. 
TEMPORARY INTERRUPTION OF STUDY DRUG, 
DISCONTINUATION OF STUDY DRUG, AND PATIENT 
CONSENT WITHDRAWAL  
Unless a safety concern arises, the investigator should make every effort to keep a patient on 
study drug for as long as possible during the trial. The degree to which a patient withdraws from 
the trial varies. There are three types of discontinuation: temporary study drug interruption, 
permanent study drug discontinuation and patient withdrawal of consent. 
7.1. 
Temporary Study Drug Interruption 
Initially, any study drug interruption should be considered temporary unless permanent study 
drug discontinuation is mandated by the protocol. 
A temporary study drug interruption: 
• Will be implemented when a predefined safety threshold has been met (see Section 7.3 
for Renal Function Monitoring. 
• May be considered by the investigator in the case of an AE/SAE or for another reason. 
If a temporary study drug interruption occurred because a safety threshold was met, blinded 
treatment may be resumed at a lower dose as outlined in Section 7.3 (Renal Function 
Monitoring). 
If the study drug was temporarily interrupted because of an AE/SAE that was not felt to be 
related to study drug, the investigator should make the best effort to resume study drug as soon 
as practically possible, assuming there are no remaining safety concerns. 
If dosing is interrupted for more than 7 consecutive days, based upon clinical judgement, the 
investigator may choose to see the patient in clinic or via telemedicine prior to study drug 
resumption. 
All temporary study drug interruptions (stop and start dates and times and reason for 
interruption) should be recorded in the CRF and the Medical Monitor should be notified. 
7.2. 
Permanent Discontinuation of Study Drug 
There are two types of permanent discontinuation of study drug: 
• Temporary study drug interruption that becomes a permanent discontinuation: 
o After a temporary study drug interruption, if a safety concern for the patient has 
not stabilized or resolved or if the investigator suspects that study drug may be 
responsible, the investigator may consider the temporary interruption to be a 
permanent discontinuation. Permanent discontinuation of study drug should be 
considered as a last resort. 
o The investigator should make best efforts to contact the Medical Monitor before 
considering any temporary interruption as a permanent discontinuation. 
• Permanent study drug discontinuation that is not preceded by a temporary study drug 
interruption 

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o The investigator should make best efforts to contact the Medical Monitor before 
considering any permanent study drug discontinuation. 
In all cases, patients should be encouraged to discuss stopping study drug with the investigator or 
the investigator’s designee. See Section 6.6 regarding potential dose reduction of study drug. 
Best efforts should be made to address the patient’s questions, adjust concomitant medical 
therapies if needed and arrange follow-up safety assessments. All patients should undergo an 
early discontinuation visit as soon as possible following their last dose taken, unless 
discontinuation is due to death, withdrawal of consent, or the patient has been lost to follow-up. 
Refer to Section 7.2.1 for management of patients that permanently discontinue study drug. 
Any permanent discontinuation of study drug should be recorded in the CRF including the 
reason for permanent discontinuation, if a patient is willing to provide it. If the patient is 
unwilling to provide the reason, that too should be documented. 
Reasons for permanent study drug discontinuation may include any of the following: 
• Patient request 
• Adverse event  
• Pregnancy 
• Criteria for possible renal toxicity are met (Section 7.3) 
• Criteria for possible hepatotoxicity are met (Section 7.4) 
• The investigator judges that continued administration of study drug would be detrimental 
to the patient’s safety or well-being 
• Protocol violation 
• Lost to follow-up 
• Any breaking of the study blind requested by the investigator 
• Death 
• The Sponsor requests that the patient permanently discontinue study drug  
7.2.1. 
Management of Patients after Permanent Discontinuation of Study Drug 
If study drug is permanently discontinued, the patient should be encouraged to remain in the trial 
to continue to obtain outcome measures and safety data. 
There are several options for a patient after permanently discontinuing study drug:  
• Patient agrees to continue to return to clinic for all remaining in-clinic study visits and 
agrees to all planned remote visits. 
• Patient only agrees to complete the early discontinuation (ED) visit as soon as possible 
after the decision is made, the follow-up visit 4 weeks after the last dose taken, and 
additional follow-up visits dependent upon lab results; it is preferred these are done in 
clinic but can be done remotely if that is not feasible. 

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• Patient only agrees to complete the ED visit; it is preferred this is done in clinic but can 
be done remotely if that is not feasible. 
• Patient only agrees to remote visits to obtain patient study data. Patients should be 
strongly encouraged to come into the clinic for Week 24. 
• Patient agrees to a mix of remote and in-clinic visits to obtain study data. Patients should 
be strongly encouraged to come into the clinic for Week 24. 
• Patient only agrees to allowing contact for determination of vital status at Week 24 and 
Week 48 
• Patient withdraws consent (see Section 7.6) and does not agree to any further study 
procedures or visits. 
Assessments obtained at the early discontinuation and subsequent follow-up visit are listed in the 
Schedule of Activities. Details of the assessments to be performed at the additional visits 
following drug discontinuation, should the patient agree to be followed via either in-clinic or 
remote visits, can be found in the Study Manual. 
 Patients that have not withdrawn consent and have difficulty returning for all remaining study 
visits can be contacted by phone or video call to obtain patient study data. 
7.3. 
Renal Function Monitoring and Study Drug Management 
Study drug will be held if: 
• eGFRCr and eGFRCysC < 30.0 ml/min/1.73m2 or 
• urine protein creatinine ratio (UPCR) is ≥ 3 mg protein/mg creatinine (or ≥339 mg 
protein/mmol creatinine )  
Study drug may be restarted at half the dose, or 1 tablet twice a day (150 mg bid for those 
assigned to reldesemtiv) when: 
• eGFRCr and eGFRCysC is > 40.0 ml/min/1.73m2 and 
• UPCR is ≤ 1.5 mg protein/mg creatinine (or ≥170 mg protein/mmol creatinine ) 
Serum cystatin C, eGFRCysC, serum creatinine, eGFRCr and urine protein/creatinine ratio in a spot 
urine will be obtained and a microscopic urinalysis will be performed to look for cells and casts 
in accordance with the schedule of events; the medical monitors will be blinded to the UPCR 
(and the associated urinary creatinine and urinary protein), creatinine, serum cystatin C, 
eGFRCysC, and eGFRCr results. These renal related laboratory results will be reviewed by an 
unblinded physician who is not serving as the medical monitor for the trial. The unblinded 
physician will be unmasked to the renal lab results but will remain blinded to treatment 
assignments. The unblinded physician will contact the clinical trial investigator and medical 
monitors if laboratory results meet the criteria as described above that necessitate a study drug 
interruption. The Sponsor, all personnel charged with conduct of the trial outside of monitoring 
these laboratory data, and study sites will be blinded to the UPCR (and the associated urinary 
creatinine and urinary protein), creatinine, serum cystatin C, eGFRCysC, eGFRCr results. 

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Abnormal renal function tests meeting the above criteria will be repeated as directed by the 
unblinded physician, who will monitor repeat testing. The site investigator and medical monitors 
should discuss and agree that study drug can be resumed or alternatively permanently 
discontinued. Agreement by the patient, site investigator, and medical monitor must occur to 
determine that: 
1. The study drug may be re-initiated at the lower dose of 150 mg bid (or placebo), or 
2. The study drug should be permanently discontinued 
To accomplish this, the unblinded physician may direct the laboratory assessments (serum 
cystatin C, eGFRCysC, serum creatinine eGFRCr, UPCR) to be repeated as often as 2-3 times 
weekly until a final disposition is reached (ie, re-initiation of study drug or placebo at 150 mg bid 
or permanent discontinuation) is reached. 
Manifestations of renal toxicity, including clinically significant decreases in eGFRCysC and 
eGFRCr, as well as increases of UPCR, as noted above, are considered adverse events of special 
interest and should be recorded on the appropriate CRF and reported to Cytokinetics Drug Safety 
within 24 hours of awareness. 
Criteria for permanent discontinuation of study drug due to potential renal toxicity 
Study drug must be discontinued permanently if the patient requires hemodialysis. 
7.4. 
Liver Function Monitoring and Study Drug Management 
ALT, AST, alkaline phosphatase (ALP) and total, direct, and indirect bilirubin will be obtained 
in accordance with the schedule of events. 
Patients with abnormal hepatic laboratory values [ie, ALP, AST, ALT, total bilirubin (TBL)] or 
signs/symptoms of hepatitis should be evaluated to determine if the criteria for permanent 
discontinuation of study drug have been met. Patients who meet the criteria for permanent 
discontinuation must not be re-challenged. If a PI decides to hold study drug for abnormal lab 
values that don’t meet the mandated threshold, this is also considered a permanent 
discontinuation and the patient must not be re-challenged. 
Criteria for permanent discontinuation of study drug due to potential hepatotoxicity 
• Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT Value 
AST or ALT Elevation 
Any 
>8 × ULN at any time 
Any 
>5 × ULN but <8 × ULN for ≥2 weeks 
Any 
>5 × ULN but <8 × ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
>3 × ULN with clinical signs or symptoms that 
are consistent with hepatitis (such as right upper 
quadrant pain/tenderness, fever, nausea, 
vomiting, jaundice) 

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OR 
• TBL >3 × ULN at any time 
 
Study drug must be also discontinued permanently if ALL of the criteria below are met: 
• TBL >2 × ULN or international normalized ratio (INR) >1.5 
AND 
• increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT Value 
AST or ALT Elevation 
<ULN 
>3 × ULN 
AND 
• no other cause for the combination of the above laboratory abnormalities is apparent. 
Important alternative causes for elevated AST/ALT and TBL values include, but are not 
limited to: 
− hepatobiliary tract disease 
− viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
− right sided heart failure, hypotension, or any cause of hypoxia to the liver causing 
ischemia 
− exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms 
− heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− alpha-one antitrypsin deficiency 
− alcoholic hepatitis 
− autoimmune hepatitis 
− Wilson’s disease and hemochromatosis 
− nonalcoholic fatty liver disease including steatohepatitis 
− nonhepatic causes (eg, rhabdomyolysis, hemolysis) 
Patients who clearly meet the criteria for permanent discontinuation must never be re-challenged. 
Additional Clinical Assessments and Observation 
All patients in whom the study drug is permanently discontinued due to meeting the hepatic 
safety threshold as described above are to undergo a repeat test and a period of “close 

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observation” until abnormalities have stabilized and returned to normal (or returned to the 
patient’s baseline levels). Assessments that are to be performed during this period include: 
• Retesting of AST, ALT, ALP, bilirubin (total and direct), and obtaining an INR within 
48 hours  
• In cases of TBL >2 × ULN or INR >1.5, retesting of liver tests, bilirubin (total and 
direct), and INR within 48 hours  
Confirmed abnormal liver function tests (LFTs) should be repeated 2-3 times weekly then 
weekly or less if abnormalities stabilize or the study drug has been discontinued and the patient 
is asymptomatic. Follow the patient and the laboratory tests (ALT, AST, TBL, INR) until all 
laboratory abnormalities return to baseline or normal. 
• Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL: 
− Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− Obtain serum acetaminophen (paracetamol) levels 
− Obtain viral serologies 
− Obtain creatine phosphokinase, haptoglobin, lactate dehydrogenase, and 
peripheral blood smear 
− Perform appropriate liver imaging if clinically indicated 
• Obtain a more detailed history of: 
‒ Prior and/or concurrent diseases or illness 
‒ Exposure to environmental and/or industrial chemical agents 
− Symptoms (if applicable) including right upper quadrant pain, hypersensitivity 
type reactions, fatigue, nausea, vomiting and fever 
‒ Prior and/or concurrent use of alcohol, recreational drugs and special diets 
− Concomitant use of medications (including non-prescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
• Obtain appropriate blood sampling for pharmacokinetics (PK) analysis if this has not 
already been collected 
• Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
Clinically significant elevated transaminases and/or bilirubin and manifestations of liver toxicity 
(eg, rash, abdominal pain, nausea and vomiting, fatigue, dark-colored urine, light-colored bowel 
movements, jaundice, loss of appetite, fever), including elevations that prompt study drug 
discontinuation, are considered adverse events of special interest and must be recorded on the 
appropriate CRF and reported to Cytokinetics Drug Safety within 24 hours of awareness. 

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7.5. 
Discontinuation from Study Procedures 
Not applicable. 
7.6. 
Patient Consent Withdrawal 
Patients have the right to withdraw consent and no longer participate in the trial at any time and 
for any reason without prejudice to their future medical care by the physician or at the institution. 
Consent withdrawal means the patient no longer wishes to undergo any follow-up visits, study 
procedures, investigator contact, and non-patient contact follow-up (eg, medical records check). 
• Discontinuing study drug should be distinguished from consent withdrawal for follow-up 
since the patient may agree to undergo study procedures or still be contacted even though 
they have stopped taking study drug. 
• Consent withdrawal should be accompanied by documentation of the reason for 
withdrawal for patients willing to provide it. If the patient is unwilling to provide the 
reason, that should be recorded. 
Patients who withdraw consent should be asked explicitly about the contribution of possible AEs 
to their decision to withdraw consent, and any AE information elicited should be documented. 
Preferably, the patient should withdraw consent in writing and, if the patient or the patient’s 
representative refuses or is physically unable, the site should document and sign the reason for 
the patient’s failure to withdraw consent in writing; if the patient is unwilling to provide the reason, 
that too should be documented. The ICF for the trial should note that although a patient is free to 
leave the trial and stop taking study drug, the investigators hope the patient will remain for 
follow-up status evaluations. 
For patients who have withdrawn consent for further follow-up, investigators and/or a third party 
retained by Cytokinetics may review public records as permitted by the ICF and applicable law 
to determine vital status of the patient at the end of the trial or before. 
7.7. 
Lost to Follow Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient or the patient’s family and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of maintaining 
the assigned visit schedule and ascertain whether the patient wishes to and/or should 
continue in the trial. 
• Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or the patient’s family (where possible, 
3 telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the patient’s medical record. 

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• Should the patient continue to be unreachable, he/she will be considered to have 
discontinued from the trial and are lost to follow-up. 
Closing of specific sites or discontinuation of the trial are handled as part of Appendix 1 
(Section 10.1.8). 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
There will be up to eight clinic visits and nine remote visits (with most requiring an 
accompanying phone or video call), with windows to aid in scheduling as shown in Table 3. If a 
patient visit must be scheduled outside the visit window, the Medical Monitor should be 
contacted. If a patient is scheduled for an in-clinic visit outside the visit window, the ALSFRS-R 
should be obtained by phone or video call during the visit window when possible, while the other 
visit related procedures will be obtained outside of the visit window when the patient is seen in 
clinic. Day 1 anchors all subsequent study visits. 
Table 3: 
CY 5031 Visit Windows 
Visit 
Visit Window 
Home FVC Window* 
Screening: clinic visit/lab 
 
 
Start of Dosing (Day 1): clinic visit/lab 
Up to 21 days following 
Screening 
1-3 days prior to Day 1 
End of Week 2: remote – lab only 
14 days ±2 days 
 
End of Week 4: clinic visit/lab 
28 days ±4 days 
±2 days of clinic visit 
End of Week 8: remote visit/lab 
56 days ±4 days 
 
End of Week 12: clinic visit/lab 
84 days ±4 days  
±2 days of clinic visit 
End of Week 16: remote visit/lab 
112 days ±4 days 
 
End of Week 20: remote visit/lab 
140 days ±4 days 
 
End of Week 24 (last dose of double-
blind dosing): clinic visit/lab 
168 days ±4 days 
1-3 days prior to clinic 
visit 
End of Week 26: remote – lab only 
182 days ±2 days 
 
End of Week 28: remote visit/lab 
196 days ±4 days 
 
End of Week 32: remote visit/lab 
224 days ±4 days 
 
End of Week 36: clinic visit/lab 
252 days ±4 days 
±2 days of clinic visit 
End of Week 40: remote visit/lab 
280 days ±4 days 
 
End of Week 44: remote visit/lab 
308 days ±4 days 
 
End of Week 48 (last dose of active 
drug dosing): clinic visit/lab 
 336 days ±4 days 
1-3 days prior to clinic 
visit 
Follow-Up (4 weeks after last dose of 
study drug): clinic visit/lab 
 364 days ±4 days 
1-3 days prior to clinic 
visit 
*With the exceptions noted, home FVC is performed on the same day as other procedures are done for the remote 
visit  
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exceptions are not allowed for inclusion/exclusion criteria. 
Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study drug. 

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Adherence to the trial design requirements, including those specified in the SoA (Section 1.3), is 
essential and required for trial conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
If scheduled in-clinic visits are not possible, remote visits will be made and documented to 
review trial assessments, safety, adverse events, provide safety laboratory samples, and 
concomitant medications as detailed in the Study Manual (see Section 4.1, Overall Study Design 
for additional details on converting in-clinic visits to remote visits). 
8.1. 
Efficacy Assessments 
The sequence of all trial related procedures including the relationship of procedures relative to 
dosing should be followed as detailed in the Study Manual. 
8.1.1. 
ALSFRS-R 
The ALSFRS-R will be performed at each study visit (both in-clinic and remote) as described in 
the Study Manual. MiToS staging will be determined based upon the responses on the applicable 
items of the ALSFRS-R. 
8.1.2. 
Pulmonary Function Assessment 
The pulmonary function assessment in this trial will be FVC. Pulmonary function assessment 
will be performed in the clinic at all in-clinic study visits (Screening, Day 1, Week 4, Week 12, 
Week 24, Week 36, Week 48 and Follow-up [FU]), safety permitting, as described in the Study 
Manual. It will also be performed using the home spirometer ±2 days of the date of the in-clinic 
visits for Weeks 4, 12, and 36 in addition to 1 to 3 days prior to Day 1, Weeks 24, 48 and FU as 
shown in Table 3. Finally, it will be done using the home spirometer during the scheduled remote 
visits at Weeks 8, 16, 20, 28, 32, 40, and 44. If a patient can be seen in the clinic for screening, 
but FVC cannot be performed for safety reasons, the patient will be provided a home spirometer 
and perform a home FVC within 2 days following the screening visit; that value will be used for 
eligibility. If on subsequent in-clinic visits, the FVC cannot be performed in the clinic for safety 
reasons, that should be documented and only the home FVC linked to that in-clinic visit will be 
obtained. For all home FVC testing, the test will be performed during a telemedicine call with a 
trained FVC evaluator. 
When an FVC falls below 50%, the site will record if the potential use of NIV was discussed, 
and if the patient refuses NIV, the reason(s) for the refusal. Details can be found in the Study 
Manual. 
8.1.3. 
Hand Grip Strength 
Hand grip strength will be assessed at all in-clinic study visits as described in the Study Manual. 
If an in-clinic visit needs to become a remote visit, it will not be performed. 

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8.1.4. 
Muscle Strength  
Muscle strength measurements of selected muscles will be performed using HHD at all in-clinic 
study visits as described in the Study Manual. If an in-clinic visit needs to become a remote visit, 
it will not be performed. 
8.1.5. 
Health Economic Outcomes Measures 
During the course of the trial, if the patient is prescribed and agrees to obtain, and/or receives 
any of the following durable medical equipment (DME), reason for obtaining, timing and extent 
of use will be recorded as described in the Study Manual: 
• Non-invasive ventilation (including type of device) 
• Gastrostomy tube 
• Manual wheelchair 
• Power wheelchair 
• Augmentative and alternative communication (including type of device) 
Obtaining information about the DME use should be obtained at every in-clinic and remote visit. 
EQ-5D-5L and the EQ-VAS are standardized measures of health status developed by the 
EuroQol Group in order to provide a simple, generic measure of health for clinical and economic 
appraisal. They will be administered at time points as indicated in the SoA (Section 1.3) and as 
described in the Study Manual. If an in-clinic visit in which the EQ-5D-5L and the EQ-VAS are 
scheduled to be performed becomes a remote visit, they will both still be obtained. 
8.1.6. 
Quality of Life 
The following quality of life questionnaire will be utilized at multiple study visits as specified in 
the SoA (Section 1.3) and described in the Study Manual: 
• ALSAQ-40 
If an in-clinic visit in which the ALSAQ-40 is scheduled to be performed becomes a remote 
visit, the ALSAQ-40 will still be obtained. 
8.1.7. 
Structured Patient Interviews 
At a subset of participating US centers, English language-speaking patients enrolled will have a 
qualitative patient interview within two weeks of completing the Week 24 visit (sometime 
between Week 22 and Week 24). 
The interview will be conducted by phone and will collect information in the patient’s words 
regarding their perceptions of functionality and ALS symptom burden, activities of daily living, 
and experiences in the trial. 
8.1.8. 
Hospitalizations 
Hospitalizations experienced by a patient following randomization and occurring in the context 
of a serious adverse event will be determined by the Investigator as being either related to ALS, 
unrelated to ALS, or indeterminate. Hospitalizations deemed related to ALS cover those that are 

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both related to disease progression, hospitalizations that may occur to address an ongoing ALS 
symptom or to be preventative (such as hospitalization for a PEG / RIG tube), as well as those to 
address a complication of a treatment being received for ALS. This information will be recorded 
and entered into the EDC. Hospitalizations that are for social reasons, or those that were planned 
prior to the patient signing the ICF are not considered SAEs and therefore relationship to ALS 
will not be recorded. Further details are described in the Study Manual. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
A routine physical examination will be performed at Screening, and an abbreviated physical 
examination (consisting of an examination of general appearance, skin, lungs, cardiovascular and 
abdomen) will be performed at the Follow-Up visit. If the Follow-up visit is converted to a 
remote visit, the parts of the exam that can be done utilizing telemedicine/video call should be 
performed. 
8.2.2. 
Vital Signs 
Heart rate, blood pressure, and respiratory rate (measured after the patient has been resting and 
seated for at least 3 minutes), will be obtained at all in-clinic study visits. Temperature will also 
be obtained at the Screening visit. Height is obtained only at the screening visit; it should only be 
a historical height if the patient is unable to stand. Weight will be obtained at each in-clinic study 
visit; and body mass index (BMI) will be calculated at screening and subsequent visits. If the 
pulse is <50 or >100 bpm, mean systolic blood pressure <90 or >160 mm Hg; mean diastolic 
blood pressure <50 or >100 mm Hg or the respiratory rate is <10 or >20 breaths per minute, the 
out of range vital sign should be re-checked following the patient resting for 10 minutes in the 
seated position. If the in-clinic visit is converted to a remote visit, vital signs will not be 
performed. 
8.2.3. 
Electrocardiograms 
A 12-lead ECG will be obtained as outlined in the SoA (Section 1.3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Patients should be sitting or supine prior to the ECG for at least 5 minutes. The investigator may 
perform additional ECG recordings as needed for the care of the patient. 
For safety monitoring purposes, the investigator or designee must review, sign, and date all ECG 
tracings. 
Unscheduled ECGs may be collected at additional time points, for example in case of an AE or 
based on vital signs, as determined by the investigator or the Medical Monitor. 
All ECG tracings will be kept as part of the patient’s permanent study file at the clinical site. 
Digital recordings will be analyzed and stored at a central ECG laboratory. 
If an in-clinic visit is converted to a remote visit, an ECG will not be obtained. 

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8.2.4. 
Neurological Examinations 
A brief neurological exam will include assessments of specific cranial nerves (eye, face, and 
tongue movements), motor strength in specific muscles, evaluation of deep tendon and bilateral 
plantar reflexes, sensory testing, and tests of co-ordination (limited to finger-to-nose and heel-to-
shin when possible to assess). This will be administered at screening, Week 24, and at Follow-
Up visit as described in the Study Manual. If the Week 24 or Follow-up visits are converted to a 
remote visit, the parts of the exam that can be performed using telemedicine/video call should be 
performed. 
8.2.5. 
Laboratory Assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and see the 
SoA (Section 1.3) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial in the AE section of the CRF. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 
disease; if the abnormal laboratory finding is felt to be associated with the underlying disease but 
is judged by the investigator to be more severe than expected for the patient’s condition it should 
be recorded as such. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
8.2.6. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) 
The BDI-Fast Screen will be assessed at all in-clinic study visits as described in the Study 
Manual. If an in-clinic visit is converted to a remote visit, the BDI-Fast Screen will not be 
obtained; however, while asking the patient about adverse events, the site will query the patient 
about symptoms of depression or suicidal thoughts. 
8.3. 
Adverse Events and Serious Adverse Events 
8.3.1. 
Adverse Events 
8.3.1.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of study drug, whether or not related to study drug. 
Adverse events include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after IP administration even though it may have 
been present before the start of the trial. 

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• Abnormal assessments, eg, change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at trial start or worsened 
during the course of the trial. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at trial start or worsened during the course of 
the trial, require treatment, or led to dose reduction, interruption or permanent 
discontinuation of IP. In general, abnormal laboratory findings without clinical 
significance (based on the investigator's judgment) are not to be recorded as adverse 
events. Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
8.3.1.2. 
Definition of Serious Adverse Event 
A SAE is defined as any untoward medical occurrence that at any dose:  
• Results in death 
• Is life threatening, NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events include invasive or malignant 
cancers; intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
An adverse event would meet the criterion of “requires hospitalization,” if the event necessitated 
an admission to a health care facility (eg, overnight stay). 
The following reasons for hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 

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• Hospitalization for pre-planned (ie, planned prior to signing informed consent) surgery or 
standard monitoring of a pre-existing disease or medical condition that did not worsen, 
eg, hospitalization for coronary angiography in a patient with stable angina pectoris. 
However, complications that occur during an exempted hospitalization are AEs or SAEs (for 
example if a complication prolongs a pre-planned hospitalization). 
8.3.1.3. 
Severity of Adverse Events 
The investigator must assess the severity for each AE and SAE reported during the trial. 
Severity describes the intensity (severity) of a specific event and is different from seriousness, 
which is based on patient/event outcome or action criteria and serves as a guide to determine the 
regulatory reporting obligations. The severity should be assessed by assigning a Grade of 1, 2, 3, 
4 or 5 according to the Common Terminology Criteria for Adverse Events (CTCAE), version 
5.0, as defined below: 
• Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2 (Moderate): minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
• Grade 3 (Severe): Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL**. 
• Grade 4 (Life-Threatening): Life-threatening consequences; urgent intervention is 
indicated 
• Grade 5 (Fatal): Death related to AE 
* Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
If the severity of an AE worsens during IP administration, only the worst severity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required. 
8.3.1.4. 
Relationship to Study Drug 
Each AE must be assessed by the investigator, based on clinical judgment, as to whether or not 
there is a reasonable possibility of causal relationship to study drug and reported as either related 
or unrelated. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study drug administration will be 
considered and investigated. 

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• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Cytokinetics. However, it is very important that 
the investigator always assesses causality for every event before the initial transmission of 
the SAE data to Cytokinetics. 
• The investigator may change his/her opinion of causality considering follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
8.3.1.5. 
Relationship to Study Procedures 
An AE is defined as related to study procedures if it appears to have a reasonable possibility of a 
causal relationship to protocol-required procedures. 
8.3.1.6. 
Reporting of AEs 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the patient that occur after starting the study drug through end of study are 
recorded in the AE CRF. In addition, during the screening period (after signing of the informed 
consent until study drug administration), serious adverse events considered related to study 
procedures are also to be recorded in the AE CRF. 
ALS is a progressive and uniformly fatal neurodegenerative disorder associated with relentlessly 
progressive loss of motor function, including appendicular, craniobulbar, and respiratory 
function due to the degeneration of the upper and lower motor neurons which control and 
innervate the voluntary skeletal muscles. The following conditions are anticipated to occur in the 
study population as signs/symptoms of ALS progression and do not need to be recorded as an 
AE unless they meet the criteria for an SAE, are felt to be related to the study drug, or they are 
occurring outside what is expected for the normal course of the disease (Brown 2017). 
Table 4: 
Signs and Symptoms Commonly Associated with ALS 
MedDRA Preferred Terma 
MedDRA Preferred Terma 
Dysarthria 
Muscle spasticity 
Dysphagia 
Muscle contractions involuntary 
Dyspnoea 
Muscle spasms 
Gait disturbance 
Muscular weakness 
a 
MedDRA Version 23.0 
8.3.1.7. 
Reporting Procedures for SAEs 
Prompt notification by the investigator to Cytokinetics of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of an IP 
under clinical investigation are met. 
The investigator is responsible for ensuring that all SAEs observed by the investigator or 
reported by the patient that occur after study drug initiation through end of study, or four weeks 

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after the last administration of study drug, whichever is later, and SAEs related to study 
procedures occurring during the screening period (from signing the informed consent until study 
drug initiation), are recorded in the AE CRF and reported to Cytokinetics on an SAE Report 
Form and within 24 hours following the investigator’s knowledge of the event. 
SAE Report forms must be emailed or faxed to Cytokinetics Drug Safety (contact details are 
provided on the SAE Report form): 
Email:  
CY5031DrugSafety@cytokinetics.com 
Facsimile:  +1 (650) 243-4199 
The investigator must attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
The investigator must complete the SAE Report form in English and must assess the causal 
relationship of the event to study drug. 
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and documentation. 
New information relating to a previously reported SAE must be reported to Cytokinetics within 
24 hours following knowledge of the new information. Cytokinetics Drug Safety may contact the 
investigator to obtain further information. 
8.3.1.8. 
Follow-up of AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Cytokinetics to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
If a patient dies during participation in the trial or during a recognized follow-up period, the 
investigator is encouraged to provide Cytokinetics with a copy of any post-mortem findings 
including histopathology if it has been performed. 
Non-serious adverse events must be followed until they resolve or until the patient completes the 
trial, whichever comes first. Serious adverse events and events of special interest still ongoing at 
the end of study must be followed up until resolution or stabilization, or until the event outcome 
is provided, eg, death. Reporting may continue after the follow-up visit and database lock. 
New SAEs occurring after the 4-week follow-up period must be reported to the Cytokinetics 
Drug Safety department within 24 hours of the investigator’s knowledge of the event, only if 
considered by the investigator to be causally related to previous exposure to the study drug. 
8.3.1.9. 
Regulatory Reporting 
The reference safety document to assess expectedness of a suspect serious adverse reaction and 
reported by Cytokinetics to Health Authorities, IRBs/IECs, and investigators is the reference 
safety information section of the IB for reldesemtiv. 

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Cytokinetics will report SAEs and/or suspected unexpected serious adverse reactions as required 
to regulatory authorities, investigators/institutions, and IRBs/IECs in compliance with all 
reporting requirements according to local regulations and good clinical practice. 
The investigator is to notify the appropriate IRB/IEC of SAEs occurring at the site and other 
adverse event reports received from Cytokinetics, in accordance with local procedures and 
statutes. 
8.3.1.10. Pregnancy and Breastfeeding 
Female Patients Who Become Pregnant 
If a female patient becomes pregnant while on study drug, study drug must be discontinued. The 
investigator must counsel the patient and discuss the risks of continuing with the pregnancy and 
the possible effects on the fetus. 
Please refer to Appendix 3 (Section 10.3) regarding contraceptive guidance. Irrespective of the 
treatment received by the patient, any pregnancy occurring in a female patient, or female partner 
of a male patient, after study drug initiation up to 4 weeks following study drug discontinuation 
must be reported to Cytokinetics within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be recorded in the CRF and reported on the Cytokinetics Pregnancy Report 
Form, which is emailed or faxed to Cytokinetics Drug Safety (contact details are provided on the 
Pregnancy Report Form): 
Email: CY5031DrugSafety@cytokinetics.com 
Facsimile: +1 (650) 243-4199 
Note: Sites are not required to provide any information on the Pregnancy Report Form that 
violates the country or region’s local privacy laws. 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study drug and until the conclusion of the pregnancy. The follow-up of 
an infant (if applicable) will be conducted up to 12 months after the birth of the child. 
Any pregnancy complication or elective termination of a pregnancy for medical reasons must be 
reported as an AE or SAE. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
A developmental delay of an infant, or suspected adverse reactions in a neonate will be reported 
as an adverse event or serious adverse event. 
Any post-study pregnancy-related SAE considered reasonably related to study drug by the 
investigator will be reported to Cytokinetics as described in Section 8. While the investigator is 
not obligated to actively seek this information in former study patients, he or she may learn of an 
SAE through spontaneous reporting. 

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Male Patients with Partners Who Become Pregnant 
If a male subject fathers a child while on study drug, he may continue receiving treatment; 
however, he must use barrier method (ie, condom) during sexual intercourse to avoid further 
fetal exposure. 
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this trial. 
After obtaining the necessary signed ICF from the pregnant female partner directly, the 
investigator must complete the Pregnancy Report Form and submit it to Cytokinetics within 
24 hours of receipt of the partner’s consent. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to Cytokinetics. 
Female Patients Who Breastfeed  
If a female patient breastfeeds while on study drug, study drug will be discontinued. 
The investigator will collect breastfeeding information on any female patient who breastfeeds 
while taking the study drug through 5 days after the end of study drug treatment. The mother and 
infant health information will be recorded on the Pregnancy Report Form and submitted to 
Cytokinetics immediately and no later than 24 hours following the investigator’s knowledge of 
event. 
8.4. 
Treatment of Overdose 
There is no established treatment for an overdose. 
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor immediately who may recommend: 
a. Close monitoring of the patient for any AEs/SAEs and laboratory abnormalities. 
b. Obtaining a plasma sample for PK analysis as soon as practical and note the date of 
the last dose of study drug. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.5. 
Pharmacokinetics 
Blood samples of approximately 6 mL will be collected for measurement of plasma 
concentrations of reldesemtiv as specified in the SoA (Section 1.3). Samples will be used to 
evaluate the PK of reldesemtiv and its metabolites. Instructions for the collection and handling of 
biological samples will be provided in the laboratory manual. 
The actual date and time (24-hour clock time) of each sample will be recorded. The time of 
administration of study drug on the day of PK sampling will be recorded in the CRF. It is 

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important to provide instructions to patients that they should not take their morning dose on the 
day of their clinic visit until in the clinic. 
See Table 5 for a summary of PK sampling time points at all sites. Drug concentration 
information that would unblind the trial will not be reported to investigative sites or blinded 
personnel until the trial has been unblinded. 
If an in-clinic visit is converted to a remote visit, PK sampling will not be performed. 
Table 5: 
Summary of PK Time Points 
Visit 
PK Time Point 
Week 4 
Pre-dose and another sample 2-4 hours post dose 
Week 12 
Pre-dose and another sample 2-4 hours post-dose 
Week 24 
Pre-dose and another sample 2-4 hours post-dose 
 
An intensive PK sub-study will be conducted in 15 patients taking reldesemtiv 300 mg BID at a 
limited number of sites at the Week 36 visit. 
Table 6: 
PK Sub-Study Time Points 
Visit 
PK Time Point 
Week 36 
Pre-dose and at 0.5, 1, 2, 3, 4 and 6 hours post-dose 
8.6. 
Genetics 
Where authorized by the applicable IRB/EC/Research Ethics Board (REB) approved informed 
consent and authorized by the patient, a blood sample of approximately 6 mL will be obtained at 
the Day 1 visit and stored for possible future genetic testing related to ALS (genes known or 
suspected to cause, modify, or alter the risk of ALS) and for research purposes only. Details on 
the process for collection and shipment of these samples can be found in the laboratory manual. 
8.7. 
Biomarkers 
Biomarkers are objective measures or indicators of normal biological processes, pathological 
processes or pharmacological responses to a therapeutic intervention. Biomarker development 
may be useful to identify disease subtypes, to guide therapy, detect a response to therapy, better 
understand the development of an adverse event, or predict disease severity. Where authorized 
by the applicable IRB/EC/REB approved informed consent, blood samples of approximately 
6 mL for biomarker development will be collected at the time points shown in Table 7. 
Table 7: 
Biomarker Samples 
Visit 
Sample Time Points 
Day 1 
Pre-AM dose 
Week 24 
Pre-AM dose 
Plasma samples will be stored for future biomarker analyses. 

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8.8. 
Immunogenicity Assessments 
No immunogenicity assessments will be done for this trial. 
8.9. 
Sample Storage 
Any laboratory samples remaining at the central laboratory or any other specialty laboratory at 
the end of the study will continue to be stored until reldesemtiv has been granted marketing 
authorization in any country or Cytokinetics decides to stop development of reldesemtiv. 
Cytokinetics may move the samples to another company where they store samples from other 
research studies. 
 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary global null hypothesis is that there is no treatment difference in the change from 
baseline to Week 24 in ALSFRS-R total score between patients randomized to placebo and those 
randomized to reldesemtiv during the double-blind, placebo-controlled period in the FAS. The 
global null hypothesis for the first secondary endpoint is that the Mann-Whitney probability is 
0.5 for the combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation (use non-invasive or invasive ventilation for ≥ 22 hours per day for ≥ 10 
consecutive days), and survival time up to Week 24 between patients randomized to placebo and 
those randomized to reldesemtiv in the FAS. 
9.2. 
Sample Size Determination 
With a 2:1 randomization ratio to reldesemtiv and placebo groups, respectively, a sample size of 
approximately 555 patients is required to achieve at least 90% power to detect a 1.8 point 
treatment difference between reldesemtiv and placebo in the change from baseline to Week 24 in 
ALSFRS-R total score. This calculation is based on a two-sample t-test with two-sided alpha at 
0.05 level, a common standard deviation (SD) of 5.5 points, and accounting for missing data and 
early treatment termination. 
9.3. 
Populations for Analyses 
The analysis populations are defined in Table 8. 
Table 8: 
Analysis Sets 
Analysis Set 
Description 
All Screened Set 
All patients who signed the ICF. 
All Randomized Set 
Patients who were randomized to receive reldesemtiv or placebo. 
Full Analysis Set 
All randomized patients who received any amount of study drug 
and have a baseline and at least one post baseline efficacy 
assessment or have survival status recorded during the double-
blind placebo-controlled period. Patients will be analyzed 
according to the treatment to which they were assigned at 
randomization.  
Safety Analysis Set 
All randomized patients who received any amount of study drug. 
Patients will be analyzed according to the actual treatment 
received during the double-blind placebo-controlled period. 
Pharmacokinetics 
Analysis Set 
All patients who have at least one measurable plasma 
concentration of reldesemtiv, provided they have no major 
protocol violations deviations that could affect the PK of 
reldesemtiv. 

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9.4. 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
Summary tables will present descriptive statistics such as number of patients, mean, median, 
standard deviation, minimum and maximum for continuous variables, and number of patients 
and the percentage for categorical variables, overall and by treatment in the planned analysis 
sets. For model-based analysis, least squares means, difference of least squares means between 
treatments, their standard errors and 95% confidence intervals (CI), and two-sided p-values for 
the relative statistical inferences will be presented. For survival analyses, time to event will be 
summarized by median, 95% CIs of median, and 1st and 3rd quartiles. Events and censored data 
points will be summarized by count and percentage. Hazard ratios between treatments and the 
corresponding 95% CIs and p-values will also be presented. Baseline is defined as the last 
available measurement taken before the first dose of randomized study drug received in the 
placebo control double-blind period unless otherwise specified. Analyses will be conducted by 
study period including the first 24-week double blind placebo-controlled period, the second 
24-week active drug period, and the randomized delayed-start 48 weeks of treatment, and 
follow-up period. 
Listings will include patient ID, demographics, treatment assigned and other relevant items, and 
sorted by treatment assignment, patient ID and date of assessment. 
Unless specified otherwise, efficacy, safety and pharmacokinetics analyses will be performed on 
the full analysis set, safety analysis set and pharmacokinetics analysis set, respectively. 
Statistical analysis methods will be detailed in the SAP. 
9.4.1.1. 
Multiplicity Adjustment 
The null hypothesis for the primary and secondary efficacy variables in the FAS will be tested in 
the pre-specified order using a closed testing procedure. The first secondary endpoint is the 
combined assessment of change in ALSFRS-R total score, time to dependence on assisted 
ventilation (use non-invasive or invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive 
days), and survival time up to Week 24. The primary endpoint will be tested first, and if this 
comparison between the two treatments is statistically significant, then the first secondary 
endpoint will be tested. The pre-specified order of the rest of the secondary efficacy endpoints 
will be provided in the SAP. This procedure will maintain the family-wise error rate at 5% for all 
hypotheses tested in a confirmatory sense. 
9.4.1.2. 
Timing of Final Analyses 
When all patients complete or discontinue from the 48 weeks of planned treatment and the safety 
follow-up visits, the database will be locked for this study and final analyses will be conducted. 

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9.4.2. 
Primary Endpoint 
The primary endpoint of the trial is the change from baseline to Week 24 in ALSFRS-R total 
score. The primary estimand is the difference in the mean changes from baseline to Week 24 in 
ALSFRS-R total score between patients randomized to placebo and those randomized to 
reldesemtiv during the placebo-controlled double-blind treatment in the full analysis set. 
The primary analysis (main estimator) of the primary endpoint is as follows: 
The primary endpoint will be analyzed using a MMRM based on a restricted maximum 
likelihood method (SAS® PROC MIXED default). The model terms will include treatment 
group, baseline ALSFRS-R total score, visit, riluzole use status at baseline, edaravone use status 
at baseline as well as baseline-by-visit and treatment group-by-visit interactions. An unstructured 
variance-covariance matrix will be used in the model. Additional important baseline covariates 
may be included to the primary analysis model if they are key predictor variables for the change 
from baseline to Week 24 in ALSFRS-R total score. Details of the selection procedure for the 
potential baseline covariates will be pre-specified in the SAP. The selection of the potential 
baseline covariates will be performed before the database lock. 
Prior to applying the MMRM, missing data will be imputed using the multiple imputation 
procedure (Rubin 1987) for the primary analysis, and the estimates from each imputed dataset 
will be combined into one set of overall estimates using the SAS® PROC MIANALYZE 
procedure. The extent of missing data and the pattern of missing data reasons will be tabulated. 
Imputation details will be pre-specified in the SAP. Least square means (LSM), LSM difference 
and the corresponding standard errors, 95% CI and p-values will be presented. 
Sensitivity analyses will be conducted to support the robustness of the primary analysis results. 
Using the ANCOVA model with the MAR-based multiple imputation for all missing ALSFRS-R 
assessments as the base model, the tipping point analyses will be conducted having the imputed 
values for the deaths successively worse only for the reldesemtiv treatment, while maintaining 
the MAR-based imputed values for the placebo treatment. Another sensitivity analysis will be to 
repeat the ANCOVA base model with missing ALSFRS-R assessments imputed as if the 
reldesemtiv patients were in the placebo arm. Other sensitivity analyses and the details will be 
included in the SAP. 
9.4.3. 
Secondary Endpoint(s) 
The secondary endpoint(s) of the trial are: 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation (invasive or non-invasive) , and survival time up to Week 24.   
o Dependence on assisted ventilation is defined as patients using non-invasive or 
invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive days 
o Patients with dependence on assisted ventilation are ranked lower than those with 
the largest drops in ALSFRS-R scores but higher than those who have died 
• Change from baseline to Week 24 in the percent predicted FVC 
• Change from baseline to Week 24 in the ALSAQ-40 total score 
• Change from baseline to Week 24 in hand grip strength (average of both hands) 

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The analyses of the secondary endpoints are as follows: 
The estimand of the first secondary endpoint of combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted ventilation, and survival time up to Week 24 is the 
Mann-Whitney probability for more favorable status at week 24 for reldesemtiv than placebo in 
the paradigm where deaths have the worst ranks, patients with dependence on assisted ventilation 
have the next worst ranks, and the more favorable changes from baseline at week 24 in ALSFRS 
total score have the better ranks using a joint-rank test in the FAS (Berry 2013). The detailed 
ranking and imputation methods for missing data will be provided in the SAP. The joint ranks 
will be determined based on the combined assessments and analyzed using a stratified Wilcoxon 
test that compares the ranks between reldesemtiv and placebo groups while adjusting for baseline 
riluzole use status and baseline edaravone use status. Stratified Mann-Whitney test statistics as 
well as the p-value will be presented. Sensitivity analyses and associated details will be included 
in the SAP. 
Analyses for the remaining other secondary endpoints will be performed using a MMRM with 
the following model terms: treatment group, baseline ALSFRS-R total score, visit, riluzole use 
status at baseline, edaravone use status at baseline as well as baseline-by-visit and treatment 
group-by-visit interactions, using an unstructured variance-covariance matrix. 
To support the analysis results of the key secondary endpoints, the joint rank analyses will also 
be performed for change from baseline up to Week 24 in the percent predicted FVC, and for 
change from baseline up to Week 24 in the ALSAQ-40 total score. 
9.4.4. 
Exploratory Endpoint(s) 
The exploratory endpoints of the trial are: 
• Time to the patient being prescribed and patient agrees to it, time to first receipt, time to 
first use, time to daily use, time to dependence and number used of any of the following 
DME items (manual wheelchair, power wheelchair, augmentative and alternative and 
augmentative communication device, NIV and/or gastrostomy tube) from randomization 
to the end of the 24-week double-blind, placebo-controlled period and to Week 48 as well 
as reasons to receive the above DME. Time to dependence for invasive ventilation will 
also be recorded. Definitions for patient being prescribed and agrees to it, first receipt, 
first use, daily use, and dependence for the DME items of interest can be found in the 
Study Manual. 
• Change from baseline to Week 24 in the four subdomain scores of the ALSFRS-R 
• Time spent in each MiToS stage and number of patients to transition stages from baseline 
to Week 24 
• Change from baseline to Week 48 in ALSFRS-R total score 
• Change from baseline to Week 48 in FVC 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation, and survival time up to Week 48 

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• Change from baseline to Week 24 in the mega-score of muscle strength measured by 
HHD in bilateral first dorsal interosseous muscles, abductor pollicus brevis muscles, and 
abductor digiti minimi muscles 
• Change from baseline to Week 24 and Week 48 in the EQ-5D-5L 
• Change from baseline to Week 24 and Week 48 in the VAS of EQ-5D 
• Time from first hospitalization through Week 24 and through Week 48 
• All above endpoints are also applied to the end of the study 
The analyses of the exploratory endpoints are as follows: 
Time-to-event analyses will be conducted for the endpoints of durable medical equipment items. 
A MMRM will be used to analyze endpoints of change from baseline to the specified time point. 
Descriptive statistics will be presented for time spent in each MiToS stage and transition of 
stages. A joint-rank test will be used to analyze the combined assessment of change in 
ALSFRS-R total score, time to dependence on assisted ventilation, and survival time up to 
Week 48. 
In addition, the comparisons listed below may also be performed as exploratory analyses of 
1) change of ALSFRS-R total score from baseline, 2) combined assessment of change of 
ALSFRS-R, dependence on assisted ventilation, and survival time, or 3) change of other 
measures (as appropriate):  
• Compare changes from baseline to Week 24 between the reldesemtiv and placebo groups 
• Compare changes from Week 24 to Week 48 between the early-start and delayed-start 
treatment groups 
• Compare changes from baseline to Week 48 between the early-start and delayed-start 
treatment groups 
• Compare changes from Week 24 to Week 48 versus those from baseline to Week 24 in 
the delayed-start group 
9.4.5. 
Safety Analysis 
Safety data will be analyzed descriptively in the safety analysis set, including all patients who 
take any amount of study drug. 
9.4.5.1. 
Adverse Events 
All AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Primary system organ class (SOC) and preferred term (PT) of the TEAEs will be tabulated by the 
early-start and delayed-start treatment groups and periods (placebo-controlled period and active 
drug period). TEAEs will also be summarized by severity and relationship to study drug. AEs 
that led to early discontinuation from treatment or the trial and events of special interest will be 
summarized. Listings will be presented for patients who discontinued due to TEAEs. 

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9.4.5.2. 
Serious Adverse Events 
All SAEs and SAEs leading to treatment discontinuation or death will be summarized by system 
organ class, preferred term, treatment and overall, and by riluzole and edaravone use status at 
baseline. Listings will be presented for patients who died and/or experienced serious AEs. 
9.4.6. 
Pharmacokinetic Endpoints 
Plasma concentrations of reldesemtiv will be summarized using descriptive statistics including 
mean, standard deviation, geometric mean, coefficient of variation, median, and range. 
Geometric mean concentrations over time will be graphically displayed. 
9.4.7. 
Patient Disposition 
The number of patients who are randomized, who complete the planned treatment, and who 
prematurely discontinue from the planned treatment and/or the trial will be presented by study 
period, treatment group and overall. Reasons for premature discontinuation as recorded on the 
termination page of the CRF will be summarized overall and by randomized treatment and for 
each period separately. 
9.4.8. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized descriptively by 
treatment and overall. To assess the comparability of treatment groups, demographic and 
baseline characteristics will be compared between treatments for the FAS using Cochran-Mantel-
Haenszel tests for binary categorical variables, van Elteren tests for ordinal categorical measures, 
or analysis of variance (ANOVA) for continuous variables, stratified by riluzole use/non-use, 
edaravone use/non-use. 
9.4.9. 
Investigational Product Exposure 
IP exposure will be summarized overall and by treatment and study period, including, total 
number of doses administered, total amount of drug administered, and the total duration of IP 
administration, defined as the date of the last dose minus the date of first dose + 1. 
9.4.10. 
Concomitant Medications 
Concomitant medications will be summarized and classified by drug class and preferred term 
using the World Health Organization (WHO) Drug Dictionary. The version of the WHO Drug 
Dictionary will be specified in the clinical study report. 
9.4.11. 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from baseline at each protocol 
specified assessment time point will be presented. 
9.4.12. 
Vital Signs 
Descriptive statistics for vital signs and changes from baseline at each protocol specified 
assessment time point will be presented. 

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9.4.13. 
Electrocardiogram 
Descriptive statistics for ECG parameters (eg, heart rate, PR interval, QRS interval, QT interval, 
and QTc interval [both Bazett’s and Fridericia’s corrections]) and changes from baseline at each 
protocol specified assessment time point will be presented. 
9.5. 
Interim Analyses 
Two interim analyses are planned for this trial. The interim analysis methods and the 
specifications of the data snapshots will be detailed in an interim analysis plan. 
Twelve (12) weeks after approximately one-third or more of the planned sample size is 
randomized, the first interim analysis may be triggered. Its purpose is to determine if there is a 
lack of effect of reldesemtiv on the ALSFRS-R in CY 5031, a finding that would be inconsistent 
with the prior observed effect on the change from baseline at 12 weeks in ALSFRS-R total score 
in the Phase 2 trial, CY 5022. At this interim analysis, the Data Monitoring Committee (DMC) 
will receive unblinded efficacy data from the independent, third-party biostatistical group 
supporting them and assess the effect of reldesemtiv on the change from baseline to Week 12 in 
the ALSFRS-R total score. At this interim assessment, if the treatment difference for change 
from baseline to Week 12 in ALSFRS-R total score has a one-sided p-value larger than or equal 
to 0.5 (ie, the estimated treatment difference of the change from baseline at Week 12 in 
ALSFRS-R total score is favoring placebo), the DMC may recommend stopping the trial due to 
futility. This futility analysis based on the data of change from baseline to Week 12 in 
ALSFRS-R will not have any alpha spending. The Sponsor will monitor the blinded aggregate 
standard deviation of the change from baseline to Week 12 in ALSFRS-R total score periodically 
and possibly adjust the specified alpha before this interim analysis is conducted. 
Twenty-four (24) weeks after at least one-third of the planned sample size is randomized; the 
second interim analysis will be triggered. The goal of the second interim analysis is to evaluate 
whether the proposed Phase 3 trial has adequate power to achieve a statistically significant effect 
on the primary endpoint in the final primary analysis, given the planned enrollment, or if 
continuing the trial is futile. At this interim analysis, the DMC will receive unblinded efficacy 
data from the independent, third-party biostatistical group supporting them and assess the effect 
of reldesemtiv on the primary endpoint. In terms of futility, the DMC may recommend stopping 
the trial if the conditional power (CP) is less than 0.10. The futility boundary is non-binding. The 
DMC is to make a recommendation to stop the trial using their collective judgment and the 
totality of evidence available. The DMC may consider the first secondary endpoint in a similar 
fashion. 
If the CP of primary endpoint is within a pre-specified promising zone from 0.40 to 0.90, the 
DMC may recommend increasing the sample size by 150 unless there is any safety concern or 
other concerns that preclude the recommendation. This method is referred to as the CDL 
adaptive method and was initially proposed by Chen, DeMets, and Lan (2004) as later extended 
by Gao, Ware and Mehta (2008) and Mehta and Pocock (2011) (Chen 2004; Gao 2008; Mehta 
2011, respectively). It is used to control type-1 error for sample size increase based on unblinded 
interim data. Within the pre-specified promising zone and a pre-specified fixed increase of the 
sample size, the CDL method could allow the final analysis to include all data before and after 
the interim look without inflating the type-1 error. This interim analysis will spend a very small 
2-sided alpha of 0.0001 for the primary endpoint as well as all individual secondary endpoints. 

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The DMC is also expected to recommend stopping this trial due to superiority if a two-sided p-
value is ≤ alpha of 0.0001 for the primary endpoint as well as all individual secondary endpoints. 
Therefore, the significance level of 2-sided alpha of 0.0499 would be used for the final analyses 
for the primary endpoint and all individual secondary endpoints to control familywise error rate 
at overall alpha of 0.05. 
9.6. 
Data Monitoring Committee 
An unblinded DMC will review the planned unblinded interim analysis results to be provided by 
an independent, third-party biostatistical group and make recommendations as to stop or 
continue the trial. The DMC may also provide recommendation(s) on the trial conduct. In 
addition, the DMC will review regularly the emerging data for safety monitoring purpose. The 
DMC or Cytokinetics can require an ad hoc DMC meeting at any time. No study activities will 
be suspended during the safety review. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the trial is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate hazard 
to patients. 
The investigator will be responsible for the following: 
• Providing summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide Cytokinetics with sufficient, accurate financial 
information as requested to allow Cytokinetics to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the trial to the patient or 
his/her legally authorized representative and answer all questions regarding the trial. 

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Patients must be informed that their participation is voluntary. Patients must be able to 
comprehend and be willing to sign a statement of informed consent that meets the requirements 
of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that informed consent was obtained before any 
study-specific activities/procedures were performed and the date the consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the trial. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
10.1.4. 
Data Protection 
Patients will be assigned a unique identifier by Cytokinetics. Any patient records or datasets that 
are transferred to Cytokinetics will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by 
Cytokinetics in accordance with local data protection law. The level of disclosure must also be 
explained to the patient who will be required to give consent for their data to be used as 
described in the ICF. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by Cytokinetics, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
The study organization will include an Executive Committee (EC), Steering Committee (SC) and 
DMC. 
The EC will contribute to trial design, implementation, data analysis, and communication of trial 
results and will consist of experts external to Cytokinetics who are qualified by their medical and 
scientific expertise and experience. The responsibilities of the EC will be described in an EC 
charter. 
The SC will contribute to implementation of the trial, data analysis, and communication of trial 
results. The SC members will be ALS experts external to Cytokinetics and represent the different 
geographies the trial will be conducted in. The responsibilities of the SC will be described in a 
SC charter. 
The DMC will be established and be responsible for periodic review of study data to ensure the 
safety of patients, and for review of SAEs on an ongoing basis. The DMC will include external 
experts with relevant expertise, including a neurologist(s) specializing in ALS, statistician, 
hepatologist and nephrologist eg, representing clinical science and biostatistics. The independent 
DMC membership will exclude the individuals from Cytokinetics or the study team involved in 
trial conduct. The DMC members will have access to treatment assignments and patient level 
data from the clinical trial database. DMC membership, responsibilities, relationship with 

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Cytokinetics, and the purpose and timing of the meetings will be further described in the DMC 
charter. 
10.1.6. 
Data Quality Assurance 
All patient data relating to the trial will be recorded on printed or electronic CRF unless 
transmitted to Cytokinetics or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
authority inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
Cytokinetics or designee is responsible for the data management of this trial including quality 
checking of the data. 
Cytokinetics assumes accountability for actions delegated to other individuals (eg, CROs). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator in accordance with the strictest regulation applicable to this study 
and as obligated by the clinical trial agreement. No records may be destroyed during the 
retention period without the approval of Cytokinetics. No records may be transferred to another 
location or party without notification to Cytokinetics. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data reported in the CRF or entered in the CRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 
10.1.8. 
Study and Site Start and Closure 
The trial start date is the date on which the clinical trial will be open for recruitment of patients. 
The first act of recruitment is the first site activated. 

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Cytokinetics or designee reserves the right to close the study site or terminate the trial at any 
time for any reason at the sole discretion of Cytokinetics. Study sites will be closed upon trial 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Cytokinetics or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local regulatory authorities, Cytokinetics’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further IP development 
If the trial is prematurely terminated or suspended, Cytokinetics shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the patient and should assure appropriate patient therapy 
and/or follow-up. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 9 will be performed by the central laboratory. 
Local laboratory testing may be used only if central laboratory testing is not feasible. If local 
testing is conducted, it is important that the sample for central analysis is obtained at the same 
time, if feasible. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5 of 
the protocol. 
Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. 
Table 9: 
Protocol-Required Safety Laboratory Assessments 
Chemistry 
Urinalysis  
Hematology 
Other 
Assessments 
Sodium 
Total bilirubin 
Specific gravity 
Hemoglobin 
 TSH at screening  
Potassium 
Direct bilirubin 
pH 
Hematocrit 
Gamma-glutamyl 
transferase 
Indirect bilirubin 
Blood 
RBC 
Serum Beta 
Human Chorionic 
Gonadotropin2 
Chloride 
CK 
Protein 
RDW 
FSH3 
Calcium 
ALP 
Glucose 
MCV 
 
Magnesium 
LDH 
Bilirubin 
MCH 
 
Phosphorus 
AST (SGOT) 
UPCR  
MCHC 
 
Urea nitrogen 
ALT (SGPT) 
Microscopy 
WBC 
 
Creatinine1 
Cystatin C1 
 
Platelets 
 
eGFRCr1 
(calculated using 
the CKD-EPI 
creatinine 
equation) 
eGFRCysC1 
(calculated using 
the CKD-EPI 
cystatin C 
equation) 
 
 
 
Glucose 
Uric acid 
 
 
 
Total protein 
Albumin 
 
 
 
Cholesterol 
Triglycerides 
 
 
 
Bicarbonate 
 
 
 
 
ALP = alkaline phosphatase; CK = creatine kinase; FSH = follicle-stimulating hormone; LDH = lactic acid 
dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; RBC = red blood cell; RDW = red cell distributions width; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell; TSH = 
Thyroid Stimulating Hormone; UPCR=urine protein creatinine ratio 
Investigators must document their review of each laboratory report. 
Laboratory results that could unblind the trial will not be reported to sites or other blinded personnel until the trial 
has been unblinded. 
1=Sites blinded to results 
2=Pregnancy test is required for WOCBP (see Appendix 3 [Section 10.3]);  
3=FSH only at Screening to confirm menopausal status if patient age < 55 years and spontaneous menses within the 
past 1 year but currently amenorrheic (eg, spontaneous or secondary to hysterectomy) to confirm FSH levels 
> 40 IU/L. 

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10.3. 
Appendix 3: Contraceptive Guidance 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining trial entry. 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal  
4. Menopause is defined as: 
o ≥ 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years 
old; or 
o no spontaneous menses for at least two years in a female < 55 years old; or  
o age < 55 years and spontaneous menses within the past 1 year but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy) and with follicle-
stimulating hormone (FSH) levels > 40 IU/L, or postmenopausal estradiol levels 
(< 5 ng/dL), or according to the definition of “postmenopausal range” for the 
laboratory involved 
Highly Effective Method of Contraception 
A highly effective method of contraception is one that has a failure rate of <1% per year when 
used consistently and correctly. 
Examples of highly effective contraception that have low user dependency are: 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 

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• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner, only when the absence of sperm has been confirmed and 
vasectomized partner is the sole sexual partner of the female patient 
Examples of highly effective contraception that are user-dependent are: 
• Combined hormonal methods of birth control include oral, intravaginal, transdermal, 
injectable, or implantable 
• Oral or injectable progestogen-only hormone contraception associated with the 
inhibition of ovulation 
• Sexual abstinence 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) 
are not acceptable methods of contraception. 
Contraception Guidance: 
Women of Childbearing Potential 
WOCBP must use at least one highly effective method of birth control. If a user-dependent, 
hormonal form of contraception is used as a highly effective method of birth control, a male 
condom must also be used. Male condom and female condom should not be used together (due 
to risk of failure with friction). 
WOCBP should refrain from donating ova/eggs at least 10 weeks after the last dose of study 
drug. 
If additional medications are given during treatment, the investigator is to review the prescribing 
information/summary of product characteristics for all concomitant therapy, as they may alter the 
contraceptive requirements. These additional medications may require an increase in the number 
of contraceptive methods and/or length of time that contraception is to be utilized after the last 
dose of protocol-required therapies. The investigator is to discuss these changes with the patient. 
 
 

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10.4. 
Appendix 4: Common Medications and Foods that Inhibit or Induce 
CYP3A4 or are OCT1/OCT2 Substrates 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
Strong Inhibitors: (Avoid) 
Strong Inducers: (Avoid) 
indinavir 
avasimibe 
nelfinavir 
carbamazepine 
ritonavir 
phenobarbital 
clarithromycin 
phenytoin 
itraconazole 
St. John’s Wort 
nefazodone 
rifampin 
ketoconazole 
rifabutin 
grapefruit 
 
Seville oranges 
 
 
 
Moderate Inhibitors: (Use with caution) 
Moderate Inducers: (Use with caution) 
erythromycin 
bosentan 
diltiazem 
efavirenz 
verapamil 
etravirine 
suboxone 
modafinil 
 
nafcillin 
 
nevirapine 
 
glucocorticoids (systemic) 
 
 
Weak Inhibitors: 
Weak Inducers: 
cimetidine 
amprenavir 
 
aprepitant 
 
armodafinil 
 
echinacea 
 
pioglitazone 
 
prednisone 
 
rufinamide 
 
clobazam 
 
lesinurad 
 
OCT1 Substrates (Avoid) 
OCT2 Substrates (Avoid) 
oxaliplatin 
pindolol 
dofetilide 
varenicline 
 
pilsicainide 
 
 
OCT1 Substrates (Use with Caution) 
OCT2 Substrates (Use with Caution) 
aciclovir 
metformin 
ganciclovir 
 
 

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10.5. 
Appendix 5: Abbreviations 
 
Abbreviation/Term 
Explanation 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALS 
Amyotrophic lateral sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear antibody 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BDI-FS 
Beck Depression Inventory-Fast Screen 
BID 
Twice a day 
BMI 
Body mass index 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatinine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CP 
Conditional power 
Cr 
Creatinine 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
CysC 
Cystatin C 
DILI 
Drug induced liver injury 
DMC 
Data monitoring committee 
DME 
Durable medical equipment 
EC 
Executive Committee 

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Abbreviation/Term 
Explanation 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
eGFR 
Estimated glomerular filtration rate 
EQ-5D-5L 
EuroQol-5D-5L 
EQ-VAS 
EuroQol Visual Analog Scale 
FAS 
Full analysis set 
FSH 
Follicle stimulating hormone 
FSTA 
Fast skeletal muscle troponin activator 
FU 
Follow-up 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HHD 
Hand held dynamometry 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
LAM 
Lactational amenorrhoea method 
LDH 
Lactic acid dehydrogenase 
LFT 
Liver function test 
LKM1 
Liver Kidney Microsomal Antibody 1 
LSM 
Least square means 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 

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Abbreviation/Term 
Explanation 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medication Dictionary for Regulatory Activities 
MiToS 
Milano-Torino Staging 
MMRM 
Mixed Model for Repeated Measures 
NIMP 
Non-investigational medicinal product 
NIV 
Non-invasive ventilation 
OCT 
Organic cation transporter 
OLE 
Open Label Extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
RBC 
Red blood cell 
RDW 
Red cell distributions width 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Steering Committee 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of activities 
SOC 
System organ class 
SVC 
Slow vital capacity 
TBL 
Total bilirubin 
TDD 
Total daily dose 
TEAE 
Treatment emergent adverse events 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UPCR 
Urine protein creatinine ratio 
WBC 
White blood cell 
WHO 
World Health Organization 

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Abbreviation/Term 
Explanation 
WOCBP 
Women of childbearing potential 

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11. 
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(1996). "Dose-ranging study of riluzole in amyotrophic lateral sclerosis." The Lancet 347: 1425-
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Lechtzin, N., Cudkowicz, M. E., de Carvalho, M., Genge, A., Hardiman, O., Mitsumoto, H., et 
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