A Phase 2, Multi-Center, Double-Blind, Randomized, Dose-Ranging, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of CK-2127107 in Patients With Amyotrophic Lateral Sclerosis (ALS)
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Cytokinetics

CONFIDENTIAL 
 
Protocol CY 5022 
CY 5022 Protocol Amendment 03: 18 Apr 2018 
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PROTOCOL CY 5022 
 
A PHASE 2, MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, DOSE-RANGING, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND 
TOLERABILITY OF CK-2127107 IN PATIENTS WITH 
AMYOTROPHIC LATERAL SCLEROSIS (ALS)  
 
Product:  
 
 
 
CK-2127107 
 
EudraCT Number:  
2018-000586-37 
 
Sponsor:  
 
 
 
Cytokinetics Inc. 
 
 
 
 
 
 
 
280 East Grand Avenue 
South San Francisco, California 94080 
 
Original Protocol: 
 
6 March 2017 
Amendment 01:  
 
23 March 2017 
Amendment 01.1: 
16 June 2017 (CANADA) 
Amendment 02: 
31 August 2017 
Amendment 02.1: 
18 February 2018 (EUROPE) 
Amendment 03: 
18 April 2018 
 
 
CONFIDENTIAL  
DO NOT COPY OR REPRODUCE 
WITHOUT CONSENT OF CYTOKINETICS, INC. 
 
 
Sponsor (Medical Monitor) Signature:___________________________________________ 
 
Lead Investigator Signature:___________________________________________________ 

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TABLE OF CONTENTS 
STUDY IDENTIFICATION ...........................................................................................................8 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
1. 
INTRODUCTION ......................................................................................................13 
1.1. 
Background .................................................................................................................13 
1.2. 
Overview of CK-2127107 Nonclinical Studies ..........................................................13 
1.3. 
Overview of CK-2127107 Clinical Studies ................................................................14 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objective .......................................................................................................17 
2.1.1. 
Primary Efficacy Endpoint .........................................................................................17 
2.2. 
Secondary Objectives .................................................................................................17 
2.2.1. 
Secondary Endpoints ..................................................................................................17 
2.3. 
Exploratory Objectives ...............................................................................................17 
2.3.1. 
Exploratory Endpoints ................................................................................................18 
2.4. 
Pharmacokinetic / Pharmacodynamic Objective ........................................................18 
3. 
STUDY OVERVIEW .................................................................................................19 
3.1. 
Study Design ...............................................................................................................19 
3.2. 
Study Rationale ...........................................................................................................20 
3.3. 
Dose Rationale ............................................................................................................20 
4. 
STUDY POPULATION .............................................................................................22 
4.1. 
Inclusion Criteria ........................................................................................................22 
4.2. 
Exclusion Criteria .......................................................................................................23 
5. 
STUDY PROCEDURES ............................................................................................25 
5.1. 
Screening ....................................................................................................................25 
5.2. 
First Dosing Day (Day 1) ...........................................................................................25 
5.3. 
Week 2 Visit ...............................................................................................................26 
5.4. 
Week 4 Visit ...............................................................................................................27 
5.5. 
Week 8 Visit ...............................................................................................................28 
5.6. 
Week 12 Visit .............................................................................................................29 
5.7. 
Follow-Up Visit ..........................................................................................................29 
5.8. 
Early Termination Visit ..............................................................................................30 

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5.9. 
Visit Windows ............................................................................................................31 
5.10. 
Diet Control ................................................................................................................31 
5.11. 
Concomitant Medications ...........................................................................................32 
5.12. 
Pharmacokinetic Sampling .........................................................................................32 
5.13. 
Clinical Safety Assessments .......................................................................................32 
5.13.1. 
Clinical Laboratory Evaluations .................................................................................32 
5.13.2. 
12-Lead Electrocardiograms .......................................................................................32 
5.13.3. 
Vital Signs ..................................................................................................................33 
5.13.4. 
AE Assessments ..........................................................................................................33 
5.13.5. 
Physical Examinations ................................................................................................33 
5.13.6. 
Neurological Examinations ........................................................................................33 
5.13.7. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) ......................................33 
5.13.8. 
Falls Assessment .........................................................................................................33 
5.13.9. 
Ashworth Scale ...........................................................................................................33 
5.14. 
Clinical and Pharmacodynamic Outcome Measures ..................................................33 
5.14.1. 
Pulmonary Function Assessment ................................................................................33 
5.14.2. 
Hand-Held Dynamometry ..........................................................................................34 
5.14.3. 
ALSFRS-R ..................................................................................................................34 
5.14.4. 
Voice Recording .........................................................................................................34 
5.14.5. 
Fine Motor Assessments (Handwriting and Figure Tracing) .....................................34 
5.14.6. 
ALSAQ-5 ....................................................................................................................34 
5.14.7. 
Health Economic Outcomes Measures .......................................................................34 
5.15. 
Removal of Patients from Study Participation ...........................................................34 
5.16. 
Assessment of Safety ..................................................................................................36 
5.17. 
Study Drug Interruption ..............................................................................................36 
5.18. 
Study Discontinuation ................................................................................................36 
6. 
INVESTIGATIONAL PRODUCT ............................................................................37 
6.1. 
Description of Investigational Product .......................................................................37 
6.2. 
Dose Administration (CK-2127107 or Placebo) ........................................................37 
6.3. 
Dosing Diary ...............................................................................................................37 
6.4. 
Randomization Schedule and Removal of Blind ........................................................37 
6.5. 
Study Drug Accountability and Disposal ...................................................................38 
7. 
ADVERSE EVENTS..................................................................................................39 

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7.1. 
Definitions ..................................................................................................................39 
7.1.1. 
Adverse Event .............................................................................................................39 
7.1.2. 
Serious Adverse Event ................................................................................................40 
7.2. 
Collection of AEs/SAEs .............................................................................................41 
7.3. 
Recording and Reporting of AEs/SAEs .....................................................................41 
7.3.1. 
Recording and Reporting of AEs ................................................................................41 
7.3.2. 
Recording and Reporting of SAEs .............................................................................41 
7.4. 
Evaluating AEs and SAEs ..........................................................................................42 
7.4.1. 
Assessment of Severity ...............................................................................................42 
7.4.2. 
Assessment of Causality .............................................................................................42 
7.4.3. 
Assessment of Expectedness ......................................................................................43 
7.5. 
Follow-Up of AEs and SAEs ......................................................................................43 
7.6. 
Post-Study AEs/SAEs .................................................................................................44 
7.7. 
Pregnancy ...................................................................................................................44 
8. 
STATISTICAL METHODS .......................................................................................45 
8.1. 
General Considerations ...............................................................................................45 
8.1.1. 
General Approach .......................................................................................................45 
8.1.2. 
Sample Size and Randomization ................................................................................45 
8.2. 
Analysis Sets ...............................................................................................................45 
8.2.1. 
Full Analysis Set (FAS) ..............................................................................................45 
8.2.2. 
Safety Analysis Set (SAS) ..........................................................................................45 
8.2.3. 
Pharmacokinetics Analysis Set (PKS) ........................................................................45 
8.3. 
Endpoints ....................................................................................................................46 
8.3.1. 
Efficacy Endpoints ......................................................................................................46 
8.3.1.1. 
Primary Efficacy Endpoint .........................................................................................46 
8.3.1.2. 
Secondary Efficacy Endpoints ....................................................................................46 
8.3.1.3. 
Exploratory Efficacy Endpoints .................................................................................46 
8.3.2. 
Safety Endpoints .........................................................................................................46 
8.3.3. 
Pharmacokinetic Measurements .................................................................................47 
8.4. 
Statistical Analysis ......................................................................................................47 
8.4.1. 
Patient Disposition ......................................................................................................47 
8.4.2. 
Demographics and Other Baseline Characteristics .....................................................47 
8.4.3. 
Prior and Concomitant Medications ...........................................................................47 

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8.4.4. 
Efficacy Analysis ........................................................................................................47 
8.4.4.1. 
Primary Efficacy Analysis ..........................................................................................47 
8.4.4.2. 
Secondary Efficacy Analysis ......................................................................................47 
8.4.4.3. 
Exploratory Efficacy Analysis ....................................................................................48 
8.4.4.4. 
Multiplicity .................................................................................................................48 
8.4.5. 
Safety Analysis ...........................................................................................................48 
8.4.5.1. 
Study Drug Exposure ..................................................................................................48 
8.4.5.2. 
Adverse Event .............................................................................................................48 
8.4.5.3. 
Serious Adverse Event ................................................................................................48 
8.4.5.4. 
Clinical Laboratory Parameters ..................................................................................48 
8.4.5.5. 
Vital Signs ..................................................................................................................49 
8.4.5.6. 
ECGs ...........................................................................................................................49 
8.4.5.7. 
Physical and Neurological Examinations ...................................................................49 
8.4.5.8. 
Ashworth Score ..........................................................................................................49 
8.4.5.9. 
Falls Assessments .......................................................................................................49 
8.4.5.10. 
Beck Depression Inventory-Fast Screen .....................................................................49 
8.4.6. 
Exposure-Response Analysis......................................................................................49 
8.4.7. 
Pharmacokinetic Analysis ..........................................................................................49 
8.5. 
Interim Analysis ..........................................................................................................50 
8.6. 
Statistical Software .....................................................................................................50 
8.7. 
Changes in Statistical Methods ...................................................................................50 
9. 
ADMINISTRATIVE ASPECTS ................................................................................51 
9.1. 
Change in Protocol .....................................................................................................51 
9.2. 
Initiation Visit .............................................................................................................51 
9.3. 
Disclosure ...................................................................................................................51 
9.4. 
Monitoring ..................................................................................................................51 
9.5. 
Institutional Review Board/Research Ethics Board/Ethics Committee ......................51 
9.6. 
Informed Consent .......................................................................................................52 
9.7. 
Records .......................................................................................................................52 
9.8. 
Reference to Good Clinical Practices (GCP) ..............................................................52 
10. 
REFERENCES ...........................................................................................................53 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................54 

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APPENDIX B. MEDICATIONS AND FOODS THAT INHIBIT OR INDUCE 
CYP3A4 OR ARE OCT1/OCT2 SUBSTRATES ......................................................55 
APPENDIX C. LIVER SAFETY MONITORING AND ASSESSMENT.................................56 
APPENDIX D. CLINICAL LABORATORY EVALUATIONS ...............................................59 
 
 
 

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LIST OF TABLES 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups ..........................................19 
Table 2: 
Visit Windows ............................................................................................................31 
Table 3: 
Pharmacokinetic (PK) Samples ..................................................................................32 
Table 4: 
Study Drug ..................................................................................................................37 
Table 5: 
MedDRA Preferred Terms .........................................................................................43 
 
LIST OF FIGURES 
Figure 1: 
Patient Visit Diagram .................................................................................................20 
Figure 2: 
CY 5013: Increases in Force during Nerve Stimulation in Healthy 
Volunteers ...................................................................................................................21 
 
 

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STUDY IDENTIFICATION 
Sponsor 
Cytokinetics, Inc. 
280 East Grand Avenue 
South San Francisco, California, 94080 
(650) 624-3000 (Main Telephone) 
(650) 624-3010 (Main Facsimile) 
 
Sponsor’s Study Contact 
Jacqueline Lee 
Director, Clinical Operations 
Cytokinetics, Inc. 
jlee@cytokinetics.com 
(650) 624-3017 (Office Telephone) 
(650) 291-5533 (Mobile Telephone) 
(650) 624-3225 (Office Facsimile) 
 
 Sponsor’s Medical Monitor  
Stacy Rudnicki, MD 
Senior Medical Director, Clinical Research, Neurology 
Cytokinetics, Inc. 
srudnicki@cytokinetics.com 
(650) 624-3269 (Office Telephone) 
(650) 515-2524 (Mobile Telephone) 
 
Lead Investigator 
Jeremy Shefner, MD, PhD 
Professor & Chair of Neurology 
Barrow Neurological Institute 
jeremy.shefner@dignityhealth.org 
(315) 378-8531 (Mobile Telephone) 
 
Study Site 
Multi-Center 
 
 
 

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Cytokinetics. 
• Not to amend the protocol without agreement, prior review, and written approval 
from the Institutional Review Board (IRB)/Ethics Committee (EC) except where 
necessary to eliminate an immediate hazard to the patients. 
• That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in this protocol and any other information provided by the 
Sponsor including, but not limited to, the following: the current Investigator’s 
Brochure (IB) or equivalent document. 
• That I am aware of, and will comply with, “Good Clinical Practices” (GCP) and all 
applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed about 
the Cytokinetics investigational product(s) and of their study-related duties and 
functions as described in the protocol. 
• That I have been informed that certain regulatory authorities require the Sponsor to 
obtain and supply, as necessary, details about the Investigator’s ownership interest in 
the Sponsor or the investigational product, and more generally about his/her financial 
ties with the Sponsor. Cytokinetics will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
Hence I: 
• Agree to supply Cytokinetics with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent children); 
• Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study; and 
• Agree that Cytokinetics may disclose any information it has about such ownership 
interests and financial ties to regulatory authorities. 
 
 
Investigator Name: 
______________________________________________________ 
 
Investigator Signature: ________________________________  
Date: ________________  

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALSAQ-5 
ALS Assessment Questionnaire Short Form 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale - Revised 
ALT 
alanine aminotransferase (alanine transaminase) 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase (aspartate transaminase) 
AT 
aminotransferase 
AUC 
area under the plasma concentration-time curve 
BDI 
Beck Depression Inventory 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
clearance divided by fraction absorbed 
Cmax 
maximum observed plasma concentration 
Ctrough 
pre-dose plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HHD 
hand-held dynamometry 

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Abbreviation or Specialist Term 
Explanation 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
IV 
intravenous 
IWRS 
interactive web response system 
LFT 
liver function tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
OCT 
organic cation transporter 
PD  
pharmacodynamic(s) 
PK  
pharmacokinetic(s) 
PKS 
pharmacokinetics analysis set 
PT 
preferred term 
QTc 
corrected QT interval 
RAC 
Accumulation ratio 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAS 
safety analysis set 
SDD 
spray dried dispersion 
SOC 
system organ class 
SVC 
slow vital capacity 
t½  
apparent plasma terminal elimination half-life 
TBL 
total bilirubin 
TDD 
total daily dose 
TEAE 
treatment emergent adverse event 
tmax  
time where maximum concentration is reached 
TSH 
thyroid stimulating hormone 
UA  
urinalysis 
ULN 
upper limit of normal 

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Abbreviation or Specialist Term 
Explanation 
V/F 
volume of distribution divided by fraction absorbed 
WBC 
white blood cells 

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1. 
INTRODUCTION 
1.1. 
Background 
CK-2127107 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. CK-2127107 selectively activates the fast skeletal muscle 
troponin complex by increasing its affinity for calcium. In intact rat skeletal muscle in vivo, 
CK-2127107 increases muscle force at sub-maximal nerve stimulation frequencies, increases 
muscle power, and decreases muscle fatigability. CK-2127107 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 CK-2127107 may provide benefit to 
patients with a wide variety of disorders characterized by muscle weakness and/or fatigue. 
ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle 
movement. In ALS, progressive death of motor neurons leads to denervation of skeletal muscles. 
Surviving motor units attempt to compensate for dying ones by innervating more muscle fibers 
(a process called sprouting) but are only partially successful (Kiernan, Vucic et al. 2011). Over 
time, progressive denervation and its consequent skeletal muscle atrophy lead to weakness, 
fatigue, and eventually complete paralysis and death, primarily from respiratory complications. 
No curative therapies for ALS exist. Rilutek® (riluzole, Sanofi-Aventis U.S. LLC) is the first 
medication approved for the treatment of ALS, and has a modest benefit on survival (Lacomblez, 
Bensimon et al. 1996). Two interventions that contribute greatly to the overall welfare and 
survival of ALS patients are the use of enteral feeding and ventilatory support. 
Radicava (edaravone) was recently approved to treat patients with ALS in the United States in 
May 2017. The efficacy of Radicava 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 
compared to those receiving a placebo (Writing Group on behalf of the Edaravone (MCI-186) 
ALS 19 Study Group. 2017). 
To date, there are no available treatments that slow the decline of skeletal muscle function, and 
in particular, slow the decline of respiratory function. This clinical protocol is a double-blind, 
randomized, dose-ranging, placebo-controlled study to evaluate the efficacy, safety, and 
tolerability of CK-2127107 in patients with ALS. 
1.2. 
Overview of CK-2127107 Nonclinical Studies 
CK-2127107 was evaluated in a series of nonclinical safety studies in rat and monkey, including 
single- and repeat-dose (28 days and 13 weeks) toxicity studies, safety pharmacology studies, 
and a core battery of genotoxicity tests. CK-2127107 was formulated from a spray dried 
dispersion (SDD), which is a stabilized amorphous form of CK-2127107, to increase its 
absorption. 
The toxicology studies conducted in rat and monkey with CK-2127107 demonstrated an 
acceptable safety profile, and supported Phase 1 clinical trials in healthy volunteers. Based on in 
vitro metabolism studies, the monkey was selected as the non-rodent toxicology species since the 

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metabolism of CK-2127107 in monkeys was qualitatively comparable to that in humans, in 
particular with respect to the production of CK-2127106, an identified inactive metabolite of 
CK-2127107. In definitive 28-day and 13-week repeat-dose toxicity and toxicokinetic studies, 
the no observed adverse effect level for CK-2127107 was 600 mg/kg/day, the highest dose level 
evaluated, in both rats and monkeys. 
The core battery of safety pharmacology studies conducted with CK-2127107 indicated no 
functional changes in vital organs or systems which are likely to be of importance in clinical 
studies of CK-2127107. 
The results of the bacterial reverse mutation, in vitro cytogenetic and in vivo rodent bone marrow 
micronucleus studies conducted with CK-2127107 indicated a lack of genotoxic hazard. 
CK-2127106 was equivocal in an in vitro cytogenetic assay conducted in human peripheral 
blood lymphocytes; in this assay, a statistically significant increase in the incidence of aberrant 
cells, compared to the vehicle control, was noted only at the highest CK-2127106 concentration 
evaluated (386 µg/mL) in the 21-hour regime. 
Additional information concerning the pharmacology, pharmacokinetics (PK), and toxicology of 
CK-2127107 is available in the Investigator’s Brochure (IB). 
1.3. 
Overview of CK-2127107 Clinical Studies 
Phase 1 Studies 
CK-2127107 has been evaluated in five Phase 1 studies. 
In a “first in human” study conducted in 35 healthy men (Study CY 5011), single oral doses of a 
SDD suspension (CK-2127107 ranging from 30 to 4000 mg were all well tolerated and no 
maximum tolerated dose was established. 
In Study CY 5012, multiple dose administration of the CK-2127107 SDD suspension at 300 and 
500 mg twice daily for either 10 or 17 days was well tolerated by 59 young and elderly healthy 
subjects and allowed the steady-state PK profile to be described. 
A 4-way crossover, single dose PK/pharmacodynamic (PD) study (Study CY 5013) performed 
with placebo, 300 mg, 1000 mg and 3000 mg of the CK-2127107 SDD suspension demonstrated 
a dose- and concentration-dependent increase in the force-frequency relationship of the tibialis 
anterior muscle with transcutaneous electric stimulation of the deep fibular nerve. 
Another study in 25 healthy men (Study CY 5014) was conducted to evaluate the relative oral 
bioavailability of a suspension of the crystalline form of CK-2127107, CK-2127107 active 
pharmaceutical ingredient (API), to the CK-2127107 SDD suspension dosed at 300 and 
1000 mg. 
Lastly, in Study CY 5015, the PK of a tablet formulated with CK-2127107 API was compared to 
CK-2127107 API suspension and found to have adequate bioavailability for use in future studies. 
The food effect of the tablet was also evaluated in Study CY 5015. 
The terminal half-life (t½) of CK-2127107 was generally around 12 hours with a time to 
maximum concentration (tmax) of 2-3 hours. The increase in exposure was largely dose-
proportional although exposure was more variable at doses ≥3000 mg. There were no observed 
differences in PK parameters between young and elderly subjects but mean exposure was 

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slightly higher in women vs. men. A food effect was demonstrated with 2.6- and 1.6-fold 
increases in Cmax and AUC∞, respectively, following administration of the tablet formulation 
(500 mg as 2 x 250 mg tablets) with a high fat meal. 
Exposure (Cmax and AUC) to the inactive metabolite, CK-2127106, was higher after multiple 
doses of CK-2127107 compared to single doses. The geometric mean half-life of CK-2127106 
ranged from 25.4 to 39.3 hours. Maximum concentrations (Cmax) and area under the 
concentration-time curve (AUC) values increased somewhat greater than dose-proportionally 
following multiple dosing. 
CK-2127107 was well tolerated at all dose levels with no serious adverse events (SAEs) or 
discontinuations due to an adverse event (AE). The most common (≥5%) AEs observed with 
CK-2127107 vs. placebo were dizziness, headache, nausea, and diarrhea. Dizziness, headache, 
and nausea appeared to be dose-related and their incidence increased at doses of 2250 mg and 
above. None of the AEs were classified as severe. Four subjects in the multiple dose study (one 
treated with placebo and three treated with CK-2127107 500 mg) had an AE of increased alanine 
aminotransferase (ALT)/hepatic enzymes; an additional three subjects (all treated with 
CK-2127107 500 mg) had at least one elevated liver enzyme during treatment with study drug 
that were not reported as an AE. Of these seven subjects, some of whom also had modest 
bilirubin elevations, none had values that met Hy’s Law criteria. Other laboratory tests remained 
normal and consistent with baseline values following dosing with the exception of elevated 
serum creatinine values in most subjects treated with CK-2127107. This was observed 
consistently across all studies. CK-2127107 has been demonstrated to inhibit organic cation 
transporter (OCT) 2, a mediator of renal tubular secretion of creatinine in the human kidney, 
with a half maximal inhibitory concentration (IC50) of 2.63 μM. Consequently, it is believed that 
inhibition of renal tubular OCT2 by CK-2127107 is the most likely reason for these generally 
small and reversible increases in serum creatinine during treatment with CK-2127107; inhibition 
of renal tubular secretion has also been observed with other drugs, such as cimetidine 
(Ducharme, Smythe et al. 1993). It is noted that a similar increase in creatinine has been 
observed in toxicology studies of CK-2127107 in monkey. In the 13-week monkey toxicology 
study, creatinine values returned to baseline after completion of dosing and there were no 
abnormalities in kidney histopathology noted, providing further support that this finding is not a 
reflection of renal toxicity. 
Additional information on the Phase 1 clinical program can be found in the IB. 
Ongoing Studies 
There are 3 ongoing studies with CK-2127107. 
3318-CL-3001 (NCT03065959) is a Phase 1b, double-blind, randomized, placebo-controlled, 
2-period cross-over study of CK-2127107 of older healthy adults with limited mobility. Subjects 
are randomized (1:1) to placebo or 500 mg twice daily CK-2127107 for 14 days. The primary 
objective is to investigate the effect of CK-2127107 in tablet form on skeletal muscle fatigue 
assessed as change from baseline versus 14 days of treatment in sum of peak torque during 
isokinetic knee extensions. 
CY 5021 (NCT02644668) is a Phase 2, double-blind, randomized, placebo-controlled, multiple-
dose study of CK-2127107 in suspension form in two ascending dose cohorts of patients with 
spinal muscular atrophy ages 12 and older. The primary objective is to determine the potential 

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PD effects of CK-2127107 API suspension after multiple doses in patients with spinal muscular 
atrophy. 
3318-CL-3002 (NCT02662582) is a Phase 2, randomized, double blind placebo-controlled, two 
period crossover study in patients with chronic obstructive pulmonary disease. The dose of 
CK-2127107 will be 500 mg twice daily and each period will be 14 days. The primary objective 
is to assess the effect of CK-2127107 in tablet form on physical function in subjects with chronic 
obstructive pulmonary disease. 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to assess the effect of CK-2127107 versus placebo on 
respiratory function in patients with ALS. 
2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Visit Week 12 in the percent 
predicted slow vital capacity (SVC). 
2.2. 
Secondary Objectives 
The secondary objectives of this study are:  
• To assess the effect of CK-2127107 versus placebo on measures of skeletal muscle 
function 
• To assess the effect of CK-2127107 versus placebo on global function 
• To evaluate the safety and tolerability of CK-2127107 administered orally to patients 
with ALS 
• To evaluate the exposure of CK-2127107 and its metabolites, when administered orally 
in tablet form to patients with ALS in the fed state 
2.2.1. 
Secondary Endpoints 
• Slope from baseline to Visit Week 12 in the mega-score of muscle strength measured 
by hand held dynamometry (HHD) and handgrip dynamometry  
• Change from baseline to Visit Week 12 in the ALS Functional Rating Scale – Revised 
(ALSFRS-R) 
• The incidence and severity of treatment-emergent adverse events (TEAEs) 
• Plasma concentrations of CK-2127107 at the sampled time points during the study 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are:  
• To assess the effect of CK-2127107 versus placebo on respiratory function self-
assessments made at home by the patient with help as needed by the caregiver 
• To assess the effect of CK-2127107 versus placebo on disease progression through 
measurement of speech production characteristics over time 
• To assess the effect of CK-2127107 versus placebo on disease progression through 
measurement of handwriting abilities over time 
• To assess the change from baseline to Visit Week 12 in quality of life (as measured by 
the ALS Assessment Questionnaire Short Form [ALSAQ-5]) and muscle strength in 
patients on CK-2127107 compared to placebo 

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• To assess the change in the slope of decline of measures of function in patients on 
CK-2127107 compared to placebo 
2.3.1. 
Exploratory Endpoints 
Endpoints assessed as a change from baseline include: 
• Change from baseline to Visit Week 12 in the percent predicted SVC measured at home  
• Change from baseline to Visit Week 12 in the components of voice analysis  
• Change from baseline to Visit Week 12 in the components of handwriting analysis  
• Percent changes from baseline in the strength of the muscle groups from baseline to 
Visit Week 12 that contribute to the Mega-score at Visit Week 12  
• Change from baseline to Visit Week 12 in the ALSAQ-5 
Endpoints assessed as a change in slope include:  
• Slope of change from baseline to Visit Week 12 in the percent predicted SVC 
• Slope of change from baseline to Visit Week 12 in the ALSFRS-R 
• Slope of change from baseline to Visit Week 12 in percent predicted SVC measured at 
home 
• Slope of change from baseline to Visit Week 12 in the components of voice analysis 
• Slope of change from baseline to Visit Week 12 in the components of handwriting 
analysis 
• Slope of change from baseline to Visit Week 12 in the ALSAQ-5 
2.4. 
Pharmacokinetic / Pharmacodynamic Objective 
The PK/PD objectives of this study are to characterize the PK of CK-2127107 following multiple 
doses in the fed state at three dose levels in ALS patients as well as to evaluate possible 
relationships between both dose and exposure of CK-2127107 and its PD effects following 
multiple oral doses in patients with ALS. 

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3. 
STUDY OVERVIEW 
3.1. 
Study Design 
This is a Phase 2, double-blind, randomized, placebo-controlled, dose ranging study of 
CK-2127107 in patients with ALS. 
Approximately 445 eligible ALS patients will be randomized (1:1:1:1) to receive the following 
doses of CK-2127107 or placebo: 
• 150 mg CK-2127107 twice a day for a 300 mg total daily dose (TDD) 
• 300 mg CK-2127107 twice a day for a 600 mg TDD 
• 450 mg CK-2127107 twice a day for a 900 mg TDD 
• Placebo twice daily 
Study medication should be taken twice daily, approximately 12 hours (± 2 hours) apart, and 
should be taken within the 2 hour period following a meal. 
An overview of the randomized treatment groups is provided in Table 1: 
Table 1: 
CY 5022 Randomized, Double-Blind Treatment Groups 
CK-2127107 
Placebo 
300 mg TDD 
1 tablet (150 mg) of 
CK-2127107 and 
2 placebo tablets twice 
daily for 12 weeks 
600 mg TDD 
2 tablets (150 mg) of 
CK-2127107 and 
1 placebo tablet twice 
daily for 12 weeks 
900 mg TDD 
3 tablets (150 mg) of 
CK-2127107 twice 
daily for 12 weeks 
3 placebo tablets twice 
daily for 12 weeks 
The screening and qualification period for the study will be no more than 14 days in duration. 
Once patients have completed screening and are considered eligible for the study, they will be 
randomized as described above and stratified by riluzole use/non-use and edaravone use/non-use. 
There will be a total of seven study visits for each patient: 
• Screening 
• First Dosing Day (Day 1) 
• Week 2 
• Week 4 
• Week 8 
• Week 12 
• Follow-Up Visit (4 weeks after last dose of study drug) 

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Figure 1: 
Patient Visit Diagram 
 
PD measures, vital signs, electrocardiograms (ECGs), and clinical laboratory evaluations will be 
performed at Screening and at specified times during the study. Patients will be evaluated at each 
study visit for signs and symptoms of intolerance to study drug. 
3.2. 
Study Rationale 
CK-2127107 is being investigated as a potential new therapy to slow the decline of skeletal 
muscle function, and in particular, slow the decline of respiratory function in patients with ALS. 
This is the first study being conducted in these patients with CK-2127107 and is designed to 
assess the effect of 12 weeks of its dosing on measures of muscle function in patients with ALS. 
The plasma concentration of CK-2127107 will be measured at selected time points during the 
course of dosing and the plasma concentrations obtained in this study may be used to conduct 
exposure-response analyses. A drug with a similar mechanism of action, tirasemtiv, is currently 
being investigated in a Phase 3 study in ALS (CY 4031, VITALITY-ALS) and in an open label 
extension study to CY 4031 (CY 4033, VIGOR-ALS). In a Phase 2b study (CY 4026, 
BENEFIT-ALS), patients on tirasemtiv had a reduction in the rate of decline in SVC compared 
to placebo. 
3.3. 
Dose Rationale 
CK-2127107 will be administered as 150 mg tablets, at doses of 300 mg/day, 600 mg/day, or 
900 mg/day TDD in the fed state as described above in Table 1. Based on initial population PK 
modeling of the Phase 1 study data, these three doses yield predicted mean Cmax values (%CV) 
ranging from approximately 1789 (44.1) to 5543 (35.9) ng/mL assuming exposures in ALS 
patients are similar to healthy volunteers. The doses selected in the current study should produce 
plasma concentrations that span the PD range observed in the healthy volunteer population in 
Study CY 5013.   

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In Study CY 5013, plasma concentrations were sampled at the time of nerve stimulation in order 
to understand the relationship between CK-2127107 plasma exposures and resulting changes 
from baseline force. Figure 2 shows that these plasma concentrations produce significant 
concentration-dependent increases in force at submaximal stimulation frequencies with the 
largest force increases at 10 Hz. 
Figure 2: 
CY 5013: Increases in Force during Nerve Stimulation in Healthy Volunteers 
 
Based on prior clinical experience, the doses selected for this study are expected to be well 
tolerated and potentially pharmacodynamically active. The information obtained in this study 
will guide the selection of doses for a potential Phase 3 clinical study of CK-2127107 in patients 
with ALS. 

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4. 
STUDY POPULATION 
Approximately 500 patients with ALS will be screened in order to enroll at least 445 patients 
with ALS who fulfill the eligibility criteria. 
4.1. 
Inclusion Criteria 
Patients who meet all the following criteria may be included in the study: 
1. Able to comprehend and willing to sign an Informed Consent Form (ICF) 
2. Males or females between the ages of 18 and 80 years of age, inclusive 
3. Diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-
supported probable, probable, or definite criteria for a diagnosis of ALS according to the 
World Federation of Neurology El Escorial criteria published in 2000 (Brooks, Miller et 
al. 2000) ≤ 24 months prior to screening 
4. Upright SVC ≥ 60% of predicted for age, height and sex at screening 
5. Able to swallow tablets 
6. A caregiver (if one is needed) 
7. Able to perform reproducible pulmonary function tests 
8. Pre-study clinical laboratory findings within the normal range or, if outside the normal 
range, deemed not clinically significant by the Investigator 
9. Male patients, who have not had a vasectomy and a confirmed zero sperm count, must 
agree after receiving the first dose of study drug until 10 weeks after the last dose to do 
either of the following: 
• use a condom during sexual intercourse with female partners who are of reproductive 
potential AND to have female partners use an additional effective means of 
contraception (e.g., diaphragm plus spermicide, or oral contraceptives) 
OR  
• abstain from sexual intercourse  
10. Female patients must be post-menopausal (≥ 1 year) OR sterilized, OR if of childbearing 
potential (i.e., females who have had their first period unless they are anatomically and 
physiologically incapable to become pregnant), must: 
• not be breastfeeding, 
• have a negative pregnancy test, 
• have no intention of becoming pregnant during the course of the study, AND do 
either of the following: 
− use contraceptive drugs or devices as detailed in item number 9 from Screening 
until 10 weeks after the last dose of study drug AND require male partners to use 
a condom during sexual intercourse 
OR 

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− abstain from heterosexual intercourse from Screening until 10 weeks after the last 
dose of study drug 
11. Patients must be either on riluzole for at least 30 days prior to screening or have not taken 
riluzole for at least 30 days prior to screening and not planning to start riluzole during the 
course of the study. 
12. Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at 
the time of screening or have not taken edaravone for at least 30 days prior to screening 
and not planning to start edaravone during the course of the study. Two cycles of dosing 
are defined as having completed Cycle 1 infusion, which is 14 consecutive days of 
intravenous (IV) edaravone followed by 14 days off edaravone, and Cycle 2, which is 10 
out of 14 days of IV edaravone. 
4.2. 
Exclusion Criteria 
Any of the following will exclude potential patients from the study: 
1. At the time of screening, any use of non-invasive ventilation, e.g. continuous positive 
airway pressure, noninvasive bi-level positive airway pressure or noninvasive volume 
ventilation, for any portion of the day, or mechanical ventilation via tracheostomy, or on 
any form of oxygen supplementation 
2. Neurological impairment due to a condition other than ALS  
3. Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal, 
musculoskeletal, or psychiatric illness that might interfere with the patient’s ability to 
comply with study procedures or that might confound the interpretation of clinical safety 
or efficacy data, including, but not limited to: 
a. A pulse <40 or >100 bpm; mean systolic blood pressure >180 mm Hg; mean diastolic 
blood pressure >100 mm Hg (based on measurements taken after rest for 3 minutes) 
that persist on 3 successive measurements taken at least 2 minutes apart. 
b. Clinically significant ECG abnormalities that require medical attention (i.e., persistent 
atrioventricular conduction block >first degree, or acute myocardial ischemic 
changes) 
c. New York Heart Association Class II or greater congestive heart failure 
d. Chronic obstructive pulmonary disease or asthma requiring daily use of 
bronchodilator medications 
e. Gastrointestinal disorder that is likely to impair absorption of study drug from the 
gastrointestinal tract  
f. ALT or aspartate aminotransferase (AST) greater than or equal to 3-times the upper 
limit of normal (ULN) or has total bilirubin (TBL) greater than or equal to 2-times the 
ULN at screening. These assessments may be repeated at the Investigator’s discretion 
(within the screening window). 
g. Poorly controlled or brittle diabetes mellitus 
h. Amputation of a limb 
i. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s 
ability to understand and/or comply with study procedures and provide informed 
consent 

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j. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of 
the cervix, or squamous cell carcinoma of the skin excised with clean margins) 
diagnosed and treated within the last five years 
k. Any other condition, impairment or social circumstance that, in the opinion of the 
Investigator, would render the patient not suitable to participate in the study 
l. Patient judged to be actively suicidal or a suicide risk by the Investigator 
m. Patient has estimated glomerular filtration rate (eGFR) less than 40 mL/min/1.73 m2 
calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
cystatin equation based on a cystatin C measurement at baseline 
4. Has taken any investigational study drug within 30 days or five half-lives of the prior 
agent, whichever is longer, prior to dosing 
5. Known to have received CK-2127107 or tirasemtiv in any previous clinical trial 
6. Has received or is considering receiving during the course of the study any form of stem 
cell therapy for the treatment of ALS 
7. Has received or is considering receiving during the course of the study any form of gene 
therapy for the treatment of ALS 
8. Has received or is considering obtaining during the course of the study a diaphragmatic 
pacing system 
9. History of substance abuse within the past 2 years 
10. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose of 
study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug 
11. Use of a medication that is an OCT1/OCT2 substrate within 7 days (see Appendix B)  

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5. 
STUDY PROCEDURES 
5.1. 
Screening 
A signed ICF will be obtained from each patient prior to performing any study-specific 
procedures. A copy of the ICF will be retained in the study file and a copy will be provided to 
the patient. 
The following screening procedures will be performed for all potential patients at a visit 
conducted within 14 days of study entry: 
1. Demographic data 
2. Medical history, including review of concomitant medications, tobacco and alcohol usage 
3. Review of inclusion/exclusion criteria 
4. Height, body weight, and calculation of body mass index (BMI) 
5. Routine physical examination 
6. Neurological examination 
7. 12-lead ECG 
8. Vital signs, including temperature, heart rate, blood pressure, and respiratory rate 
measured after the patient has been resting for at least 3 minutes 
9. Clinical laboratory evaluations, including complete blood count (CBC) and white blood 
cells (WBC) with differential, serum chemistries, cystatin C, urinalysis (UA), and thyroid 
stimulating hormone (TSH) 
10. Pregnancy test for all females of childbearing potential 
11. SVC 
12. Muscle strength measurements 
13. ALSFRS-R 
14. Voice recording 
15. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
16. Ashworth score 
17. ALSAQ-5 
18. Beck Depression Inventory-Fast Screen (BDI-Fast Screen) 
Once a patient is confirmed eligible to participate and before the first dose on Day 1, patients 
will be randomized to receive either CK-2127107 or placebo. 
5.2. 
First Dosing Day (Day 1) 
Prior to study drug dosing on Day 1, the following procedures will be performed: 

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1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
4. PK blood sample 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their first dose of study drug (CK-2127107 or placebo) within 2 hours of a 
meal. 
The following assessment will be performed after the first dose of study drug is given: 
16. PK blood sample at 1 hour post-dose 
Training will also be provided to the patient for the measurements patients will perform at home. 
•  For patients who have access to a mobile device, the application will be downloaded 
to the device and instructions provided as detailed in the study manual on recording 
voice. 
• All patients will be trained in performing SVC using a portable spirometer (if the 
device is suitable for use in that region) as detailed in the study manual. 
Home voice recordings and SVC testing will be performed by the patient weekly for the duration 
of the study following Day 1. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks. A dosing diary will be provided for patients to record the date and time of 
twice daily study drug administration. 
5.3. 
Week 2 Visit 
Prior to study drug dosing at the Week 2 Visit, the following procedures will be performed: 

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1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample  
4. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. Patients should be reminded to bring their unused study drug with them to the clinic and 
that they will be taking their dose of study drug while at the clinic. The following assessment 
will be performed after the dose of study drug is given: 
16. PK blood sample at 1 hour post-dose  
Patients will have already been given their supply of study drug (CK-2127107 or placebo) to 
take twice daily at home until their next clinic visit at Week 4. A dosing diary will be provided 
for patients to record the date and time of twice daily study drug administration. 
5.4. 
Week 4 Visit 
Prior to study drug dosing at the Week 4 Visit, the following procedures will be performed:  
1. 12-lead ECG 
2. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight and calculation of BMI 
4. PK blood sample 
5. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 

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6. SVC 
7. Muscle strength measurements 
8. ALSFRS-R 
9. Voice recording 
10. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
11. Ashworth score 
12. Falls assessment 
13. ALSAQ-5 
14. Record Health Economic Outcomes Measures 
15. AE/SAE evaluation and concomitant medication assessment (since last visit) 
16. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks at home until their next clinic visit at Week 8. A dosing diary will be provided 
for patients to record the date and time of twice daily study drug administration. 
5.5. 
Week 8 Visit 
Prior to study drug dosing at the Week 8 Visit, the following procedures will be performed: 
1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample 
4. SVC 
5. Muscle strength measurements 
6. ALSFRS-R 
7. Voice recording 
8. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
9. Ashworth score 
10. Falls assessment 
11. ALSAQ-5 
12. Record Health Economic Outcomes Measures 
13. AE/SAE evaluation and concomitant medication assessment (since last visit) 

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14. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. 
Patients will be given an adequate supply of study drug (CK-2127107 or placebo) to take twice 
daily for 4 weeks at home. A dosing diary will be provided for patients to record the date and 
time of twice daily study drug administration. 
5.6. 
Week 12 Visit 
Prior to the last dose of study drug at the Week 12 Visit, the following procedures will be 
performed:  
1. Vital signs, including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
2. Weight and calculation of BMI 
3. PK blood sample 
4. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
5. SVC 
6. Muscle strength measurements 
7. ALSFRS-R 
8. Voice recording 
9. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
10. Ashworth score 
11. Falls assessment 
12. ALSAQ-5 
13. Record Health Economic Outcomes Measures 
14. AE/SAE evaluation and concomitant medication assessment (since last visit) 
15. BDI-Fast Screen 
Patients will receive their dose of study drug (CK-2127107 or placebo) within 2 hours of eating a 
meal. The following assessment will be performed after the last dose of study drug is given: 
16. PK blood sample at 1 hour post-dose  
5.7. 
Follow-Up Visit  
The following procedures will be performed at a Follow-Up Visit 4 weeks after each patient’s 
final dose of study drug: 
1. 12-lead ECG 

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2. Vital signs including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight and calculation of BMI 
4. Abbreviated physical examination  
5. Neurological examination 
6. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C, UA, and TSH 
7. Pregnancy test for all females of childbearing potential 
8. SVC 
9. Muscle strength measurements 
10. ALSFRS-R 
11. Voice recording 
12. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
13. Ashworth score 
14. Falls assessment 
15. ALSAQ-5 
16. Record Health Economic Outcomes Measures 
17. AE/SAE evaluation and concomitant medication assessment (since last visit) 
18. BDI-Fast Screen 
5.8. 
Early Termination Visit 
If a patient decides to terminate early from the study, they should be seen in the clinic as soon as 
possible following discontinuation of study drug. The following procedures will be performed: 
1. 12-lead ECG 
2. Vital signs including heart rate, blood pressure, and respiratory rate measured after the 
patient has been resting for at least 3 minutes 
3. Weight 
4. Abbreviated physical examination  
5. Neurological examination 
6. Clinical laboratory evaluations, including CBC and WBC with differential, serum 
chemistries, cystatin C and UA 
7. SVC 
8. Muscle strength measurements 
9. ALSFRS-R 

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10. Voice recording 
11. Fine motor measurement of handwriting and tracing of forms via an app (if the device is 
suitable for use in that region) 
12. Ashworth score 
13. Falls assessment 
14. ALSAQ-5 
15. Record Health Economic Outcomes Measures 
16. AE/SAE evaluation and concomitant medication assessment (since last visit) 
17. BDI-Fast Screen 
If a patient decides to terminate early from the study but does not wish to return to the clinic for 
an Early Termination Visit, they should be contacted by phone whenever possible and the 
following information should be collected: 
1. ALSFRS-R 
2. ALSAQ-5 
3. Record Health Economic Outcomes Measures 
4. Falls Assessment 
5. AE/SAE evaluation and concomitant medication assessment (since last visit) 
5.9. 
Visit Windows 
To aid in scheduling patient visits, the following study visit windows are considered acceptable 
(Table 2). If a patient visit must be scheduled outside the visit window, the Medical Monitor 
should be contacted. 
Table 2: 
Visit Windows 
Visit 
Visit Window 
Screening 
Up to 14 days prior to Day 1 visit (as per protocol) 
Day 1 
First day of randomized, double-blind dosing 
Week 2 (Day 15) 
± 2 days 
Week 4 (Day 29) 
± 2 days 
Week 8 (Day 57) 
± 4 days 
Week 12 (Day 85) 
± 4 days 
Follow-Up 
4 weeks after last dose of study drug ± 4 days 
5.10. 
Diet Control 
All doses of study drug should be taken within 2 hours following a meal. 
Subjects will abstain from consuming grapefruit and Seville oranges along with foods or 
beverages containing them from Day 1 through the Follow-Up visit. 

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5.11. 
Concomitant Medications 
All prescription drugs, over-the-counter medications, nutraceuticals and herbal remedies taken 
by the patient from the time of screening through the Follow-Up visit should be entered into the 
electronic case report form (eCRF). 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 
(End of Week 8). 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 12). Please 
refer to Appendix B  for 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 CK-2127107 may have the potential to inhibit OCT1 and OCT2-
mediated transport. Please refer to Appendix B  for OCT1/OCT2 substrates that should be 
avoided or used with caution. 
5.12. 
Pharmacokinetic Sampling 
Blood samples for analysis of CK-2127107, its metabolites, and riluzole will be collected from 
patients at the nominal time points listed in Table 3. 
Table 3: 
Pharmacokinetic (PK) Samples 
Day 
Sample Time Points 
Day 1 
Pre-dose and 1 (±15 min) hour post-dose  
Week 2 
Pre-dose and 1 (±15 min) hour post-dose 
Week 4 
Pre-dose 
Week 8 
Pre-dose 
Week 12 
Pre-dose and 1 (±15 min) hour post-dose 
If an indwelling catheter is used, saline flushes will be used. In some cases, sites may be unable 
to obtain the 6 hour timepoint at Week 2 or Week 12 for logistical reasons; these cases should be 
discussed with the medical monitor preferably ahead of time.  
After completion of bioanalysis, remaining plasma samples will be retained consistent with the 
Sponsor’s standard operating procedures. These samples will not be used for pharmacogenomic 
testing. 
5.13. 
Clinical Safety Assessments 
5.13.1. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be collected at Screening, Day 1, Week 2 visit, Week 4 visit, 
Week 12 visit, and at the Follow-Up Visit as described in Appendix D. 
5.13.2. 
12-Lead Electrocardiograms 
A 12-lead ECG, including ECG parameters of RR, PR, QRS, QT and QTc intervals as well as 
significant findings will be obtained at Screening, Week 4 visit, and at the Follow-Up Visit. 

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When 12-lead ECGs are scheduled at the same time as blood draws, the order of evaluation will 
be ECG, vital signs, and then blood draw. 
5.13.3. 
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 every visit. Temperature will also be obtained at 
the Screening visit. Height is obtained only at the screening visit. Weight will be obtained at each 
visit; and BMI will be calculated at screening and subsequent visits. 
When vital signs are scheduled at the same time as blood draws, the order of evaluation will be 
ECG, vital signs, and then blood draw. 
5.13.4. 
AE Assessments 
Patients will be asked how they are feeling from the first administration of study drug through 
the Follow-Up visit (see Section 7.2). Patients will also be encouraged to voluntarily report any 
AEs they experience during the study. 
5.13.5. 
Physical Examinations 
A routine physical examination will be performed at Screening, and an abbreviated physical 
examination (consisting of an examination of general appearance, skin, lungs, cardiovascular and 
abdomen) will be performed at the Follow-Up Visit. 
5.13.6. 
Neurological Examinations 
A neurological examination will be administered at Screening and at the Follow-Up Visit as 
described in the Study Manual. 
5.13.7. 
Beck Depression Inventory-Fast Screen (BDI-Fast Screen) 
The BDI-Fast Screen will be assessed at all study visits as described in the Study Manual. 
5.13.8. 
Falls Assessment 
Falls assessment will be performed at each study visit except Screening as described in the Study 
Manual. 
5.13.9. 
Ashworth Scale 
The Ashworth scale to assess spasticity will be performed at each study visit. Further description 
of the Ashworth Scale can be found in the Study Manual. 
5.14. 
Clinical and Pharmacodynamic Outcome Measures 
5.14.1. 
Pulmonary Function Assessment 
The pulmonary function assessment in this study will be SVC. Pulmonary function assessment 
will be performed at each study visit as described in the Study Manual. Patients will also perform 
home SVC assessments weekly through the course of the study following Day 1 (if the device is 
suitable for use in that region) as described in the Study Manual. 

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5.14.2. 
Hand-Held Dynamometry 
Muscle strength measurements of selected muscles will be performed using HHD and hand grip 
dynamometry at each study visit as described in the Study Manual. 
5.14.3. 
ALSFRS-R 
The ALSFRS-R will be performed at each study visit as described in the Study Manual. 
5.14.4. 
Voice Recording 
Voice recording will be performed at each study visit and for patients who have access to mobile 
devices weekly at home as described in the Study Manual. 
5.14.5. 
Fine Motor Assessments (Handwriting and Figure Tracing) 
The handwriting and figure tracing assessments will be done at each study visit (if the device is 
suitable for use in that region) as described in the Study Manual. 
5.14.6. 
ALSAQ-5 
The ALSAQ-5 will be performed at each study visit as described in the Study Manual. 
5.14.7. 
Health Economic Outcomes Measures 
During the course of the study, if the patient is prescribed and agrees to receive any of the 
following, it will be recorded including the date prescribed: 
• Non-invasive ventilation 
• Gastrostomy tube 
• Manual wheelchair 
• Power wheelchair 
• Augmentative and alternative communication 
5.15. 
Removal of Patients from Study Participation 
Patients will be informed that they are free to discontinue study drug or withdraw from the study 
at any time and for any reason. The Investigator may discontinue study drug or withdraw a 
patient from the study if, in the Investigator's opinion, it is not in the best interest of the patient to 
continue the study. Patients may discontinue study drug or withdraw from the study due to the 
following: 
a. A change in compliance with inclusion/exclusion criteria that is clinically relevant 
and/or affects patient safety, and/or study assessments/objectives, etc. 
b. Occurrence of intolerable AEs 
c. Changes in vital signs, ECGs, or clinical laboratory results that, in the opinion of the 
Investigator, pose a significant health risk 
d. Intake of non-permitted concomitant medication that might affect patient safety or 
study assessments/objectives, etc. 

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e. eGFR calculated using the CKD-EPI cystatin equation (Inker, Schmid et al. 2012) 
shows a >25% decline compared to baseline (defined as Day 1 or Screening if Day 1 
value is not available) as long as the decline is not related to dehydration or a 
superimposed reversible process such as infection or nausea. 
f. Changes in liver function tests (LFTs) as outlined in Appendix C   
g. Receiving any form of stem cell therapy for ALS either as part of a clinical trial or 
outside of a clinical trial 
h. Having a diaphragmatic pacing system implanted either as part of a clinical trial or 
outside of a clinical trial 
i. Initiating edaravone after screening. 
j. Initiating riluzole after screening. 
k. Initiating gene therapy for ALS either as part of a clinical trial or outside of a clinical 
trial after screening. 
Patients should be strongly encouraged to perform the early termination visit as soon as possible 
following last dose of study drug taken, and the Follow-Up Visit should be performed 28 days 
after last dose taken of study medication. In addition, they should be encouraged to return for all 
remaining study visits and assessments (with the exception of 12-lead ECG, clinical laboratory 
and PK sampling) for the duration of the study following study drug discontinuation. These 
remaining study visits should be performed according to the original study visit windows. 
Patients who decide to start or stop edaravone or riluzole after screening and before 
randomization, will no longer be eligible to be randomized and should not be followed 
subsequently. If a patient decides to start edaravone or riluzole after randomization, they will be 
terminated from taking study medication once that is known by the site. They should return to 
the clinic for their early drug termination visit as soon as possible following last dose of study 
drug taken and return 28 days after last dose taken for the Follow-Up Visit. They will not be 
followed thereafter. 
For patients who terminate early from the study and do not want to return to the clinic for the 
visits as described in the above paragraph, phone call visits should be performed to collect the 
information if the patient is willing (see Section 5.8). 
Notification of discontinuation will immediately be made to the Sponsor’s Medical Monitor. In 
case of withdrawal of study participation, efforts will be made to perform Early Termination 
(Section 5.8) and Follow-Up visit assessments (Section 5.7). The date the patient is withdrawn 
from the study and the reason for discontinuation will be recorded on the patient’s eCRF. All 
patients who prematurely discontinue from the study for AEs will be followed for up to 30 days, 
until the AE resolves, or until the unresolved AE is judged by the Investigator to have stabilized. 
The primary reason for a patient prematurely withdrawing from the study should be selected 
from the following categories and documented in the source documents: 
a. Patient Death 
b. Adverse Event:  One or more clinical or laboratory events which, in the medical 
judgment of the Investigator, are grounds for discontinuation even if the event does 
not appear to be related to study medication. The patient may withdraw because of an 
AE even if the Investigator does not feel that the event is grounds for discontinuation. 
c. Protocol Violation:  The patient’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements 

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d. Patient Withdrawal of Consent:  Patient desires to withdraw from further participation 
in the study and reason for doing so. 
e. Administrative/Other:  Any cause of premature termination from the study other than 
the above, such as illness of investigator, loss of study drug, or termination of study 
by the Sponsor. 
5.16. 
Assessment of Safety 
An independent Data Monitoring Committee (DMC) will periodically assess patient safety in an 
unblinded manner during the course of the study. No unblinded data will be accessible to site 
staff, the Sponsor, study monitors, and personnel of the electronic data capture vendors before 
the database is locked. The specific activities and responsibilities of the DMC are defined in the 
DMC Charter for CY 5022. 
Dosing of an individual will be stopped and not resumed if treatment-related AEs, changes in 
vital signs, ECGs, or clinical laboratory results are observed and these changes pose a significant 
health risk, in the opinion of either the Investigator or the Sponsor Medical Monitor. A blood 
sample for PK analysis should be collected at the time of the event or as close as possible to the 
time of the event. 
In the event of a confirmed, marked hepatic abnormality as defined in Appendix C  (Liver Safety 
Monitoring and Assessment), it is the Investigator’s responsibility to ensure contact with the 
Sponsor immediately (i.e., within 24 hours of awareness or at the earliest possible time point). 
Patients with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored. 
5.17. 
Study Drug Interruption 
Patients who do not take the total assigned daily dose of study drug due to conditions of 
hospitalization or other circumstances should be encouraged to return to treatment. The Medical 
Monitor should be contacted for a patient who has discontinued treatment for more than one 
week (prolonged study drug interruption). 
If study drug interruption for more than one week has occurred, the Investigator should evaluate 
the patient in clinic to ensure that it is safe for the patient to resume study drug dosing and 
consult with the Medical Monitor for the appropriate course of action. 
5.18. 
Study Discontinuation 
The study may be discontinued by the Sponsor for the following reasons: 
• Excessive rates of AEs  
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
• A decision to cease or delay further development of the drug 

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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Description of Investigational Product 
This is a double-blind, placebo-controlled study. As such, the site pharmacy staff, the 
Investigator, the patient, remaining study site clinical staff, and the Sponsor will be blinded to 
treatment assignment. 
CK-2127107 study drug is supplied as immediate release, white to off-white, modified capsule-
shaped tablets at a dose strength of 150 mg of CK-2127107 per tablet, which are to be stored 
under secure conditions at ≤25°C (77°F) with excursions allowed up to 30°C (86°F). 
Matching placebo tablets will be supplied and should also be stored at controlled room 
temperature under secure conditions. 
Active CK-2127107 tablets contain 150 mg of CK-2127107 plus excipients. Placebo tablets 
contain excipients only. 
Table 4: 
Study Drug 
Study Drug 
CK-2127107 
Placebo for CK-2127107  
Form 
Tablet 
Tablet 
Supplier 
Cytokinetics, Inc. 
Cytokinetics, Inc. 
Manufacturer 
Patheon, Inc. 
Patheon, Inc. 
CK-2127107 and matching placebo tablets will be supplied to the clinical site in blister strips 
inside labeled wallets. Patients will receive one or more wallets of study drug, CK-2127107 or 
matching placebo at the appropriate visit. Each wallet is sufficient for one week of dosing, plus 
overage. Double-blind wallets will be labeled with a unique random kit number. 
The study research coordinator or designated site staff will be responsible for patient 
randomizations, using an interactive web response system (IWRS). 
6.2. 
Dose Administration (CK-2127107 or Placebo)  
This study drug will be administered orally as tablets to patients with ALS. Doses (CK-2127107 
or placebo) for each of the treatment groups will be dispensed in accordance with the study 
randomization prior to the patient’s first dose. 
6.3. 
Dosing Diary  
A dosing diary will be maintained by the patient to record date and time of twice daily study 
drug administration. The dosing diary should be returned at each clinic visit. 
6.4. 
Randomization Schedule and Removal of Blind  
An IWRS will provide patient randomization assignments for this study. The site pharmacist or 
other qualified person responsible for randomizing patients will receive the appropriate kit 
numbers through the IWRS and provide it to the site staff who will be distributing study drug to 
the patient. RANDOMIZATION INFORMATION MAY BE MADE AVAILABLE TO THE 

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INVESTIGATOR ONLY IN THE EVENT OF A MEDICAL EMERGENCY OR AN AE THAT 
NECESSITATES IDENTIFICATION OF THE STUDY DRUG (CK-2127107 or placebo) FOR 
THE WELFARE OF THAT PATIENT. Except in a medical emergency, the Investigator (or 
designee) and study site clinical staff will remain blinded during the conduct of the study and 
until such time that all discrepancies in the clinical database are resolved (i.e., at the time of the 
database lock). The date/initials and reason for study blind removal by the Investigator and/or 
clinical staff will be documented. The Investigator will contact the Sponsor as soon as possible 
before or immediately following the emergency unblinding of any patient. 
6.5. 
Study Drug Accountability and Disposal   
The site pharmacist or other qualified person responsible for managing study drug supplies will 
maintain an accurate record of the receipt of the investigational study drug as shipped by the 
Sponsor (or designee), including the kit number and date received. One copy of this receipt will 
be returned to the Sponsor when the contents of the investigational study drug shipment have 
been verified. An accurate drug disposition record will be kept, specifying the study drug 
provided to each patient and the dates of dose administration. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
The patient should be instructed to return all unused study drug to the designated clinical site 
staff at each study visit. Study drug accountability is to be conducted by the designated study 
staff member with the patient at each study visit. The dosing diaries should also be referenced 
when completing drug accountability. 
All unused drug supplies will be returned to the Sponsor (or designee) or disposed of by the 
clinical research unit, per the Sponsor’s (or designee’s) instructions at the end of the study. 

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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
7.1.1. 
Adverse Event 
As defined by the International Conference on Harmonisation (ICH), an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered an investigational 
product, and which does not necessarily have to have a causal relationship with the 
investigational product. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the investigational product. 
Examples of an AE: 
• Conditions newly detected or diagnosed after the administration of the investigational 
product, including conditions that may have been present but undetected prior to the 
start of the study 
• Conditions known to have been present prior to the start of the study that increase in 
severity or frequency after the administration of the investigational product 
• Signs, symptoms, or the clinical sequelae of a suspected drug interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose (overdose per se 
should not be reported as an AE term) 
• Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other 
abnormal assessments (e.g., ECGs, vital signs, etc.) that are considered by the 
Investigator as a clinically significant change after the first dose of the investigational 
product. The Investigator will exercise his/her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is a 
clinically significant change after the first dose of the investigational product. 
Issues Not Considered AEs: 
• Medical or surgical procedures (e.g., appendectomy). The AE is the condition that 
leads to the procedure (e.g., appendicitis) if it qualifies according to the definition 
above. 
• Hospitalizations where an untoward medical occurrence did not occur. Examples 
include: 
− hospitalization for social reasons such as unavailability of a caregiver outside of 
the hospital due to living situation, OR 
− hospitalization for percutaneous endoscopic gastrostomy placement prior to 
signing the ICF 
• Fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not represent a clinically significant change after the first dose of 
the investigational product. 

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• Abnormal laboratory or test findings that are not assessed by the Investigator as a 
clinically significant change after the first dose of the investigational product. 
7.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that: 
a. Results in death 
NOTE: Death is selected as a seriousness criterion ONLY when the event is the cause 
of death. Death is an outcome and the event which led to the death should be the 
reported event term. 
b. 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 that hypothetically might have caused death if it were more severe, prolonged, 
or untreated. 
c. Requires hospitalization or prolongation of existing hospitalization  
NOTE: Hospitalization signifies that the subject has been admitted to the hospital as 
an in-patient for any length of time. Emergency room treatment does not qualify for 
this category, but may be appropriately included in category f (see below). If a 
complication prolongs the hospitalization or fulfills any other seriousness criterion or 
criteria, the complication will be considered an additional SAE. When in doubt as to 
whether ‘hospitalization’ occurred, consult the Medical Monitor. 
Hospitalization should not be considered an AE term in itself. It will be considered an 
outcome of an AE. For example, hospitalization for an elective treatment of a pre-
existing condition that did not worsen after the first dose of the investigational 
product will not be considered an AE. 
d. Results in disability/incapacity 
NOTE: The term disability means a substantial or permanent disruption of a person’s 
ability to conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) that may temporarily interfere with or prevent everyday life functions 
but do not constitute a substantial or permanent disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding if an event 
should be reported as serious. Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition may be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development 

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of drug dependency or drug abuse. If in doubt as to whether or not an event qualifies 
as an “important medical event”, consult the Sponsor’s Medical Monitor. 
7.2. 
Collection of AEs/SAEs 
During each scheduled visit, ask about potential AEs or SAEs using the following standard 
questions: 
1. Have you had any medical problems since your last visit? 
2. Have you taken any new medications since your last visit? 
7.3. 
Recording and Reporting of AEs/SAEs 
7.3.1. 
Recording and Reporting of AEs 
Events occurring between the Screening Visit and just prior to the first dose of the 
investigational product on Day 1 should be recorded in the Medical History eCRF unless the 
event is related to a protocol-mandated procedure. If the event is deemed related to a protocol-
mandated procedure (e.g., hematoma at the puncture site) and deemed clinically significant by 
the Investigator, the event should be reported as an AE or an SAE (if applicable). 
AEs will be documented from the first administration of the investigational product through the 
Follow-Up Visit. The Investigator will review all documentation (e.g., hospital progress notes, 
laboratory and diagnostic reports) relevant to the event. A diagnosis will then be determined 
based on signs, symptoms, and/or other clinical information. The diagnosis and not the 
individual signs/symptoms should be reported as the AE term. 
ALS progression and signs/symptoms that are expected as part of ALS progression (see 
Section 7.4.3) will not be collected as AEs unless they meet seriousness criteria and should be 
recorded as SAEs. 
7.3.2. 
Recording and Reporting of SAEs 
If an AE meets any of the seriousness criteria (see Section 7.1.2), it must be reported using the 
SAE report form within 24 hours of the site’s knowledge. At a minimum, the following 
information should be included: 
• Patient number 
• Event term, including an onset date and stop date, if applicable, and a brief 
description 
• Seriousness criterion/criteria 
• Causality assessment in relation to the investigational product 
If all information regarding the SAE is not initially available, the site should still report the SAE 
within 24 hours of awareness/discovery. Additional information should be reported when it 
becomes available and no later than 24 hours after receipt of such information. 

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7.4. 
Evaluating AEs and SAEs 
7.4.1. 
Assessment of Severity 
The Investigator should assess the severity of each AE/SAE. The severity of AEs/SAEs will be 
assessed by assigning a Grade of 1, 2, 3, 4 or 5 according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, except for ALT, AST, 
and TBL levels as described in Appendix C. 
When an AE/SAE cannot be graded by CTCAE, the following severity grade may be used: 
• Grade 1 (Mild): Aware of sign or symptom, but easily tolerated and intervention is 
not indicated 
• Grade 2 (Moderate): Discomfort enough to cause interference with usual activity, 
local or non-invasive intervention is indicated 
• Grade 3 (Severe): Incapacitating with inability to work or do usual activity, not 
immediately life-threatening; hospitalization or prolongation of hospitalization may 
be indicated 
• Grade 4 (Life-Threatening): Refers to an event in which the patient was, in the view 
of the Investigator, at risk of death at the time of the event. (This category is not to be 
used for an event that hypothetically might have caused death if it were more 
severe.); urgent intervention is indicated 
• Grade 5 (Fatal): Death related to AE 
Severity should not be confused with seriousness. Severity is a category for rating the intensity 
of an event, and an event becomes serious when it meets one of the outcomes described in 
Section 7.1.2 “Serious Adverse Event”. 
7.4.2. 
Assessment of Causality 
The Investigator will assign causality to each SAE (related or unrelated). When assessing 
relationship to study drug, the Investigator will consider the following factors: 
• Temporal association between the administration of the investigational product and 
the event 
• Cessation of the AE following discontinuation of dosing 
• Recurrence of the AE with reintroduction of study drug, if performed 
• Similarity to known class effects 
• Alternative causes, such as:  
− Known effects of concomitant medications 
− Pre-existing risk factors 
− Concurrent illnesses 
The assessment of causality will be based on the information available, and may be changed 
upon receipt of additional information. 

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7.4.3. 
Assessment of Expectedness 
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 events, in addition to death due to ALS 
progression, are anticipated to occur in the study population as signs/symptoms of ALS 
progression which may or may not lead to hospitalization. 
Table 5: 
MedDRA Preferred Terms 
MedDRA Preferred Terma 
MedDRA Preferred Terma 
Dysarthria 
Muscle spasticity 
Dysphagia 
Muscle weakness 
Dyspnoea 
Pneumonia aspiration 
Gait disturbance 
Respiratory failure 
Muscle contractions involuntary 
Weight decreased/Abnormal loss of weight 
Muscle spasms 
 
a MedDRA Version 19.1 
7.5. 
Follow-Up of AEs and SAEs 
After the initial recording of an AE/SAE, the Investigator should proactively follow the patient. 
Non-serious AEs that are still ongoing at the end of the study should be reviewed by the 
Investigator to determine if further follow up is required. The Investigator will document on the 
AE eCRF any/all ongoing non-serious AEs that will not be followed up further after the patient 
exits the study. If in doubt, the Investigator should consult the Medical Monitor. 
All SAEs should be followed until resolution, until the condition stabilizes, or until the patient is 
lost to follow-up. Once the seriousness criterion no longer applies to the SAE (e.g., patient was 
discharged), the corresponding AE eCRF page should be updated. All relevant additional 
information collected regarding an SAE, including laboratory test reports, consultation reports 
from other health care professionals, discharge summaries, or other information should be 
transmitted to Cytokinetics with the follow-up SAE report form within 24 hours of receipt or 
awareness. 
Cytokinetics may request the Investigator to perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
any AE/SAE. 
If a patient dies during participation in the study or during the follow-up period, the Investigator 
will provide Cytokinetics with a copy of any post-mortem findings, including an autopsy report 
if obtainable. 

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7.6. 
Post-Study AEs/SAEs 
A post-study AE/SAE is defined as any event that occurs outside of the AE detection period 
defined in Section 7.3.1. 
Investigators are not obligated to actively solicit AEs from former study participants. However, 
if the Investigator learns of an SAE that he/she considers reasonably related to the investigational 
product at any time after a patient has been terminated from the study, the Investigator will 
promptly notify Cytokinetics. 
7.7. 
Pregnancy 
Pregnancy is not an AE; however, information on pregnant female patients and partners of male 
patients will be collected if the pregnancy occurs after the patient receives the first dose of the 
investigational product until 10 weeks after the last dose. The pregnancy information and its 
outcome will be collected using the Pregnancy Report Form. If the pregnancy occurs in a partner 
of a male patient, the partner’s consent will be obtained before collecting information regarding 
the pregnancy and its outcome. 
If the pregnancy test (urine or serum) is positive, the pregnancy should be immediately reported 
to the Investigator and the Sponsor. Any female patient who becomes pregnant during the study 
is not eligible to continue the study and should complete the study procedures as soon as 
possible. 
If a partner of a male patient becomes pregnant during the study, the male patient may opt to 
continue his participation but must use barrier method (condom) to prevent fetal exposure. 
Accidental, therapeutic, or spontaneous abortions and congenital anomalies or birth defects will 
be reported as SAEs. 

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8. 
STATISTICAL METHODS 
8.1. 
General Considerations 
8.1.1. 
General Approach 
All pre-specified hypothesis tests will be 2-sided with a significance level of 0.05. Descriptive 
statistics for categorical variables will include frequency and percentage, and for continuous 
variables will include number of patients, mean, median, standard deviation, standard error, 
minimum and maximum. Baseline is defined as the last available measurement taken before the 
first dose of study medication unless otherwise specified. Missing data will not be imputed 
unless otherwise specified. 
8.1.2. 
Sample Size and Randomization 
Approximately 445 patients will be randomized to receive either one of the three CK-2127107 
doses (300 mg/day, 600 mg/day and 900 mg/day TDD) or matching placebo tablets in a ratio of 
1:1:1:1. Randomization will be stratified by riluzole use/non-use and edaravone use/non-use. The 
dropout rate at Visit Week 12 is estimated to be 10%, thus approximately 400 patients are 
expected to complete 12 weeks of double-blind treatment. The effect of CK-2127107 on the 
change from baseline to Week 12 in percent predicted SVC will be analyzed using a mixed 
model for repeated measures (MMRM) with the contrast (-5, -1, 3, 3) to reflect the assumed 
relationship for the placebo, 300 mg/day, 600 mg/day and 900 mg/day dose groups. The analysis 
is estimated to provide 90% power to detect 2.75, 5.5 and 5.5 percentage points advantage over 
placebo for the 300 mg/day, 600 mg/day and 900 mg/day CK-2127107 dose groups, 
respectively, in change from baseline of percent predicted SVC, at the end of the double-blind 
treatment (Visit Week 12). This calculation is based on a two-sided test with alpha set at 0.05 
and a common standard deviation of 14 percentage points. 
8.2. 
Analysis Sets 
8.2.1. 
Full Analysis Set (FAS) 
The FAS will consist of all randomized patients who receive at least one dose or portion of a 
dose of study drug and who have a baseline and at least one post-baseline efficacy assessment 
during the double-blind treatment. 
8.2.2. 
Safety Analysis Set (SAS) 
The SAS will consist of all randomized patients who receive at least one dose or portion of a 
dose of study drug. 
8.2.3. 
Pharmacokinetics Analysis Set (PKS) 
The PKS will consist of all randomized patients who have at least one evaluable plasma 
concentration of CK-2127107, provided they have no major protocol violations that could affect 
the PK of CK-2127107.  

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8.3. 
Endpoints 
8.3.1. 
Efficacy Endpoints 
8.3.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to Visit Week 12 in the percent SVC. 
8.3.1.2. 
Secondary Efficacy Endpoints 
• Slope from baseline to Visit Week 12 in the mega-score of muscle strength measured 
by HHD and handgrip dynamometry  
• Change from baseline to Visit Week 12 in the ALSFRS-R 
8.3.1.3. 
Exploratory Efficacy Endpoints 
Change from Baseline Endpoints  
• Change from baseline to Visit Week 12 in the percent predicted SVC measured at 
home  
• Change from baseline to Visit Week 12 in the components of voice analysis  
• Change from baseline to Visit Week 12 in the components of handwriting analysis  
• Percent changes from baseline in the strength of the muscle groups from baseline to 
Visit Week 12 that contribute to the Mega-score at Visit Week 12 
• Change from baseline to Visit Week 12 in the ALSAQ-5 
Slope Endpoints:  
• Slope of change from baseline to Visit Week 12 in the percent predicted SVC 
• Slope of change from baseline to Visit Week 12 in the ALSFRS-R 
• Slope of change from baseline to Visit Week 12 in percent predicted SVC measured 
at home  
• Slope of change from baseline to Visit Week 12 in the components of voice analysis  
• Slope of change from baseline to Visit Week 12 in the components of handwriting 
analysis  
• Slope of change from baseline to Visit Week 12 in the ALSAQ-5 
8.3.2. 
Safety Endpoints 
The safety endpoints are listed in the following: 
• The incidence and severity of TEAEs 
• Clinically important changes in safety assessment results [including, as appropriate, 
vital signs, clinical laboratory tests, ECGs, Ashworth score, falls assessment, physical 
and neurological examinations, BDI-Fast Screen and suicidality assessment]. 

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8.3.3. 
Pharmacokinetic Measurements 
The plasma concentrations of CK-2127107 and possible metabolites will be measured at the 
sampled time points during the study. 
8.4. 
Statistical Analysis 
8.4.1. 
Patient Disposition 
The number and percentage of patients randomized, receiving any study drug, completing the 
study, prematurely discontinuing treatment and prematurely discontinuing from the study will be 
summarized by dose group, treatment and overall. Reasons of premature discontinuation will 
also be summarized. 
8.4.2. 
Demographics and Other Baseline Characteristics 
Patient demographics and other baseline characteristics will be summarized by dose group, 
treatment and overall using descriptive statistics. 
8.4.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be classified using the World Health Organization Drug 
dictionary, and summarized by drug class and preferred term (PT). 
8.4.4. 
Efficacy Analysis 
Efficacy analyses will be conducted for the FAS. 
8.4.4.1. 
Primary Efficacy Analysis 
The hypothesis for the primary efficacy analysis is that there is a positive treatment difference 
(CK-2127107 minus placebo) in change from baseline to Week 12 in the percent predicted SVC. 
The effect of CK-2127107 on the change from baseline to Week 12 in percent predicted SVC 
will be analyzed using a MMRM with the contrast (-5, -1, 3, 3) to reflect the assumed 
relationship for the placebo, 300 mg/day, 600 mg/day and 900 mg/day dose groups. The 
response variable in the model will be the change in the percent predicted SVC from baseline to 
each post-baseline visit. The model will include the terms of treatment, baseline value, pooled 
site, visit, randomization stratification factors of riluzole use/non-use and stratified edaravone 
use/non-use, as well as treatment-by-visit and baseline-by-visit interactions. An unstructured 
variance-covariance structure will be used to model the within-subject errors. 
8.4.4.2. 
Secondary Efficacy Analysis 
Slope from baseline in the mega-score of muscle strength will be analyzed using a MMRM. The 
response variable will be the change from baseline to each post-baseline visit. The model will 
include the terms of treatment, the baseline value, pooled site, time, randomization stratification 
factors of  riluzole use/non-use, and stratified edaravone use/non-use as well as treatment-by-
baseline and treatment-by-time interactions. A random slope effect will be assumed in the model. 
Change from baseline in the ALSFRS-R will be analyzed using the same method as for the 
primary efficacy analysis. 

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8.4.4.3. 
Exploratory Efficacy Analysis 
Exploration of the dose-response relationship will come from model-based analyses that will use 
various assumptions of an implicit dose-response relationship. In addition, placebo will be tested 
against each dose group of CK-2127107 for specified endpoints and the 600 mg/day and 
900 mg/day dose groups combined.  
8.4.4.4. 
Multiplicity 
The global null hypothesis for the primary and secondary efficacy endpoints will be tested in a 
pre-specified order using a closed testing procedure. This procedure will maintain the family-
wise error rate at two-sided significance level of 0.05 for all hypotheses tested in a confirmatory 
sense. Details of the procedures will be provided in the Statistical Analysis Plan. 
Hypotheses other than the primary and secondary efficacy endpoints will also be tested with a 
significance level of 0.05. However, no adjustments for multiple comparisons will be made for 
these tests. 
8.4.5. 
Safety Analysis 
Safety analyses will be conducted for the SAS. Safety data will be summarized by dose group, 
treatment and overall using descriptive statistics. 
8.4.5.1. 
Study Drug Exposure 
The amount of study drug received and duration of study drug exposure will be summarized. 
8.4.5.2. 
Adverse Event 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
tabulated by system organ class (SOC) and PT. Individual events (PT) within each SOC will be 
presented in order of descending frequency. 
An AE (or SAE) will be regarded as treatment emergent if it starts or worsens (e.g., increases in 
severity or frequency) during or after the first dose of study drug. TEAEs will be summarized by 
maximum severity, and by relationship to the study treatment. All AEs will be listed. 
8.4.5.3. 
Serious Adverse Event 
Treatment emergent SAEs will be summarized by maximum severity, and by relationship to the 
study treatment. All SAEs will be listed. 
8.4.5.4. 
Clinical Laboratory Parameters 
For each laboratory parameter, the number and percentage of subjects with alert values or values 
outside the normal range during the study will be tabulated. All laboratory evaluations identified 
as outside the normal range or as alerts by the central laboratory will be listed. The value and 
change from baseline in continuous laboratory parameters will be summarized at each scheduled 
visit where laboratory measurements are taken. 

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8.4.5.5. 
Vital Signs 
For each measurement of heart rate, blood pressure, respiratory rate, and BMI, the number and 
percentage of subjects with clinically relevant abnormalities during the study will be tabulated. 
All measurements identified as clinically relevant abnormalities will be listed. The value and 
change from baseline in heart rate, blood pressure, respiratory rate and BMI will be summarized 
at each scheduled visit where vital signs are taken. 
8.4.5.6. 
ECGs 
For each ECG measurement, the number and percentage of subjects with clinically relevant 
abnormalities during the study will be tabulated. ECG measurements identified as clinically 
relevant abnormalities will be listed. The value and change from baseline in ECG measurements 
will be summarized at each scheduled visit where measurements are taken. 
8.4.5.7. 
Physical and Neurological Examinations 
The number and percentage of subjects deemed by the investigators to have clinically significant 
abnormalities will be tabulated by type of exam at each scheduled visit where physical or 
neurological examinations are taken. All measurements identified as clinically relevant 
abnormalities will be listed. 
8.4.5.8. 
Ashworth Score 
Ashworth score will be determined bilaterally at the elbows and knees with the results 
summarized at each body location. 
8.4.5.9. 
Falls Assessments 
The number and percentage of subjects with falls will be tabulated at each scheduled visit where 
falls assessments are taken. Activities engaged at the time of the fall, physical symptoms 
experienced immediately preceding the fall, and if the fall resulted in injury will also be 
summarized. 
8.4.5.10. Beck Depression Inventory-Fast Screen 
The total score of the BDI-Fast Screen is determined by summing the scores from the 
7 questions, and can range from 0 to 21, with higher scores indicating greater depression 
severity. The value and change from baseline in the total score of the BDI-Fast Screen will be 
summarized at each scheduled visit where scores are taken. 
8.4.6. 
Exposure-Response Analysis 
The relationship of drug exposure with efficacy and safety endpoints of interest will be explored. 
Graphical and tabular presentations will be provided as appropriate. 
8.4.7. 
Pharmacokinetic Analysis 
PK analyses will be conducted using the PKS.  All of the PK samples collected, including those 
obtained at Hour 3 on Day 1 as well as Hour 3 and Hour 6 at Week 2 and Week 12 from patients 
enrolled prior to Amendment 03, will be used for PK analyses. PK parameters such as tmax, Cmax, 

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Ctrough, AUC0-24, AUC∞, CL/F, V/F, t½ and RAC will be summarized by dose group using 
descriptive statistics as appropriate.  Nominal sample times will be presented in all statistical and 
graphical summaries.   
The observed plasma concentrations of CK-2127107 and its metabolites (if applicable) and 
riluzole at planned sampling time points will be summarized and listed. The potential for drug-
drug interaction between CK-2127107 given alone and in the presence of riluzole will also be 
assessed. 
The PK parameters with and without co-administration of riluzole will also be summarized. Box-
whiskers-plots of AUC and Cmax at Visit Week 12 with and without co-administration of riluzole 
will be presented. 
8.5. 
Interim Analysis  
After the last patient completes dosing, an interim analysis may be conducted by the Sponsor. 
8.6. 
Statistical Software 
Statistical analyses will be performed using SAS® version 9.4 or greater. 
8.7. 
Changes in Statistical Methods 
All changes in statistical methods that are described in the statistical analysis plan will be 
documented in the clinical study report. 

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9. 
ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. There will be no alterations in the protocol without the express written approval of 
the Sponsor, Investigator, and the Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) and regulatory authorities, as applicable. 
9.2. 
Initiation Visit 
Prior to the start of the clinical study at each site, the representative(s) of the Sponsor will meet 
with the Investigator(s) and appropriate clinical staff to familiarize the Investigator and clinical 
staff with the materials necessary for conducting the clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential. The Investigator agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts, etc.) by the Investigator(s) or their representative(s), shall require 
prior notification and review, within a reasonable time frame, by the Sponsor, and cannot be 
made in violation of the Sponsor’s confidentiality restrictions or to the detriment of the 
Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate site monitors who will be responsible for monitoring this clinical 
trial. The site monitor will monitor the study conduct, proper eCRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, the monitor will 
visit the study site at suitable intervals and be in frequent contact through verbal and written 
communication. It is essential that the site monitor have access to all documents (related to the 
study and the individual participants) at any time these are requested. In turn, the site monitor 
will adhere to all requirements for patient confidentiality as outlined in the ICF. The Investigator 
and other study personnel will be expected to cooperate with the site monitor, to be available 
during a portion of the monitoring visit to answer questions, and to provide any missing 
information. 
9.5. 
Institutional Review Board/Research Ethics Board/Ethics Committee  
In accordance with the US Code of Federal Regulations (CFR), 21 CFR 56, the protocol, subject 
recruitment advertisements (if applicable), and ICF will be submitted to the IRB/REB/EC for 
review and subsequent written approval by the IRB/REB/EC must be received before 
proceeding. The Sponsor will supply relevant material for the Investigator to submit to the IRB 
for the protocol’s review and approval. Verification of the IRB/REB/EC unconditional approval 
of the protocol and the written ICF statement will be transmitted to the Investigator. 

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The IRB/REB/EC will be informed by the Investigator of subsequent protocol amendments and 
of serious and unexpected AEs. Approval for protocol amendments will be transmitted in writing 
to the Investigator. If requested, the Investigator will permit audits by the IRB/REB/EC and 
regulatory inspections by providing direct access to source data/documents. 
The Investigator will provide the IRB/REB/EC with progress reports at appropriate intervals (not 
to exceed one year) and a Study Progress Report following the completion, termination, or 
discontinuation of the Investigator’s participation in the study. 
9.6. 
Informed Consent 
Before protocol-specific procedures are carried out, written informed consent for the study will 
be obtained from patients. The ICF generated by the Investigator (or designee) will be approved 
(along with the protocol) by the IRB/REB/EC and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The patients will be informed that participation is voluntary and that patients can 
withdraw from the study at any time. In accordance with 21 CFR 50, informed consent shall be 
documented by the use of a written ICF approved by the IRB/REB/EC and will be signed by the 
patient prior to protocol-specific procedures being performed. A copy of the signed consent, and 
the original will be maintained with the patient’s records. A copy of the IRB/REB/EC approved 
ICF must be sent to the Sponsor (or designee). 
9.7. 
Records 
The results from data collected during the study will be recorded in the patient’s eCRF. To 
maintain confidentiality, the patient will be identified only by a unique identification number. 
The completed eCRFs will be transferred to the Sponsor or designee. All source documents, 
records, and reports will be retained by the study site in accordance with 21 CFR 312.62(c). All 
primary data, or copies thereof (e.g., laboratory records, source documents, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the study site archives. 
9.8. 
Reference to Good Clinical Practices (GCP) 
The study procedures outlined in this protocol will be conducted in accordance with the CFR 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application 
(21 CFR 312), and Applications for FDA Approval to Market a New Drug (21 CFR 314), as 
appropriate. As such, these sections of U.S. Title 21 CFR, along with the applicable ICH 
Guidelines, are commonly known as Good Clinical Practices (GCP). 

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10. 
REFERENCES 
Brooks, B. R., R. G. Miller, et al. (2000). "El Escorial revisited: revised criteria for the diagnosis 
of amyotrophic lateral sclerosis." Amyotroph Lateral Scler Other Motor Neuron Disord 
1(5): 293-299. 
CTCAE. "Common Terminology Criteria for Adverse Events (CTCAE) v4.0." from 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40. 
Ducharme, M. P., M. Smythe, et al. (1993). "Drug-induced alterations in serum creatinine 
concentrations." Ann Pharmacother 27(5): 622-633. 
FDA (2009). Guidance for Industry, Drug-induced liver injury: Premarketing clinical evaluation. 
D. Safety. 
Inker, L. A., C. H. Schmid, et al. (2012). "Estimating glomerular filtration rate from serum 
creatinine and cystatin C." N Engl J Med 367(1): 20-29. 
Kiernan, M., S. Vucic, et al. (2011). "Amyotrophic lateral sclerosis." Lancet 377(9769): 942-
955. 
Lacomblez, L., G. Bensimon, et al. (1996). "Dose-ranging study of riluzole in amyotrophic 
lateral sclerosis." The Lancet 347: 1425-1431. 
Temple, R. (2006). "Hy's law: predicting serious hepatotoxicity." Pharmacoepidemiol Drug Saf. 
15(4): 213-220. 
Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. (2017). "Safety and 
efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a 
randomised, double-blind, placebo-controlled trial." Lancet Neurol 16(7): 505-512. 
 
 

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APPENDIX A. SCHEDULE OF EVENTS 
Study Procedures 
Screening 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 
FU Visit 
Informed Consent 
X 
 
 
 
 
 
 
Incl/Excl Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Physical Exama 
X 
 
 
 
 
 
X 
Neurological Exam 
X 
 
 
 
 
 
X 
Height  
X 
 
 
 
 
 
 
Weight & BMI 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
X 
 
 
X 
Vital Signs 
Xb 
X 
X 
X 
X 
X 
X 
Clinical Safety Labsc 
X 
X 
X 
X 
 
X 
X 
Pregnancy Testd 
X 
 
 
 
 
 
X 
PK Samplee 
 
X 
X 
X 
X 
X 
 
SVC 
X 
X 
X 
X 
X 
X 
X 
Muscle Strength 
X 
X 
X 
X 
X 
X 
X 
ALSFRS-R 
X 
X 
X 
X 
X 
X 
X 
Voice recording 
X 
X 
X 
X 
X 
X 
X 
Fine Motor Skillsf 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-5 
X 
X 
X 
X 
X 
X 
X 
Health Economic 
Outcomes Measurements 
 
X 
X 
X 
X 
X 
X 
Ashworth Scale 
X 
X 
X 
X 
X 
X 
X 
Falls Assessments 
 
X 
X 
X 
X 
X 
X 
Study Drug Dosing 
 
X 
X 
X 
X 
X 
 
AE/SAE Evaluations 
 
X 
X 
X 
X 
X 
X 
BDI-Fast Screen 
X 
X 
X 
X 
X 
X 
X 
a Complete physical examination at Screening Visit, abbreviated physical examination at FU visit 
b Temperature only at Screening 
c TSH only at Screening and Follow-Up Visit 
d Serum pregnancy test only for females of childbearing potential 
e PK sampling on Day 1 visit, Week 2 visit, Week 4 visit, Week 8 visit, and Week 12 visit; refer to Table 3 in 
protocol  
f If the device is suitable for use in that region 
 
Schedule of Events for Home Testing 
SVC* 
To be done every Saturday (± 1 day) independent of day of first dose 
Voice recording 
To be done every Saturday (± 1 day) independent of day of first dose 
  
 
 
 
*if the device is suitable for use in that region 

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APPENDIX B. 
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:  
Moderate Inducers: 
erythromycin 
bosentan 
diltiazem 
efavirenz 
verapamil 
etravirine 
suboxone 
modafinil 
 
nafcillin 
 
nevirapine 
 
 
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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APPENDIX C. LIVER SAFETY MONITORING AND ASSESSMENT 
Any patient enrolled in a clinical study with active drug therapy who reveals an increase of 
serum aminotransferase (AT) to > 3 x ULN or bilirubin > 2 × ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, alkaline phosphatase [ALP], and TBL). 
Testing should be repeated within 48-72 hours of notification of the test results. For studies for 
which a central laboratory is used, alerts will be generated by the central laboratory regarding 
moderate and severe liver abnormality to inform the Investigator, study monitor and study team. 
Patients should be asked if they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe as follows: 
 
 ALT or AST 
 
Total Bilirubin 
Moderate 
 > 3× ULN  
or 
> 2× ULN 
Severe 
 > 3× ULN 
and > 2× ULN 
In addition, the patient should be considered to have severe hepatic abnormalities for any of the 
following: 
• ALT or AST > 8× ULN 
• ALT or AST > 5× ULN for more than 2 weeks   
• ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)  
The investigator may determine that abnormal LFTs, other than as described above, may qualify 
as moderate or severe abnormalities and require additional monitoring and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. Patients with confirmed abnormal LFTs should be followed as 
described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or less 
if abnormalities stabilize or the study drug has been discontinued and the patient is 
asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology, 
may be considered an important medical event and may be reported as a SAE. The Sponsor 
should be contacted and informed of all patients for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
• Obtain a more detailed history of symptoms and prior or concurrent diseases. 
Symptoms and new onset-diseases should be recorded as ‘adverse events’ on the AE 

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page of the eCRF. Illnesses and conditions such as hypotensive events, and 
decompensated cardiac disease that may lead to secondary liver abnormalities should 
be noted. Non-alcoholic steatohepatitis is seen in obese hyperlipoproteinemic, and/or 
diabetic patients and may be associated with fluctuating aminotransferase levels. The 
investigator should ensure that the medical history form captures any illness that pre-
dates study enrollment that may be relevant in assessing hepatic function. 
• Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. 
• Obtain a history of exposure to environmental chemical agents. 
• Based on the patient’s history, other testing may be appropriate including:  
− acute viral hepatitis (A, B, C, D, E or other infectious agents)  
− ultrasound or other imaging to assess biliary tract disease 
− other laboratory tests including international normalized ratio (INR), direct 
bilirubin 
• Consider gastroenterology or hepatology consultations 
Patient Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease or exposure to other agents associated with liver injury, the patient may be 
discontinued from the study. The investigator may determine that it is not in the patient’s best 
interest to continue study enrollment. Discontinuation of treatment should be considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5 × ULN for more than 2 weeks 
• ALT or AST > 3 × ULN and TBL > 2 × ULN 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)   
In addition, if close monitoring for a patient with moderate or severe hepatic laboratory tests is 
not possible, drug should be discontinued. 
Hy’s Law Definition - Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality (or 
transplant) (Temple 2006; FDA 2009). 
The three “requirements” for Hy’s Law are:  
1. Patients with ALT or AST ≥ 3 × ULN compared to placebo, AND 
2. For patients with AT elevations (often much greater than 3 × ULN), elevation of serum 
TBL > 2 × ULN, without initial findings of cholestasis (elevated serum ALP), AND 

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3. No other reasons can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 

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APPENDIX D. CLINICAL LABORATORY EVALUATIONS 
All Visits: 
TBL 
Urea nitrogen 
Globulin 
Magnesium 
Direct bilirubin 
Creatinine 
Triglycerides 
Cystatin C 
Indirect bilirubin 
Glucose 
Cholesterol 
UA 
ALP 
Uric acid 
Creatine kinase 
CBC with 
differential 
ALT 
Calcium 
Sodium 
AST 
Phosphorus 
Potassium 
eGFR (calculated 
by CKD-EPI 
Cystatin C 
equation) 
Gamma-glutamyl 
transferase 
Total protein 
Bicarbonate 
Lactate 
dehydrogenase 
Albumin 
Chloride 
Screening and Follow-Up only: 
TSH 
Serum Beta Human Chorionic Gonadotropin