Clinical trial NCT05442775
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis ALS CK-2127107 Reldesemtiv
Sponsor: Cytokinetics
Start date: 2022-08-04; Completion date: 2023-06-07
Enrollment: 71 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the long-term safety and tolerability of reldesemtiv in patients with ALS who have successfully completed dosing in the Phase 3 clinical trial, CY 5031 (also known as COURAGE-ALS)

Detailed description:
CY 5032 is an open-label extension (OLE) study of the selective fast skeletal muscle troponin activator, reldesemtiv, in patients with ALS who finished dosing (through Week 48) in CY 5031 (COURAGE-ALS). Approximately 400 patients from the sites that participated in CY 5031 are expected to be enrolled in the open-label extension, CY 5032.

Following enrollment, patients will continue dosing with reldesemtiv, 300 mg twice a day for a 600 mg total daily dose (TDD) for a period of 48 weeks.

At the end of 48 weeks, patients may transition to a reldesemtiv Managed Access Program (MAP) if the treating physician agrees to participate in the program.

Arms: arm 1: Patients in this arm take 1 reldesemtiv 300 mg oral tablet twice a day for a 600 mg total daily dose (TDD). Participants who had been down titrated during the parent trail take 150 mg by mouth twice a day.
Interventions: intervention 1: Reldesemtiv
Intervention descriptions: intervention 1: Oral tablet

Protocol documents:
Prot_000.pdf: 
PROTOCOL CY 5032 
A PHASE 3, OPEN-LABEL EXTENSION OF COURAGE-ALS (CY 5031) 
  
 
Trial Name: 
COURAGE-ALS OLE 
Protocol Version and Date: 
Amendment 1: 16 December 2022 
Previous Version(s): 
17 March 2022 
Product: 
CK-2127107 
Product Name: 
Reldesemtiv 
Regulatory Authority 
Identifier Number(s): 
IND 134567 
NCT 05442775 
EudraCT 2021-004727-33 
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. 
 
 


Protocol CY 5032 
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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
CY 5032 
Protocol Title: 
A Phase 3, Open-Label Extension of COURAGE-ALS 
(CY 5031) 
Protocol Version and Date: 
Amendment 1: 16 December 2022 
 
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 5032 
Protocol Title: 
A Phase 3, Open-Label Extension of COURAGE-ALS 
(CY 5031) 
Protocol Version and Date: 
Amendment 1: 16 December 2022 
Sponsor: 
Cytokinetics, Inc. 
350 Oyster Point Blvd 
South San Francisco, CA 94080 
 
 
 
 
 
 
Andrew Wolff, MD, FACC 
Senior Vice President 
Senior Fellow, Clinical Research and Development 
 
Date: 
 


Protocol CY 5032 
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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 ........................................................................................................................13 
1.3. 
Schedule of Activities .................................................................................................14 
1.4. 
Key Contacts ...............................................................................................................16 
2. 
INTRODUCTION ......................................................................................................17 
2.1. 
Study Rationale ...........................................................................................................17 
2.2. 
Background .................................................................................................................17 
2.2.1. 
Amyotrophic Lateral Sclerosis ...................................................................................17 
2.2.2. 
Reldesemtiv ................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................18 
2.3.1. 
Risk Assessment .........................................................................................................18 
2.3.1.1. 
Mitigation Strategy .....................................................................................................18 
2.3.2. 
Benefit Assessment .....................................................................................................18 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................20 
4. 
STUDY DESIGN .......................................................................................................21 
4.1. 
Overall Design ............................................................................................................21 
4.2. 
End of Study Definition ..............................................................................................22 
5. 
STUDY POPULATION .............................................................................................23 
5.1. 
Inclusion Criteria ........................................................................................................23 
5.2. 
Exclusion Criteria .......................................................................................................24 
5.3. 
Lifestyle Considerations .............................................................................................24 
6. 
INVESTIGATIONAL PRODUCT ............................................................................25 
6.1. 
Study Drug Administered ...........................................................................................25 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................25 
6.3. 
Study Drug Compliance .............................................................................................26 


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6.4. 
Concomitant Therapy .................................................................................................26 
6.5. 
Dose Modification ......................................................................................................27 
6.6. 
Access to Investigational Product after the End of the Study ....................................28 
7. 
TEMPORARY INTERRUPTION OF STUDY DRUG, 
DISCONTINUATION OF STUDY DRUG, AND PATIENT CONSENT 
WITHDRAWAL ........................................................................................................29 
7.1. 
Temporary Study Drug Interruption ...........................................................................29 
7.2. 
Permanent Discontinuation of Study Drug .................................................................29 
7.2.1. 
Management of Patients after Permanent Discontinuation of Study Drug .................30 
7.3. 
Renal Function Monitoring and Study Drug Management ........................................31 
7.4. 
Liver Function Monitoring and Study Drug Management .........................................32 
7.5. 
Discontinuation from Study Procedures .....................................................................34 
7.6. 
Patient Consent Withdrawal .......................................................................................34 
7.7. 
Lost to Follow up ........................................................................................................35 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
8.1. 
Efficacy Assessments .................................................................................................37 
8.1.1. 
ALSFRS-R ..................................................................................................................37 
8.1.2. 
Health Economic Outcomes Measures .......................................................................37 
8.1.3. 
Hospitalizations ..........................................................................................................37 
8.2. 
Safety Assessments .....................................................................................................38 
8.2.1. 
Physical Examinations ................................................................................................38 
8.2.2. 
Vital Signs ..................................................................................................................38 
8.2.3. 
Neurological Examinations ........................................................................................38 
8.2.4. 
Laboratory Assessments .............................................................................................38 
8.3. 
Adverse Events and Serious Adverse Events .............................................................39 
8.3.1. 
Adverse Events ...........................................................................................................39 
8.3.1.1. 
Definition of Adverse Event .......................................................................................39 
8.3.1.2. 
Definition of Serious Adverse Event ..........................................................................39 
8.3.1.3. 
Definition of Adverse Event of Special Interest .........................................................40 
8.3.1.4. 
Severity of Adverse Events ........................................................................................41 
8.3.1.5. 
Relationship to Study Drug ........................................................................................41 
8.3.1.6. 
Relationship to Study Procedures ...............................................................................42 
8.3.1.7. 
Reporting of AEs ........................................................................................................42 


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8.3.1.8. 
Reporting Procedures for SAEs ..................................................................................43 
8.3.1.9. 
Follow-up of AEs and SAEs .......................................................................................43 
8.3.1.10. 
Regulatory Reporting ..................................................................................................44 
8.3.1.11. 
Pregnancy and Breastfeeding .....................................................................................44 
8.4. 
Treatment of Overdose ...............................................................................................45 
8.5. 
Pharmacokinetics ........................................................................................................45 
8.6. 
Immunogenicity Assessments ....................................................................................45 
8.7. 
Sample Storage ...........................................................................................................46 
9. 
STATISTICAL CONSIDERATIONS .......................................................................47 
9.1. 
Populations for Analyses ............................................................................................47 
9.2. 
Statistical Analyses .....................................................................................................47 
9.2.1. 
General Considerations ...............................................................................................47 
9.2.2. 
Primary Endpoint ........................................................................................................48 
9.2.3. 
Secondary Endpoint(s) ................................................................................................48 
9.2.3.1. 
Time-to Event Endpoints ............................................................................................48 
9.2.3.2. 
Change from Baseline Endpoints ...............................................................................48 
9.2.4. 
Safety Analysis ...........................................................................................................49 
9.2.4.1. 
Adverse Events ...........................................................................................................49 
9.2.4.2. 
Serious Adverse Events ..............................................................................................49 
9.2.5. 
Patient Disposition ......................................................................................................50 
9.2.6. 
Demographics and Other Baseline Characteristics .....................................................50 
9.2.7. 
Investigational Product Exposure ...............................................................................50 
9.2.8. 
Concomitant Medications ...........................................................................................50 
9.2.9. 
Clinical Laboratory Parameters ..................................................................................50 
9.2.10. 
Vital Signs ..................................................................................................................50 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................51 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................51 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................51 
10.1.2. 
Financial Disclosure ...................................................................................................51 
10.1.3. 
Informed Consent Process ..........................................................................................51 
10.1.4. 
Data Protection ...........................................................................................................52 
10.1.5. 
Data Quality Assurance ..............................................................................................52 


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10.1.6. 
Source Documents ......................................................................................................53 
10.1.7. 
Study and Site Start and Closure ................................................................................53 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................54 
10.3. 
Appendix 3: Contraceptive Guidance .........................................................................55 
10.4. 
Appendix 4: Common Medications and Foods that Inhibit or Induce 
CYP3A4 or are OCT1/OCT2 Substrates ....................................................................57 
10.5. 
Appendix 5: Abbreviations .........................................................................................58 
11. 
REFERENCES ...........................................................................................................61 


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LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................20 
Table 2: 
Study Drug ..................................................................................................................25 
Table 3: 
CY 5032 Visit Windows .............................................................................................36 
Table 4: 
Signs and Symptoms Commonly Associated with ALS ............................................42 
Table 5: 
Analysis Sets ...............................................................................................................47 
Table 6: 
Protocol-Required Safety Laboratory Assessments ...................................................54 
LIST OF FIGURES 
Figure 1:  Study Schema .............................................................................................................13 
 
 


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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, Open-Label Extension of COURAGE-ALS (CY 5031) 
Protocol Number: CY 5032 
Protocol Name: COURAGE-ALS OLE 
Phase of Development: Phase 3 
Rationale: 
Reldesemtiv, a fast skeletal muscle troponin activator, is being investigated as a potential therapy to 
slow the decline of skeletal muscle function in patients with ALS. Patients who have completed the 
Phase 3 clinical trial (COURAGE-ALS [CY 5031]) of reldesemtiv in patients with ALS may continue 
to receive reldesemtiv in the open label extension (OLE), CY 5032. During the last 24 weeks of dosing 
in CY 5031, all patients receive open-label reldesemtiv; consequently, all patients eligible for and 
entering CY 5032 will have already demonstrated acceptable tolerance of reldesemtiv when they begin 
dosing. The OLE permits patients to continue to receive reldesemtiv after completion of CY 5031. The 
study will extend the overall duration of long-term safety, tolerability, and durability of effect during 
treatment of patients with ALS with reldesemtiv. 
Objectives and Endpoints: 
Objectives 
Endpoint(s) 
Primary 
• To assess the long-term safety and tolerability of 
reldesemtiv in patients with ALS 
• The incidence of adverse events (AEs) in the 
patient population 
Secondary 
• To assess the long-term effect of reldesemtiv 
on ALSFRS-R functional outcomes and 
hospitalization by comparing early-start to 
delayed-start groups from CY 5031 
• 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 from 
baseline of CY 5031 through CY 5032 Week 48 
and from Week 24 of CY 5031 through CY 5032 
Week 48 
• Time to the first occurrence of dependence on 
assisted ventilation or death from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Changes in ALS Functional Rating Scale – 
Revised (ALSFRS-R) total score from baseline of 


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CY 5031 through CY 5032 Week 48 and from 
Week 24 of CY 5031 through CY 5032 Week 48  
• Slopes of the changes in ALSFRS-R total score 
from baseline of CY 5031 through CY 5032 
Week 48 and from Week 24 of CY 5031 through 
CY 5032 Week 48 
• Time to the first hospitalization from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Time to recurrent hospitalizations from Day 1 in 
CY 5031 through CY 5032 Week 48 
 
Overall Design: 
CY 5032 is an open-label extension with the selective fast skeletal muscle troponin activator, 
reldesemtiv, in patients with ALS who finished dosing (through Week 48) in CY 5031 (COURAGE-
ALS). Approximately 400 patients from the sites that participated in CY 5031 are expected to be 
enrolled in the open-label extension, CY 5032. 
Following enrollment, patients will continue dosing with reldesemtiv, 300 mg twice a day for a 600 mg 
total daily dose (TDD) for a period of 48 weeks; however, a patient down-titrated for any reason to 
150 mg twice daily in CY 5031 will continue with the down-titrated dose in CY 5032. Reldesemtiv 
should be taken twice daily, morning and afternoon (at least 8 hours apart). 
At the end of 48 weeks, patients may transition to a reldesemtiv Managed Access Program (MAP). If 
the treating physician agrees to participate in the program, the treating physician’s patient(s) may be 
eligible to transition from the OLE to the MAP. 
Study Visits: 
Patient visits will occur as follows (6 in clinic, 2 remote lab visits, and 8 remote visits): 
• Day 1 (will be dependent upon protocol approval at the site, can be Week 48 or Week 52 visit for 
CY 5031 or later when approval is received) 
• End of Week 4 (remote visit) 
• End of Week 6 (remote lab visit) 
• End of Week 8 (remote visit) 
• End of Week 12 (in clinic) 
• End of Week 16 (remote visit) 
• End of Week 18 (remote lab visit) 
• End of Week 20 (remote visit) 
• End of Week 24 (in clinic) 
• End of Week 28 (remote visit) 
• End of Week 32 (remote visit) 
• End of Week 36 (in clinic) 
• End of Week 40 (remote visit) 
• End of Week 44 (remote visit) 
• End of Week 48 (in clinic) 


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• FU: End of Week 52 (in clinic) 
 
If a patient decides to discontinue reldesemtiv, the patient will come into the clinic for the Reldesemtiv 
Discontinuation Visit as soon as possible after the last dose was taken. 
Study Center(s): 
Patients will be enrolled from approximately 85 clinical trial sites in the US, Canada, Europe, and 
Australia. 
Assessments: 
The following assessments will be performed: 
• 
Collection of Demographic Data 
• 
Physical Exam / Neurological Exam 
• 
Vital Signs 
• 
Clinical Safety Labs 
• 
Serum Pregnancy Test for Women of Childbearing Potential 
• 
ALSFRS-R 
• 
AE evaluation and concomitant medication assessment (since last visit) 
 
Eligibility Criteria:  
Key Inclusion Criteria  
• 
Able to comprehend and willing to sign an Informed Consent Form (ICF). If patient is able to 
comprehend, but non-written consent is given, an impartial witness must sign the ICF form 
• 
Completed dosing in CY 5031  
Key Exclusion Criteria  
• 
Has taken an investigational study drug (other than reldesemtiv) prior to dosing, within 30 days or 
five half-lives of the prior agent, whichever is greater  
 
Investigational Product: 
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 supplied to the clinical site in bottles. Patients will receive one or more 
bottles of study drug (reldesemtiv) at each clinic visit. 
Patients must interrupt reldesemtiv for certain specified laboratory abnormalities until the laboratory 
value in question has returned to the threshold specified in the protocol for re-initiation of treatment. 
Patients must 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. 


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Patients who experience a laboratory abnormality requiring interruption of reldesemtiv while receiving 
150 mg twice daily may resume reldesemtiv 150 mg twice daily once the laboratory value in question 
has returned to the threshold specified in the protocol for re-initiation of reldesemtiv; however, should 
the same laboratory abnormality requiring interruption of reldesemtiv recur, the patient must be 
permanently discontinued from reldesemtiv. 
Statistical Methods:  
Unless specified otherwise, efficacy analyses will be performed to compare early-start and delayed-
start treatment groups based on the data collected during CY 5031 from the patients in the full analysis 
set (FAS) of CY 5031 plus the data collected during CY 5032 from the patients who were in the FAS 
of CY 5031 and enrolled into CY 5032. 
The combined assessment of change in ALSFRS-R total score, time to dependence on assisted 
ventilation, and survival time from baseline of CY 5031 through CY 5032 Week 48 will be analyzed 
using the joint-rank test. A stratified Wilcoxon test will be applied to compare the standardized joint 
ranks between the early-start and delayed-start treatment groups with adjustment for riluzole and 
edaravone use at CY 5031 baseline. The stratified Mann-Whitney probability as well as the p-value 
will be presented. 
If data permit, the analyses of change from baseline 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 early-start and delayed-start treatment groups, CY 5031 
baseline ALSFRS-R total score, visit, riluzole use at CY 5031 baseline, edaravone use at CY 5031 
baseline as well as the interaction terms of baseline-by-visit and treatment-by-visit. Least square means 
(LSM), LSM difference and the corresponding standard errors, 95% confidence intervals (CI) and p-
values will be presented. 
Slope endpoints will be analyzed using a mixed model which will include early-start and delayed-start 
treatment groups, CY 5031 baseline value, time from CY 5031 baseline, riluzole use at CY 5031 
baseline, edaravone use at CY 5031 baseline as well as interaction terms for treatment-by-baseline, and 
treatment-by-time, assuming random slope effect. The estimated slope and the slope difference as well 
as their standard errors will be presented. 
The time to event analyses will be conducted using proportional hazard Cox regression models and 
the Kaplan-Meier method. Time to event will be summarized by number of events, number of 
patients at risk, 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 early-start and delayed-start 
treatment groups and the corresponding 95% CIs and p-values will also be presented. A negative 
binomial regression method will be used to analyze for time to recurrent hospitalizations. Number of 
hospitalizations and total number of days in hospital will be summarized descriptively. 
Safety data will be analyzed descriptively in the safety analysis set of CY 5032, including all 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. 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 
 
 
Day 11 
Week 
4 
Week 
6 
Week 
8 
Week 
12 
Week 
16 
Week 
18 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
FU (or ED): 
Week 52* 
In Clinic 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Remote Visit 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination  
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Exam  
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight & BMI 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Concomitant Med Review  
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
AE/SAE Evaluation 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Safety Labs3 
X 
 
X4 
 
X 
 
X4 
 
X 
 
 
X 
 
 
X 
X 
Pregnancy test (WOCBP only)  
X5 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Study Drug Dosing 
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 
Hospitalizations 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DME Use 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ED=Early discontinuation; AE=adverse event; BMI=body mass index; SAE=serious adverse event; WOCBP=women of childbearing potential; ALSFRS-
R=Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; DME=Durable Medical Equipment  
*Drug dosing will not occur at the ED visit 
1=Day 1 of CY 5032 may occur on the same day as the Week 48 Visit or the FU Visit of CY 5031 or as a separate Day 1 Visit unique to CY 5032 that occurs after the 
CY 5031 FU Visit. If Day 1 in CY 5032 occurs more than 6-weeks after completion of the FU Visit in CY 5031, the initial dose of study drug will not be taken by the 
patient until their safety lab results are available and the estimated Glomerular Filtration Rate (eGFR)CysC ≥ 45 ml/min/1.73m2 and eGFRCr ≥ 45 ml/min/1.73m2, alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) <3 × upper limit of normal (ULN), and bilirubin is normal or if abnormal reported as non-clinically significant 
by the investigator. 
2=Physical Exam and Neurological Exam: Day 1 exams are only required if the patient enrolls in the OLE on the same day as the Week 48 visit in CY 5031 or at a 
separate Day 1 Visit unique to CY 5032 that occurs after the CY 5031 FU Visit; however, if a patient enrolls in the OLE at the FU visit in CY 5031, these exams do not 
need to be repeated on Day 1 of the OLE. 


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3=Clinical safety labs to include: Chemistry (collected every 3 months): 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, and glucose 
Urinalysis (collected every 3 months): specific gravity, pH, blood, protein, glucose, bilirubin, UPCR and microscopy 
TSH on Day 1, bHCG as applicable for WOCBP, FSH as required to determine menopausal status at Day 1 per Appendix 3 (Section 10.3). 
4=Remote clinical safety labs to include: Chemistry (collected at Week 6 and Week 18): ALP, ALT (SGPT), AST (SGOT), direct bilirubin, and total bilirubin. Remote 
clinical safety labs may be collected by a home health vendor in the patient’s home, or in the clinic, or by another method approved by the Sponsor. 
5=Pregnancy test: If a WOCBP has had a negative pregnancy test within 30 days, a pregnancy test is not needed on Day 1. If it has been >30 days, then it is required. 


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1.4. 
Key Contacts 
Sponsor’s Study Contact: 
Jacqueline Lee 
Senior Director, Clinical Operations 
Email:  CY5032ClinicalOperations@cytokinetics.com 
Phone:  +1 (650) 624-3017 
Cell:  
+1 (650) 291-5533 
Sponsor’s Medical Monitor: 
Andrew Wolff, MD, FACC 
Senior Vice President 
Senior Fellow, Clinical Research and Development 
Email:  CY5032MedicalMonitor@cytokinetics.com 
Phone:  +1 (650) 624-3008 
Cell:  
+1 (415) 603-9353 
Serious Adverse Event Reporting: Drug Safety 
Email:  CY5032DrugSafety@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 
 


Protocol CY 5032 
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2. 
INTRODUCTION 
This open-label extension trial of reldesemtiv is being conducted in patients with amyotrophic 
lateral sclerosis (ALS). 
2.1. 
Study Rationale 
Reldesemtiv, a fast skeletal muscle troponin activator, is being investigated as a potential therapy 
to slow the decline of skeletal muscle function in patients with ALS. Patients who have 
completed the Phase 3 clinical trial of reldesemtiv in patients with ALS, CY 5031, may continue 
to receive reldesemtiv in CY 5032. During the last 24 weeks of dosing in CY 5031, all patients 
receive open-label reldesemtiv; consequently, patients eligible for and entering CY 5032 all will 
have already demonstrated acceptable tolerance of reldesemtiv when they begin dosing. The 
OLE permits patients to continue to receive reldesemtiv after completion of CY 5031. The study 
will extend the overall duration of long-term safety, tolerability, and durability of effect during 
treatment of patients with ALS with reldesemtiv. 
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 United States (US) and European Union (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). 
Intravenously administered Radicava® (edaravone) was approved to treat patients with ALS in in 
Japan, South Korea, 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 was approved in Canada 
and the US on the basis of a 6-month clinical trial conducted in the US involving 


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137 participants randomized to 2 to 1 to 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). 
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 
All patients enrolled in CY 5032 will have completed dosing in CY 5031, and therefore will 
have tolerated reldesemtiv at a daily dose of at least 150 mg twice a day (BID) for at least 
24 weeks (and potentially for as long as 48 weeks) before enrolling in CY 5032. 
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 this OLE is reldesemtiv 300 mg twice a day and careful monitoring of renal function and liver 
enzymes will be implemented during the trial. 
Renal Safety  
For renal safety, the mitigation strategy includes renal function monitoring and detailed study 
drug dose management with the potential for a dosing interruption and down-titration of dose, as 
described in Section 7.3. 
Hepatic Safety  
For hepatic safety, the mitigation strategy includes liver function monitoring and reldesemtiv 
discontinuation criteria as described in Section 7.4. 
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 an opportunity to slow the decline in their function. 


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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 long-term safety and 
tolerability of reldesemtiv in patients with 
ALS 
• The incidence of adverse events (AEs) in the 
patient population 
Secondary 
• To assess the long-term effect of 
reldesemtiv on ALSFRS-R functional 
outcomes and hospitalization by 
comparing early-start to delayed-start 
groups from CY 5031 
• 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 from 
baseline of CY 5031 through CY 5032 Week 48 
and from Week 24 of CY 5031 through 
CY 5032 Week 48 
• Time to the first occurrence of dependence on 
assisted ventilation or death from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Changes in ALS Functional Rating Scale – 
Revised (ALSFRS-R) total score from baseline 
of CY 5031 through CY 5032 Week 48 and 
from Week 24 of CY 5031 through CY 5032 
Week 48 
• Slopes of the changes in ALSFRS-R total score 
from baseline of CY 5031 through CY 5032 
Week 48 and from Week 24 of CY 5031 
through CY 5032 Week 48 
• Time to the first hospitalization from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Time to recurrent hospitalizations from Day 1 
in CY 5031 through CY 5032 Week 48 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label extension with the selective fast skeletal muscle troponin activator, 
reldesemtiv, in patients with ALS who finished dosing (through Week 48) in CY 5031. 
Approximately 400 patients from the sites that participated in CY 5031 are expected to be 
enrolled in the open-label extension, CY 5032. 
Following enrollment, patients will continue the same dosing regimen of reldesemtiv as in the 
parent study (CY 5031); either 300 mg twice a day for a 600 mg total daily dose (TDD) for a 
period of 48 weeks, or if a patient down-titrated for any reason to 150 mg twice daily in 
CY 5031, will continue with the down-titrated dose in CY 5032. Reldesemtiv should be taken 
twice daily, morning and afternoon (at least 8 hours apart). 
At the end of 48 weeks, patients may transition to a reldesemtiv Managed Access Program 
(MAP). If the treating physician agrees to participate in the program, the treating physician’s 
patient(s) may be eligible to transition from the OLE to the MAP. 
Study Visits: 
Patient visits will occur as follows (6 in-clinic, 2 remote lab visits, and 8 remote visits): 
• Day 1 (will be dependent upon protocol approval at the site, can be Week 48 or Week 52 visit 
for CY 5031 or later when approval is received) 
• End of Week 4 (remote visit) 
• End of Week 6 (remote lab visit) 
• End of Week 8 (remote visit) 
• End of Week 12 (in clinic) 
• End of Week 16 (remote visit) 
• End of Week 18 (remote lab visit) 
• End of Week 20 (remote visit) 
• End of Week 24 (in clinic) 
• End of Week 28 (remote visit) 
• End of Week 32 (remote visit) 
• End of Week 36 (in clinic) 
• End of Week 40 (remote visit) 
• End of Week 44 (remote visit) 
• End of Week 48 (in clinic) 
• FU: End of Week 52 (in clinic) 
If a patient decides to discontinue reldesemtiv, the patient will come into the clinic for the 
Reldesemtiv Discontinuation Visit as soon as possible after the last dose was taken. 
Remote Visits 
Remote visits are defined as any contact with the patient at their home (or other location outside 
of the clinic) via telephone calls, telemedicine, and video contact. Day 1 visit must occur in-


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clinic. 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 and approve the change. 
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. 
4.2. 
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 and 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, the first dose on Day 1 may be administered. The site is 
to document the informed consent signature and the Day 1 date in the patient’s medical record 
and in/on the case report form (CRF). 
Prospective approval of a protocol deviation to recruitment and enrollment criteria, also known 
as a protocol waiver or exception, 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, but non-written consent is given, 
an impartial witness must sign the ICF form. 
102. Completed dosing in CY 5031  
103. 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 (as described in Appendix 3 [Section 10.3]) 
104. 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 (as described in 
Appendix 3 [Section 10.3]) and her male partner agrees 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)  


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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. 
5.2. 
Exclusion Criteria 
Patients will be excluded from the trial if any of the following criteria apply: 
201. Has taken investigational study drug (other than reldesemtiv) prior to dosing, within 
30 days or five half-lives of the prior agent, whichever is greater 
202. Presence on Day 1 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. 
203. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose 
of reldesemtiv in CY 5032 or a strong CYP3A4 inducer within 14 days prior to first 
dose of reldesemtiv in CY 5032 per Appendix 4 (Section 10.4) 
204. Use of a medication that is an OCT1/OCT2 substrate within 7 days prior to first dose of 
reldesemtiv in CY 5032 per Appendix 4 (Section 10.4) 
205. 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 Day 1. Patients also cannot be taking outside of a clinical 
trial certain investigational drugs (which includes drugs, supplements, and 
nutraceuticals) 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. 
5.3. 
Lifestyle Considerations 
Not applicable. 


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6. 
INVESTIGATIONAL PRODUCT 
This section describes the: investigational product (IP) (ie, reldesemtiv) intended to be 
administered to a trial patient according to the protocol. 
6.1. 
Study Drug Administered 
Table 2: 
Study Drug 
Arm Name 
Active 
IP/Product Name 
Reldesemtiv 
Type  
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
150 mg 
Dosage Level(s) 
2 tablets twice a day for 600 mg TDD 
Route of 
Administration 
Oral or via gastrostomy tube 
Use 
Experimental 
IMP  
IMP 
Sourcing 
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 
Excipients in Active 
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 ensure that any discrepancies are reported and 
resolved before use of the IP. 
Only patients enrolled 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. 
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). 


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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. 
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, 
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. 
A patient who has lost the ability to swallow tablets may crush the 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 percutaneous endoscopic gastrostomy (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. 
6.4. 
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. 


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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. 
Riluzole, edaravone, and the combination product of sodium phenylbutyrate and taurursodiol are 
permitted in the countries in which they are approved for the treatment of ALS. Patients who 
start or stop edaravone, riluzole, or the combination product of sodium phenylbutyrate and 
taurursodiol following Day 1 will be permitted to continue in the trial. 
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 
induce the activity of CYP3A4 should be avoided from 14 days before the start of dosing 
(Day 1) through the last day of dosing (Week 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. 
6.5. 
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 abnormal laboratory values, see Section 7.3. 
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 a phone or video 
call 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. 
Patients who experience a laboratory abnormality or adverse event requiring interruption of 
reldesemtiv while receiving 150 mg twice daily may resume reldesemtiv 150 mg twice daily 
once the laboratory value in question has returned to the threshold specified in the protocol for 
re-initiation of reldesemtiv; however, should the same laboratory abnormality requiring 
interruption of reldesemtiv recur, the patient must be permanently discontinued from 
reldesemtiv. 


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6.6. 
Access to Investigational Product after the End of the Study 
Cytokinetics plans to put in place a MAP for patients who complete 48 weeks of dosing in 
CY 5032. If the treating physician agrees to participate in the program, the treating physician’s 
patient(s) may be eligible to transition from the OLE to the MAP. 


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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, treatment 
may be resumed at a lower dose as outlined in Section 7.3 (Renal Function Monitoring). 
Patients who experience a laboratory abnormality or adverse event requiring interruption of 
reldesemtiv while receiving 150 mg twice daily may resume reldesemtiv 150 mg twice daily 
once the laboratory value in question has returned to the threshold specified in the protocol for 
re-initiation of reldesemtiv; however, should the same laboratory abnormality requiring 
interruption of reldesemtiv recur, the patient must be permanently discontinued from 
reldesemtiv. 
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 a phone or video call 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. 


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o The investigator should make best efforts to contact the Medical Monitor before 
considering any temporary interruption as a permanent discontinuation. 
• Permanent study drug discontinuation that is not preceded by a temporary study drug 
interruption 
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 6.5 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. 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 
• ALS progression 
• Patient wants to enter another ALS trial or receive an experimental therapy for the 
treatment of ALS  
• 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 via a phone or video call. 
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. 


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• 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. 
• 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. 
• Patient agrees to a mix of remote and in-clinic visits to obtain study data 
• Patient only agrees to allowing contact for determination of vital status  
• Patient withdraws consent (see Section 7.6) and does not agree to any further study 
procedures or visits. 
Assessments obtained at the early discontinuation (same as FU Visit at Week 52) 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 
Reldesemtiv will be held if: 
• Both 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) 
Reldesemtiv may be restarted at half the dose, or 1 tablet twice a day (150 mg BID) when: 
• Both 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, and eGFRCr will be obtained. These renal related 
laboratory results will be reviewed by the local investigator and the study drug should be held or 
restarted in the event the above criteria are met. 
Abnormal renal function tests meeting the above criteria will be repeated. The site investigator 
and medical monitor 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 for study drug to be resumed at a reduced dose. 
1. If reldesemtiv is re-initiated, it must be at the lower dose of 150 mg BID,  
or 
2. If the abnormal renal function test requiring interruption of reldesemtiv occurred during 
administration of 150 mg twice daily, reldesemtiv 150 mg twice daily may be resumed 
once the laboratory value in question has returned to the threshold specified in the 


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protocol for re-initiation of reldesemtiv; however, should the same abnormal renal 
function test requiring reldesemtiv interruption recur, the patient must be permanently 
discontinued from reldesemtiv. 
To accomplish this, the medical monitor may direct the laboratory assessments (serum cystatin 
C, eGFRCysC, serum creatinine, eGFRCr, and UPCR) to be repeated as often as twice a week until 
a final disposition is reached (ie, re-initiation of study drug at 150 mg BID or permanent 
discontinuation) is reached. 
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 (and if available, direct) 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 as described below meet the criteria for permanent discontinuation 
of reldesemtiv. Patients who meet the criteria for permanent discontinuation must not be re-
challenged. 
Criteria for permanent discontinuation of reldesemtiv 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) 
OR 
• TBL >3 × ULN at any time 
If any of the criteria above are met, reldesemtiv must be permanently discontinued. 
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: 


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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 
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, total (and if available, direct) bilirubin, and obtaining an 
INR within 48 hours  
• In cases of TBL >2 × ULN or INR >1.5, retesting of liver tests, total (and if available, 
direct) bilirubin, and INR within 48 hours  
Confirmed abnormal liver function tests (LFTs) and INR 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. 


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• Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL, 
as warranted: 
− 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 hepatology consult, as warranted (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. 
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. 


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• 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 may review public 
records as permitted by 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. 
• 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 10.1.7). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
There will be up to six clinic visits, two remote lab visits, and eight remote visits (that requires a 
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 5032 Visit Windows 
Visit 
Visit Window 
Start of Dosing (Day 1): clinic visit 
 
End of Week 4: remote visit 
28 days ±4 days 
End of Week 6: remote lab visit 
42 days ±4 days 
End of Week 8: remote visit 
56 days ±4 days 
End of Week 12: clinic visit 
84 days ±4 days  
End of Week 16: remote visit 
112 days ±4 days 
End of Week 18: remote lab visit 
126 days ±4 days 
End of Week 20: remote visit 
140 days ±4 days 
End of Week 24: clinic visit 
168 days ±4 days 
End of Week 28: remote visit 
196 days ±4 days 
End of Week 32: remote visit 
224 days ±4 days 
End of Week 36: clinic visit 
252 days ±4 days 
End of Week 40: remote visit 
280 days ±4 days 
End of Week 44: remote visit 
308 days ±4 days 
End of Week 48: clinic visit 
 336 days ±4 days 
FU: End of Week 52: clinic visit 
 364 days ±4 days 
Study procedures and their timing are summarized in the SoA (Section 1.3). If Day 1 in CY 5032 
occurs more than 6-weeks after completion of the FU Visit (Week 52) in CY 5031, the initial 
dose of study drug will not be taken by the patient until their safety lab results are available and 
the eGFRCysC ≥ 45 ml/min/1.73m2 and eGFRCr ≥ 45 ml/min/1.73m2, ALT/AST < 3 × ULN, and 
bilirubin is normal or if abnormal reported as non-clinically significant by the investigator. 
Prospective approval of a protocol deviation to recruitment and enrollment criteria, also known 
as a protocol waiver or exception, is not permitted. 
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. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Remote lab visits at Week 6 and Week 18 may occur in-clinic or by another method approved by 
the Sponsor if arrangements cannot be made for the home health vendor to draw lab samples at 
the patient’s home. 
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. 
8.1.2. 
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. 
8.1.3. 
Hospitalizations 
Hospitalizations experienced by a patient following enrollment in CY 5032 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 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 / radiologically 
inserted percutaneous gastronomy (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 
electronic data capture (EDC) system. Hospitalizations that are for social reasons, or those that 


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were planned 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 on Day 1 if the patient enrolls in the OLE on 
the same day as the Week 48 visit in CY 5031. If a patient enrolls in the OLE at the follow-up 
visit in CY 5031, a physical exam does not need to be repeated on Day 1 of the OLE. 
An abbreviated physical examination (consisting of an examination of general appearance, skin, 
lungs, cardiovascular and abdomen) will be performed at the Week 52 visit. 
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 Day 1 visit. Height that was recorded in CY 5031 can be used to calculate the 
body mass index (BMI). 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. 
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 on Day 1 if the patient enrolls in the 
OLE on the same day as the Week 48 visit in CY 5031. If a patient enrolls in the OLE at the 
follow-up visit in CY 5031, a neurological exam does not need to be repeated on Day 1 of the 
OLE. It will also be performed at the Week 52 visit as described in the Study Manual. 
8.2.4. 
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). 


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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 (a condition that occurred 
before the patient was exposed to reldesemtiv) 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. 
• Abnormal assessments, eg, change on physical examination, electrocardiogram (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 


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• 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. 
• 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. 
Definition of Adverse Event of Special Interest 
Adverse events of special interest (AESI) in the CY 5032 study are defined based on clinical and 
laboratory parameters. 
  
Clinically significant elevated transaminases and/or (total and if available, direct) bilirubin and 
manifestations of liver toxicity (e.g., 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 should be reported to Cytokinetics Drug Safety within 24 hours of awareness on an 
AESI Report Form. 
Any of the following criteria should be reported as Liver-Related AESIs: 
• Manifestations of liver toxicity 
• ALT or AST >8 × ULN  
• ALT or AST >5 × ULN but <8 × ULN for ≥2 weeks;  
• ALT or AST >5 × ULN but <8 × ULN and unable to adhere to monitoring;  
• ALT or AST >3 × ULN w/signs or symptoms consistent with hepatitis (ie, right upper 
quadrant pain /tenderness, fever, nausea, vomiting, jaundice) 
• TBL >3 X ULN 
• TBL >2 X ULN or INR >1.5 AND ALT or AST >3 x ULN AND no alternative cause is 
apparent 
 


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Manifestations of renal toxicity, including clinically significant decreases in eGFRCr and 
eGFRCysC and increases of UPCR, are also 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 on an AESI Report Form. 
 
Any of the following criteria should be reported as Renal-Related AESIs: 
• Manifestations of renal toxicity 
• Both eGFRCr, eGFRCysC < 30.0 ml/min/1.73m2  
• UPCR ≥ 3 mg protein/g creatinine (or ≥ 339 mg protein/mmol creatinine)  
In addition, if reldsemtiv has been temporarily interrupted or permanently discontinued related to 
renal labs that don’t meet the above criteria, this is also considered as Renal-Related AESIs. 
8.3.1.4. 
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 noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (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. 
8.3.1.5. 
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. 


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• 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. 
• 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. 
8.3.1.6. 
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. 
8.3.1.7. 
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. 
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 
aMedDRA Version 23.0 


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8.3.1.8. 
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 
after the last administration of study drug, whichever is later, are recorded in the AE CRF and 
immediately reported to Cytokinetics on an SAE Report Form (no later than 12 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:  
CY5032DrugSafety@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 immediately reported to 
Cytokinetics (no later than 12 hours following knowledge of the new information). Cytokinetics 
Drug Safety may contact the investigator to obtain further information. 
8.3.1.9. 
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 adverse 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. 


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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. 
8.3.1.10. 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. 
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. 
8.3.1.11. 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: CY5032DrugSafety@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. 


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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. 
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. 
• 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 
No pharmacokinetic testing will be done for this trial. 
8.6. 
Immunogenicity Assessments 
No immunogenicity assessments will be done for this trial. 


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8.7. 
Sample Storage 
The central laboratory will perform the standard safety testing described in this protocol. Any 
laboratory samples remaining after analysis may be temporarily stored for retesting and then will 
be destroyed. Laboratory samples will not be retained beyond the end of the study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Populations for Analyses 
The analysis populations are defined in Table 5. Efficacy comparisons will be based on the data 
collected during CY 5031 from the patients in the full analysis set (FAS) of CY 5031 plus the 
data collected during CY 5032 from the patients who were in the FAS of CY 5031 and enrolled 
into CY 5032. Safety comparisons will be based on the data collected during CY 5032. 
To minimize bias, the randomized treatment assignments in CY 5031 for those in the Safety 
Analysis Set in CY 5032 will be remained blinded to the site staff until the patients complete or 
terminate from the OLE. 
Table 5: 
Analysis Sets 
Analysis Set 
Description 
Full Analysis Set 
All enrolled patients who received any amount of study drug and 
have a baseline and at least one post baseline efficacy assessment 
during CY 5031, regardless of the enrollment status in the OLE.  
Safety Analysis Set 
All enrolled patients who received any amount of study drug in 
the OLE. 
9.2. 
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. 
9.2.1. 
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 early-start and delayed-start 
treatment groups in the planned analysis sets for all endpoints. For model-based analyses, least 
squares means, difference of least squares means between early-start and delayed-start treatment 
groups, their standard errors and 95% confidence intervals (CI), and two-sided p-values 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 the early-start and delayed-start treatment groups and the 
corresponding 95% CIs and p-values will also be presented. Analyses for comparisons will be 
conducted from baseline of CY 5031 through CY 5032 Week 48 and from Week 24 of CY 5031 
through CY 5032 Week 48. 
Comparisons between the delayed-start treatment group and the early-start treatment group will 
be presented using the nominal p-values at the two-sided 5% significance level. 
Listings will include patient ID, demographics, treatment assigned and other relevant items, and 
sorted by treatment assignment, patient ID and date of assessment. 


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Unless specified otherwise, efficacy and safety analyses will be performed on the full analysis 
set and safety analysis set respectively. Statistical analysis methods will be detailed in the SAP. 
9.2.2. 
Primary Endpoint 
The primary safety endpoint is the incidence of adverse events (AEs) in the patient population. 
9.2.3. 
Secondary Endpoint(s) 
The secondary outcome endpoint(s) of the OLE are: 
• 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 from baseline of CY 5031 through CY 5032 
Week 48 and from Week 24 of CY 5031 through CY 5032 Week 48 
• Time to the first occurrence of dependence on assisted ventilation or death from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Changes in ALSFRS-R total score from baseline of CY 5031 through CY 5032 Week 48 
and from Week 24 of CY 5031 through CY 5032 Week 48 
• Slopes of the changes in ALSFRS-R total score from baseline of CY 5031 through 
CY 5032 Week 48 and from Week 24 of CY 5031 through CY 5032 Week 48 
• Time to first hospitalization from Day 1 in CY 5031 through CY 5032 Week 48 
• Time to recurrent hospitalizations from Day 1 in CY 5031 through CY 5032 Week 48 
The analyses of the secondary endpoints in the FAS are as follows: 
9.2.3.1. 
Time-to Event Endpoints 
Time to event endpoints, such as time to first occurrence of dependence on assisted ventilation or 
death, time to first hospitalization will be estimated using the Kaplan-Meier method. A 
proportional hazards Cox regression model will be used to estimate the hazard ratio between the 
early-start and delayed-start treatment groups. The model may adjust for baseline riluzole use 
and baseline edaravone use. If the proportionality assumption does not hold, the log rank test will 
be used. More details will be described in the SAP. 
Time to recurrent hospitalizations will be assessed by a negative binomial regression where 
hospitalizations are considered as events, including terms for the stratification factors and 
treatment groups. Number of hospitalizations and total number of days in hospital will be 
summarized descriptively. 
9.2.3.2. 
Change from Baseline Endpoints 
Analyses for change from baseline of CY 5031 through CY 5032 Week 48 and from Week 24 of 
CY 5031 through CY 5032 Week 48 endpoints will be based on the data collected in CY 5031 in 
the FAS plus data collected during CY 5032 and performed with the methods below. 
The estimand of the first secondary endpoint (combined assessment of change in ALSFRS-R 
total score, time to dependence on assisted ventilation, and survival time from baseline of 
CY 5031 through CY 5032 Week 48 and from Week 24 of CY 5031 through CY 5032 Week 48) 
is the stratified Mann-Whitney probability of a more favorable status at CY 5032 Week 48 in the 
early-start group compared to the delayed-start group in the FAS, based on the joint ranks of the 


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combined assessments collected up to Week 48 in CY 5032, and accounting for the intercurrent 
events of deaths, onset of dependence on assisted ventilation and decline in ALSFRS-R total 
score. The detailed ranking methods for missing data for all intercurrent events 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 the early-start and delayed-start 
groups while adjusting for baseline riluzole use and baseline edaravone use. Stratified Mann-
Whitney probability as well as the p-value will be presented. 
If data permit, the change from baseline endpoints will be analyzed using a MMRM based on a 
restricted maximum likelihood method (SAS® PROC MIXED default). The model terms will 
include the early-start and delayed-start treatment groups, CY 5031 baseline value, visit, riluzole 
use at baseline, edaravone use at baseline as well as baseline-by-visit and treatment-by-visit 
interactions. An unstructured variance-covariance matrix will be used in the model. 
Observed data up to Week 48 of CY 5032 in the FAS will be included in the model. 
Assumptions for statistical models will be evaluated. If assumptions are substantially violated, 
alternative analysis methods will be considered. Missing data will not be imputed unless 
specified. Every attempt will be made to obtain ALSFRS-R measurements. 
Slope endpoints will be analyzed using a mixed model which will include the early-start and 
delayed-start treatment groups, CY 5031 baseline value, time, riluzole use at baseline, edaravone 
use at baseline as well as interaction terms of the treatment-by-baseline and treatment-by-time, 
assuming random slope effect. The estimated slope, the slope difference and the corresponding 
standard errors, and 95% CIs and p-values will be presented. 
9.2.4. 
Safety Analysis 
Safety data collected on or after the date that reldesemtiv was first dispensed in the CY 5032 
study up to the date of the last dose of reldesemtiv in the CY 5032 study will be summarized 
overall and by the early-start and delayed-start treatment groups in the safety analysis set, 
including all patients who take any amount of study drug. 
9.2.4.1. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is an AE with an onset after initiation of study drug 
dosing in CY 5032, or an AE present at initiation of study drug dosing that worsens in severity 
after initiation of study drug dosing. 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. TEAEs will 
also be summarized by severity and relationship to study drug. AEs that led to early 
discontinuation from treatment or the trial and adverse events of special interest will be 
summarized. Listings will be presented for patients who discontinued due to TEAEs. 
9.2.4.2. 
Serious Adverse Events 
All SAEs will be summarized by system organ class, preferred term, the early-start and delayed-
start treatment groups and overall, and by riluzole and edaravone use at baseline. Listings will be 
presented for patients who died and/or experienced serious AEs. 


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9.2.5. 
Patient Disposition 
The number of patients who are enrolled, who complete the planned treatment, and who 
prematurely discontinue from the planned treatment and/or the trial will be presented by the 
early-start and delayed-start treatment groups and overall. Reasons for premature discontinuation 
as recorded on the termination page of the CRF will be summarized by the early-start and 
delayed-start treatment groups and overall. 
9.2.6. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized descriptively by the 
early-start and delayed-start treatment groups 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. 
9.2.7. 
Investigational Product Exposure 
IP exposure will be summarized by the early-start and delayed-start treatment groups and overall, 
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. 
9.2.8. 
Concomitant Medications 
Concomitant medications will be summarized and classified by drug class and preferred term by 
the early-start and delayed-start treatment groups and overall using the World Health 
Organization (WHO) Drug Dictionary. The version of the WHO Drug Dictionary will be 
specified in the clinical study report. 
9.2.9. 
Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values and changes from baseline at each protocol 
specified assessment time point will be presented. 
9.2.10. 
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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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 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. 
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, contract 
research organizations (CROs)]. 


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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. 
10.1.6. 
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. 
10.1.7. 
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. 
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 
• 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 6 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 6: 
Protocol-Required Safety Laboratory Assessments 
Chemistry 
Urinalysis  
Other Assessments 
Sodium 
Total bilirubin1 
Specific gravity 
 TSH 
Potassium 
Direct bilirubin1 
pH 
Gamma-glutamyl 
transferase 
Indirect bilirubin1 
Blood 
Serum Beta Human 
Chorionic Gonadotropin2 
Chloride 
CK 
Protein 
FSH3 
Calcium 
ALP1 
Glucose 
 
Magnesium 
LDH 
Bilirubin 
 
Phosphorus 
AST (SGOT)1 
Microscopy 
 
Urea nitrogen 
ALT (SGPT)1 
UPCR 
 
Creatinine 
Cystatin C 
 
 
eGFRCr 
(calculated using the CKD-
EPI creatinine equation) 
eGFRCysC (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; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; 
TSH = Thyroid Stimulating Hormone; UPCR=urine protein creatinine ratio 
Investigators must document their review of each laboratory report. 
1=Additional remote clinical safety labs will be performed at Week 6 and Week 18 to include: ALP, ALT (SGPT), 
AST (SGOT), direct bilirubin, and total bilirubin. Remote clinical safety labs may be collected by a home health 
vendor in the patient’s home, or in the clinic, or by another method approved by the Sponsor. 
2=Pregnancy test is required for WOCBP (see Appendix 3 [Section 10.3]);  
3=FSH only at Day 1 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: 
Women 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). 
Female participants of childbearing potential should refrain from donating ova during the trial 
and for at least 10 weeks after the last dose of reldesemtiv. 
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 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALS 
Amyotrophic lateral sclerosis 
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 
BID 
Twice a day 
BMI 
Body mass index 
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 
DME 
Durable medical equipment 
EC 
Executive Committee 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
EDC 
Electronic Data Capture 


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Abbreviation/Term 
Explanation 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
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 
MedDRA 
Medication Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
NIMP 
Non-investigational medicinal product 
NIV 
Non-invasive ventilation 
OCT 
Organic cation transporter 
OLE 
Open Label Extension 
PT 
Preferred term 
REB 
Research Ethics Board 
SAE 
Serious adverse event 


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Abbreviation/Term 
Explanation 
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 
WHO 
World Health Organization 
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. 
 
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. 
 
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. 
 
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. 
 
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. 
 
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. 
 
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. 
 
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: 1.0 
DATE OF PLAN: 
16-JUN-2023 
 
 
STUDY DRUG: 
Reldesemtiv 
PROTOCOL NUMBER: 
CY 5032 
 
STUDY TITLE: 
A Phase 3, Open-Label Extension of COURAGE-ALS (CY 5031) 
 
BASED ON: 
Protocol Amendment 1: 16 December 2022 
 
SPONSOR: 
Cytokinetics, Inc. 
350 Oyster Point Blvd, 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*: 
 
 
 
 
 
 
Michael Chiu, MS 
Associate Director, Biostatistics 
Biometrics, Cytokinetics, Inc. 
 
Signature 
 
Date 
 
 
*See electronic signatures at the end of the document. 
 
This document has been reviewed and accepted by*: 
 
 
 
 
 
 
Lisa Meng, PhD 
VP, Biometrics 
Biometrics, Cytokinetics, Inc. 
 
Signature 
 
Date 
 
 
 
 
 
 
Andrew Wolff, MD 
SVP, Senior Fellow, Clinical Research and 
Development, Cytokinetics, Inc. 
 
Signature 
 
Date 
 
 
 
 
 
 
Stuart Kupfer, MD  
SVP, Chief Medical Officer 
Cytokinetics, Inc. 
 
Signature 
 
Date 


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
OBJECTIVES AND ENDPOINTS ..............................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.1.1. 
Primary Objective .........................................................................................................9 
2.1.2. 
Secondary Objective .....................................................................................................9 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary Endpoints ........................................................................................................9 
2.2.2. 
Secondary Endpoints ....................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Overall Design ............................................................................................................10 
3.1.1. 
Study Drugs ................................................................................................................10 
3.1.2. 
Dates and Points of Reference ....................................................................................10 
3.2. 
Sample Size Considerations .......................................................................................11 
3.3. 
Schedule of Assessment .............................................................................................11 
3.4. 
Clinical Assessments ..................................................................................................14 
3.4.1. 
Efficacy Assessments .................................................................................................14 
3.4.1.1. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-
R). ...............................................................................................................................14 
3.4.2. 
Safety Assessments .....................................................................................................14 
4. 
PLANNED ANALYSES ............................................................................................15 
4.1. 
Interim Analyses .........................................................................................................15 
4.2. 
Final Analyses ............................................................................................................15 
5. 
STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................16 
5.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........16 
5.2. 
Data Management .......................................................................................................16 
5.3. 
Data Presentation Conventions ...................................................................................16 
5.4. 
Analysis Population ....................................................................................................17 


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5.4.1. 
Safety Analysis Set .....................................................................................................17 
5.5. 
Baseline Definition .....................................................................................................17 
5.6. 
Derived and Transformed Data ..................................................................................17 
5.6.1. 
Demographics and Other Baseline Characteristics Variables ....................................17 
5.6.2. 
Study Day ...................................................................................................................17 
5.6.3. 
Change from Baseline .................................................................................................17 
5.6.4. 
Analysis Visit Windows .............................................................................................17 
5.6.5. 
Multiple Assessments .................................................................................................18 
5.7. 
Handling of Missing or Incomplete Dates/Times .......................................................18 
5.7.1. 
Medication Start and Stop Dates ................................................................................18 
5.7.2. 
Adverse Event Start and Stop Dates ...........................................................................18 
6. 
STUDY POPULATION .............................................................................................20 
6.1. 
Subjects Dispositions ..................................................................................................20 
6.2. 
Protocol Deviations ....................................................................................................20 
6.3. 
Demographics and Baseline Characteristics ...............................................................20 
7. 
EFFICACY .................................................................................................................21 
8. 
SAFETY AND TOLERABILITY ..............................................................................22 
8.1. 
Overall Summary of Tolerability ................................................................................22 
8.2. 
Adverse Events ...........................................................................................................22 
8.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects.................................22 
8.2.2. 
Summaries of Adverse Events of Special Interest ......................................................23 
8.3. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................24 
8.4. 
Concomitant and Other Medications ..........................................................................24 
8.5. 
Clinical Laboratory Data ............................................................................................24 
9. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ..........................................26 
10. 
REFERENCES ...........................................................................................................27 
11. 
APPENDIX.................................................................................................................28 
11.1. 
Table of Contents for Data Display Specifications ....................................................28 
11.2. 
Data Display Specifications ........................................................................................28 
11.3. 
Analysis Windows ......................................................................................................28 
 


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LIST OF TABLES 
Table 1:  
Schedule of Activities .................................................................................................12 
Table 2:  
Analysis Windows for ALSFRS-R .............................................................................28 
Table 3. 
Analysis Windows for Clinical Safety Laboratory Measurements ............................29 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline Phosphatase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
ED 
Early Discontinuation 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FU 
Follow-Up 
ICH 
International Council for Harmonisation 
LLN 
Lower Limit of Normal 
LSM 
Least Squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
OLE 
Open-label extension 
PCS 
Potential Clinical Significance 
PT 
Preferred Term 
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 


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Abbreviation 
Term 
TESAE 
Treatment-Emergent Serious Adverse Event 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization  
 


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1. 
INTRODUCTION 
This document describes the plan for the summarization and analysis of clinical data collected in 
CY 5032, an open-label extension of CY 5031. CY 5031 was terminated early by the Sponsor 
due to meeting the futility criteria at the CY 5031 second planned interim analysis. As a result, 
the analysis scope has been abbreviated, and certain analyses outlined in the protocol will not be 
conducted, see Section 9 for details. 
 
 


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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to assess the long-term safety and tolerability of 
reldesemtiv in patients with ALS. 
2.1.2. 
Secondary Objective 
The secondary objective of the study is to assess the long-term effect of reldesemtiv on 
ALSFRS-R functional outcomes and hospitalization by comparing early-start to delayed-start 
groups from CY 5031. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
The primary safety endpoint is the incidence of adverse events (AEs) in the patient population. 
2.2.2. 
Secondary Endpoints 
The secondary outcome endpoints are listed as follows: 
• Combined assessment of change in ALSFRS-R total score, time to dependence on 
assisted ventilation, and survival time from baseline of CY 5031 through CY 5032 
Week 48 and from Week 24 of CY 5031 through CY 5032 Week 48. Dependence on 
assisted ventilation is defined as using non-invasive or invasive ventilation for ≥ 22 hours 
per day for ≥ 10 consecutive days. 
• Time to the first occurrence of dependence on assisted ventilation or death from Day 1 in 
CY 5031 through CY 5032 Week 48 
• Changes in ALSFRS-R total score from baseline of CY 5031 through CY 5032 Week 48 
and from Week 24 of CY 5031 through CY 5032 Week 48 
• Slopes of the changes in ALSFRS-R total score from baseline of CY 5031 through 
CY 5032 Week 48 and from Week 24 of CY 5031 through CY 5032 Week 48 
• Time to the first hospitalization from Day 1 in CY 5031 through CY 5032 Week 48 
• Time to recurrent hospitalization from Day 1 in CY 5031 through CY 5032 Week 48 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is an open-label extension study with, reldesemtiv, in patients with ALS who finished 
dosing (through Week 48) in CY 5031 (COURAGE-ALS). 
Following enrollment, patients will continue the same dosing regimen of reldesemtiv, as in the 
parent study (CY5031); either 300 mg twice a day for a 600 mg total daily dose (TDD) for a 
period of 48 weeks; a patient who down-titrated for any reason to 150 mg twice daily in 
CY 5031 will continue with the down-titrated dose in CY 5032. Definitions 
3.1.1. 
Study Drugs 
This section describes the investigational product (IP) (ie, reldesemtiv) intended to be 
administered to a trial patient according to the protocol. 
Arm Name 
Active 
IP/Product Name 
Reldesemtiv 
Type  
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
150 mg 
Dosage Level(s) 
2 tablets twice a day for 600 mg TDD 
Route of Administration 
Oral or via gastrostomy tube 
Use 
Experimental 
IMP  
IMP 
Sourcing 
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 
Excipients in Active tablets Microcrystalline cellulose       Lactose monohydrate  
Croscarmellose sodium           Providone 
Sodium lauryl sulfate              Magnesium stearate  
IMP = investigational medicinal product; NIMP = non-investigational medicinal product 
3.1.2. 
Dates and Points of Reference 
First dose date of CY 5032 (OLE Day 1) 
For patients who roll over to the open-label extension from the parent study, the first dose date of 
CY 5032 will be defined as the date of first dose of study drug administration in CY 5032. The 
first dose date of CY 5032 may occur on the same day as the CY 5031 Week 48 visit if the 
rollover visit occurs in the morning, the next day following completion of the CY 5031 Week 48 


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visit if the rollover occurs in the afternoon, the Follow-Up (FU) visit of CY 5031, or as a 
separate Day 1 visit unique to CY 5032 that occurs after the CY 5031 FU visit. 
3.2. 
Sample Size Considerations 
This is an open-label, continuation study. Sample size will be determined by those eligible after 
successful completion of the preceding study, CY 5031. It is anticipated approximately 
400 patients will be enrolled. 
3.3. 
Schedule of Assessment 
Schedule of activities and assessments for the CY 5032 study are defined in the study protocol in 
section 1.3 and provided in Table 1. 
 
 
 


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Table 1:  
Schedule of Activities 
 
Day 
11 
Week 
4 
 
 
Week 
6 
Week 
8 
Week 
12 
Week 
16 
 
 
Week 
18 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48  
FU (or 
ED): 
Week 
52* 
In Clinic 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Remote Visit 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination  
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Exam  
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight & BMI 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Concomitant Med Review  
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
AE/SAE Evaluation 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Safety Labs3 
X 
 
X4 
 
X 
 
X4 
 
X 
 
 
X 
 
 
X 
X 
Pregnancy test (WOCBP 
only)  
X5 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Study Drug Dosing 
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 
Hospitalizations 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DME Use 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ED=Early discontinuation; AE=adverse event; BMI=body mass index; SAE=serious adverse event; WOCBP=women of childbearing potential; ALSFRS-
R=Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; DME=Durable Medical Equipment; FU = Follow-Up 
*Drug dosing will not occur at the ED visit 
1=Day 1 of CY 5032 may occur on the same day as the Week 48 Visit or the FU Visit of CY 5031 or as a separate Day 1 Visit unique to CY 5032 that occurs after the 
CY 5031 FU Visit. If Day 1 in CY 5032 occurs more than 6-weeks after completion of the FU Visit in CY 5031, the initial dose of study drug will not be taken by the 
patient until their safety lab results are available and the estimated Glomerular Filtration Rate (eGFR)CysC ≥45 ml/min/1.73m2 and eGFRCr ≥45 ml/min/1.73m2, alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) <3 × upper limit of normal (ULN), and bilirubin is normal or if abnormal reported as non-clinically significant 
by the investigator. 


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2=Physical Exam and Neurological Exam: Day 1 exams are only required if the patient enrolls in the OLE on the same day as the Week 48 visit in CY 5031 or at a 
separate Day 1 Visit unique to CY 5032 that occurs after the CY 5031 FU Visit; however, if a patient enrolls in the OLE at the FU visit in CY 5031, these exams do not 
need to be repeated on Day 1 of the OLE. 
3=Clinical safety labs to include: Chemistry (collected every 3 months): 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, and glucose 
Urinalysis (collected every 3 months): specific gravity, pH, blood, protein, glucose, bilirubin, UPCR and microscopy 
TSH on Day 1, bHCG as applicable for WOCBP, FSH as required to determine menopausal status at Day 1 per Appendix 3 (refer to study Protocol section 10.3) 
4=Remote clinical safety labs to include: Chemistry (collected at Week 6 and Week 18): ALP, ALT (SGPT), AST (SGOT), direct bilirubin, and total bilirubin. Remote 
clinical safety labs may be collected by a home health vendor in the patient’s home, or in the clinic, or by another method approved by the Sponsor. 
5=Pregnancy test: If a WOCBP has had a negative pregnancy test within 30 days, a pregnancy test is not needed on Day 1. If it has been >30 days, then it is required. 


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3.4. 
Clinical Assessments 
3.4.1. 
Efficacy Assessments 
3.4.1.1. 
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. 
3.4.2. 
Safety Assessments 
Safety assessments include adverse events and serious adverse events, laboratory assessments, 
neurological examinations, physical examinations and vital signs. 
 
 


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
No formal interim analysis is planned for this open-label study. 
4.2. 
Final Analyses 
The final analysis was planned to be performed when all patients who enrolled in the CY 5032 
study have completed the study, all outstanding queries resolved, and the database cleaned and 
finalized. 
Since the study was terminated early by the Sponsor due to futility in the parent study, after the 
database has been cleaned to the extent for safety assessments and locked, one final analyses of 
all data will be conducted for an abbreviated CSR. 
 
 


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5. 
STATISTICAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
5.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Unless specified otherwise, analyses of efficacy endpoints will be performed based on the data 
collected during CY 5032. 
Descriptive statistics to be presented in a table include count of patients, mean, median, standard 
deviation, Q1, Q3, minimum and maximum for continuous variables, and count of patients and 
the percentage for categorical variables. 
For model-based analyses, least squares means and the corresponding standard errors and 95% 
confidence intervals (CIs) for the relative statistical inferences will be presented. 
5.2. 
Data Management 
Data will be entered into the clinical database with programmed edit checks and direct visual 
inspection to ensure integrity. Adverse events and concomitant medications will be coded 
programmatically while unique terms will be reviewed visually. Clinical safety laboratory will 
be provided in the pre-specified format from external laboratories or research organizations. 
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. 
Every attempt will be made to obtain measurements to minimize the percent of missing data. 
5.3. 
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. 
• Clinical safety laboratory test values will be presented in conventional and/or System 
International (SI) units. 
The tables and listing shells and the table of contents as part of this SAP provide the expected 
layout and title of the tables, listings and figures. Any changes to format, layout, titles, 
numbering, or any other minor deviation will not necessitate a revision to this 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. 


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5.4. 
Analysis Population 
5.4.1. 
Safety Analysis Set 
The Safety Analysis Set consists of all patients who receive any amount of study drug in this 
study. 
5.5. 
Baseline Definition 
For eligible patients who consent to participate in the open-label extension, the last available 
assessment taken prior to the administration of the first dose of CY 5032 study drug will serve as 
the baseline of CY 5032. 
5.6. 
Derived and Transformed Data 
5.6.1. 
Demographics and Other Baseline Characteristics Variables 
Demographics and baseline characteristics will be obtained from the information collected at 
CY 5032 baseline. 
5.6.2. 
Study Day 
Study day will be using the CY 5032 first dose date (OLE Day 1) as reference. If the date of 
interest occurs on or after the first dose date in CY 5032, then study day will be calculated as 
(date of interest – OLE Day 1) + 1. If the date of interest occurs prior to the first dose date in 
CY 5032, then study day will be calculated as (date of interest – OLE Day 1). 
5.6.3. 
Change from Baseline 
For efficacy endpoints (e.g., ALSFRS-R), change from baseline will be calculated as (post-
baseline value – baseline value). If either the baseline or the post-baseline value is missing, the 
change from baseline will be set to missing. 
5.6.4. 
Analysis Visit Windows 
All assessments will be summarized using analysis windows. 
Measurements taken on or after the first dose of open-label study drug (i.e., OLE Day 1) will be 
assigned to the next scheduled analysis window. 
For data collected at a scheduled post OLE Day 1 visit, the analysis window will be assigned 
based on the scheduled study day of the nominal visit as collected on the eCRF. Visits are 
identified as the nominal visits according to the eCRFs. Each visit will be identified with the visit 
descriptor (eg, “OLE Week 24”). 
For unscheduled post-baseline visits, early discontinuation visits or follow-up visit, 
measurements taken on or after the first dose of open-label 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 11.3). 


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Visits are identified as the nominal visits according to the eCRFs. Each visit will be identified 
with the visit descriptor (eg, “OLE 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. 
5.6.5. 
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. 
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 more than one assessment from visits other than ET or EOS visits mapped to the same 
analysis visit and on the same day, the later one will be used for analysis. 
• 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” 
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. Composite scores such as ALSFRS-R total score will be calculated based on the 
“analyzed record”. 
5.7. 
Handling of Missing or Incomplete Dates/Times 
5.7.1. 
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 of CY 5032. 
• 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. 
5.7.2. 
Adverse Event Start and Stop Dates 
Events where the onset date is the same as study drug start date are assumed to be treatment-
emergent. If an incomplete onset date was collected for an adverse event, the event will be 
assumed to be treatment-emergent unless there is other evidence that confirms that the event was 
not treatment-emergent (e.g., the event end date was prior to the study drug start date). 


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For missing or partial onset dates: 
• If date is completely missing, assign the first dose date of CY 5032 unless there is other 
evidence that confirms that the event was not treatment-emergent (e.g., the event end date 
was prior to the first dose of CY 5032). 
• If the day is missing, and the month and year match the month and year of the first dose 
date in CY 5032, then the day of the first dose date of CY 5032 will be used. Otherwise, 
the first of the month will be used and the treatment emergent status will be assessed 
relative to the first dose date of CY 5032. 
• If the day and month are missing, and the year matches the year of the first dose date of 
CY 5032, the month and day of the first dose date of CY 5032 will be used. Otherwise, 
January 1st will be used and the treatment emergent status will be assessed relative to the 
first dose date of CY 5032. 
For missing or partial end dates: 
• If the day is missing and month and year are present, then assign to the last day of the 
month or the date of last contact with the patient, whichever is the earlier. 
• If the day and month are missing and only the year is present, then assign to December 31st 
or the last date of contact with the patient, whichever is the earlier. 
• For patients who discontinued early from the study drug and have missing end dates, 
assign to the last dosing date + 28 days or the last contact date with the patient, whichever 
is the later. 
• For patients who completed the study and have missing end dates, assign to the date of 
the Follow-Up visit. 
• If the end date is missing and the event is ongoing, the event will be noted as ‘ongoing’ in 
the end date column in data listings. 
 
 


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6. 
STUDY POPULATION 
6.1. 
Subjects Dispositions 
The count and percentage of patients who were enrolled, who received at least one dose of study 
drug, who completed the study treatment, and who prematurely discontinued from the study drug 
and/or from the study will be presented. Reasons for premature discontinuation will also be 
summarized. 
6.2. 
Protocol Deviations 
The clinical team will identify deviations and deviations will be recorded into the database. 
6.3. 
Demographics and Baseline Characteristics 
Demographic data, including age (in years), sex, race, ethnicity, height, weight, BMI, tobacco 
and alcohol use, etc., will be summarized in the FAS. 
 
 


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7. 
EFFICACY 
The analysis on the efficacy endpoints has been condensed due to futility in the parent study. The 
change in ALSFRS-R from CY 5032 baseline will be summarized descriptively by visit. 
 
 


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8. 
SAFETY AND TOLERABILITY 
All safety analyses will be performed by overall in the Safety Analysis Set. Safety assessments 
include: 
• AE 
• Laboratory tests 
• Vital signs including temperature, blood pressure, pulse rate, and weight 
• Physical and neurological examinations 
Baseline is defined as last available assessment obtained in the preceding study CY 5031 or 
taken prior to the administration of the first dose of CY 5032 study drug. 
8.1. 
Overall Summary of Tolerability 
Overall summary table, including number of patients with: 
• TEAEs 
• Serious AEs (TESAEs) 
• Study drug related TEAEs 
• TEAEs by severity 
• TEAEs leading to dose reduction 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to death 
8.2. 
Adverse Events 
8.2.1. 
Summaries of Adverse Event Incidence Rates for All Subjects 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities(MedDRA) version 26.0. 
Analyses of AEs will be performed for those events that are considered treatment emergent AEs 
(TEAEs), where treatment emergence is defined as any adverse events with an onset after 
initiation of study drug dosing in CY 5032, or an AE present at initiation of study drug dosing 
that worsens in severity after initiation of study drug dosing. If an AE had the onset in the 
preceding study CY 5031 and carry over to the open-label extension, it will not be considered as 
treatment emergent in CY 5032 data. 
The following summaries of AEs and serious AEs (SAEs) will be presented by overall:  
• TEAEs by SOC and PT 
• TEAEs by PT 
• TEAEs by SOC, PT and Severity (Grade 1-5) 
• TEAEs related to study drug by SOC and PT 


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• TEAEs related to study drug by PT 
• TESAEs by SOC and PT 
• TESAEs by PT 
• TESAEs related to study drug by PT 
• TEAEs leading to drug discontinuation by PT 
• TEAEs leading to death 
AE summaries will be presented by descending order of PT in the overall column, and if 
applicable, SOC will be ordered first, with PT sorted within the SOC. 
A patient will be counted only once within each SOC and PT. For the summary of AEs by 
severity, patients will be counted only once within each primary SOC/preferred term and will 
only be counted under the maximum severity. 
8.2.2. 
Summaries of Adverse Events of Special Interest  
Adverse events of special interest (AESI) in the CY 5032 study are defined based on clinical and 
laboratory parameters. Results for AESI will be reviewed individually. No summary table will be 
provided. 
Clinically significant elevated transaminases and/or (total and if available, direct) bilirubin and 
manifestations of liver toxicity (e.g., 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 should be reported to Cytokinetics Drug Safety within 24 hours of awareness on an 
AESI Report Form. 
Any of the following criteria should be reported as Liver-Related AESIs: 
• Manifestations of liver toxicity 
• ALT or AST >8 × ULN  
• ALT or AST >5 × ULN but <8 × ULN for ≥2 weeks 
• ALT or AST > 5 × ULN but <8 × ULN and unable to adhere to monitoring 
• ALT or AST >3 × ULN w/signs or symptoms consistent with hepatitis (i.e., right upper 
quadrant pain /tenderness, fever, nausea, vomiting, jaundice) 
• TBL >3 X ULN 
• TBL >2 X ULN or INR >1.5 AND ALT or AST >3 x ULN AND no alternative cause is 
apparent 
 
Manifestations of renal toxicity, including clinically significant decreases in eGFRCr and 
eGFRCysC and increases of UPCR, are also 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 on an AESI Report Form. 
 
Any of the following criteria should be reported as Renal-Related AESIs: 
• Manifestations of renal toxicity 
• Both eGFRCr, eGFRCysC < 30.0 ml/min/1.73m2  


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• UPCR ≥ 3 mg protein/g creatinine (or ≥ 339 mg protein/mmol creatinine)  
In addition, if reldsemtiv has been temporarily interrupted or permanently discontinued related to 
renal labs that don’t meet the above criteria, this is also considered as Renal-Related AESIs. 
Study drug dose management with the potential for a dosing interruption and down-titration of 
dose will be applied. 
8.3. 
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 overall. 
8.4. 
Concomitant and Other Medications 
Concomitant medications reported on the eCRF will be listed. The WHO Drug Dictionary will 
be used to classify medications by therapeutic class (ATC Class 3) and preferred name. Coding 
will be performed using WHO Drug Dictionary Enhanced with Herbal Dictionary, B3, SEP 
2020. 
8.5. 
Clinical Laboratory Data 
Abnormal post-baseline results in Alanine Aminotransferase (ALT), Aspartate Aminotransferase 
(AST), Alkaline Phosphatase (ALP) and Total Bilirubin (BILI) will be summarized by overall in 
the Safety Analysis Set, with the following categories: 
For ALT or AST: 
• ≤ Upper Limit of Normal (ULN),  
• >ULN - 3x ULN,  
• >3x ULN - 5x ULN,  
• >5x ULN - 8x ULN,  
• >8x ULN 
For Total Bilirubin: 
• ≤ ULN,  
• >ULN - 2x ULN,  
• >2x ULN – 3x ULN 
• >3x ULN 
For more than one liver function test: 
• ALT or AST > 3x ULN and total bilirubin > 2x ULN 
• ALT or AST > 3x ULN and total bilirubin > 2x ULN and ALP < 2xULN 
• ALT or AST > 3 x ULN with signs/symptoms including nausea, vomiting, abdominal 
pain, fatigue, rash, dark-colored urine, light-colored bowel movements, jaundice, loss of 
appetite or fever. 
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 


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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. 
Patients fulfilling any of the individual criteria (ALT/AST, ALP, or BILI) will be listed, and the 
listing will include all available ALT, AST, BILI, and ALP, sorted by assessment date in 
ascending order. 
 
 


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9. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
As the study is prematurely stopped by Sponsor’s decision, no formal statistical analysis will be 
produced. Only disposition, demographic and baseline characteristics, an overview of AEs and 
abnormal liver lab results will be summarized by table. By-subjects data listing will be produced 
for those with liver abnormality. 


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10. 
REFERENCES 
 
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. 
 


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11. 
APPENDIX 
11.1. 
Table of Contents for Data Display Specifications 
Table of contents for data display specifications will be provided in a separate document. 
11.2. 
Data Display Specifications 
Data display specifications will be provided in a separate document. 
11.3. 
Analysis Windows 
Table 2:  
Analysis Windows for ALSFRS-R 
Visit 
Scheduled Day [Lower bound, Upper bound] 
OLE Day 1 
1 [<=OLE Day 1] 
OLE Week 4 
29 [2, 42] 
OLE Week 8 
57 [43, 70] 
OLE Week 12 
85 [71, 98] 
OLE Week 16 
113 [99, 126] 
OLE Week 20 
141 [127, 154] 
OLE Week 24 
169 [155, 182] 
OLE Week 28 
197 [183, 210] 
OLE Week 32 
225 [211, 238] 
OLE Week 36 
253 [239, 266] 
OLE Week 40 
281 [267, 294] 
OLE Week 44 
309 [295, 322] 
OLE Week 48 
337 [323, 350] 
OLE Week 52 
365 [>=351] 
 
 
 


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Table 3. 
Analysis Windows for Clinical Safety Laboratory Measurements 
Visit 
Scheduled Day [Lower bound, Upper bound] 
OLE Day 1 
1 
OLE Week 6 
43 [2, 63] 
OLE Week 12 
85 [64, 105] 
OLE Week 18 
127 [106, 147] 
OLE Week 24 
169 [148, 210] 
OLE Week 36 
253 [211, 294] 
OLE Week 48 
337 [295, 350] 
OLE Week 52 
365 [>=351] 
 


Signature Manifest
Document Number: PRD-0368
Revision: 00
Title: CY 5032 - Abbreviated SAP Version1 - A Phase 3, Open-Label Extension of COURAGE-ALS
(CY 5031)
Effective Date: 28 Jun 2023
All dates and times are in Pacific Time.
CY 5032 - Abbreviated SAP Version1 - A Phase 3, Open-Label Extension of COURAGE-ALS (CY 5031)
 
1: Electronic Approvals
Name/Signature
Title
Date
Meaning/Reason
Stuart Kupfer (SKUPFER)
SVP, Chief Medical Officer
27 Jun 2023, 10:40:54 AM
Approved
Michael Chiu (MCHIU)
Associate Director, Biostatistics 27 Jun 2023, 10:42:08 AM
Approved
Lisa (Lixin) Meng (LMENG)
Vice President, Biometrics
27 Jun 2023, 09:05:27 PM
Approved
Andrew Wolff (AWOLFF)
SVP Senior Fellow, CR&D
28 Jun 2023, 11:16:30 AM
Approved