Study Protocol

Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL numberMedical Amgen Information documenthow youregardingthis have questions If Amgen Inc. of writtenconsent prior the without clinicalinvestigation of conduct the evaluationor theotheranythan bepurpose useddocumentcannot this in informationfor The scientific the of members anyonetheothertothan documentnot disclosed be must This Amgenofinformation Inc. documentcontains confidential This Date: 20120227 Number: Protocol Local Sponsor: Local Key Sponsor Contact(s): KeySponsor Date: ClinicalSponsor: Study Evaluate the Safety the Evaluate Title: 23 23

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Placebo- AentitledDouble - attached havetheread protocol I Agreement Investigator’s 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol Efficacy Ejection Fraction, datedFraction, Ejection Guideline on Good ClinicalPractice on Good Guideline Harmonisationon Conference International comply agree with the to I therein. regulations/guidelines Ordinance No. 28, 27 No. Ordinance Healthand Drugsof Clinical(Ministry Welfare Practice for on Good Ordinance without the prior written consent of Amgenof consent writtenInc. prior the without of clinicalinvestigation evaluationtheorother any purpose conduct the than used for willbe in document information thisnot contained ensure agreeconfidential that the to I Name of Name Signature 23 23

of Omecamtiv Mecarbil in JapaneseSubjects in MecarbilOmecamtiv of

controlled, Multicenter Study to Evaluate the Safety Evaluatetheto Study Multicenter controlled, Oct Investigator

ober

2015

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The study will be conducted in compliancewithMinisterial will thein study The be conducted 23 October 23

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(GCP) 2015

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Date (DD MonthYYYY)(DD Date

blind, Randomized, blind,

With With national or regional or national Heart Failure Heart , Pha , rmacokinetic (ICH) (ICH)

With With Tripartite Tripartite Page Page s, Reduced and 2 of 73

Approved

Study Design: A • Primary Endpoints: ( Hypotheses: (DMC) will perform perform will (DMC) independent independent 8 visits week and 4 week at supply IP new ive rece will subjects all blinding, maintain To team. study the to blinded be will assignment dose and dose dose BID mg 25 at administration initiate dose target • • randomized randomized compared with placebo. with compared 50 and BID, mg 37.5 BID, mg (25 levels dose 3 at formulation mecarbil omecamtiv (MR) 2 investigational product ( product investigational C • SafetyEndpoints outpatient basis. Subjects randomized to to randomized Subjects basis. outpatient or week 8 visit week or • the study. the Study Phase: Study With • • Primary Indication: Pharmacokinetic Title: Synopsis Protocol 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Secondary Objective Date: 20120227 Number: Protocol week have a week 2 PK value in time for dose adjustment at the week 4 visit will will 4 visit week the at adjustment dose for time in value 2 PK week a have • SecondaryEndpoint: twice daily [ daily twice

fraction ejection reduced with HF stable chronic with subjects Japanese 80 pproximately predose study Concentrations prior to administration (C administration to prior Concentrations Changes from baseline in electrocardiogram (ECG electrocardiogram in baseline from Changes signs and vital values laboratory in baseline from Changes of treatment of Subject incidence of adverse events events adverse of incidence Subject To measure changes in systolic ejection time (SET) time ejection insystolic changes measure To valuate the safety and tolerability of of and tolerability safety the evaluate To failure (HF) evaluate To Changes from baseline in SET in baseline from Changes 16, and area under the curve (AUC) curve the under area and 16, Reduced Ejection Fraction Ejection Reduced

at the week 4 visit based on steady state C state on steady based 4 visit week the at 23 23 8 based on based 8 - ADouble

≥ 200 ng/ 200 ≥ in Japanese Japanese in

Objectives:

Oct 25 to or placebo to randomized Subjects of e of BID in a 1:1:1:1 manner manner a 1:1:1:1 in Heart Failure Heart C

ober s s

linical linical No formal hypothesis testing will be performed. PK parameters following chronic chronic following PK parameters performed. be will testing hypothesis formal No 2 2 ither ither with reduced ejection fraction ejection reduced with will occur occur will

] This is a a is This pharmacokinetics ( pharmacokinetics - Placebo Randomized, blind, s, s, mL mL

for 16 for the the :

and Efficacy Efficacy and 2015 a

(or not available at week 8) week at available not (or 25 mg BID (n=20), 37.5 mg BID (n=20), BID mg 37.5 (n=20), BID mg 25 HF E

regular formal unblinded review of the accumulating study data. An data. study accumulating the of review unblinded formal regular steady state C state steady

s: vents vents

IP week

subjects

- double

only if the week 2 week the if only ) ) (omecamtiv mecarbil or placebo) throughout the study. the throughout placebo) or mecarbil (omecamtiv Classification (CEC) (CEC) Classification s ) dosing will be estimated. be will dosing )

of Omecamtiv Mecarbil in Japanese Subjects inJapanese Mecarbil Omecamtiv of to to

blind, blind, - - modified oral of administration of weeks 16 evaluate to

receive receive

by echocardiography by ) PK) and predose - placebo randomized, of omecamtiv mecarbil in Japanese subjects with heart heart with subjects Japanese in mecarbil omecamtiv of

will be up be will at week week at

result from week 2, i week from result the the either placebo (n=20) or omecamtiv mecarbil at a at mecarbil omecamtiv or (n=20) placebo either C

predose oral oral

controlled, Multicenter Study to Evaluate the Safety the Evaluate to Study Multicenter controlled, predose 37.5 mg BID and 50 mg BID treatment arms treatment BID mg 50 and BID mg 37.5

der remain the for BID mg 25 at continue will predose

omecamtiv mecarbil mecarbil omecamtiv 8 8 C - ) of omecamtiv mecarbil at weeks 4, 2, weeks at mecarbil omecamtiv of ) . titrated to 37.5 mg BID or 50 mg BID BID mg 50 or BID mg 37.5 to titrated ommittee will will ommittee

is < is An independent independent An mg BID will receive the assigned assigned the receive will BID mg

result from week 2. Subjects Subjects 2. week from result ) )

200 ng/mL. ng/mL. 200 by echocardiography by

at week 16 week at

controlled, multicenter, phase phase multicenter, controlled, or f f

available 50 mg BID mg 50 ths, all all ths, dea adjudicate

Subjects D

ata ata . M Up

an on an (n=20) be up- be onitoring onitoring -

W titration with a week 2 week a with following 16 weeks weeks 16 following ith Heart Failure ithFailure Heart titrated at at titrated

PK analysis analysis PK who who Page Page C at week 4 week at ommittee ommittee t targe mg BID), BID), mg do not not do 12, release release

will be be will will 3

of of of and and

Approved

estimated glomerular filtration rate (eGFR) < (eGFR) rate filtration glomerular estimated > judgment; investigator’s per arrhythmia major disease; heart congenital significant clinically or pericarditis, constrictive or myocarditis, active cardiomyopathy, obstructive hypertrophic disease; heart valvular uncorrected severe transplant; cardiac or care, hospice therapy, inotropic intermittent or continuous device, assist ventricular the in randomization, 30within(ICD) defibrillator cardioverter implantable or (CRT) therapy resynchronization cardiac of implantation - beta and digoxin, amiodarone, (except therapy antiarrhythmic chronic randomization; to prior days 30 within rest at angina persistent The following are the major exclusion criteria: New York Heart Association ( Association Heart York New criteria: exclusion major the are following The ( system response Web system/interactive response voice of absence or presence by stratified study. inthe enrollment planned of 20% approximately to up to limited reading of the screening echocardiogram. Enrollment of subjects wit subjects of Enrollment echocardiogram. screening the of reading scheduled ultrafiltration; systolic blood pressure (BP) > 160 mm Hg or < or Hg mm >160 (BP) pressure blood systolic ultrafiltration; scheduled routinely or diuretics) carperitide], [eg, vasodilators inotropes, (eg, HF for s infusion intravenous week 2 ( week reduced ejection fraction; treated with with treated fraction; ejection reduced tolerated; and and tolerated; (ARB) - angiotensin an either and Section to refer please procedure, each of timing the including procedures, study of list a full For All study site at weeks at site study and week 8 week and week 2 week Summary of SubjectEligibility Criteria: Size: Sample infarction possible (including events (CV) cardiovascular nonfatal selected and hospitalizations, 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol cannot be pregnant cannot (AST) aminotransferase ≥ any subjects randomized to omecamtiv mecarbil 37.5 mg BID or 50 mg BID mg 50 or BID mg 37.5 mecarbil omecamtiv to randomized subjects Japanese Japanese For a full list of eligibility criteria, please refer to to refer please criteria, eligibility of list a full For IP. with treatment 5 additional an for and IP with treatment during control birth effective abstinence, sexual practice randomization. randomization. investigator. bythe stable clinically considered also may Subjects . fraction ejection reduced and HF stable chronic have they if screening for eligible are Subjects Procedures F1 Amgen InvestigationalProduct DosageAdministration:and 2 90

visits tablets tablets times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aspartate or (ALT) aminotransferase alanine or (ULN), normal of limit upper the times major organ transplant or receiving renal replacement therapy by dialysis; total bilirubin (TBL) (TBL) bilirubin total dialysis; by therapy replacement renal receiving or transplant organ major

mm 23 23 that is expected to remain stable over the period of participation in the study, unless not not unless study, the in participation of period the over stable remain to expected is that C 7 - after after

3 days), week 4 ( week days), 3

predose Hg, or heart rate ( rate heart or Hg, or ischemia) or and and Oct m will be dosed orally at 25 mg BID, 37.5 mg BID, and 50 mg BID mg 50 and BID, mg 37.5 BID, 25 mg at orally dosed be will visit female aleand : ober D

the Schedule of Assessments of Schedule the left ventricular ejection fraction ( fraction ejection ventricular left

Approximately 80 Japanese subjects with chronic stable stable chronic with subjects Japanese 80 Approximately is is days days ay 1 include a visit window of of window a visit include 1 ay s s At

< to ensure IP compliance and for safety observation, and will be seen at the the at seen be will and observation, safety for and IPcompliance ensure to t

be screened in the hospital setting once they have recovered and are are and recovered have they once setting hospital inthe screened be

2015

he 200 ng/mL. ng/mL. 200 2, 4, 8, 12, and 16, and for the end of study ( study of end the for and 16, and 12, 8, 4, 2, or or prior to randomization; likely to receive the following following the receive to likely randomization; to prior i

nvestigator . week 4 visit 4 week planning to become pregnant, pregnant, become to planning

≥ 3 times ULN at screening. at ULN times 3 ≥ converting enzyme enzyme converting +3

) >HR) subject or surgical contraceptive methods or use 2 use or methods contraceptive surgical or

days) and the EOS visit at week 20 (+3 days). 20 (+3 week at visit EOS the and days)

Subjects will be contacted contacted be will Subjects ’s opinion: ’s 110

(or at week 8 visit if the week 2 C week the if 8 visit week at (or s atrial fibrillation atrial ≥

optimal optimal beats per minute (bpm) or HR < HR or (bpm) minute per beats 20 and and 20 blocker therapy), or routinely scheduled outpatient outpatient scheduled routinely or therapy), blocker

revascularization, implantation of ICD or CRT, CRT, or ICD of implantation revascularization,

( mL/min/1.73 m 30 mL/min/1.73 a ± ± Table Table (ACE) (ACE) pharmacological therapy, including a beta blocker blocker beta a including therapy, pharmacological ≤ LVEF

cute myocardial infarction, unstable angina, or or angina, unstable infarction, myocardial cute 3 days with the exception of of exception the with days 3

Section Section Subjects must be outpatients at the time of of time the at be outpatients must Subjects 85 years of age with chronic stable stable chronic with age of years 85

/flutter 2 ) ) inhibitor or an angiotensin receptor blocker blocker receptor angiotensin an or inhibitor

) or or must be must Female subjects of childbearing potential potential childbearing of subjects Female . . 4 , breastfeeding .

). ). IVRS/IWRS at the time of screening screening of time the at on on day 7 and 6 days after the week 4 week the after days 6 and 7 day ≤ 2 2

40% as determined by central central by determined as 40% at screening; past recipient of of recipient past screening; at ) ) EOS Omecamtiv mecarbil Matrix Matrix mecarbil Omecamtiv predose h atrial fibrillation atrial h days after the end of of end the after days

visit at at visit 50 and must be willing to to willing be must and Randomization will be be will Randomization

acceptable method(s) of of method(s) acceptable

will be up be will HF 90

within 3 months after after 3 months within

. bpm result result

NYHA week

Hg or diastolic BP BP diastolic or Hg is is

- screening titrated ) ) not available) not via via

HF 20. 20. class IV; Page Page /flutter myocardial myocardial interactive interactive

with with if the the if 4 ;

of is is 73 ,

Approved

For a full description a full For be adjudicated. will 20 week at study the of completion until randomization subject . All Committee (CEC) Classification Events Clinical independent an by This study will adjudicate deaths, all hospitalizations, and selected nonfatal cardiovascular events cardiovascular nonfatal selected and hospitalizations, all deaths, adjudicate will study This evaluated. Secondary randomization. at fibrillation/flutter atrial of absence or presence of factor effect mecarbil omecamtiv each between difference the and group treatment randomized by descriptively summarized be group treatment The echocardiographic secondary echocardiographic The evaluable omecamtiv mecarbil PK parameter parameter PK mecarbil omecamtiv evaluable one least at have subjects where FAS of subset in the performed be will analyses endpoints PK will be summarized arm randomized subjects who have received at le at received have who subjects randomized randomized treatment group. group. treatment randomized any of incidence In the analyses of primary endpoints, PK parameters will be calculated using non using calculated be will parameters PK endpoints, primary of analyses the In the in analyzed assignment. group treatment dose target randomized their to according methods. I methods. All non All Statistical Considerations: 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Sponsor Date: 20120227 Number: Protocol Version(s)/Date(s): Standards Element Data

23 23 in the SET in the - PK endpoints analyses will be performed on the full analysis set (FAS) which includes all all includes which (FAS) set analysis full on the performed be will analyses endpoints PK : Oct

, safety ndividual PK PK ndividual Amgen, Inc. Amgen, ober subjects and the titration status titration the and

treatment and ,

and exploratory endpoints will be summarized descriptively by randomized randomized by descriptively be summarized will endpoints exploratory and 2015

dose level and placebo will be estimated. be will placebo and level dose of statistical analysis methods, please refer to to refer please methods, analysis statistical of its

and Amgen Astellas BioPharma K.K. (AABP) K.K. BioPharma Astellas Amgen and

with descriptive statistics descriptive with parameters parameters

relationship to omecamtiv mecarbil plasma concentrations will be be will concentrations plasma mecarbil omecamtiv to relationship that that - ly by by ly descriptive summarized be will event adverse emergent receiv

No formal statistical hypothesis will be tested. tested. be will hypothesis statistical formal No

endpoint 5: 20 March 2015 March 20 5: ed of omecamtiv mecarbil mecarbil omecamtiv of

at least 1 dose of IP. The safety endpoint of subject subject of endpoint safety The IP. of dose 1 least at . T he treatment effect on change from baseline in SET will SET in baseline from on change effect treatment he

will be summarized and analyzed by the stratification stratification the by analyzed and summarized be will ast 1 ast ( C max

. dose of of dose

C predose IP ) collected in in collected .

(omecamtiv mecarbil or placebo). placebo). or mecarbil (omecamtiv

Generally, subjects will be grouped grouped be will subjects Generally, The relationship of treatment treatment of relationship The Section Section

events occurring after after occurring events mecamtiv mecarbil mecarbil omecamtiv the Safety endpoints will be be will endpoints Safety

- compartmental compartmental

Page Page 5 of 73

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occur ± Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL p or BID 3 2 1 BL= baseline; PK=pharmacokinetic;BID=twice daily Date: 20120227 Number: Protocol dose Blinded titration step Randomization will be stratified by presence or absence of IP administration. should be performed as close possibleas after the collection of PK sample at 2 hours be performed a administration. PK samples at predose and at 2 hours PK samples at predose, at 2 hours ± C 30 predose

minutes after IP

will be up-titrated in subjects subjects in 23 23

lacebo will in in the morning, at study site Oct ober s close as possible as close s only if the week 2

receive

at week 4 visit 2015 administration administration based on steady state C

the assigned IP throughout the study Study Design and Treatment Schema and Treatment Design Study

after C in all arms. arms. all in in in the morning

predose 30

± the minutes; 4 hours ± 30 min

is < is collection of PK sample at

200 Subjects Subjects predose s followings IP administration.

(0 h (0

;EOS=end ng/mL result from week 2. Subjects randomized to 25 mg

ours randomized to 37.5 BIDmg or 50 BIDmg target .

atrial fib

= start IP)of 30 of study;Wk=week minutes; 6 hours ± 30 minutes; 8 . . Up rillation -titration 2 hours . /flutter Echocardiogram

at week 4 or week 8 visit Echocardiogram at week 16

via via . IVRS/IWRS minutes ± 30 minutes following at week

following IP Page Page hours

8 8 6 should s s will of 73

Approved

Study Glossary Study 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol ARB ALT ALP AHF AE ACE AABP Term or Abbreviation eGFR EDC eCRF ECG DMC DILI 1 Day CTCAE CRT C C CK CI potential Childbearing CEC BNP BMI B BP BID AUC AST pm predose max

23 23

Oct ober

2015

Definition/Explanation electronic data capture data electronic car Events Clinical B- curve the under area blocker receptor angiotensin aminotransferase alanine Committee Monitoring Data - drug index mass body pressure blood concentration prior to the investigational product administration product investigational the to prior concentration maximum observed concentration observed maximum acute heart failure heart acute event adverse - angiotensin BioPharma Astellas Amgen electronic case report case electronic administered first is product investigational day fraction MB kinase creatine interval confidence involved laboratory the for range" "postmenopausal of definition the to according or ng/dL) 5 (< levels estradiol postmenopausal follicle and (LH) hormone (luteinizing levels gonadotropin postmenopausal 1 minute per beats daily twice aminotransferase aspartate phosphatase alkaline central laboratory and provided to the investigator. the to provided and laboratory central the by calculated be will eGFR rate; filtration glomerular estimated e Events Adverse for Criteria Terminology Common 2 least at for menses no spontaneous but years 55 age < months; age as: defined is Menopause postmenopausal). is she or salpingectomy bilateral or oophorectomy, bilateral hysterectomy, a had has (she sterilized a lectrocardiogram female is considered of childbearing potential unless permanently permanently unless potential childbearing of considered is female year, but currently currently but year, years; age < 55 years and spontaneous and years 55 < age years; type natriuretic peptide natriuretic type

therapy resynchronization diac induced liver injury liver induced - stimulating hormone levels (FSH) > 40 IU/L) or or IU/L) 40 > (FSH) levels hormone stimulating

converting enzyme converting

Classification

≥ 55 years with cessation of menses for 12 or more more or 12 for menses of cessation with years 55 ≥

amenorrheic amenorrheic

form

K.K.

(spontaneous), AND with with AND (spontaneous),

menses within the past past the within menses

Page Page 7

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Report Form Form Report Contingency eSAE EOS Enrollment study of End EM Term or Abbreviation PT interval PR PM PK/PD PKAS PK PEP NYHA NT MR LVESD LVEF LVEDD LH IVRS/ IV IR IPIM IP IRB INR IEC ICH GCP ICD HR HF FSH

proBNP

23 23

RS Oct

ober

2015

real time as an interface to collect and process information process and collect to an interface as time real in computer a central to linked is that technology telecommunication a study subject is given a randomization number a randomization given is subject study a Definition/Explanation n- - modified - end ventricular left luteini system/ response voice interactive Manual Instruction Product Investigational end- for assessments the completes study this in subject randomized last the which on day last the as defined is study the of end the p Association Heart York New failure heart e measured by ECG by measured metabolizers poor pharmacokinetic/pharmacodynamic endpoint potential - end ventricular left imme board review institutional committee ethics independent follicle (paper form report contingency event adverse serious electronic study of end prothrombin time prothrombin heart's inthe complex QRS the of beginning the to wave P the of beginning the from measured is interval PR set analysis pharmacokinetic fraction ejection ventricular left I product investigational ratio normalized international Practice Clinical Good Harmonisation on Conference International defibrillator cardioverter implantable time of unit per cycles cardiac of number rate; heart ntravenous harmacokinetic xtensive metabolizers xtensive terminal pro B- pro terminal

of diaterelease zing hormone hormone zing - - - hormone stimulating study visit (week 20) or terminates the study early study the terminates or 20) (week visit study based form) form) based release

(s) (s)

type natriuretic peptide natriuretic type

systolic diameter systolic diastolic diameter diastolic

(omecamtiv mecarbil or placebo) or mecarbil (omecamtiv

Web interactive

electrical cycle as as cycle electrical

response system; system; response

Page Page

8 of

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol SD SAE interval QTc interval QT complex QRS Term or Abbreviation URL ULN TBL Data Source SET

23 23 Oct

ober

2015

Definition/Explanation randomization number, and stratification value. stratification and number, randomization Ex [E6]). Guideline Harmonisation on Conference (International copies). certified or records (original documents source in contained are data Source trial. the of evaluation and reconstruction the for necessary trial clinical a in activities other or observations, findings, research. clinical in use for information patient containing record original the of copy certified or record an original from information total bilirubin total serious adverse event adverse serious upper reference limit reference upper normal of limit upper s deviation standard methodology accepted using rate heart for corrected interval QT ECG by measured as cycle electrical heart's the in wave T the measure ventricles the of depolarization the for it takes time the represents ECG; by measured as cycle electrical heart's inthe wave S the and wave Q the between interval time ejection ystolic

amples of source data include subject identification number, number, identification subject include data source of amples

of the time between the start of the Q wave and the end of of end the and wave Q the of start the between time the of The information may include, but is not limited to, clinical clinical to, limited not is but include, may information The

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5. 4. 3. 2. 1. Study Glossary Study Study Design andSchema Design Treatment Study 6. Protocol Synopsis Protocol Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

23 23 SUBJECT ENROLLMENT SUBJECT 4.1 SUBJECT ELIGIBILITY SUBJECT 3.5 3.4 3.3 3.2 3.1 PLAN EXPERIMENTAL 2.4 2.3 2.2 6.2 2.1 RATIONALE AND BACKGROUND 6.1 1.2 S OBJECTIVE 1.1 TREATMENT P TREATMENT 5.2 5.1

Oct ober 4.1.2 4.1.1 Inclusion and Exclusion Criteria and Exclusion Inclusion 3.5.2 3.5.1 DurationStudy Estimated Replacement of Subjectsof Replacement Number of Subjectsof Number Number of Sitesof Number Study Design Study ClinicalHypotheses Rationale 2.2.2 2.2.1 Omecamtiv MecarbilOmecamtiv Background 6.2.1 Product Investigational Disease Classification of Product(s) and/orProduct(s)Medicalof Device(s) Classification Secondary Primary Site Personnel Access to Individual Treatment Assignments Access Individual toPersonnel Treatment Site Randomization/Treatment Assignment Randomization/Treatment

...... 7

2015

...... 3 ......

...... RO

...... Exclusion Criteria Exclusion Inclusion Criteria Inclusion End of Study of End Study Duration for Duration Study Clinical Experien Clinical Preclinical Information Preclinical al Product (Omecamtiv Mecarbil) Product (Omecamtiv al Amgen Investigation 2.2.2.3 2.2.2.2 2.2.2.1 6.2.1.1

...... CEDURES

......

TABLE OF CONTENTS OF TABLE ......

...... Study in Japanese Subjects Japanese inStudy Studies in Subjects With Heart Failure Subjects in Heart Studies With Studies in HealthyVolunteers in Studies Dosage, Administration, and Schedule Administration, and Dosage,

......

...... 6

......

ce ce ......

...... Subjects ......

......

...... Page 10 of Page

......

27 25 24 24 24 24 24 24 24 23 23 22 22 22 20 20 17 16 15 15 15 29 29 29 14 28 14 14 28 14 14 28 27 73

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7. Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

23 23 7.2 7.1 STUDY PROCEDURES STUDY 6.6 6.5 6.4 7.4 6.3 7.3

Oct ober 7.2.13 7.2.12 7.2.11 7.2.10 7.2.9 7.2.8 7.2.7 7.2.6 7.2.5 7.2.4 7.2.3 7.2.2 7.2.1 General Study Procedures General Schedule of Assessments of Schedule During Study Period During Procedures MedicalDevices and/or ExcludedTreatments, Product Complaints Product Concomitant Therapy Concomitant 6.3.3 6.3.2 7.4.1 Period Treatment 6.3.1 Hepatotoxicity Stopping and Rechallenge Rules Rechallenge and Stopping Hepatotoxicity 7.3.2 7.3.1 and Enrollment Screening

2015

Echocardiograms Laboratory Assessments Laboratory Electrocardiogram Physical Measurements Physical PhysicalExamination Hospitalizations Potential Endpoints Potential Adverse EventsAdverse Investigational Product Administration Diary Administration Product Investigational Signs Vital Concomitant Therapy Concomitant Medical History Medical Informed Consent Informed Criteria for Criteria Criteria for Conditional Withholding of Omecamtivof Withholding Conditional for Criteria Telephone Contact Days 7, 34, and 62 ContactDays34,7, Telephone Criteria for Permanent Discontinuation of OmecamtivDiscontinuation Permanent for Criteria Rescreening Screening 7.2.12.6 7.2.12.5 .12.47.2 7.2.12.3 7.2.12.2 7.2.12.1 Potential Hepatotoxicity Potential Mecarbil due to Potential Hepatotoxicity Potential Mecarbildue to Mecarbil due to Potential Hepatotoxicity Potential Mecarbilto due 6.2.1.2

......

...... Rechalleng

Pharmacogenomic Studies Pharmacogenomic Assay Monitoring MecarbilOmecamtiv Therapeutic Digoxin Mecarbilof Omecamtiv Pharmacokinetics Troponin Pregnancy Test Pregnancy Heart Rate Heart orBloodAbnormal Pressure Infarction, orMyocardial Ischemia due to Product Investigational Rules for Withholding ......

......

...... e After MecarbilOmecamtivof

......

...... Page 11 of Page

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41 39 41 41 39 41 40 38 37 37 37 37 37 36 36 36 36 36 36 36 33 33 33 33 33 33 32 43 43 31 42 42 30 42 73 31

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10. 9. 8. Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

23 23 10.3 10.2 10.1 CONSIDERATIONS STATISTICAL 9.3 9.2 9.1 SAFETY DATA COLLECTION, RECORDING, ANDREPORTING RECORDING, COLLECTION, DATA SAFETY 8.3 8.2 8.1 WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY AND PROCEDURES, FROMTREATMENT, WITHDRAWAL 7.6 10.5 7.5 10.4

Oct

ober or Designees or byAmgen Assignments Treatment Individualto Subject Access Sample Size ConsSample 10.1.3 10.1.2 10.1.1 Study Endpoints, Analysis Sets, andCovariatesAnalysis Sets, Endpoints, Study Pregnancy and Lactation Reporting and Lactation Pregnancy 9.2.2 9.2.1 Reporting of Adverse EventsAdverseof Reporting 9.1.2 9.1.1 Adverse EventsAdverse 8.3.2 8.3.1 Reasons for RemovalStudy or From Reasons Treatment for Subjects’ Participation Prior to Study Completion Study to Prior Participation Subjects’ orSponsor or to Terminate Decision Investigator Withdraw Subjects’ Decision toDecision Subjects’ Withdraw Sample Storage andDestructionStorage Sample 10.5.4 Follow Safety 10.5.3 10.5.2 10.5.1 Planned Methods of Analysis Methodsof Planned 10.4.2 10.4.1 Planned AnalysesPlanned

2015

Covariates and Subgroups Covariates Analysis Sets Analysis Study Endpoints Study Reporting Procedures for Serious Adverse EventsSeriousAdverse Procedures for Reporting Reporting Procedures for Adverse EventsdoAdverse not Procedures That for Reporting Definition of Definition Definition of Adverseof Events Definition Reasons Reasons for Removal From Reasons Treatment for Safety Endpoints Safety Secondary EndpointSecondary Endpoint Primary General Consi General Primary Data Monitoring Committee(DMC) Monitoring Data 10.1.1.4 10.1.1.3 10.1.1.2 10.1.1.1 9.2.2.2 9.2.2.1 Meet Serious Criteria MeetSerious

...... - up Visit/End of Study VisitStudyof Visit/End up

......

Analysis iderations ......

for RemovalStudy From for Exploratory Endpoints Exploratory Safety Endpoint Safety EndpointSecondary Endpoints Primary Endpoint as aSafety Endpoint Reporting the Protocol the After Events SeriousAdverse Reporting

Serious Adverse EventsSeriousAdverse

...... de

...... rations

......

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...... required Reporting PeriodReporting required ......

...... s

......

aStudy

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...... Page 12 of Page

53 53 53 52 52 52 51 51 51 51 51 51 51 49 49 47 47 47 46 46 46 46 46 46 46 45 45 44 55 43 55 55 55 54 54 54 56 73

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Table 14. 13. 12. 11. Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol Table Table Table Appendix D. Excluded Medications and Foods Medications ExcludedAppendix D. Appendix A. Additional Safety Assessment Information Assessment Additional Safety Appendix A. Appendix B. Sample Serious Adverse Event ReportEventFormSeriousAdverse Sample Appendix B. Appendix C. Pregnancy and Lactation Notification Lactation Pregnancy and Appendix C. Worksheets

23 23 APPENDICES 12.7 REFERENCES 11.1 11.2 OBLIGATIONS AND LEGAL ADMINISTRATIVE 11.4 11.3 12.1 12.2 12.3 12.4 12.5 12.6 REGULATORY OBLIGATIONS 1

2. Schedule of AssessmentsofSchedule 2. 3. AnalyteListing 3. 4. PK ParameterPKConfidenceIntervals 4. 95% . Oct Comparison of Omecamtiv Mecarbil Steady State C ofComparison MecarbilOmecamtivState Steady

ober Compensation Informed Consent Informed Institutional Review Board/Independent Ethics CommitteeEthics Review Board/Independent Institutional Investigator Signatory Obligations Investigator Confidentiality Subject Protocol Study Documentation andArchive Documentation Study Study Monitoring and Data Collection and Data Monitoring Study Investigator Responsibilities for DataCollection Responsibilities for Investigator Language Publication PolicyPublication Subjects Following BID Dosing of MRof - Dosing BID Following

2015

......

...... AmendmentsandStudy Termination

10.5.4.4 10.5.4.3 10.5.4.2 10.5.4.1 ......

......

List of Appendicesof List Electrocardiogram Vital Sig Vital Laboratory Tests Safety Adverse EventsAdverse

...... List of Tablesof List

......

ns F1

......

Table ......

......

...... ts in Healthy ts Japanese

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...... Page 13 of Page

65 63 61 62 56 56 57 58 58 59 59 59 60 61 61 56 56 56 56 22 34 39 71 73 66 53 68 73

Approved

studyare this of objectivesprimary The 1.1 1. 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol The s The • • • 1.2 final pathway for a diversity of diseases that afflict the hearttheafflict diseasesthat pathway a diversity of final for failure Heart 2.1 2. 6 cardio of rate The Kitabatake, 2003, Kitabatake, ( haveHFbelieved are approximatelypeople to Japan, 1 million In rate neuroendocrineincreasedactivation, constriction, arterialand venous retention, sodium including targets diverseaimedatare availablethat these treatments addition, ( pacingand biventricular antagonists,revascularization, coronary aldosterone angiotensin - including mortality, andhospitalizationsimprove HFrateof the reduce have been shown to interventions al,2009). et Hamaguchi 2005 ; Bureau, population( Japan’s rapidlydecades, aging mainlydue to coming in that than can occur characterized by increased sympathetic tone and peripheral vasoconstriction, and peripheral tone sympathetic characterizedbyoccurincreased can compensatorychangesof output, cardiacpreservea series an to inattempt time, Over dysfunction. commonlysystolicby cardiac most is marked a condition HF contractility. improvemyocardial is HFto of treatment target Anotherfor life. of quality restore 1- Krum

months in patients hospitalized for HF hospitalized ( in patients months for year readmissions range from 7.6 readmissions rangeyear from

To e To with To e To To 16 w 16 ( 23 23 HR) econdary objectives econdary

and measure changes in systolic ejection time (SET) intime measure changes ejection systolic valuate the safety and tolerability of of andsafetytolerabilitythe valuate valuate heart failure (HF) heart failure eeks of treatment eeks Oct , cardiac dyssynchrony, and arrhythmias often fail to control symptomsor control to often fail dyssynchrony,and cardiacarrhythmias ,

Teerlink, Western ober is a clinical syndrome marked by impaired cardiac contractility and is the contractilityand is bycardiacimpaired marked syndrome isa clinical

Primary OBJECTIVES Secondary Disease BACKGROUND ANDRATIONALE BACKGROUND Okura et 2008). Okura al,

the the

2015

vascular mortality or HF hospitalization approaches 25% to 30%at25%HF approaches hospitalizationto or vascular mortality Okur pharmacokinetics

2011),morta industrialized countries, it is expected to rise substantially in the substantiallythe rise toinitis expected industrialized countries,

). aal,2008). et

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with reduced ejection ejection withfractionreduced of of

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(PK) Although the prevalence of HF (< 1%) islower1%) (< HFof prevalenceAlthough the to 17.8%( to pharmacological and non pharmacological year mortality due to HF is 4.3HFfrom% yeardue to mortality to:

Konstam et al, 2007; Gheorghiade et al, 2013 al, al,2007;etet Gheorghiade Konstam

of omecamtiv mecarbil in Japanesesubjects omecamtivinof mecarbil oral oral

Shiba et al, 2004; Tsutsui et al,2007; al,2004; et Tsutsui et Shiba omecamtivmecarbil

by by following echocardiography following

( Hilfiker - pharmacological Japanese Statistics Okamoto and Okamoto - ). al,2006). et Kleiner

- blockers, blockers, Page 14 of Page to 9%and to heart heart

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cardiac contractility using adrenergic receptor agonists receptor (ie, adrenergic contractilityusing cardiac improve neurohormonal variousto pathways. Attempts activationof wellthe as as 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol phosphodiesterase inhibitors (ie, milrinone) have met with little success have with little (ie, inhibitorsmet milrinone) phosphodiesterase consumption, intracellular calcium, andarrhythmias( calcium, intracellular consumption, oxygenincreasedto attributable safety liabilities havesignificant mechanisms not inhibit phosphodiesterase type 3. In dog phosphodiesterase inhibit3. In type not does myocytes. isolatedIt cardiac in transient calcium changing intracellular the without In intravenous ( intravenous Felker without increasing cardiac myocyte intracellular calciumintracellular myocyteincreasingcardiac without (BP), or coronary bloodcoronaryor flow ( (BP), pressure bloodoxygenuptake, upon myocardial effect noticeable without wereachieved omecamtivofmecarbil salutaryeffects symptoms. HFdrive The hemodynamics that andsystoli SETof increased prolongation providingevidence that decreased, resistancevascular peripheral and total pressure, leftatrial pressure, filling ventricular left or Additionally, (dP/dt) HR. development of pressure rate increasingthe SET without leftventricular byincreasing the output omecamtiv 2.2.1 2011 al, et Malik T CY (ESRD) 9 and 1 completed phase 2b study in acute heartacute in ( failurestudy phase 2b 1 completed and CY1121,CY 1021, HF (Studies chronic in subjects studies 2a myosin heavy chain, the force the heavymyosin chain, cardiacdomainenzymaticof the activating contractilitybyand directly selectively cardiac CK- 423, (AMGmecarbil Omecamtiv 2.2 liabilities. these without contractility myocardial increase designed specifically to class mechanistic 2.2.2 he safety, tolerability,

completed phase 1 clinical studies in healthy volunteers/healthyin phase1 clinical studies completed vitro experiments demonstrated that omecamtivexperiments that demonstrated vitro

1211

23 23

et al,et subjects (Studies CY 1111, CY 1011, CY 1013, CY 1015, CY 1016,CYCY1011, 1015,(StudiesCYCY 1111, 1013,CY subjects Oct

[20120255], 20080676, 20090229, and 20090229,20080676,and in [20120255], 20090727);

mecarbil significantly augmented left ventricular systolic function and cardiac and cardiac systolicventricular function left augmented significantlymecarbil

). Cardiac myosin activators like omecamtiv mecarbil are a neware omecamtivlikemecarbil activators Cardiac myosin 2003). ober IV Preclinical Information Preclinical Omecamtiv Mecarbil Omecamtiv Clinical Experience Clinical ) )

). formulations of omecamtivmecarbilin of have been evaluated formulations

2015

pharmacokinetic ( pharmacokinetic

Shen et al,2010 et Shen - generating motor protein of the cardiac of sarcomer cardiac protein the motor generating

1827452) is a novel small molecule that increases that is 1827452)small a novelmolecule

Background

PK c function can favorably impact the can favorablyimpact c function )

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Malik

pharmacodynamic ( mecarbil augmentscontractility mecarbil s

Cuffe of et al,2011). et systolic AHF ( Teerlink,

end-

et dobutamine) ordobutamine) ) )

subjects (Studysubjects al,

stage renal disease CYand 1221); 1124,CY HF, infusion of of infusion HF,

2002

2009 4completedphase ;

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20100754). 20100754). e , t hese 73

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ketoconazole or diltiazem. or ketoconazole combinationwith mecarbiland in omecamtiv alone oral receivedCYP2D6 genotype defined their to withrespect (PMs)metabolizers poor or (EMs) extensivemetabolizers omecamtivmecarbil. of elimination P450enzymes CYP3A4cytochrome and CYP2D6of contributionthe to the evaluate an open 1013 wasCY ( ejection fraction ventricular AUC when given in combination with ketoconazole which contributed to observed theto whichwithketoconazole contributed combinationAUC whenin given omecamtivinmecarbil decrease had a 1 PM subject respectively; PM and subjects, EMinomecamtivAUC ofinmeanincreases the mecarbil and 31% 51% approximately placebo corrected increases from baseline in SET,Dopplerinbaseline increases from corrected placebo echocardiography were observed. were These echocardiography observed. - Concentration 905 30400 ng30400 Efficacy was also evaluated in completedStudy in evaluated wasalso Efficacy 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL a 1111, first CY Date: 20120227 Number: Protocol clearance clearance for those for infusions demonstrated with - PKdose generallyinfusions linear evaluate the safe ty the evaluate double- 2.2.2.1 information. additional for mecarbil the below.to Refer summarizedare study ) ng deviation ) distribution volume distribution and hours 23.2 IV to healthy male volunteers volunteers healthy( to male IV 0.005 33 of as measuredby as (C

max 0.5 mg/kg/hr over 6mean overhours,the 0.5 mg/kg/hr subjects who received infusions of omecamtiv mecarbil at dosesrangingomecamtivatof mecarbil who from infusions subjects received (183) ), 23 23 mg/kg/hr to 1. to mg/kg/hr

were approximately dose proportional, with an AUC of 159of(57 with an AUC wereapproximatelyproportional, dose blind, placebo- blind,

Oct • administration rates were 8.70 (2.20) ng/mLand1340 ng/mL.were8.70 (2.20) rates administration

hr/mL . ng/mL

ranged from 125 to 207 mL/hr/kg andmeanthe 125 207 tomL/hr/kg ranged from ober • hr/mL Studies in Healthy in Volunteers Studies dependent

- increased slightly with increasing doses. increasing doses. slightly with increased

in when administered at a rate of 1 mg/hr/kg; corresponding C 1 ofwhenmg/hr/kg; a administeredatrate area under the curveunder( the area

2015

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0 for treatment for tolerability, and PK/PD profile of omecamtiv mecarbil administered omecamtivofprofilemecarbil and PK/PD tolerability, mg/kg/hr for up to 6 up to for mg/kg/hr

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Ketoconazole (a potent inhibitor of CYP3A4) causedCYP3A4)potentinhibitorof Ketoconazole (a

LVEF effects on cardiac function asmeasuredby effects on cardiac function Teerlink et al,2011 et Teerlink

administered at an infusion rate of 0.005 mg/hr/kg and 0.005 of mg/hr/kg administeredatinfusion rate an )

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period crossover, dose escalation studyescalation to perioddose crossover,designed Healthy volunteer subjects who were either whosubjects wereeither Healthy volunteer

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PD PD hours. Investigator’s Brochure Investigator’s

and effects included statistically significant significant included statistically effects

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(990 in PMsubjects higher AUCwas alone,approximately 37% mean the wasadministered In Study 20090727, which20090727, Study compared In 44 ofa total Theenrolled omecamtiv ofstudiesoralpreparationsmecarbil. of evaluate designedthe andto parameters 1016 were 1015,PKCYCY1011, CY Studies omecamtivofmecarbil. metabolism theinvolvementin CYP3A4 and CYP2D6of minor 14 - withno treatment wellwastolerated absorption.Omecamtiv of extent not but the rate appeared the reduce to food f bioavailability 3 metabolism, andorally excretionof metabolism, 20090229 Study variability. oralMR and the of PK CYP3A4 omecamtivAUCwasofthemecarbilsimilar. inhibitorof CYP3A4), moderate (a differences between2 groups. these differences 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol decarbamylation of omecamtivof decarbamylation urine. in appeared andomecamtiv Less10%ofthanmecarbil urine inwererecoveredfeces. mecarbil MR formulation, 20 that enrolled 5 sequential cohorts of 5sequentialcohorts enrolled that double- a randomized, 1121 wasCYStudy M3)abundantofthe metabolites lactam most M4 (a component,abundantwithand M3 omecamtiv wasmost mecarbilthe plasma, [LVEF 2.2.2.2 sarcomerevitro in cardiac and feces. drug and treated with study drug infusions ranging from 272 hours( to infusions ranging from drugwith study treated and times a day for 7 aday times for females. Maximal duration of exposure was 10 days and maximal dose was30 exposure and dose ofwas maximal 10 days Maximal duration females. healthy volunteers. Approximately 85% of the IV and oral dosesof and [ theoral of IV Approximately85% volunteers. healthy - F2 and SCTF2 - 23 23 ng related AUC, respectively. M3 and M4 were also the major metabolites in urinein themetabolites M3also major AUC,and M4were respectively. related

≤ •

hr/mL,

30% Oct inhibition had little impact onC impact had little inhibition

Of note, the biological activity of M3 and M4 when assayed against the M3 andM4whennote, theactivityof against assayed biological Of

the the ober

in cohort in or omecamtiv mecarbil approaching 100% under all conditions studied; studied; conditions allomecamtiv100%underorapproaching mecarbil Studies in in Studies

n = n mean -

wasan open- F2 2015

days. Results from the studies veryoral demonstrated highdays. the Results from 8) than in EM subjects (720 ng(720 EM inthan 8) subjects The major clearance pathway (primarily metabolism) was pathway clearance metabolism) (primarily The major

and

bioavailability of the MR formulations wasMR thebioavailability formulations of

i 4]). A total 45 4]). total A mmediate release ( release mmediate C Subjects max was

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five In the presence and absence of diltiazemof and absence presence theIn subjects max max

modified- Heart Failure Heart IR - blind, blind, placebo- and administered[

) with stable HF (LVEF withstable

formulations but reduced interreducedbut formulations (39 males and 6 females) were enrolled were and 6males (39 females) time to C to time • release ( release hr/mL, n = 8).

at 6.0% and3.3%total 6.0% ofat

max controlled, crossoverstudy controlled, 14 . C] MR

When omecamtivmecarbil When - omecamtivin mecarbil ) ) formulations to the IRtheto formulations ~

Cleland et al, 2011 al, Clelandet These results indicate results These 80%withMR ≤

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cardiac systolic function. cardiac indicesof echocardiographic in increases produced study.mecarbilOmecamtiv the in to drug) was unrelated study considered pneumonia studythat drug; and to unrelated ] reaction adverse unexpected assuspected serious and a reported studyto drug related considered wasevent overdoseandrug of[this inadvertent setting thein which occurred infarction Three 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL an open 1021 wasCY HF double- a randomized, 1221 wasCYStudy Date: 20120227 Number: Protocol a MR and an IR oral formulation of omecamtivinof mecarbil oral formulation MRa and anIR 94 37.5 mg IR 3 times a day, or 100 mg MR BID under fed conditions. A 100conditions. orMRa mgunder3day, times BID fed IR mg 37.5 50 MRofmgdailywith a dose were ( twice 35 ofand treated subjects enrolled total 7 formulation. The formulation. subject ( electrocardiograms vitalsigns, secondary endpoints, anythe safetyof torespect with mecarbil omecamtiv ofhigherdosing andregimens lowerwereobserved or betweenplacebo differences noaddition,consistent dose regimen.In eitheromecamtiv atmecarbil receiving in occur anyand didnotsubject placebo 1 subject receiving inwas observed endpoint baseline. atthanearlierThis stagean exercise unacceptable angina due to infusion during test subjects tolerance ofan exercise proportionasstopping the wasdefined primarydose endpoint a safety higher and regimen, regimen. 34 at The lower dose a enrollment into the study, the into the enrollment to the the to ClassAnginaSociety Cardiovascular Canadian and Day thedose6, on Day last Shortlythe prescribed. after he as study was the medicationtaking that reported and approximately 120 to 210 ng/mL. 120 to approximately days of oral dosing; 29 subjects received placebo, 31omecamtivplacebo,receivedreceived 29 dosing; subjects oral daysof subjects were enrolled and treated with 20 hour infusions of studyinfusionsofdrug with by 20 hour followed and treated wereenrolled subjects subjects 1 23 23 subject plasma concentrations, the predicted range of Day 6 plasma concentrations were concentrations plasmaDay predicted oftherange6 concentrations, plasma subjects experienced sudden death in this study after 6 days of dosing withdosing ofafter IR the 6 days study thisin sudden death experienced Oct

ober with ischemic cardiomyopathy and angina withLVEFcardiomyopathy and angina with ischemic on Day 6 just prior to the last administereddose.complaints Hehadno priorlast theto onDay6 just

on- events experienced(n adverse serious

; septicemia in the setting of a diabetic foot ulcer that wasconsidered that ulcer a diabeticsetting offoot in septicemia the ; 2015 subject’s ECG

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study subject ess and died. Basedand on suddenlydied. consciousnlost ess with the objective to evaluate the PK andPKtoler the evaluate objective to withthe was was

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baseline. baseline. inURLpost URL> absenceofI were> troponin no troponin subjects the T with There ). AppendixB). limit( reference upperabovethe had subjects I HF and 8troponin volunteers phase 2a studies who received2a studies phase in and147 HFsubjects the13 ESRD subjects) 250 healthyvolunteers the(including Of 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL between similar ATOMICin academic wereadjudicatedbyan independent, events cardiovascular Major Date: 20120227 Number: Protocol discontinuation of omecamtiv ofmecarbil. discontinuation 1121),CY (Study respectively. infarction. withconsistentmyocardial I, troponin andofand ECGchanges, and rise dizziness), fall discomfort, chest (tachycardia, andSubjectHF (Study1121), CY ofsymptoms/signs terms their inclinical presentation had similar 3 subjects These Subject 1456 occurred at omecamtiv mecarbil C omecamtivatmecarbil occurred respectively deaths ( deaths Committee equal numberreceived placebo. equal 1leastomecamtivdoseand an of mecarbil at received 303 AHF subjects of total A cohort. next thetoproceeding (DMC) before Committee Monitoring dyspnea symptom r dyspneasymptom treatment and groups treatment mecarbil withURL,omecamtiv a causal relationship > I troponin groups. groups. inplacebo subjects the comparedwithdied39 (12.9%) groups mecarbil omecamtiv myocardial infarctions and a small numeric imbalance wasnumeric noted and a small infarctions myocardial 3 systolic dysfunction hospitalized for acute HF. Th acute hospitalized dysfunction for systolic omecamtiv double- Acute Heart Failure, ATOMICFailure, Heart Acute inMecarbil ContractilityIncrease to withOmecamtiv (Acute Treatment 20100754, Study dose escalation cohorts with review of data by an independent externalbydata independent withcohortsan escalationreviewof dose 23 23 ng/mL, and 1345 ng/mL in healthy volunteer Subject (Study CY 1111),CYHF (Study Subject volunteer healthyng/mLinand 1345 ng/mL, blind, placebo - blind, 2.6 T Oct

here were a limited number (10) of positively adjudicated postnumber positivelyofwerea here limited (10) adjudicated These 14 subjects are included in the Investigator Brochure inInvestigator included theare 14 subjects These

. - % vs. 3. vs. % mecarbil compared with placebo on dyspnea in subjects with left ventricularwith left onsubjects withdyspneain placebo compared mecarbil . . AHF ( AHF A ober At the 6 month vital status assessment, 38 (12.5%) subjects in the38in (12.5%) subjects assessment, vitalstatus 6 the At month In 3 of the 14 subjects with troponin I > URL, the troponin I >URLI URL, troponin> the Iwith troponin 3 thesubjects of 14 In dverse events (58% vs. 63%), serious adverse events (21.8% vs. 23.1%),eventsvs. (21.8% adverse serious 63%), dverse vs. events (58%

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2015 Duke Clinical Research Institute ClinicalEvent Institute Duke ClinicalResearch 3 esponse pooled %), and rehospitalization within 30 days (9.6% vs. 12.2%) were12.2%) vs. (9.6%within 30 days rehospitalization and %), the the

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(primary efficacy endpoint) betweenmecarbilendpoint) efficacy omecamtiv (primary - AHF) at least 1 dose of omecamtiv mecarbil, 6healthydose of mecarbil, 1 least omecamtiv at

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mecarbil treated groups (total of 7) compared with 3 in placebo groups (2.3% vsplacebo(2.3% with 7)3 in of groups compared (total groups treated mecarbil 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol respectively). respectively). intervention. intervention. acoronarypercutaneous subsequent occurred infusionand to drug of1 completion after mecar each dosing period. dosing each volunteers. Caucasian the comparing study omecamtiv mecarbil or placebo, multiple 25 mg doses of a25 dosesofplacebo,mg multiple or mecarbil omecamtiv inhibitor with reduced ejection fraction ( ejection fraction reduced with Om ard MedDRAard [ (stand query 18 placebo singleIwas 1211) a phasecenter, 20120255 (CY Study n of omecamtivplacebo.orof n mecarbil formulatio adoseof 50 singlemg and placebo7 a overdays, or mecarbil omecamtiv 2.3 tolerated. well1211 were CYomecamtivindosesof mecarbil and all volunteers healthyCaucasian observedthe in differences 2.2.2.3 Broch Investigator’s please theure. consult omecamtivmecarbil with experience simila was placebo the group. than omecamtivgroupmecarbil rateswere lowerthe incohort, within and, each placebo on patients HF intoclinical benefits for could whichtranslate ultimately remodeling, ventricular evenpreventorreverse and includingneurohormonalactivation,to mechanisms attenuate compensatory the output, cardiacto approachpreserve to therapeutic would dysfunction withsystolic subjects in contractility myocardial well nois becausethere 3studiesclinicaloutcomes phase benefit:risk in large of balance assessmenttheof careful hasrequired drugs heart failure of development Historically,

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Direct Direct MR Page 20 of Page

oral oral

. . 1%, 1%, HF een blind

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therapy therapy dysfunctionsystolic ventricular with patients in positivelyclinicaloutcomes can cardiacimpact of function increase 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol appear generally well tolerated by well generallyappear tolerated - concentration hasdose a that cardiac- is activator myosin mecarbil double- 20110151Study(COSMICongoing The 2011) formulation, MR formulation, MR 96a singleoral subjects, of a total anddata PKsafety from reviewof Following hasofcompleted. study the phase escalation evaluations).The echocardiographic with BID of a single oral MR formulation compared with placebo over 20overweeks withplacebo compared oralMR a single offormulation BID and50 mgBID mg (25 dose ranging studyexpansion phase the in for further formulation suitable most the7select daysto BID BIDof and 50 phase) 25 mg for mg (escalation dysfunction. Enro of repeated 25 mg BID, 25 mg repeated of Japanese planned of initiation to Prior 450approximatelyjects. andsub in 50 BID) mg mg (25 levels body weight of bodyweight median basedthe82 thandefinedkg as bodygreater with a higher weight, subjects to 25% approximately wereof with HF, Japanesedistribution subjects medianbody theweight on lessthan as 58 withdefined lowweight,subjectsexposures in body mecarbil Simulatedplacebo.omecamtivBID),or mg,50 or37.5 mg mg, (25 mecarbil omecamtiv enroll 20120227 willStudy studyphase20120227). 2 in (Study this studied expected llment is complete andisthe complete llment 23 23 .

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( Table Table . It is left left s 1 73 ).

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Japanese Japanese This is a a is This fraction A randomization.ofat be outpatientstime themust Subjects investigator. by the stable clinicallyonceconsidered have andare recoveredtheyin hospital setting the screened Subjects maybe ejectionalso reducedstable and fraction. HFhave chronic they enter the study within 30 study thedaysprior enter withplacebo. compared and 50 BID,BID), mg37.5 levels BID,mg 3(25 atdose formulation mecarbil 3.1 3. ( PK chronic followingparameters will hypothesis beperformed. testing No formal C 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL 25BID atmg administration willinitiate dose Subjects randomized basis. outpatient on(n=20)an 50 placeboBID doseormg BID(n=20)mgdose (n=20), 37.5 (n=20), 2.4 PD include will study this wasclearanceadjustedessentiallyidentical, body and that weight the different, wassignificantlystatistically notsubjectsJapaneseand inCaucasian clearance Thou Data presented as mean [median] (standard deviation); Date: 20120227 Number: Protocol BID for max pproximately 80 Japanese subjects with chronic stable HF withstable with chronic subjects 80 Japanese pproximately

BID Dose

parameters with chronic repeated oraldosing. with repeated chronic parameters =maximum plasma concentration; HF=heart failure; BID =twice daily 23 23 gh the results of completed theresults the gh Table (mg) 37.5 50 25 Following BID Dosing BID MR of Following will be randomized 16 double- Oct

HF week 1 ober

subjects Design Study EXPERIMENTAL PLAN EXPERIMENTAL Hypotheses Clinical Comparison of Omecamtiv Mecarbil Steady State C of Mecarbil Comparison OmecamtivSteadyState

blind, s

2015 additional an ) w ) 614 [557] 614 [252] 277 461 [418] 461 (ng/mL) illbe estimated C (286) (129) (214)

randomized, placebo- randomized, max,ss to evaluate 16 weeksevaluate to Simulated Japanese Simulated Potential subjects will be screened to assess their eligibility to assesseligibilityto to their screened will subjects be Potential

1:1:1:

tablet strength of 37.5 mg BID to further exploreBID37.5 of further mg to strength tablet 1 to receive to 1 to enrollment. to . . 6143 [5539] 6143 [2501] 2759 4613 [4171] 4613 phase1 Studysystemic that 20120255 showed (ng*hr/mL) - F1 Tablets in HealthyTablets F1 in Japanese Subjects (2929) (1305) (2185) AUC

to 37.5 mg BID target doseand50 37.5BID mgtargetto BID mgtarget

ss ss

controlled, multicenter, phasestudy 2 multicenter, controlled,

of of and omecamtiv mecarbil omecamtiv AUC

administration of oralMRofadministration omecamtiv

will be up be will

Subjects are eligible for screening ifeligible are screening Subjects for = = area under the curve, steady state; 469 [427] 469 [193] 211 351 [319] 351 (ng/mL) C (209) (155) SimulatedNon (94) - max,ss titrated to 37.5 mg BID or

reduced ejection either 25 mg BID dose25 BID mgeither max - Japanese

4707 [4265] 4707 2115 [1918] 2115 ] ] [3201 3521 and AUC (ng*hr/mL) Page 22 of Page (2130) (1585) AUC (962) PK ss ss

dosing

in in and

Approved

fraction Approximately Participants in this clinic this in Participants 3.3 subjects within subjects A < < will Subjects be up investigational product (IP)product investigational administration 50 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol up- week 4 visit at dosewilladjustment the be 2 PK havevaluetimea weekin for not 3.2 protocol theof end The study endpoints are defined inareendpoints study defined The Assessments willat be performed medications will continue at 25 mg BID for the remaining ofremaining thestudy. the25 BID mg at for willcontinue (see evaluationsclinicallaboratory assessments, l receive the assigned IP throughout the study. throughout the assigned BIDIP 25 mg to the wilor receivel placebo Vital ( 8 and week 4 supplyat subjects all IP willblinding, new maintain receive study To team. the toassignmentanalysiswill PK be blinded dose and will be monitored. compliance also (Week 20 20 (Week end of study of( end selected nonfatal cardiovascular (CV) events (including possible MI or ischemia)possible MI or events (CV)(including nonfatal cardiovascular selected and hospitalizations, alldeaths,independentCEC will An data. adjudicate study accumulating the DMCregular reviewunblindedformal of perform independent willAn system response (IVRS/IWRS) system/interactive voiceresponse Web interactive will b Randomization planned enrollment. of approximatelyto be limited20% of will screening time the , week screening , pproximately 50 centers in Japan in 50 centers pproximately 200ng/mL.

mg BID at the week 4 visit based on steady stateon steady 4 atbased visitweek the BID mg titrated at week 8basedweekon at titrated signs, physical examinations, ECGs, Adverse Event/Serious Adverse EventAdverseAdverseEvent/Serious physicalECGs, examinations, signs, 23 23 willbe enrolled. Oct + 3 days). 3 ober

) EOS ( visit

Subjects Number of Subjects of Number Number of Number Table Table 80 Japanese subjects with chronic stable HF withwithstable chronic subjects Japanese 80

3 months

2015 8 s. - , and week 16). 16). and ,week synopsis section.synopsis titrated at4visitweek orweek 8 the visit will be performed 4 weeks after the last dose IPdose lastofthe after 4 weeksvisit willbe performed

e stratified by presence or absence of atrial fibrillation/flutter viathe atrialabsenceof or fibrillation/flutter by presence stratified e The The 2

) .

with a week 2 C a week with al investigation shall be referred to as“subjects”. be shallreferred to investigation al The overall study design is described described design overallis study The of site initiation may beinitiationmay site closed. of study Sites

the includes transthoracic echocardiographic assessments echocardiographic includes transthoracic

creening and at specified times per the Schedule of theper of Schedule attimes screeningand specified

steady state C steadystate

Section will participate in the study thein will participate Enrollment of subjects with atrial fibrillation/flutter at withatrial of fibrillation/flutter Enrollment subjects

predose

(C 10.1.1

predose ≥ 200 ng/ 200 ≥ predose Table Table ) .

result from week 2 week result from concentration prior concentrationto m result from week 2 week from result s 3 L only if the week 2 week the onlyif )

, and collection of concomitant and collection ,of Subjects randomized to randomizedSubjectsto (or not available at week 8) week availableatnot (or . Sitesenroll not that do in in reduced ejection a studyschema .

Subjects whoSubjectsdo

, if ,

C IP IP Page 23 of Page

available. predose the the .

at the the at . .

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Approved

104 103 101 Before any Before screening). ofdate (eg, candidatepotential the about information includes limited that candidates I 4. early. study study completes the this in subjectlast dayonrandomized definedlast as the studythewhichis end of the The 4.1.1 102 105 3.5.2 andEOSvisit). period, treatment screening, 6 ormonths 24 weeks approximately of studyofparticipation duration maximal 4.1 obtained be (see must 30 After signing the informedthesigning After 3.5.1 Rationale for the sample size can be found in sample thebe found size can Rationale for 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL 3.5 study the withdrawprematurely from 3.4 Date: 20120227 Number: Protocol Subjects who Subjects rs rs nvestigato

days.

23 23 - will a beta includetreatment w HF for Treated screeningtoof weeks a priorHF minimum 4 for for treatment definedas ,requiring ejection fraction withreduced HF stable chronic of History consent informed anystudy prior initiation of to consent Subject not tolerated not unlessstudy,the participationperiodin of stableremainthe toover expected is or femaleJapanese male LVEF LVEF Oct T

reatment reatment

study

ober will be expected to maintain a screening log of all potential ofastudy log screening potential all maintain willto be expected lly40%echocardiogram screeningread by centra ≤ are withdraw are Inclusion Criteria Inclusion SUBJECT ELIGIBILITY Study of End Inclusion andExclusion Criteria Inclusion Study Duration for Duration Study Estimated Study Estimated Duration Replacement

or their legally authorized representative has provided written informed written provided legally has representativetheir or authorized -specific

2015

duration

Section ith optimal pharmacological therapy. In general, optimal general, In therapy. pharmacologicaloptimal ith

assessm activities/ consent, n

removed from treatment or the study, or whoorstudy, voluntarily theor treatment removed from of of will be for 16 weeks with the EOSatvisit 16 weekswith the will be for 11.1 Subjects

≥ 20 yearsand 20 ≥ ents for for ents nsentwritteninformedco the procedure, appropriate Subjects ) all eligible eligible all blocker and either an ACE inhibitor or anor an and ACEinhibitor blockereither .

will not bereplaced will. not

end

- specific activities/procedures specific - Section subjects should berandomizedshould subjects within of - ≤ study visit (week 20) or20) terminates the (week visit study

8 5 years of age at the time of agewritten theofat yearstime 5 10.2

week

Page 24 of Page 20 for a 20 for ARB

(includes (includes

that 73

Approved

201 212 4.1.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol 203 202 210 209 208 207 206 205 204 214 213 211 215 218 217 216

23 23 Implantation of Implantation nevirapine, phenobarbital, phenytoin, phenytoin, phenobarbital, nevirapine, CYP3A4 inducer (eg, (eg, carbamaz CYP3A4inducer a potent randomization, to priorwithin hasortaken28 days taking, Currently i ofopinion in the randomization, the after withinreceiveto 3 months Likely IV class NYHA Estimated glomerular filtration rate (eGFR) rate < (eGFR) filtration glomerular Estimated > Hg,or90 > diastolic orBPmm HgHg,HR 160 90 < ormm > BPSystolic ultrafiltration ordiuretics) scheduled routinely carperitide], [eg, vasodilatorsinotropes,HF (eg, infusions for IV outpatient Routinely scheduled - beta exceptionamiodarone ofwith the therapy, antiarrhythmic Chronic randomizationto daysprior 30 withinatangina rest persistent angina,orunstable infarction, myocardial Acute heart disease congenital clinicallyor significant pericarditis, constricti oractive myocarditis, obstructivecardiomyopathy, Hypertrophic disease valvularheart uncorrected Severe transplant cardiaccare, or therapy, hospice inotropic intermittent or continuous device, renal) or receiving renal replacement therapybydialysisrenalreplacementor receiving renal) r Past l expectancyto expectedreducetois life noncardiovascular disease that concomitant Severe, tel saquinivir, ritonavir, nelfinavir, itraconazole,indinavir, erythromycin, delaviridine, (amprenav CYP3A4inhibitor a potent randomization, to priorwithin hasortaken14 days taking, Currently duringscreening laboratory Malignancy within within Malignancy the efficacy and safety assessments in the study thein and efficacyassessments safety the of, interpretationtheof,withmeasurementor the interfere or participation study leadof premature terminationcould to investigator, theof in judgment the that, arrhythmia) dysfunction, endocrineormajor lic, gastrointestinal metabo renal, co seriousor Anyacute (AST) aminotransferase aspartate (ALT) or aminotransferase alanineor (ULN), normal (TBL)bilirubin definedbyimpairmenta total Hepatic collagen disease vascular due to vasculitis active adrenal insufficiency, hyperthyroidism, hypothyroidism or Knownuntreated neoplasia cervicalorof intraepithelialskin squamous thecarcinoma cell or basal localized , implantation of ICD or CRT,assist ventricular implantation ICD ofor , revascularization nvestigator, Oct 110 beats per minute (bpm) or HR < 50 bpm

2015 verapamil, voriconazole, grapefruit juice) verapamil,voriconazole,grapefruit

ess than 1 year 1 ess than CRT or ICD implantation within 30 within implantation or ICD CRT 1 1

year prior to randomization with the following exceptions: exceptions: the randomizationwith following to prior year

- morbid condition (eg, major infection or hematologic,or infection condition (eg, major morbid

ir, ir,

cobicistat, cobicistat, e

pine, dexamethasone, efavirenz, etravirine, efavirenz,etravirine, dexamethasone, pine,

rifabutin, rifampi rifabutin, cyclosporine,clarithromycin,

mL/min/1.73m

days prior to daysprior

≥ ci

2 times the upper limitofupper 2 times the n, St.

John’s wort) John’s 2 randomization

by central , digoxin, and Page 25 of Page ve ve

Approved

219 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol 223 222 221 220 224 23 23 Previously received omecamtiv mecarbil omecamtiv Previouslyreceived methods controlor birth effective use twotoclinical inand study this participation her ofpartner informher to willing whonot potential is childbearing of subject Female withI endtreatment of the ormecarbil placebo) with(omecamtiv IP treatment during Female self 3 (withinRecent study(s) drug 30 than less study,drug or anotherdeviceinvestigationalor in receiving treatment Currently • IP doselastof the after 5 anandadditional placebo) orfor with(omecamtivmecarbilIP treatment • Known sensitivity to any of the products to be administered during dosingbe administeredduring products to anythe of to Known sensitivity

Oct - partner) partner) o ,and barrier methodwith spermicide system , withspermicide barrier method and birth hormonalcontrol , method deviceand intrauterine , withspermicide barrier method and combinations: of methods acceptable discuss these changesdiscuss thewith studysubject. len change inchange the and/ortype length of time contraception is that beto utilized may require additional medications (these requirements contraceptive areadditional medications given during treatment which may alter the Note: useadiaphragm) must female report "postmenopausal range" for the laboratory involved. laboratorythe range" for "postmenopausal definition according orof the 5 ng/dL)to estradiol levels postmenopausal (< hormone ( currently butpastamenorrheic 1 year, within mensesthe spontaneous 2 leastand atyears;55 years < no age spontaneous menses for but ≥ is she or postmenopausal salpingectomy steriliz unlesspotential childbearing ofconsidered is A female ober spontaneous), AND with postmenopausal gonadotropin levels (luteinizing ANDwith postmenopausal gonadotropin spontaneous),

55 years with cessation of menses for 12 or more months; 12 or more menses months; of for with 55cessation years gth of time gth breastfeedingthat is beto avoided) is the investigator to

subject is pregnant or breastfeeding or is planning to become pregnant pregnant is becomeorto planning pregnantbreastfeeding or is subject

(vasectomy (vasectomy

spermicides and arediaphragm not approved 2015

ed (she has had a hysterectomy, bilateral oophorectomy, or bilateraloroophorectomy, bilateral hashad a hysterectomy, (she ed with spermicide (the male male (the withspermicide days since ending treatment on another investigational deviceinvestigationalordayssinceon another treatment ending

(LH) (LH)

months) history of alcohol or illicit drug abuse basedon abuse drugillicit or alcohol of history months)

and follicle

) during /occlusion ) bilateral tuballigation or [male partner]

practice sexual practice

P effective birth controltheinclude following effectivebirth

- stimulating hormonelevels stimulating

partner partner abstinence or surgical surgical contraceptiveor abstinence or or or

two n hormo intrauterine ) . Menopause is definedas Menopauseis . must usea must

(2) barrier methods (one by barriermethods(oneeach (2) r h ormonal birth ormonalcontrol method (2) acceptable methods ofacceptable methods

and male male (FSH) or or . I in Japan. use for permanently intrauterine deviceintrauterine withindays 5 after al condom andcondom the - > 40 IU/L) or or IU/L) 40 > releasing releasing a ge < 55

days a ge ge o 73 f r

Approved

S A commencementstudy before of form consent anddate personally the legallymust sign representative authorized their applicable if (see material, and/or recruitment information unique subject identification number before before anystudyidentification number subject unique 5.1 study. the assigned for rescreened. aisif subject including assignment, initialafter be changed itmustnot study; entiretheclinical throughout constant number must remain identification subject The subject. that to studyrelatedall documentation on used beand must clinicalstudy throughout identify subjectthe the to willbe used number performed. legalor subject representative the which All target dose pres Review(IRB)/ Institutional Board written site’s athecopyof requires 225 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL 25 atmg BID administration dose50will BIDdosetarget initiate and mgtarget 37.5 tomg BID randomized (n=20)placebo doseor(n=20)mecarbil omecamtiv 50 BIDmg omecamtiv dose 37.5(n=20), mecarbil dose mg (n=20), mecarbil enrollment andin/onthe medical record subject’s the decisionin document and date, this to C Date: 20120227 Number: Protocol Before subjects Before 5. 226 ubjects ommittee ommittee

subject is considered enrolled upon randomization in I randomizationinisenrolled consideredupon subject subjects ence or absenceofor ence 23 23 Subject not Subject or interfere with the study evaluation, procedures or completionor withstudy the interfere procedures evaluation, or subjectwould a to risk safety pose consulted, Amgenphysician,or if investigator intheofopinion theabove) that, outlined those ofexception the (with disease conditionordisorder, clinicallyevidenceany of significant or other History andknowledgesubjectinvestigator’s the of best the to studyprocedures, required complyalland/or with to procedures,

Oct willbe randomized electronic case report form ( casereport electronic form ( at the week 4 visit based on steady state C stateonweek thesteady at based visit 4 period screeningintothe who enter The subject identification number assigned willidentification be subject The IEC ober

This number will not necessarily be the same as the randomizationasthesamethe number numberbe willnecessarily This not Randomization SUBJECT ENROLLMENT SUBJECT

) begin participation participation begin

approval of the protocol, informed consent form, and all other subjectinformed protocol,and all other approval consent form, the of 2015 likely to be available to complete all protocol all complete be availabletoto likely

atrial fibrillation atrial

and in

/Treatment Assignment /Treatment a 1:1:1:1 manner to receive either 25 BIDmgomecamtiveither receive manner to 1:1:1:1 a will be up willbe in anystudyin /flutter eCRF

signs the informed consent) will signs informed consent) the

- titrated titrated

) -

. specific activities specific via via - Randomization will be stratified by Randomizationwillbe stratified for the study for the specific activities/procedures, activities/procedures, specific IVRS/IWRS. to the 37.5 mg BID mgorBID mg37.5 the to50

on an outpatient basis on an outpatient - related related predose V

RS/IWRS Section

result from week 2. week from result (defined as the point at point as the(defined activities

by by / - procedures. procedures. required s required I 11.2 VR .

I ndependent The investigator is investigator The S/I . ). / procedures are procedures WR informed A receive a receive . tudy visits or or visits tudy ll subjects subjects ll Page 27 of Page S. Subjects

BID BID Amgen Amgen

This This

Ethics or or 73

Approved

6. The Amgen Investigational Product Product AmgenInvestigational The week 8) will continue at 25 mg BID for the BID atmgfor the will25 8)continue week within within representative 6.1 omecamtiv mecarbil omecamtiv 4 Subjects 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol C avai randomization assigned.A randomization theandconfirmhas tobeen information entered correct verifythat tothe site 48 visits. and weekweek will subjectsall supplyIP at blinding, new receive maintain study the throughoutIP BID assigned willor placebo25 tomg the receive to i of management the is further essential for treatment theonlyof assignmentbe should whenunblindedtreatment subject’s knowledge A at the study site for any other reason will be considered a protocol deviation.a protocol anywill reason be considered study for site other the at study. 5.2 assigned.is when randomizationnumber study a thedetailedin information theto randomizationcall The theto call randomization the make willrepresentative studya site been confirmed, eligibility the has into Once su 1 to will number be assigned and onlyeach randomization randomizationnumber one subject study.A may of onlybystart Amgenbeforethe receivethe prepared schedule armswillon acomputer treatment theto be based Assignment study.duringthe individualadjustmentsubjects no other for isdose There nvestigator predose

visit will be up be will visit

lable bject. 23 23

is is working day after the event. event.day after the working . Subjects willbe up Subjects . Oct who

< <

200 ng/mL.200 is strongly encouraged to contact stronglyencouraged the contact is to ober

do not have a week 2 PK value in time for dose adjustmentweek dose value time the infor at have2 PK a weeknot do TREATMENT PROCEDURES TREATMENT Classification of Product(s)ofDevice(s) and/or Medical Classification Site Personnel Access to Individual Treatment Assignments AccessTreatmentPersonnel Individual to Site before unblinding any subject’s treatment assignm unblindingtreatment anysubject’s before

- titrated at week 8 based on steady state C weekon steady8 based state titrated at

2015 and in placebo. No

Subjects IVRS/ IVRS/

subject will be considered enrolledand randomizedwill subject into be considered - IVRS/ titrated at the week 4 or week 8 visit only if the week 2 week theweek8 onlyvisitat week orif the 4 titrated IW IW

with a week with2 C a RS to assign a randomization number to the subject. to a RS randomizationnumber the assign to RS user manual. A confirmation will be sent to theto RS sentwill userconfirmation A manual. be IW and/

tinent RSpertinent theisby accomplishedentering vestigational medical devices are used in thisdevicesarein medical used vestigational or placeboor

remainder remainder

predose appropriate Amgen studyappropriate contact (IP) a subject a of the study.of the

≥ 200 ng/ 200 ≥ used in this study includes: studyusedincludes: in this predose

on on - generated generated randomization , if if week2, from result m ent, but must do ent, butso must this study. Unblinding Unblinding study.this

L ndomized ra Subjects (or not availablenot (or at

Page 28 of Page .

The The To To

the the

Approved

6.2 omecamtivofmecarbil administration destruction, storage, the regardingdetailed informationcontains protocol, externalthis to Manuala document Product (IPIM), Instruction Investigational The 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL by the morningevening orallythe and in BID will IP be administered randomization.5daysaftercalendar later notthan but ormecarbil placebo). (omecamtiv Eligible 6.2.1 Date: 20120227 Number: Protocol using Amgen clinical study drug distribution procedures. distribution Amgen clinicalstudydrug using Omecamtiv mecarbil first dosefirst ofIP isco is to be taken at approximately the same time of day (12 ±of approximately at bedaysame(12 takenthe time to is orundernditions. co fed fasted taken p with water as instructed in the IPIM.thein asinstructed water with dayof randomizationshouldIPthe ofbe on administration The first initiated. is IP with completed before initiation of IPinitiationof before completed accounting procedures accounting packaging, labeling, dispensation, condition, storage IP detailsregarding Further number. bottle previous dose). previous omecamtiv Pl morning dose on the day of the subject’s week 16visit.week subject’sdose ontheday ofthe morning A atdose next betaken should and as missedthe be recorded should 6.2.1.1 number, number, eCRF. resented as as tablets resented dministration of IP will start with the morning dose on day 1 and willthe1 and dose on day withmorning the end with willIPofstart dministration acebo will be presented in identical containers and stored/packaged the same as samestored/packaged the containers and identical in willbe presented acebo

23 23

outpatient outpatient andbottle Oct

mecarbil ober

Investigational Product Investigational Dosage, Administration,andSchedule Dosage, AmgenI

If If

2015 subjects will be randomized and will initiate administration of IPof administration willand subjectswill initiate be randomized IP cannot be taken or has not been taken withinbeenhasornotbetakenthis taken cannotIP number of investigational productnumberinvestigationalof mpleted is definedas=ishours. Time 0 mpleted . .

in individually labeled 35ct bottles. individuallyin 35ct labeled will be manufactured and packaged by Amgen Inc. and distributed anddistributed by AmgenInc. and packaged manufactured will be

,destruction and nvestigational Product

and

Day 1 is defined as the calendar daydefinedwhen treatment Day calendar as 1 is the

can be performed on the same day.onsamecanthe be performed ach morning and each eveningmorningof Administration

IP will be swallowed whole swallowed willbe IP d placeboand .

are outlined in the IPIM.theoutlinedarein

( Omecamtiv Mecarbil

The time when ingestion of when the time ingestion The to be recorded on each subject’s on each be torecorded The quantity

Each bottle willEachbottle havean unique Omecamtiv mecarbil Omecamtiv

3 Baseline procedures must be must procedures Baseline hours from

(not chewed) andchewed)taken (not

subjects andcansubjectsbe , , the regular time. regular the date

window, the dose window, the

) the most most recent the

and

and Page 29 of Page

will be be will time, lot

dose dose

Approved

infarction ma mecarbil Omecamtiv , hypotension, chest discomfort or pain, ST pain, or- discomfort chest dyspnea hypotension, dizziness, , HR, 6.2.1.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL symptoms troponin and/orinelevations ECG, on Date: 20120227 Number: Protocol symptoms symptoms exists The following are mandatory rules for withholding IP rules mandatory are for The following in in i observedare results laboratory ECGs,clinicalor changesin or vital signs, adverse reactions drug suspected If dosing of anofindividual dosing If administration of IP is stopped (up to 5 days after last IP) for any of the reasons above, reasons theanyof IP) last 5for daysafter is of to (up IP stopped administration If or infarction, the subject should receive immediate medical attention according to the according attention the to immediate subjectmedical receive should infarction, the or with ischemia symptomsconsistent myocardialor experiences clinical signs a subject If sampleblood a nvestigator BP • • • • • • • •

23 23 Standard medical therapies should be used in the presence of presencebe theusedshouldin . Standard medical therapies or or

The subject experiences a symptomatic decrease in systolic BP on 2 BPdecrease systolicsymptomatic experiencesin subject a The i infarctionbyordeterminedthe as ischemia withmyocardial consistent includingECGchanges, symptoms, or experiences subjectclinical signs The measurements The subject experiences an asymptomatic decrease in decrease asymptomaticexperiences subjectan The (measured at 3 successive timepoints over approximately3 at15 minutes) successive timepoints (measured The subject experiences symptoms associated with a HR associated> experiences subjectsymptoms The i > 3 Hgat170 (measuredBPmm systolic > experiences subjectsustained The timepoints over approximately 15 minutes) 15 approximatelyminutes) over timepoints successive3 at 120 bpm HR> (measured sustainedexperiences subjecta The 3 Hg110 (measuredBPmm at > diastolic sustainedexperiences subjecta The at least 15incrHRleastminutes) at overtimepoints3 atsuccessive (measured sustainedexperiences subjecta The > > HR nvestigator nvestigator HR Oct , asdescribed , successive timepoints over approximately 15 minutes) approximatelyovertimepoints successive successive timepoints over approximately 15 minutes) 15 minutes) approximately over timepoints successive 170 mm Hg, or diastolic BP > 110 mm Hg that are determined bydeterminedtheHg 110 >diastolic that Hg,orBPmm are 170 mm suggestiveof ofischemia. myocardial

, or the Study Medical Monitor, these changes pose a significant health risk, healthrisk, changesposea significant these StudyMonitor, the or Medical ober withholding 100bpm Ischemia for Withholding Rules

of of

2015 5

to wa to mL mL

subject should subject in for PK analysis is to be collected as soonaspossiblebe toas analysiscollected PK is for

y result in signs and symptoms of myocardial ischemia or ofischemia signs and symptoms inmyocardial yresult myocardial rrant termination of the dosing theof termination rrant or Infarction of IP should be red. conside should IP of S

ection 7.1 ection during during

ease ease

ischemia or infarction, and/or experiences changesand/orexperiences infarction, or ischemia bestopped and not resumed. of the the of , , I or I T). the study and, in the opinion of eitherofopinion study in the the the and, Investigational Product Investigational Abnormal Blood Pressure or Heart Rate orHeartBloodPressure Abnormal

≥

25 bpm from screening or baseline ANDbpmbaselineor screening25 from

Brochure Investigator’s I f a subject reports clinical signs or clinical signs reports subject a f

: No No

antidote systolicBP to <

due to Myocardial Myocardial to due to omecamtiv to

segmentdepres 120bpm,systolic BP (eg, signsor

increases i increases Page 30 of Page successive

. 80

mecarbil mecarbil

mmHg

sion n 73

Approved

Subjects with abnormal hepatic laboratory valueslaboratorywith abnormal hepatic Subjects institution’s usual standard of care. Serialof usual standard institution’s 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL • troponin cardiac samples for serial laboratory central analysis addition,of In laboratory. localthe be analyzedshould at Date: 20120227 Number: Protocol 6.3 beomecamtivshould mecarbil discontinued. permanently then rechallenge, unanimously by the subject, investigator, andAmgen. investigator, subject, unanimouslybythe beand agreeduponshould subject rechallenge the todiscussed decision The infarction. or ischemia immediately as serial 12 serial as phosphatase or permanent discontinuation permanent or below)hepatitisdescribedof(as signs/symptoms Injury: therapies Services followed according to the recommendations in recommendations theto followedaccording mecarbil Omecamtiv Assessment Infor • below met:are criteria 6.3.1 •

< value ALT or AST Baseline ULN

− − − limitedto:notvalues include, but are TBL immediately apparent; important important apparent; immediately is abnormalities abovetheof combinationcause laboratory the for ANDno other TBL AND increased AST or ALT from the relevant baseline specified below: relevant valueALTorthe as AST from ANDincreased

23 23

ischemi sided Right Viral hepatitis (e hepatitis Viral Herpes Simplex Virus, Varicella,SimplexVirus, Herpes disease Hepatobiliarytract PremarketingClinicalEvaluation, >

Oct Food and Drug Administration Food

asspecifiedin the 2x ULN or INR > or INR ULN 2x -

lead ECGsshouldleadbe c ober of any subject experiencing clinical signs or symptoms of myocardial symptomsofor experiencingclinical signs anysubject of [ ], ], ALP Hepatotoxicity Stopping and Rechallenge Rulesand Rechallenge Stopping Hepatotoxicity Criteria for Permanentfor Criteria to Potential Hepatotoxicity Potential to a

mation) for possible mation) for

2015 HF AST, ALT, ALT, TBL AST,

shouldbe

, hypotension or any cause of hypoxia to the liver causing hypoxiatheanycauseof hypotension , or to

g, Hepatitis A/B/C/D/E, Epstein

1.5 Guidance for IndustryDrug for Guidance of

discontinued permanently discontinued Amgen Amgen I ollected. ) and/or alternative and/ drug Discontinuation Discontinuation , , investigational productinvestigational toxoplasmosis, and

July2009 . U or internationalor normalized ratio

- cardiac troponin cardiac .S. induced liver injury ( inducedliver injury

creatine kinase MB fraction ( MB creatine kinase fraction

The investigator must notifyinvestigator must The

Departmentof Appendix causes for > 3 elevation ALT or AST

during the study during the may meet the criteria for withholding criteriawithholding for meet the may

x ULN x

- If signs or symptoms recur with signssymptoms recur or If Barr Virus, cytomegalovirus, Virus,cytomegalovirus, Barr - Induced LiverInduced

A of of a

elevated AST/ALTelevatedand/or (Additional Safety (Additional samples nd the subjectbe should nd the Omecamti Parv Health and Health Human

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Page 31 of Page MB ) ) and/ - req

as well as d uired ue or or

Approved

Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL • Date: 20120227 Number: Protocol • beevaluatedDILI: should for subject andtheare met, criteria theANYof following should mecarbilif be withheld omecamtiv subjects For 6.3.2 beimmediately contactedshould monitor , discontinued protocoland other - product hepatotoxicityevent) population the and/orof severityor patient what developedthan conditionsstringent less or identified hepatotoxicityis cause an alternative for If • DILI. If DILI. mecarbil Omecamtiv recommendations in recommendations

Any Any Any Any value ALT or AST Baseline − Or Elevation of eitherAST Elevationof − − − − − Or − −

23 23 : TBL > TBL : : ALP ALP > :

Non Nonalcoholic Wilson’s diseaseand hemochromatosis Wilson’s Autoimmune hepatitis Autoimmune - Crigler Syndrome, Gilbert’s (eg, causingimpaired disorders glucuronidation Heritable andmushrooms plants supplements, dietary Alcoholichepatitis Alp (eg, investigational productinvestigational to xposure Oct ha-

- indinavir, atazanavir) indinavir, hepatic causes (eg, hepatic ober who

one antitrypsin deficiencyantitrypsin one as deemed appropriate for the safety of the subject, andAmgen subject, medical the safety asthedeemed of for appropriate 3x ULN at any3xtime atULN 8x ULN at any8xatULN time Criteria for for Criteria Potential Najjar syndrome) and drugs that inhibitsyndrome) Najjarand drugs that

2015 do not meet the criteria for permanent withholding of IP outlined above, outlined IPofwithholding permanent criteria for thenot do meet hepatotoxic agents/drugs hepatotoxicor agents/drugs

Fatty Liver Disease including including DiseaseLiver Fatty Appendix should be withheld pending investigation into alternative causes ofintoalternative causes investigation shouldpending be withheld are are

Hepatotoxicity noted above, the investigator should investigatorthe above, noted

Conditional required therapies should be withheld should or be therapies required or ALT accordingschedule: ALTtheor to following

(s) A rhabdomyolysis

for possible DILI. Rechallenge may be considered if an if possible Rechallengebe considered DILI. may for

isthe withheld, subject pain/tenderness, fever, nausea, vomiting, jaundice). jaundice). vomiting, nausea, fever, pain/tenderness, quadrant upper right as (such hepatitis with consistent are that symptoms or signs clinical with ULN >3x s monitoring > > > AST or ALT or AST 5x ULN but < but ULN 5x < but ULN 5x time any at ULN 8x

Withholding ofWithholding

c elevation elevation hedule

, hemolysis ,

hepato 8x ULN and unable to adhere to enhanced enhanced to adhere to unable and ULN 8x for ULN 8x Ste

atohepatitis (NASH) (NASH) atohepatitis bilirubin glucuronidation bilirubin glucuronidation

toxins Omecamtiv Mecarbil is to is ≥ ) )

2 weeks 2

, , be to according followed determine including herbal and herbal including if if Amgen investigational permanently

(based on (based

Page 32 of Page

due to due to

Approved

, discovered, elevated AST,ALP) and/or TBL (ALT, liverimpairedtests cause for alternative 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol ( (see CYP3A4ofinhibitorsor inducers arepotent known that foodsor Medications prohibited.are study whilethisin procedures participating investigational Other If signs or symptoms recur with rechallenge, then omecamtivsymptomsthenrecurorwithmecarbil rechallenge, signs If 7.1 byAmgen. device(s)provisioned orrepackaged/modified any includesand/or drug(s) This material. theandwhomAmgenmanufactures partners for byAmgenordistributors bycliniceither of performance or effectiveness, safety, durability,reliability, quality, identity, theto related deficiencies alle that oralcommunicationor g is electronic complaintany product written, A subject, unanimouslybythe beand agreeduponshould subject rechallenge the todiscussed decision The 6.3.3 7. week 6.6 discontinuation (as described(as in discontinuation permanent criteria for thewho Subjects clearlymeet discontinued. permanently 6.5 beare study to on complaint instructions provided in thein provided instructions toreported aredevice(s)supplied or be by Amgen product(s) in listed except those deemed supportivecare for adequate providenecessaryto treatments study,the Throughout 6.4 Section

Section 23 23

20. Section 6.3.3

Oct (s)

Drug(s) or device(s) includes investigational product. Any product product. investigationaldevice(s)includes or Drug(s) and the laboratory abnormalities resolve to normal or baselineor normal laboratoryresolve abnormalities to and the

ober associated with an investigational productassociated an investigational with 4.1.2 ) . . Schedule of Assessmentsof Schedule Period Study Hepatotoxicity Rechallengeoffor Criteria , Medical DevicesTreatments , Medical Excluded STUDY PROCEDURES STUDY Complaints Product Concomitant Therapy Concomitant

g(s) or device(s) after it is released for distribution to market or distribution to market itis for afterreleased device(s) or g(s) dru a . 6.6

2015

recorded and

All appropriate concomitant medications taken by a subjec takenconcomitant medications Allappropriate

i nvestigat Appendix IPIM.

. i nvestigator

or Section

D s may prescribe any concomitant medications or medications prescribes anymayconcomitant ) a

re prohibited up to up t prohibitedto re

, and,Amgen.

6.3.1 Om

)

shouldbe rechallenged. never ecamtiv Mecarbilecamtiv

(s) he EOS visit, occurringonEOS visit, he and/orProcedures or non or

according to according the - investigational A fter Potential Potential fter

shouldbe Page 33 of Page

es es During

is is t while t 73

Approved Product: Omecamtiv Mecarbil (AMG 423) Protocol Number: 20120227 Date: 23 October 2015 Page 34 of 73

Table 2. Schedule of Assessments a W16 W20 W2 W4 D34 W8 D62 W12 D112 D140(+3) Timepoint - Day/Week/Month (window)* Screen D1 D7 D15 (-3) D28 (+3) (+3) D56 (±3) (+3) D84 (±3) (±3) EOS General Procedures Informed consent X Medical history and demographics X Vital Signs (HR, BP) X Xc X X Xj X Xk X AEs/SAEs/PEPsb X X X X X X X X AEs/SAEs and IP compliance verification by X X X phone or other contact Concomitant therapy X X X X X X X X Physical examination X X Body height X Body weight X X X X X X ECG X Xc X X Xd X Xd X Echocardiogram X Xj Xk Central Laboratory PK samplese Xc Xc Xc Xj Xc Xk Chemistry (including eGFR at screening) X X X X X X Hematology X X X X X X Urinalysis X X X Approved Troponin I, CK-MB e Xc X X X X X X NT-proBNP Xc X X X Samples for Development Therapeutic X X Monitoring Assay Serum pregnancy, FSH/LH or estradiolf X X Digoxin sample (in subjects receiving X X digoxin) Investigational Productg IP dispensation and/or administration at site X X X X X Xh IP diary dispensation or collectioni X X IP reconciliation (tablet count) X X X X X Footnotes displayed on the next page of the Table

CONFIDENTIAL

Product: Omecamtiv Mecarbil (AMG 423) Protocol Number: 20120227 Date: 23 October 2015 Page 35 of 73

AE = adverse event; BP = blood pressure; CK-MB = creatine kinase-MB; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = end of study; HR = heart rate; IP = investigational product; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PEP = potential endpoint; PK = pharmacokinetic; SAE = serious adverse event. Please note: vital signs, ECGs, and laboratory samples can be collected at any time during the study visit, unless otherwise specified below. Visit Windows: For week 2 visit, the visit date could be 3 days prior to the scheduled date of W2; for week 4 visit, the visit date could be 3 days after the scheduled date of W4; for weeks 8, 12, and 16, the visit dates could be 3 days prior to or after the scheduled date of W8, W12, and W16, respectively; for week 20 visit (EOS), the visit date could be up to 3 days after the scheduled date of W20. The Day 34 and 62 telephone calls could be 3 days after the scheduled date of contact. a If early discontinuation, week 20 (EOS) assessments should be performed as close as possible to time of discontinuation b Serious adverse events are collected from signing the informed consent until 30 days after the last dose of IP or EOS, whichever is later, adverse events and PEPs from randomization until EOS, recording of PEPs and hospitalization only during visits to the study site (day 1, weeks 2, 4, 8, 12, 16, 20 [EOS]); if subject is not seen at the study site, AEs/SAEs/PEPs can be collected by phone c Predose in the morning, at study site d Performed as close as possible after the collection of PK sample at 2 hours ± 30 minutes following IP administration. e If cardiac troponin is measured locally to evaluate suspected myocardial ischemia or infarction, send samples for troponin I/CK-MB, and PK (up to 5 days after last dose of IP) to the central laboratory f Serum pregnancy testing in females of childbearing potential, FSH/LH or estradiol at screening only, and only if applicable per exclusion criteria. g IP is taken twice daily except on the last day of administration (week 16 visit). Subjects randomized to 37.5 mg BID target dose and 50 mg BID target dose will initiate administration at 25 mg BID. Subjects will be up-titrated to 37.5 mg BID or 50 mg BID target dose at the week 4 visit based on steady state Cpredose result from week 2. Subjects who do not have a week 2 PK value in time for dose adjustment at the week 4 visit, will be up-titrated at week 8 based on steady state Cpredose result from week 2, if available. Subjects will be up-titrated at the week 4 or week 8 visits only if the week 2 Cpredose is < 200 ng/mL. Otherwise, they will continue at 25 mg BID. h Details of IP dispensation and reconciliation are described in the IPIM; dispensation and reconciliation timepoints may differ from the timepoints shown above; IP not dispensed at week 16 visit. i Paper Diary will be dispensed at Day 1 and will be collected at week 16. Subjects will be instructed to enter each administration of IP from Day 1 to week 16 or early termination. The date and time of administration will be noted. j Vital signs and PK samples at predose, at 2 hours ±30 minutes; 4 hours ±30 minutes; 6 hours ±30 minutes; 8 hours ±30 minutes after IP administration in the morning Approved (0 h = start of IP); echocardiogram performed as close as possible after the collection of PK sample at 2 hours ±30 minutes following IP administration. k Vital signs and PK samples at predose and at 2 hours ± 30 mins following IP administration. Echocardiogram should be performed as close as possible after the collection of PK sample at 2 hours ± 30 minutes following IP administration..

CONFIDENTIAL

events and serious adverse events.adverse and serious events to Refer 7.2.6 participation. study oncedocumentation source asthepartof site study Report Form Completion and Query Resolution FormGuideCompletionand Query . Report Case Electronicby theas directed each of taken, IPdose andof evening morning time study site staffeachand visitatdiary willthe copyof a make Day during diarythe with a will supplied Subjects be review the diary with the subject at each clinic visit for compliance withIP compliance dosing. for eachvisit clinicat subject withdiarythe reviewthe IPofeach administration of time and withintaken30 werebeing that therapies Prior 7.2.1 7.2.3 in eCRF. therecorded and prior enrollment to historywill beobtained medicaland surgical relevant subject’s The 7.2.2 See performed. are procedures approvedbeforeany study informedconsent specific IRB/IEC legallyrepresentativetheir or authorized Allsubjects 7.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol 7.2.5 source on the documents. verifiable beAll valuesandon eCRF. must reportedthe be mayrepeated measurements eCRF. Any abnormal onvitalsign study thethe throughout and documented used thatisbe samethe ashould selected subject for position measurements. The vitalsign oraseated semi be in should and BP HR. be performed: systolic/diastolic must measurements The following completion of study the completion 7.2.4 eCRF.berecordedin should dateand the date stopand start route, frequency, dose,

Section Oct ober 2015 ober Informed Consent Informed Concomitant Therapy Concomitant History Medical General Study Procedures General In Vital Signs Vital AdverseEvents

v 9 Section estigational Product Administration DiaryAdministration Product estigational

for information on the definitions and reporting proceduresadverse and on definitionsfor reporting theinformation for

. on eCRFthe should . be reported 11.1

- for further details. for further ast 5 minutes before taking taking before 5 minutes le atast position recumbent for

taken taken

away from the site awaythe from

days days

the prior to screening to prior record which invisit to 1 must must

The diary The subject has completed his/her his/her has completed subject The therapy nam therapy The personally

transcribe transcribe .

Study

will be retained at theat willbe retained sign and date thedate sign and

site staff will staff site through the the through the date and datethe e, indication, indication, e, Page 36 of Page the date the Subjects

The The

Approved

deterioration, is to be recorded onisthebe torecorded deterioration, which physicalrepresents baselineexamination, the change from clinicallysignificant Any physicalexamination. the anychanges screening for monitor to from examination an of consist 20will week atphysicalvisit the at eCRF. EOS examination The surgical and in medical atbe the to recorded are screening Physicalfindings examination care. standardofwiththe accordance inwarranted evaluation is specific unless visit notanyarestudy at requiredexaminations and rectal Breast, genital, and weight. height including physicalexamination willphysicalscreeningbe acomplete examination The Height and weight should be measured without shoesat without be measured should and weight Height 7.2.10 7.2.9 willEOS20) (week the be collected. hospitalizationsallto about up Information measured at weeks 2, 8, 12, 16,12, weeks8, at2, measured studythewillof be a completion randomizationuntil subject after occurring death. sudden angina,and unstableresuscitated ischemia, myocardial willadjudicatedevents ischemia). include, MI or The possible (including events 7.2.8 death, cardiovascular following: be the limited to not At each scheduled visit where ECGs are being obtainedbeingvisitare , th each scheduled whereECGs At 7.2.11 CEC CEC potential (PEP endpoints Amgenas designee, basis orto ongoing an and hospitalizations Deaths, 7.2.7 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol before ECG assessment is conducted. If the subject is unable to be intheisto subjectunable supine conducted.assessmentIf the is ECG before leastat a 5 inrestedand for state calm position supinemustbe in Subject Amgen. available made be to should originalsponsor, ECG documents.request thesourceAtthe subject’s the of the withbe retainedoriginal should ECG (1) tracing Onesigned, ECGs. willreviewacquired designatedor physician investigator principalservices provider.The ECG centralized supplied to each site, all each site, protocol to supplied consecutively collected

committee committee 23

Oct ober 2015 ober Physical Examination Physical Physical Measurements Physical Hospitalizations Potential Endpoints Potential Electrocardiogram

will adjudicate deaths, all hospitalizations, and selected nonfatal CV and nonfatal selected hospitalizations, alldeaths,will adjudicate

approximately 30 seconds to 1 minute apart. Usingequipment apart.1 tominute 30 seconds approximately

selected

and - specified ECGs will be acquired and transmitted to the the to and specifiedECGstransmitted acquired willbe

at at nonfatal cardiovascular events willbe reported cardiovascularevents nonfatal

vents eCRF.Events week20

(EOS)

HF . , acute myocardial infarction, , Day 1 Day ree ree . . 12- Weight only will be be will only Weight lead s)

. A .

ECGs will be willbe ECGs Onlyevents n independent n djudicated. djudicated. minutes minutes Page 37 of Page

but maybut

Approved

interpretation of - anyprotocol interpretation investigator’s If the upon ECGreceipt. reportsthe and date mustinitial Investigators study thesite. toprovided will be reviewedcardiologistreport A ECG tracings. allofinterpretations standard will perform servicescardiologists centralized ECG The intervals. and PR HR,QTc,QRS, measurements: QT, followinthe g include possible. position ECG as must recumbent The should subjectbe in most the position, 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL as eCRF and documents in sourceappropriate needbe documented theto results on these based Any clinicalinterventions servicesbycardiologists. centralizedsupplied ECG that with dec clinical final investigator the make to the isof responsibilitythe servicesit provider, ECG centralized Date: 20120227 Number: Protocol services equipment or equipment on equipment or equipment services ECG using centralized of subject, the clinicalmanagement the for ECGs required Further details regarding ECG collection requirements ECG collection regardingdetails Further Central laboratory assessments are to be used to assess subject eligibility subjectbe assessused areto assessments to laboratory Central 7.2.12 startenrollment. of before sites the ECGManualto Investigator distributed an the pregnancytest, the and Table Table at documents site. sourcethe thein willbe recorded collection proceduresall for shipping andlabeling, outlines handling, manualthat willlaboratorya study provide central The analysis. alaboratoryorspecialty for Amgen tosamples mayPKlaboratory ship central The e be localmay testing results atSelected documents site. sourcethe the in maintained be willlocaltheof testing be collected. results must The laboratory central analysisbythe infarction, or ischemia myocardial cardiac If laboratory. central be bywill also assessments ntered into the eCRFby Amgen. asinstructed into the ntered other testing to be conducted onandbloodurinesamples. be conducted to other testing

below outlines the specific analytes for serum chemistry, hematology, urinalysis, hematology, serumchemistry,analytes for specific belowthe outlines

Oct bio ober 2015 ober markers (troponin markers

applicable. It is the responsibility of the investigator to obtain additional to investigator the of is applicable.responsibilitythe It Laboratory Assessments Laboratory

isions. The investigator’s interpretation does not needdoesbe nottoreconciled interpretation investigator’s The isions.

section

blood and urine samples. The date and time ofanddatesamples. sample time The and urine blood

7.2.12.1 specified or unscheduled ECG differs from that supplied bysupplied differs that unscheduled from orECG specified I or T) are analyzed locally to evaluate suspected suspected evaluateanalyzedarelocally or to T) I

additional bloodCKI additional samplestroponin and/or for ) - . All other All . site.

screening

for this study will be provided inprovidedwill study this be for or scheduled study scheduled or laboratory

(except for (except

Page 38 of Page

- MB MB 73

Approved

Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL onlaboratory,depending perlocally central performed or pregnancytesting willbe chorionic gonadotropin humanquantitativeor Qualitative 7.2.12.1 c b a CK Date: 20120227 Number: Protocol ( Scheduleper of isas requiredAssessments testing operations.Pregnancy trial facilitate ( ; in samples may be batched for be troponmaybatched laboratorysamples in central study.The in this laboratory bywill protocol) in central astroponin this bemeasured referred (alsoto I Troponin 7.2.12.2 ratio NT Total protein Total Bicarbonate Chloride Potassium Sodium Chemistry Triglycerides Low High Cholesterol Magnesium aminotransferase Aspartate aminotransferase Alanine phosphatase Alkaline bilirubin Direct TBL kinase creatine Total Creatinine nitrogen urea Blood Glucose Albumin

Section Section Section Only in subjects receiving digoxin Performed as given in A pregnancy test requiredis for females of childbearing potential in in - -proBNP = N- terminal= -proBNP pro-B-type natriuretic peptide; PT/INR = prothrombin time/international normalized MB = creatine kinase-MB; FSH = follicle ; TBL=total bilir Section Section -

- sity lipoprotein sity den

density lipoprotein density 23

7.1 4.1.2 Oct

4.1.2

)

ober 2015 ober for all females of childbearing potential as defined in the exclusion thecriterion definedin potential as childbearingall of females for

). . PregnancyTest Troponin

ubin.

Appendix

Urinalysis Protein gravity Specific Bilirubin Glucose Blood pH

only if DILIonly follow if

Table

- stimulating hormone;

3 . Analyte Listing .

-up is needed (see

Platelets Hemoglobin Hematology • • • Differential blood cells White volume corpuscular Mean Hematocrit • •

Lymphocytes Basophils Eosinophils Monocytes neutrophils Total

LH= luteinizing hormone ;

FSH/

investigator

LH LH Section

or estradiol only per exclusion

6.3.2)

preference andtopreference Pharmacokinetics

Other Labs Other NT CK Digoxin I Troponin estradiol FSH test Pregnancy PT/INR

- - proBNP MB / LH Page 39 of Page

b c

a or or

a a

Approved

At any time during a subject’s study duringa subject’s anytime At investigator the to providedbe routinelyanalysis will laboratorynot central troponin theof results the after Therefore, collection. months or weeks be assayedseveral analysis and may 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL (omecamtivmecarbil).treatment active not investigational receiving subjects Date: 20120227 Number: Protocol Omecamtiv mecarbil mecarbil Omecamtiv PKof samples. shipping and processing,collection, on sample laboratoryinstructions central manual for the to or Pleaserefer log requisition. onshipping thebe clearlydocumented must samples collect ofdateand time theand information identification willsubject orincludea log shipping that requisition complete to expected laboratory central manual. theper willand frozen Samples be processed bePKcollected.aanalysis samplemust IP, dose lastof for the of troponin cardiac additional infarction, or ischemia myocardial suspected evaluate whentroponin local during astudysubject’s participation time AssessmentSchedule thelistedin of samples PK addition the to In point. 7.2.12.3 al,2012). et Thygesen ( MyocardialofInfarction Universal Definition on the Document ExpertConsensus (ESC/ACCF/AHA/WHF) Heart Federation /World Association ischemia myocardial suspected evaluate Assessments ( Schedule shownthein of at timepoints the product investigationalof administration Bl So Europeanper the acceptable” anas “guidelineassay I, designated Troponin Ultra Study 20120227 assay for troponin cardiacselected The the hasbeen it aswell beanalysisunless collected PKshould for and/orCK troponin ood ciety of Cardiology/American CollegeCardiology/ ofFoundation Cardiology/American of ciety last last

23 samples samples administration of IP.

Oct . ober 2015 ober cokinetics ofcokinetics MecarbilOmecamtivPharma Section

for measurement of omecamtiv mecarbil will be drawn before andafter omecamtivbefore willof measurementmecarbil bedrawn for I and/or CK - MB analysis by the central laboratory must be collected. A samplebeA laboratory collected. central must MBthe analysis by wi

7.1 ll

not be measured in screening samples andsamplessamplesbescreening measuredin not from ) . Approximately .

- MB analysis by the central laboratory and, ifand,laboratory5 days within central MBbythe analysis

participation whentroponin local

or infarction or ion for each sample shipped.sample Missing each ion for 5

mL of blood will be collected at eachtime will blood at be collected of mL , additional samples for cardiacsamples additional for , is the SiemensADVIAthe Centaur is

more than more than I or T are drawnare orI T to Apple FS,Apple 2009; blood

AmericanHeart , Section I or T are drawn to ordrawnto areI T samples for

5 days since dayssince 5 The site will site The Page 40 of Page

7.1 , at anyat be 73

Approved

( 7.2.12.4 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL drawnon subjects digoxinin(onlyofmeasurement levels for samples Blood Date: 20120227 Number: Protocol sampling mecarbil dose titration in dosetitration mecarbil 7.2.12.6 Laboratory Requisition Form Requisition Laboratory acquiring, storing, and transmitting the echocardiograms. andthestoring,transmitting acquiring, echocar the to refer Please echocardiography central will the to be sent echocardiograms beThe maypotentially echocardiograms the unblinding. that in observations echocardiograms. viewnot studyshould theof study and evaluation subject treatment involvedthe in Assessments inof( Schedule thedetailed timepoints intothe enrolled subjects for Assessments 7.2.13 analyses,collected. already samplesDNA from beextracted these mayto whosubjects study. consent For of the part this for collected will samples be additional omecamti to responsewho negativehavemay or positivesubjects identify HF of and/or to inhelpinvestigation the markers useto of genetic the include optionalthestudies of goals study.The thisused in therapies theto responsiveness disease theand/or to possible theircorrelation evaluateto variations genetic inherited on analyses optionalfocus pharmacogenomic These performed. be analysesmay study,of DNA portion this pharmacogenomic optional theconsents to subject the If omecamtiv mecarbil TDMmecarbila fast omecamtivis assay in of samples Blood 7.2.12.5 point. time Section

Table Table

2 7.1 Oct collection and the date and time of blood sampling sampling bloodof and and datetime the collection D

to validate the omecamtiv mecarbil drug monitoring monitoring drug(TDM)assay. omecamtivvalidatethetomecarbil ay1 and . ). ober 2015 ober Date, time Digoxin Echocardiograms Omecamtiv Mecarbil Mecarbil Omecamtiv

harmacogenomic Studies harmacogenomic

5 Further, the sonographer should abstain from commenting onany sonographer shouldFurther,thefrom abstain mL each will be collected from all subjects at the time points outlined points at timesubjects all the from eachmLwill becollected week

, , subjects subjects

and dose of digoxinof andtak dose 2 visits 2 diography instruction manual for detailed information on detailedinformation manual for instruction diography

. . Approximately 2.5 mL of blood will be collected at eachatwill blood of becollected mL Approximately2.5

receiving treatment. receiving as as shown in the Schedule of Assessments ofSchedule shownthe in Therapeutic Assay Monitoring

- turn study

- around intended toassay omecamtiv aid

includes echocardiograms at theat echocardiograms includes en wit Section

h in 3 days prior to theto prior 3 days in

must 7.1 laboratory for analysis. analysis. laboratory for ).

be record be v mecarbil. No No mecarbil. v taking digoxin) Where possible, staff staff possible, Where

Page 41 of Page ed The The blood in the will be be will

Approved

The following procedures The following the Schedule of As ofSchedule the 7.3.1 • • • 7.3 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL • Date: 20120227 Number: Protocol • • • • • • recorded as screen failed in IVRS as inscreen failed recorded be rescreeningneed or duringscreeningto eligibilitycriteria whoanytheof Subjects fail may limit the number theof rescreens. paidlimit may IVRS in reregistered number identification subject originallywill assigned the maintainsubjects Rescreened procedures.screening all whowillreconsentedsubjects arerepeat Rescreened 4 due to fail 4 leastat after schedule and rescreened new medication (e theofwhoopinion the in Subjects consent form. informed should of be the 30 days randomizedsigning withinconfirmed, subjects eligibility is If 7.3.2

S V

P C

B E weeks after prior afterscreen fail weeks g,

impact impact treatment effectiveness Written therapies. order studyto in collected Demographic data includingsex,data Demographic Medical ECG and LH and serum central laboratory and provided to the investigator for eligibility) investigatorthe laboratory for and providedto central

uptitration of BP medications, uptitration of diabetes medications) can on diabetesputof the medications) be uptitration medications, BPof uptitration

erious BP) (HR, signs ital hysical examination as per standard of carestandardof as per hysicalexamination lood samples for samples lood chocardiogram oncomitant therapy oncomitant 23

Oct (central a pregnancy testing, and, if necessary to determine childbearing potential determine ifnecessarytoand, pregnancytesting,

of of , ,

/surgical history /surgical Informed Consent Informed adver or estradiolor transient laboratory abnormality can be considered for rescreening at leastat can laboratoryconsideredrescreening abnormality be for transient ober 2015 ober biomarker variability and pharmacokinetics of variabilitybiomarkerpharmacokinetics and

Screening Screening Rescreening

ly se event se

sessments read)

/IWRS (centrall

chemistry, hematology, chemistry,

to are

andEnrollment

assessment (from signing of informed consent) informed of signing (from assessment

. central laboratory (note that eGFR will be calculated by the bythe eGFRwill that laboratory be calculated (note central

for rescreening. Please note that the clinical trial agreement clinicaltrial that the Pleasenote rescreening. for

yread) Additionally demographic data will be used to studywillto the databe used Additionally demographic

. Rescreening requires signing of aconsent.ofnew signing informed Rescreeningrequires .

their possible association withassociation possible their (to be completed prior to any screening procedures) anyscreening to prior be completed (to ( Table be completed during the screening period as outlined periodas screeningduringthe be completed /IWRS i nvestigator, require nvestigator,

age 2 ) :

before be reconsented and they can

at time of enrollment of time at

, for women of childbearing potential, childbearing womenofpotential, and, for

major medication changes major medication weeks. Subjects who screen whoweeks. screen Subjects the protocol the subject safety andsafety subject , race, and ethnicity willrace,and ethnicitybe ,

- required

Page 42 of Page

, FSH , in in . 73

Approved

reported until EOS at weekat20. until EOS reported 7.4 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL events Adverse Date: 20120227 Number: Protocol events the study duringthe willproceduresbe completed The following please to refer andadverse seriousevents, events adverse of reporting • • • • • • • • • • • • • • • • • • • • The following procedures will be completed at thewillprocedures be completed The following • • AssessmentsofSchedule the 7.4.1 7.5 C

A V

Body height, at Day 1 visit onlyDayat 1 visit Bodyheight, Adverse signs Vital ECG weight Body PK sa PK week Dayat1 digoxin),and taking levelssubjects digoxinin(only for samples Blood for samples Blood w at Echocardiogram, Urine sample for u for sample Urine Blood samples for troponin I, CK troponin I, for samples Blood Therapeutic Monitoring AssayTherapeutic NT IP dosing IP IP dispensation IP Diary dispensation, Day1 Diarydispensation, 4,and2, 12,16 8, weeks count)at (tablet reconciliation IP AEs/SAEs and IP compliance and IP AEs/SAEs 16 diary,week Return Schedule of Assessments ofSchedule

dverse events/serious adverse events/PEPs, if if applicableevents/PEPs, events/serious adverse dverse signs ital oncomitant therapy oncomitant 23 / - serious adverseevents serious proBNP

2 Oct (centrall mple collection mple ober 2015 ober events/serious adverse events/PEPs, if if applicable events/PEPs, events/serious adverse

, at Day 1, weeks 2, 4, 8, 12,8,Day weeks4,at 2, 1, , site on

(HR, BP) (HR, Treatment Period Treatment Telephone Contact Telephone SafetyFollow

, at Dayand1, , , at Day 1, weeks 2, 8, 12,weeks8, 2, Day at1, , seriousevents adverse yread) , at Day 1

rinalysis chemistry and hematology chemistry

, eeks eeks at Day 1, weeks 2, 8, 12,8,2, weeks at Day1,

at Day1,

, , -

week 4 and week 8 weekweek 4 and up Visit/End of Study Visit/Endof up Visit , at Day 1 and week 8 Dayweek at1 and , ( ( /PEPs w 8 Table Table If a subject is not seen at the study thesite, atnot a is seen subject If eeks eeks

and16 will be be will sample sample

weeks 2, 4, 8,4, 2, 12, weeks Daysand 62 34,7, -

MB should beby collectedshould 2 2 4 ) . ). , 8, and8,16 , .

, at at , , will be willbe medicationPEPs, ,concomitant and s, verifi (centrally read) (centrally

collection at weeks12 4 and collection at and16 Day1 and

, at w at , by phone or other contact other by phone or

and16 w and16 eek 20 EOS visit as designated indesignated 20 EOSas visit eek

and 16 and eeks 2, 8,12, and16 8,12, 2, eeks w

eeks 2, 8, 12, and12,16 8, 2, eeks

phone. at times the designated

For detailson For

Section adverse

Page 43 of Page

9 .

in in 73

Approved

• • 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol • Any blood sample collected according to the Schedule of AssessmentsSchedule theto of accordingcollected Anysample blood • • • produce ensureto includes testing study subjects.This to risks minimize out tests e th anyof analyzedfor 7.6 • • If informed consent is providedis subject, informed consent byIf the confidentiality. ensurein database stored secureto study.are thesamples a Results for the assignedtois identifier that a unique using will Samples storage. be tracked analysis or site being for shipped the will from to results prior and associatedbe coded Allsamples and transfercomparability. method and analyses for reanalysis, incurred unexpected sample ofresults, investigation limitedto, not is but include, provide the sponsor with the required studyand subject with sponsor required the the provide the contacting bebydestroyed material sample thatthe request to retains right the subject The parties third other to course, results the treatment tothe alter directlysubjector the benefit areevaluations expected notto the Since conditions, cardiovascular other back samplesresidual and (ie, remaining samples and any other components from the cells can beand destroyed.located cellscan components and the any other from samples 20 upto can study.be Samples retainedof for this part necessarily as reported not anal this from Results action/target). and mecarbil, omecamtiv P C B B B U be made available to the subject, members of the family, the personal physician,personal or the theof subject, membersfamily, thebeavailable made to

years ECG Serum pregnancy Serum

hysicalexamination ody weight ody lood samples for cardiac for samples lood for samples lood oncomitant therapy oncomitant rine sample for urinalysis for sample rine 23

, in accordance with applicable law and subject informedconsent. inapplicablelaw accordance with and subject , reliable and valid data and valid reliable Oct (centrallyread) ober 2015 ober

investigator Sample Storage andDestruction Sample

, asspecified except

chemistry and hematology chemistry

characterize aspects of the molecule (eg, mechanismofof molecule (eg, theaspects characterize . Following the request from the subject,the the request from the Following.

I troponin re not placed in the subject’s medical record and are not and are in medical record subject’s placed thenotre

throughout the course of study course the the throughout

lined in the protocol and for any tests necessaryanyto protocoltests and in for lined the the dose response and/or prediction ofto prediction dose responseresponse and/or the ysis are to be documented and maintained, but are but be to ysisdocumentedand are maintained, in the informed consent.in informed the , CK ,

- up) to investigate and better understand and better up) investigate to -

Amgen can Amgen

number so that anynumber so that remaining

do additional testing on testing do additional

analytical methods analyticalmethods . This canalso This . i ( nvestigator nvestigator Table

Page 44 of Page 2 )

canbe HF or or HF is to to is 73

Approved

Samples will be destroyed once all protocol all once will Samples be destroyed 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL subjectthe of through request at sample(s) the of destruction the responsibleandsamplethe is for materials the sponsor The byAmgen. retained priorrequest for samplesthe to from collected information However, Date: 20120227 Number: Protocol See producedsample.orthe materials gained from derivative or discoveries, and rights suchproduct to commercial subject the appropriate the subject sponsor theproject, research developedthisis a commercialfrom product sample).If the justifies keeping longer no experimentationcertain typesample with a for rationale scientific (eg, the appropriate of of events 8. 8.1 continue participation in study theparticipation continue protocol other and/or Subjects prejudiceto without anyreasonand anyfor time studytheat withdraw to righthave from the Subjects therapies and therapies ( further protocol further doesnot the a subject consentstudy that means of for Withdrawal records medical reviewthe of physicians, from tele will be included in the analysis of the study analysisthe the of in will be included studycontinueparticipation further to unable the procedures listed under the final study visit shouldbe performed. visit listedstudy proceduresunder final the the possible, study.a if At minimum, the withdrawal for procedures appropriatefrom subject data data Table

Assessments

phone/mail, through family/friends, in correspondence/communication with other other correspondence/communication in with through family/friends, phone/mail, Section Section can can

23 2 . T )

Oct (or arepresentative) legally (or acceptable The afterincluded The withdrawalconsent. be of and the level ofand the he ober 2015 ober 11.3 i the exclusive owner of any data, discoveries, or derivative materials from anyderivative data,discoveries,ormaterials from exclusive of owner the is nvestigator must must Subject WITHDRAWAL WITHDRAWAL -

required therapies required therapies (

2 Table for subject confidentiality.subject for

discuss their - required therapies or procedures at any time duringanyat procedures study or the time therapies required

s’ s’ processes

) future medical care medical future must document must Decision to Decision Withdrawto follow and

with with own the i the collection of data, including endpoints andendpointsadverse data, including of collection FROM TREATMENT, PROCEDURES, ANDSTUDY PROCEDURES, TREATMENT, FROM - up the t subjectthe . If . s for for nvest or proceduresor that is agreed to by the subject ( subjectbythe agreed is to that the commercial product. commercialsubject the The product.

this theoccurs, this discontinuation has igator

the changethe , , no commercial rights to the data, information, data,information, rights the commercialto no

- and whereper s aredefined s completed. procedure

. Su . he he by the physician or at the institution. at the physicianbytheor , ). ). at the end of the storageperiod endtheof at, the options for options for

, can

bject data up to withdrawal of consent upwithdrawal datatoof bject and investigator investigator decline to continue receivingcontinueto decline to the the to from the subject does notis or wishdoes subject the to investigator investigator mitted, publically mitted, available IP continuation of continuation S

chedule of chedule or other protocol other or is to discuss with the iswithdiscussthe to wish receiveto is to is eg, eg,

destruction, willdestruction, be

in person, byin person, discuss withthe discuss Assessments has no has

the S the Page 45 of Page - required required

chedule or as as or

but but

Approved

Reasons for removal Reasons for • followingthe of • T 8.3.1 • • • ofsubject removal a Reasons for • investigator investigator The subject. ainclinicaltrial defined anyisuntoward event medical as occurrence adverse An Worsening indicates that Worsening 8.3 with on consistent parameters based mechanism, regulatory country’s The 9. • • 8.3.2 9.1.1 • 8.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL protocol Amgentreatment continued with eligible for be maySubjects studycompletion . to prior protocol Date: 20120227 Number: Protocol 9.1

he definition of adverse events includesadverseofevents he definition

subject request subject criteria non- deviation, protocol ineligibilitydetermined, event, due an adverse concernto (eg, safety lost to follow to lost death decision bySponsor decision lost lost death withdrawal of withdrawalof investigator investigator i

nvestigator and nvestigator

23 to follow to - -

required therapies bya therapies required therapies, required The event does not necessarily have a causal relationship with study treatment. withstudy treatment. relationship necessarilydoes notevent have a causal The Oct

[see or reported by the subject are recorded in the subject’s medical record. medicalrecord. subject’sthe recorded in are subjectby reportedor the ober 2015 ober by by Reasons for Removal From TreatmentFrom Removal for Reasons Reasons for Reasons Reasons for Removal for Reasons Definition of Adverseof Events Definition Subjects’ Participation Participation Subjects’ orSponsor Decision Withdrawto Investigator SAFETY DATA COLLECTION, RECORDING, ANDREPORTING RECORDING, COLLECTION, DATA SAFETY AdverseEvents :

sponsor sponsor TREATMENT PROCEDURES TREATMENT - - is responsible for ensuring that anyobserved by events the that ensuring adverseis responsible for up up

consent compliance, requirement for alternative therapy, protocol alternative for therapy, compliance, requirement

/ or or from protocol from

sponsor

(other than subject request, safety concern, lost tolostconcern, follow subjectsafety (other request, than the pre the

from study from

prot Removal

ocolprocedures - can decide to withdraw can from decide a subject(s) to separate existing medical existing condition from the study the from - required required

F F Prior to Studyto Completion Prior rom rom Study rom

worsening protocol or as provided for byas provided localthe protocol for or IP

TreatmentorStudy ]

, pregnancy) , or procedural assessmentsprocedural or

, , :are or the study the or

of a pre a of

or underlying disease underlying or - existing medical condition. medicalexistingcondition. IP(s) as a whole at anyatime whole as at

or Terminate or

and/or and/or other

Section IP include - Page 46 of Page

specified and/or other and/or 12.1 -

up) any .

Approved

an intervention such as elective cosmetic surgery or a medical procedurea medical whileon study or suchassurgeryelective intervention cosmetic an studyduringthedisease) of moreusual anticipated thanfluctuation (ie, than outcome worse duration (eg, 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol legally acceptable representative legallyacceptable adversean to due treatment removed from The The event.anadverse considered not is or the study the or • • • criteria: serious following 1 of the leastat as an adverse adversethat meets eventdefined event is serious A the procedures recommended for safe withdrawal from protocol withdrawalsafe recommended procedures from the for 9.1.2 study. the • The The 9.2.1 i • • drug bloodbronchospasm,convulsions, dys allergic include event”.suchevents ofExamplescould serious of medically important “other criterion the aadverseunder beseriousevent classified as could criteria, event serious the the of an If overnight stay). care(eg, an admissiona healthfacility to necessitated if event the hospitalization”, of “requires criterion wouldtheevent adversemeet An 9.2 intervention. urgent or surgery, outpatient visit, room nvestigator

requires in requires death)of immediate risk at subject the (places threatening life fatal results in persistent or significant disability/incapacity significantor persistent in results other medically important serious eventserious medicallyimportant other congenital anomaly/birth defect congenital

diabetes, migraine headaches, gout) has increased in severity, frequency, and/or severity, frequency, inhasincreased headaches, gout) diabetes, migraine investigator’s investigator’s i -

nvestigator i

induced liverinjury induced nvestigator considers an event to be clinically important, but it doesanynot meet it but beanclinicallyimportant, eventconsiders to nvestigator 23

more than would be expected,wouldbe than more Oct

or reported by the subject that occurafter that subjectby reportedor the due to anadverse eventdue to ober 2015 ober - Definition of Serious AdverseSeriousof Events Definition Reporting Criteria Reporting of A of Reporting patient hospitalization or prolongation of existing hospitalizationexistingprolongation of patientor hospitalization

. Apre expected . than

is responsible for ensuring that all adverse events observed by the bythe observed all events that adverseensuring is responsible for clinical judgment is used to determine whether a subject is to be is to whether determineuseda subject is clinicaljudgment to

reporting criteria), or events that necessitate an emergency an emergency necessitate events orthat criteria), reporting

Procedures for Adversefor Procedures Events

dverse dverse request

, , - refer to to refer existing condition that has not worsenedhasnot condition existing that E

and/or has an association witha significantlyand/or hasan association vent

s to to

event. event.

s withdraw from Section In the event a subject, or subject’ssubject,event a or the In

8.1 randomization crasias,

for additional instructions on additional instructions for - protocol That That DILI - required therapies or therapies required

o (see required therapies required throughthe n ot Meet Meet ot

Appendix Page 47 of Page or involves or more Serious Safety Safety A

for for

, ,

Approved

Follow 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol (eg, Event (eg, • The • • • Adverse Events (CTCAE) grading sc (CTCAE) grading Events Adverse usedwill scale event be the adversegrading The • The The eCRF.Event level on the severity of each a event single date for record resolution, of the to onset in described response to the to response “no”or by a “yes” indicated is relationship orThis mecarbil placebo). (omecamtiv been causedbybeen that the event havethebeen caused may that a possibilityreasonable “Is there response theto “no” orquestion: by a “yes” indicated anprocedure(s)) screening and/orprocedure (including therapies, study The investigational product, protocol product, investigational reversibility. reversibility. abnormality) laboratory(not the clinicalsequelae applicable, adverse consideredevents. current intherapyare Where adjustment or treatment that require value changes adverse laboratory However,events. as recorded on (basedthe clinicalsignificance without findings abnormallaboratory Inbaseline general, values. subject’s thechange from significant aclinically represents valuean individualsubject in study an abnormal whether The The The event. A D S A A investigator investigator investigator investigator investigator investigator investigator investigator i ported is expected ported follow to re nvestigator

dverse event diagnosis or syndrome(s), if known (if not known, signs or signs symptoms) notif (if known, known syndrome(s), ordiagnosis event dverse everity [and/or toxicity per protocol] toxicityper everity[and/or ssessment of relatedness to investigational productinvestigationaltoof relatedness ssessment ction taken ction ates of onset andresolutiononset of ates - mandated activity mandated

23 - up Visit/ up

Oct eCRF ober 2015 ober

Appendix

End of Studyof End(

question: question: IP must assign the following adverse event attributes: event adverse assign followingthe must must assess whether the adverse event is possibly related to possiblyrelated is event whether adverse assessthe must must assess whether the adverse event is possibly related to anytopossibly related is event whether adverse assessthe must is responsible for reviewing laboratory test results and determining results test laboratory reviewing is responsible for ) , including events that are reported to the CEC for adjudicationCEC are the. toevents reported that for including ,

(omecamtiv mecarbil or placebo)ormecarbil (omecamtiv

, , (eg . If the severity of an adverse event changes from the date ofdateevent the changes from an adverse ofseveritythe If “ Is there a reasonable possibility that the event havethemay a possibilityreasonable that there Is

administration of in of administration ) EOS - required therapies, therapies, required (if resolved)(if are reported using the applicable case report applicable form case reportedthe are using ale

by a study activity bya study .

The grading scale used instudyscale thisused is The grading

a vestigational product, protocolproduct, vestigational dverse are to to are C investigator's investigator's ommon ommon Te ?)”and/orprocedure ” ? ?

e be recorded asbe recorded adverse the

vents until stabilization orstabilization until vents (eg. administration ofadministration (eg. rminology Criteria for for Criteria rminology judgment) judgment) . This is relationship This .

are are Page 48 of Page

- IP IP required required not not to to be be

Approved

response to theto question: response ormecarbil placebo) (omecamtiv The Serious eventtheof knowledge investigator’s within tothe report24 hours following to Amgen them is investigatorthe reported, are endstudy.ofafter aware of become that they events adverse are reportto seri required investigators states), memberEuropeanUnion (eg, Amgen. canbe toseriousreported events these adverse However, EDC system when the system is againwhenis available.system the EDC system EventAdverse Serious Amgenviaistotheeventreported aadverse ofserious notification the first If . reporting purposestheexpeditedof for cases asclinicaltrial safety database withinthe captured serious staff sitethe unavailable is capture(EDC) systemto data electronic the If anystudy The causedbyIP been protocol the eventsadverse serious studysubjects no for requirement monitor is to There Adverse EventAdverse W i within the 24 hours of Form Event Adverse ReportContingency (eSAE) Serious 9.2.2.1 the investigator the The 9.2.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL the following Amgen tosubmitted and are in medical record subject’s the recorded are later, whicheveris consent Date: 20120227 Number: Protocol nvestigator’s nvestigator’s i investigator investigator investigator investigator nvestigator must assess whether the serious adverse event is possibly related to isIP eventpossibly related adversewhether seriousassess the must nvestigator

All serious adverse events must be submitted to submittedevents must be adverse Allserious adverse eventadverse a

until until Oct dverse - mandated activity or procedure. This relationship is indicated by a “yes” or by indicated a “yes” procedure. is relationship This activityor mandated

- ober 2015 ober required reporting period defined above or after the end of the study end thetheof perioddefined aboveafter reporting or required i 30 days after the last daysafter the 30 nvestigator’s knowledge of the event via the viaapplicableeventthe the of knowledge nvestigator’s knowledge of the event. theof knowledge Reporting Period Reporting AdverseProtocolAfter EventsSeriousthe Reporting Reporting Procedures for Serious AdverseSerious for ProceduresEvents Reporting

or reported by the subject that occur after signing of the informedof signing the after occur that subject bythe reportedor must assess whether the serious adverse event is possibly related to iseventpossibly related adversewhether seriousassess the must is responsible for ensuring that all serious adverse events observed byeventsobserved adverse all that serious ensuring is responsible for e orksheet vents reported outside of the protocol theof ventsoutside reported (omecamtiv mecarbil or placebo)ormecarbil (omecamtiv , the ,

Contingency Report Form, the data must be entered intotheForm, be entered dataReport the must Contingency “ /e

information is to be reported to Amgen via an electronic Amgenviabetoan toreported electronic is information Is there a reasonable possibility that the event havethemay a possibilityreasonable that there Is

lectronic This relationship is indicated by a “yes” or “no”or by a “yes” indicated isrelationship . This

dose of IP of dose . Serious Adverse Event Contingency Report Form. Contingency EventSeriousAdverse Report

See

Appendix

or or Safety Follow Safety

?” B

- for a for required reporting period period reportingrequired

Amgenwithin 24 hours sample -

If serious adverseseriousevents If up Visit/ up

In some countriessomeIn

of the the of e CRF. E - nd of nd required to report report to S

Page 49 of Page erious erious

ous ous electronic following following S tudy . will the the , be 73

Approved

If a subject iswithdrawnpermanently a subject from If clinical practice clinical and regulations localto according withrequirements reporting all compliance in authorities, regulatoryto as required reactions Amgen accordancewithrequirements. inlocal authorities regulatoryto sent reports adverse seriousevents related of willnotification receive submission authorities. byregulatory Amgenbefore to be unblinded may adverseandunexpected,events related subjects ofwhoserious, developassignment events, treatment adverse the serious for withregulations reporting complyworldwide To Amgen.betosubmitted event, must adverse information this serious or designee. or CEC The CECmanual. theto according reviewa CEC adjudication for will and be provided to documentation) and packagesupporting (worksheet Each iswhen eventreported. thecenter study investigative bythedesignee Amgenor will event to cardiovascular be provided each supporting documentationSource center. study investigative byworksheetsthe specific onwill events and be recorded cardiovascular deaths of occurrence addition, the In The e applicable recordedon the with that mustbe consistent event adverse providedserious the about Information record. medical the extracts from or summary additionalprovide tofollow be asked may local procedures and statutes. procedures local within accordance Amgen, eventreceived adversereports from andsite other the at Amgen Amgen Amgen . to submitted beevent adversemust a previously serious reported to relating Newinformation or reversibility or The activity/procedure”? causedbya study been eventthehave may areasonablepossibility that “Isthere to question: response the “no” 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol CRF). i investigator investigator nvestigator nvestigator

will within within

Oct report serious adverse events and/or suspected unexpected serious adverse serious unexpected events and/or adversesuspected serious report

ober 2015 ober . 24 hours following knowledge of the newthehoursof infor knowledge 24 following

. . is to to is is expected to follow reported serious adverse events untilevents adverse seriousis expected followto reported

notify the appropriate IRB notify the All new information for serious adverse events must be sent to sent events must be adverse serious All for newinformation

committee committee

will pro will

- up information, which may include a discharge whicha discharge include may information, up vide the results of the adjudicationAmgentoof the results videthe protocol

i /IEC nvestigators

required therapies required of serious adverse events occurringadverseevents serious of /institutions, andIRBs /institutions, mation. mation. The The

because of a becauseof e CRFEvent (eg, i nvestigator Investigator stabilization Page 50 of Page good /IECs

s 73

Approved

subject is taking protocol - is taking subject whilea ofsubject, the subject,or male inpartner female a occurs a pregnancyfemale If 9.3 theto reported CECare that Visit/ theor respectively, through informedconsent randomization, the t subjectby or the reported investigator bytheobserved events events/adverse adverse all that ensuring serious is responsible investigator for The below report In addition to reporting any pregnancies occurring during the study, occurringanyduring the addition reporting pregnancies to In 9.2.2.2 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol The 5 In addition to reporting a lactation caseduringthea study, addition reporting tolactation In Amgenasspecifiedbelow.case lactation to the report the the Any 5 - protocol doselastof after occurthe cases that lactation If a lactation case occurs while the female subject is taking protocol taking is subjectcaseoccurs while a lactation female the If Pregnancy Notification Worksheet Worksheet Notification Pregnancy • 10.1.1.1 10.1.1 10. Notification Worksheet the 10.1 • 10.1.1.2

days following the last dose of IP lastof dose the days following wing the last dose of IP.lastof dose the dayswing follo

4, 12, and 16, and area under the curve(AUC) andand area the 12,under 16, 4, weeksat2, omecamtivof(Cpredose)mecarbil administration prior to Concentrations Changes from baseline in SETin baseline Changes from i i

nvestigator’s nvestigator’s

lactation case should be reported to Amgen be to reported caseshould lactation pregnancy should be reported to Amgen beto reported should pregnancy EOS are reported using the applicable eCRF (eg, Event eCRF), includingeventseCRF),applicableeCRFEvent using (eg, the are reported EOS

. .

pregnancies that occur after occur pregnancies that

Oct ober 2015 ober ncy ncy Pregna Reporting a Safety Endpoint as a Studyas a Endpoint a Safety Endpoint Reporting STATISTICAL CONSIDERATIONS PrimaryEndpoint Endpoints Study Study Endpoints, Analysisand Covariates Sets, Endpoints, Study SecondaryEndpoint

knowledge of the eventtheof knowledge knowledge of eventof knowledge

( Appendix required therapies required and Lactation and

committee committee

s C ( . by echocardiography at weekbyechocardiography at the the Appendix ).

. last dose of protocol doseof last Report a lactation case onLactationathelactation Report case for adjudication. for

of aofpregnancy Reporting

report report

C Global Patient Safety GlobalPatient ) . Global Patient Safety Patient Global

the pregnancy to Amgen as specified pregnancy Amgenas to the at8 week

through required therapies . o shouldrep investigators Report apregnancyReport on the - required therapies through required

hat occur after signing of of signing after occur hat

16 Safety Follow Safety

- within within

i requi nvestigators nvestigators should

within within red therapies therapies red 24 hours 24 Page 51 of Page 24 hours 24 - up rt

of of

73 of of

Approved

• • 10.1.1.3 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol ifordata key deviations the protocol unlesshaveaffected significant endpoints, • as arefollows: endpoints Exploratory 10.1.1.4 • one dose of IP (omecamtiv mecarbil or placebo). placebo). or of (omecamtivmecarbil IP dose one least whorandomizedallsubjectsat have includes received (FAS)analysis set The full used. PKASwillin a whichmodified sampling be information case missing, are or completed IP administration. IP completed completers The non- analyses. • • • • PK parameter (C parameter PK oneevaluable mecarbil omecamtivandof omecamtivleast have at dose mecarbil one whorandomizedall leas have(PKAS)includesanalysis received PKset subjects at The 10.1.2

o o

Changes from baseline in laboratory valueslaboratoryand in vitalsigns baseline Changes from eventsadverse of incidence Subject left ventricular end- ventricular left ECGin baseline Changes from VEDD (L diameter observed values and change from baseline to assessed timepoints oftimepointsassessed to baseline values and change observed from arrhythmias requiring treatment from initiation of IP to EOS to IPinitiationof from treatment requiring arrhythmias tachycardiaventricular and tachycardia of incidence supraventricular subject subjec PK endpoints.PK bserved values and change from baseline to assessed timepoints of stroke volume, volume, strokeoftimepoints assessed to baseline values and change bserved from bserved values and change from baseline to assessed timepoints of HRoftimepoints assessed to baseline values and change bserved from

• • • • •

Oct

t incidence of the following clinicaloutcomeendpoints: ofthe incidence following t cardiovascular death or HF hospitalization until EOS or deathuntil hospitalization HF cardiovascular - all cardiovascular death cardiovascular to: include,be limited noteventsevents may untilbut EOS; adjudicated all - all atrial fibrillation/flutter newonset death sudden angina,and resuscitated unstable ober 2015 ober cause death or HF hospitalizationEOS HFor deathuntil cause cause death cause SafetyEndpoints ExploratoryEndpoints AnalysisSets

analysis max

, C ).

pre systolic diameter ( diameter systolic dose set is a subset of the FAS and includes subjects FASwhothe isof and includes havea subset set

). ).

The completers The the willallanalysesof for analysisset be used This , HF , acute myocardial infarction, myocardial acuteinfarction, myocardial ,

) ) LVESD

analysis analysis This set will be used for willanalysesallof set for be used This and left ventricular end ventricular left set will be used willfor sensitivitybe used set

dyastolic NT Page 52 of Page

ischemia, ischemia, proBNP dosing

PK PK

Approved

covariates include theinclude following: covariates fac stratification The their designees will not have access to unblinding information until the studythe until unblindinginformationisto have formally designeeswillaccess not their Amgenorand personnel, sitestaff subjects, section, thisin specified otherwise Unless PKAS)will a 2 provide from (ass 19subjects eachtreatment in20 group, n= subjects a 4090,sizesampleoftoof range 10.1.3 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL 10.3 studydose20090727. from single dos 41. Date: 20120227 Number: Protocol SDs in this range for 19 subjects per19 treatment for range group. this subjects in SDs parameter’s mean will be estimated. willmeanbe estimated. parameter’s The primary endpoints of this study are the omecamtiv mecarbil PK parameters PKomecamtivthemecarbil areof study this endpoints primary The 10.2

es for Matrix F1 formulation based on simulations performed using PK onperformed following Matrix data simulations based F1 formulation es for uming 5% subjects out of a total n = 20 subjects per treatment arm areper arm excluded subjects treatment n a20 = oftotal out uming 5%subjects BIDPK25andmg 50 steady mg predicted thefor estimatesSD state are from The

StandardDeviation 23

Oct • • • • • • •

ober 2015 ober 40 90 80 70 60 50 age (< 65, 65, (< age and Subgroups Covariates Designees Body mass Index ( IndexBody mass LVEF sex presence of disease arterycoronary presence NT Sample Size Considerations Sample HF treatment at baselineat treatment HF Access to Individual Subject Treatment AssignmentsAmgenSubjectby Treatment or Access Individual to

- Table

proBNP tor is is tor

4 ≥

. PK Parameter PKIntervals 95%Confidence . presence or absenceofor presenceatrial fibrillation/flutter

65) sided 95%sided interval confidence

BMI Table Table

Assuming the SDs for C for SDs the Assuming ) )

below presents

Confidence Interval HalfWidth

(CI) CI

max halfwidths particular given with half width of 18 to 18 ofto with halfwidth

and AUC are in the are AUCand

. O

N=19 18.0 40.5 36.0 31.5 27.0 22.5 Page 53 of Page ther baseline ther . PK PK .

Approved

assignments in this study, but will not have access to subject willtohaveaccess study, in but not this assignments PKto unblinded and samples assaying are management, sample assignment, involved treatment randomized Staff in studyis formallyunblinded. the individualsblindeduntil todistributed not are data andpotentially unblinding information unblinded. 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL data. Date: 20120227 Number: Protocol DMC for data reviews.DMCfor aggregateandsubject including results, willunblinded provideand toassignments willtreatment independentbiostatistics access group external have The before bylabeled analias areIDs; samples subject of have knowledge not responsible for 10.4 ongoing omecamtivmecar ongoing Amgen’sdata accumulating from independentthe external review DMCAn will formally 10.4.1 changes (eg, including, but not limited to, dosechangestoppingor limitedto, including,notbut (eg, changes any make protocolwhether orto according the study to thewhethercontinue to sponsor Based on the totality of on totality the Based review unblinded data approximately everyreviewdata month unblinded variability).duePK tounexpected concentration subjectsPK (eg, to protect the status of status the protect Section LeadClinical byAmgenstaff Pharmacology designated(eg, supported and whichindependentbiostatistics group bythe be provided DMCwill the enrolled subjects in the study either completetheeither study thein enrolled subjects the HF with Japanesesubjects omecamtivin mecarbil of PD, tolerability PK, thesafety, evaluate To willbe taken. studyearly. the 10.4.2 be tested in this study and all statistical approacheshypothesisare and in statistical allstudy this tested be endpoints. all for estimation includeanalysisprimary will The

Staff in Amgen’s Clinical Pharmacology Modeling & Simulationwho & are Amgen’sModeling Clinicalin Staff Pharmacology

10.3 with reduced ejection fraction, the primary analysis will be conducted when allprimary will be conducted the analysis ejection withfraction, reduced

Oct

Unblinded individuals, as designated in this section, are to ensure unblindingensureto section,are designated this as in Unblindedindividuals, ober 2015 ober )

, ifneeded., At this stage, Planned Analyses Planned DataMonitoring Committee (DMC) Primary Analysis Primary

PK data analysis and interpretation during the conductthisof data PKduring the analysisand interpretation

At that time, the database will be cleaned, processedsnapshot and will a database theAttime, be cleaned, that the blind and to minimize potential operational bias, operational potentialminimize and to blindthe

evidence, the DMCrecommendationan overallevidence, the willmake

Details will be provided in the DMCthe will charter. Details in be provided bil studies to facilitate detection of any increased risk for harmof riskanyincreased for facilitate detection to studies bil

t he study will be unblinded to conduct the primary analysis.conductprimary the studyto willhe be unblinded

while subjects are receivingIP. while subjects

IP EOS

packaging

visit (week 20) or terminate 20) terminate or (week visit -

levelsafety No formal hypotheses will hypotheses No formal

and labeling, biologic andlabeling, the treatment the - - is is enrollment). enrollment). level data, to theto level data, generating. The DMCwill The

external to Amgen externalto

analyses for the analyses the for

or efficacy or analysis. Page 54 of Page in

study will study

To To to the the to

73 al al

Approved

collected in the study the in collected 10.5 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL zero. valuetheof assigned quantifplasmaallbelowanalysis, PK concentrations the the In Date: 20120227 Number: Protocol median, SD, median, mean,subjects,of number variableswillcontinuousinclude for statistics Summary willandcharacteristicsbe summarized. baseline demographics disposition, Subject nature. descriptivearein study analysesin this Statistical 10.5.1 Individual willbe provided. t non-- of variation will also be included. willvariation be included. also of (C may calculation of PK parameters. of calculation nt. each nt. treatme parameter for The primary endpoints areparameters omecamtiv PKthemecarbil endpoints primary The 10.5.2 assignm willbe presented Echocardiographic parameter Echocardiographic 10.5.3 PKAS. of set primaryin analysis the assessment, scheduled descriptivelyeach will be summarized at Individualparameters PK summarized by treatment group and scheduled assessment. and scheduled group bytreatment summarized omecamtiv mecarbil exposure andchangesexposure inmecarbil baseline omecamtivfrom addition, In treatment in groups treatment estimates and their 95%andtheir estimates abulated max

be plotted. be , C ,

compartmental methods. compartmental methods. 23

pre ent. ent.

Oct for omecamtivmecarbil for dose omecamtiv mecarbil omecamtiv analysis or ober 2015 ober

) can be adequately estimated. be adequatelyestimated. can Planned Methods of Analysisof Methods Planned General Considerations General PrimaryEndpoint SecondaryEndpoint

standard error, minimum, and standardminimum,maximum. error,

The PKAS will contain all subjects for whom at least one PK parameter one parameter leastwhomPKat for PKASsubjects allThe willcontain .

treatment group willrandomized on their based Subjects be analyzed SET will be performed to explore the potential relationshippotential explore the to willbe performed (

Section

CI will be estimated via estimated be will s

For any data excluded from the analyses, specific reasonsspecific analyses, theexcluded anyFordata from presented.

SET

10.1.1.1

Descriptive statistics will be generated for eachPK willfor be generated Descriptivestatistics concentration Actual dosing and sampling times will be used willfor and be used sampling dosingtimes Actual

For categorical variables,

Individual, and

) . its its

The modelwillincludeThe change from baseline at week at16 baselinechange from

time data and sum data time

PK parameters will be calculated using willPK parameters be calculated mean - repeated

, , and measures model, with difference difference with model, measures

SD concentration - SD For PKFor

freque

SET iable limits will be will limits iable the the marystatistics

. parameters, coefficient coefficient parameters,

ncyand percentage C Differences betweenDifferences stratifica predose between

and time data data time Page 55 of Page tion factor, tion factor, will be be will willbe , , AUC

Approved

treatment group, visit andvisitthe group, treatment 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol preferred term. term. preferred andorgana system adverseclass all a events to (AE) lockcode datawillto be used the of time the at Activitiesversion Regulatory(MedDRA) Medical current for The Dictionary 10.5.4.1 analysesby 10.5.4 serious adverse events, adverse events leading to withdrawal from withdrawaltoleading events, events from adverse adverse serious tabulated language(s) of potential the language(s) laboratory values between baseline and the most extreme post and valuesmost extreme baselinebetweenthe laboratory and group. by assessmenttreatment cohort scheduled statisticseach atwillsummary endpoints laboratoryinclude safetyanalysesof The 10.5.4.2 emergenteventsbe will adverseprovided. also treatment 10.5.4.3 bycohor tabulated i the writing from communicated formallybe in are to Upda testemplate site. atthe her orto be documenthis used consent to informed 11.1 inbaseline changemaximum QT Subjects’ from parameters. ECG all will time for over baselineoverand/orbe provided changes from time Summaries 10.5.4.4 bycohortandtreatment group. assessment eachscheduledat vitalsignswillsummary include statistics analysesof The An initial initial An 11. willin subjects each ofgroup be summarized. percentage numberand and the be categorizedwill postalsomaximum valuesbaseline Subjects’ eachwillofin besummarized. and subjects percentage group number the and nvestigator

Oct sample sample by system organ class andorgan bypreferred systemterm. class . The written informed consent document is to be prepared documentis to writteninformed consent . The

ober 2015 ober baseline covariates in covariates baseline SafetyEndpoints Safety Vital Signs Vital Informed Consent Informed OBLIGATIONS REGULATORY Electrocardiogram AdverseEvents

Subject incidence of all treatment emergent adverse eventswilladverse be emergent treatment allof Subjectincidence informed consent form is provided the informedconsent form for t and ttreatment group.

Laboratory Tests Laboratory

subject population. subject

interaction of treatment group and visit.of treatment interaction group

Section Section

10.1.3

appropriate Amgenrepresentativeappropriate

will ridericia corrected ridericia

Tables of fatal adverseevents, of fatal Tables be provided. be

Shifts inof Shifts safety grades

i nvestigator - baseline valuesbaselinewill be

will be categorized categorized willbe , and significant and,significant

Subgroup tothe prepare in the the in Page 56 of Page

to theto

Approved

protocol anyand before study the of anticipatedand potentialhazards benefits,methods, aims, theexplanationof adequate after subject writteninformedconsent the from obtaining the clinicalstudy,the in participation asubject’s Before 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL havehisagrees the to physician and if subject care The Date: 20120227 Number: Protocol The acquisition of informed consent and the subject’s agreement orhis agreement andsubject’s refusalthe informedconsent of of acquisition The phys care have doesa notprimary the clinicalsubject study. If in the participation subject’s the notification, subjec the of informed information, and any proposed advertising material must be submitted to thebeto submitted must advertising proposedmaterial and any information, writtensubject proposedother protocol, informedconsent form, the copyof A 11.2 wasand underst given freely consent thatinformed attest consent toinformedform signand witnessthe must subject theboth Thereafter, allow questions. and subjectmust for the consent to form informed the representative, acceptable havea legallynot and does visually orilliterate is subjectimpaired a potential If signed consent of form a copy the and consentinformed form signed original informed discussion. person consent whothe The and bythe conducted subject andinformedconsent theform records, primaryphysician of the care notification medical record. subject’s suchin the document document. The document. s all for from Amgen,accordancewithprocedures. inlocal from eventreceived adversereports at and othereventssite theoccurring adverse serious The The Amgenof shipment studyinto subjects ofthe and be by before receivedrecruitment must Amgen form consent protocoland informed approval the of written the copyof A approval. written

investigator investigator i ician and the and the ician nvestigator nvestigator

23 ubsequent protocol amendments and changes to the informedconsent and theprotocolchangesto amendments ubsequent -

specific screening procedures or anyorscreening specific procedures Oct ober 2015 ober Institutional Review Board/IndependentReview Institutional

investigator i must submit and, where necessary, obtain approvalwherenecessary, theand,obtain submit from must is also responsible for asking the subject if the subject has a primary subject if the asking subjectthe responsibleisalso for nvestigator i nvestigator will be acting in that capacity, thecapacity, in that willbe acting nvestigator IP

t’s participation in the clinical study. If the subject agrees to suchagrees subject to If the in clinicalstudy. the participation t’s .

is to inform the subject’s primary care physician of the the of physician care primary subject’s the inform to is is to is is t is i nvestigator

o notify the notifythe be retained in accordance with institutional policy,within beinstitutional retained accordance ood. is to is

is to is

must provide an impartial witness to read towitness the an impartial must provide IRB be providedsubject.be the to

be signed and personally dated by the bythe signed and personallybe dated

be documented in the subject’s in medical be the documented IPs IPs /IEC

are administered. administered. are

of deviations from the protocol ordeviations protocol the from of or or her primary care physiciancareprimary her investigator investigator

EthicsCommittee investigator is responsible for

Page 57 of Page is to to is IRB

IRB /IEC

or or /IEC her

for for

Approved

• • • • submitted Amgen. to documents The The 11.3 Amgen.tobe approval sent must of The The 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Copies ofthe of study. the duration Date: 20120227 Number: Protocol • i therequired itisthat compliancewith GCP Federalregulations/ICH Guidelines, In 11.4 study obtain the consent of the subject to permit such individual such permitofto subject consent the the obtain andthe agency(s), regulatory Each clinical study report clinicalstudy Each investigator study.The investigator the of evaluation important theto are portsanyandre records and verifying,analyzing,reproducing examining, includes that study of verification for records medical - multi • The • • nvestigator nvestigator S

local laws and regulations lawslocal within accordance bedocumentedand formatted isdate to birth of permitted, Where For For number, include the age at time of age enrollment include time at the number, the On to identificationsubjectnumber unique Documents that that are Documents regulations birth of and date and regulations), lawslocal a recognized expert in the therapeutic inarea therapeutic theexpert recognized a interpretation of study the interpretation an an

investigator investigator i Coordinating Coordinating nvestigator nvestigator

ubjects are ubjects - center

related records, including personal information.includingpersonal records, related be kept in confidence in be bythe kept 23 i i nvestigator nvestigator serious adverse eventsadverse serious

Oct e

and institution permit authorized representatives of the companytheauthorizedof representatives institutionpermit and CRF demographicsCRF addition the to in page, studies, the studies, the ober 2015 ober ). entiality Confid Subject Investigator

must ensure that the subject’s confidentiality is maintainedconfidentiality subject’sis the ensure that must is is to i

nvestigator

responsible for obtaining annual obtaining responsible for contributing a high numbereligibleofsubjects a high contributing design or either tothe whocontributions significant provided bebyidentifieda

not submi coordinating coordinating is to is

SignatoryObligations

, identified by Amgen, willidentifiedbyAmgen, be , .

IRB be signed bybe thesigned

reported to Amgen , to reported

/IEC tted investigator

i nvestigator unique i

nvestigator

to Amgen (eg, signed inforAmgensigned (eg, to direct access to review the subject’s original accessoriginal subject’sreview todirect the - , related procedures and data. Direct access and data. Direct procedures related

initials

. number. identification subject , except as described belowasdescribed except ,

investigator investigator ’s reports and thereports ’s ( in accordancewith faxed (for reports, . . . in accordance with local laws and accordancelawswithinlocal

subjects IRB

/IEC unique s any or all of theof all following: anyor to have access to his haveaccess to to

or, in the case of of case the in or, approval throughout the throughoutapproval the are are is obligated to inform and obligated inform tois subject identification subject to med consent forms) consent medforms)

IRB

be identified by their bebyidentifiedtheir /IEC

. . continuance continuance

for for Page 58 of Page , of the the of ,

or her her or

are are 73

Approved

Subjects may be eligible for continued Amgen treatment continued with eligible for be maySubjects Amgenand . sendnotification early to orthe copyof a completion termination study’s according to the study contract. studyThe contract. the to according IRB approval the copyof from a the send letter IRB/IEC 12.1 IP whetherto determine supplytoAmgen discretion, sole itsatunilateralright, the reserves mechanism. regulatory bythe as country’s provided local for or i Amgenthe any Both time.atand study the terminate to right the Amgen reserves 12. 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL agreementtheprotocol, Amgenamends the from If Date: 20120227 Number: Protocol 12.2 availablecommercially. recording (ie, recording e ndence.correspo and radiographs, diaries, laboratorymicrofiches, pharmacyrecords, charts, and office and e documents Source on and/orcorrections entries authorizedmaketo Allpersons duties. delegatedstudy has The The The authorities. Elements authorities. Amgenand/orapplicableregulatory byrepresentativesanytime at from inspection - study all of system lized filing centra • • nvestigator tudy files containing the protocol with all amendments, withamendments, all protocol containing the study files ubject files containing completed completed containing files subject CRF entries may be considered source data ifdata be source themayconsidered entries CRF clinical hospital records, limitedtonot arebut include obtained. are These data CRF

and by what mechanism, after termination of termination theand after bywhatmechanism,

e identification list identification copies of pre of copies and Amgen and

CRFs will be included on the AmgenDelegationForm. Authorityof on the will CRFs be included i i nve nvestigator

stigatorto is must be informed of all amendments and give approval. The and The beamendmentsall approval. informedof give must Oct

reserve the right to terminate the terminate tothe right thereserve ober 2015 ober

there is no other written or electronic record of data).of electronic orrecord no iswritten there other Protocol A Protocol Study Documentation and Archive and Documentation Study ADMINISTRATIVEAND LEGAL OBLIGATIONS

- and study staff are responsible for maintaining a comprehensivea andaremaintaining study and responsible for staff study documentation, and all correspondence to and theandtofrom correspondenceall documentation, study

are original documents, data, and records from which the subject’s subject’s which fromrecords the documents,data, and originalare

maintain a list of appropriately qualified personswhomhe to appropriatelyof a list qualified maintain

shouldinclude

mendments and StudyTermination and mendments

related (essential) documentation,suitable for (essential) related i the followingthe : nvestigator e CRF

, informedand subject consent , forms, i nvestigator /IEC is to to is

study e

i to nvestigator CRF is the site ofsite original the isCRF the

notify the notify the Amgen. ’s participation in the studyin ’s the participation and before Investigator ’s

IRB must be The must obtained.

by anprotocol extension However, Amgen

/IEC the product the investigator

i n writing of the writing n B rochure, Page 59 of Page IRB is is

or or must /IEC she she

Approved

• 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol The Amgen Amgen The confidentialityprovidedsubject respec data) isthat pertinent (eg, of clinicalstudy therecords varioustheinspecting request, upon 12.3 Agreement. ClinicalbystudyTrial will of documents the governed Retention be maintained andbe readilyavailable. maintained beCRFs in must the entries supportingdocuments source originalall addition, In contacting and visiting the and visiting contacting Amgenrepresentative The (s) monitoring visits, including delays in completing completing includingdelaysin visits, monitoring Amgen representative The study other Amgenrepresentative appropriate clinical research. of The onconduct the regulations data;and adherencetheconsistency completeness, of accuracy, protocol; adherencethe tostudy verify to throughout the CRFsintervals regular at the verifying designees). Inspection of site facilities (eg, pharmacy, (eg, siteof facilities Inspection designees). (or Auditing Amgen’s Global function Complianceby representatives from audit for accordancewith ICH GCP In requirements. regulatory and applicable and ICH complianceGCP,protocol, the with conduct study and reviewlaboratories)of areas, • beelectronic: study to plannedcapture this is Data for • •

IP Final Investigational Product Reconciliation StatementProductReconciliation Investigational Final Destruction of Product Investigational s,for Record Return Accountability readilyavailable. All source documentation supporting entri documentation supporting Allsource discrepancies. In addition, the data addition, the In discrepancies. data subject review, During dataAmgen. this at received on subject reviewmanagement performed is To trail”. to Updates

i nvest

- 23 related correspondence including ProofReceiptsof including correspondence related ensure the quality of clinical data across all subjects and sites, a clinical data aclinicaldata and sites, subjectsall across clinicaldata of theensure quality

Oct igator igator - related records needed to verify the entries entries verifythe needed to related records Clinical M Clinical ober 2015 ober

Study Monitoring and Data Collection and Data Monitoring Study

e CRFs will be automatically documented through the software’s “audit software’swillthe CRFs documented through be automatically agrees to cooperate withtheagrees cooperate to

onitor

to ensure that any problems detected in the course of these course anythethese problemsof in detected that ensureto are are i nvestigator nvestigator

checked for consistency, omissions, andany apparent omissions, consistency, for checked and/or appropriate Amgenappropriate and/or representative and the sponsor’s audit plans, this study may be selected study thisplans,may and sponsor’s beselected theaudit and regulatory authority inspectors aresponsible re inspectors and authority regulatory for is to is

for the purpose of inspecting the facilities and, and, theinspecting of purpose facilities the for

have access to subject medical records and records subjectto have access medical - are

related records will occur to evaluate the studyevaluate towill the records occur related

reviewed for adherence to the protocoltheand to adherence reviewedfor

es into es the Amgen C Amgen e CRFs, are resolved.are CRFs, Amgen Amgen

protocol

linical linical in e

CRFs must beand CRFsmaintained must , , , Investigational Product Product Investigational , the the as as ted. Clinic M e applicable. - CRFs. onitor onitor ytherap required

al Mo al

and/or appropriate and/or is responsible for CRFsotherand nitor and/or nitor Page Page Forms

to local local to storage storage 60 , of 73

Approved

The The 12.4 closeout. study at and trialtheinitiation of at data the study toapplied corrections ofof types the a list provided willsitebe investigative Each physical examination). providedrace, are (eg, data visitwith different date twicewithsamethe sent same data results (eg, duplicate obvious of deletion include designee)by Amgen (or bethat maycorrected obviouserrors ofdata Examples Plan. SelfEvidentCorrections in Study theasdocumented Specific database, clinicaltrial selfwill perform designee) Amgen (or • to completion of al of completion to whosubjects withdrawprior For in subjectstudy. theprotocol each in the for stipulated and data collection (including subjects notsubjects receivingprotocol (including collection data and Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol committee is expected to solicit input and assistance from other other inputand assistance from expected solicit tois committee ainPublication Charter set whichforth are and responsibilitiesof governance the severalof committee consisting publication a ofencourages study,the data Amgen formation of this dissemination from coordinate To asappropriate. Amgen from staff assistance study, data the of this dissemination from coordinate To 12.6 are clearlythat usevocabulary and language must investigative staff and by subjects be used to and informationother material written All 12.5 possible. as comprehensiveas is/are asstudy antheoutcomeof produced ascertainsurvivalpermitted) status. (where to records S collaborate with authors and Amgen staff asappropriate Amgenstaff withauthors and collaborate

chedule of of chedule Amgen Amgen reviewer. resolution, will be closed by the CEC. willbythe be closed resolution, process, data queries and/or site notifications and/orsite data queries process, GCP. database for site resolution and resolution site for database The The e s indicate signature This

i CRF, the data queries, and the site notifications, and agrees withcontent.the and agrees notifications, site the dataand the queries, CRF, nvestigator

23 i

nvestigator Oct To resolve any questions arising from the clinical data managementclinical the review arising data from anyquestions resolve To ober 2015 ober A ssessments Investigator Publication Policy Publication Language

isresponsi l protocol l

signsonly the

Additional queries may be sent out by Additionalout besent mayqueries

- week 4 and early termination) and clarifying “other, specify” if if and“other, specify” clarifying termination) early4 and week

( Table Table ble -

that that Responsibilities for DataCollection for Responsibilities required visits andvisitsare required for for i nvestigator 2

comply Investigator ) , subsequently closed closed subsequently the the - evident corrections to obvious data errors in obviouserrors the data corrections evidentto

nvestigator ing

inspected or reviewed the data onthe data reviewedorinspected the with the requirements for all withrequirements for theassessments i nvestigators nvestigators

Verification Form for this Form for Verification are are understood. understood. unabl can search can created in the EDCsystemthe in created Th investigator e or unwilling to continue thecontinue to unwilling or e as defined in theasdefinedin Publication by the EDCbysystem the or is ensures that the data set(s) set(s) dataisthe ensures that andAmgenstaff, appropriate

- the CEC and, uponCECand,the required therapies) required therapies) investigato

publicallyavailable will solicit input and and input willsolicit EDC rs rs Page 61 of Page

and to to and study. study. by by as as . The The .

an 73

Approved

• not guarantee authorship guarantee not 2014) Scholarly Work in Medicalin Journals Scholarly Work the of basis the on willany publications bedetermined ofresultingstudy this from Authorship publication. Charter 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol • • • • associated withstudy associated inconveniencesnot other for subjects becompensated may guidelines, regulatory document. a separate availableas is that InformedConsentthe of inInjurydescribedCompensationsection the for are study in arises illness the that injuryor subjects compensationtofor for Anyarrangements 12.7 Amgen’spublications. of, reviewtiming and of study on this based book chapters) oral/slideabstracts, presentations, manuscripts, (eg, Allpublications Agreement among the institution, among the Agreement

work are appropriatelyinvestigated are work anytheofintegrityofaccuracy part or the ensuringto in related that questions work of bethe aspects allagreement for to (4) accountable be published; and to version article or revising it critically for important revisingit criticallyor for article data; (2) theofdrafting data,analysisorofand interpretation acquisition design, credit Authorship 1, When a large, multicenteralarge, When should individuals manuscript. theThese direct responsibility individualswhofor accept the group, alone, doesnotauthorship. justify alone, group, research the of data,supervisionor ofcollectiongeneral of funding, Acquisition responsibility for appropriate portions of the content.of portions the appropriate for responsibility author Each qualify qualify should asdesignatedauthors Allpersons

, which, states: 2, 3, 3, 2, 23 Recommendations for the Conduct, Reporting, Editing, and Publication ofand PublicationEditing, Conduct,RecommendationsReporting, the for . Membership on the committee (both for on committee Membership(both thefor .

Oct should fully meet the criteria for authorshipdefinedabove. criteria the for meet fully and

ober 2015 ober Compensation

4. should be listed.be

must be submitted to Amgen for review. The ClinicalAmgenreview. for The mustbe submitted to should -

related injuries (eg, travelcosts). injuries (eg, related

have participated sufficiently in the work to take public take toworkthe in sufficiently haveparticipated . T

he be based on (1) substantial contributions to conception and conceptionto on (1) substantialbased contributions be

group has conducted the work, the group hasconducted work, group the group

criteriadescribed below , and Amgen will detail the procedures for, andthe Amgenwill detail , investigator

( International Committee of MedicalEditors of Committee Journal International

If permitted under applicable regional lawspermittedapplicableregional and under If

and resolved. Authors and resolved.

intellectual content; (3) final approval the (3) final of intellectualcontent; qualify for authorship, and all those whoandthoseauthorship,all qualify for

i nvestigators nvestigators

to are

be met for ev for met be should anddoesAmgen staff) meet conditions meet should Trial Trial ery ery Page 62 of Page

identify 73 ,

Approved

p Cannomal.Cardiac DS,etHall Moss AJ, WJ, approach for sy for approach al. et KA, Elias JJ, Hartman FI, Malik 2011;378(9792):713 heart failure. chronic MedicalJR.for and HTeerlink therapy Krum Medicalin Scholarly andJournals Publication of Editing, Work Reporting, International Committee International Cardiol and apotosis. angiogenesis, hypertrophy, inflammation, on cardiac Focus Hilfiker EVEREST Outcome Trial. Trial. Outcome EVEREST the worsening heart failure: hospitalized patients oralofinfor tolvaptan Effects al.Swedberget Maggioni L,A, J,K, Grinfeld M,Burnett M,Gheorghiade Konstam 2014. a Census.AvailablePopulation 2005. Affairs. Internal Bureau of MinistryStatistics Japan http://www.icmje.org/ July 2009:73(11):2084 Heart J Heart directions. and inotropes:futureagents current Cardiac JR. G, Teerlink Hasenfuss Cardiac Registry of Heart Failure in(JCAREFailure Cardiology Heart of Registry Cardiac a reportJapanese the from Japan: inheart failure patientshospitalized in for outcomes onatriallongof - fibrillation Effects al. etKinugawaS, Yokoshiki S, H, Hamaguchi Gu in: in: Clin Chem Clin Scorecard.Keep to a Assays: NewIt’s Time A Cardiac Season FS. AppleTroponin for edition). current theto most Brochure refer (always Investigator's MecarbilOmecamtiv Amgen. placebo- double- a in heart failure: systolicon mecarbil, function cardiac omecamtiv activator, ofmyosin cardiac the effects al.et JR,R, The Senior ClelandTeerlink JG, heart failure: the ASTRONAUTrandomized JAMA thetrial. heart failure: hospitalized readmissionspatients amongfor and heart failure mortality postdischarge on aliskiren al.Effect etof FonarowS, Lewis M, Böhm E, G, M, Greene Gheorghiade OPTIME the heart decompensatedresults from in failure: milrinone toand response etiology MS,al.etCuffe Leimberger AB, JD, Chandler Benza RL, GM,Felker JAMA a trial. randomized heartcontrolled chronic exacerbationof acute failure: milrinone for Cuffe MS, Califf MR, Adams KF, Benza R, Bourge R, et al.Shortet BenzaKF, R,BourgeMS, MR,Califf Adams Cuffe 13. 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol revention of of revention t:shttp://www.stat.go.jp/english/data/kokusei/2005/poj/mokuji.htm. Accessed August 14,August Accessed t:shttp://www.stat.go.jp/english/data/kokusei/2005/poj/mokuji.htm. idance for Industry Drug - Industry idance for JAMA

2009.

541 2002;287(12):1 . 23 - . 2006;48(9) Suppl2006;48(9)- A:A56 . - 2011;32:1838 . Kleiner D, Landmesser U, Drexler H. Molecular mechanisms in heart mechanismsin H.Molecular U,DrexlerLandmesserfailure. Kleiner D,

- - dose crossover, controlled, . 2013;309(14)1461. . Oct CHF study. study. CHF . .

http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 2009;55(7):1303- ober 2015 ober h REFERENCES eart

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21. . 2003;41(6):997 . J Cardiol Am Coll

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. 2009;361:1329 - . . 2011;331:1439 .

-r esynchronization Recommendations for the Conduct,Recommendations for the 31. . 2013;309(11):1125 - . - - 1003. CARD). CARD).

1338. eting Clinical Evaluation, Evaluation, Clinical eting Lancet - 1443.

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Approved

first systolic f Dose al. et KG, CP, Saikali Clarke JR, Teerlink Tohoku District District Tohoku in the registry al.Analysisheart failure etchronicof Shinozaki J, T, N, Shiba Watanabe dogsheart consciouswithfailure. insystolic activator bya cardiacMyosin cardiacof al. function et Improvement MalikFI, Zhao X, YT, Shen 2055.year the Japanto inheart of projection failure future epidemic: al.ImpendingM, etMitsuma K,Ito RamadanY, Y,M,Tanaka Ohno Okura W, 2003;61: 709- 2003;61: epidemiologyheartKitabatakeof H, failure The A. Okamoto 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol (JCARE inFailure General Heart of CardiacRegistry and hospitals: Japanese practices in with heart failure general patients andofoutcomes Characteristics Investigators. H, Tsuchihashi Tsutsui Myocardialof Infarction. Definition ConsensusDocumenton al.Universal et theExpert JaffeAS, JS, Alpert K, Thygesen activators. activators. cardiac improve performance: myosinnovelcardiac Aapproach to JR. Teerlink - in

- 23 man study. man -

unction with the selective cardiac myosin activator, omecamtiv mecarbil: aomecamtiv mecarbil: with activator, themyosin cardiac selectiveunction GENERAL). GENERAL). Oct Heart Fail Rev. Fail Heart ober 2015 ober 714.

– third yea follow third r

Lancet Circ J Circ

- Makaya M, Kinugawa S, et al. for the al.JCAREthe for M,Kinugawaet S, Makaya . 2011;378:667 .

. 2007;71:449 .

- 2009;14:289 - up. up. Circ Circ J Circ ulation

298. - - 454. 675. . 2004;68:427 .

2012; 126:002012;-

- dependent augmentationcardiac of dependent . 2010;3:522 . Fail Heart Circ. - 434. Circ J Circ 00. inJapan.

. 2008;72:489. –491. - GENERAL GENERAL Nippon Rinsho. Page 64 of Page Practice Practice - 527.

Approved

14. 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct ober 2015 ober APPENDICES

Page 65 of Page 73

Approved

Adverse Events ( Events Adverse and TBL and TBL Potential usedwill scale event be the adversegrading The Scale AdverseEventGrading 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Sections asinspecified DILI potential due to conditionally) permanently or (either withheld protocol orproduct(s)whominvestigational in Allsubjects AssessmentsClinical and Observation Additional • following: the concurrentofASTcases of signals DILI, appropriate monitoring for To facilitate Reporting Date: 20120227 Number: Protocol • events if they meet the criteria for a serious adverse a serious criteria for meet the if they events to DILI are eventshepatotoxicity of andpotential Other http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm link: following the at • include: are that Assessments levels.baseline subject’s normaltheto or to abnormalities return ofuntil observation”a “closeperiod undergo • stabilize or the investigational product(s) or protocolorinvestigational product(s) the stabilizeor abnormalities theif mayteststhe decrease of above laboratory frequency Testing discontinued AND the subject is asymptomaticis subjectANDthe discontinued

facilitate the evaluationof treatment the facilitate eventThe The appropriate appropriate The havebeen concluded) investigations additionaletiologic eventbefore (ie, notification the of discoveryor and sent to the Amgen.theto sent and Repeat AST, ALT, ALP, AST,ALP, ALT, Repeat In cases of TBL > 2 > TBL of cases In and INR is to be performed every 24 hours until laboratoryimprove until abnormalities every isbe performed24hours to INR and

Oct and/or 6.3.1

Drug ober 2015 ober

is to is Appendix and

induced Liver Injury Reporting & Additional AssessmentsAdditional Injury Liver Reporting &induced INR CTCAE

be reported to Amgen as a serious adverse event withinevent 24 aadversehours serious Amgenas beto reported 6.3.2

eCRFEvent (eg, elevation according to the criteria specifiedin criteria theto elevationaccording

) ) or who experience AST or ALT elevationsALTwho AST> experience or or INR or ULN A

version 4.0.version .

bilirubin

Additional Safety AssessmentAdditionalSafetyInformation

(total and direct), and INR withinand24 hours INR and direct), (total testing of liver tests, BIL (total and(total BILdirect), liver tests, testing of re 1.5, > e

CRF) that captures information necessaryinformation CRF) that captures As of the protocol date, the CTCAEdate, available protocol Asthethe is of - emergent liver abnormalities abnormalities emergent liver

. to Common Terminology Criteria for Common Criteria Terminology

be performed during this period performedperiod duringthisbe - required therapies has/have been therapies required event definedin event

be reported as adversebeas seriousreported - required therapies is/are is/are required therapies Section 3 x Section is is to ULN ULN

be completed completed be

6.3

Page 66 of Page 9.2.2 to are require require

or to to

ALT ALT .

of of 73

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• • 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol • • medications and laboratory results must be captured in correspondingin and mustbe captured laboratory results medications ashistory, concomitant such medical information additionalevent and DILI potential The

− already been collected been collected already has this not analysis bloodpharmacokineticif appropriate sampling for Obtain − − − − − − TBL: ALTorAST and/or elevated elevated alternativeof investigationfor causes Initiate Obtain hepatology( consult Obtain hepatologist) product(s) and product(s) continue for a4 week minimum of for continue period” observation “close normal. The baseline or to return abnormalities laboratoryall until INR) (ALT, tests and AST, laboratoryTBL, subjectthe Followthe

23 o o o o Obtain a more detailed hista detailed more Obtain Smooth Muscle Antibody, and Liver Kidney Microsomal antibodyandMicrosomalKidneyLiver 1 ( Muscle Smooth Antibody, Perform appropriate liver imaging ifclinicallyindicated liverimaging appropriate Perform peripheral blood smear blood peripheral Obtain Obtain Obtain viralserologies Obtain o Obtain serum acetaminophen (paracetamol) levelsacetaminophen(paracetamol) serum Obtain IgG, immunoglobulin serum total Obtain eosinophilassess for withto differentialcount blood (CBC) complete Obtain assess for autoimmune for hepatitis assess

Oct Prior and/or concurrent diseases or illnessdiseasesorand/or concurrent Prior Prior and/or concurrent use of alcohol, recreational drugs and special dietsandspecial alcohol, userecreationaldrugs ofand/or concurrent Prior hypersensitivity pain, upper quadrant including right applicable) (if Symptoms environmentalchemicalagentsindustrial and/or to Exposure herbal and dietary supplements), plants, and plants, mushrooms supplements), and dietary herbal non medications useof(including Concomitant ober 2015 ober creatine phosphokinase creatine

protocol

- - type reactions, fatigue, nausea,andvomiting fever reactions, typefatigue,

required therapies. required

liver liver ory of: biopsy s after after s , haptogl ,

may be considered in consultation with an consultation with in be considered may

discontinuationof

obin Anti - lactate dehydrogenase, anddehydrogenase, lactate nuclear antibodynuclear (

prescription medicines prescription

all all investigational

e ANA CRFs.

LKM1 ) Page 67 of Page , Anti

is to is ) ) and to to

Approved

Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct ober 2015 ober Appendix

Sample eSAEForm Report Sample Contingency B .

Sample Serious AdverseSampleSerious Event

Report Form Report

Page 68 of Page 73

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct ober 2015 ober

Page 69 of Page 73

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct ober 2015 ober

Page 70 of Page 73

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct Appendix ober 2015 ober

. Pregnancy and Lactation NotificationWorksheets Pregnancy . and Lactation

Page 71 of Page

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol

Oct ober 2015 ober

Page 72 of Page 73

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Product: Omecamtiv Mecarbil (AMG 423) (AMG Mecarbil Omecamtiv Product: CONFIDENTIAL Date: 20120227 Number: Protocol wort John’s St. Rifampicin Rifabutin Phenytoin Phenobarbital Nevirapine Etravirine Efavirenz Dexamethasone Carbamazipine Inducers CYP3A4

Oct

ober 2015 ober

Appendix

D . Excluded Medications and Foods Excluded Medications .

Nelfinavir Voriconazole Verapamil Tel Saquinivir Ritonavir Delaviridine Itraconazole Indinavir juice Grapefruit Erythromycin Clarithromycin Cyclosporine Amprenavir Inhibitors CYP3A4 Cobicistat a previr

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