Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis ALS CK-2127107 Reldesemtiv COURAGE-ALS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 489
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the effect of reldesemtiv versus placebo on functional outcomes in ALS.

Detailed description:
COURAGE-ALS 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 during the 24 weeks of blinded dosing

Arms:
arm 1: Participants in this arm take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Day 1 until Week 24. arm 2: Participants in this arm take 2 placebo oral tablets twice a day from Day 1 until Week 24. arm 3: Participants in this arm were those who received placebo in the double-blind period and reldesemtiv in the active drug period. Participants take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Week 24 until Week 48. Patients who were down-titrated for any reason during the 24 weeks of blinded dosing take 1 reldesemtiv 150 mg oral tablet twice a day for a 300 mg total daily dose from Week 24 until Week 48. arm 4: Participants in this arm were those who received reldesemtiv in the double-blind and active drug periods. Participants take 2 reldesemtiv 150 mg oral tablets twice a day for a 600 mg total daily dose from Week 24 until Week 48. Patients who were down-titrated for any reason during the 24 weeks of blinded dosing take 1 reldesemtiv 150 mg oral tablet twice a day for a 300 mg total daily dose from Week 24 until Week 48.

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

Protocol document:
Prot_000.pdf: 
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 
phenylbutyrate and taurursodiol, must be on it for ≥ 51 days prior to rescreening or not 


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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 
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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. 
REFERENCES 
 
Abe, K., Aoki, M., Tsuji, S., Itoyama, Y., Sobue, G., Togo, M., et al. (2017). "Safety and 
efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: A randomised, 
double-blind, placebo-controlled trial." The Lancet Neurology 16(7): 505-512. 
 
Berry, J. D., Miller, R., Moore, D. H., Cudkowicz, M. E., Van Den Berg, L. H., Kerr, D. A., et 
al. (2013). "The combined assessment of function and survival (cafs): A new endpoint for als 
clinical trials." Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(3): 162-168. 
 
Bourke, S. C., Tomlinson, M., Williams, T. L., Bullock, R. E., Shaw, P. J. and Gibson, G. J. 
(2006). "Effects of non-invasive ventilation on survival and quality of life in patients with 
amyotrophic lateral sclerosis: A randomised controlled trial." The Lancet Neurology 5(2): 140-
147. 
 
Brooks, B. R., Miller, R. G., Swash, M. and Munsat, T. L. (2000). "El escorial revisited: Revised 
criteria for the diagnosis of amyotrophic lateral sclerosis." Amyotrophic Lateral Sclerosis and 
Other Motor Neuron Disorders 1(5): 293-299. 
 
Brown, R. H. and Al-Chalabi, A. (2017). "Amyotrophic lateral sclerosis." New England Journal 
of Medicine 377(2): 162-172. 
 
Burkhardt, C., Neuwirth, C., Sommacal, A., Andersen, P. M. and Weber, M. (2017). "Is survival 
improved by the use of niv and peg in amyotrophic lateral sclerosis (als)? A post-mortem study 
of 80 als patients." PLOS ONE 12(5): e0177555. 
 
Chen, Y. H. J., DeMets, D. L. and Gordon Lan, K. K. (2004). "Increasing the sample size when 
the unblinded interim result is promising." Statistics in Medicine 23(7): 1023-1038. 
 
Forbes, R. B., Colville, S., Swingler, R. J. and Scottish Motor Neurone Disease Research, G. 
(2004). "Frequency, timing and outcome of gastrostomy tubes for amyotrophic lateral 
sclerosis/motor neurone disease." Journal of Neurology 251(7): 813-817. 
 
Gao, P., Ware, J. H. and Mehta, C. (2008). "Sample size re-estimation for adaptive sequential 
design in clinical trials." Journal of Biopharmaceutical Statistics 18: 1184-1196. 
 
Kiernan, M., Vucic, S., Cheah, B., Turner, M., Eisen, A., Hardiman, O., et al. (2011). 
"Amyotrophic lateral sclerosis." Lancet 377(9769): 942-955. 
 
Kleopa, K. A., Sherman, M., Neal, B., Romano, G. J. and Heiman-Patterson, T. (1999). "Bipap 
improves survival and rate of pulmonary function decline in patients with als." Journal of the 
Neurological Sciences 164(1): 82-88. 
 
Lacomblez, L., Bensimon, G., Leigh, N. P., Guilet, P., Meininger, V. and II, f. t. A. L. S. R. S. G. 
(1996). "Dose-ranging study of riluzole in amyotrophic lateral sclerosis." The Lancet 347: 1425-
1431. 


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Amendment 5: 24 FEB 2023 
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Lechtzin, N., Cudkowicz, M. E., de Carvalho, M., Genge, A., Hardiman, O., Mitsumoto, H., et 
al. (2018). "Respiratory measures in amyotrophic lateral sclerosis." Amyotrophic Lateral 
Sclerosis and Frontotemporal Degeneration 19(5-6): 321-330. 
 
Mehta, C. R. and Pocock, S. J. (2011). "Adaptive increase in sample size when interim results 
are promising: A practical guide with examples." Statistics in Medicine 30(28): 3267-3284. 
 
Paganoni, S., Macklin, E. A., Hendrix, S., Berry, J. D., Elliott, M. A., Maiser, S., et al. (2020). 
"Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis." N Engl J Med 
383(10): 919-930. 
 
Quanjer, P. H., Stanojevic, S., Cole, T. J., Baur, X., Hall, G. L., Culver, B. H., et al. (2012). 
"Multi-ethnic reference values for spirometry for the 3–95-yr age range: The global lung 
function 2012 equations." European Respiratory Journal 40(6): 1324-1343. 
 
Shimizu, H., Nishimura, Y., Shiide, Y., Yoshida, K., Hirai, M., Matsuda, M., et al. (2021). 
"Bioequivalence study of oral suspension and intravenous formulation of edaravone in healthy 
adult subjects." Clin Pharmacol Drug Dev 10(10): 1188-1197. 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
VERSION: 2.0 
DATE OF PLAN: 
24-February-2023 
 
 
STUDY DRUG: 
Reldesemtiv 
PROTOCOL NUMBER: 
CY 5031 
STUDY 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) 
 
BASED ON: 
Protocol Amendment 5, 24 February 2023 
 
SPONSOR: 
Cytokinetics, Inc. 
350 Oyster Point Boulevard, South San Francisco, CA 94080 
650-624-3000 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 


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SIGNATURE PAGE 
 
This document has been prepared and/or reviewed by*: 
 
 
 
 
 
 
Jenny Wei, PhD, Director, Biostatistics 
Cytokinetics, Inc. 
 
Signature 
 
        Date 
 
This document has been reviewed and accepted by*: 
 
 
 
 
 
 
Lisa Meng, PhD, VP, Biometrics, 
Cytokinetics, Inc. 
 
 
    Signature 
 
Date 
 
 
 
 
 
 
Stacy Rudnicki, MD, VP, Clinical Research & 
Therapeutic Area Lead, Neuromuscular, 
Cytokinetics, Inc. 
 
 
 
Signature 
 
Date 
 
 
 
 
 
Stuart Kupfer, MD, SVP, Chief Medical Officer 
Cytokinetics, Inc. 
 
Signature 
 
Date 
 
*See electronic signatures at the end of the document. 
 


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TECHNICAL SUMMARY REPORT (TSR) 
Name of Sponsor/Company 
Cytokinetics, Inc. 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use Only): 
Name of Finished Product: 
No generic or trade name assigned 
Page: 
 
Name of Active Ingredient: 
Reldesemtiv (CK-2127107) 
 
 
Title of Study: 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)  
Investigators: 
Study Center(s): Patients will be enrolled from approximately 80 clinical trial sites, in the US, Canada, 
the United Kingdom, Ireland, France, Germany, Italy, Belgium, Portugal, Spain, Sweden, Poland, 
Switzerland, Australia, and the Netherlands.  
Studied period (years): 2021 to 
2023 
Phase of development: Phase 3 
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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Methodology: 
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 and edaravone use at baseline) 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 or within the 2-hour period following food. 
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. 
Number of Subjects (planned and analyzed): 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 placebo-controlled period of the trial. 


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Diagnosis and main criteria for inclusion:  
The key inclusion criteria are below. A full listing of eligibility criteria can be found in protocol Section 
5. 
• 
Males or Females between the ages of 18 and 80 years of age, inclusive, at screening. 
• 
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 race at screening according to 
Global Lung Initiative equation (Quanjer 2012). 
• 
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. 
• 
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 
  


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Test product, dose and mode of administration: 
Reldesemtiv will be administered as 150 mg tablets, at a dose of 300 mg twice a day for a 600 mg TDD. 
Reldesemtiv tablets will be taken orally. 
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 tablet 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. A physician unblinded to 
renal laboratory results directs drug interruptions due to renal lab findings.  
Duration of treatment: 
The treatment period of the study is 48 weeks. Patients randomized to receive 300 mg reldesemtiv twice 
a day for a 600 mg TDD will receive reldesemtiv for the entire 48-week treatment period; patients 
randomized to receive placebo twice daily will receive placebo for the first 24 weeks and receive 
reldesemtiv for the next 24 weeks.  
Reference therapy, dose and mode of administration: 
Matching placebo will be administered as tablets, at a dose of 2 tablets twice a day. Matching placebo 
tablets will be taken orally. 
In order to maintain the blind to site staff and the study operation team, a small portion of placebo 
patients will be randomly selected for down-titration to 1 tablet twice a day during the study by the CRO 
physician unblinded to the renal laboratory results. 
Criteria for evaluation (see protocol Section 3): 
Efficacy:  
The primary efficacy endpoint is change from baseline to Week 24 in ALSFRS-R total score. 
The secondary endpoints are as follows: 
• 
Combined assessment of change in ALSFRS-R total score, time to dependence on assisted 
ventilation (either invasive or non-invasive), 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)  
Safety:  
Patient incidence of adverse events and serious adverse events.  


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Statistical methods: 
Unless otherwise specified, efficacy analyses will be performed on the full analysis set (FAS) by 
randomized treatment group. The FAS consists of all randomized patients who receive any amount of 
study drug and have a baseline and at least one post baseline efficacy assessment or have survival status 
recorded during the 24-week double-blind placebo-controlled period. 
The global null hypothesis for the primary endpoint 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. 
The primary analysis will be conducted using a Mixed Model for Repeated Measures (MMRM) with a 
restricted maximum likelihood method (SAS® PROC MIXED default). The model terms will include 
treatment group, baseline ALSFRS-R total score, visit, baseline riluzole use, and baseline edaravone use 
as well as the following interaction terms: baseline ALSFRS-R total score-by-visit and treatment group-
by-visit interactions. Other baseline covariates identified by stepwise selection in a regression model 
will also be included in the primary analysis model if they are key predictor variables for the change 
from baseline to Week 24 in ALSFRS-R total score based on the blinded data. The regression model 
used to identify baseline covariates will include pre-study disease progression rate, age and 
baseline percent predicted FVC as model terms. An unstructured variance-covariance matrix will be 
used in the primary analysis 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. 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 detailed in Section 8.5. 
Safety data will be summarized using descriptive statistics for the safety analysis set that consists of 
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 
TEAEs will be tabulated by the early-start and delayed-start treatment groups and by the study periods 
(double-blind 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.  
 


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
TECHNICAL SUMMARY REPORT (TSR) ..................................................................................3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................12 
1. 
LIST OF ABBREVIATIONS .....................................................................................13 
2. 
INTRODUCTION ......................................................................................................15 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................16 
3.1. 
Study Objectives .........................................................................................................16 
3.1.1. 
Primary Objective .......................................................................................................16 
3.1.2. 
Secondary Objective ...................................................................................................16 
3.2. 
Study Endpoints ..........................................................................................................16 
3.2.1. 
Primary Endpoints ......................................................................................................16 
3.2.2. 
Secondary Endpoints ..................................................................................................16 
4. 
STUDY DESIGN .......................................................................................................17 
4.1. 
Summary of Study Design ..........................................................................................17 
4.2. 
Definition of Study Drugs ..........................................................................................17 
4.3. 
Sample Size Considerations .......................................................................................18 
4.3.1. 
Sample Size Justifications ..........................................................................................18 
4.3.2. 
Sample Size Re-estimation .........................................................................................18 
4.4. 
Randomization ............................................................................................................18 
4.5. 
Clinical Assessments ..................................................................................................19 
4.5.1. 
Efficacy Assessments .................................................................................................19 
4.5.1.1. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-
R) ................................................................................................................................19 
4.5.1.2. 
Percent Predicted Force Vital Capacity (Percent Predicted FVC) .............................19 
4.5.1.3. 
Milano-Torino Staging (MiToS) ................................................................................20 
4.5.1.4. 
Handgrip Strength .......................................................................................................22 
4.5.1.5. 
Muscle Strength ..........................................................................................................22 
4.5.2. 
Safety Assessments .....................................................................................................22 
4.5.2.1. 
Beck Depression Inventory (BDI) ..............................................................................22 
4.5.3. 
Pharmacokinetic Assessments ....................................................................................23 
4.5.4. 
Health Economic Outcome Measures and Quality of Life Assessments ...................23 


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4.5.4.1. 
EQ-5D-5L and EQ-VAS .............................................................................................23 
4.5.4.2. 
Use of Durable Medical Equipment (DME) ...............................................................24 
4.5.4.3. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) ..................25 
4.5.5. 
Other Research Assessments ......................................................................................25 
5. 
PLANNED ANALYSES ............................................................................................26 
5.1. 
Interim Analyses .........................................................................................................26 
5.2. 
Final Analyses ............................................................................................................27 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................28 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........28 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................28 
6.3. 
Data Management .......................................................................................................28 
6.4. 
Data Presentation Conventions ...................................................................................29 
6.5. 
Analysis Populations ..................................................................................................29 
6.5.1. 
Screen Failures ............................................................................................................29 
6.5.2. 
All Randomized Set ....................................................................................................29 
6.5.3. 
Safety Analysis Set .....................................................................................................30 
6.5.4. 
Full Analysis Set .........................................................................................................30 
6.5.5. 
Pharmacokinetic Analysis Set ....................................................................................30 
6.6. 
Baseline Definition .....................................................................................................30 
6.7. 
Derived and Transformed Data ..................................................................................30 
6.7.1. 
Baseline Age ...............................................................................................................30 
6.7.2. 
Study Day ...................................................................................................................30 
6.7.3. 
Change from Baseline .................................................................................................30 
6.7.4. 
Analysis Windows ......................................................................................................30 
6.7.5. 
Multiple Assessments .................................................................................................31 
6.8. 
Handling of Missing Data ...........................................................................................32 
6.8.1. 
Missing Efficacy Endpoints ........................................................................................32 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................32 
6.8.3. 
Missing Start and Stop Dates for Adverse Events ......................................................32 
7. 
STUDY POPULATION .............................................................................................34 
7.1. 
Subjects Disposition ...................................................................................................34 


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7.2. 
Screen Failures ............................................................................................................34 
7.3. 
Protocol Deviations ....................................................................................................34 
7.4. 
Demographic and Baseline Characteristics ................................................................34 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................34 
7.6. 
Medical History and Medical Conditions Present at Entry ........................................34 
7.7. 
Prior Medication History and Medications Present at Entry ......................................35 
7.7.1. 
Non-Diagnosis Related Prior Medication History ......................................................35 
7.7.2. 
Prior Diagnosis Related Medication History ..............................................................35 
7.8. 
Baseline Physical Examination ...................................................................................35 
7.9. 
Baseline Vital Signs ....................................................................................................35 
7.10. 
Baseline Laboratory Data ...........................................................................................35 
7.11. 
Baseline Primary and Secondary Efficacy Evaluations ..............................................35 
8. 
EFFICACY .................................................................................................................36 
8.1. 
General Considerations ...............................................................................................36 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................36 
8.3. 
Statement of the Null and Alternate Hypotheses ........................................................36 
8.4. 
Subgroup Analyses .....................................................................................................36 
8.4.1. 
Subgroups for Explanation of Potential Heterogeneous Treatment Effect ................36 
8.4.2. 
Subgroups Supportive Analyses for the Primary Analyses of Primary 
Endpoint and First Secondary Endpoint .....................................................................37 
8.5. 
Multiple Comparisons and Multiplicity ......................................................................38 
8.6. 
Analysis of the Primary Efficacy Endpoint ................................................................39 
8.6.1. 
Primary Efficacy Analysis ..........................................................................................39 
8.6.1.1. 
Imputation of the Missing Data for the Primary Efficacy Analysis ...........................41 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Endpoint .............................................41 
8.7. 
Analysis of the Secondary Efficacy Endpoints ..........................................................44 
8.7.1. 
Analysis of the First Secondary Efficacy Endpoint ....................................................44 
8.7.1.1. 
Imputation of the Missing Data for the First Secondary Efficacy Analysis ...............45 
8.7.2. 
Sensitivity Analysis of the First Secondary Efficacy Endpoint ..................................45 
8.7.3. 
Analysis of the Remaining Secondary Efficacy Endpoints ........................................48 
8.8. 
Analysis of the Exploratory and Additional Efficacy Endpoints ...............................48 
8.8.1. 
Analysis of the Exploratory and Additional Efficacy Endpoint .................................50 
8.8.2. 
Exploratory Analyses Evaluating Effect of Reldesemtiv ...........................................50 


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8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................51 
9. 
SAFETY AND TOLERABILITY ..............................................................................52 
9.1. 
Overall Summary of Tolerability ................................................................................52 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............52 
9.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects .................................52 
9.2.2. 
Missing and Partial AE Onset Dates ..........................................................................52 
9.2.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death ..........................................................................53 
9.2.4. 
Summaries of Adverse Events of Special Interest ......................................................53 
9.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................53 
9.4. 
Concomitant and Other Medications ..........................................................................54 
9.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........54 
9.5. 
Routine Laboratory Data ............................................................................................54 
9.6. 
Vital Signs ..................................................................................................................55 
9.7. 
Electrocardiogram .......................................................................................................56 
9.8. 
Physical Examination .................................................................................................57 
9.9. 
Beck Depression Inventory Fast Screen Version .......................................................57 
9.10. 
Study Termination Status ...........................................................................................57 
10. 
PHARMACOKINETICS ...........................................................................................58 
11. 
REFERENCES ...........................................................................................................59 
12. 
APPENDIX .................................................................................................................61 
12.1. 
Table of Contents for Data Display Specifications ....................................................61 
12.2. 
Data Display Specifications ........................................................................................61 
12.3. 
Analysis Windows ......................................................................................................62 
12.4. 
Mspline Value for Calculation of Predicted FVC ......................................................65 
12.5. 
Sample SAS Codes .....................................................................................................66 
 


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LIST OF TABLES 
Table 1: 
MiToS Domain Scores Mapping from ALSFRS-R Item Scores ................................21 
Table 2: 
Depression Level Classification by BDI Total Score .................................................23 
Table 3: 
Definitions of Receipt, First Use, Daily Use and Dependent of the Durable 
Medical Equipment .....................................................................................................24 
Table 4: 
Components of the Main Estimator and Analytical Approach for the Primary 
Efficacy Endpoint .......................................................................................................40 
Table 5: 
Sensitivity Estimators of the Primary Efficacy Endpoint ...........................................42 
Table 6: 
Sensitivity Estimator of the First Secondary Efficacy Endpoint ................................46 
Table 7: 
Criteria of Potentially Clinically Significant (PCS) Vital Signs ................................55 
Table 8: 
Criteria of Abnormal and PCS ECG Values ...............................................................56 
Table 9: 
Analysis Windows for ALSFRS-R, FVC (Remote Visits) and DME ........................62 
Table 10: Analysis Windows for FVC (in Clinic), Handgrip and Muscle Strength, 
BDI-FS, Vital Signs, Weight and BMI .......................................................................62 
Table 11: Analysis Windows for EQ-5D-5L, EQ-VAS and ALSAQ-40 ...................................63 
Table 12: Analysis Windows for Neurological Exam ................................................................63 
Table 13: Analysis Windows for ECG .......................................................................................63 
Table 14: Analysis Windows for PK Concentration ...................................................................63 
Table 15: Analysis Windows for Clinical Safety Laboratory Measurements ............................64 
Table 16: Mspline Value .............................................................................................................65 
 
 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area under the ROC Curve 
BDI-FS 
Beck Depression Inventory (BDI®) - Fast Screen 
CI 
Confidence Interval 
CP 
Conditional Power 
CYP3A4 
Cytochrome P450 Family 3 Subfamily A Member 4 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DME 
Durable Medical Equipment 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EQ-VAS 
EuroQol - Visual Analogue Scale 
FAS 
Full Analysis Set 
FVC 
Force Vital Capacity 
HHD 
Hand Held Dynamometry 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
LLN 
Lower Limit of Normal 
LSM 
Least Squares Mean 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 


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Abbreviation 
Term 
MiToS 
Milano-Torino Staging 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
NIV 
Non-Invasive Ventilation 
OCT1 
Organic Cation Transporter 1 
OLE 
Open Label Extension 
PCS 
Potential Clinical Significance 
PK 
Pharmacokinetics 
PT 
Preferred Term 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System (SAS®) 
SOC 
System Organ Class 
TDD 
Total Daily Dose 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization  
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a technical elaboration of the 
planned analyses and detailed data displays to be included in the Clinical Study Report (CSR) for 
CY 5031 study. 
This SAP was developed in accordance with ICH E9 and ICH E9 (R1) guideline. All decisions 
regarding final analysis, as defined in this SAP document, will be made prior to the study 
database lock. Further study information can be found in the protocol. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of the study is to assess the effect of reldesemtiv versus placebo on 
functional outcomes in ALS. 
3.1.2. 
Secondary Objective 
The secondary objectives of the study are listed as follows: 
• 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 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The primary endpoint of the study is change from baseline to Week 24 in ALSFRS-R total score. 
3.2.2. 
Secondary Endpoints 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation and survival time up to Week 24. Dependence on assisted ventilation 
is defined as using non-invasive or invasive ventilation for ≥22 hours per day for ≥10 
consecutive days. 
• Change from baseline to Week 24 in the percent predicted forced vital capacity (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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4. 
STUDY DESIGN 
4.1. 
Summary of Study 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 at baseline and 
edaravone use at baseline) 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 
during the 24 weeks of blinded dosing 
For the entire 48 weeks of dosing, patients, sites, Sponsor personnel and their contractors 
employed to work in any way on the conduct of the trial (with the exception of the unblinded 
medical monitor) shall remain blinded to the randomized treatment assignment for 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. 
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. 
4.2. 
Definition of Study Drugs 
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. 
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  
Oral  
Use  
Experimental  
Placebo  
IMP and NIMP  
IMP  
IMP  


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Arm Name 
Active 
Placebo 
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  
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
With a 2:1 randomization ratio to reldesemtiv and placebo groups, respectively, an initial 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 of 5.5 points, and accounting for data missing and early 
treatment termination. 
4.3.2. 
Sample Size Re-estimation 
The sample size will not be re-estimated based on the results of the 1st interim analysis. 
The 2nd interim analysis will be triggered 24 weeks after at least one-third of patients required to 
be enrolled are randomized, and will be based on the data from all patients who are expected to 
complete 24 weeks of treatment. The sample size may be re-estimated based on the 2nd interim 
analysis results being reviewed by the DMC. For the primary endpoint, if futility criterion is not 
met (see Section 5.1 for the futility criterion) and the conditional power under the current trend at 
the time of the interim look is within the pre-specified promising zone from 0.40 to 0.90, the 
DMC may recommend increasing the sample size by a pre-specified fixed number of 150 to 
ensure sufficient power. 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. 
4.4. 
Randomization 
Eligible ALS patients will be randomized in a 2:1 ratio to receive 300 mg reldesemtiv twice daily 
or placebo twice daily, respectively, for the first 24 weeks (double-blind, placebo-controlled 
period). The stratification factors for randomization are baseline riluzole use and baseline 
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4.5. 
Clinical Assessments 
4.5.1. 
Efficacy Assessments 
Efficacy assessments include Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
(ALSFRS-R), forced vital capacity (FVC), handgrip strength and muscle strength. Additionally, 
Milano-Torino staging (MiToS) will be derived based on the ALSFRS-R item scores. 
4.5.1.1. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) 
The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is a validated 
rating instrument for monitoring the progression of disability in patients with ALS (Cedarbaum 
1999). The assessment is based on 12 clinical ratings that are categorized in four domains: bulbar 
(speech, salivation, swallowing), fine motor skills (handwriting, cutting food and handling 
utensils, dressing hygiene), gross motor skills (turning in bed and adjusting bedclothes, walking, 
climbing stairs) and respiratory function (dyspnea, orthopnea, respiratory insufficiency). Each 
clinical rating is assessed using an ordinal scale that ranges from 0 to 4, with a score of 4 
representing normal function and lower scores indicating worse function. 
The score of each of the four domains (bulbar, fine motor skill, gross motor skill, and respiratory 
function) is calculated as the sum of the three ratings within each domain and can range from 
0 to 12. If a single rating is missing, the score of the corresponding domain will be set to missing. 
The ALSFRS-R total score is calculated as the sum of the 12 ratings and can range from 0 to 48 
with higher scores indicating less functional impairment. If a single rating is missing, the 
ALSFRS-R total score will be set to missing. 
The score change from baseline will be calculated as the post baseline score minus the baseline 
score, so that a negative number for change from baseline indicates greater impairment relative 
to baseline. A positive treatment difference in the change from baseline (reldesemtiv minus 
placebo) favors reldesemtiv. 
4.5.1.2. 
Percent Predicted Force Vital Capacity (Percent Predicted FVC) 
The forced vital capacity (FVC) measures the amount of air a person can forcefully and quickly 
exhale after inhaling as deeply as possible. FVC measurements will be collected in clinic and 
remotely. The patient will perform the maneuver 3 times; up to 5 measurements will be taken if 
the variability of the two highest measurements is ≥10%. Variability is calculated as (highest 
FVC measurement - 2nd highest FVC measurement) / highest FVC measurement. FVC tracings 
for this study will be reviewed centrally by independent pulmonologists. Volume time curves 
will be reviewed for acceptability guided by criteria from the American Thoracic Society and the 
European Respiratory Society (American Journal of Respiratory and Critical Care Medicine 
2019; Vol 200, Number 8). Tracings with variability ≥10% between the 2 highest values are not 
acceptable. Those tracings that are viewed as acceptable will be ‘evaluable’ and will be included 
in the analysis. Furthermore, among FVC measurements collected during a visit, the highest 
result of the evaluable measurements will be used for analysis as long as the pulmonologist has 
confirmed it is acceptable. FVC measurements collected in clinic and remotely may be combined 
for analysis if a systematic difference across the entire study population is not observed; 
otherwise, they will be analyzed separately given that some clinic sites may only collect FVC 
data remotely during the COVID-19 pandemic due to safety and local health regulations. The 


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evaluation of whether the systematic difference exists will be performed before the database 
lock. 
The percent predicted FVC represents the FVC measurement as a percent of the predicted values 
based on sex, age, height, and race. It is calculated as: Percent Predicted FVC = (Trial FVC / 
Predicted FVC) x 100 (%). 
The predicted FVC is calculated using the Quanjer GLI-2012 Regression Equation (Quanjer 
2012) that factor the characteristics of sex, age, height and race into the prediction. 
For males, 
Predicted FVC = exp [ –11.2281 + 2.4135 x ln(Height)(cm) + 0.0865 x ln(Age)(yrs) 
– 0.1684 x AfrAm – 0.0405 x NEAsia – 0.1177 x SEAsia – 0.0825 x Other + Mspline] 
For females, 
Predicted FVC = exp [ –10.403 + 2.2633 x ln(Height)(cm) + 0.0234 x ln(Age)(yrs) 
– 0.1555 x AfrAm – 0.0262 x NEAsia – 0.1516 x SEAsia – 0.0833 x Other + Mspline] 
where 
ln( ) = natural log transformation 
AfrAm = 1 if a patient is African American; otherwise = 0 
NEAsia = 1 if a patient is from North East Asia; otherwise = 0 
SEAsia = 1 if a patient is from South East Asia; otherwise = 0 
Other = 1 if a patient belongs to other ethnic group except for Caucasian, or has mixed 
race/ethnicity; otherwise = 0 
(See https://www.ers-education.org/guidelines/global-lung-function-initiative/faq/what-
reference-equations-do-i-apply-for-non-caucasians/ for the definitions of regions used in the 
Quanjer GLI-2012 Regression Equation.) 
Mspline is determined by age and sex as shown in Section 12.4. 
Generally, the percent predicted FVC declines over time in patients with ALS. The change from 
baseline in percent predicted FVC will be calculated as the post baseline value minus the 
baseline value, so that a negative number for change from baseline indicates respiratory function 
decline relative to baseline, and a positive treatment difference (reldesemtiv minus placebo) 
favors reldesemtiv. 
4.5.1.3. 
Milano-Torino Staging (MiToS) 
Milano-Torino staging (MiToS) was developed to measure loss of independence in the 4 key 
domains on ALSFRS (Chio 2015): movement (walking/self-care), swallowing, communicating 
and breathing. Each MiToS domain score is derived from related ALSFRS-R item scores as 
shown in Table 1. The sum of the 4 MiToS domain scores has a range from 0 to 4 that 
corresponds to MiToS Stage 0, Stage 1, Stage 2, Stage 3 and Stage 4, where Stage 0 represents 
possible functional involvement but no loss of independence on any domain, and Stages 1 to 4 
represent number of domains in which independence was lost. In addition, MiToS Stage 5 
represents death. 


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Table 1: 
MiToS Domain Scores Mapping from ALSFRS-R Item Scores 
Domain 
ALSFRS-R Items Used for Mapping 
Mapping Algorithms 
Movement 
(walking/self-
care) 
Q8: Walking 
4=Normal 
3=Early ambulation difficulties 
2=Walks with assistance 
1= Non-ambulatory functional moment only 
0= No purposeful leg movement 
If Q8 or Q6 has an item score=0 
or 1 then MiToS movement 
domain score=1; else MiToS 
movement domain score=0 
Q6: Dressing and hygiene 
4= Normal function 
3= Independent and complete self-care with effort or 
decreased efficiency 
2= Intermittent assistance or substitute methods 
1= Needs attendant for self-care 
0= Total dependence 
Swallowing 
Q3: Swallowing 
4= Normal eating habits 
3= Early eating problems; occasional choking 
2= Dietary consistency changes 
1= Needs supplemental tube feeding 
0= NPO (exclusively parenteral or enteral feeding) 
If Q3 has an item score=0 or 1 
then MiToS swallowing domain 
score=1; else MiToS swallowing 
domain score=0  
Communicating 
Q1: Speech 
4= Normal speech processes 
3= Detectable speech with disturbances 
2= Intelligible with repeating 
1= Speech combined with non-vocal communication 
0= Loss of useful speech 
If both Q1 and Q4 have items 
scores= 0 or 1 then MiToS 
communicating domain score=1; 
else MiToS communicating 
domain score=0.  
Q4: Handwriting 
4= Normal 
3= Slow or sloppy; all words are legible 
2= Not all words are legible 
1= Able to grip pen but unable to write 
0= Unable to grip pen 
Breathing 
Q10: Dyspnea 
4= None 
3= Occurs when walking 
2= Occurs when one or more of: eating, bathing, 
dressing 
1= Occurs at rest, difficulty breathing when either 
sitting or lying 
0= Significant difficult, considering using mechanical 
respiratory support 
If Q10 has an item score=0 or 1 
or Q12 has an item score=0, 1 or 
2 then MiToS breathing domain 
score=1; else MiToS breathing 
domain score=0 
Q12: Respiratory insufficiency 
4= None 
3= Intermittent use of NIPPV 
2= Continuous use of NIPPV during the night 
1= Continuous use of NIPPV during the night and day 
0= Invasive mechanical ventilation by intubation or 
tracheostomy 


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4.5.1.4. 
Handgrip Strength  
Handgrip strength will be measured bilaterally by an electronic hand dynamometer with grip 
extenders to be attached to the front and/or back handle as needed dependent upon patient’s hand 
size. The width of the grip (with no extender, 1 grip extender or 2 grip extenders) will be used 
consistently throughout the study. Patients will be asked to squeeze the device with the 
maximum possible force for a short interval to establish the maximum voluntary contraction. The 
greater of the two maximum handgrip strength attempts for each hand will be used. The 
secondary endpoint, change from baseline to Week 24 in handgrip strength, will be analyzed 
using the average grip strength of both hands. 
4.5.1.5. 
Muscle Strength   
Patients’ muscle strength will be measured bilaterally using hand held dynamometry (HHD). The 
HHD testing will measure muscle strength of three intrinsic hand muscle groups tested 
bilaterally: abductor pollicus brevis, first dorsal interosseous, and abductor digiti minimi. Two 
measurements will be obtained for each muscle tested. If the 2 measurements have a variability 
> 0.15 then a 3rd test will be performed. The variability is calculated as: (Max Value - Min 
Value) / Max Value. The maximum result of the 2 or 3 measurements obtained will be used for 
analysis. 
The muscle strength will be recorded as 0 (pounds) on the electronic case report form (eCRF) for 
the following situations: 
• A patient is able to assume the correct position but unable to exert any force. 
• A patient is unable to assume the correct position, and the evaluator is able to determine 
the cause as muscle weakness or contracture. 
The muscle strength of each measured body location will be transformed as a percent change 
from baseline using the equation: [(post baseline value – baseline value) / baseline value] x 100. 
The transformed muscle strength will be set to missing if the baseline value is zero. 
The mega score is a composite score that averages strength across muscle groups. It is calculated 
as the mean of the non-missing transformed muscle strength scores among the  three muscle 
groups of the hands measured bilaterally by the HHD. 
A greater muscle strength mega score indicates less muscle strength loss, and a positive 
treatment difference (reldesemtiv minus placebo) favors reldesemtiv. 
4.5.2. 
Safety Assessments 
Safety assessments include adverse events and serious adverse events, Beck Depression 
Inventory-Fast Screen (BDI-Fast Screen), electrocardiograms, laboratory assessments, 
neurological examinations, physical examinations and vital signs. 
4.5.2.1. 
Beck Depression Inventory (BDI) 
The Beck Depression Inventory (BDI®) ─ Fast Screen (BDI-FS) is a shortened version of the 
BDI-II that evaluates key symptoms of depression. It was developed to factor out co-occurring 
depression symptomatology that may be related to a medical condition (Steer 1999), and 
concentrate on factors of depression that relate solely to depression. The BDI-FS contains 7 self-


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reported items that evaluate major depressive symptoms over the past 2 weeks, including 
sadness, pessimism, past failure, loss of pleasure, self-dislike, self-criticalness, and suicidal 
ideations (Beck 2000; Steer 1999). Individual scale items are scored on a 4-point continuum 
(0=least, 3=most). The total score is calculated as the sum of the scores from the 7 items and can 
range from 0 to 21. Higher scores indicate greater depressive severity. Patient’s depression level 
will be classified using the BDI total score as shown in Table 2. The BDI total score will be set 
to missing if an answer to any of the 7 items is missing. 
Table 2: 
Depression Level Classification by BDI Total Score 
Depression Level 
BDI Total Score 
Minimal Depression 
0 – 3 
Mild Depression 
4 – 6 
Moderate Depression 
7 – 9 
Severe Depression 
10 – 21 
4.5.3. 
Pharmacokinetic Assessments   
Single blood samples will be collected to evaluate plasma concentrations of reldesemtiv and its 
metabolite, CK-2127106 at Weeks 4, 12 and 24. An optional intensive PK substudy will be 
conducted at Week 36. Pharmacokinetic (PK) parameters, such as trough concentration 
(Ctrough), maximum observed concentration (Cmax), Tmax, AUCtau, AUClast and CL/F (reldesemtiv 
only) and metabolite ratio, if available, will be calculated. 
4.5.4. 
Health Economic Outcome Measures and Quality of Life Assessments  
4.5.4.1. 
EQ-5D-5L and EQ-VAS 
The instrument EQ-5D is a standardized measure of health status for clinical and economic 
appraisal (EuroQol Group 1990), which consists of two parts: a short descriptive system 
questionnaire (EQ-5D-3L) and a visual analogue scale (EQ-VAS). 
EQ-5D-5L is the 5-level version of EQ-5D introduced to improve the instrument’s sensitivity 
and to reduce ceiling effects (EuroQol Group 2009). The descriptive system comprises 
5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension has 5 levels indicating no problems, slight problems, moderate problems, severe 
problems or extreme problems. Five responses with a response from each of the 5 dimensions 
form a 5-digit number that defines a patient’s health state profile. A health state can potentially 
be assigned a summary index score based on societal preference weights (societal perspective) 
for the health state. The health state preferences often represent national or regional values and 
can therefore differ between countries/regions. The health state index scores will be calculated 
using the composite time trade-off (cTTO) method based on the United States valuation of EQ-
5D-5L (Pickard 2019) for patients from the United States and for the FAS. The health state index 
score ranges from less than 0 to 1 with higher scores indicating higher health utility; a score 0 
represents death, negative values represent worse than death, and 1 represents full health. 


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EQ-VAS rates a patient’s perceived heath on a vertical visual analogue scale from 0 to 100, 
where 0 represents the worst imaginable health and 100 represents the best imaginable health. 
The VAS can be used as a quantitative measure of health outcome that reflects the patient’s own 
judgement. 
4.5.4.2. 
Use of Durable Medical Equipment (DME) 
At screening and on Day 1, patients will be asked if they have any of the listed durable medical 
equipment (DME) (manual wheelchair, power wheelchair, non-invasive ventilation (NIV), 
gastrostomy tube, augmentative and alternative communication) and if so, the extent of current 
DME use (has obtained but not using, first use, daily use  or dependent) as defined in Table 3, or 
patient stopped using and the reason of stopping using (as applicable). In the subsequent visits 
that collect the DME assessments, patients will be asked if any of the listed DME has been 
prescribed for them and they have agreed to it since the last visit. And if yes, the date of 
prescription. Patients will also be asked for the extent of current DME use or if they have 
changed their extent of DME use since the last visit. 
Table 3: 
Definitions of Receipt, First Use, Daily Use and Dependent of the Durable 
Medical Equipment 
 
Durable Medical Equipment 
Category 
Manual 
Wheelchair 
Power 
Wheelchair 
Non-invasive 
Ventilation 
Gastrostomy 
Augmentative 
and Alternative 
Communication 
Receipt 
Has received  
(either through 
insurance or other 
source) 
Has received  
(either through 
insurance or 
other source) 
Has received  
Has received 
 
Has received 
(either through 
insurance or other 
source) 
First use 
Use for any reason 
and in any location 
Use for any 
reason and in 
any location 
Any use outside 
of being 
instructed on how 
to use it – can be 
day or night use 
Any use outside of being 
instructed on how to use 
it or flushing it – can be 
for the purposes of 
administering medicines, 
free water, nutrition 
Any use for the 
purposes of 
communication 
outside of being 
instructed on how 
to use device  
Daily use 
Daily use (any 
duration) 
Daily use (any 
duration) 
Daily use (can be 
day or night use) 
for 4 or more total 
hrs/24 hrs 
Daily use for replacing 
or supplementing one or 
more meals per day 
Daily use for the 
purposes of 
communication 
Dependent 
Non-ambulatory, 
wheelchair 
dependent 
Non-
ambulatory, 
wheelchair 
dependent 
Use 22 or more 
hrs/day 
Use for essentially all 
nutrition, may still take 
food by mouth for 
pleasure 
Use for all 
communication 


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4.5.4.3. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) is a 40-item  
questionnaire that was created specifically to assess health-related quality of life in patients with 
ALS. ALSAQ-40 includes 40 items for the 5 domains: physical mobility (10 items), activities of 
daily living and independence (10 items), eating and drinking (3 items), communication 
(7 items) and emotional reactions (10 items). Based on a two-week recall of experiences patients 
may have had, each item is rated by frequency of occurrence on a five-point Likert scale 
(1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always or cannot do at all). For each 
domain, the sum of scores from all items of a domain is then converted to a summary score from 
0 (best health status) to 100 (worst health status) using the equation: (sum of all non-missing 
item scores / maximum possible sum of all non-missing item scores) x 100. The ALSAQ-40 total 
score is calculated as the sum of the summary scores from the 5 domains. A lower score 
corresponds to better health-related quality of life. 
4.5.5. 
Other Research Assessments 
Structured patient interviews will be conducted within two weeks before completing the Week 
24 visit for a subset of English language-speaking patients (up to 50 patients) enrolled at US 
centers. 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. 
Hospitalizations experienced by a patient following randomization 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 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. 
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, 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 for biomarker 
development will be collected pre-AM dose on Day 1 and Week 24. Plasma samples will be 
stored for future biomarker analyses. 
Where authorized by the applicable IRB/EC/REB approved informed consent and authorized by 
the patient, a blood sample will be obtained at the Day 1 visit and stored for possible future 
genetic testing related to this study and for research purposes only. 
 


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5. 
PLANNED ANALYSES 
5.1. 
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 safety analysis will include all data points 
collected from available patients at the time of the interim data review. The efficacy analysis will 
include patients who would be expected to complete 24 weeks of the study by the time of data 
cut off for the second interim data review, i.e., those who complete 24 weeks of the study and 
those who are expected to complete 24 weeks of the study but early terminate prior to Week 24. 
Those patients who have not had the opportunity to reach Week 24 by the time of the data cutoff 
will not be included in the second interim efficacy analysis. 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) under the current trend is less 
than 0.10 for the primary endpoint. 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 a pre-specified fixed number of 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, 
later extended by Gao, Ware and Mehta, and Mehta and Pocock (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 


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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. 
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. 
5.2. 
Final Analyses 
When all patients complete or discontinue from the study, the final analyses will be conducted. 
If the interim analysis result leads to an increase of the sample size, the final primary analyses 
will be further stratified by the status of being included or excluded from the 2nd interim 
analysis. As a sensitivity analysis, the adjusted point estimation and confidence interval after the 
adaption (Lawrence 2003) will also be provided. For the joint rank test on the first secondary 
endpoint, the ranking will be made separately for the cohort that is included in the 2nd interim 
analysis and for the subsequent cohort that is not included in order to maintain independence of 
the results for the cohort included in the interim analysis and the subsequent cohort that is not 
eligible for inclusion in the interim analysis. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Unless otherwise specified, analyses will be conducted for the first 24-week double blind 
placebo-controlled period and the second 24-week active drug period. 
Efficacy data will be summarized by randomized treatment group based on the full analysis set 
(FAS). Safety data will be summarized by treatment received based on the safety analysis set, 
and PK data will be summarized for patients who receive reldesemtiv based on the 
pharmacokinetics analysis set. 
Descriptive statistics to be presented in a table include count of patients, mean, median, standard 
deviation, minimum and maximum for continuous variables, and count of patients and the 
percentage for categorical variables. 
For model based analysis, least squares mean, difference of least squares means between 
treatment groups and the corresponding standard errors, 95% confidence intervals (CIs) and 
two-sided p-values for the relative statistical inferences will be presented. 
For survival analyses, time to event will be summarized by median, 95% CI of median, and 1st 
and 3rd quartiles using Kaplan-Meier technique. Counts and percentages of events and censored 
will be presented. Hazard ratio between treatment groups and the corresponding 95% CI and 
p-value will also be presented. 
Listings will include patient ID, demographics, randomized treatment group and other relevant 
items, and sorted by randomized treatment group, patient ID and date of assessment. 
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Post text tables and individual subject data listings are prepared according to ICH Guideline E3. 
6.3. 
Data Management 
Data will be entered into the clinical database with programmed edit checks and direct visual 
inspection to ensure integrity. Adverse events, concomitant medications and medical history will 
be coded programmatically while unique terms will be reviewed visually. Clinical safety 
laboratory, ECG and PK data and FVC measurements collected from a spirometry at remote 
visits will be provided in the pre-specified format from external laboratories or research 
organizations. ALSAQ-40 data collected on CRF and from spirometry will be combined for 
analysis. Every attempt will be made to obtain measurements to minimize the percentage of 
missing data. 
Critical data will be identified at an early stage of the study to allow sufficient time to have data 
entered, reviewed, queried and cleaned throughout the study. In preparation for the interim data 
snapshot, clean CRFs will be soft-locked, which will prevent sites from modifying data on those 
CRFs. 


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The final analyses will include data included in the interim analyses, plus additional data that are 
collected after the interim analyses. The data that are soft locked for the interim analyses will not 
be modified for the final analyses unless permission is granted from Cytokinetics that a site 
needs to change the data based on the SOPs. The data management group may break a soft lock 
to issue a query as needed. Changes for log records such as AE end dates may be updated as 
appropriate. 
6.4. 
Data Presentation Conventions 
The following conventions will be applied to data presentations: 
• For continuous variables, mean and median values are formatted to one more decimal 
place than the measured value. Standard deviation values are formatted to two more 
decimal places than the measured value. Minimum and maximum values are presented 
with the same number of decimal places as the measured value. 
• For categorical variables, the count and percentage of responses are presented in the form 
XX (XX.X%). 
• Date variables are formatted as DDMMMYYYY for presentation. Time is formatted 
from 0:00 to 23:59 as HH:MM for presentation. 
• P-values, if applicable, will be presented to 4 decimal places. If the p-value is less than 
0.0001 then it will be presented as <0.0001. If the rounded result is a value of 1.000, it 
will be displayed as >0.9999. 
• Unless otherwise stated, any statistical tests performed following the second interim 
analysis (which will be performed at a significance level of 0.0001) will use 2-sided tests 
at the 0.0499 significance level. 
The table and listing shells and table of contents as part of this SAP provide the expected layout 
and titles of the tables, listings and figures. Any changes to format, layout, titles, numbering, or 
any other minor deviation will not necessitate a revision to the SAP nor will it be considered a 
deviation from planned analyses. Only differences in the analysis methods or data handling will 
require such documentation. The appropriate listings supporting the tables will be included and 
are not specified in the individual sections throughout the document. 
6.5. 
Analysis Populations  
6.5.1. 
Screen Failures 
Screen Failures include patients who sign the informed consent form but are not eligible for 
study enrollment; therefore, they were not dispensed study drug. Screen failures will not be 
included in the efficacy and/or safety analyses. However, reasons for screen failures will be 
summarized. For patients who failed at the first screening and were rescreened, the eligibility at 
the rescreening visit will be used to determine if the patients are screen failures. 
6.5.2. 
All Randomized Set 
All Randomized Set includes patients who are randomized to receive reldesemtiv or placebo. 


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6.5.3. 
Safety Analysis Set 
Safety analysis set will include all randomized patients who receive any amount of study drug. 
Patients will be analyzed according to the actual treatment received during the double-blind 
placebo-controlled period. 
6.5.4. 
Full Analysis Set 
Full Analysis Set (FAS) consists of randomized patients who receive any amount of study drug 
and have a baseline and at least 1 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 are assigned at randomization. 
6.5.5. 
Pharmacokinetic Analysis Set 
Pharmacokinetic Analysis Set includes all patients who have at least one measurable plasma 
concentration of reldesemtiv, provided that they have no major protocol violations or deviations 
that could affect the PK of reldesemtiv. 
6.6. 
Baseline Definition 
Unless otherwise specified, baseline is defined as the last available measurement taken prior to 
administration of the first dose of study drug. 
6.7. 
Derived and Transformed Data 
6.7.1. 
Baseline Age  
Age at screening will be collected on the eCRF and used as the baseline age and for all data 
derivations involving age regardless of age changes during the study. 
6.7.2. 
Study Day 
If the date of interest occurs on or after the first dose date, then study day will be calculated as 
(date of interest – date of first dose) + 1. If the date of interest occurs prior to the first dose date, 
then study day will be calculated as (date of interest – date of first dose). There is no study day 0. 
6.7.3. 
Change from Baseline 
Change from baseline is calculated as (post baseline result – baseline result). 
Percent change from baseline is calculated as (change from baseline / baseline result) x 100%. 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline will be set to missing. 
6.7.4. 
Analysis Windows 
Since study visits do not always take place exactly as scheduled per protocol, it is necessary to 
assign the actual observation dates to analysis windows for analysis purposes. 


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For measurement taken prior to the first dose of study drug, the analysis window is defined as the 
interval of time prior to the first dose of study drug. Measurements taken on or after the first dose 
of study drug will be assigned to the next scheduled analysis window. 
For data collected at a scheduled post baseline visit, the analysis window will be assigned based 
on the scheduled study day of the nominal visit as collected on the eCRF. 
For unscheduled post baseline visits, early discontinuation visit or follow-up visit, measurements 
taken on or after the first dose of study drug will be assigned to an analysis window using 
defined lower and upper bounds for each analysis window. Measurements assigned in an 
analysis window will have study day greater than or equal to the lower bound but no greater than 
the upper bound of the analysis window. The lower bound and the upper bound for the analysis 
windows are defined as the midpoints of the scheduled visits for all assessments (see 
Section 12.3). 
Visits are identified as the nominal visits according to the eCRFs. Each visit will be identified 
with the visit descriptor (eg, “Week 24”). If a patient has two or more study visits in one analysis 
window, one record will be flagged as the “analyzed record” for that analysis window. 
6.7.5. 
Multiple Assessments 
Once analysis windows are assigned, a patient’s individual analysis window could potentially 
contain more than one visit. Records from all visits, including scheduled, unscheduled and early 
discontinuation visits could be flagged as the “analyzed record” within the analysis window, 
although the records from scheduled visit will take priority. 
For measurement taken prior to the first dose of study drug, in the event of multiple visits falling 
within an analysis window, the following rule will be used to determine the “analyzed record”: 
• The record closest to, but prior to the first dose of study drug should be selected as the 
baseline “analyzed record.” This could include scheduled visits and other screening 
visits. 
For post baseline visits, measurements taken during the 24-week double-blind, placebo-
controlled period will be included only in the analysis windows up to Week 24. Measurements 
taken after patients transition to the active drug period will be included only in the analysis 
windows after Week 24. Once patients transition to the active drug period, all measurements 
collected on or after the transition date will not be included in the analysis windows for the first 
24 weeks double-blind placebo-controlled period. Furthermore, in the event of multiple visits 
falling within an analysis window, the following rules will be used in sequence to determine the 
“analyzed record” for the analysis window: 
• If a scheduled visit occurred during the analysis window, then the measurement taken 
from the scheduled visit will be used. 
• If no scheduled visit occurred during the analysis window, the measurement taken closest 
to the scheduled day will be used as the “analyzed record.” 
• If no scheduled visit occurred during the analysis window and there is a tie between 
unscheduled visits in the number of days before and after the scheduled day, 
measurements from the later visit will be used as the “analyzed record.” 


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For all analyses, only the “analyzed record” within each analysis window will be summarized in 
a table. If there are other visit records within the analysis window, they will only be included in 
data listings. In addition, composite scores (eg, ALSFRS-R total score or muscle strength mega 
score) will be calculated based on the “analyzed record.” 
6.8. 
Handling of Missing Data 
6.8.1. 
Missing Efficacy Endpoints 
For the primary endpoint, sensitivity analyses with missing data being imputed will be conducted 
to support the robustness of the analysis result. The base imputation scenario will be based on an 
ANCOVA model with the MAR-based multiple imputation (Rubin 1987) for all missing 
ALSFRS-R total scores, and imputation will be performed for each randomized treatment group 
separately. Imputation based on the distribution of ALSFRS-R total score in the placebo group 
will also be performed for both reldesemtiv and placebo groups. 
Tipping point analyses will be conducted by setting the imputed values for the deaths 
successively worse only for the reldesemtiv group while maintaining the MAR-based imputed 
values for the placebo group. Imputation by setting the imputed values successively worse for 
data missing due to any reasons in the reldesemtiv group will also be performed. 
For the first secondary endpoint, sensitivity analyses will be conducted with imputing ALSFRS-
R total scores based on the distribution of that in the placebo group. Tipping point analyses will 
be performed by setting the imputed values successively worse only for the reldesemtiv group 
while maintaining the MAR-based imputed values for the placebo group. 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Imputation of missing/partial dates will not be performed. The available year or year and month 
in a partial date will be used and will be compared to first dosing year, month and day to 
determine whether to include the medication in the medication history or as a concomitant 
medication. If the available data do not give sufficient information to classify the medication, the 
medication will be classified as concomitant medication. 
6.8.3. 
Missing Start and Stop Dates for Adverse Events 
For AEs with incomplete date information recorded in the eCRF, the imputation will follow the 
following algorithm: 
For missing AE onset Day and Time: 
• If an AE onset Day is missing and the Month of AE onset is known, then the first day of 
the month of AE onset will be imputed as the AE onset date. 
• If AE onset information is not available, then the first dosing date will be imputed as the 
AE onset date. 
For missing AE end Day and Time: 
• If the AE end Day is missing and the AE end Month is earlier or later than that of the 
Follow-Up Visit, then the last day of the AE end month will be the imputed as the AE 
end date. 


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• If the AE end Day is missing and the AE end Month is the same as that of the Follow-Up 
Visit, then the date of the Follow-Up Visit will be the imputed as the AE end date. 
• If no AE end information is available, then 
- For patients who discontinued early from study drug, the imputed AE end date 
will be on the later of the last dosing date + 28 days or the last visit or contact 
date. 
- For patients who completed the study, the imputed AE end date and time will be 
the date of the Follow-Up Visit. 
- If the stop date is missing and the event is ongoing, the event will be noted as 
ongoing” in the stop date column in data listings. 


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7. 
STUDY POPULATION 
7.1. 
Subjects Disposition 
Count of patients in each analysis set will be presented. The count and percentage of patients 
who were randomized, who received at least one dose of study drug, who completed the study 
treatment at each study period, and who prematurely discontinued from the study drug and/or 
from the study at each study period will be presented by randomized treatment. Reasons for 
premature discontinuation will also be summarized. 
All enrolled patients will be included in the listing of subjects disposition. In addition to patient 
ID, demographics (age, sex and race) and randomized treatment group, the listing will include 
screening date, first dose date, last dose date, last contact date, and reasons for discontinuation 
from the study treatment and/or from the study. 
7.2. 
Screen Failures 
Screen failures will be listed and summarized by reasons of screening failure. 
7.3. 
Protocol Deviations 
Protocol deviation is any divergence from the protocol that impacts a patient's safety, rights, or 
welfare or materially reduces the quality or completeness of the data. Patients meeting the 
protocol deviation criteria will be summarized by randomized treatment group and listed. The 
listing of protocol deviations will also include severity of deviation (major or minor) and indicate 
if a protocol deviation is COVID-19 related based on the reported data. 
7.4. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including age, sex, race, ethnicity, height, weight, 
BMI, tobacco and alcohol use, etc., will be summarized by randomized treatment group for the 
FAS. All enrolled patients will be included in the listing of demographic and baseline 
characteristics. 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of randomized patients who violate the inclusion and exclusion criteria will be 
provided. 
7.6. 
Medical History and Medical Conditions Present at Entry 
Medical history will be summarized by treatment received for the Safety Analysis Set. The count 
and percentage of patients with each medical history item will be presented by system organ 
class (SOC) and preferred term (PT). Listing of medical history and medical conditions present 
at entry will include each medical history item, start date, stop date, system organ class and 
preferred term. 
Medical history of ALS will be summarized by treatment received for the Safety Analysis Set. 
The count and percentage of patients with or without family history of ALS or a known mutation 
in an ALS related gene, onset site of ALS, and the descriptive statistics of time since first 


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symptom onset and time since first diagnosis will be provided. Patient listing containing 
symptom onset date, and diagnosis date will be provided along with diagnostic time (time 
between onset of symptoms and diagnosis of ALS). 
7.7. 
Prior Medication History and Medications Present at Entry 
7.7.1. 
Non-Diagnosis Related Prior Medication History 
Non-diagnosis related prior medication history will be summarized by treatment received for the 
Safety Analysis Set. Prior medication history and medication present at entry will be coded using 
World Health Organization (WHO) Drug Dictionary Enhanced with Herbal, B3, SEP 2020. The 
count and percentage of patients with each medication history item will be presented by 
therapeutic class (ATC Class 3) and preferred name. If ATC Class 3 is not available, ATC Class 
2 will be used in the summary. 
Listing of medication history will include each medication, start date, stop date, therapeutic class 
and preferred name. 
7.7.2. 
Prior Diagnosis Related Medication History 
Prior diagnosis related medication history will be summarized by treatment received for the 
Safety Analysis Set. The count and percentage of patients who received riluzole and/or 
edaravone and who received the branded combination product of sodium phenylbutyrate and 
taurursodiol (also known as TUDCA, ursodoxicoltaurine or Tauroursodeoxycholic acid) will be 
presented. 
7.8. 
Baseline Physical Examination 
Baseline physical examination results will be summarized for the Safety Analysis Set. Counts 
and percent of patients judged to be normal, abnormal, or not performed will be presented. 
7.9. 
Baseline Vital Signs 
Baseline measurements of vital signs, such as heart rate, blood pressure, respiratory rate, weight, 
BMI and body temperature, will be summarized for the Safety Analysis Set. 
7.10. 
Baseline Laboratory Data 
Baseline laboratory data, including hematology, serum chemistry and urinalysis, will be 
summarized for the Safety Analysis Set. The laboratory parameters to be included in the 
summary are listed in the protocol Appendix 2. 
7.11. 
Baseline Primary and Secondary Efficacy Evaluations 
Baseline measurements of the primary and secondary efficacy analyses will be summarized by 
randomized treatment group for the FAS with appropriate descriptive statistics. 


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8. 
EFFICACY  
8.1. 
General Considerations 
Unless otherwise specified, inferential statistical tests will be two-sided and will be performed at 
alpha levels of 0.05 to declare the significance of effects. 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline 
Assumptions for statistical models will be evaluated graphically. If assumptions are substantially 
violated, additional analysis methods will be performed. 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 and edaravone use at baseline. 
8.3. 
Statement of the Null and Alternate Hypotheses 
The null hypothesis (H0) and alternative hypothesis (HA) for the primary and the first secondary 
endpoints are listed below: 
For the primary endpoint:  
H0: 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. 
HA: There is a 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. 
For the first secondary endpoint: 
H0: The Mann-Whitney probability of a more favorable status in either reldesemtiv or placebo 
group in the FAS is 0.5. The status is quantified by joint ranks based on the combined 
assessment of change in ALSFRS-R total score, time to dependence on assisted 
ventilation (either invasive or non-invasive), and survival time up to Week 24. 
HA: The Mann-Whitney probability of a more favorable status in reldesemtiv group in the FAS 
is greater than 0.5. The status is quantified by joint ranks based on the combined 
assessment of change in ALSFRS-R total score, time to dependence on assisted 
ventilation (either invasive or non-invasive), and survival time up to Week 24. 
8.4. 
Subgroup Analyses 
8.4.1. 
Subgroups for Explanation of Potential Heterogeneous Treatment Effect 
Subgroup analyses with relatively moderate sample size will be performed to examine the 
consistency of the observed treatment effect and to gain insight into the effectiveness of 
reldesemtiv in subpopulations. Analyses of the primary endpoint and the first secondary endpoint 
will be conducted for the following subgroups: 


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• Sex (male, female) 
• Age group (< median, ≥ median) 
• Race (white, non-white) 
• BMI at baseline (< 25 kg/m2, ≥ 25 kg/m2) 
• Riluzole and edaravone use status at baseline (use riluzole, use edaravone, use neither). 
• Percent predicted FVC at baseline (< median, ≥ median) 
• ALSFRS-R total score at baseline (< median, ≥ median) 
• Geographic region (North America, Europe, Australia) 
• Anatomic site of disease onset (upper limb, lower limb, limb, bulbar, cognitive, 
respiratory) 
• Time since ALS symptom onset (< 1.5 years, ≥ 1.5 years) 
• Pre-study rate of disease progression (1st tertile, 2nd tertile, and 3rd tertile) 
• MiToS at baseline (Stage 0, Stage 1, Stage 2, Stage 3 and Stage 4) 
 
For the primary endpoint (ALSFRS-R total score change from baseline to Week 24):  
• The MMRM with the subgrouping factors being added to the primary analysis model (see 
Section 8.6.1) will be used to produce treatment comparisons at each visit for each 
subgroup. The subgrouping factors include: the “subgroup” listed above as well as 
“subgroup-by-treatment”, “subgroup-by-visit”, and “subgroup-by-treatment-by-visit” 
interactions. If the MMRM fails to converge, an ANCOVA model with change from 
baseline to Week 24 as response variable and model terms listed as follows will be used 
to perform the analysis: treatment, baseline riluzole use, baseline edaravone use, baseline 
ALSFRS-R total score, covariates identified before the database lock (see Section 8.6.1), 
subgroup and subgroup-by-treatment interaction. 
For the first secondary endpoint (combined assessment of change in ALSFRS-R total score, time 
to dependence on assisted ventilation (either invasive or non-invasive), and survival time up to 
Week 24): 
• The joint rank test subsequent to the MAR imputation of missing ALSFRS-R total scores 
at Week 24 (see Section 8.7.1) will be applied for all subgroups. 
8.4.2. 
Subgroups Supportive Analyses for the Primary Analyses of Primary Endpoint 
and First Secondary Endpoint  
To explain potential heterogeneity and identify treatment effect modifiers from the baseline 
characteristics, covariates used to define pre-specified subgroups and these covariates by 
treatment interaction terms will be included in the primary analysis MMRM model as supportive 
analysis. Covariates measured as continuous will be introduced to the model as continuous 
variable. Global test of covariates by treatment interactions will be performed. Stepwise model 
selection method will be used based on the default stay or entry level of 0.1 to evaluate 


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significant baseline covariates. The p-value of global test of covariates by treatment group 
interaction terms as well as the p-values in an ascending order and treatment difference 
evaluating individual covariates by treatment interactions will be provided from the final 
multivariate interaction model. 
If the primary analysis for the primary endpoint or the first secondary endpoint is significant and 
the global test of covariates by treatment interactions are having 2-sided p-value less than 0.05, 
the selected baseline covariate(s) will be considered as treatment effect modifier(s). The 
corresponding pre-specified subgroup analyses will be considered to explain the potential 
heterogenous treatment effect. 
8.5. 
Multiple Comparisons and Multiplicity 
The null hypothesis for the primary and secondary efficacy endpoints will be tested in a 
prespecified order using a closed testing procedure. This procedure will maintain the family-wise 
error rate at two-sided significance level of 0.0499 for all primary and secondary hypotheses 
tested in a confirmatory sense. The testing steps are described as follows: 
Step 1: The null hypothesis for the primary endpoint H01 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 in the FAS. The hypothesis 
will be tested at the two-sided significance level of 0.0499. If this hypothesis is rejected, 
testing will proceed to Step 2; otherwise testing will stop. 
Step 2: The null hypotheses for the first secondary endpoint H02 is that the Mann-Whitney 
probability of a more favorable status in reldesemtiv or placebo group in the FAS is 0.5. 
The status is quantified by joint ranks based on the combined assessment of change in 
ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to 
Week 24. The hypotheses will be tested at the two-sided significance level of 0.05. If this 
hypothesis is rejected, testing will proceed to Step 3; otherwise testing will stop. 
Step 3: The null hypotheses H03 is that there is no treatment difference in change from baseline 
to Week 24 in the percent predicted FVC between patients randomized to placebo and 
those randomized to reldesemtiv in the FAS. The hypotheses will be tested at the two-
sided significance level of 0.05. If this hypothesis is rejected, testing will proceed to Step 
4; otherwise testing will stop. 
Step 4: The null hypotheses H04 is that there is no treatment difference in change from baseline 
to Week 24 in the ALSAQ-40 total score between patients randomized to placebo and 
those randomized to reldesemtiv in the FAS. The hypotheses will be tested at the two-
sided significance level of 0.05. If this hypothesis is rejected, testing will proceed to Step 
5; otherwise testing will stop. 
Step 5: The null hypotheses H05 is that there is no treatment difference in change from baseline 
to Week 24 in handgrip strength (average of both hands) between patients randomized to 
placebo and those randomized to reldesemtiv in the FAS. The hypotheses will be tested 
at the two-sided significance level of 0.05. No further hypothesis testing will be carried 
out in this closed testing procedure. 


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8.6. 
Analysis of the Primary Efficacy Endpoint 
8.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint of the trial is the change from baseline to Week 24 in ALSFRS-R 
total score. The estimand of the primary efficacy endpoint 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 in the FAS. 
The analysis for the primary efficacy endpoint will be conducted using a mixed model for 
repeated measures (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 at baseline, edaravone use at baseline as well as baseline-by-visit and treatment 
group-by-visit interactions. In addition, other baseline covariates identified by stepwise selection 
in a regression model will also be included in the model if they are key predictor variables for the 
change from baseline to Week 24 in ALSFRS-R total score. The regression model used to 
identify baseline covariates will include change from baseline to Week 24 in ALSFRS-R total 
score as response variable and pre-study disease progression rate, age and baseline percent 
predicted FVC as model terms. The stepwise selection process with significance at 0.25 level for 
a variable to be entered to the model and with significance at 0.1 level for a variable to remain in 
the model will be used. The best-fit model according to AIC will be selected. The evaluation will 
be performed based on the blinded data before the database lock. An unstructured variance-
covariance matrix will be used for the model. Observed data collected up to Week 24 in the FAS 
will be included in the model. 
Prior to applying the MMRM, multiple imputation with fifty invocations under the MAR paradigm 
will be performed to impute missing data (see Section 8.6.1.1 for imputation method). 
Least squares mean (LSM), LSM difference and the corresponding standard error, 95% CI and 
p-value will be presented. The components used to derive main estimator of the primary analysis 
are shown in Table 4. 
Sensitivity analyses will be conducted to support the robustness of conclusions based on the 
primary analysis results. See Section 8.6.2 for sensitivity analyses. 
 
 
 
 
 
 
 


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Table 4: 
Components of the Main Estimator and Analytical Approach for the 
Primary Efficacy Endpoint 
Estimator 
Attribute 
Analytical Approach 
Population 
Variable 
Intercurrent event 
Population-
level 
summary 
Main 
Estimator  
FAS 
Change 
from 
baseline 
to Week 
24 in 
ALSFRS-
R total 
score 
 ALSFRS-R total 
score collected up to 
Week 24 will be 
included in the 
MMRM. Missing 
data will be imputed 
using the method 
described in 
Section 8.6.1.1.  
Difference 
in variable 
means 
between 
reldesemtiv 
and placebo 
groups 
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 at baseline, 
edaravone use at 
baseline as well as 
baseline-by-visit and 
treatment group-by-visit 
interactions and other 
baseline covariates 
identified by stepwise 
selection. 
 
 
 


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8.6.1.1. 
Imputation of the Missing Data for the Primary Efficacy Analysis 
The extent of missing data and the pattern of missing data reasons will be tabulated. Missing 
ALSFRS-R total score will be imputed for the primary efficacy analysis described in 
Section 8.6.1. For each randomized treatment group, the missing data will be filled sequentially 
starting at the earliest time point and progressing until the last time point based on a multivariate 
joint normal imputation model (Schafer 1997). The imputation model will include the following 
terms: ALSFRS-R total score at previous visits including baseline (in reldesemtiv or placebo 
group), riluzole use and/or edaravone use at baseline, and other covariates selected using 
stepwise regression for the primary analysis (see Section 8.6.1) such as pre-study disease 
progression rate, age and/or baseline percent predicted FVC. Fifty set of complete data will be 
generated for analysis to produce 50 sets of estimates. Rubin’s imputation rules (Rubin 1987) 
will be used to combine the LSM estimates of the treatment difference, 95% confidence interval 
and p-value. The example SAS code can be found in Section 12.5. 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Endpoint 
Sensitivity analyses for the primary efficacy endpoint will be conducted based on the FAS and 
with the common outcome variable and population-level summary. The outcome variable is 
change from baseline to Week 24 in ALSFRS-R total score, and the population-level summary is 
the difference of the variable means between reldesemtiv and placebo groups. The sensitivity 
estimators and the corresponding approach for handling intercurrent events, imputation method 
and analytical method are shown in Table 5. 
In addition, analysis of the primary endpoint will be conducted for the subgroups listed below to 
evaluate consistency of the observed treatment effect. Same analysis method as described in 
Section 8.6.1 will be applied to support the analysis result of the primary endpoint. 
• Patients with down titration to 150 mg BID at Week 24 (yes, no) 
• Patients with COVID-19 related intercurrent events requiring hospitalization (yes, no) 
• Patients with COVID-19 related fatal event (yes, no) 
 


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Table 5: 
Sensitivity Estimators of the Primary Efficacy Endpoint 
Estimator 
Approach for Intercurrent 
Events 
Imputation Method 
Analytical Method 
Sensitivity 
Estimator 1 
Observed ALSFRS-R total score 
collected up to Week 24 will be 
included in the analysis and missing 
data will not be imputed. 
Not applicable. 
MMRM described in Section 8.6.1. 
Sensitivity 
Estimator 2 
All missing ALSFRS-R total score, 
regardless of which intercurrent 
event causes data missing, will be 
imputed under a MAR paradigm. 
 
Imputation will be performed for each 
randomized treatment group and will 
include the following factors in the 
model: ALSFRS-R total score at previous 
visits including baseline, riluzole use at 
baseline, and edaravone use at baseline. 
ANCOVA model with ALSFRS-R 
total score change from baseline to 
Week 24 as the response variable. 
The model terms will include 
treatment group, baseline ALSFRS-
R total score, riluzole use status at 
baseline and edaravone use status at 
baseline. 
Sensitivity 
Estimator 3 
For both reldesemtiv and placebo 
groups, missing ALSFRS-R total 
score will be imputed based on the 
distribution of the placebo group.  
For each treatment group, missing 
ALSFRS-R total scores will be imputed 
using the parameters from the imputation 
model of the placebo distribution. The 
following terms will be included in the 
imputation model: ALSFRS-R total score 
at previous visits including baseline, 
riluzole use at baseline, and edaravone use 
at baseline. 
ANCOVA model with ALSFRS-R 
total score change from baseline to 
Week 24 as the response variable. 
The model terms will include 
treatment group, baseline ALSFRS-
R total score, riluzole use status at 
baseline and edaravone use status at 
baseline. 
Sensitivity 
Estimator 4 
For reldesemtiv group, tipping point 
analyses will be conducted by 
setting the imputed values for the 
deaths successively worse (starting 
from 5% worse and with an 
increment of 5% worse for each of 
the next step) until a reverse result 
is obtained. (Ratitch 2013). For 
reasons of missing other than 
deaths, missing data will be 
For reldesemtiv group, an increment of 1 
for the range of shift parameters that 
reverses the study result will be applied in 
the multiple imputation. 
For placebo group, the imputation will be 
performed with the following factors 
included in the imputation model: 
ALSFRS-R total score from previous 
ANCOVA model with ALSFRS-R 
total score change from baseline to 
Week 24 as the response variable. 
The model terms will include 
treatment group, baseline ALSFRS-
R total score, riluzole use status at 
baseline and edaravone use status at 
baseline. 


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Estimator 
Approach for Intercurrent 
Events 
Imputation Method 
Analytical Method 
imputed with MAR-based imputed 
values. 
For placebo group, missing 
ALSFRS-R total score will be 
imputed with MAR-based imputed 
values. 
visits including baseline, riluzole use at 
baseline, and edaravone use at baseline. 
Sensitivity 
Estimator 5 
For reldesemtiv group, tipping point 
analyses will be conducted by 
setting the imputed values for all 
missing data, regardless of reasons 
of missing, successively worse 
(starting from 5% worse and with 
an increment of 5% worser for each 
of the next step) until a reverse 
result is obtained (Ratitch 2013). 
For placebo group, missing 
ALSFRS-R total score will be 
imputed with MAR-based imputed 
values. 
For reldesemtiv group, an increment of 1 
for the range of shift parameters that 
reverses the study result will be applied in 
the multiple imputation. 
For placebo group, the imputation will be 
performed with the following factors 
included in the imputation model: 
ALSFRS-R total score from previous 
visits including baseline, riluzole use at 
baseline, and edaravone use at baseline. 
ANCOVA model with ALSFRS-R 
total score change from baseline to 
Week 24 as the response variable. 
The model terms will include 
treatment group, baseline ALSFRS-
R total score, riluzole use status at 
baseline and edaravone use status at 
baseline. 
Sensitivity 
Estimator 6 
(COVID-19 related) 
Data collected after the occurrences 
of COVID-19 related intercurrent 
events will be excluded. 
After excluding the data that were 
collected after the occurrences of COVID-
19 related intercurrent events, imputation 
will be performed for each randomized 
treatment group and including the 
following factors in the imputation model: 
ALSFRS-R total score from previous 
visits including baseline, riluzole use at 
baseline, and edaravone use at baseline. 
ANCOVA model with ALSFRS-R 
total score change from baseline to 
Week 24 as the response variable. 
The model terms will include 
treatment group, baseline ALSFRS-
R total score, riluzole use status at 
baseline and edaravone use status at 
baseline. 
 


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8.7. 
Analysis of the Secondary Efficacy Endpoints 
The secondary endpoint(s) of the trial are: 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation (either invasive or non-invasive), 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) 
The analyses of the secondary endpoints are described in Sections 8.7.1, 8.7.2 and 8.7.3. 
8.7.1. 
Analysis of the First Secondary Efficacy Endpoint 
The estimand of the first secondary endpoint (combined assessments of change in ALSFRS-R 
total score, time to dependence on assisted ventilation (either invasive or non-invasive), and 
survival time up to Week 24) is the stratified Mann-Whitney probability of a more favorable 
status in the reldesemtiv group compared to the placebo group in the FAS, based on the joint 
ranks of the combined assessments collected up to Week 24, and accounting for the intercurrent 
events of death, dependence on assisted ventilation (either invasive or non-invasive) and decline 
in ALSFRS-R total score. Dependence on assisted ventilation is defined as patients using 
invasive or non-invasive ventilation for ≥ 22 hours per day for ≥ 10 consecutive days. 
The joint rank comparison method developed by Berry et al. (Berry 2013) will be applied for the 
first secondary endpoint. Each patient will first be compared with all others in the analysis 
population in a pairwise manner on their combined assessments. A score of +1, 0 or -1 will be 
assigned if one has better, tie or worse outcome than the other, respectively. The worst rank is 
assigned to patients who die during the trial, followed by ranking on severity of the health status 
for patients who survive according to their dependence on assisted ventilation and ALSFRS-R 
total score. The ranking hierarchy is listed as follows:  
• Patients who died rank worse than patients who survived. 
- Patients who died earlier rank worse than patients who died later. 
• Being dependent upon assisted ventilation is likely to permit patients to survive longer 
and who would have otherwise died without the intervention. Thus, patients who met the 
definition of dependence on assisted ventilation (either invasive or non-invasive) rank 
better than those who died, but worse than those who did not meet the definition of 
dependence on assisted ventilation (either invasive or non-invasive), regardless of 
whether the decline in ALSFRS-R total score is smaller or not. 
- Among patients who survived but dependence on assisted ventilation (either 
invasive or non-invasive), patients with the dependence earlier rank worse. 
• Among patients who survived and without dependence on assisted ventilation (either 
invasive or non-invasive), patients with greater decline in ALSFRS-R total score from 
baseline rank worse. 


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- For patients who discontinued early, comparison is based on the last time-point 
measurements that are both available for the patients in pairs. 
• If it is not possible to assign either patient as having the better outcome, then the score 
assigned to the pair is 0. 
For each patient, the assigned scores (+1, -1 or 0) from the pairwise comparisons with all others 
will be summed, then all patients in the FAS will be ranked according to their summed scores to 
create a rank score from 1 for the lowest possible summed score to N (total number of patients in 
the analysis population) for the highest possible summed score. If ties occur, each of the tied 
summed scores will be assigned the average of the ranks the tied summed scores would have if 
there were no ties. 
A stratified Wilcoxon test will be applied to compare the standardized joint ranks between 
reldesemtiv and placebo groups (as ranks divided by pooled group sample size plus one) 
adjusting for baseline riluzole use and baseline edaravone use. The win probability, win ratio, 
van Elteren (or stratified Wilcoxon) test statistic, and p-value will be presented. 
In the event that mortality rate up to week 24 is higher than expected, the first secondary 
endpoint may be considered as the primary efficacy endpoint before database lock for the Week 
24 primary analysis. 
8.7.1.1. 
Imputation of the Missing Data for the First Secondary Efficacy Analysis 
Missing ALSFRS-R total score will be imputed for the first secondary analysis. See 
Section 8.6.1.1 for the imputation method. 
Every effort will be made to collect or derive vital status at Week 24 and Week 48. In the event 
that missing rate of vital status is higher than expected, the missing vital status will be imputed 
and sensitivity analyses will be performed. 
8.7.2. 
Sensitivity Analysis of the First Secondary Efficacy Endpoint 
Sensitivity analyses for the first secondary efficacy endpoint will be conducted based on the FAS 
and with the common outcome variable and population-level summary. The outcome variable is 
the joint-rank based on the combined assessments collected up to Week 24, and the population-
level summary is the stratified Mann-Whitney probability of a more favorable status in the 
reldesemtiv group compared to the placebo group, based on the joint ranks of the combined 
assessments collected up to Week 24. The sensitivity estimators and the corresponding approach 
for handling intercurrent events, imputation method and analytical method are shown in Table 6. 
Likewise, sensitivity analyses will be repeated for the joint rank test with the considerations for 
patients with COVID-19 related deaths vs. not COVID-19 related deaths. 


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Table 6: 
Sensitivity Estimator of the First Secondary Efficacy Endpoint 
Estimator 
Approach for Intercurrent Events 
Imputation Method 
Analytical Method 
Sensitivity 
Estimator 7 
Observed ALSFRS-R total score collected up to 
Week 24 will be included in the analysis and 
missing data will not be imputed. 
Not applicable. 
Ranking and analysis 
methods described in 
Section 8.7.1. 
Sensitivity 
Estimator 8 
For both reldesemtiv and placebo groups, 
missing ALSFRS-R total score due to reasons 
other than death will be imputed based on the 
distribution of the placebo group.  
For each treatment group, missing ALSFRS-
R total scores will be imputed using the 
parameters from the imputation model of the 
placebo distribution. The following terms 
will be included in the imputation model: 
ALSFRS-R total score from previous visits 
including baseline, riluzole use at baseline, 
and edaravone use at baseline. 
Ranking and analysis 
methods described in 
Section 8.7.1. 
Sensitivity 
Estimator 9 
For reldesemtiv group, missing ALSFRS-R total 
score due to reasons other than death will be 
imputed successively worse (starting from 5% 
worse and with an increment of 5% worser for 
each of the next step) using tipping point 
approach (Ratitch 2013) until a reverse result is 
obtained. 
For placebo group, missing ALSFRS-R total 
score due to reasons other than death will be 
imputed with MAR-based imputed values. 
Missing ALSFRS-R total score due to death will 
be assigned a worst rank, and patients who died 
earlier rank worse than patients who died later.  
For reldesemtiv group, an increment of 1 for 
the range of shift parameters that reverses 
the study result will be applied in the 
multiple imputation. 
For placebo group, the imputation will be 
performed with the following factors 
included in the imputation model: ALSFRS-
R total score from previous visits including 
baseline, riluzole use at baseline, and 
edaravone use at baseline. 
Ranking and analysis 
methods described in 
Section 8.7.1. 


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Table 6: 
Sensitivity Estimator of the First Secondary Efficacy Endpoint (Continued) 
Estimator 
Approach for Intercurrent Events 
Imputation Method 
Analytical Method 
Sensitivity 
Estimator 10 
(COVID-19 
related) 
Missing ALSFRS-R total score due to COVID-
19 related deaths or reasons other than death will 
be imputed under a MAR paradigm. 
Missing ALSFRS-R total score due to not 
COVID-19 related death will be assigned a worst 
rank, and patients who died earlier rank worse 
than patients who died later. 
Ranking from worst to best in the following 
order will be applied: 
• Not COVID-19 related death (worst) 
• COVID-19 related death 
• With dependence on assisted ventilation 
(either invasive or non-invasive) 
• More decline in ALSFRS-R total score 
• Less decline in ALSFRS-R total score (best)  
The imputation will be performed for each 
randomized treatment group and including 
the following factors in the model: 
ALSFRS-R total score from previous visits 
including baseline, riluzole use at baseline, 
and edaravone use at baseline. 
Ranking and analysis 
methods described in 
Section 8.7.1. 
 


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8.7.3. 
Analysis of the Remaining Secondary Efficacy Endpoints 
For the secondary endpoint of change from baseline to Week 24 in the percent predicted FVC, 
analysis will be based on in clinic measurements collected from the Easy One (in clinic) 
spirometers. Additional analyses of percent predicted FVC that include remote measurements 
collected from the NuvoAir spirometers will be explored (see Section 8.8). 
Analyses for the remaining secondary endpoints will be performed using a MMRM with the 
following model terms: treatment group, baseline ALSFRS-R total score, visit, riluzole use at 
baseline, edaravone use at baseline as well as baseline-by-visit and treatment group-by-visit 
interactions. An unstructured variance-covariance matrix will be specified in the models. 
8.8. 
Analysis of the Exploratory and Additional Efficacy Endpoints 
The exploratory endpoints of the trial are: 
• Time to the patient being prescribed and patient agrees to  any of the following DME 
items (manual wheelchair, power wheelchair, augmentative and alternative and 
augmentative communication device, NIV and/or gastrostomy tube),time to first receipt, 
time to first use, time to daily use, time to dependence and number used of any of the 
specified DME items from baseline to the Week 24 and Week 48 as well as reasons to 
receive the above DME 
• Changes from baseline to Week 24 and Week 48 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 and Week 48 
• Change from baseline to Week 48 in ALSFRS-R total score 
• Change from baseline to Week 48 in FVC (liters) 
• Change from baseline to Week 48 in grip strength 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation (either invasive or non-invasive), and survival time up to Week 48 
• Changes from baseline to Week 24 and Week 48 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 
• Changes from baseline to Week 24 and Week 48 in the EQ-5D-5L 
• Changes 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 
Additional endpoints listed below will be analyzed: 
• Time to event for all-cause death from baseline to Week 24 and Week 48 
• Time to event for first hospitalization or all-cause death from baseline to Week 24 and 
Week 48   


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• Time to event for first ALS related hospitalization or all-cause death from baseline to 
Week 24 and Week 48 
• Time to event for first ALS related hospitalization from baseline to Week 24 and Week 
48 
• Time to event for first ALS related hospitalization (without hospitalization for a PEG / 
RIG tube) from baseline to Week 24 and Week 48 
• Time to event for first invasive mechanical ventilation by intubation or tracheostomy 
• Time to event for first non- invasive mechanical ventilation 
• Combined assessment of change in ALSFRS-R total score and survival time up to Week 
24 and Week 48 (joint ranks analysis) 
• Combined assessment of change in the percent predicted FVC, time to dependence on 
assisted ventilation (either invasive or non-invasive), and survival time up to Week 24 
• Combined assessment of change in the ALSAQ-40 total score, time to dependence on 
assisted ventilation (either invasive or non-invasive), and survival time up to Week 24 
• Change from baseline to Week 24 in FVC (liters) 
• Change from baseline to Week 48 in percent predicted FVC 
• Slope of change from baseline to Week 24 in percent predicted FVC 
• Changes from baseline to Week 24 and Week 48 in forced expiratory volume in the first 
second 
• Change from baseline to Week 24 and Week 48 in percent predicted FVC measured 
remotely  
• Change from baseline to Week 48 in the ALSAQ-40 total score 
• Changes from baseline to Week 24 and Week 48 in the subscores of ALSAQ-40 
• Time to event for the first intrinsic hand muscle reaches zero from baseline to Week 24 
and Week 48   
• Time to event for all intrinsic hand muscles reach 0 from baseline to Week 24 and Week 
48   
• Progression in the degree use of both new and pre-existing DMEs from baseline up to 
Week 48 
The following analyses will also be conducted if a systematic difference between in clinic 
measurements (from the Easy One spirometers) and remote measurements (from the NuvoAir 
spirometers) is not observed: 
• Change from baseline to Week 24 and Week 48 in percent predicted FVC, with remote 
measurements collected in the same analysis windows as those used to substitute for the 
missing in clinic measurements. 
• Change from baseline to Week 24 and Week 48 in percent predicted FVC measured in 
clinic and remotely. In clinic measurements take precedence if both in clinic and remote 
measurements are collected in the same analysis window. 


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8.8.1. 
Analysis of the Exploratory and Additional Efficacy Endpoint 
Exploratory analyses will be conducted based on the FAS and by the randomized treatment 
groups. 
Proportional hazard Cox regression models will be applied for the time-to-event endpoints. For 
patients who had the events, the date of the first event will be used as the event date. For patients 
who did not have the event, data will be censored at the specified analysis time point (Week 24 
or Week 48). Kaplan-Meier method will be used to summarize the time to event, and median, 
95% CIs of the median, 1st and 3rd quartiles, and range will be provided. 
The joint-rank test as described in Section 8.7.1 will be used to analyze the endpoints of 
combined assessments up to the specified analysis time points, where the assessments of the 
endpoints will be used for ranking. 
The MMRM as specified for the primary efficacy analysis (see in Section 8.6.1) except for the 
outcome variable, will be used for the endpoints of change from baseline to a specified time 
point. 
A mixed linear model will be used for the endpoint of slope of change from baseline to a 
specified time point. The response variable will be the change from baseline to each post 
baseline visit up to the specified analysis time point, and the model terms will include treatment 
group, baseline value of the response variable, time from the first dose (a continuous variable), 
riluzole and edaravone use at baseline, treatment-by-baseline interaction and treatment-by-time 
interaction. The intercept will be set to zero. 
In addition, descriptive statistics will be presented for time spent in each MiToS stage, transition 
of stages and progression in the degree use of both new and pre-existing DMEs (eg, from daily 
use progresses to dependence). 
8.8.2. 
Exploratory Analyses Evaluating Effect of Reldesemtiv 
To characterize the effect of reldesemtiv, additional comparisons will be conducted based on 
delayed-start design features. 
• The early-start treatment group includes patients who are randomized to receive 
reldesemtiv. Patients in this group are to receive reldesemtiv during both double-blind, 
placebo-controlled period and active drug period for a total of 48 weeks. 
• The delayed-start treatment group includes patients who are randomized to receive 
placebo. Patients in this group are to receive placebo during the double-blind, placebo-
controlled period for 24 weeks, and then switch to receive reldesemtiv during the active 
drug period for 24 weeks. 
Comparisons listed below will be performed to evaluate treatment differences in 1) change of 
ALSFRS-R total score from baseline, and 2) combined assessment of change of ALSFRS-R, 
dependence on assisted ventilation (either invasive or non-invasive), and survival time. 
• 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 


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• Compare changes from Week 24 to Week 48 versus those from baseline to Week 24 in 
the delayed-start group  
The analysis will include all data collected up to Week 48 (including data from the patients who 
discontinued the study treatment early but remained in the study and had data being collected). 
The analysis will also be conducted for patients who were on treatment (ie, excluding data 
collected after the discontinuation of the study treatment). 
8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses 
Efficacy analyses will be performed based on the FAS. Reason of excluding patients from the 
FAS will be summarized or listed. 


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9. 
SAFETY AND TOLERABILITY 
Safety and tolerability analyses will be based on the Safety Analysis Set. Safety data will be 
analyzed descriptively and tabulated by the early-start and delayed-start treatment groups for the 
double-blind placebo-controlled period and active drug period). 
9.1. 
Overall Summary of Tolerability 
Overall summary of tolerability will include the following: 
• Number of patients treated and patient years of drug exposure (mean, min, max, and 
median) 
• Number of patients with treatment-emergent adverse events (TEAEs) 
• Number of patients with treatment-emergent serious adverse events (TESAEs) 
• Number of patients with TEAEs leading to permanent dose reduction 
• Number of patients with TEAEs leading to premature treatment discontinuation  
• Number of patients with TEAEs leading to premature study discontinuation  
• Number of Deaths 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
9.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects 
All AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
TEAEs and TESAEs will be summarized by primary SOC and PT, by PT, and also by severity 
(Grades 1 to 5) and relationship to study drug (related and not related). For a TEAE reported 
more than once from a patient, the TEAE will be counted only once in the SOC or PT category 
using the most severe occurrence and/or closer relationship to the study drug. All AEs will be 
listed. 
9.2.2. 
Missing and Partial AE Onset Dates 
For AEs with incomplete date information recorded on the eCRF, imputation will be performed 
following the algorithm below: 
For missing AE onset Day and Time: 
• If an AE onset Day is missing and the Month of AE onset is known, then the first day of 
the month of AE onset will be imputed as the AE onset date. 
• If AE onset information is not available, then the first dosing date will be imputed as the 
AE onset date. 
 
 
 


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For missing AE end Day and Time: 
• If the AE end Day is missing and the AE end Month is earlier or later than that of the 
Follow-Up Visit, then the last day of the AE end month will be the imputed as the AE 
end date. 
• If the AE end Day is missing and the AE end Month is the same as that of the Follow-Up 
Visit, then the date of the Follow-Up Visit will be the imputed as the AE end date. 
• If no AE end information is available, then 
- For patients who discontinued early from study drug, the imputed AE end date 
will be on the later of the last dosing date + 28 days or the last visit or contact 
date. 
- For patients who completed the study, the imputed AE end date and time will be 
the date of the Follow-Up Visit. 
- If the stop date is missing and the event is ongoing, the event will be noted as 
ongoing” in the stop date column in data listings. 
9.2.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death 
Serious Adverse Events (SAEs) and AEs leading to premature treatment or study discontinuation 
and death will be summarized by SOC and PT, and by PT. Listings will be presented for patients 
who died and/or experienced serious AEs and for patients who discontinued prematurely due to 
TEAEs. 
9.2.4. 
Summaries of Adverse Events of Special Interest  
The following events are considered adverse events of special interest: 
• Manifestations of renal impairment and toxicity defined in the protocol Section 7.3, 
including clinically significant decreases in eGFRCysC and increases of urine protein 
creatinine ratio  
• Clinically significant elevated transaminases and/or bilirubin and manifestations of liver 
toxicity defined in the protocol Section 7.4 (eg, rash, abdominal pain, nausea and 
vomiting, fatigue, dark-colored urine, light-colored bowel movements, jaundice, loss of 
appetite, fever) 
Adverse events of special interest recorded on the CRF will be summarized by SOC and PT. 
Patients with adverse events of special interest and their laboratory values will be listed. 
9.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
Total duration of treatment and exposure of study drug per day will be summarized. All doses 
taken, date/time of dose, dose reduction (yes/no) and reason of dose reduction will be listed. 


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9.4. 
Concomitant and Other Medications 
Concomitant medications reported on the eCRF will be summarized. Medications with a start 
date that is 28 days after the last dose of the study drug will be excluded from the summary. The 
WHO Drug Dictionary will be used to classify medications by therapeutic class (ATC Class 3) 
and preferred name. If ATC Class 3 is not available, ATC Class 2 will be used in the summary. 
Coding will be performed using WHO Drug Dictionary Enhanced with Herbal Dictionary, B3, 
SEP 2020. 
CYP3A4 strong inhibitors should be avoided from 7 days before the start of dosing through the 
last day of dosing. CYP3A4 strong inducers should be avoided from 14 days before the start of 
dosing through the last day of dosing. OCT1/OCT2 substrates should be avoided from 7 days 
before the start of dosing or should be used with caution during the study. Patients who take 
CYP3A4 strong inhibitors, CYP3A4 strong inducers, or OCT1/OCT2 substrates prior or during 
the study treatment will be listed. 
Concomitant medications taken throughout the study will be listed. The listing will include 
concomitant medication, start/stop date, study day, dose / unit / route / frequency, indication and 
purpose of concomitant medications. 
9.4.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Incomplete concomitant medication start and/or stop dates will be imputed as follows. If either 
the start of medication date is completely missing or the month and/or year of the start date is 
missing, the start date will be set to the first dose date. If only the day is missing, the day will be 
set to the first day of the month except if the start month is the same as the first dose month. If 
the latter is true, the start day will be set to the first dose day. No imputations will be applied to 
the stop date. 
9.5. 
Routine Laboratory Data 
Clinical chemistry, hematology and urinalysis laboratory measurements and value changes from 
baseline at each laboratory blood sample collection time point will be summarized. The count 
and percentage of patients who had normal or missing laboratory values at baseline and 
abnormal laboratory values post baseline will be presented. The lower limit of normal (LLN) and 
upper limit of normal (ULN) provided by the laboratories will be used as the criteria to 
determine abnormality. For each parameter, the denominator of the percentage will include 
patients with normal or missing assessments at baseline, and with at least one assessment post 
baseline. The numerator of the percentage will include patients who had at least one abnormal 
assessment post baseline among the patients that were counted in the denominator. Assessment 
collected at unscheduled visits or the Follow-up Visit will be included in the summary. 
Shift of clinical laboratory results from baseline severity to the maximum post baseline severity 
will be presented for selected laboratory parameters. Clinical laboratory values will be also 
listed. Values outside the Laboratory’s normal ranges and potentially clinically significant 
abnormal values will be flagged. 
Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI cystatin 
equation (Inker 2012) and summarized as change from baseline, percentage change from 


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baseline, by categories (15 to <30, 30 to < 45, 45 to < 60, 60 to <90 and ≥90, as well as ≥10%, 
≥25% and >= 50% decline from baseline) and by shift in categories. 
Liver function test results will be summarized as change from baseline and as count and 
percentage of patients with normal baseline and abnormal post-baseline results in Alanine 
Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and 
bilirubin, with the following categories:  
• ALT > 3xULN, > 5xULN, > 8xULN 
• AST > 3xULN, > 5xULN, > 8xULN 
• ALT and/or AST > 3xULN, > 5xULN, > 8xULN 
• ALT and/or AST > 3xULN and total bilirubin > 2xULN and ALP < 2xULN 
• ALT and/or AST > 3xULN and total bilirubin > 2xULN 
• Bilirubin (total, indirect or direct) > 2xULN, >3xULN 
• ALT or AST > 3 x ULN with symptoms including nausea, vomiting, anorexia, abdominal 
pain, fatigue, rash, dark-colored urine, light-colored bowel movements, jaundice, or fever 
In addition, time to ALT, AST or bilirubin elevation since the first dose will be summarized by 
treatment groups. 
9.6. 
Vital Signs 
Blood pressure, heart rate, respiratory rate, body weight and oral temperature will be collected at 
the time points specified in the protocol. For each assessment time point, absolute values and 
changes from baseline of the vital signs will be summarized. 
The count and percentage of patients who had normal or missing values at baseline and 
Potentially Clinically Significant (PCS) values post baseline will be presented. The PCS criteria 
are specified in Table 7. For each parameter, the denominator of the percentage will include 
patients with non-PCS or missing assessments at baseline, and with at least one assessment post 
baseline. The numerator of the percentage will include patients who had at least one PCS 
assessment post baseline among the patients that were counted in the denominator. Assessment 
collected during unscheduled visits or the Follow-up Visit will be included in the summary. 
All collected vital signs and assessment time will be listed, and values outside the normal ranges 
will be flagged. 
Table 7: 
Criteria of Potentially Clinically Significant (PCS) Vital Signs 
Vital Sign Parameter 
Flag 
Criteria 
Systolic Blood Pressure (mmHg) 
High 
≥160 mmHg 
Low 
≤80 mmHg 
Diastolic Blood Pressure (mmHg) 
High 
≥100 mmHg 
Low 
≤ 50 mmHg 
Respiration Rate (Breaths per minute) 
Respiration Rate (Breaths per minute) (Cont’d) 
High 
>18 bpm 
Low 
<8 bpm 
Pulse (bpm) 
High 
≥120 bpm 


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Table 7: 
Criteria of Potentially Clinically Significant (PCS) Vital Signs (Continued) 
Vital Sign Parameter 
Flag 
Criteria 
 
Low 
≤50 bpm 
Weight (kg) 
Clinically 
Significant 
≥5% reduction from baseline 
Temperature (oC) 
High 
≥ 38 oC 
Low 
< 35 oC 
9.7. 
Electrocardiogram 
A 12-lead ECG will be obtained at the time points specified in the protocol using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Descriptive statistics of absolute value and change from baseline of ECG parameters 
(PR interval, RR interval, QRS duration, QT interval, QTc interval [Bazett’s and Fridericia’s], 
Ventricular Heart Rate) at each assessment time point will be presented. 
The count and percentage of patients who had normal or missing values at baseline and PCS 
values post baseline will be presented. ECG parameters are regarded as PCS if the value meets 
the criterion shown in Table 8. For each parameter, the denominator of the percentage will 
include patients with non-PCS or missing assessments at baseline, and with at least one 
assessment post baseline. The numerator of the percentage will include patients who had at least 
one PCS assessment post baseline among the patients that were counted in the denominator. 
Assessment collected at an unscheduled visits or the Follow-up Visit will also be included in the 
summary. 
All collected 12-lead ECG parameters, assessment time, ECG findings and interpretations will be 
listed. PCS ECG values will be flagged. 
 
Table 8: 
Criteria of Abnormal and PCS ECG Values 
ECG Variable 
Units 
Upper Limit of Normal 
PCS 
High Values 
QRS Interval 
msec 
80 
≥120 
PR Interval 
msec 
200 
≥240 
QTcB Interval 
msec 
Males: 450 
Females: 460 
>500 
QTcF Interval 
msec 
Males: 450 
Females: 460 
>500 
QT Interval 
msec 
— 
> 500 
Ventricular Heart Rate 
bpm 
— 
≤50 
>100 


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9.8. 
Physical Examination 
Reported abnormal and clinically significant findings in physical examinations will be 
summarized as Medical History or Adverse Events. 
9.9. 
Beck Depression Inventory Fast Screen Version 
The BDI-FS will be assessed at the time points specified in the protocol. Descriptive statistics of 
the BDI total score will be provided for each assessment time point. The actual assessment date 
and all reported items will also be listed. 
9.10. 
Study Termination Status 
Count and percentage of patients who completed or prematurely discontinued planned study 
dosing will be presented. Reasons of prematurely discontinuation will be tabulated. For patients 
who discontinued prematurely, the date and reason of premature discontinuation will be listed. 
 
 
 


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10. 
PHARMACOKINETICS 
Plasma concentrations of reldesemtiv and its metabolite CK-2127106 at each collection time 
point will be summarized using descriptive statistics including mean, standard deviation, 
geometric mean, coefficient of variation, median, and range. Mean plasma concentrations over 
time will be graphically displayed. PK Parameters, such as Ctrough,  Cmax, Tmax, AUCtau, AUClast 
and CL/F (reldesemtiv only) and metabolite ratio, if available, will be summarized. Population 
PK modeling based on the plasma concentrations of reldesemtiv from this study and previous 
studies will be conducted; results will be shown in a separate report. 
 


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11. 
REFERENCES 
 
Beck, A. T., Steer, R. A. and Brown, G. K. (2000). Bdi-fast screen for medical patients manual. 
San Antonio, TX, Psychological Corporation. 
 
Berry, J. D., Miller, R., Moore, D. H., Cudkowicz, M. E., Van Den Berg, L. H., Kerr, D. A., et 
al. (2013). "The combined assessment of function and survival (cafs): A new endpoint for als 
clinical trials." Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(3): 162-168. 
 
Brooks, B. R., Miller, R. G., Swash, M. and Munsat, T. L. (2000). "El escorial revisited: Revised 
criteria for the diagnosis of amyotrophic lateral sclerosis." Amyotrophic Lateral Sclerosis and 
Other Motor Neuron Disorders 1(5): 293-299. 
 
Cedarbaum, J. M., Stambler, N., Malta, E., Fuller, C., Hilt, D., Thurmond, B., et al. (1999). "The 
alsfrs-r: A revised als functional rating scale that incorporates assessments of respiratory 
function." Journal of the Neurological Sciences 169(1): 13-21. 
 
Chen, Y. H. J., DeMets, D. L. and Gordon Lan, K. K. (2004). "Increasing the sample size when 
the unblinded interim result is promising." Statistics in Medicine 23(7): 1023-1038. 
 
Chio, A., Hammond, E. R., Mora, G., Bonito, V. and Filippini, G. (2015). "Development and 
evaluation of a clinical staging system for amyotrophic lateral sclerosis." Journal of Neurology, 
Neurosurgery & Psychiatry 86(1): 38-44. 
 
EuroQol Group (1990). "Euroqol - a new facility for the measurement of health-related quality of 
life." Health Policy 16(3): 199-208. 
 
EuroQol Group. (2009). "Eq-5d-5l." from https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/, 
Updated Date Accessed Date. 
 
Gao, P., Ware, J. H. and Mehta, C. (2008). "Sample size re-estimation for adaptive sequential 
design in clinical trials." Journal of biopharmaceutical statistics 18: 1184-1196. 
 
Inker, L. A., Schmid, C. H., Tighiouart, H., Eckfeldt, J. H., Feldman, H. I., Greene, T., et al. 
(2012). "Estimating glomerular filtration rate from serum creatinine and cystatin c." New 
England Journal of Medicine 367(1): 20-29. 
 
Lawrence, J. and Hung, H. M. J. (2003). "Estimation and confidence intervals after adjusting the 
maximum information." Biometrical Journal 45(2): 143-152. 
 
Mehta, C. R. and Pocock, S. J. (2011). "Adaptive increase in sample size when interim results 
are promising: A practical guide with examples." Statistics in Medicine 30(28): 3267-3284. 
 
Pickard, A. S., Law, E. H., Jiang, R., Pullenayegum, E., Shaw, J. W., Xie, F., et al. (2019). 
"United states valuation of eq-5d-5l health states using an international protocol." Value in 
Health 22(8): 931-941. 


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Quanjer, P. H., Stanojevic, S., Cole, T. J., Baur, X., Hall, G. L., Culver, B. H., et al. (2012). 
"Multi-ethnic reference values for spirometry for the 3–95-yr age range: The global lung 
function 2012 equations." European Respiratory Journal 40(6): 1324-1343. 
 
Ratitch, B., O'Kelly, M. and Tosiello, R. (2013). "Missing data in clinical trials: From clinical 
assumptions to statistical analysis using pattern mixture models." Pharmaceutical Statistics 
12(6): 337-347. 
 
Rubin, D. B. (1987). Multiple imputation for nonresponse in surveys. New York, John Wiley & 
Sons, Inc. 
 
Schafer, J. L. (1997). Analysis of incomplete multivariate data. New York, Chapman and 
Hall/CRC. 
 
Steer, R. A., Cavalieri, T. A., Leonard, D. M. and Beck, A. T. (1999). "Use of the beck 
depression inventory for primary care to screen for major depression disorders." General 
Hospital Psychiatry 21(2): 106-111. 


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12. 
APPENDIX 
12.1. 
Table of Contents for Data Display Specifications 
Table of contents for data display specifications will be provided in a separate document. 
12.2. 
Data Display Specifications 
Data display specifications will be provided in a separate document. 
 
 


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12.3. 
Analysis Windows 
Measurements collected during the 24-week double-blind placebo-controlled period will be 
included only in the analysis windows up to Week 24; measurements collected after patients 
transition to the active drug period will be included only in the analysis windows after Week 24. 
Table 9: 
Analysis Windows for ALSFRS-R, FVC (Remote Visits) and DME 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screeninga 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 4 
29 
2 
42 
Week 8 
57 
43 
70 
Week 12 
85 
71 
98 
Week 16 
113 
99 
126 
Week 20 
141 
127 
154 
Week 24 
169 
155 
182 
Week 28 
197 
183 
210 
Week 32 
225 
211 
238 
Week 36 
253 
239 
266 
Week 40 
281 
267 
294 
Week 44 
309 
295 
322 
Week 48 
337 
323 
350 
Follow-up 
365 
351 
>351 
a Not applicable for FVC (Remote Visits) 
Table 10: 
Analysis Windows for FVC (in Clinic), Handgrip and Muscle Strength, BDI-
FS, Vital Signs, Weight and BMI 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 4 
29 
2 
56 
Week 12 
85 
57 
126 
Week 24 
169 
127 
210 
Week 36 
253 
211 
294 
Week 48 
337 
295 
350 
Follow-up 
365 
351 
>351 
 


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Table 11: 
Analysis Windows for EQ-5D-5L, EQ-VAS and ALSAQ-40 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 12 
85 
2 
126 
Week 24 
169 
127 
210 
Week 36 
253 
211 
294 
Week 48 
337 
295 
350 
Follow-up 
365 
351 
>351 
 
Table 12: 
Analysis Windows for Neurological Exam 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Week 24 
169 
1 
266 
Follow-up 
365 
267 
>267 
 
Table 13: 
Analysis Windows for ECG 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 24 
169 
2 
252 
Week 48 
337 
253 
350 
Follow-up 
365 
351 
>351 
 
Table 14: 
Analysis Windows for PK Concentration 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Week 4 
29 
2 
49 
Week 12 
85 
50 
126 
Week 24 
169 
127 
>210 
Week 36 
253 
211 
>211 
 
 
 


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Table 15: 
Analysis Windows for Clinical Safety Laboratory Measurements 
Visit 
Scheduled Day 
Lower Bound 
Upper Bound 
Screening 
<1 
<1 
<1 
Day 1 
1 
1 
1 
Week 2 
15 
2 
21 
Week 4 
29 
22 
42 
Week 8 
57 
43 
70 
Week 12 
85 
71 
98 
Week 16 
113 
99 
126 
Week 20 
141 
127 
154 
Week 24 
169 
155 
175 
Week 26 
183 
176 
189 
Week 28 
197 
190 
210 
Week 32 
225 
211 
238 
Week 36 
253 
239 
266 
Week 40 
281 
267 
294 
Week 44 
309 
295 
322 
Week 48 
337 
323 
350 
Follow-up 
365 
351 
>351 
 
 
 


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12.4. 
Mspline Value for Calculation of Predicted FVC 
Table 16: 
Mspline Value 
Age (yrs) 
Male 
Female 
Age (yrs) 
Male 
Female 
18 
0.147849088 
0.135507529 
50 
-0.006647706 
0.028303776 
19 
0.160315109 
0.140628299 
51 
-0.014542406 
0.020206649 
20 
0.167159394 
0.143647414 
52 
-0.022604908 
0.011905392 
21 
0.169722148 
0.145330204 
53 
-0.030845244 
0.00339698 
22 
0.16923214 
0.146039097 
54 
-0.039274925 
-0.005323975 
23 
0.166543254 
0.145870185 
55 
-0.04790158 
-0.014258162 
24 
0.162315681 
0.144942845 
56 
-0.056735557 
-0.023411261 
25 
0.157092735 
0.143626724 
57 
-0.065782826 
-0.032797239 
26 
0.151293448 
0.142211366 
58 
-0.07504859 
-0.042417299 
27 
0.145106883 
0.140771596 
59 
-0.084531216 
-0.052260185 
28 
0.138681964 
0.13919976 
60 
-0.094214527 
-0.062313185 
29 
0.132266867 
0.137441293 
61 
-0.104078877 
-0.072556666 
30 
0.125876212 
0.135494281 
62 
-0.114093666 
-0.082975133 
31 
0.119459845 
0.133330256 
63 
-0.124218952 
-0.093558031 
32 
0.113049003 
0.130878076 
64 
-0.134413719 
-0.104301259 
33 
0.106735805 
0.12804587 
65 
-0.14465155 
-0.115203896 
34 
0.100550635 
0.124811373 
66 
-0.154914171 
-0.126261624 
35 
0.094499318 
0.121203564 
67 
-0.165181495 
-0.137466925 
36 
0.088531508 
0.117238065 
68 
-0.175439763 
-0.148808471 
37 
0.082567889 
0.112889589 
69 
-0.185681902 
-0.160268368 
38 
0.076537303 
0.108171834 
70 
-0.195901978 
-0.171827557 
39 
0.070402479 
0.103107309 
71 
-0.20609542 
-0.183468534 
40 
0.064129074 
0.097699941 
72 
-0.216260542 
-0.195173143 
41 
0.057677943 
0.091939589 
73 
-0.226393699 
-0.206921242 
42 
0.051046568 
0.085825419 
74 
-0.236485333 
-0.218692812 
43 
0.04427255 
0.079389589 
75 
-0.246523325 
-0.230468005 
44 
0.037387387 
0.07268763 
76 
-0.256496316 
-0.242227571 
45 
0.030394993 
0.06577409 
77 
-0.266395583 
-0.253951742 
46 
0.023277783 
0.058677615 
78 
-0.276212134 
-0.265621352 
47 
0.01602077 
0.051384134 
79 
-0.285939277 
-0.277219902 
48 
0.008623361 
0.043889005 
80 
-0.295573257 
-0.288731661 
49 
0.001072775 
0.036196648 
 
 
 
 


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12.5. 
Sample SAS Codes 
The followings are the prototype of the SAS codes that will be used for the analysis. The final version of the statistical programming 
codes to be used will be determined prior to the database lock. 
1. MMRM for the primary endpoint 
proc mixed data = artot method = reml; 
   class <usubjid> <visit> <treatment> <baseline riluzole use> <baseline edaravone use>; 
   model <change in ALSFRS-R total score> = <visit> <treatment> <baseline ALSFRS-R total score>  
              <baseline riluzole use> <baseline edaravone use> <visit>*<treatment>  
              <visit>*<baseline ALSFRS-R total score>/ddfm=kr; 
   repeated <visit> / subject = <usubjid> type = un;  
   lsmeans <visit>*<treatment> / pdiff cl; 
run; 
 
Note: If the 2nd interim analysis result leads to an increase of the sample size, the final analyses will include the status of being 
included or excluded from the 2nd interim analysis as a covariate in the model. 
 
2. Multiple imputation within each treatment group under MAR assumption 
 
proc mi data=datain minimum=0 maximum=48 round=1 nimpute=50 out=dataout; 
class <baseline riluzole use> <baseline edaravone use>; 
   fcs reg(<Week 4 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>); 
   fcs reg(<Week 8 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                        <Week 4 ALSFRS-R total score>); 
   fcs reg(<Week 12 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>); 
   fcs reg(<Week 16 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  
                                                                          <Week 12 ALSFRS-R total score>); 
   fcs reg(<Week 20 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  


Statistical Analysis Plan - Protocol CY 5031 
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Cytokinetics, Inc. 
                                                                          <Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score>); 
   fcs reg(<Week 24 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  
                                                                          <Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score>  
                                                                          <Week 20 ALSFRS-R total score>); 
 
var <baseline riluzole use> <baseline edaravone use> <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score> 
<Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score> <Week 20 ALSFRS-R total score>  
<Week 24 ALSFRS-R total score>; 
run; 
 
3. Multiple imputation for missing values in the reldesemtiv group with placebo distribution 
Missing data in the reldesemtiv group will be combined with all data in the placebo group for imputation, and will be filled 
sequentially starting at the earliest time point and progressing until the last time point. Below is an example of filling missing data 
at Week 8 for the reldesemtiv group using placebo data. 
 
data imp; set pbo act_mis(where=(Wk8=.));  
  
proc mi data=imp seed=&seed out=miout NIMPUTE=50; 
   mcmc IMPUTE=FULL; 
   var Wk4 Wk8; 
run; 
 
4. Tipping point analysis  
proc mi data=datain minimum=0 maximum=48 round=1 nimpute=50 out=dataout; 
class <baseline riluzole use> <baseline edaravone use> <treatment>; 
   fcs reg(<Week 4 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>); 
   fcs reg(<Week 8 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                        <Week 4 ALSFRS-R total score>); 
   fcs reg(<Week 12 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>); 
   fcs reg(<Week 16 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  
                                                                          <Week 12 ALSFRS-R total score>); 
   fcs reg(<Week 20 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  


Statistical Analysis Plan - Protocol CY 5031 
                                                                                                                      Reldesemtiv 
Version 2.0, February 24, 2023 
Confidential and Proprietary 
Page 68 of 69 
Cytokinetics, Inc. 
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  
                                                                          <Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score>); 
   fcs reg(<Week 24 ALSFRS-R total score> = <baseline riluzole use> <baseline edaravone use>  
                                                                          <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score>  
                                                                          <Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score>  
                                                                          <Week 20 ALSFRS-R total score>); 
 
var <baseline riluzole use> <baseline edaravone use> <Week 4 ALSFRS-R total score> <Week 8 ALSFRS-R total score> 
<Week 12 ALSFRS-R total score> <Week 16 ALSFRS-R total score> <Week 20 ALSFRS-R total score>  
<Week 24 ALSFRS-R total score>; 
mnar adjust (<Week 24 ALSFRS-R total score> / shift=xx adjustobs=(<treatment>='1')); 
run; 
 
5. Pooled estimates from the 50 imputed datasets 
For p-value from MMRM, use the combined dataset with estimates and standard errors from the 50 times of imputation 
proc mianalyze data=est;  
  modeleffects estimate; 
  stderr; 
run; 
 
For p-value from Wilcoxon test, apply Wilson-Hilferty transformation (Wilson & Hilferty, 1931; Goria, 1992) to the Chi-square 
statistic in the dataset CMH from the PROC FREQ. Note that the van Elteren test is the test comparing the rows (treatments) of 
the table. This is the second CMH statistic labeled "Row Mean Scores Differ", and the p-value matches the two-sided p-value 
from PROC NPAR1WAY (see http://support.sas.com/kb/25/022.html). 
 
proc npar1way wilcoxon; 
  strata <stratum1> <stratum2>; 
  class <treatment>; 
  var <rank>; 
run; 
 
proc freq; 
  table <stratum1>*<stratum2>*<treatment>*<rank> / cmh scores=modridit noprint; 
  ods output cmh=cmh; 
run; 


Statistical Analysis Plan - Protocol CY 5031 
                                                                                                                      Reldesemtiv 
Version 2.0, February 24, 2023 
Confidential and Proprietary 
Page 69 of 69 
Cytokinetics, Inc. 
 
Data cmh_combine; set cmh;  
If AltHypothesis=’Row Mean Scores Differ’; 
chi_value_wh=((Value/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF));  
chi_sterr_wh=1;  
run; 
 
Use the combined dataset with the transformed statistics from the 50 times of imputation 
 
Proc mianalyze data=cmh_combine;  
 modeleffects chi_value_wh;  
 stderr chi_sterr_wh;  
run; 
 
 
 
 
 
 


Signature Manifest
Document Number: PRD-0314
Revision: 00
Title: CY 5031 - Statistical Analysis Plan - Version 2.0 - 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)
Effective Date: 27 Feb 2023
All dates and times are in Pacific Time.
CY 5031 - Statistical Analysis Plan - Version 2.0 - 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)
 
1: Electronic Approvals
Name/Signature
Title
Date
Meaning/Reason
Jenny Hsiao-Lan Wei (JWEI)
Director, Biostatistics
27 Feb 2023, 01:39:08 PM
Approved
Stacy Rudnicki (SRUDNICKI)
Vice President, Clinical
Research
27 Feb 2023, 01:50:28 PM
Approved
Stuart Kupfer (SKUPFER)
SVP, Chief Medical Officer
27 Feb 2023, 02:45:25 PM
Approved
Lisa (Lixin) Meng (LMENG)
Vice President, Biometrics
27 Feb 2023, 04:10:30 PM
Approved