Conditions: Heart Failure Healthy Volunteer
Keywords: Heart Failure Cardiovascular Diseases Heart Diseases Ejection fraction Heart Failure with reduced ejection fraction Heart Failure with preserved ejection fraction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 182
Healthy volunteers: yes

Brief summary:
To evaluate the safety and tolerability of ascending single (Part A) and ascending multiple (Part B) doses of AMG 986 in healthy adults and of ascending multiple oral doses of AMG 986 in heart failure patients (Part C).

Detailed description:
This study is a randomized, placebo-controlled, double-blind, single day ascending dose (SDAD) study (Part A), a multiple daily ascending dose (MDAD) study (Part B), in healthy adults, and a MDAD study (Part C) in heart failure patients. In Parts A and B of the study, healthy volunteers will receive AMG 986 by continuous IV infusion or by oral administration in a fasted state. IV Infusions will be divided into an initial loading dose (LD) for the first hour followed immediately by a maintenance dose (MD).

In Part C of the study, patients with heart failure and either reduced (HFrEF) or preserved (HFpEF) ejection fraction will receive MDAD of AMG 986 or matching placebo once daily by oral administration for 21 days.

Arms:
arm 1: Healthy participants were administered placebo either intravenously (IV) or by mouth (PO) to match the 5 IV cohorts and 6 PO cohorts of AMG 986. arm 2: Healthy participants were administered a single dose of AMG 986 either IV or PO. The 5 IV cohorts started at a 0.5 mg loading dose over one hour up to to the Cohort 5 IV dosage consisting of a 60 mg loading dose over 1 hour and a 360 mg maintenance dose lasting 23 hours. The 6 PO cohorts started at a single 5 mg dose up to the Cohort 6 PO dose of 650 mg. arm 3: Healthy participants were administered placebo either IV for 4 consecutive days or PO for 7 days to match the 2 IV cohorts and 6 PO cohorts of AMG 986. arm 4: Healthy participants were administered AMG 986 either IV or PO. IV cohort 1 was administered a loading dose of 6 mg over one hour followed by maintenance doses of 36 mg lasting 23 hours on Day 1 and 38 mg lasting 24 hours on Days 2-4. IV cohort 2 was administered a loading dose of 60 mg over one hour followed by maintenance doses of 360 mg lasting 23 hours on Day 1 and 376 mg lasting 24 hours on Days 2-4. The 6 PO cohorts started at 5 mg for 7 days up to Cohort 6 PO dose of 650 mg for 7 days. arm 5: Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO placebo tablet daily from Days 1-21. arm 6: Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO placebo tablet daily from Days 1-21. arm 7: Participants with heart failure with reduced ejection fraction (HFrEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21. arm 8: Participants with heart failure with preserved ejection fraction (HFpEF) were administered a single PO AMG 986 tablet daily from Days 1-21 in ascending doses of 10 mg for Days 1-7, 30 mg for Days 8-14 and 100 mg for days 15-21.

Interventions: intervention 1: AMG 986 IV intervention 2: AMG 986 PO intervention 3: Placebo PO intervention 4: Placebo IV
Intervention descriptions: intervention 1: AMG 986 solution for infusion intervention 2: AMG 986 tablets for oral (PO) administration intervention 3: Matching placebo tablets for oral administration intervention 4: Matching placebo solution for infusion

Protocol document:
Prot_000.pdf: 
Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 1 of 114
CONFIDENTIAL
Title:  A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients
Amgen Protocol Number (AMG 986) 20150183
IND Number 129185
Eudra-CT 2017‐002940‐34
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Phone: +1 805-447-1000
Key Sponsor 
Contact(s):
, M.D. 
Executive Medical Director, Translational Medicine
Telephone: 
Email:
Clinical Research Study Manager
Telephone: 
Email: 
Date:
Amendment 1:
Amendment 2:
Amendment 3:
Amendment 4:
31 March 2016
08 July 2016
27 October 2016
06 December 2016
31 January 2017
Amendment 5:
15 May 2017
Amendment 6:
31 October 2017
Amendment 7:
14 Mar 2018
Amendment 8:
27 July 2018
Approved
NCT Number: NCT03276728
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 2 of 114
CONFIDENTIAL
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Amgen’s general 
number in the US (1-805-447-1000).
Approved


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 3 of 114
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled: A Phase I, Randomized, Double-Blind, 
Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects
and Heart Failure Patients dated 27 July 2018, and agree to abide by all provisions set 
forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by:

me (including, if applicable, my spouse [or legal partner] and dependent children)

my sub-investigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
Signature
Name of Investigator
Date (DD Month YYYY)
Approved


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 4 of 114
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending 
Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
AMG 986 in Healthy Subjects and Heart Failure Patients
Study Phase: 1
Indication:  Heart Failure
Primary Objective:  

To evaluate the safety and tolerability of ascending single (Part A) and ascending 
multiple (Part B) doses of AMG 986 in healthy subjects, who received AMG 986 by 
constant intravenous (IV) infusion or oral (PO) administration and of ascending multiple 
PO doses of AMG 986 in heart failure patients (Part C).
Secondary Objectives:  

To characterize AMG 986 pharmacokinetics (PK) after IV infusion and oral administration
in healthy subjects and heart failure patients.

To characterize the pharmacodynamic (PD) effects of AMG 986 in healthy subjects and 
in heart failure patients.
Exploratory Objectives:

To characterize AMG 986 excretion in urine.

To evaluate AMG 986 impact on heart failure prognostic markers in heart failure patients.

To evaluate AMG 986 impact on endothelial function markers including 
endothelin-1 (ET-1), angiotensin II (ANG II), and apelin. 

To characterize the effect of AMG 986 administration on free water clearance by the 
kidney into the urine after multiple doses of AMG 986.

To evaluate the impact of AMG 986 administration on glucose and lipid metabolism.

To explore the relationship between changes in QTc and AMG 986 exposure.
Hypotheses:  

AMG 986 will be safe and well tolerated in healthy subjects and in heart failure patients 
after single and multiple dosing by IV infusion and oral administration.
Primary Endpoint:  

Subject incidence of treatment-emergent adverse events.

Subject incidence of clinically significant changes in physical examinations, vital signs,
laboratory safety tests, and electrocardiograms (ECGs).
Secondary Endpoints:  

AMG 986 PK parameters including, but not limited to, maximum observed concentration 
(Cmax), the time of maximum observed concentration (tmax), area under the 
concentration-time curve (AUC), and oral bioavailability.

Changes over time from baseline in echocardiographic parameters of left ventricular 
systolic and diastolic functions (left ventricular ejection fraction, fraction shortening, stroke 
volume, wall thickening, end-systolic and end-diastolic volumes and indexes, septal and
lateral e’, E/A ratio, E/e’ ratio, E wave deceleration time, left atrial volume index) in both 
healthy subjects and heart failure patients, as well as changes in ventriculo-arterial 
coupling and global strain in heart failure patients only.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 5 of 114
CONFIDENTIAL
Exploratory Endpoints:

AMG 986 excretion in urine.

Characterization of potential metabolites of AMG 986 in plasma and urine (if appropriate).

Change from baseline in free water clearance in the urine after multiple daily doses of 
AMG 986 (Part B).

Change from baseline in fasting glucose and fasting lipid profiles after AMG 986 
administration.

Change from baseline of heart failure prognostic markers, eg, NT-pro-BNP, Troponin, 
Galectin-3, soluble ST-2, and GDF-15 (Part C)

Change from baseline of endothelial functional markers, eg, endothelin-1 and 
angiotensin II, apelin, ADMA and SDMA (Parts B and C)

Change from baseline for QTc and relationship to AMG 986 exposure.
Study Design:  This study is a randomized, placebo-controlled, double-blind, single day 
ascending dose (SDAD) study (Part A), a multiple daily ascending dose (MDAD) study (Part B), in 
healthy subjects, and a MDAD study (Part C) in heart failure patients. In Parts A and B of the 
study, healthy volunteers will receive AMG 986 by continuous IV infusion or by oral administration 
in a fasted state.  IV Infusions will be divided into an initial loading dose (LD) for the first hour 
followed immediately by a maintenance dose (MD).  In Part C of the study, patients with heart 
failure and either reduced (HFrEF) or preserved (HFpEF) ejection fraction will receive MDAD of 
IP by once daily oral administration for 21 days.
All available safety and laboratory data will be reviewed in an unblinded fashion by the members 
of the Dose Level Review Meeting (DLRM) prior to the first dose administration of IP at the higher 
dose level.  For study Part A, PK assessments will be part of each DLRM.  For study Parts B and 
C, vital signs, and all available PK and PD data will also be reviewed at the DLRM.  All cohorts in 
Part B will enroll sequentially after review of safety data at the previous dose level. Both cohorts 
in Part C (HFrEF cohort and HFpEF cohort) will enroll concurrently after completion of study 
Part B. 
Based on emerging safety and tolerability data and upon assessment by the Principal Investigator 
(PI), Medical Monitor and Global Safety Officer (DLRM members), cohorts may be removed or 
additional cohorts may be added.  Subject numbers within each cohort may also be increased or 
decreased based on the decision from the DLRM.  Doses to be administered within each cohort 
may be higher or lower than the last.  Dosing of any subject shall not exceed the highest planned 
IV and PO cohorts.  
Refer to the study schema at the end of the protocol synopsis for an overall summary of the study 
design.
Part A
Part A is a randomized, parallel group, double-blind, SDAD study consisting of 11 cohorts 
(5 IV infusion dose cohorts and 6 oral dose cohorts).  Within each cohort, a total of 8 subjects will 
be randomized to receive AMG 986 or placebo in a 3:1 ratio.
Starting doses of 0.5 mg by IV infusion lasting 1 hour and 5 mg given by oral administration are 
planned.  The sequence of escalation for IV dosing and PO dosing will partially overlap to achieve 
step-wise increases in AMG 986 exposure.  Dose escalations in Part A will initially be sequential, 
with AMG 986 dosing to begin at the starting IV dose of 0.5 mg infused over 1 hour, followed by 
escalation to IV Cohort 2 dosing at 3 mg infused over 1 hour.  After the safety and tolerability of 
AMG 986 in IV Cohort 2 are demonstrated and reviewed at a DLRM, escalation to IV Cohort 
3 (6 mg LD + 36 mg MD) and initiation of oral dosing at the proposed 5 mg starting dose will be 
permitted.  Subsequent IV and oral dose cohort escalations and DLRM reviews will occur as 
shown in the study schema.  
After the safety and tolerability of AMG 986 in IV Cohort 4 (20 mg LD + 120 mg MD) and PO 
Cohort 4 (200 mg) are demonstrated and reviewed at a DLRM, escalation to IV Cohort 5 (60 mg 
LD + 360 mg MD) and PO Cohort 5 (400 mg) will be permitted.  Enrollment for IV Cohorts will end 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 6 of 114
CONFIDENTIAL
after IV Cohort 5.  After the safety and tolerability of AMG 986 at 400 mg are demonstrated and 
reviewed at a DLRM, escalation to PO Cohort 6 (650 mg) will be permitted.  
A DLRM will be held once safety data through at least 4 days post dose become available for all 
subjects in a treatment cohort.  Escalation to a higher dose within a cohort, between cohorts, and 
enrollment of Part B, will proceed only when the previous doses have been found to be tolerated
and, in the case of initiation of Part B, after drug exposures from the preceding single dose 
cohorts have been evaluated.  
Part B
Part B is a randomized, parallel group, double-blind, MDAD study consisting of 8 cohorts 
(2 IV infusion dose cohorts and 6 oral dose cohorts).  Within each cohort, a total of 8 subjects will 
be randomized to receive AMG 986 or placebo in a 3:1 ratio.  Prior to the transition from Part A to 
Part B, verification of PK model assumptions is planned as AMG 986 human PK data become 
available from individual IV and oral single dose cohort escalations in Part A.
In the IV cohorts, AMG 986 will be dosed as a series of IV infusions, each with duration of 
24 hours, for 4 consecutive days.  On study Day 1, IV infusions will be divided into an initial 
loading dose infusion for 1 hour followed immediately by a maintenance dose with duration for 
23 hours.  On study days 2 to 4, maintenance doses will be administered as constant infusions 
with duration for 24 hours.  The transition from SDAD in Part A to MDAD in Part B is planned to 
occur after confirmation of AMG 986 safety and tolerability in IV Cohort 4 (20 mg LD + 120 mg 
MD) of Part A.  The starting IV dose in Part B at 6 mg (LD) + 38 mg/24 hour (MD; 1.57 mg/h,
36 mg/ 23 h on Day 1 and 38 mg/ 24 h on Days 2-4) infused over 4 days will have been 
previously evaluated over 24 hours in IV Cohort 3 (6 mg LD + 36 mg MD) of Part A.
In the PO cohorts, AMG 986 will be dosed once daily for 7 consecutive days.  Parts A and B will 
partially overlap for the oral dose cohorts.  Transition to the first PO cohort of Part B (5 mg QD) is 
planned to occur upon a DLRM decision to proceed after the 30 mg PO single dose cohort in Part 
A has been made.  Subsequent oral dose escalations to 200 mg QD will occur in Part B as shown 
in the study schema.  Escalation to 400 mg QD in Part B will be allowed after the safety and 
tolerability of AMG 986 at 400 and 650 mg in Part A (PO cohorts 5 and 6, respectively) are
demonstrated and reviewed at each DLRM.  Subsequent oral dose escalations to 400 mg and 
650 mg QD will occur in Part B as shown in the study schema.  
The safety and tolerability of each dose level (including the last dose cohort) in Part B will be
assessed at the DLRM once safety data through at least 4 days post dose become available for 
all subjects in a treatment cohort. Escalation to a higher dose within a cohort, between cohorts, 
and enrollment of Part B, will proceed only when the previous doses have been found to be 
tolerated.
The impact of AMG 986 on PD measures of cardiovascular function in study subjects will be 
determined using echocardiography and evaluated at each DLRM as data become available. 
Sample Size:

Part A IV Dose Cohorts: 40 subjects (8 subjects per cohort)

Part A Oral Dose Cohorts: 48 subjects (8 subjects per cohort)

Part B IV Dose Cohorts: 16 subjects (8 subjects per cohort)

Part B Oral Dose Cohorts: 48 subjects (8 subjects per cohort)
The above sample sizes, for both Parts A and B, are based on practical considerations and are 
consistent with the number of subjects enrolled in similar studies.
Part C
A total of up to 40 subjects, 20 with HFrEF and 20 with HFpEF, will be randomized to receive 
AMG 986 or placebo in a 3:1 ratio (15 treated and 5 placebo).  Subjects will receive once daily 
oral administration of IP at 10 mg for the first 7 days, 30 mg for the next 7 days and 100 mg for 
the last 7 days.  
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 7 of 114
CONFIDENTIAL
Summary of Subject Eligibility Criteria:  
For Parts A and B: Healthy male and female subjects age 18 to 55 years (inclusive) with body 
mass index between 18 and 35 kg/m2 (inclusive). 
For Part C:

Criteria for HFrEF- Patients between the ages of 18 and 85 years with stable NYHA class 
II or III chronic HF in sinus rhythm on optimal therapy and a left ventricular ejection 
fraction of ≤40% and NT-proBNP level of > 250 pg/mL. 

Criteria for HFpEF- Patients between the ages of 18 and 85 years with stable NYHA 
class II or III chronic HF, in sinus rhythm on optimal standard of care therapy with a left 
ventricular ejection fraction of > 50% and NT-proBNP level of > 250 pg/mL.
For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2.
Investigational Product
Investigational product for IV infusion will be prepared by an unblinded pharmacist in normal 
saline bags for loading and maintenance doses (as per instructions provided in the Investigational 
Product Instruction Manual - IPIM). Investigational product for oral administration will be 
prepared as tablets in strengths of 5 mg and 25 mg.  The oral doses proposed for this study 
range from 5 mg to 650 mg and the total cumulative daily intravenous doses proposed range from 
0.5 mg to 420 mg. 
In Part A, subjects will receive AMG 986 or placebo by either IV infusion lasting up to 24 hours or 
as a single oral dose.  The planned IV dose cohorts include IV infusions of 0.5 mg over 1 hour, 
3 mg over 1 hour, 6 mg over 1 hour immediately followed by 36 mg over 23 hours, 20 mg over 
1 hour immediately followed by 120 mg over 23 hours and 60 mg over 1 hour immediately 
followed by 360 mg over 23 hours.  The planned single oral doses are 5, 30, 100, 200, 400, and
650 mg.
In Part B, subjects will receive AMG 986 or placebo by either IV infusion lasting for 4 days 
(96 hours, equivalent to 4 repeat 24-hour infusions) or once daily (QD) oral dose administrations 
for 7 consecutive days.  The planned IV dose cohorts include IV infusions of 6 mg over 1 hour 
immediately followed by 38 mg per day over 4 days (36 mg/ 23 h on Day 1 and 38 mg/ 24 h on 
Days 2-4) and 60 mg over 1 hour immediately followed by 376 mg per day over 4 days
(360 mg/23 h on Day 1 and 376 mg/ 24 h on Days 2-4).  Subjects in the IV cohorts will remain in 
residency at the study site during 4 days of IV infusion administration plus one day of follow up.  
The planned oral doses are 5, 30, 100, 200, 400, and 650 mg QD for 7 days.  Oral dosing will be 
initiated in the morning at approximately the same time each day.  Subjects in the oral cohorts will 
remain in residency at the study site during 7 days of oral administration plus one day of follow 
up. 
In Part C, subjects will receive AMG 986 or placebo by oral IP for 21 days starting at 10 mg daily 
for the first 7 days, followed by 30 mg daily for the next seven days, and ending with 100 mg daily 
for the last 7 days. There are two planned cohorts defined by their heart failure diagnosis of 
HFrEF and HFpEF, and both cohorts will receive the same dose of IP. 
For Parts A, B and C, AMG 986 dose adjustments (if any) will be made on a treatment cohort and 
not on an individual basis, and will be agreed upon by Amgen in coordination with the 
investigators.  IV dosing regimen may be modified based on emergent PK or safety data.
Control Group: For Parts A, B and C, the control group will be subjects who receive placebo.
Procedures:  After informed consent is obtained, all screening procedures and tests establishing 
eligibility will be performed within 28 days prior to study product administration for the subjects. 
Subjects will be admitted to the research facility on Day -1 for further baseline/eligibility 
assessments. 
After completion of all pre-dose procedures on the day of dosing (Day 1), subjects will receive 
AMG 986 or Placebo.  Subjects will reside at the research facility according to the schedule of 
assessments for the assigned cohort after dosing and then be discharged and provided with 
instructions to return to the research facility according to the procedures provided in the Schedule 
of Assessment (Section 7.1).
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 8 of 114
CONFIDENTIAL
For a full list of study procedures, including the timing of each procedure, please refer to 
Schedule of Assessments (Section 7.1).
Statistical Considerations:  Data will be analyzed for each Part of the study and each route of 
administration separately.  Descriptive statistics by cohort will be provided for selected 
demographics, safety, PK, and PD data.  After review, data for subjects receiving placebo will be 
combined across all dose escalation cohorts for each Part and route of administration separately.  
Descriptive statistics on continuous measurements will include means, medians, 25th and 
75th percentiles, standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages.  PK, PD, and clinical lab data will be summarized at each 
time point when samples are collected. 
The number and percentage of subjects reporting any treatment-emergent adverse events will be 
tabulated by system organ class and preferred term, and will be further classified by relationship 
to treatment.  Serious adverse events and clinically significant changes in clinical laboratory test 
values, ECG, or vital signs will be noted.  Both exploratory graphical and model-based PK/PD 
analyses may be conducted with selected PD markers.  Modeling of single-dose PK data 
obtained in Part A may be used to guide selection of doses and dosing intervals in the 
multiple-dose segment (Parts B and C).  
The sample size for all Parts of the study is based on practical considerations and is consistent 
with the number of subjects enrolled in similar studies. Approximately 152 healthy subjects 
(8 subjects per cohort in 19 cohorts for Parts A and B) and up to 40 heart failure patients in Part C
are expected to be enrolled.  For safety considerations, with up to 144 subjects receiving 
AMG 986 (114 healthy and 30 patients), there is a 99.94% chance of detecting an adverse event 
with a true incidence rate of 5% or greater and a 99.99 % chance of detecting a more common 
adverse event with a true incidence rate of 10%. A rare event with a true incidence rate of 1% will 
have a chance of 76.48% to being detected with the current sample size.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:  Amgen, Inc
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 Jul 2018
Page 9 of 114
CONFIDENTIAL
Study Design and Treatment Schema
Part A: Single Day Ascending 
Dose (SDAD)
Cohort 2
IV (Part A) 
LD: 3 mg 
for 1 h 
infusion
[total 
infusion 
= 1 h]
Cohort 3
IV (Part A)
LD: 6 mg 
for 1 h 
infusion
MD: 36 mg 
for 23 h 
infusion
[total 
infusion 
= 24 h]
Cohort 1 
PO (Part A)
5 mg
Cohort 5
IV (Part A)
LD: 60 mg 
for 1 h 
infusion
MD: 360 
mg for 23 h 
infusion
[total 
infusion 
= 24 h]
Cohort 3 
PO (Part A)
100 mg
Cohort 2 
PO 
(Part A)
30 mg
Cohort 4 
PO (Part A)
200 mg
Cohort 1 
IV (Part A) 
LD: 0.5
mg for 1 h 
infusion
[total 
infusion 
= 1 h]
DLRM
DLRM
DLRM
Cohort 4 
IV (Part A)
LD: 20 mg 
for 1 h 
infusion
MD: 120 mg 
for 23 h 
infusion
[total 
infusion 
= 24 h]
DLRM
DLRM
Part B: Multiple Daily Ascending
Dose (MDAD) 
Cohort 1 
PO (Part B)
5 mg QD for 
7 days
Cohort 2 
PO (Part B)
30 mg QD 
for 7 days
Cohort 
3 PO 
(Part B)
100 mg 
QD for 7 
days
DLRM
Cohort 1 IV 
(Part B)
LD: 6 mg / 1 
h
MD: 36 mg / 
23h (Day 1)
MD: 38 mg /
24h (Days 2-
4) [total 
infusion = 96 
h]
Cohort 2 IV 
(Part B)
LD: 60 mg / 
1 h
MD: 360 mg 
/ 23h (Day 
1)
MD: 376 mg 
/ 24h (Days 
2-4) [total 
infusion = 
96 h]
Cohort 
4 PO 
(Part B)
200 mg 
QD for 7 
days
DLRM
DLRM
DLRM
DLRM
DLRM
DLRM
Cohort 5
PO (Part A)
400 mg
Cohort 6
PO (Part A)
650 mg
DLRM
Cohort 6 
PO (Part B)
650 mg QD 
for 7 days
Cohort 5 
PO (Part B)
400 mg QD 
for 7 days
DLRM
DLRM
DLRM
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 Jul 2018
Page 10 of 114
CONFIDENTIAL
Study Design and Treatment Schema
Part C
Abbreviations:  
DLRM = Dose Level Review Meeting                       LD = IV Loading Dose           
h = Hour                                                                    MD = IV Maintenance Dose
IV = Intravenous                                                       PO = Oral Dose
QD = Once Daily Dosing
Part C: HFrEF and HFpEF Cohorts
HFrEF (PO)
10 mg QD 
for 7 days
(Days 1-7)
HFpEF (PO)
10 mg QD 
for 7 days
(Days 1-7)
HFrEF (PO)
30 mg QD 
for 7 days
(Days 8-14)
HFpEF (PO)
30mg QD 
for 7 days
(Days 8-14)
DLRM
HFrEF (PO)
100 mg QD
for 7 days
(Days 15-21)
HFpEF (PO)
100 mg QD
for 7 days
(Days 15-21)
DLRM
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 11 of 114
CONFIDENTIAL
Study Glossary
Abbreviation or Term
Definition/Explanation
AE
ALT
Adverse Event
alanine aminotransferase
ALP
alkaline phosphatase
ANA
APJ
AST
Anti-nuclear antibody
apelin receptor
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24h
area under the concentration-time curve from time 0 to 24 hours
BMI
body mass index
BP
blood pressure
CL
Cmax
Clearance
maximum observed concentration
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug induced liver injury
DLRM
dose level review meeting
DLRT
dose level review team
dP/dtmax
ECG
Maximal rate of left ventricular systolic pressure increase
Electrocardiogram
CRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
end of study for individual 
subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
end of treatment
defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject
end of study (primary 
completion)
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint
end of study (end of trial)
defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts
Enrollment
FIH
When the investigator decides that the subject has met all eligibility 
criteria
first-in-human
GCP
good clinical practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 12 of 114
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
hERG
HepCAb
HFrEF
HFpEF
human Ether-à-go-go-Related Gene
hepatitis C antibody
heart failure with reduced ejection fraction
heart failure with preserved ejection fraction
HIV
human immunodeficiency virus
HR
heart rate
IC50
ICF
concentration at which 50% of the maximum inhibition is observed
informed consent form
ICH
International Conference on Harmonization
INR
international normalized ratio
IP
investigational product
IPIM
investigational product instruction manual
IKr
IUD
delayed rectifier potassium current
intrauterine device
IV
Intravenous
LD
Loading dose
MDAD
Multiple Daily Ascending Dose for the oral route and multiple 24 hour 
infusions that follow an initial loading dose on Day 1
MD
Maintenance dose
MDRD
NASH
NOAEL
Modification of Diet in Renal Disease
Nonalcoholic Fatty Liver Disease including Steatohepatitis
No observed adverse effect level
NOEL
No observed effect level
PD
Pharmacodynamics
PDE5
Phosphodiesterase 5
PK
Pharmacokinetics
PO
Oral dose
QD
Once daily dosing
Randomization
SAE
SAER
SDAD
Once eligibility into the study has been confirmed, the subject will be 
randomized on Day 1 to receive either AMG 986 or placebo
Serious Adverse Event
Serious Adverse Event Report Form
Single Day Ascending Dose for the oral route and single 24 hour 
infusion divided into an initial loading dose plus a maintenance dose 
for the intravenous route
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 13 of 114
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Abbreviation or Term
Definition/Explanation
Source Data
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). 
(ICH Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value.
study Day 1
defined as the first day that protocol specified investigational 
product/protocol-required therapies is/are administered to the 
subject
TBL
total bilirubin
Tmax
time of maximum concentration
ULN
Vss
upper limit of normal
steady-state volume of distribution
Approved 
 
 


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Protocol Number:  20150183
Date:  27 July 2018
Page 14 of 114
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TABLE OF CONTENTS
Protocol Synopsis............................................................................................................4
Study Design and Treatment Schema .............................................................................9
Study Glossary..............................................................................................................11
1.
OBJECTIVES .......................................................................................................20
1.1
Primary .....................................................................................................20
1.2
Secondary.................................................................................................20
1.3
Exploratory................................................................................................20
2.
BACKGROUND AND RATIONALE.......................................................................20
2.1
Disease.....................................................................................................20
2.2
Amgen Investigational Product Background..............................................21
2.2.1
Pharmacology ...........................................................................21
2.2.2
Pharmacokinetics......................................................................22
2.2.3
Toxicology.................................................................................23
2.3
Clinical Experience....................................................................................24
2.4
Risk/Benefit Assessment...........................................................................25
2.4.1
Risk Assessment.......................................................................25
2.4.2
Benefit Assessment...................................................................27
2.4.3
Overall Benefit/Risk Assessment...............................................27
2.5
Non-Amgen Medicinal Product Background..............................................28
2.6
Pediatric Risk Assessment........................................................................28
2.7
Rationale...................................................................................................28
2.8
Clinical Hypotheses...................................................................................34
3.
EXPERIMENTAL PLAN........................................................................................34
3.1
Study Design.............................................................................................34
3.2
Number of Sites ........................................................................................39
3.3
Number of Subjects...................................................................................39
3.4
Replacement of Subjects ..........................................................................39
3.5
Estimated Study Duration..........................................................................39
3.5.1
Study Duration for Subjects.......................................................39
3.5.2
End of Study..............................................................................40
4.
SUBJECT ELIGIBILITY ........................................................................................40
4.1
Inclusion Criteria .......................................................................................40
4.2
Exclusion Criteria ......................................................................................42
5.
SUBJECT ENROLLMENT....................................................................................44
5.1
Randomization/Treatment Assignment......................................................45
5.2
Site Personnel Access to Individual Treatment Assignments ....................46
6.
TREATMENT PROCEDURES..............................................................................46
Approved 
 
 


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Protocol Number:  20150183
Date:  27 July 2018
Page 15 of 114
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6.1
Classification of Product and/or Medical Device........................................46
6.2
Investigational Product..............................................................................46
6.2.1
Amgen Investigational Product AMG 986 and Placebo..............47
6.2.1.1
Dosage, Administration, and Schedule....................47
6.2.1.2
Dose-cohort Study Escalation and 
Stopping Rules........................................................49
6.2.1.3
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation........................................................49
6.2.2
Non-Amgen Investigational Product ..........................................57
6.3
Non-Investigational Product ......................................................................57
6.3.1
Non-Amgen Non-Investigational Product...................................57
6.4
Other Protocol-required Therapies ............................................................57
6.5
Hepatotoxicity Stopping and Rechallenge Rules .......................................57
6.5.1
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................57
6.5.2
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................58
6.5.3
Criteria for Re-challenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity.............................................................59
6.6
Concomitant Therapy................................................................................59
6.7
Alcohol and Tobacco Restrictions .............................................................59
6.8
Other Treatment Procedures.....................................................................60
6.9
Medical Devices........................................................................................60
6.10
Product Complaints...................................................................................60
6.11
Excluded Treatments, Medical Device use, and/or Procedures 
During Study Period..................................................................................60
7.
STUDY PROCEDURES .......................................................................................61
7.1
Schedule of Assessments.........................................................................61
7.2
General Study Procedures........................................................................76
7.2.1
Screening..................................................................................77
7.2.2
Baseline / Day -1.......................................................................77
7.2.3
Treatment..................................................................................78
7.2.4
Safety Follow-up Visit(s)/End of Study Visit ...............................78
7.2.5
Long-term Follow-up..................................................................78
7.2.6
Demographics ...........................................................................78
7.2.7
Medical History..........................................................................78
7.2.8
Physical Examination ................................................................79
7.2.9
Physical Measurements.............................................................79
7.2.10
Vital Signs .................................................................................79
Approved 
 
 


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Protocol Number:  20150183
Date:  27 July 2018
Page 16 of 114
CONFIDENTIAL
7.2.11
Serum Follicle-stimulating Hormone Test (Females 
Only) .........................................................................................80
7.2.12
Drug, Alcohol and Cotinine Screening .......................................80
7.2.13
Electrocardiogram .....................................................................80
7.2.14
Echocardiograms ......................................................................82
7.2.15
Clinical Chemistry......................................................................82
7.2.16
Hematology...............................................................................83
7.2.17
Urinalysis...................................................................................84
7.2.18
Estimated Glomerular Filtration Rate.........................................84
7.2.19
Hepatitis B Surface Antigen and Core Antibody, 
Hepatitis C Antibody and HIV Status.........................................84
7.2.20
Concomitant Medications and Adverse Event 
Reporting ..................................................................................84
7.3
Antibody Testing Procedures ....................................................................85
7.4
Biomarker Development............................................................................85
7.5
Pharmacogenetic Studies .........................................................................85
7.6
Optional Sub-studies.................................................................................85
7.7
Sample Storage and Destruction...............................................................85
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY..................87
8.1
Subjects’ Decision to Withdraw .................................................................87
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion......................................87
8.3
Reasons for Removal From Washout, Run-in, Invasive 
Procedures, Treatment, or Study ..............................................................88
8.3.1
Reasons for Removal From Treatment......................................88
8.3.2
Reasons for Removal from Study..............................................88
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................88
9.1
Definition of Safety Events ........................................................................88
9.1.1
Disease-related Events .............................................................88
9.1.2
Adverse Events .........................................................................88
9.1.3
Serious Adverse Events ............................................................89
9.2
Safety Event Reporting Procedures ..........................................................89
9.2.1
Reporting Procedures for Disease-related Events .....................89
9.2.2
Adverse Events .........................................................................90
9.2.2.1
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria............................90
9.2.2.2
Reporting Procedures for Serious Adverse 
Events.....................................................................91
9.2.2.3
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ...................91
9.2.2.4
Reporting a Safety Endpoint as a Study 
Endpoint..................................................................93
Approved 
 
 


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Protocol Number:  20150183
Date:  27 July 2018
Page 17 of 114
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9.2.2.5
Serious Adverse Events That are not to be 
Reported by the Sponsors to Regulatory 
Agencies in an Expedited Manner...........................93
9.3
Pregnancy and Lactation Reporting ..........................................................93
10.
STATISTICAL CONSIDERATIONS ......................................................................94
10.1
Study Endpoints, Analysis Sets, and Covariates .......................................94
10.1.1
Study Endpoints ........................................................................94
10.1.1.1
Primary Endpoints...................................................94
10.1.1.2
Secondary Endpoints ..............................................94
10.1.1.3
Exploratory Endpoints .............................................94
10.1.2
Analysis Sets.............................................................................95
10.1.2.1
Safety Analysis Set .................................................95
10.1.2.2
Pharmacokinetic (PK) Analysis Set .........................95
10.1.2.3
Pharmacodynamics (PD) Analysis Set ....................95
10.1.3
Covariates and Subgroups ........................................................95
10.2
Sample Size Considerations .....................................................................95
10.3
Access to Individual Subject Treatment Assignments by Amgen 
or Designees.............................................................................................96
10.4
Planned Analyses .....................................................................................96
10.4.1
Interim Analysis.........................................................................96
10.4.2
Data Monitoring Committee (DMC), Data Review 
Team (DRT) or Dose Level Review Team (DLRT) ....................96
10.4.3
Primary Analysis........................................................................97
10.4.4
Final Analysis ............................................................................97
10.5
Planned Methods of Analysis ....................................................................97
10.5.1
General Considerations.............................................................97
10.5.2
Primary Endpoints .....................................................................97
10.5.2.1
Safety Endpoints.....................................................97
10.5.3
Secondary Endpoints ................................................................98
10.5.3.1
Pharmacokinetics Analysis (PK)..............................98
10.5.3.2
Echocardiographic Measures..................................99
10.5.4
Exploratory Endpoints ...............................................................99
10.5.4.1
AMG 986 in Urine....................................................99
10.5.4.2
AMG 986 Metabolites..............................................99
10.5.4.3
Free-water Clearance in Urine ..............................100
10.5.4.4
Fasting Glucose and Fasting Lipid Levels .............100
10.5.4.5
AMG 986 Impact on Heart Failure 
Prognostics ...........................................................100
10.5.4.6
AMG 986 Impact on Endothelial Function .............100
10.5.4.7
AMG 986 Exposure vs. QT/QTc Changes.............100
11.
REGULATORY OBLIGATIONS..........................................................................100
11.1
Informed Consent....................................................................................100
Approved 
 
 


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Protocol Number:  20150183 
Date:  27 July 2018 
Page 18 of 114 
CONFIDENTIAL 
 
11.2 
Institutional Review Board/Independent Ethics Committee ...................... 101 
11.3 
Subject Confidentiality ............................................................................. 102 
11.4 
Investigator Signatory Obligations ........................................................... 102 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 103 
12.1 
Protocol Amendments and Study Termination ........................................ 103 
12.2 
Study Documentation and Archive .......................................................... 103 
12.3 
Study Monitoring and Data Collection ..................................................... 104 
12.4 
Investigator Responsibilities for Data Collection ...................................... 105 
12.5 
Language ................................................................................................ 105 
12.6 
Publication Policy .................................................................................... 105 
12.7 
Compensation ......................................................................................... 106 
13. 
REFERENCES ................................................................................................... 107 
14. 
APPENDICES .................................................................................................... 108 
List of Tables 
Table 1.  Predicted Human Exposures After AMG 986 IV Infusion Over 
one day and Ratios Relative to Exposures at NOEL IV Doses 
in 14-Day rat and dog Toxicology Studies ............................................... 30 
Table 2.  Predicted Human Exposures After AMG 986 Single Oral Dosing and 
Ratios Relative to Exposures at NO(A)EL Oral Doses in 
1-month rat and dog Toxicology Studies ................................................. 32 
Table 3.  Preliminary Observed AMG 986 PK Estimates in Healthy Subjects 
After Single Oral Dose Administration and Exposure Margins ................ 33 
Table 4.  Intravenous Infusion and Oral Dose Escalations for Part A ............................. 36 
Table 5.  Intravenous Infusion and Oral Dose Escalations for Part B ............................. 38 
Table 6.  Dose Regimen for HFrEF and HFpEF Patient Subjects in Part C ................... 38 
Table 7.  Cohort Investigational Product Dose Administration ....................................... 48 
Table 8.  Cohort Dose Stopping Rules........................................................................... 54 
Table 9.  Schedule of Assessments for Cohorts 1 & 2 IV Part A .................................... 62 
Table 10.  Schedule of Assessments for Cohorts 3 to 5 IV Part A ................................. 64 
Table 11.  Schedule of Assessments for Cohorts 1-6 PO Part A ................................... 66 
Table 12.  Schedule of Assessments for IV Cohorts Part B ........................................... 67 
Table 13.  Schedule of Assessments for PO Cohorts Part B ......................................... 69 
Table 14.  Schedule of Assessments for Patient Cohort Part C ..................................... 72 
Table 15.  Study Visit Windows ..................................................................................... 76 
Table 16.  List of Analytes ............................................................................................. 83 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 19 of 114
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List of Figures
Figure 1.  Part A Predicted Human AMG 986 Concentration-time Profiles 
After Single 24 Hour Intravenous Infusions of AMG 986 
Comprised of an Initial Loading Dose (IV Cohorts 1-5) and 
Immediately Followed by a Maintenance Dose (IV Cohorts 3-5).............30
Figure 2.  Part A Predicted Human AMG 986 Concentration-time Profiles by 
Treatment Group Following a Single Oral Dose of AMG 986..................31
List of Appendices
Appendix A.  Additional Safety Assessment Information..............................................109
Appendix B.  Sample Serious Adverse Event Report Form .........................................111
Appendix C.  Pregnancy and Lactation Notification Worksheets..................................113
Approved 
 
 


Product:  AMG 986
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Page 20 of 114
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1.
OBJECTIVES
1.1
Primary

To evaluate the safety and tolerability of ascending single (Part A) and ascending 
multiple (Part B) doses of AMG 986 in healthy subjects, who received AMG 986 
by constant intravenous (IV) infusion or oral (PO) administration, and of 
ascending multiple PO doses of AMG 986 in heart failure patients (Part C).
1.2
Secondary

To characterize AMG 986 pharmacokinetics (PK) after IV infusion and PO 
administration in healthy subjects and heart failure patients. 
To characterize the pharmacodynamic (PD) effects of AMG 986 in healthy 
subjects and in heart failure patients.  
1.3
Exploratory

To characterize AMG 986 excretion in urine.

To characterize potential metabolite(s) of AMG 986 in plasma and urine (if 
appropriate).

To evaluate AMG 986 impact on heart failure prognostic markers in heart failure 
patients.

To evaluate AMG 986 impact on endothelial function markers including 
endothelin-1 (ET-1), angiotensin II (ANG II), and apelin. 

To characterize the effect of AMG 986 administration on free water clearance by 
the kidney into the urine.

To evaluate the impact of AMG 986 administration on glucose and lipid 
metabolism.

To explore the relationship between changes in QTc and AMG 986 exposure.
2.
BACKGROUND AND RATIONALE
AMG 986 is a novel apelin receptor (APJ) small molecule agonist that binds and 
activates APJ receptor to improve cardiac function by increasing left ventricular 
contractile function and cardiac reserve without a significant impact on heart rate.  
AMG 986 is being developed as a potential treatment for heart failure. 
2.1
Disease
Heart failure (HF) refers to a clinical condition in which the cardiac output is insufficient 
to meet the metabolic needs of body organs and is marked by cardiac systolic and/or 
diastolic dysfunction.  Heart failure with predominantly systolic dysfunction, which is 
identifiable as decreased contraction, is more aptly described as heart failure with 
reduced ejection fraction (HFrEF).  Alternatively, heart failure with a predominantly
diastolic component, identifiable by decreased relaxation, is referred to as heart failure 
with preserved ejection fraction (HFpEF). Common to both types of heart failure is 
Approved 
 
 


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uncoupling of left ventricular and arterial interaction. In an attempt to preserve cardiac 
output, a series of compensatory changes occur over time, which include increased 
sympathetic tone and peripheral vasoconstriction, as well as activation of the 
renin-angiotensin-aldosterone system as key features.  
Heart failure is a common and debilitating disease, affecting almost 6 million Americans, 
or more than 2% of the United States population (McMurray and Pfeffer, 2005; 
Roger et al, 2012).  However, cumulative evidence from epidemiologic studies shows 
that there has been only modest improvement in the prognosis of HF over the past 
40 years despite numerous clinical advances (Khand et al, 2000).  With a 1-year rate of 
cardiovascular mortality or HF hospitalizations of 30% to 40% in patients recently 
hospitalized for HF, symptomatic HF is associated with a worse prognosis than the 
majority of cancers.  
Heart failure is a progressive disorder with a natural history punctuated by frequent 
recurrent hospitalizations and ultimately death.  Long-term goals of HF therapy are to 
implement chronic interventions that decrease death and hospital readmission 
(Jessup et al, 2009; McMurray et al, 2012), both of which occur frequently 
(Lloyd-Jones et al, 2010).  More recently, efforts have been made in developing 
therapies that improve cardiac reserve, symptoms of HF and functional capacity.  While 
several interventions have been shown to reduce the rate of HF hospitalizations and 
improve mortality, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin 
receptor blockers, beta-blockers, aldosterone antagonists, and biventricular pacing
(Krum and Teerlink, 2011), mortality and morbidity still remain high.  In addition, these
available treatments that are aimed at diverse targets often fail to control symptoms or 
restore quality of life.
AMG 986 was developed to explore the therapeutic potential associated with the 
APJ pathway. AMG 986 is a long-acting small-molecule agonist that binds to the APJ 
receptor and activates Gαi and beta-arrestin with sub-nM potency.
AMG 986 may have therapeutic potential for both HFrEF and HFpEF.
2.2
Amgen Investigational Product Background 
2.2.1
Pharmacology
Nonclinical Pharmacology
The cardiovascular effects of AMG 986 in vivo were studied in both rodent and canine 
models.  In the ZSF1 rat (a model reproducing diastolic heart failure), AMG 986 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 22 of 114
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increased cardiac contractile reserve, ejection fraction and stroke volume.  
Improvements in ventriculo-arterial coupling were also observed in ZSF1 rats. In a 
canine heart failure model (tachypacing), AMG 986 improved left ventricular contractile 
function without affecting heart rate.  These nonclinical findings support the hypothesis
that AMG 986 would be beneficial in addressing the underlying pathophysiology of heart 
failure in patients with either reduced or preserved ejection fraction.  Details of AMG 986 
nonclinical pharmacology are summarized in the AMG 986 Investigator’s Brochure.
2.2.2
Pharmacokinetics
Non-clinical Pharmacokinetics
AMG 986 PK after single IV or oral dose administration was characterized in male 
CD1 mice, male Sprague-Dawley rats, male beagle dogs, and male cynomolgus 
monkeys.  Following a single IV dose, the clearance (CL) of AMG 986 was low in mouse 
and dog and moderate in rat and monkey, relative to hepatic blood flow.  Estimates of 
apparent steady-state volume of distribution (Vss) were variable across species and 
mean estimates of elimination half-life (t1/2,z) ranged from 2.26 hours in mice to 
7.47 hours in monkeys.  Metabolism was the primary pathway of AMG 986 clearance in 
rats.  After single oral dosing in rats and dogs, AMG 986 was rapidly absorbed with peak 
concentrations achieved within 0.25 to 0.5 hours and oral bioavailability was 
approximately 73% in rats and 98% in dogs.
AMG 986 was highly bound to plasma protein and did not preferentially distribute into 
blood cells when assessed in vitro across species.  AMG 986 was 99.6% bound in 
human plasma.  The metabolism of AMG 986 in vitro was principally catalyzed by 
human CYP3A.  Oxidized metabolites of AMG 986 were formed across species with no 
unique human metabolites observed in liver microsome and hepatocyte incubations.  
AMG 986 was an inducer of CYP3A4 in vitro at clinically relevant AMG 986 
concentrations, as determined by increases in CYP3A4 mRNA levels in primary human 
hepatocytes.  AMG 986 was not an inhibitor in vitro of any of the major drug 
metabolizing human CYP enzymes.  AMG 986 was characterized in vitro as a substrate 
of P-glycoprotein (P-gp) and organic anion-transporting polypeptide 1B3 (OATP1B3) 
transporters.  Details of AMG 986 nonclinical pharmacokinetics are summarized in the 
AMG 986 Investigator’s Brochure.
Predictions of Human Pharmacokinetics
Human PK parameters were predicted using in vitro and in vivo nonclinical data.  
AMG 986 CL and Vss in humans were predicted to be 45.0 mL/h/kg and 463 mL/kg, 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
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Page 23 of 114
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respectively, with a projected half-life in plasma of approximately 12 hours.  
Bioavailability after oral dosing was predicted to be 85%.
A linear two-compartment PK model with first-order elimination was used to estimate
human exposures and simulate concentration-time profiles after AMG 986 administration 
by constant IV infusion.  The same PK model with first-order absorption was used to 
estimate human exposures and perform simulations at the oral doses planned for the 
study.
Human PK model predictions were used to support selections of IV and oral doses, as 
described in Section 2.7 of the protocol.    
2.2.3
Toxicology
Nonclinical Toxicology
The nonclinical toxicology package for AMG 986 included repeat dose toxicology studies 
with both oral (up to 6-months in duration in rats and 9-months in duration in dogs) and 
IV (14-day studies in rat and dog) dose routes and genetic toxicology, phototoxicity and 
safety pharmacology studies. 
Repeat Dose Toxicology Studies:
The no-observed-adverse effect-levels (NOAEL) in all of the repeat dose oral and 
IV toxicology studies in rat and dog were the highest doses evaluated. For the 28-day 
oral studies, the no-observed-effect-levels (NOEL) in rats was 1000 mg/kg/day (limit 
dose) and the NOAEL in dogs (based on clinical signs of emesis) was 300 mg/kg/day.  
Estimates of AUC24h exposures in rats at the NOEL dose and dogs at the NOAEL dose 
were 150-fold and 219-fold greater than observed human exposure at the 5 mg oral 
dose and 2.2-fold and 3.2-fold greater than the observed human exposure at 650 mg, 
respectively (Table 3).  The margins from the toxicology studies support administration 
of the oral dose up to 650 mg planned for the current study.
In developmental and reproductive toxicology studies in rats and rabbits, oral 
administration of AMG 986 resulted in embryo-fetal toxicity and malformations.  In rats, 
AMG 986-related fetal tail abnormalities and skeletal dysmorphogenesis were observed.  
In rabbits there were abortions, lower maternal body weights/ body weight gains
associated with decreases in embryo-fetal survival, and external, visceral and skeletal 
malformations.
AMG 986 was negative in both in vitro and in vivo genetic toxicology studies and in an in 
vitro phototoxicity assay.
Approved 
 
 


Product:  AMG 986
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Safety Pharmacology:
The NOEL for effects on neurobehavioral and respiratory function in rats was 
1000 mg/kg (single oral dose).  In an anesthetized beagle dog cardiovascular (CV) 
study, with IV dose administration in a cumulative dose escalation design, 
AMG 986-related CV effects were limited to small dose-independent increases (10%) in 
the rate of left ventricular pressure rise in early systole (dP/dtmax) and similar increases 
(10%) in mean blood pressure at plasma concentrations greater than 1.34 µg/mL.  In 
the conscious dog telemetry study, there were no AMG 986-related effects on 
hemodynamics (blood pressure and heart rate) or ECG parameters (PR, QRS, QT or 
heart rate-corrected QTc intervals [individual subject correction method]) after single oral 
doses up to 300 mg/kg (telemetry monitoring for at least 24 hours).  No effects on 
QT/QTc interval were observed in the anesthetized dog study or the conscious dog 
telemetry study.  Further, there were no changes in QTc interval in the 28-day oral dog 
toxicology (ECGs assessed in weeks 2 and 4) or in the 14-day IV dog toxicology study.
The IC50 value for inhibitory effect of AMG 986 on hERG current (IKr current; potassium 
channel in human ventricles primarily responsible for repolarization) was estimated to be 
300 µM (157 µg/mL, unbound concentration), approximately 1000X higher than the 
predicted human maximum unbound concentrations at an oral dose of 650 mg and 
approximately 5000X higher than the highest planned IV infusion dose (60 mg loading 
dose + 360 mg/24 hours maintenance dose).  
Details of AMG 986 nonclinical toxicology are summarized in the AMG 986 Investigator’s 
Brochure.
2.3
Clinical Experience
The AMG 986 clinical program thus far consists of 5 studies (4 ongoing, 1 completed).
In addition to ongoing Study 20150183, there are three phase 1, open-label, single-dose 
studies of AMG 986, including, Study 20150186 (renal impairment), Study 20150187 
(healthy Japanese subjects), and Study 20170553 (tablet vs capsule formulation).  
Enrollment and dosing have been completed for all 3 of these studies.  Study 20150185 
is a completed, phase 1, open-label study to evaluate the effect of food and concomitant 
itraconazole administration on the pharmacokinetics of AMG 986 in heathy subjects.  
Overall, up to the 01 June 2018 cutoff date, data from these 5 studies indicate that 
AMG 986 has an acceptable safety and tolerability profile at all doses tested in healthy 
subjects, in subjects with heart failure who have been evaluated thus far, in healthy 
Approved 
 
 


Product:  AMG 986
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Japanese subjects, and in subjects with renal impairment.  No serious or fatal adverse 
events have been reported, most reported adverse events in these studies were CTCAE 
grade 1, and no trends or specific safety concerns have been identified based on the 
types and frequency of adverse events that have occurred.
Refer to the AMG 986 Investigator’s Brochure for details on AMG 986 clinical 
experience.
2.4
Risk/Benefit Assessment
2.4.1
Risk Assessment
AMG 986 has an identified risk of embryo-fetal toxicity and malformations.  In 
developmental and reproductive toxicology studies in rats and rabbits, oral 
administration of AMG 986 resulted in abortions, embryo-fetal toxicity and external, 
visceral and skeletal malformations.  Women of childbearing potential are not eligible to 
participate in this study, and male subjects must agree to practice an acceptable method 
of effective birth control and not donate sperm while on study and through 11 weeks 
after receiving the last dose of AMG 986.  These inclusion/exclusion criteria will mitigate 
the risk of embryo-fetal toxicity. 
AMG 986 has a potential risk of causing changes in blood pressure. Studies have shown 
that the principal effect of the apelin/APJ system is to counterbalance the 
renin-angiotension-aldosterone system, and apelin affects vascular tone and blood 
pressure.  AMG 986-related cardiovascular changes in the nonclinical program were 
limited to modest and reversible decreases in mean blood pressure at the highest IV 
dose in the rat and small dose-independent increases in mean blood pressure in the 
anesthesized dog.  Subjects will be closely monitored for changes in cardiovascular 
parameters, such as blood pressure, heart rate, and ECG measurements, and for signs 
and symptoms suggesting adverse events.
The nonclinical (toxicology and safety pharmacology) package suggests a safe profile 
for the initiation of clinical trials with AMG 986.  Genetic toxicology and photosafety 
evaluations indicated that AMG 986 is not genotoxic or phototoxic.  No AMG 986-related 
toxicity was identified in the rat or dog toxicology studies that were conducted with oral 
(6- and 9-months duration in rats and dogs, respectively) or IV (14-day studies) dose 
administration.  The AUC-based exposure margins based on NO(A)EL doses from the 
rat and dog toxicology studies support the planned oral and IV infusion clinical dose 
ranges.  Additionally, no AMG 986-related effects in the safety pharmacology studies 
were identified, including data indicating that QTc interval prolongation risk is low.  
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 26 of 114
CONFIDENTIAL
As of 01 June 2018, safety and tolerability data on clinical exposure to AMG 986 from 
FIH study 20150183 were available and reviewed for 19 fully implemented cohorts of 8 
to 9 healthy subjects each.  The subjects reviewed included those who received single 
oral doses of AMG 986 up to 650 mg, oral doses of AMG 986 up to 650 mg for 
7 consecutive days, IV-infused doses of AMG 986 up to 24 hours (loading doses up to 
60 mg over 1 hour followed by maintenance doses up to 360 mg over 23 hours), 
IV-infused doses of AMG 986 over 4 days (loading dose up to 60 mg over 1 hour 
followed by maintenance doses up to 360 mg over 23 hours and subsequent 
maintenance doses up to 376 mg over 24 hours for 3 additional days), and placebo.  
There was a total of 116 subjects who received AMG 986 and 38 subjects who received 
placebo.  Of these 154 subjects, 151 completed the investigational product, and 
3 subjects withdrew after receiving investigational product due to subject request and not 
related to an adverse event.  
For these 154 subjects there were no serious adverse events and no adverse events 
with fatal outcome.  There were no adverse events from the cardiac disorders system 
organ class.  Twenty-three subjects (14.9%) were reported to have treatment emergent 
adverse events during double-blind treatment.  The most common event was headache, 
which occurred in 8 subjects (5.2%).  The event of headache was reported as a common 
terminology criteria for adverse events (CTCAE) severity grade 1 in 7 of the subjects, 
and CTCAE grade 2 in 1 subject.  The majority of the adverse events were CTCAE 
grade 1 events.  There were 7 CTCAE grade 2 events (the only grade 2 event that 
occurred in more than 1 subject was toothache), and no grade 3 events.  One CTCAE 
grade 4 event was reported; this event (blood creatine phosphokinase increased as high 
as 9927 U/L) occurred in a
-year-old
 subject in the 650 mg PO multiple dose 
cohort on study day 5, was nonserious, resulted in no action/change to the 
investigational product administration, was not associated with clinical symptoms (eg, 
myalgia) or worsening renal function tests, occurred concurrently with a CTCAE grade 2 
event of aspartate aminotransferase increased and a grade 1 event of alanine 
aminotransferase increased, did not require any treatment, and was reported as 
resolved on study day 29 (22 days after the last dose of investigational product).Overall, 
the prevalence of adverse events was comparable across all the cohorts and did not 
show higher incidence with increasing doses.  The adverse event terms represented a 
variety of system organ classes and did not suggest a trend or indicate a specific safety 
concern.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 27 of 114
CONFIDENTIAL
After each dose cohort completed and before any dose escalation, an aggregate 
evaluation of adverse events, vital signs, ECG and laboratory parameters was 
performed in unblinded DLRMs.  No clinically meaningful individual subject changes in 
vital signs (including blood pressure) were identified within or across any of the 
19 cohorts. There were no notable variations in vital signs with increasing doses of 
AMG 986 throughout the study.  Additionally, no trends in laboratory or ECG 
abnormalities (eg- QTc interval) were detected.
Additionally, data from 12 heart failure subjects enrolled in study 20150183 were 
available and reviewed.  Eight subjects received oral doses of AMG 986 for 21 days 
(consisting of consecutive doses of 10, 30, and 100 mg for 7 days each) and 4 subjects 
received placebo.  Four of the 12 subjects (33.3%) reported treatment-emergent adverse 
events during the double-blind treatment.  No serious or fatal adverse events were 
reported.  There was no discontinuation of investigational product due to an adverse 
event.  All the events were CTCAE grade 1 events.
Refer to the AMG 986 Investigator’s Brochure for further details on AMG 986 clinical 
experience.
In summary, the clinical experience accumulated with AMG 986 to date suggests that 
the administration of AMG 986 results in no safety concern up to the doses tested.
Taken together, the non-clinical data and clinical experience accumulated with AMG 986 
suggest that the administration of AMG 986 at the proposed scheme is safe. All doses 
tested thus far were generally well tolerated and an acceptable safety profile was 
observed.  Pregnant women should not take AMG 986.
2.4.2
Benefit Assessment
Patients enrolled in part C of the study will be treated with stable, optimal 
pharmacological therapy for a minimum of 4 weeks prior to randomization.  Patients will 
be randomized to receive AMG 986 or a matching placebo.  It is expected that patients 
participating in this study may derive benefits overall from the care and monitoring from
the experts in the field. Those patients receiving AMG 986 may benefit from the 
additional positive contribution of AMG 986 on their disease. 
2.4.3
Overall Benefit/Risk Assessment
The nonclinical (toxicology and safety pharmacology) package suggests a safe profile 
for the initiation of clinical trials with AMG 986.  The AUC-based exposure margins 
based on NO(A)EL doses from the rat and dog toxicology studies support the planned 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 28 of 114
CONFIDENTIAL
dose ranges.  To date, the clinical experience accumulated with AMG 986 provides 
evidence that the administration of AMG 986 has an acceptable safety profile in all
doses tested.
Considering the mechanism of action of AMG 986, the nonclinical safety profile, and the 
acceptable tolerability and safety of AMG 986 in humans thus far, together with the risk 
mitigation measures taken for the proposed study, the benefit/risk profile for AMG 986 in 
study 20150183 is positive.
2.5
Non-Amgen Medicinal Product Background
Not applicable for this study.
2.6
Pediatric Risk Assessment
Not applicable for this study.
2.7
Rationale
This study will evaluate the safety, tolerability, PK and PD of AMG 986 in healthy male 
and female subjects, and in heart failure patients with reduced (HFrEF) or preserved 
(HFpEF) ejection fraction, after AMG 986 dosing by IV or oral routes of administration.  
In all Parts of the study, healthy subjects and heart failure patients will receive 
investigational product in a fasted state.
IV infusion doses planned for the FIH study will be divided into an initial loading dose 
(LD) for the first hour followed immediately by a maintenance dose (MD) over the 
remainder of the dosing interval.  Total continuous infusion up to 24 hours is planned for 
Part A of the study and up to 96 hours is planned for Part B.  For Part C, heart failure 
patients will receive only oral IP once daily for up to 21 days. 
The proposed loading dose infusion is supported by the planned use of AMG 986 in 
acute clinical settings and its anticipated rapid onset of pharmacological response.  
Selection of a 1 hour loading dose infusion will allow rapid titration to therapeutic 
concentration levels.  Establishment of therapeutic concentrations early in the treatment
course would also take advantage of the rapid rate of pharmacological response 
anticipated for AMG 986.  Systemic apelin administration was shown within minutes to 
cause reductions in peripheral vascular resistance accompanied by increases in cardiac 
output in healthy subjects (Japp et al, 2010).
AMG 986 oral tablet administration is planned as a single dose in Part A of the study and 
as a once-daily (QD) dosing for 7 consecutive days in Part B and for 21 days in Part C.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 29 of 114
CONFIDENTIAL
Rationale for Dose Selection in Part A
Selection of the dose range for evaluation in healthy subject cohorts who receive 
AMG 986 by IV infusion or by single oral administration was based on model predictions 
of human exposure, target exposure associated with a 10% increase in ejection fraction 
in an ischemic heart failure dog model, and observed exposures in GLP toxicology 
studies.
IV Cohorts 1 to 5:
The IV dose regimen proposed for Part A of the study will start at 0.5 mg administered 
as a 1-hour infusion.  Escalation of IV doses will continue with 3 mg infused over 1 hour.  
The IV cohorts 1 and 2 will be comprised of a single 1 hour infusion without a 
maintenance dose.  Subsequent escalation of IV cohorts will continue with 6 mg over 
1 hour (LD) followed by infusion of 36 mg over 23 hours (MD; 1.57 mg/hour); with 20 mg 
over 1 hour (LD) followed by infusion of 120 mg over 23 hours (MD; 5.22 mg/hour); and 
60 mg over 1 hour (LD) followed by infusion of 360 mg over 23 hours (MD; 
15.7 mg/hour).  
A clinical starting IV dose of 0.5 mg infused over 1 hour is not expected to elicit 
pharmacological activity based on observations in normal healthy dogs (Study 118965).  
In healthy subjects an IV dose of 0.5 mg infused over 1 hour is predicted to achieve a 
maximum plasma concentration of 0.0501 g/mL (Table 1), approximately one-half the 
nonclinical target plasma concentration of 0.135 g/mL (0.258 M) associated with a 
10% increase in both ejection fraction and fractional shortening in the dog heart failure 
model.  Model predictions of human maximal exposures for the next IV cohort dose of 
3 mg infused over 1 hour is anticipated to approximate the target concentration 
associated with cardiovascular function improvement in the dog model (Figure 1).
Relative to human exposure predictions at the starting single IV dose, mean AUC24h
exposures achieved at IV NOEL doses in the 14 day toxicology studies in male rats 
(300 mg/kg/day) and in dogs (100 mg/kg/day; sexes combined) were approximately 
7090-fold and 4550-fold greater than human AUC24h exposure predicted at the 0.5 mg 
IV starting dose, respectively.  At the highest planned clinical IV dose, AUC24h and Cmax
exposures in male rats and in dogs at NOEL doses were approximately 11-fold and 
6.7-fold greater than human AUC24h exposure and 48-fold and 20-fold greater than 
human Cmax exposure predicted for infusions at 60 mg LD for 1 hour followed by 360 mg 
MD for 23 hours, respectively (Table 1).
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 30 of 114
CONFIDENTIAL
Figure 1.  Part A Predicted Human AMG 986 Concentration-time Profiles After 
Single 24 Hour Intravenous Infusions of AMG 986 Comprised of an Initial Loading 
Dose (IV Cohorts 1-5) and Immediately Followed by a Maintenance Dose 
(IV Cohorts 3-5)
Table 1.  Predicted Human Exposures After AMG 986 IV Infusion Over one day and 
Ratios Relative to Exposures at NOEL IV Doses in 14-Day rat and dog Toxicology 
Studies
Clinical IV Dose
1Predicted Human PK
2Exposure Ratios
LD
(mg/ 1 h)
MD
(mg/ 23 h)
Day 1 AUC24h
(µg*h/mL)
Day 1 Cmax
(µg/mL)
3Rat-Human 
Exposure Ratios
(5AUC24h; Cmax)
4Dog-Human 
Exposure Ratios
(5AUC24h; Cmax)
0.5
0
0.151
0.0501
7090; 5750
4550; 2440
3
0
0.908
0.300
1180; 960
757; 407
6
36
10.2
0.601
105; 479
67; 203
20
120
34.0
2.00
32; 144
20; 61
60
360
102
6.01
11; 48
6.7; 20
1 Human PK predictions using a linear 2-compartment model with clearance (45 mL/h/kg) and apparent 
steady-state volume of distribution (463 mL/kg) parameters.  Estimate of elimination half-life was 
approximately 12 hours.
2 Exposure ratios calculated as Rat (Dog) / Human
3 Mean of observed Cmax and AUC24h exposures at NOEL IV dose (300 mg/kg/day) on day 14 in male rats 
were 288 ug/mL and 1070 ug.h/mL, respectively.  (Study: 120832)
4 Mean of observed Cmax and AUC24h exposures at NOEL IV dose (100 mg/kg/day) on day 14 in dogs (sexes 
combined) were 122 ug/mL and 687 ug.h/mL, respectively.  (Study: 120833)
5 AUC exposure ratio calculated as rat (dog) day 14 AUC24h / human day 1 AUC24h
Abbreviations: Area under concentration-time curve from time 0 to 24 h after dosing, AUC24h; maximum 
concentration, Cmax; intravenous, IV; loading dose LD; maintenance dose, MD; no observed effect level, 
NOEL
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 31 of 114
CONFIDENTIAL
Oral Cohorts 1 to 4:
The proposed single oral dose regimen for Part A will be 5, 30, 100 and 200 mg.  
Relative to human exposure predictions at the starting single oral dose, mean AUC24h
exposures achieved at an oral NOEL dose in male rats (1000 mg/kg/day) and NOAEL 
dose in dogs (300 mg/kg/day; sexes combined) in the 28-day toxicology studies were 
approximately 297-fold and 434-fold greater than human AUC24h exposure predicted at 
the 5 mg oral starting dose, respectively.  At the highest planned single oral dose in the 
clinic, AUC24h and Cmax exposures in male rats at a NOEL dose and in dogs at a NOAEL 
dose were approximately 7.4-fold and 11-fold greater than human AUC24h exposure and 
20-fold and 14-fold greater than human Cmax exposure predicted at 200 mg single oral 
administration, respectively (Table 2).  Model predictions of human maximal exposures
at the starting dose of 5 mg are anticipated to approximate the target concentration 
associated with cardiovascular function improvement in the dog model (Figure 2).
Figure 2.  Part A Predicted Human AMG 986 Concentration-time Profiles by 
Treatment Group Following a Single Oral Dose of AMG 986
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 32 of 114
CONFIDENTIAL
Table 2.  Predicted Human Exposures After AMG 986 Single Oral Dosing and 
Ratios Relative to Exposures at NO(A)EL Oral Doses in 1-month rat and dog 
Toxicology Studies
Clinical Dose
1Predicted Human PK
2Exposure Ratios
Oral Dose
(mg)
Day 1 AUC24h
(µg*h/mL)
Day 1 Cmax
(µg/mL)
3Rat-Human 
Exposure Ratios
(5AUC24h; Cmax)
4Dog-Human 
Exposure Ratios
(5AUC24h; Cmax)
5
1.24
0.180
297; 783
434; 543
30
7.42
1.08
50; 131
73; 91
100
24.7
3.61
15; 39
22; 27
200
49.5
7.21
7.4; 20
11; 14
1 Human PK predictions using a linear 2-compartment model with clearance (45 mL/h/kg), apparent 
steady-state volume of distribution (463 mL/kg) and oral bioavailability (85%) parameters.
2 Exposure ratios calculated as Rat (Dog) / Human
3 Mean of observed Cmax and AUC24h exposures at NOEL PO dose (1000 mg/kg/day) on day 28 in male rats 
were 141 ug/mL and 368 ug.h/mL, respectively.  (Study: 118964)
4 Mean of observed Cmax and AUC24h exposures at NOAEL PO dose (300 mg/kg/day) on day 28 in dogs 
(sexes combined) were 97.7 ug/mL and 538 ug.h/mL, respectively.  (Study: 118965)
5 AUC exposure ratio calculated as rat (dog) day 28 AUC24h / human day 1 AUC24h
Abbreviations: Area under concentration-time curve from time 0 to 24h after dosing, AUC24h; maximum 
concentration, Cmax; loading dose LD; maintenance dose, MD; no observed (adverse) effect level 
NO(A)EL; oral, PO
Oral Cohorts 5 and 6:
After confirmation of safety and tolerability of oral AMG 986 at doses that range from 5 to 
200 mg in Parts A and B, further escalations in dose are planned.  The proposed single 
oral dose regimen extended for Part A will be 400 and 650 mg.  Selection of the 
extended range of oral doses was based on the following: (1) acceptable safety and 
tolerability of oral does up to 200 mg, (2) observed AMG 986 PK results and (3) 
exposure margins projected for AUC exposures up to 650 mg relative to exposures 
observed at NOEL and NOAEL doses in GLP toxicology studies.  Although dose 
proportionality was not formally evaluated in the FIH study, increases in AUC and Cmax
exposures appeared to be linear and proportional to dose over the 5 to 200 mg oral dose 
range tested.  Assuming dose proportional increases in AMG 986 exposure at 650 mg, 
estimates of AUC24h exposures in rats at the NOEL dose and dogs at the NOAEL dose 
were approximately 1.4-fold and 2.0-fold greater than the predicted human exposure at 
650 mg, respectively. Estimates of AUC24h exposures in rats at the NOEL dose and 
dogs at the NOAEL dose were 2.2-fold and 3.2-fold greater than the observed human 
exposure at the 650 mg oral dose, respectively (Table 3).
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 33 of 114
CONFIDENTIAL
Table 3.  Preliminary Observed AMG 986 PK Estimates in Healthy Subjects After
Single Oral Dose Administration and Exposure Margins
Dose
(mg)
Obs/
Pred
Cmax
(ng/mL) 
(CV%)
AUCinf
(ng*h/mL) 
(CV%)
1Rat-
Human 
Ratio Cmax
1Rat-
Human 
Ratio 
AUC
2Dog-
Human 
Ratio 
Cmax
2Dog-
Human 
Ratio 
AUC
5
Obs
334 (22)
2460 (34)
422X
150X
293X
219X
30
Obs
1850 (33)
12600 (25)
76X
29X
53X
43X
100
Obs
5760 (24)
34100 (5)
24X
11X
17X
16X
200
Obs
12200 (34)
85600 (33)
12X
4X
8X
6X
400
Obs
16200 (33)
102000 
(53)
9X
3.6X
6X
5.3X
650
Obs
18400 (35)
169000 
(61)
8X
2.2X
5.3X
3.2X
1 Ratio of mean observed Cmax and AUC24h exposure at NOEL PO dose (1000 mg/kg/day; Study: 118964) 
on day 28 in male rats (141 ug/mL and 368 ug.h/mL, respectively) and human observed or predicted Cmax
and AUCinf estimates.
2 Ratio of mean observed Cmax and AUC24h exposure at NOAEL PO dose (300 mg/kg/day; Study: 118965) 
on day 28 in dogs (sexes combined; 97.7 ug/mL and 538 ug.h/mL, respectively) and human observed or 
predicted Cmax and AUCinf estimates. 
3 Predictions of human Cmax and AUCinf exposures were estimated by linear regression of observed data
Abbreviations: AUC24h=area under the curve from 0h to 24h; AUCinf=area under the curve from 0h to infinity; 
Cmax=maximum concentration; CV%=coefficient of variation; Obs=observed; Pred=predicted
Rationale for Dose Selection in Part B
Prior to the transition from Part A to Part B, verification of PK model assumptions is 
planned as AMG 986 human PK data become available from individual IV and oral 
single dose cohort escalations in Part A.  The IV dose regimen proposed for Part B of 
the study will include multiple 24 hour infusions administered for 4 consecutive days at a 
starting dose of 6 mg over 1 hour (LD) plus 38 mg/ 24 hours (MD; 1.57 mg/h, 36 mg/ 
23 h on Day 1 and 38 mg/ 24 h on Days 2-4).  A second IV cohort is proposed at 60 mg 
over 1 hour (LD) plus 376 mg/ 24 hours (MD; 15.7 mg/h, 360 mg/ 23 h on Day 1 and 
376 mg/ 24 h on Days 2-4.  The proposed once-daily (QD) oral dose regimen for Part B 
will be 5, 30, 100, 200, 400, and 650 mg QD for 7 consecutive days.
After confirmation of safety and tolerability of oral AMG 986 at doses that range from 5 to 
200 mg in Parts A and B, further escalations in dose are planned.  The proposed 
multiple oral dose regimen extended for Part B will be 400 mg QD and 650 mg QD for 
7 consecutive days.  
The planned dose escalation schedules for Part B may be modified based on 
treatment-emergent data (Part A or Part B safety and/or PK data).  Dose adjustments, if 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 34 of 114
CONFIDENTIAL
any, will be made for a full treatment cohort and not on an individual basis.  Any dose 
adjustments will be agreed upon by Amgen in coordination with the investigator(s).
Rationale for Dose Selection in Part C
The starting dose of 10 mg by oral route daily in Part C was based on:

Safety and tolerability observed with an up to 200 mg single oral dose in healthy 
subjects, as described in the Risk Assessment section (2.3).

Pharmacodynamic response (change in stroke volume) measured (by 
echocardiography) at the 5 mg and 30 mg oral single and multiple doses in 
healthy volunteers.
In order to evaluate a potential effect of AMG 986 in patient subjects with heart failure, a 
starting dose of 10 mg has been proposed that is considered safe and could also 
potentially be sufficient to elicit a pharmacodynamic response by echocardiography.
Prior to the transition from Part B to Part C, verification of the safety, tolerability and PK 
model assumptions are planned as data become available from individual IV and oral 
multiple dose cohort escalations in Part B.  Subjects will receive AMG 986 by oral 
administration at a dose of 10 mg daily for the first 7 days followed by 30 mg daily for the 
next 7 days and ending with 100 mg daily for the last 7 days. 
The planned dose schedules for Part C may be modified based on treatment-emergent 
data (Part A or Part B safety and/or PK data).  Pre-dosing adjustments, if any, will be 
made for a full treatment cohort and not on an individual basis.  Any dose adjustments 
will be agreed upon by Amgen in coordination with the investigator(s).
2.8
Clinical Hypotheses
AMG 986 will be safe and well tolerated in healthy subjects and in heart failure patients
after single and multiple dosing by IV infusion and oral administration.
3.
EXPERIMENTAL PLAN
3.1
Study Design
This study is a randomized, placebo-controlled, double-blind, single day (Part A) and 
multiple daily (Part B) ascending dose study in healthy male and female adult subjects, 
between 18 and 55 years of age.  Subjects will receive AMG 986 by IV infusion or by 
oral administration.  In Parts A and B of the study, healthy subjects will receive 
investigational product in a fasted state.  In Part C of the study, patients between the 
ages of 18 to 85 years with heart failure and either reduced (HFrEF) or preserved 
(HFpEF) ejection fraction will receive ascending doses of IP by once daily oral 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 35 of 114
CONFIDENTIAL
administration for 21 days.  The overall study design is described by a study schema at 
the end of the protocol synopsis section.  The study endpoints are defined in 
Section 10.1.1.
At the conclusion of each cohort, a DLRM will convene to review all available data in an
unblinded fashion in order to evaluate AMG 986 safety and tolerability before advancing 
to the next dose cohort.  In support of escalation to the next planned dose level, a review 
of AMG 986 exposure and dose predictions will be conducted using available PK data 
from all dose cohorts.
Based on emerging safety and tolerability data and upon assessment by the DLRM 
members, cohorts may be removed or additional cohorts may be added. Subject 
numbers within each cohort may also be increased or decreased based on the decision 
from the DLRM.  Doses to be administered within each cohort may be higher or lower 
than the last.  Dosing of any subject shall not exceed the highest planned IV and PO 
cohorts for Parts A and B. (Refer to Table 7).
Part A.
Part A will consist of 5 IV infusion dose cohorts and 6 PO dose cohorts. Within each 
cohort, a total of 8 subjects will be randomized to receive AMG 986 or placebo in a 
3:1 ratio.  Subjects of IV dose cohorts will be in residence for at least 48 hours.  Subjects 
of PO dose cohorts will be in residence for at least 24 hours. 
IV dosing will occur by an infusion lasting 24 hours.  Infusions will be divided into an 
initial loading dose for the first hour followed immediately by a maintenance dose for the 
remainder.  Subjects in the first two IV dose cohorts will receive a loading dose only with 
no maintenance dose.  Subjects in the oral dose cohorts will receive AMG 986 as a 
single oral administration.  The sequence of escalation for IV dosing and PO dosing will 
partially overlap to achieve step-wise increases in AMG 986 exposure.  
In Part A of the study, AMG 986 safety and tolerability will be evaluated at an unblinded
DLRM before advancing to the next dose cohort.  In support of escalation to the next 
planned dose level, a review of AMG 986 exposure and dose predictions will be 
conducted using available PK data from all dose cohorts.  At the conclusion of each 
cohort, predictions of exposure and dose will be reviewed using PK data from the most 
recent cohort.  A review of AMG 986 safety and tolerability will adhere to these 
guidelines during each DLRM governing dose escalations in Part A beginning with the 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 36 of 114
CONFIDENTIAL
starting dose cohort (cohort 1 IV, 0.5 mg) through cohort 5 IV (60 mg LD + 360 mg MD), 
as shown in the study schema at the end of the protocol synopsis section.  
Dose escalations in Part A will initially be sequential, with AMG 986 dosing to begin at 
the starting IV dose of 0.5 mg infused over 1 hour, followed by escalation to IV cohort 
2 dosing at 3 mg infused over 1 hour.  After the safety and tolerability of AMG 986 in 
IV Cohort 2 are demonstrated and reviewed at a DLRM, escalation to IV Cohort 3 and 
initiation of oral dosing at the proposed 5 mg starting dose will be permitted.
After the safety and tolerability of AMG 986 in IV Cohort 4 (20 mg LD + 120 mg MD) is 
demonstrated and reviewed at a DLRM, escalation to IV Cohort 5 (60 mg LD + 360 mg 
MD) will be permitted. After the safety and tolerability of AMG 986 in PO Cohort 4 
(200 mg) is demonstrated and reviewed at a DLRM, escalation to PO Cohort 5 (400 mg) 
will be permitted. Enrollment for IV Cohorts will end after IV Cohort 5.  After the safety 
and tolerability of AMG 986 (at 400 mg) are demonstrated and reviewed at a DLRM, 
escalation to PO Cohort 6 (650 mg) will be permitted.  
Table 4.  Intravenous Infusion and Oral Dose Escalations for Part A
Intravenous Infusion
(up to 24 hours)
Oral Administration
(single dose)
Cohort
LD
(mg/1 hour)
MD
(mg/23 hours)
Cohort
Dose
(mg)
Cohort 1 IV (Part A)
0.5
0
Cohort 1 PO (Part A)
5
Cohort 2 IV (Part A) 
3
0
Cohort 2 PO (Part A)
30
Cohort 3 IV (Part A)
6
36
Cohort 3 PO (Part A)
100
Cohort 4 IV (Part A)
20
120
Cohort 4 PO (Part A)
200
Cohort 5 IV (Part A)
60
360
Cohort 5 PO (Part A)
400
Cohort 6 PO (Part A)
650
The safety and tolerability of each dose level (including the final IV and PO dose 
cohorts) in Part A will be assessed after all subjects have been enrolled and followed 
through at least for 4 days post dose.  
Part B.
Part B will consist of 2 IV infusion dose cohorts and 6 PO dose cohorts.  Within each 
cohort, a total of 8 subjects will be randomized to receive AMG 986 or placebo in a 
3:1 ratio.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 37 of 114
CONFIDENTIAL
In Part B of the study, AMG 986 safety and tolerability will be evaluated at a DLRM 
before advancing to the next dose cohort.  In support of escalation to the next planned 
dose level, AMG 986 exposure and dose predictions will be updated using available PK 
data that will include observed PK exposure after single day dosing in Part A of the 
study. Predictions of AMG 986 exposure anticipated for cohort 2 IV (60 mg LD 
+ 360 mg/ 23 hours MD on Day 1 and 376 mg/24 hours MD on Days 2-4) will be 
reviewed using available PK data from cohort 1 IV (6 mg LD + 36 mg/ 23 hours MD on 
Day 1 and 38 mg/24 hours MD on Days 2-4). 
In the IV cohorts, AMG 986 will be dosed as a series of IV infusions, each with duration 
of 24 hours, for 4 consecutive days.  Subjects of the IV dose cohorts will be in residence 
for up to 24 hours after the completion of IV infusions.  On study Day 1, IV infusions will 
be divided into an initial loading dose infusion for 1 hour followed immediately by a 
maintenance dose with duration for 23 hours.  On study days 2 to 4, maintenance doses 
will be administered as constant infusions with duration for 24 hours.
The transition from ascending single day doses in Part A to ascending multiple daily 
doses in Part B is planned to occur after confirmation of AMG 986 safety and tolerability 
in IV Cohort 4 of Part A.  The starting IV dose in Part B at 6 mg (LD) + 36 mg/ 23 hours 
MD on Day 1 and 38 mg/24 hours MD on Days 2-4 will have been previously evaluated 
over 24 hours in IV Cohort 3 of Part A.  The rationale for an earlier partial overlap 
between IV dose cohorts in Parts A and B is supported by the anticipated exposure, 
safety and tolerability of AMG 986 in IV Cohort 4 of Part A at 20 mg (LD) + 120 mg (MD).
In the PO cohorts, AMG 986 will be dosed once daily for 7 consecutive days.  Subjects 
of the PO dose cohorts will be in residence for at least 24 hours after the completion of 
the last dose on day 7.
Parts A and B will partially overlap for the oral dose cohorts.  Transition to the first PO 
cohorts of Part B (5 mg QD) is planned to occur upon a DLRM decision to proceed after 
the 30 mg PO single dose cohort in Part A has been made.  Subsequent oral dose 
escalations to 200 mg QD will occur in Part B as shown in the study schema.  Escalation 
to 400 mg QD in Part B will be allowed after the safety and tolerability of AMG 986 at 
both 400 and 650 mg in Part A (PO cohorts 5 and 6, respectively) are demonstrated and 
reviewed at each DLRM.  
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 38 of 114
CONFIDENTIAL
Table 5.  Intravenous Infusion and Oral Dose Escalations for Part B
Intravenous Infusion
(for 4 days)
Oral Administration
(once daily for 7 days)
Cohort
Day 1 LD
(mg/1 hour)
MD
(mg/24 hours)
Cohort
Dose
(mg)
Cohort 1 IV (Part B)
6
38 a
Cohort 1 PO (Part B)
5
Cohort  2 IV (Part B)
60
376 b
Cohort 2 PO (Part B)
30
Cohort 3 PO (Part B)
100
Cohort 4 PO (Part B)
200
Cohort 5 PO (Part B)
400
Cohort 6 PO (Part B)
650
The safety and tolerability of each dose level (including the final IV and PO dose 
cohorts) in Part B will be assessed after all subjects have been enrolled and followed 
through at least 4 days post dose.  
Part C.
Part C will consist of 2 PO dose cohorts, one cohort for HFrEF patients and one cohort 
for HFpEF patients. Within each cohort, 20 subjects will be randomized to receive 
AMG 986 or placebo in a 3:1 ratio. Subjects will receive AMG 986 by oral administration 
at a dose of 10 mg daily for the first 7 days followed by 30 mg daily for the next 7 days 
and ending with 100 mg daily for the last 7 days for a total of 21 days of treatment. In 
Part C of the study, AMG 986 safety and tolerability will be evaluated at the end of the 
21 day dosing period in an unblinded DLRM. 
Table 6.  Dose Regimen for HFrEF and HFpEF Patient Subjects in Part C
Day(s)
Route
AMG 986 Dose
1-7
PO
10 mg daily
8-14
PO
30 mg daily
15-21
PO
100 mg daily
a. Cohort 1 IV (Part B)
LD: 6 mg / 1 h
MD: 36 mg / 23h (Day 1)
MD: 38 mg / 24h (Days 2-4)
[total infusion = 96 h]
b. Cohort 2 IV (Part B)
LD: 60 mg / 1 h
MD: 360 mg / 23h (Day 1)
MD: 376 mg / 24h (Days 2-4) 
[total infusion = 96 h]
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 39 of 114
CONFIDENTIAL
3.2
Number of Sites
This study will be conducted in 15 or more sites in the United States, Europe, Canada
and Asia.  Additional sites and/or countries could be added as necessary to complete 
enrollment.
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.
Approximately 152 healthy volunteer subjects and 40 heart failure patient subjects will 
be enrolled into the study.  In Part A PO Dose Cohorts, 8 subjects per cohort will be 
enrolled for a total of 48 subjects across 6 cohorts.  In Part A IV Dose Cohorts, 
8 subjects per cohort will be enrolled for a total of 40 subjects across 5 cohorts.  In Part 
B PO Dose Cohorts, 8 subjects per cohort will be enrolled for a total of 48 subjects 
across 6 cohorts.  In Part B IV Dose Cohorts, 8 subjects per cohort will be enrolled for a 
total of 16 subjects across 2 cohorts. In Part C, up to 20 HFrEF patient subjects and up 
to 20 HFpEF patient subjects will be enrolled. 

Part A IV Dose Cohorts: 40 subjects (8 subjects per cohort)

Part A PO Dose Cohorts: 48 subjects (8 subjects per cohort)

Part B IV Dose Cohorts: 16 subjects (8 subjects per cohort)

Part B PO Dose Cohorts: 48 subjects (8 subjects per cohort)

Part C HFrEF cohort: Up to 20 HF patient subjects

Part C HFpEF cohort: Up to 20 HF patient subjects
3.4
Replacement of Subjects
Subjects who are withdrawn or removed from treatment or the study prior to receiving 
AMG 986 will be replaced at the discretion of the Amgen Medical Monitor and Principal 
Investigator. Subjects who are withdrawn or removed from treatment or the study may 
be replaced.  This decision will be made by the Amgen Medical Monitor in consultation 
with the Principal Investigator and the Amgen Global Safety Officer.
The new subject will receive the identical treatment as the replaced subject, but will be 
assigned a replacement randomization number associated with this new record. 
3.5
Estimated Study Duration
3.5.1
Study Duration for Subjects
For both healthy volunteer subjects and heart failure patient subjects, the planned length 
of participation in the study is approximately 58 days, which includes a 28 day screening 
period followed by 30 days on study. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 40 of 114
CONFIDENTIAL
3.5.2
End of Study
The EOS is the last planned clinic visit for each subject enrolled in this study, which is at 
Day 30. 
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis; 
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study. 
4.
SUBJECT ELIGIBILITY
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  
4.1
Inclusion Criteria
101
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures.
102
Male and female subjects ≥ 18 to ≤ 55 years old with no history or evidence of 
clinically relevant medical disorders as determined by the investigator and the 
Amgen physician (Parts A and B only)
103
Body mass index (BMI) between 18 and 35 kg/m2, inclusive, at screening.
104
Physical examination including vital signs, clinical laboratory values, and ECGs 
are clinically acceptable to the investigator. Abnormal findings for healthy 
volunteers and unexpected findings for heart failure patient subjects will be 
discussed with Amgen prior to study enrollment.
105
Women must be of non-reproductive potential (ie, postmenopausal)
1. Age of ≥55 years with no menses for at least 12 months OR
2. Age of < 55 years with no menses for at least 12 months AND with 
postmenopausal gonadotropin levels (follicle-stimulating hormone 
levels > 40 IU/L or according to the definition of “postmenopausal range” for 
the laboratory involved) OR 
3. History of hysterectomy OR 
4. History of bilateral oophorectomy.
106
Men must agree to practice an acceptable method of effective birth control while 
on study through 11 weeks after receiving the last dose of investigational product 
(AMG 986 or placebo).  Acceptable methods of effective birth control include 
sexual abstinence; vasectomy and testing that shows there are no sperm in the 
semen; or a condom with spermicide (men) in combination with barrier methods 
(diaphragm, cervical cap or cervical sponge), hormonal birth control or IUS
(women). 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 41 of 114
CONFIDENTIAL
107
Men must be willing to abstain from sperm donation while on study through
11 weeks after receiving the last dose of investigational product (AMG 986 or 
placebo).
108
This inclusion criterion only applies to Parts B and C cohorts. Before inclusion in 
the study, subjects will undergo a screening echocardiogram to ensure that the 
following parameters can be accurately measured: left ventricular end-systolic 
and end-diastolic volumes, left atrial end-systolic and end-diastolic volumes, 
ejection fraction, fraction shortening, and end-systolic septal and posterior wall 
thickness.
For Part C
Additional Inclusion Criteria for HFrEF Patients
109
Subject must be of age 18 to 85 years, have a diagnosis of HF confirmed by 
medical records for ≥3 months, and be in stable condition for at least 4 weeks. 
110
Left ventricular ejection fraction (LVEF) ≤40% confirmed by echocardiogram, 
radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast 
ventriculography within 12 months prior to randomization.
111
NYHA class II or III at screening
112
Sinus rhythm
113
NT-proBNP level ≥ 250 pg/ml 
114
Patients will be treated with stable, optimal pharmacological therapy for a 
minimum of 4 weeks prior to randomization.  Treatment of HFrEF includes at 
least beta-blockers (carvedilol, metoprolol succinate or bisoprolol) and a RAAS 
inhibitor (ACEi, ARB or sacubitril/valsartan).  
Additional Inclusion Criteria for HFpEF patients
115
Subject must be of age of 18 to 85 years, have a diagnosis of HF confirmed by 
medical records for ≥3 months, and be in stable condition for at least 4 weeks. 
116
Left ventricular ejection fraction (LVEF) ≥50% confirmed by echocardiogram, 
radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast 
ventriculography within 12 months prior to randomization.
117
Left ventricular ejection fraction (LVEF) never ≤40% in the past
118
NYHA class II or III at screening
119
Sinus rhythm
120
NT-proBNP level ≥ 250 pg/ml 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 42 of 114
CONFIDENTIAL
121
Patients will be treated with stable, optimal pharmacological therapy for a 
minimum of 4 weeks prior to randomization.  Treatment of HFpEF includes at 
least a daily dose of diuretics equivalent to furosemide 40 mg.
122
For subjects in Parts A, B and C: Women must have negative results for both the 
screening (serum) and day -1 (serum or urine) pregnancy tests
4.2
Exclusion Criteria
201
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days or 5 half-lives (whichever is longer), since ending treatment on 
another investigational device or drug study(s) prior to receiving the first dose of 
investigational product (AMG 986 or placebo).  
202
Female subjects who are lactating/breastfeeding or who plan to breastfeed while 
on study through 11 weeks after receiving the last dose of investigational product 
(AMG 986 or placebo).
203
Male subjects with partners who are pregnant or planning to become pregnant 
while the subject is on study through 11 weeks after receiving the last dose of 
investigational product (AMG 986 or placebo).  
204
Female subjects of reproductive potential.
205
Subjects in Parts A and B of the study: estimated glomerular filtration rate 
(eGFR) within the screening period of less than 60 mL/min/1.73m2 as calculated 
using the estimated Modification of Diet in Renal Disease (MDRD) formula.
206
Current or prior malignancy within 5 years of randomization, with the exception of 
non-melanoma skin cancers, cervical or breast ductal carcinoma in situ, and 
adenocarcinoma of the prostate Stage I or IIa (defined as T1, T2a or T2b, N0, M0 
with documented serum PSA < 20 ng/mL and Gleason score ≤7) per the 
American Joint Committee on Cancer (AJCC) primary tumor, regional lymph 
nodes, and distant metastasis system.
207
Positive results for Human Immunodeficiency Virus (HIV), antibodies, hepatitis B 
surface antigen (HBsAg), or hepatitis C antibodies (HepCAb).
208
Subject has known sensitivity to any of the products or components to be 
administered during dosing.
209
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge.
210
History or evidence of any other clinically significant disorder, condition or 
disease with the exception of those outlined above that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion.
211
Subject previously has entered this study or has been previously exposed to 
AMG 986.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 43 of 114
CONFIDENTIAL
212
Concurrent or prior use of strong CYP3A4 inhibitors within 14 days of study 
Day 1, including (not limited to): macrolide antibiotics (eg, clarithromycin, 
telithromycin), antifungals (eg, itraconazole, voriconazole), antivirals 
(eg, ritonavir, saquinavir, indinavir, nelfinavir), nefazodone.
213
Concurrent or prior ingestion of grapefruit or grapefruit products and other foods 
that are known to inhibit CYP3A4 within 7 days of study Day 1.
214
Concurrent or prior use of strong CYP3A4 inducers within 28 days of study 
Day 1, Including (not limited to): phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital.  Subjects should also not take St John's Wort.
215
Concurrent or prior use of strong P-glycoprotein inhibitors within 28 days of study 
Day 1, including (not limited to): elacridar and valspodar. 
216
All herbal supplements, vitamins, and nutritional supplements taken within the 
last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be 
reviewed and approved by the PI and Amgen Medical Monitor.
217
For subjects enrolled under Amendments 1-6, inclusive: QTc > 450 msec or 
history/evidence of long QT syndrome.
218
Planned elective surgery within 30 days of study completion or before return of 
red blood cell parameters to normal values.
219
Blood donation ≥ 500 mL within 60 days of Day 1.
220
Systolic blood pressure > 150 mm Hg or < 90 mm Hg, or diastolic blood pressure
> 95 mm Hg or < 60 mm Hg, assessed on 2 separate occasions prior to 
enrollment (Parts A and B only).
221
Heart rate ≥ 100 beats per minute after 5 minutes of rest or an untreated
symptomatic bradyarrhythmia within 1 month prior to enrollment.
222
For Parts A and B: Troponin I at screening > upper limit of normal (ULN).
223
In the opinion of the Investigator, a condition that compromises the ability of the
subject to give written informed consent or to comply with study procedures.
224
Unwilling or unable to abstain from nicotine or tobacco containing products 
(including but not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or 
nicotine patches) throughout the screening period and for the duration of the 
study.
225
Subjects who are unwilling or unable to limit alcohol consumption to 1 units/day 
(1 unit = 1 drink and 1 drink is equivalent to 12 ounces of regular beer, 8 to 
9 ounces of malt liquor, 5 ounces of wine or 1.5 ounces of 80 proof distilled 
spirits). 
226
Subjects with a positive urine drug screen or alcohol breath test. 
227
Known history of drug or alcohol abuse.
228
Concurrent use of Phosphodiesterase 5 (PDE5) inhibitors including (not limited 
to) avanafil, sildenafil, tadalafil, vardenafil. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 44 of 114
CONFIDENTIAL
229
Concurrent use of vasodilators by healthy subjects in Parts A and B that could in 
the opinion of the investigator potentially lead to a drop in blood pressure in 
combination with investigational product.
230
Severe uncorrected valvular heart disease, or hypertrophic obstructive 
cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically 
significant congenital heart disease. 
231
For subjects in Part C of the study: estimated glomerular filtration rate (eGFR) 
within the screening period of less than 30 mL/min/1.732m2 as calculated using 
the Modification of Diet in Renal Disease (MDRD) formula. 
232
For subjects in Part C of the study: Systolic blood pressure > 160 mm Hg or 
< 100 mm Hg, or diastolic blood pressure > 110 mm Hg or < 60 mm Hg, 
assessed on 2 separate occasions prior to enrollment.
233
For subjects in Part C of the study: Troponin I > ULN if there is also evidence of 
an acute cardiovascular event.
234
For subjects enrolled in Part C under Amendment 7: QTc > 500 msec or 
history/evidence of long QT syndrome.
5.
SUBJECT ENROLLMENT
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board (IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable (see Section 11.2).
All subjects must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.  
The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment CRF.
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria. The Investigator is to document the enrollment decision and date, in 
the subject’s medical record and in/on the enrollment CRF.
Provided all eligibility criteria have been met, subjects will be asked to return to the 
research facility for admission on Day -1 (Baseline Visit) where additional assessments 
will be performed to confirm that the subject remains eligible for the study. If subject 
eligibility is confirmed, the subject will be randomized on Day 1 to receive either 
AMG 986 or universal placebo.
Each subject who enters into the screening period for the study (defined as the point 
when the subject signs and dates the IRB approved consent form) receives a unique 
subject identification number before any study procedures are performed.  The subject 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 45 of 114
CONFIDENTIAL
identification number will be assigned manually.  This number will be used to identify the 
subject throughout the clinical study and must be used on all study documentation 
related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  
The identification number will be 11 digits: the first 3 are the protocol identifier (183), the 
next 5 digits represent the site number, which consists of the 2-digit country code 
(66) and 3-digit study-specific site number (001), and the last 3 digits are assigned in 
sequential order as subjects are screened (eg, 001, 002, 003, etc.). Thus, the first 
subject screened at site 66001 would be 18366001001, and the second subject would 
be 18366001002, and so forth.
If the investigator has any questions regarding a subject’s eligibility, he/she should 
contact the Amgen Medical Monitor. The site is to document the enrollment date in the 
subject’s medical record and the electronic case report form (CRF). 
Rescreening will be allowed for this study on a case-by-case basis at the discretion of 
the Amgen Medical Monitor in consultation with the Principal Investigator.
5.1
Randomization/Treatment Assignment
In study Parts A and B, 8 subjects will be enrolled in each cohort and will be randomized 
such that 6 subjects receive AMG 986 and 2 subjects receive placebo (3:1 ratio). In 
study Part C, up to 20 patient subjects will be enrolled in each of 2 cohorts to receive 
AMG 986 or placebo in a 3:1 ratio. Randomization to AMG 986 or placebo will be based 
on a randomization schedule (following a sentinel dosing design) prepared by Amgen 
before the start of the study. In all cohorts, eligible subjects will be randomized prior to 
dosing on Day 1 (day of investigational product AMG 986 or placebo administration). 
They will receive a unique randomization number and will be assigned to receive either 
AMG 986 or placebo. Once eligibility for study participation has been confirmed (based 
on data collected during the Screening visit and Day -1), a randomization number will be 
assigned in sequential order in which eligibility was met. At no time will the same 
randomization number be assigned to more than one subject. No more than 2 sentinel 
subjects will be dosed and observed for at least 24 hours before the remaining subjects
in the cohort are dosed, provided there are no safety or tolerability concerns as 
assessed by the Principal Investigator (Part A and B).  
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 46 of 114
CONFIDENTIAL
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.
5.2
Site Personnel Access to Individual Treatment Assignments
A subject’s treatment assignment should only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of subjects currently enrolled or subjects in 
subsequent cohorts.  Unblinding at the study site for any other reason will be considered 
a protocol deviation.  An unblinded pharmacist (and/or qualified designee) will have 
access to the treatment assignment and will be responsible for preparing the appropriate 
treatment based on the randomization list provided by Amgen (Part A and B) and from 
IVRS in Part C. Emergency unblinding at the site level for subject safety reasons will be 
done by the unblinded pharmacist upon investigator’s request. The unblinded 
pharmacist will be responsible for securing any unblinded pharmacy records in a secure 
location.
It is encouraged that the Amgen Medical Monitor and/or Clinical Study Manager be 
notified before the blind is broken, unless the investigator believes that identification of 
the study treatment is required for a medical emergency. In this case, the Amgen Trial 
Manager must be notified within 24 hours after breaking the blind.
Treatment assignments will be unblinded after final lock. Upon receipt of written 
authorization from Amgen to unblind, the unblinded pharmacist will release the specified 
unblinded pharmacy records to site staff designated to enter the subject Package Lot 
Number (PLN) into each subject’s Investigational Product Administration CRF.
6.
TREATMENT PROCEDURES
6.1
Classification of Product and/or Medical Device
The Amgen investigational product and/or placebo used in this study include: AMG 986 
and placebo.  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 986 and placebo.
6.2
Investigational Product
All investigational products will be administered at the research facility by a qualified staff 
member. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 47 of 114
CONFIDENTIAL
A physician or qualified designee must be available at the time of administration of 
investigational product.
6.2.1
Amgen Investigational Product AMG 986 and Placebo
AMG 986 for PO administration will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical investigational product distribution procedures. 
AMG 986 for PO administration will be presented as tablets available in 15-count bottles. 
Placebo for PO administration will be presented in identical containers and 
stored/packaged the same as AMG 986.
AMG 986 for IV infusion will be manufactured by Integrity Bio Inc., and distributed using 
Amgen clinical investigational product distribution procedures. AMG 986 for IV infusion 
will be supplied with 4 mL deliverable volume in a single use 5 cc CZresin vial stored at 
or below 25C, protected from light.  AMG 986 is formulated as a sterile solution for 
infusion at a concentration of 10 mg/mL in 100 mM glycine at pH 9.4.  Placebo for IV 
administration will be 0.9% w/v sodium chloride/ saline solution.
6.2.1.1
Dosage, Administration, and Schedule
In Parts A and B of the study, healthy subjects will receive investigational product
(AMG 986 or placebo) in a fasted state.  Subjects in the IV dose cohorts of Parts A and 
B will receive investigational product on an empty stomach (no food or liquids, except 
water, at least 2 hours prior to initial IV infusion) and refrain from food and liquid (except 
water) intake until after completion of the initial 1 hour infusion loading dose on study 
Day 1.  Subjects in the PO dose cohorts of Parts A and B will receive investigational 
product on an empty stomach (no food or liquids, except water, at least 2 hours prior to 
drug administration) and refrain from food and liquid (except water) intake for at least
2 hours post dose. 
In Part C of the study, subjects will receive oral investigational product administered on 
an empty stomach (no food or liquids, except water, at least 2 hours prior to drug 
administration) and refrain from food and liquid (except water) intake for at least 2 hours 
post dose. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 48 of 114
CONFIDENTIAL
Table 7.  Cohort Investigational Product Dose Administration
Study 
Part
Cohort Name
Dosing 
Route
No. Doses
AMG 986 Total Dose (mg)
Part A
Cohort 1 IV (Part A) 
IV
Single
0.5 mg LD
Part A
Cohort 2 IV (Part A) 
IV
Single
3 mg LD
Part A
Cohort 3 IV (Part A)
IV
Single
6 mg LD + 36 mg MD
Part A
Cohort 4 IV (Part A)
IV
Single
20 mg LD + 120 mg MD
Part A
Cohort 5 IV (Part A)
IV
Single
60 mg LD + 360 mg MD
Part A
Cohort 1 PO (Part A)
PO
Single
5
Part A
Cohort 2 PO (Part A)
PO
Single
30
Part A
Cohort 3 PO (Part A)
PO
Single
100
Part A
Cohort 4 PO (Part A)
PO
Single
200
Part A
Cohort 5 PO (Part A)
PO
Single
400
Part A
Cohort 6 PO (Part A)
PO
Single
650
Part B
Cohort 1 IV (Part B) a
IV
Multiple
6 mg LD + 38 mg MD
Part B
Cohort  2 IV (Part B) b
IV
Multiple
60 mg LD + 376 mg MD
Part B
Cohort 1 PO (Part B)
PO
Multiple
5
Part B
Cohort 2 PO (Part B)
PO
Multiple
30
Part B
Cohort 3 PO (Part B)
PO
Multiple
100
Part B
Cohort 4 PO (Part B)
PO
Multiple
200
Part B
Cohort 5 PO (Part B)
PO
Multiple
400
Part B
Cohort 6 PO (Part B)
PO
Multiple
650
Part C
Cohort- HFpEF (Part 
C)
PO
Multiple
10 mg QD (Days 1-7)
30 mg QD (Days 8-14)
100 mg QD (Days 15-21)
Part C
Cohort- HFrEF (Part C)
PO
Multiple
10 mg QD (Days 1-7)
30 mg QD (Days 8-14)
100 mg QD (Days 15-21)
Investigational product for oral administration will be prepared as tablets in strengths of 
5 mg and 25 mg.  The tablets will be swallowed whole (not chewed) with a total volume 
of 240 mL (8 fluid ounces) of water. A mouth check will be performed by the principal
investigator or qualified designee to ensure all tablets have been properly ingested. 
a. Cohort 1 IV (Part B)
LD: 6 mg / 1 h
MD: 36 mg / 23h (Day 1)
MD: 38 mg / 24h (Days 2-4)
[total infusion = 96 h]
b. Cohort 2 IV (Part B)
LD: 60 mg / 1 h
MD: 360 mg / 23h (Day 1)
MD: 376 mg / 24h (Days 2-4) 
[total infusion = 96 h]
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 49 of 114
CONFIDENTIAL
Investigational product for IV infusion will be prepared by an unblinded pharmacist in 
normal saline bags for loading and maintenance doses.  Additional details on 
administration of IP can be obtained in the Investigational product instruction manual 
(IPIM).
The dosing schedule is illustrated in a study schema in the protocol synopsis. 
6.2.1.2
Dose-cohort Study Escalation and Stopping Rules
The progression of dose cohorts will initially be sequential with some overlap within and 
across study Parts. Dose escalation will occur after the DLRM voting members have 
reviewed available safety data through at least 4 days post-dose for single dose cohorts 
and through at least 4 days post-dose for multiple dose cohorts. Following the dose 
escalation decision, the next cohort(s) will be open for enrolment. There will be at least 
2 weeks between the end of a dosing cohort and the start of a subsequent cohort(s) as 
proposed in the study schema.
Based on emerging safety and tolerability data and upon assessment by the DLRM 
members, cohorts may be removed or additional cohorts may be added. Subject 
numbers within each cohort may also be increased or decreased based on the decision 
from the DLRM.  Doses to be administered within each cohort may be higher or lower 
than the last.  Dosing of any subject shall not exceed the highest planned IV and PO 
cohorts for Parts A and B. (Refer to Table 7).
The dosing schedule is described by a schema in the protocol synopsis.
6.2.1.3
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.1.3.1
Dose Level Review Meetings
The DLRM will be held to review data, monitor safety and make dose change decisions. 
The DLRM team members will consist of the principal investigator or designee, Amgen 
medical monitor, Amgen Global Safety officer or designees, Amgen clinical study 
research manager or designee and biostatistics representative or designee. Additional 
members may be added as needed (eg, PK scientist). The voting members include the 
principal investigator or designee, Amgen medical monitor and Amgen Global safety 
officer or designee. The DLRM meeting will be conducted in an unblinded manner and 
attendees will be approved to access treatment assignments for the cohorts reviewed 
following Amgen standard procedure.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 50 of 114
CONFIDENTIAL
In Part A of the study, AMG 986 safety and tolerability will be evaluated at a DLRM 
before advancing to the next dose cohort.  In support of escalation to the next planned 
dose level, a review of AMG 986 exposure and dose predictions will be conducted using 
available PK data from all dose cohorts.  At the conclusion of each IV cohort, predictions 
of exposure and dose will be reviewed using PK data from the most recent cohort.  A 
review of AMG 986 safety and tolerability will adhere to these guidelines during each 
DLRM governing dose escalations in Part A beginning with the starting dose cohort 
(cohort 1 IV, 0.5 mg) through cohort 5 IV (60 mg LD + 360 mg MD), as shown in the 
study schema at the end of the protocol synopsis section.  
In Part B of the study, AMG 986 safety and tolerability will be evaluated at a DLRM 
before advancing to the next dose cohort.  In support of escalation to the next planned 
dose level, AMG 986 exposure and dose predictions will be updated using available 
PK data that will include observed PK exposure after single day dosing in Part A of the 
study.  Predictions of AMG 986 exposure anticipated for cohort 2 IV will be reviewed 
using available PK data from cohort 1 IV (6 mg LD + 36 mg/ 23 hours MD on Day 1 and 
38 mg/24 hours MD on Days 2-4).
In Part C of the study, safety and tolerability will be evaluated at a DLRM at the end of 
the dosing period for each cohort. 
The DLRM members are responsible for dosing decisions, which may include escalation 
to the next planned dose, escalation to an intermediate dose (a dose lower than the next 
planned dose), de-escalation to a lower dose, continuation, delay or termination of 
dosing, or repetition or expansion of a cohort. Dosing decisions will be made based on 
unanimous agreement between the Amgen medical monitor, Amgen Global safety 
officer or designee and principal investigator or designee participating in the unblinded 
DLRM. 
All available study data including echocardiograms, demographics, IP administration, 
medical history, concomitant medications, adverse events, ECG’s, vital signs, plasma 
PK and laboratory results will be reviewed. Pharmacokinetic data for past cohorts, if 
available, may be reviewed at the DLRM’s. DLRM will not require that all queries be 
resolved or source verified. 
Data will be reviewed unblinded (eg, treatment assignment will be revealed) since 
unblinding is deemed necessary for the review team to make dosing decisions. Study 
sites will report all AEs categorized as CTCAE v.4 Grade 2 or higher to the unblinded 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 51 of 114
CONFIDENTIAL
medical monitor (eg, Amgen study clinical director or medically qualified designate) via 
email within 24 hours of event occurrence.  Study sites will include all available clinical 
information regarding an event as part of this report and provide follow-up information as 
it becomes available.  The medical monitor will be responsible to complete the unblinded 
review of the information within 24 hours of receipt in order to look for any emerging 
safety signal (from either a single AE or pattern of AEs).
6.2.1.3.2
Dose Level Determination
To avoid exposing multiple subjects at the same time to an untested treatment, this 
study will use a sentinel dosing design. Within each cohort, the first 2 subjects enrolled 
will be randomized such that 1 subject will receive AMG 986 and the other receives 
matching placebo. Provided there are no safety signals up to 24 hours after completion 
of dosing for the sentinel subject(s), the remaining subjects in the cohort will be dosed 
thereafter. 
The dose escalation schedule may be modified based on emerging PK, PD and safety 
findings. Dose adjustments will be made on a treatment cohort basis (not on an 
individual basis). The review of available safety data and dosing change decisions will 
be documented and Amgen will issue a written notification of the dose change to the 
investigators. 
Following the dose escalation decision, the next cohort(s) will be open for enrolment. 
6.2.1.3.3
Dose Stopping Rules
IV or PO dosing will be stopped or modified by the DLRM if suspected adverse drug 
reactions and/or changes in safety data (including but not limited to vital sign, ECG or 
clinical laboratory results) are observed and these changes pose a significant health risk
in the opinion of either the investigator or Amgen.
No antidote to AMG 986 exists. Standard medical therapies should be used to treat
adverse signs or symptoms that do not promptly resolve with discontinuation of the IP. 
Investigators must follow patients until the complete resolution of any clinically significant 
event, irrespective of an IP dosing change.
For subjects receiving IV investigational product the following scheme should be applied 
in the occurrence of a significant change in blood pressure, heart rate, other vital sign, 
ECG, laboratory result or any other significant adverse event considered by the 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 52 of 114
CONFIDENTIAL
investigator to be clinically relevant and directly related to infusion of investigational 
product. 

A change from baseline systolic or diastolic blood pressure levels ≥15% or a 
change in heart rate ≥25% during infusion should be followed by a 50% reduction 
of infusion rate for at least 15 minutes. 

If 3 consecutive assessments of blood pressure, heart rate, or other vital signs
taken 5 minutes apart are considered to be back to pre-dose levels, restoration of 
initial infusion rates should be attempted with close monitoring.

If subsequent assessments show a persistent and significant change in the same 
vital signs or adverse event considered by the investigator to be related to 
investigational product, a decision by the investigator can be made to
o
Continue at the reduced rate of infusion.
o
Further reduce infusion rate or stop infusion rate entirely. 

If other clinically relevant adverse event considered by the investigator to be 
related to investigational product occurs, a decision by the investigator can be 
made to:
o
Reduce rate of infusion by 50%.
o
Stop infusion rate entirely.
In either case, subsequent assessments, as described above, should guide 
investigational product administration.
In the event that a change from initial dosing rate is necessary, the Amgen medical 
monitor should be informed as soon as possible.  
For subjects receiving ascending multiple doses of oral IP in Part C of the study, the 
following scheme should be applied to the occurrence of a significant change in blood 
pressure, heart rate, other vital sign, ECG, laboratory result or any other significant 
adverse event considered by the investigator to be clinically relevant and directly related 
to the PO administration of IP. 

During the observation period after administration of the oral IP, a persistent 
(lasting more than 2 assessment time-points) adverse event, change in baseline 
systolic or diastolic blood pressure ≥ 15% or a change in heart rate ≥ 25% 
deemed clinically significant by the investigator should prompt a possible change 
for the next oral IP administration.

The decision to completely withhold IP, to resume IP or to resume with a reduced 
dose will be made with agreement of Amgen, the investigator and the subject.

The dose reduction after a clinically significant event should follow the guidelines 
below:
o
If the subject does not tolerate the 10 mg dose, IP should be completely 
withheld.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 53 of 114
CONFIDENTIAL
o
If the subject does not tolerate the 30 mg dose, IP should be reduced to 
15 mg for the next administration. Upon occurrence of a novel event of 
intolerance with 15 mg, dosage will be reverted to 10 mg in the next IP 
administration and maintained at 10 mg until the end of the 21-day 
dosage period.
o
If the subject does not tolerate the 100 mg dose, IP should be reduced to 
75 mg for the next administration. Upon occurrence of a novel event of 
intolerance with 75 mg, dosage will be reverted to 50 mg in the next IP
administration and maintained at 50 mg until the end of the 21-day 
dosage period.
o
Patients will be observed for at least 6 hours after the first administration 
of a new dose.
For more details on the administration of oral or intravenous investigational product, 
refer to the Investigational Product Instruction Manual. 
The quantity, volume, start date/time, stop date/time, and the amount of IP used as 
applicable to prepare the dose on the individual subjects will be entered in each
subject’s Investigational Product Administration CRF prior to receipt of unblinded 
authorization. Upon receipt of written authorization from Amgen to unblind, the 
unblinded pharmacist will release the specified unblinded pharmacy records to site staff 
designated to enter the subject PLN into each subject’s Investigational Product 
Administration CRF. The effects of overdose of AMG 986 are not known. All overdose 
occurrences must be documented and corresponding adverse events must be recorded 
on the appropriate CRF and in source documents. 
The study may be terminated at any point in time at the discretion of the sponsor. 
In addition, dosing will be stopped or modified as shown in Table 8. 
Clinically or medically significant suspected adverse drug reactions and serious adverse 
events considered to be related to study procedures will be followed until resolved or 
considered stable.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 54 of 114
CONFIDENTIAL
Table 8.  Cohort Dose Stopping Rules
Scenario
Action
Any occurrence of a single CTCAE v4 Grade 
2 adverse drug reaction or higher in a cohort, 
or occurrence of an event (including but not 
limited to abnormalities in vital sign, ECG or 
clinical laboratory results) suspected of being 
caused by administration of IP.
Stop dosing index subjects and additional 
subjects and convene DLRM (if event occurs 
outside the regularly scheduled DLRM window)
Review adverse event and all relevant safety 
data for evidence of relationship to treatment 
and clinical or medical significance.
Treatment unblinding to support evaluation of 
safetya
Upon unanimous decision by the DLRM 
members, one of the following decisions may 
be made:

Resume dosing of index subject 
(if applicable)

Stop enrollment of the cohort 
(if applicable)

Resume enrollment of the cohort as 
planned

Resume enrollment of the cohort at a 
lower dose

Expand the cohort at the same dose

Add a lower dose cohort to the study

Escalate to an intermediate dose 
(a dose lower than the next planned 
dose)

Escalate to the next planned dose
Page 1 of 3
Abbreviations: CTCAE = Common terminology Criteria for Adverse Events; 
a Finding must be confirmed by repeat measurement, whenever possible
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 55 of 114
CONFIDENTIAL
Table 8.  Cohort Dose Stopping Rules
Scenario
Action
Any occurrence of a CTCAE v4 Grade 2 
suspected adverse drug reaction in 2 or 
more subjects in the same cohort, or 
occurrence of two events (including but not 
limited to abnormalities in vital sign, ECG or 
clinical laboratory results) requiring reduction 
in the dose administered in the same cohort.
Stop dosing index subjects and additional 
subjects and convene DLRM (if event occurs 
outside the regularly scheduled DLRM window)
Review adverse event and all relevant safety 
data for evidence of relationship to treatment 
and clinical or medical significance.
Treatment unblinding to support evaluation of 
safetya
Upon unanimous decision by the DLRM 
members, one of the following decisions may 
be made:

Resume dosing of index subject 
(if applicable)

Stop enrollment of the cohort 
(if applicable)

Resume enrollment of the cohort as 
planned

Resume enrollment of the cohort at a 
lower dose

Expand the cohort at the same dose

Add a lower dose cohort to the study

Escalate to an intermediate dose 
(a dose lower than the next planned 
dose)

Escalate to the next planned dose
Any occurrence of a CTCAE v4 Grade 3 or 
greater suspected adverse drug reaction or 
occurrence of an event (including but not 
limited to abnormalities in vital sign, ECG or 
clinical laboratory results) requiring complete 
withdrawal of IP administration in the same 
cohort.
Stop dosing index individual and additional 
subjects in the cohort and convene DLRM 
(if event occurs outside regularly scheduled 
DLRM window)
Review adverse event and all relevant safety 
data for evidence of relationship to treatment 
and clinical or medical significance
Treatment unblinding to support evaluation of 
safety a
If an adverse event is determined by 
unanimous decision of the DLRM members to 
be related to investigational product and 
clinically or medically significant, no further 
doses should be administered at this dose and 
no dose escalation should proceed. Enrollment 
of the study may continue at a lower dose or a 
lower dose cohort may be added to the study
Page 2 of 3
Abbreviations: CTCAE = Common terminology Criteria for Adverse Events; 
a Finding must be confirmed by repeat measurement, whenever possible
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 56 of 114
CONFIDENTIAL
Table 8.  Cohort Dose Stopping Rules
Scenario
Action
Any occurrence of a CTCAE v4 Grade 3 or 
greater suspected adverse drug reaction or 
occurrence of an event (including but not 
limited to abnormalities in vital sign, ECG or 
clinical laboratory results) requiring complete 
withdrawal of IP administration in the same 
cohort.(Continued)
Otherwise, upon unanimous decision of the 
DLRM members, one of the following decisions 
may be made:

Resume dosing of index subject(s) if 
applicable

Resume enrollment of the cohort as 
planned

Resume enrollment of the cohort at a 
lower dose

Expand the cohort at the same dose

Add a lower dose cohort to the study

Escalate to the next planned dose

Escalate to an intermediate dose 
(a dose lower than the next planned 
dose)
Confirmed QTc ≥ 500 msecs or prolonged to 
≥ 60 msecs from baseline in 2 subjects in the 
cohort within the first 6 hours post dose
Dosing will be stopped for any subject that 
meets this criterion.
Serum potassium, magnesium and calcium will 
be measured immediately and the patient will 
receive supplementation to correct any low 
values. The investigator should notify the 
Amgen medical monitor immediately. 
Electrocardiogram monitoring will continue 
hourly for at least 3 hours until the QTc interval 
decreases to < 480 msecs. If hourly ECG’s 
demonstrate a rising QTc interval or QTc 
prolongation >515 msecs, the subject will 
continue to be monitored for at least 24 hours 
until the QTc decreases to < 480 msecs. 
A DLRM will be held to analyze all relevant 
safety and PK data (if available) and decide on 
the following options

Resume dosing of index subject(s) 
(if applicable)

Stop enrollment of the cohort

Complete enrollment of the cohort at 
the same dose level

Expand the cohort at the same dose 
level

Open a new cohort at a lower dose 
level

Escalate to an intermediate dose 
(a dose lower than the next planned 
dose)

Escalate to the next planned dose level
Page 3 of 3
Abbreviations: CTCAE = Common terminology Criteria for Adverse Events; 
a Finding must be confirmed by repeat measurement, whenever possible
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 57 of 114
CONFIDENTIAL
6.2.2
Non-Amgen Investigational Product
Not applicable for this study.
6.3
Non-Investigational Product
Not applicable for this study.
6.3.1
Non-Amgen Non-Investigational Product
Not applicable for this study.
6.4
Other Protocol-required Therapies
Not applicable for this study.
6.5
Hepatotoxicity Stopping and Rechallenge Rules
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009).
6.5.1
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity
Investigational product should be discontinued permanently and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met: 

TBL > 2x upper limit of normal (ULN) or INR > 1.5

AND increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT value
AST or ALT elevation
< ULN
> 3x ULN

AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to:

Hepatobiliary tract disease

Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus)

Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.  
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 58 of 114
CONFIDENTIAL

Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms  

Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir)

Alpha-one antitrypsin deficiency

Alcoholic hepatitis

Autoimmune hepatitis 

Wilson’s disease and hemochromatosis

Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 

Non-hepatic causes (eg, rhabdomylosis, hemolysis)
6.5.2
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational product and other 
protocol-required therapies: 

Elevation of either AST or ALT according to the following schedule:
Baseline AST or ALT value
AST or ALT elevation 
Any
> 8x ULN at any time
Any
> 5x ULN but < 8x ULN for ≥2 weeks
Any
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule
Any
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).  

OR: TBL > 3x ULN at any time

OR: ALP > 8x ULN at any time
Investigational product should be withheld pending investigation into alternative causes 
of DILI.  If investigational product is withheld, the subject is to be followed according to 
recommendations in Appendix A for possible DILI.  Re-challenge may be considered if 
an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is 
discovered and the laboratory abnormalities resolve to normal or baseline 
(Section 6.5.3).
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 59 of 114
CONFIDENTIAL
6.5.3
Criteria for Re-challenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential Hepatotoxicity
The decision to re-challenge the subject should be discussed and agreed upon
unanimously by the subject, investigator, and Amgen.
If signs or symptoms recur with re-challenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate should be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Section 6.5.1) should never be re-challenged. 
6.6
Concomitant Therapy
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.11.
Concomitant therapies are to be collected from informed consent through EOS. Therapy 
name, indication, dose, unit, frequency, route, start date and stop date should be 
collected. 
Acetaminophen (no more than 325 mg per dose and 2 g per day) for analgesia and 
hormone replacement therapy (eg, estrogen, thyroid hormone) will be allowed. Any 
herbal medicines, vitamins and supplements consumed by the subject within 30 days 
prior to receiving the first dose of AMG 986 and continuing use if considered, will be 
reviewed by the principal investigator and Amgen medical monitor. Written 
documentation of this review and Amgen acknowledgment are required for subject 
participation. Details of all concomitant medications will be recorded in the subject’s 
source documents and on the CRF.  
Subjects must not consume grapefruit or grapefruit products during the study or within 
7 days of study Day 1.
6.7
Alcohol and Tobacco Restrictions
Subjects are not permitted to consume any alcohol while in residence and within 
24 hours prior to a study visit (including screening). 
During the study, the use of alcohol will be limited to no more than 1 drink per day 
(1 drink being the equivalent of 12 ounces of regular beer, 5 ounces of wine or 
1.5 ounces of 80 proof distilled spirits). 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 60 of 114
CONFIDENTIAL
Subjects are not permitted to use nicotine or tobacco containing products (including but 
not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches) 
throughout the screening period and for the duration of the study.
There will be no restrictions regarding caffeine intake during the screening period or at 
any time during the study. 
6.8
Other Treatment Procedures
Not applicable for this study.
6.9
Medical Devices
Not applicable for this study.
6.10
Product Complaints
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s), device(s) or combination product (s) provisioned 
and/or repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational 
product.  
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM.
6.11
Excluded Treatments, Medical Device use, and/or Procedures 
During Study Period 
During the study period, use of strong CYP3A4 inhibitors is not allowed, including (not 
limited to): macrolide antibiotics (eg, clarithromycin, telithromycin), antifungals (eg, 
itraconazole, voriconazole), antivirals (eg, ritonavir, saquinavir, indinavir, nelfinavir), 
nefazodone.
During the study period, ingestion of grapefruit or grapefruit products and other foods 
that are known to inhibit CYP3A4 is not allowed.
During the study period, use of strong CYP3A4 inducers is not allowed, Including (not 
limited to): phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital.  
Subjects should not take St John's Wort.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 61 of 114
CONFIDENTIAL
During the study period, use of strong P-glycoprotein inhibitors is not allowed, including 
(not limited to): elacridar and valspodar.
During the study period, use of PDE5 inhibitors including but not limited to avanafil, 
sildenafil, tadalafil, vardenafil is not allowed. 
During the study period, use of vasodilators that could in the opinion of the investigator 
potentially lead to a drop in blood pressure in combination with investigational product is 
not allowed.
7.
STUDY PROCEDURES
7.1
Schedule of Assessments
A complete schedule of assessments has been included in Section 7.1.
Refer to the applicable supplemental (eg, laboratory, imaging, ECG) manuals for 
detailed collection and handling procedures. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 62 of 114
CONFIDENTIAL
Table 9.  Schedule of Assessments for Cohorts 1 & 2 IV Part A
Activity
Screening
Check-in
Treatment Period
Study Day
-28 to -2
-1
1
Study Time (Hours)
Predose
0
0.25
0.5
1
1.25
1.5
2
3
4
6
8
12
General & Safety Assessments
Informed Consent
X
Residency A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
Physical Examination
X
X
Weight
X
X
Height
X
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
Troponin I
X
X
FSH (postmenopausal females only) D
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X G
X
X
X
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK
X H
X I
Page 1 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 63 of 114
CONFIDENTIAL
Table 9.  Schedule of Assessments for Cohorts 1 & 2 IV Part A
Activity
Follow Up Period
EOS
Study Day
2
3
4
5
14
30
Study Time (Hours)
24
48
72
96
General & Safety Assessments
Informed Consent
Residency A
X
X
Medical History
Physical Examination
X
X
X
X
Weight
Height
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
ECG C
X
X
X
Concomitant Medications
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
X
Troponin I
X
X
FSH (postmenopausal females only) D
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
X
Echocardiographic Assessments
M-mode and 2-D
M-mode, 2-D, Flow & Tissue Doppler
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X
Cumulative Urine Collection for AMG 986 PK
X J
X K
Page 2 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 64 of 114
CONFIDENTIAL
Table 10.  Schedule of Assessments for Cohorts 3 to 5 IV Part A
Activity
Screening
Check-in
Treatment Period
Study Day
-28 to -2
-1
1
Study Time (Hours)
Predose
0
0.25
0.5
1
1.25
1.5
2
6
12
General & Safety Assessments
Informed Consent
X
Residency A
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
Physical Examination
X
X
Weight
X
X
Height
X
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
Troponin I
X
X
FSH (postmenopausal females only) D
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
X
IP Administration (MD, 23 hr infusion)
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X G
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK 
X H
X I
Page 1 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 65 of 114
CONFIDENTIAL
Table 10.  Schedule of Assessments for Cohorts 3 to 5 IV Part A
Activity
Treatment Period
Follow-Up Period
EOS
Study Day
2
3
4
5
6
7
14
30
Study Time (Hours)
24
24.25
24.5
25
26
27
29
31
36
48
72
96
120
144
General & Safety Assessments
Informed Consent
Residency A
X
X
X
X
X
X
X
X
X
X
Medical History
Physical Examination
X
X
X
X
Weight
Height
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
XT
X
X
ECG C
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
XT
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
XT
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
XT
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
X
Troponin I
X
X
FSH (postmenopausal females only) D
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
X
Echocardiographic Assessments
M-mode and 2-D
X
X
XU
M-mode, 2-D, Flow & Tissue Doppler
X
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
IP Administration (MD, 23 hr infusion)
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X G
X
X
X
X
X
X
X
X
X
X
X
X
XT
Cumulative Urine Collection for AMG 986 PK
X J
X K
Page 2 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 66 of 114
CONFIDENTIAL
Table 11.  Schedule of Assessments for Cohorts 1-6 PO Part A
Activity
Screening Check-in
Treatment Period
Follow Up Period
EOS
Study Day
-28 to -2
-1
1
2
3
4
5
14
30
Study Time (Hours)
Predose
0
0.5
1
2
3
4
6
8
12
24
48
72
96
General & Safety Assessments
Informed Consent
X
Residency A
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
Physical Examination
X
X
X
X
X
Weight
X
X
Height
X
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
X
X
Troponin I
X
X
X
X
FSH (postmenopausal females only) D
X
Pregnancy
X
X
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
X
Investigational Product Administration
IP Administration
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
X
X
X
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK
X H
X I
X J
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 67 of 114
CONFIDENTIAL
Table 12.  Schedule of Assessments for IV Cohorts Part B
Activity
Screening
Check-in
Treatment Period
Study Day
-28 to -2
-1
1
2
3
4
Study Time (Hours)
Predose
0
0.25
0.5
1
1.25
1.5
2
6
12
24
48
72
General & Safety Assessments
Informed Consent
X
Residency A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
Physical Examination
X
X
X
Weight
X
X
Height
X
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
Troponin I
X
X
X
Plasma Osmolality
X E
X
X
Urine Osmolality
X N
X S
X S
FSH (postmenopausal females only) D
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
X
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
X
IP Administration (MD, 23 hr infusion [Day 1])
X
IP Administration (MD, 24 hr infusion [Days 2-4])
X
X
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X G
X
X
X
X
X G
X G
X G
Cumulative Urine Collection for AMG 986 PK 
X M
Page 1 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 68 of 114
CONFIDENTIAL
Table 12.  Schedule of Assessments for IV Cohorts Part B
Activity
Follow-Up Period
EOS
Study Day
5
5
5
5
5
5
5
5
5
6
7
8
10
14
30
Study Time (Hours)
96
96.25
96.5
97
98
99
101
103
108
120
144
168
216
General & Safety Assessments
Informed Consent
Residency A
X
X
X
X
X
X
X
X
X
X
Medical History
Physical Examination
X
X
X
X
Weight
Height
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
Troponin I
X
Plasma Osmolality
X
Urine Osmolality
X S
FSH (postmenopausal females only) D
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
X
Echocardiographic Assessments
M-mode and 2-D
X
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
X
X
Investigational Product Administration
IP Administration (LD, 1 hr infusion)
IP Administration (MD, 23 hr infusion [Day 1])
IP Administration (MD, 24 hr infusion [Days 2-4])
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X G
X
X
X
X
X
X
X
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK 
X M
Page 2 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 69 of 114
CONFIDENTIAL
Table 13.  Schedule of Assessments for PO Cohorts Part B
Activity
Screening
Check-in
Treatment Period
Study Day
-28 to -2
-1
1
2
3
4
5-6
Study Time (Hours)
Predose
0
0.5
1
2
3
4
6
8
12
24 Q
48 Q
72Q
73-143 Q
General & Safety Assessments
Informed Consent
X
Residency A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical History
X
Physical Examination
X
X
X
Weight
X
X
Height
X
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X P
Troponin I
X
X
X
X R
Plasma Osmolality
X E
X
Urine Osmolality
X N
X S
FSH (postmenopausal females only) D
X
Pregnancy
X
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
X
Investigational Product Administration
IP Administration L
X
X
X
X
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
X
X
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK
X M
Page 1 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 70 of 114
CONFIDENTIAL
Table 13.  Schedule of Assessments for PO Cohorts Part B
Activity
Treatment Period
Follow-Up Period
EOS
Study Day
7
8
9
10
11
14
21
30
Study Time (Hours)
144 Q
144.5
145
146
147
148
150
152
156
168
192
216
240
General & Safety Assessments
Informed Consent
Residency A
X
X
X
X
X
X
X
X
X
X
Medical History
Physical Examination
X
X
X
X
X
Weight
Height
Vital Signs (BP F, HR, RR, TEMP) B
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG C
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
X
Troponin I
X
X
Plasma Osmolality
X
Urine Osmolality
X S
Pregnancy D
X
FSH (postmenopausal females only) D
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
X
X
X
Echocardiographic Assessments
M-mode and 2-D
X
X
X
X
M-mode, 2-D, Flow & Tissue Doppler
X
X
X O
Investigational Product Administration
IP Administration L
X
Pharmacokinetic Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
X
X
X
X
X
X
X
X
Cumulative Urine Collection for AMG 986 PK
XK
Page 2 of 2
Footnotes defined on page 71
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 71 of 114
CONFIDENTIAL
A Subjects in study Parts A and B will remain in-house from Day -1 through the completion of all assessments designated in the SOA.
B Vital signs will be performed pre-dose for each day in residency and at time points in the SOA. 
C.ECGs will be performed on Day 1 pre-dose.  Study eligibility QTc must be < 450 msec as mentioned in section 122.  Consultation with the medical monitor is required 
prior to dosing if QTc > 450 msec on Day 1 pre-dose.  At screening a single ECG will be performed.  At baseline, ECGs will be performed on 3 occasions separated 
by at least 30 minutes all in triplicate for a total of 9 ECGs. At all other time points ECGs will be performed in a standardized method, in triplicate and approximately 
30 seconds apart, prior to blood draws or other invasive procedures. 
D.Female subjects only.
E Should be collected for subjects who qualify for enrollment. 
F.BP measurements will be obtained in triplicate approximately 2 minutes apart in a semi-Fowler position at pre-dose and at time points corresponding to ECG 
monitoring.
G PK sample collection to occur just prior to the end of infusion.
H Urine sample obtained at pre-dose void collection (5mL to 10mL aliquot).
I Aliquot (5mL to 10mL) of cumulative urine collection (0h to 12h) taken for PK sample.
J.Aliquot (5mL to 10mL) of cumulative urine collection (12h to 24h) taken for PK sample.
K Aliquot (5mL to 10mL) of cumulative urine collected over past 24h taken for PK.
L Once daily PO AMG 986/placebo administration for 7 consecutive days.
M Aliquot (5mL to 10mL) of 24h urine collection taken for PK sample.
N Cumulative collection of urine over past 24 h required for baseline assessment. Required for subjects who meet eligibility requirements for enrollment. Not a 
requirement to assess eligibility for enrollment.
O This assessment will be performed only if deemed necessary by the investigator upon review of the prior assessment.
P.Chemistry, Hematology, & Urinalysis to be collected on Day 5.
Q Procedures to be completed prior to dosing: physical examination, vital signs, ECGs, laboratory assessments, echocardiographic assessments, pharmacokinetic 
assessments.
R Troponin I to be collected on Day 5.
S Cumulative collection of urine over past 24 h required for osmolality assessment
T.To be collected for only Cohort 5 IV Part A
U.To be collected for only Cohorts 4 and 5 IV Part A
V.If dose is reduced, patients will be observed for at least 6 hours after the first administration of a new dose
W.Adverse events possibly related to any study procedures/study activity are reported from signing of the ICF. 
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 72 of 114
CONFIDENTIAL
Table 14.  Schedule of Assessments for Patient Cohort Part C
Activity
10 mg PO Treatment
Study Day
-28 to 
-2k
-1
1
2
3
4
5
6
7
Study Time (Hours)
Predose
0
1
2
4
6
24G
48G
72G
96G
120G
144G
General & Safety Assessments
Informed ConsentJ
X 
Medical History
X
Physical Examination
X
X
X
Weight
X
X
Height
X
Vital Signs (BPE, HR, RR, TEMP)A
X
X
X
X
X
X
X
X
X
X
X
X
ECGB
X
X
X
X
X
X
Concomitant Medications
Adverse EventsI
Serious Adverse Events
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
Troponin I
X
X
X
X
NT-proBNP
X
FSH (postmenopausal females only) C
X
Pregnancy C
X
X
HIV, HepCAb, HBsAg, HBcAb
X
Drug, Alcohol, & Cotinine Screen
X
X
Echocardiographic Assessments
M-mode, 2-D, Flow & Tissue Doppler
X
X
X
X 
Investigational Product AdministrationE
IP Administration PO (10 mg, Days 1-7)
X
X
X
X
X
X
X
Pharmacokinetic/Biomarker 
Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
X
Plasma and Serum Biomarker Collection
X
Cell Pellet Collection
X
Page 1 of 3
Footnotes defined on page 75
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 73 of 114
CONFIDENTIAL
Table 14.  Schedule of Assessments for Patient Cohort Part C
Page 2 of 3
Footnotes defined on page 75
Activity
30 mg PO
Study Day
8
9
10
11
12
13
14
Study Time (Hours)
168G
(Predose)
170
172
174
192G
216G
240
G
264G
288G
312G
General & Safety Assessments
Informed Consent
Medical History
Physical Examination
Weight
Height
Vital Signs (BPE, HR, RR, TEMP)A
X
X
X
X
X
X
X
X
ECGB
X
X
Concomitant Medications
Adverse EventsI
Serious Adverse Events
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
Troponin I
X
X
NT-proBNP
FSH (postmenopausal females only)C
PregnancyC
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
Echocardiographic Assessments
M-mode, 2-D, Flow & Tissue Doppler
X
X
X
Investigational Product 
Administration
IP Administration PO (30 mg, Days 8-
14)E
X
X
X
X
X
X
X
Pharmacokinetic/Biomarker 
Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
Plasma and Serum Biomarker 
Collection
X
Cell Pellet Collection
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 74 of 114
CONFIDENTIAL
Table 14.  Schedule of Assessments for Patient Cohort Part C
Activity
100 mg
EOS
Study Day
15
Predose
16
17
18
19
20
21
30
Study Time (Hours)
336G
337
338
340
342
360G
384G
408G
432G
456G
480 G
General & Safety Assessments
Informed Consent
Medical History
Physical Examination
X
X
X
Weight
Height
Vital Signs (BPE HR, RR, TEMP)A
X
X
X
X
X
X
X
X
X
X
ECGB
X
X
X
X
X
Concomitant Medications
Adverse EventsI
Serious Adverse Events
Laboratory Assessments
Chemistry, Hematology, & Urinalysis
X
X
X
X
Troponin I
X
NT-proBNP
FSH (postmenopausal females only)C
PregnancyC
X
HIV, HepCAb, HBsAg, HBcAb
Drug, Alcohol, & Cotinine Screen
Echocardiographic Assessments
M-mode, 2-D, Flow & Tissue Doppler
X
X
X
X
X
Investigational Product 
Administration
IP Administration PO (100 mg, Days 
15-21)E
X
X
X
X
X
X
X
Pharmacokinetic/Biomarker 
Assessments
AMG 986 Plasma PK Collection
X
X
X
X
X
X
X
Plasma and Serum Biomarker 
Collection
X
X
Cell Pellet Collection
Page 3 of 3
Footnotes defined on page 75
 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 75 of 114
CONFIDENTIAL
A.Vital signs will be performed pre-dose for each day and at time points in the SOA. 
B.ECGs will be performed on Day 1 pre-dose and may be repeated.  .  At screening a single ECG will be performed.  At baseline, a single ECG will be performed. . At 
all other time points single ECGs will be performed in a standardized method, and prior to blood draws or other invasive procedures. 
C.Female subjects only.
D.BP measurements will be obtained in a semi-Fowler position at pre-dose and at time points listed in the SOA.
E.Once daily PO AMG 986/placebo administration for 7 consecutive days.
F.This assessment will be performed only if deemed necessary by the investigator upon review of the prior assessment.
G.Procedures to be completed prior to dosing: physical examination, vital signs, ECGs, laboratory assessments, echocardiographic assessments, pharmacokinetic 
assessments.
H.If dose is reduced, patients will be observed for at least 6 hours after the first administration of a new dose
I.Adverse events possibly related to any study procedures/study activity are reported from signing of the ICF. 
J.At the discretion of the PI and with safety considerations paramount, subjects may undergo study procedures on an inpatient basis.
k.Screening and Day -1 activities may be performed on the same day.
 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  27 July 2018 
Page 76 of 114 
CONFIDENTIAL 
 
7.2 
General Study Procedures 
Before any study-related screening or baseline procedure can be completed, a subject 
must sign and date the IRB-approved ICF.  After informed consent has been obtained, 
all screening procedures and tests establishing eligibility will be performed.  Screening 
procedures are summarized in the Schedule of Assessments (Section 7.1). 
During the study, every effort should be made to perform study procedures as indicated 
in the Schedule of Assessments (Section 7.1).  Additional procedures deemed 
necessary as part of standard of care or as required by local laws and regulations may 
be performed at the investigator’s discretion. 
Throughout the study, the permitted time windows for scheduled assessments will be as 
follows: 
Table 15.  Study Visit Windows 
Study Part 
Cohort Name 
Visit Window 
PK Plasma Collection 
Window 
PK Urine 
Collection Window 
Part A 
Cohorts 1-2 IV 
(Part A) 
Days 14 & 30: ± 1 day 
Days 1-2: 
 ± 10 minutes 
Days 3-5: ± 1 hour 
Day 1: ± 1 hour 
Days 2-5:  
± 2 hours 
Cohorts  3-5 IV 
(Part A) 
Days 14 & 30: ± 1 day 
Days 1-2: 
± 10 minutes 
Days 3-6: ± 1 hour 
Day 1: ± 1 hour 
Days 2-6:  
± 2 hours 
Cohorts 1-4 PO 
(Part A) 
Days 14 & 30: ± 1 day 
Day 1: ± 10 minutes 
Days 2-5: ± 1 hour 
Day 1: ± 1 hour 
Days 2-5:  
± 2 hours 
 
Cohorts 5-6 PO 
(Part A) 
Days 14 & 30: ± 1 day 
Day 1: ± 10 minutes 
Days 2-5: ± 1 hour 
Day 1: ± 1 hour 
Days 2-5:  
± 2 hours 
Part B 
Cohorts 1-2 IV 
(Part B) 
Days 14 & 30: ± 1 day 
Days 1-5:  
± 10 minutes 
Days 6-8: ± 1 hour 
Day 5: ± 2 hours 
 
Cohorts 1-4 PO 
(Part B) 
Days 11, 14, & 21: 
± 1 day 
Day 1: 
 ± 10 minutes 
Day 7:  
± 10 minutes 
Days 2-6:  
± 1 hour 
Days 8-10:  
± 1 hour 
Day 8:  
± 2 hours 
 
Cohorts 5-6 PO 
(Part B) 
Days 11, 14, & 21: 
± 1 day 
Day 1: 
 ± 10 minutes 
Day 7:  
± 10 minutes 
Days 2-6:  
± 1 hour 
Days 8-10:  
± 1 hour 
Day 8:  
± 2 hours 
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Table 15.  Study Visit Windows 
Study Part 
Cohort Name 
Visit Window 
PK Plasma Collection 
Window 
PK Urine 
Collection Window 
Part C 
HFrEF and 
HFpEF 
Not Applicable 
Days 1: 
 ± 10 minutes 
Days 2-4: ± 1 hour 
Day 5: 
 ± 10 minutes 
Days 6-8: ± 1 hour 
Day 9: 
 ± 10 minutes 
Days 10-16: 
 ± 1 hour 
Days 17-21: ± 1 hour 
Not collected 
Page 2 of 2 
Meal Restrictions: 
The clinical site will provide standardized meals to the subjects during the in-house 
residency period. 
Subjects are required to refrain from food and drinks (except water) 8 hours prior to each 
laboratory measurement. 
Exercise Restrictions: 
Subjects are required to refrain from strenuous exercise during screening, during 
in-house residency period and 48 hours prior to each outpatient visit. 
7.2.1 
Screening 
After informed consent is obtained, screening procedures are to be completed during the 
screening period at time points designated in the Schedule of Assessments 
(Section 7.1). 
For Rescreen Subjects:  A new informed consent form must be signed unless it has 
been < 30 days since the previous ICF signature was obtained. 
Repeat Assessments: Screening assessments (eg, vital signs, ECGs, laboratory 
assessments, cotinine and urine drug screen) may be repeated during screening.  The 
decision regarding whether a subject has failed screening after repeat assessment will 
be decided on a case-by-case basis at the discretion of the Principal Investigator.  The 
decision to re-screen a subject will be made on a case-by-case basis at the discretion of 
the Amgen Medical Monitor in consultation with the Principal Investigator. 
7.2.2 
Baseline / Day -1 
Baseline is defined as assessments completed on Day -1 or Day 1 pre-dose, when the 
procedure is performed on Day 1 pre-dose.  Subjects will be admitted to the research 
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facility on the day before IP administration (Day-1).  The baseline / Day -1 procedures 
are to be completed at time points designated in the Schedule of Assessments 
(Section 7.1).  
7.2.3 
Treatment 
Treatment begins when the first dose of protocol-required therapies is administered to a 
subject.  The treatment procedures are to be completed during the Treatment Visits at 
time points designated in the Schedule of Assessments (Section 7.1).  
If any subject stops treatment (eg, due to an adverse event), the subject will be asked to 
continue to complete protocol-required visits for safety monitoring as determined by the 
Principal Investigator in consultation with the Amgen Medical Monitor and Amgen Global 
Safety Officer.   
When multiple post dose procedures are required to be conducted at the same nominal 
time point, the following order of precedence will be used: (1) vital signs, (2) ECGs, 
(3) PK sample collection, (4) Echocardiogram.   
7.2.4 
Safety Follow-up Visit(s)/End of Study Visit 
Subjects will return to the clinic for follow-up visits in accordance to the Schedule of 
Assessments (Section 7.1) and be followed through the completion of the EOS 
procedures on Day 30.  If an EOS test result demonstrates a clinically significant clinical 
or laboratory abnormality, the subject will be followed until resolution of the abnormality 
or until it is considered clinically stable by the investigator.   
7.2.5 
Long-term Follow-up 
Not applicable for this study.  
7.2.6 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and association to AMG 986. 
7.2.7 
Medical History 
The investigator or designee will collect a complete medical history from birth to 
enrollment at screening and other times shown in Section 7.1.  Any unresolved medical 
history will be graded according to Common Terminology Criteria for Adverse Events 
CTCAE version 4.0 (Appendix A) unless specified otherwise.  Medical history will include 
information on the subject’s concurrent medical conditions.  All findings will be recorded 
on the relevant CRF. 
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7.2.8 
Physical Examination 
The investigator or qualified designee will perform a physical examination at the time 
points indicated in Section 7.1.  Pre-dose abnormal findings will be reported on the 
medical history CRF.  Any adverse change from the Baseline physical examination 
(Screening and Day -1 physical examination) will be documented on the Event CRF. 
7.2.9 
Physical Measurements 
Height measurement (in cm and without shoes) and weight measurement (in kg and 
without shoes) will be obtained.  Body mass index (BMI) will be calculated using height 
and weight measurements taken at screening and using the following formula: 
BMI (kg/m2) = weight (kg)/[height (cm/100]2 
7.2.10 
Vital Signs 
Safety vital signs will be recorded by the investigator or designee at time points specified 
in Section 7.1. 
The following measurements must be performed: systolic/diastolic BP, HR, respiratory 
rate, and temperature. 
Blood pressure will be measured in the following manner: 
 
Subjects should be lying in a semi-Fowler position quietly and comfortably for at 
least 5 minutes.  The upper arm should be bare without constrictive clothing and 
supported at heart level. 
 
An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) 
should be used to ensure accuracy.  Neither the subject nor the observer 
(measurer) should talk during measurement. 
In Parts A and B, BP measurements will be performed in a standardized method in 
triplicate approximately 2 minutes apart.  Triplicate measurements of BP will be obtained 
at pre-dose and at time points corresponding to ECG monitoring.  At time points in which 
ECG monitoring is not performed, single measures of BP will be obtained as part of the 
safety vital signs monitoring.  In Part C, single BP measurements will be performed in a 
standardized method at pre-dose and at time points corresponding to ECG monitoring.  
At time points in which ECG monitoring is not performed, single measures of BP will be 
obtained as well. PK sample collection should occur after blood pressure measurements 
and ECG monitoring are completed.   
Respiratory rate will be assessed by a full minute count.  Abnormal measurements 
maybe repeated at the investigator’s discretion.  All data collected will be entered on the 
CRF. 
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The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF. 
Record all measurements on the vital signs CRF.  Abnormal measurements may be 
repeated at the discretion of the investigator and must be reported on the corresponding 
CRF page.  When vital signs and blood sample collection occur at the same time, vital 
signs should be performed before blood samples. 
7.2.11 
Serum Follicle-stimulating Hormone Test (Females Only) 
Additional serum will be collected for an FSH test for females at screening.  Females 
must be of non-reproductive potential (ie, postmenopausal – age of ≥ 55 years with no 
spontaneous menses for at least 12 months, or age of < 55 years with no menses for at 
least 12 months AND with postmenopausal gonadotropin levels (follicle-stimulating 
hormone levels > 40 IU/Lor according to the definition of “postmenopausal range” for the 
laboratory involved) OR history of hysterectomy; OR history of bilateral oophorectomy 
OR history of bilateral salpingectomy). 
Results must be consistent with postmenopausal status per local laboratory ranges for 
inclusion in this study.  Postmenopausal status will be recorded on the medical history 
CRF. 
7.2.12 
Drug, Alcohol and Cotinine Screening 
Drug, alcohol, and cotinine assessments are to be completed at screening, Day -1, and 
other times as listed in the Schedule of Assessments including amphetamines, 
barbiturates benzodiazepines, cocaine, ethanol, opiates, and tetrahydrocannabinol. 
Subjects with a positive cotinine or drug test at screening may be retested once at the 
discretion of the investigator.  Subjects with a positive test for cotinine at screening will 
be asked to refrain from being around second-hand smoke for 24 hours prior to Day -1.  
Subjects who test positive at Day -1 for drug, alcohol or cotinine will not qualify for 
investigational product administration and will be withdrawn from study participation. 
7.2.13 
Electrocardiogram 
Electrocardiograms (henceforth referred to as electrocardiogram or ECG) will be 
performed using standard electrocardiogram machine at the times shown in the 
Schedule of Assessments (Section 7.1). 
In Parts A and B, electrocardiograms will be collected as follows: 
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With the exception of the Screening ECG, which will be performed as a single 
electrocardiogram, all ECGs should be performed in a standardized method, in triplicate, 
and approximately 30 seconds apart, prior to blood draws or other invasive procedures. 
At screening a single ECG will be performed.  At baseline (on day 1 pre-dose) ECGs will 
be performed on 3 occasions separated by at least 30 minutes all in triplicate for a total 
of 9 ECGs (3 sets of triplicate).  At all other time points, ECGs will be performed in a 
standardized method, in triplicate, and approximately 30 seconds apart, prior to blood 
draws or other invasive procedures.  
Subject must be in a semi-Fowler position in a rested and calm state for at least 
5 minutes before the electrocardiogram is obtained. 
If the subject is unable to be in the semi-Fowler position, the subject should be in the 
most recumbent position possible.  The electrocardiogram will be performed prior to any 
blood draws.  The interval and frequency of electrocardiogram assessments may be 
modified based on emerging PK, and/or PD, and/or safety data but the number of ECG 
measurements should not exceed what is planned in the specific cohort. 
The electrocardiogram must include the following measurements:  RR, QRS, QT, QTc, 
and PR intervals. 
The Principal Investigator or designated site physician will review all electrocardiograms.  
Once signed, the original electrocardiogram tracing will be retained with the subject’s 
source documents.  At the request of the sponsor, a copy of the original 
electrocardiogram will be made available to Amgen. 
In Part C, electrocardiograms will be collected as follows: 
At screening a single ECG will be performed.  At baseline (on day 1 pre-dose) a single 
ECG will be performed on 1 occasion for a total of 1 ECG.  At all other time points, 
ECGs will be performed in a standardized method, prior to blood draws or other invasive 
procedures. 
Subject must be in a semi-Fowler position in a rested and calm state for at least 
5 minutes before the electrocardiogram is obtained. 
If the subject is unable to be in the semi-Fowler position, the subject should be in the 
most recumbent position possible.  The electrocardiogram will be performed prior to any 
blood draws.  The interval and frequency of electrocardiogram assessments may be 
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modified based on emerging PK, and/or PD, and/or safety data but the number of ECG 
measurements should not exceed what is planned in the specific cohort. 
The electrocardiogram must include the following measurements:  HR, QRS, QT, QTc, 
and PR intervals. 
The Principal Investigator or designated site physician will review all electrocardiograms.  
Once signed, the original electrocardiogram tracing will be retained with the subject’s 
source documents.  At the request of the sponsor, a copy of the original 
electrocardiogram will be made available to Amgen. 
7.2.14 
Echocardiograms 
Echocardiograms will be completed at the time points detailed in the Schedule of 
Assessments in Section 7.1.  Where possible, staff involved in the treatment and 
evaluation of the study subject should not view study echocardiograms (with the 
exception of the screening echocardiogram which should be reviewed by site staff to 
confirm subject eligibility).  Further, the sonographer should abstain from commenting on 
any observations in the echocardiograms that may be potentially unblinding.  The 
echocardiograms will be sent to the core imaging vendor for analysis.  Please refer to 
the echocardiography instruction manual for detailed information on acquiring, storing, 
and transmitting the echocardiograms. 
7.2.15 
Clinical Chemistry 
Blood samples for clinical chemistry will be collected at the time points specified in the 
Schedule of Assessments (Section 7.1).  Baseline assessments will be taken on Day-1. 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety.   
The tests listed in   
Table 16 will be conducted and analyzed by standard laboratory procedures. 
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Table 16.  List of Analytes 
Chemistry 
Hematology 
Urinalysis 
Alanine Aminotransferase 
(ALT / SGPT) 
Albumin 
Alkaline Phosphatase (ALP) 
Aspartate Aminotransferase 
(AST / SGOT) 
Bicarbonate (HCO3) or 
Carbon Dioxide (CO2) 
Direct Bilirubin 
Total Bilirubin (TBIL) 
Blood Urea Nitrogen (BUN) or 
Urea 
Calcium 
Chloride 
Troponin I 
NT-proBNP 
Creatinine 
Total Creatine Kinase 
Glucose 
Lipid Profile  
Total Cholesterol 
HDL 
LDL 
Triglycerides 
Magnesium 
Phosphorus or Phosphate 
Plasma Osmolality 
Potassium 
Total Protein 
Sodium 
Uric acid 
Mean Corpuscular 
Hemoglobin Concentration 
Mean Corpuscular 
Hemoglobin 
Mean Corpuscular Volume 
Hematocrit 
Hemoglobin 
Platelets 
Red Blood Cells 
White Blood Cells 
White Blood Cell Differential 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Total Neutrophils (OR 
segmented 
neutrophils and band 
cells) 
Bilirubin 
Blood 
Glucose 
Ketones 
Microscopic Exam 
(performed at the 
discretion of the PI or 
qualified designee) 
White blood cells 
Red blood cells 
Epithelial Cells 
Casts 
Bacteria 
Crystals 
pH 
Protein 
Specific Gravity 
Urobilinogen 
 
Urine Collection 
24 hour urine collection 
Urine Volume 
Urine Osmolality 
FSH 
Pregnancy 
*Hepatitis B surface antigen, Hepatitis C antibody, PCR for Hepatitis C RNA (if Hepatitis C antibody is 
positive), and HIV assessments are recommended. 
*The estimated blood volume required for this study is approximately 222 mL. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.16 
Hematology 
Blood samples for hematology tests will be collected at the time points as specified in 
Section 7.1.  All laboratory tests must be reviewed and signed by the principal 
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investigator or qualified designee.  Additional safety laboratory assessments may be 
performed for subject safety. 
Table 16 will be conducted using standard laboratory procedures. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.17 
Urinalysis 
Urine samples will be collected at Screening and as specified in Section 7.1.  All 
laboratory tests must be reviewed and signed by the Principal Investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety. The tests listed in  
Table 16 will be conducted using standard laboratory procedures. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.18 
Estimated Glomerular Filtration Rate  
For determining eligibility, estimated glomerular filtration rate (eGFR) will be calculated 
by the estimated Modification of Diet in Renal Disease (MDRD) formula based on serum 
creatinine, age, sex and race values at time points indicated in the Schedule of 
Assessments (Section 7.1). 
7.2.19 
Hepatitis B Surface Antigen and Core Antibody, Hepatitis C 
Antibody and HIV Status 
Hepatitis B surface antigen and core antibody, Hepatitis C antibody, and human 
immunodeficiency virus (HIV) titers will be assessed at screening only and must be 
confirmed negative to be eligible for this study.  
7.2.20 
Concomitant Medications and Adverse Event Reporting 
Subjects will be assessed for concomitant medication(s) usage during each out-patient 
visit.  Any concomitant medication use reported throughout the study will be recorded in 
the source documents and the CRF. 
Subjects will be assessed for adverse events/serious adverse events at least daily 
during resident periods and during each outpatient visit.  Determination of the severity of 
all adverse event(s) will be consistent with Common Terminology Criteria for Adverse 
Events (CTCAE) V4 (Appendix A) unless specified otherwise.  Adverse events will be 
captured in the source documents and on the CRF when reported or observed. 
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7.3 
Antibody Testing Procedures 
Not applicable for this study.   
7.4 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development may be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity. 
Amgen may attempt to develop blood tests designed to identify subjects most likely to 
respond positively or negatively to AMG 986.   
Blood Samples 
Where authorized by the IRB/IEC-approved informed consent, blood samples are to be 
collected for biomarker development at the time points detailed in the Schedule of 
Assessments in Section 7.1 
7.5 
Pharmacogenetic Studies 
In Part C patient cohorts, if the subject consents to the optional pharmacogenetic portion 
of this study, DNA analyses may be performed.  These optional pharmacogenetic 
analyses focus on inherited genetic variations to evaluate their possible correlation to the 
disease and/or responsiveness to the therapies used in this study.  The goals of the 
optional studies include the use of genetic markers to help in the investigation of HF 
and/or to identify subjects who may have positive or negative response to AMG 986.  No 
additional samples will be collected for this part of the study.  For subjects who consent 
to these analyses, DNA may be extracted from samples already collected. 
Cell pellets will be collected at pre-dosing from subjects who consent to 
pharmacogenetics testing.  
7.6 
Optional Sub-studies 
Not applicable for this study. 
7.7 
Sample Storage and Destruction 
Any blood sample (eg, biomarker, PK, pharmacogenetics) collected according to the 
Schedule of Assessments (Section 7.1) can be analyzed for any of the tests outlined in 
the protocol and for any tests necessary to minimize risks to study subjects.  This 
includes testing to ensure analytical methods produce reliable and valid data throughout 
the course of the study.  This can also include, but is not limited to, investigation of 
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unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing (not 
pharmacogenetics testing) on remaining samples (ie, residual and back-up) to 
investigate and better characterize aspects of the AMG 986 (eg, mechanism of 
action/target, metabolites) and to be applied in assay development.  Results from this 
analysis are to be documented and maintained, but are not necessarily reported as part 
of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of these exploratory studies are not placed in the subject’s 
medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed 
consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the Investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Section 7.1) 
and collection of data, including endpoints and adverse events.  The Investigator must 
document the change to the Schedule of Assessments (Section 7.1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
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8.3 
Reasons for Removal From Washout, Run-in, Invasive Procedures, 
Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
subject request 
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
 
death 
 
lost to follow-up 
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
Reasons for Removal from Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Not applicable for this study. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study, or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
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If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria:  
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
Information for a serious adverse event is collected from signing of the ICF through 
30 days post last dose of AMG 986 or placebo.   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Reporting Procedures for Disease-related Events 
Not applicable for this study. 
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9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Adverse events possibly related to any study procedures/study-activity are reported from 
signing of the ICF.  All other adverse events are reported from the time of randomization 
(first dose of investigational product).  The investigator is responsible for ensuring that all 
adverse events observed by the investigator or reported by the subject that occur from 
signing of the ICF or from the time of randomization (after the first dose of IP) through 
the End of Study are reported using the Event CRF.   
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity [and/or toxicity per protocol], 
 
Assessment of relatedness to IP (AMG 986 or placebo),  
 
Assessments of relatedness to any study-mandated activity/procedure and 
 
Action taken 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.  
The investigator must assess whether the adverse event is possibly related to the 
investigational product (AMG 986 or placebo).  This relationship is indicated by a “yes” 
or “no” response to the question:  Is there a reasonable possibility that the event may 
have been caused by the investigational product (AMG 986 or placebo)? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity [eg, administration of investigational product, protocol-required 
therapies, use of medical device(s) and/or procedure (including any screening 
procedure(s)].  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by a study 
activity [eg, administration of investigational product, protocol-required therapies, use of 
medical device(s)], and/or procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the Investigator's judgment) are not to be 
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recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
The investigator will report all AEs categorized as CTCAE v.4 Grade 2 or higher to the 
Medical Monitor (eg, Amgen Study Clinical Director or medically qualified designate) via 
email within 24 hours of event occurrence.  The investigator will include all available 
clinical information regarding an event as part of this reporting procedure and provide 
follow-up information as it becomes available.  The Amgen Medical Monitor will be 
responsible to complete the unblinded review of the information within 24 hours of 
receipt in order to look for any emerging safety signal (from either a single AE or pattern 
of AEs). 
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval of investigational 
product or end of study, whichever is later, are recorded in the subject’s medical record 
and are submitted to Amgen.  All serious adverse events must be submitted to Amgen 
within 24 hours following the investigator’s knowledge of the event via the Serious 
Adverse Event Report Form (SAER). The SAER Form may also be utilized to report 
serious adverse events after the end of study (refer to Section 9.2.2.3).   
See Appendix B for a sample of the Serious Adverse Event Report (SAER) Form. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event.  
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Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
See Appendix B for a sample of the Serious Adverse Event Report Form. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product (AMG 986 or placebo).  This relationship is indicated by a 
“yes” or “no” response to the question:  Is there a reasonable possibility that the event 
may have been caused by the investigational product (AMG 986 or placebo)? 
Relatedness means that there are facts or reasons to support a relationship between 
investigational product and the event.  
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs in 
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compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB of serious adverse events occurring at 
the site and other adverse event reports received from Amgen, in accordance with local 
procedures and statutes. 
9.2.2.4 
Reporting a Safety Endpoint as a Study Endpoint 
Not applicable for this study. 
9.2.2.5 
Serious Adverse Events That are not to be Reported by the 
Sponsors to Regulatory Agencies in an Expedited Manner  
Not applicable for this study. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking IP (AMG 986 or placebo) report the pregnancy to Amgen Global Patient 
Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 11 weeks after the last dose of IP (AMG 986 or 
placebo). 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. If the outcome 
of the pregnancy meets a criterion for immediate classification as a Serious Adverse 
Event (eg, female subject experiences a spontaneous abortion, stillbirth, or neonatal 
death or there is a fetal or neonatal congenital anomaly) the investigator will report the 
event as a Serious Adverse Event. 
If a female subject breastfeeds while taking IP (AMG 986 or placebo) report the lactation 
case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur through 11 weeks after the last dose IP (AMG 986 or 
placebo). 
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Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints  
 
Subject incidence of treatment-emergent adverse events 
 
Subject incidence of clinically significant changes in physical examinations, vital 
signs, laboratory safety tests, and electrocardiograms (ECGs) 
10.1.1.2 
Secondary Endpoints 
 
AMG 986 PK parameters including, but not limited to, maximum observed 
concentration (Cmax), the time of maximum observed concentration (tmax), area 
under the concentration-time curve (AUC), and oral bioavailability  
 
Changes over time from baseline in echocardiographic parameters of left 
ventricular systolic and diastolic functions (left ventricular ejection fraction, 
fraction shortening, stroke volume, wall thickening, end-systolic and end-diastolic 
volumes and indexes, septal and lateral e’, E/A ratio, E/e’ ratio, E wave 
deceleration time, left atrial volume index in healthy subjects, and for Part C, 
additionally, global strain, and ventriculo-arterial coupling in heart failure patients. 
10.1.1.3 
Exploratory Endpoints  
 
AMG 986 excretion in urine 
 
Characterization of potential metabolites of AMG 986 in plasma and urine 
(if appropriate)  
 
Change from baseline in free water clearance in the urine after multiple daily 
doses of AMG 986  (Parts B) 
 
Change from baseline in fasting glucose and fasting lipid profiles after AMG 986 
administration 
 
Change from baseline of heart failure prognostic markers, eg, NT-pro-BNP, 
Troponin, Galectin-3, soluble ST-2, and GDF-15 (Part C) 
 
Change from baseline of endothelial functional markers eg, endothelin-1 and 
angiotensin II, apelin, ADMA and SDMA (Parts B and C) 
 
Change from baseline for QTc and relationship to AMG 986 exposure 
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10.1.2 
Analysis Sets 
For all analyses, subjects will be analyzed according to the dose and treatment they 
received, not the dose and treatment to which they were randomized.   
10.1.2.1 
Safety Analysis Set 
The safety set will consist of all study subjects who receive at least one dose of 
AMG 986 or placebo.  Subjects withdrawing prior to AMG 986 or placebo administration 
due to adverse events related to study procedure will not be included in the safety 
analysis set but those adverse events will be included in the adverse events listing for all 
enrolled subjects. 
10.1.2.2 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will consist of all subjects for whom at least one PK parameter or 
endpoint can be reliably estimated.   
10.1.2.3 
Pharmacodynamics (PD) Analysis Set 
The PD analysis set will consist of all subjects for whom at least one PD parameter, 
including echocardiographic parameters, can be reliably estimated. 
10.1.3 
Covariates and Subgroups 
Baseline values may be used as a covariate in analyses.  For any variable, unless 
otherwise defined, baseline is defined as the last assessment taken prior to the first 
administration of AMG 986 or Placebo. 
No subgroup analyses are planned.  Within each cohort for Parts A and B, subjects will 
be randomized so that 6 subjects receive AMG 986 and 2 subjects receive placebo. 
Within each cohort for Part C, 15 subjects will receive AMG 986 and 5 subjects will 
receive placebo.  Data from placebo-treated healthy subjects in each of Parts A and B 
will be pooled across the Part’s cohorts for analysis.  Data for placebo-treated subjects 
in Part C will not be pooled together. 
10.2 
Sample Size Considerations 
This is a Phase 1 study and no formal statistical hypothesis testing will be performed.  
The study is designed to characterize the safety, tolerability, and PK/PD following single 
and multiple administration of AMG 986 by descriptive summaries based on the 
observed data.  The sample size for all Parts A, B, and C of this study is based on 
practical considerations and is consistent with the number of subjects enrolled in similar 
studies.  Approximately 152 healthy subjects (8 subjects per cohort in 11 cohorts for Part 
A and 8 cohorts in Part B) are expected to be enrolled.  Part C will enroll an additional 
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40 patient subjects. For safety considerations, with up to 144 subjects receiving 
AMG 986 (114 healthy and 30 patients), there is a 99.94% chance of detecting an 
adverse event with a true incidence rate of 5% or greater and a 99.99 % chance of 
detecting a more common adverse event with a true incidence rate of 10%.  A rare event 
with a true incidence rate of 1% will have a chance of 76.48% to being detected with the 
current total sample size receiving AMG986. For Part A, with 66 subjects receiving 
AMG 986, there is a 96.6% chance to detect an AE with a 5% incidence rate and for 
Part B, with 48 subjects receiving AMG 986, a 91.5% chance to detect and AE with the 
same 5% incidence. For Part C, with 30 subjects receiving AMG 986, there is a 78.5% 
chance of observing an AE with a 5% incidence rate and 95.7% chance of observing a 
more common AE with a 10% incidence rate. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Amgen staff and their designees involved in the study will not be 
blinded, but will be given treatment assignments only when there is a need to use the 
information for analysis discussion and internal decision-making, in particular, when 
concerning safety issues.  Access to treatment assignments and other restricted data 
are described in Amgen standard documents.  Unblinded individuals will ensure the 
keeping of the blind.  Unblinding and potentially unblinding information should not be 
distributed to the investigators or subjects prior to a study cohort being formally 
unblinded. An exception is the unblinding of the Principal Investigator or designee who, 
as a member of the DLRM, will have access to the unblinding DLRM outputs. 
10.4 
Planned Analyses 
10.4.1 
Interim Analysis 
Not applicable for this study.  
10.4.2 
Data Monitoring Committee (DMC), Data Review Team (DRT) or Dose 
Level Review Team (DLRT) 
A Dose Level Review Team (DLRT) will be used to oversee progress of the study and 
make recommendations relating to early closure/extension or alteration of the study 
based on ongoing monitoring of the study data (ICH GCP 5.5.2).  The DLRT members 
will consist of the principal investigator or designee, Amgen Medical Monitor, Amgen 
Global Safety Officer or designee, Amgen Clinical Research Study Manager or 
designee, and a Biostatistics representative or designee.  Additional members may be 
added as needed (eg, PK scientist).  The key objectives of the DLRT are to review data, 
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monitor study’s safety, and make dose change decisions.  DLRMs will be conducted in 
an unblinded manner.  Amgen standard procedures will be followed to unblind the DLRM 
attendees specifically the Principal Investigator or designee. 
10.4.3 
Primary Analysis 
The primary analysis will occur after the database lock following last subject last visit. 
10.4.4 
Final Analysis 
The primary analysis will be the final analysis.  
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, adverse events, vital 
signs, ECG, PK, selected laboratory measurements, and selected echocardiographic 
measures.  Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages. 
Placebo-treated subjects in Part A and separately, subjects in Part B will be combined to 
form composite placebo groups for each Part.  Separate summaries and analyses will be 
performed for Cohorts in Parts A and B of the study.  Placebo-treated subjects in Part C 
will be separated per cohort (HFrEF versus HFpEF).  Graphical summaries of the data 
may also be presented.  When data are summarized by time, the values recorded 
against the scheduled time points listed in the protocol will be used.  When assessing 
minimum/maximum increases or decreases over the study, all assessments, including 
unscheduled assessments will be used.  Unless stated otherwise in the statistical 
analysis plan, the data analysis will be conducted using subjects in the safety analysis 
set.  For statistical analyses comparing change from baseline, only subjects with both 
baseline and at least one post-baseline assessment will be included. 
Results from the intravenous and from the oral portion of the study will be reviewed 
separately and together as well in some cases as appropriate. 
10.5.2 
Primary Endpoints 
10.5.2.1 
Safety Endpoints 
10.5.2.1.1 
Adverse Events 
All subjects who receive a dose of AMG 986 or placebo will be included in the safety 
analyses.  Subject incidence of all treatment-emergent adverse events will be tabulated 
by system organ class and preferred term according to the medical dictionary for 
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regulatory activities (MedDRA) terminology.  Tables of events, fatal adverse events, 
serious adverse events, adverse events leading to withdrawal from investigational 
product or other protocol-required therapies, and significant treatment emergent adverse 
events will also be provided if observed. 
10.5.2.1.2 
Vital Signs 
Subject-level data for vital signs including blood pressure, heart rate, respiratory rate, 
and body temperature will be presented and reviewed for each subject.  The analyses of 
vital signs will include summary statistics over time (for each protocol scheduled study 
visit) by cohort by Part.  Depending on the size and scope of changes, summaries of 
changes from baseline over time may be provided. 
10.5.2.1.3 
Electrocardiogram 
All on-study ECG data will be listed and may be plotted.  Summaries over time and/or 
changes from baseline over time will be provided for all ECG parameters (eg, RR, PR, 
QRS, QTc).  Subjects’ maximum change from baseline in QTcF will be categorized and 
the number and percentage of subjects in each group will be summarized.  Subjects’ 
maximum post-baseline values will also be categorized and the number and percentage 
of subjects in each group will be summarized.  For Parts A and B, baseline ECG 
recording is defined as the mean of the 3 sets of triplicate ECG results at Day 1 pre-dose 
(a total of 9 assessments).  The ECG measurements from Part C of this clinical study 
will not be performed as triplicates but as single assessments per standard of care for 
routine safety monitoring, rather than for purposes of assessment of potential QTc effect.  
Since these evaluations may not necessarily be performed under the rigorous conditions 
expected to lead to meaningful evaluation of QTc data; summaries and statistical 
analyses of ECG measurements are not planned, and these data would not be expected 
to be useful for meta-analysis with data from other trials. 
10.5.2.1.4 
Clinical Laboratory 
Analyses of laboratory values will include summary statistics over time (for each protocol 
scheduled visit) by cohort.  Additional summaries may include descriptive statistics of 
changes from baseline over time. 
10.5.3 
Secondary Endpoints 
10.5.3.1 
Pharmacokinetics Analysis (PK) 
Plasma samples will be analyzed for AMG 986 concentrations using a validated assay.  
Individual concentration-time plots for AMG 986 will be presented for each subject as 
well as mean concentration-time plots for each cohort.  Pharmacokinetic parameters 
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including but not limited to AUC, Cmax, and tmax will be estimated using 
non-compartmental methods.  Actual dosing and sampling times will be used for 
calculation of PK parameters. 
Summary statistics will be generated for each PK parameter for each dose cohort for 
each Part of the study.  A population PK analysis may also be performed to obtain 
additional PK parameters for each Part of the study. 
Bioavailability may also be calculated and summarized if data collected is deemed 
adequate.  
10.5.3.2 
Echocardiographic Measures 
Echocardiographic parameters of left ventricular systolic function (left ventricular ejection 
fraction, stroke volume, wall thickening and end-systolic volume index) and left 
ventricular diastolic function (E/e’ ratio, E-wave deceleration time, and left atrial volume 
index) in healthy subjects participating in all Parts of the study will be measured and 
analyzed for changes from baseline.  In Part C, additional echocardiographic measures 
such as ventriculo-arterial coupling and global strain patterns in heart failure patients will 
be evaluated. Changes from baseline for these parameters will be summarized by cohort 
and treatment group and by schedule assessment for all Parts of the study. Statistical 
modeling of a potential dose-response relationship may be pursued for a few key 
echocardiographic parameters in Part C as appropriate. 
10.5.4 
Exploratory Endpoints 
The statistical analyses in this section are considered exploratory in nature and will be 
performed only when deemed appropriate. 
10.5.4.1 
AMG 986 in Urine 
Urine samples will be collected and AMG 986 in urine will be analyzed so that fractions 
of dose eliminated unchanged in urine may be determined.  Subject-level data and 
cohort summary statistics will be presented as appropriate. 
10.5.4.2 
AMG 986 Metabolites  
If data allows, metabolites of AMG 986 will be identified in plasma as well as urine 
samples and their relative expression will be estimated from individual or pooled 
samples.  Subject-level data and cohort summary statistics will be presented as 
appropriate. 
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10.5.4.3 
Free-water Clearance in Urine 
If data allows, free-water clearance in urine in response to administration of AMG 986 
will be measured and their relative amounts estimated from individual or pooled 
samples.  Subject-level data and cohort summary statistics will be presented as 
appropriate. 
10.5.4.4 
Fasting Glucose and Fasting Lipid Levels 
If data allows, glucose tolerance and lipid levels for fasting subjects after dosing with 
AMG 986 will be measured and summarized as changes from baseline over time.   
10.5.4.5 
AMG 986 Impact on Heart Failure Prognostics 
If data allow, heart failure prognostic markers, eg, NT-pro-BNP, Troponin, Galectin-3, 
soluble ST2 and GDF-15 will be measured in patients in Part C after dosing with 
AMG 986 and summarized as changes from baseline over time.   
10.5.4.6 
AMG 986 Impact on Endothelial Function 
If data allow, endothelial functional markers, eg, endothelin-1, angiotensin II, apelin, 
ADMA and SDMA will be measured in Parts B and C after dosing with AMG 986 and 
summarized as changes from baseline over time.   
10.5.4.7 
AMG 986 Exposure vs. QT/QTc Changes 
If data allow, the relationship between AMG 986 exposure and QT/QTc interval changes 
will be inspected graphically and model-based PK/PD analyses may be conducted to 
examine the relationship further. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Clinical Study Manager to the investigator.  
The written informed consent document is to be prepared in the language(s) of the 
potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol specific screening procedures or any 
investigational product(s) is/ are administered.  A legally acceptable representative is an 
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individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician is 
to be documented in the subject’s medical records, and the informed consent form is to 
be signed and personally dated by the subject or a legally acceptable representative and 
by the person who conducted the informed consent discussion.  The original signed 
informed consent form is to be retained in accordance with institutional policy, and a 
copy of the signed consent form is to be provided to the subject or legally acceptable 
representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB of deviations from the protocol or serious adverse events 
occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures. 
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The investigator is responsible for obtaining annual IRB approval/renewal throughout the 
duration of the study.  Copies of the investigator’s reports and the IRB continuance of 
approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment.   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB direct access to review the subject’s original medical 
records for verification of study related procedures and data.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named such individuals to have access to 
his/her study related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an investigator contributing a high number of eligible subjects 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the IRB and 
Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
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In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the investigator inspected or reviewed 
the data on the CRF, the data queries, and agrees with the content. 
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Amgen (or designee) will perform self-evident corrections (SECs) to obvious data errors 
in the clinical trial database. SECs will be documented in the Standard Self Evident 
Corrections document and the CRF Specific Instructions, both of these will be available 
through the EDC system.  Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date but different visits eg, week 4 and early termination) and 
updating a specific response if the confirming datum is provided in the “other, specify” 
field (eg, for race, reason for ending study).  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Section 7.1), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
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Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
AMG 986 Investigator's Brochure (always refer to the most current edition).  Thousand 
Oaks, CA:  Amgen Inc. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 
Publication. 2013. http://www.icmje.org/ 
Japp AG, Cruden NL, Barnes G, et al.  Acute cardiovascular effects of apelin in humans.  
Potential role in patients with chronic heart failure.  Circulation. 2010;121:1818-1827. 
Jessup M, Abraham WT, Casey DE., et al.  2009 focused update: ACCF/AHA 
Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the 
American College of Cardiology Foundation/American Heart Association Task Force on 
Practice Guidelines: developed in collaboration with the International Society for Heart 
and Lung Transplantation.  Circulation.  2009;119:1977-2016. 
Khand A, Gemmel I, Clark AL, Cleland JG.  Is the prognosis of heart failure improving? 
J Am Coll Cardiol.  2000;36:2284-2286. 
Krum H, Teerlink JR.  Medical therapy for chronic heart failure.  Lancet.  2011;378: 
713-721. 
Lloyd-Jones D, Adams RJ, Brown TM, et al.  Heart disease and stroke statistics--2010 
update: a report from the American Heart Association.  Circulation.  2010;121:e46-e215. 
McMurray JJ, Pfeffer MA.  Heart Failure.  Lancet.  2005;365:1877-1889. 
McMurray JJ, Adamopoulos S, Anker SD, et al.  ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of 
Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the 
ESC.  Eur Heart J.  2012;33:1787-1847. 
Roger VL, Go AS, Lloyd-Jones DM, et al.  Heart disease and stroke statistics--2012 
update: a report from the American Heart Association.  Circulation.  2012;125:e2-e220, 
2012.  Published online. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE version 4.0 is available at the following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.5 require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.5 or who experience AST or ALT elevations > 3 x ULN are to undergo a period 
of “close observation” until abnormalities return to normal or to the subject’s baseline 
levels.  Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
 
Obtain serum acetaminophen (paracetamol) levels 
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 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Obtain viral serologies 
 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
 
Perform appropriate liver imaging if clinically indicated 
 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
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Appendix B.  Sample Serious Adverse Event Report Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Approved 
 
 


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Protocol Amendment 8
Title:  A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients
Amgen Protocol Number (AMG 986) 20150183
IND Number 129185
Eudra-CT 2017-002940-34
Amendment Date:
27 July 2018
Rationale:

Aligned information in the protocol with the AMG 986 Investigator’s Brochure 
Edition 3.0, including revising the nonclinical pharmacology package, updating 
the nonclinical toxicology package to reflect chronic studies of up to 6- and 
9-months duration in rats and dogs, respectively, updating the clinical 
experience, and clarifying language in the Risk Assessment

Inconsistencies and typographical errors were corrected throughout the protocol
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Description of Changes: 
Header (throughout entire protocol)
Replace: 
14 Mar 2018
With:
27 July 2018
Title Page, Key Sponsor Contact(s):
Replace:
 M.D., M.Sc
Medical Director
Telephone: 
Email:
With:
, M.D. 
Executive Medical Director, Translational Medicine
Telephone: 
Email:
Title Page, amendment #
Added:
Amendment 8:
27 July 2018 
Investigator’s Agreement
Added bolded items and deleted strikethrough text:
I have read the attached protocol entitled: A Phase I, Randomized, Double-Blind, 
Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects 
and Heart Failure Patients dated 27 14JulyMar 2018, and agree to abide by all 
provisions set forth therein.  
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Protocol Synopsis, Study Design: Part C
     Added bolded items and deleted strikethrough text:
Part C
A total of up to 40 subjects, 20 with HFrEF and 20 with HFpEF, will be randomized to 
receive AMG 986 or placebo in a 3:1 ratio at sites located in the United States, Canada, 
Australia, New Zealand, Sweden, Germany, France, Poland, Slovakia, Czech Republic,
Bulgaria, Belgium, Singapore and The Netherlands, (15 treated and 5 placebo).  
Section 2, Background and Rationale
Added bolded items and deleted strikethroughs:
AMG 986 is a novel apelin receptor (APJ) small molecule agonist that binds and 
activates APJ receptor to improve cardiac function by increasing left ventricular 
contractile function and cardiac reserve without a significant impact on heart rate
cardiac contraction and relaxation, by improving cardiac reserve, and by decreasing 
systemic vascular resistance without a significant impact on heart rate and myocardial 
oxygen consumption.  AMG 986 is being developed as a potential treatment for heart 
failure. 
Section 2.1, Disease
Added bolded items and deleted strikethroughs:
Heart failure (HF) refers to a clinical condition in which the cardiac output is 
insufficient to meet the metabolic needs of body organs and is marked by cardiac 
systolic and/or diastolic dysfunction.  Heart failure with predominantly systolic 
dysfunction, which is identifiable as decreased contraction, is more aptly 
described as heart failure with reduced ejection fraction (HFrEF).  Alternatively, 
heart failure with a predominantly diastolic component, identifiable by decreased 
relaxation, is referred to as heart failure with preserved ejection fraction (HFpEF).  
Common to both types of heart failure is uncoupling of left ventricular and arterial 
interaction. In an attempt to preserve cardiac output, a series of compensatory 
changes occur over time, which include increased sympathetic tone and 
peripheral vasoconstriction, as well as activation of the 
renin-angiotensin-aldosterone system as key features.
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is a clinical syndrome marked by impaired cardiac function and is the final pathway for a 
diversity of diseases that afflict the heart.  With a 1-year rate of cardiovascular mortality 
or HF hospitalizations of 30% to 40% in patients recently hospitalized for HF, 
symptomatic HF is associated with a worse prognosis than the majority of cancers.
Heart failureIt is a common and debilitating disease, affecting almost 6 million 
Americans, or more than 2% of the United States population (McMurray and 
Pfeffer, 2005; Roger et al, 2012).  However, cumulative evidence from epidemiologic 
studies shows that there has been only modest improvement in the prognosis of HF over 
the past 40 years despite numerous clinical advances (Khand et al, 2000).  With a 
1-year rate of cardiovascular mortality or HF hospitalizations of 30% to 40% in
patients recently hospitalized for HF, symptomatic HF is associated with a worse 
prognosis than the majority of cancers. The pathophysiologic mechanisms for the 
progressive nature of HF are complex and include neurohormonal activation in addition 
to deranged cardiovascular hemodynamics.  Injury may occur following acute damage to 
heart muscle, such as with myocardial infarction, infection, or inflammatory processes, or 
may have a more gradual onset as in the case with infiltrative diseases, hemodynamic 
pressure or volume overloading, or hereditary cardiomyopathy.  HF
Heart failure is a progressive disorder with a natural history punctuated by frequent 
recurrent hospitalizations and ultimately death. Long-term goals of HF therapy are to 
implement chronic interventions that decrease death and hospital readmission (Jessup 
et al, 2009; McMurray et al, 2012), both of which occur frequently (Lloyd-Jones et al, 
2010).  More recently, efforts have been made in developing therapies that improve 
cardiac reserve, symptoms of HF and functional capacity.  
AMG 986 was developed to explore the therapeutic potential associated with the 
APJ pathway.  AMG 986 is a long-acting small-molecule agonist that binds to the 
APJ receptor and activates Gαi and beta-arrestin with sub-nM potency.
AMG 986 may have therapeutic potential for both HFrEF heart failure with reduced 
ejection fraction and as well as HFpEF heart failure with preserved ejection fraction.
Another target for treatment of HF is to improve myocardial contraction and relaxation.  
HF is a condition most commonly marked by cardiac systolic dysfunction but 
increasingly noted to have a diastolic dysfunction component.  Systolic dysfunction 
predominates in the condition of heart failure with reduced ejection fraction (HFrEF), 
whereas diastolic dysfunction predominates in the condition of heart failure with 
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preserved ejection fraction (HFpEF).  Over time, in an attempt to preserve cardiac 
output, a series of compensatory changes can occur in both conditions, characterized by 
increased sympathetic tone and peripheral vasoconstriction, as well as the activation of 
various neurohormonal pathways.  Accordingly, improvement of cardiac contraction and 
relaxation would appear to be a rational therapeutic approach to the treatment of HF 
(Hasenfuss and Teerlink, 2011).  Attempts to improve cardiac contractility using 
adrenergic receptor agonists (ie, dobutamine) or phosphodiesterase inhibitors 
(ie, milrinone) have been met with little success, however.  These mechanisms have 
significant safety liabilities attributable to increased oxygen consumption, intracellular 
calcium, and arrhythmias (Cuffe et al, 2002; Felker et al, 2003).  AMG 986 is being 
developed to address the unmet needs not only in heart failure with a systolic 
component but with a diastolic component as well, without the aforementioned safety 
liabilities.
Section 2.2.1, Pharmacology, Nonclinical Pharmacology
Added bolded items and deleted strikethroughs:
The cardiovascular effects of AMG 986 in vivo were studied in both rodent and 
canine models.  In the ZSF1 rat, (a model reproducing diastolic heart failure), AMG 
986 increased cardiac contractile reserve, ejection fraction and stroke volume.  
Improvements in ventriculo-arterial coupling were also observed in ZSF1 rats. In 
a canine heart failure model (tachypacing), AMG 986 improved left ventricular 
contractile function without affecting heart rate.  AMG 986 increased cardiac 
contraction and relaxation in isolated perfused rat hearts.  AMG 986 augmented the 
load-independent contractility without change in calcium transients in adult rat 
cardiomyocytes.  The inotropic effects of AMG 986 are specific through APJ receptor 
since the compound has no impact on phosphodiesterase inhibition.  In rats with systolic 
heart failure, AMG 986 increased cardiac output, reduced systemic vascular resistance 
and improved ventricular arterial resistance.  Administration of AMG 986 in obese ZSF1 
rats with metabolic dysfunction and preserved ejection fraction increased stroke volume, 
ventricular arterial coupling and cardiac reserve.  In canine models of heart failure from 
ischemic and dilated cardiomyopathies, AMG 986 improved left ventricular contractile 
function and increased coronary flow without significant impact on heart rate and 
myocardial oxygen consumption.  In the canine model of ischemic heart failure, AMG 
986 exhibited a statistically significant increase of 10% in ejection fraction relative to 
vehicle at plasma concentrations of 0.210 µM (0.110 µg/mL) and greater.  Additionally, 
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AMG 986 exhibited additive effects when added to the standard of care drug captopril in 
a rat model of systolic heart failure.  These nonclinical findings support the hypothesis
that AMG 986 would be beneficial in addressing the underlying pathophysiology of heart 
failure in patients with either reduced or preserved ejection fraction.  Details of AMG 986 
nonclinical pharmacology are summarized in the AMG 986 Investigator’s Brochure.
Section 2.2.2, Pharmacokinetics, Predictions of Human Pharmacokinetics
Added bolded items and deleted strikethroughs:
Human PK model predictions were used to support selections of IV and oral doses, as 
described in Section 2.6 Section 2.7 of the protocol.  Details of AMG 986 human PK 
predictions are summarized in the AMG 986 Investigator’s Brochure.
Section 2.2.3, Toxicology, Nonclinical Toxicology
Added bolded items and deleted strikethroughs:
The nonclinical toxicology package for AMG 986 included repeat dose toxicology studies 
with both oral (up to 6-months in duration in rats and 9-months in duration in 
dogs28 day studies in rat and dog) and IV (14-day studies in rat and dog) dose routes 
and genetic toxicology, phototoxicity and safety pharmacology studies. 
Repeat Dose Toxicology Studies:
The no-observed-adverse effect-levels (NOAEL) in all of the repeat dose oral and 
IV toxicology studies in rat and dog were the highest doses evaluated. For the 28-day 
oral studies, the no-observed-effect-levels (NOEL) in rats was 1000 mg/kg/day (limit 
dose) and the NOAEL in dogs (based on clinical signs of emesis) was 300 mg/kg/day.  
Estimates of AUC24h exposures in rats at the NOEL dose and dogs at the NOAEL dose 
were 150-fold and 219-fold greater than observed human exposure at the 5 mg oral 
dose and 2.21.4-fold and 3.22.0-fold greater than the observed predicted human 
exposure at 650 mg, respectively (Table 3).  The margins from the toxicology studies 
support administration of the oral dose up to 650 mg planned for the current study.
In developmental and reproductive toxicology studies in rats and rabbits, oral 
administration of AMG 986 resulted in embryo-fetal toxicity and malformations at all 
doses tested. In rats, AMG 986-related fetal tail abnormalities and skeletal 
dysmorphogenesis were observed.  In rabbits there were abortions, lower maternal body 
weights/ body weight gains, associated with and decreases in embryo-fetal survival, 
and external, visceral and skeletal malformations.
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AMG 986 was negative in both in vitro and in vivo genetic toxicology studies and in an in 
vitro phototoxicity assay.
Section 2.2.3, Toxicology, Safety Pharmacology
Added bolded items and deleted strikethroughs:
The NOEL for effects on neurobehavioral and respiratory function in rats was 
1000 mg/kg (single oral dose).  In an anesthetized beagle dog cardiovascular (CV) 
study, with IV dose administration in a cumulative dose escalation design, 
AMG 986-related CV effects were limited to small dose-independent increases (10%) in 
the rate of left ventricular pressure rise in early systole (dP/dtmax) and similar increases 
(10%) in mean blood pressure at plasma concentrations greater than 1.34 µg/mL.  
These observations were consistent with the pharmacology of AMG 986 (positive 
inotropy).
The IC50 value for inhibitory effect of AMG 986 on hERG current (IKr current; potassium
channel in human ventricles primarily responsible for repolarization) was estimated to be 
300 µM (157 µg/mL, unbound concentration), approximately 1000X higher than the 
predicted human maximum unbound concentrations at an oral dose of 650 mg and 
approximately 5000X higher than the highest planned IV infusion dose (60 mg loading 
dose + 360 mg/24 hours maintenance dose).  
Details of AMG 986 nonclinical toxicology are summarized in the AMG 986 Investigator’s 
Brochure.
Section 2.3, Clinical Experience
(Added section 2.3 subsequently updated numbering of the section)
The AMG 986 clinical program thus far consists of 5 studies (4 ongoing, 1 
completed).  In addition to ongoing Study 20150183, there are three phase 1, 
open-label, single-dose studies of AMG 986, including, Study 20150186 (renal 
impairment), Study 20150187 (healthy Japanese subjects), and Study 20170553 
(tablet vs capsule formulation).  Enrollment and dosing have been completed for 
all 3 of these studies.  Study 20150185 is a completed, phase 1, open-label study 
to evaluate the effect of food and concomitant itraconazole administration on the 
pharmacokinetics of AMG 986 in heathy subjects.  
Overall, up to the 01 June 2018 cutoff date, data from these 5 studies indicate that 
AMG 986 has an acceptable safety and tolerability profile at all doses tested in 
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healthy subjects, in subjects with heart failure who have been evaluated thus far, 
in healthy Japanese subjects, and in subjects with renal impairment.  No serious 
or fatal adverse events have been reported, most reported adverse events in these 
studies were CTCAE grade 1, and no trends or specific safety concerns have been 
identified based on the types and frequency of adverse events that have occurred.
Refer to the AMG 986 Investigator’s Brochure for details on AMG 986 clinical 
experience.
Section 2.4.1, Risk Assessment
Added bolded items and deleted strikethroughs:
AMG 986 has an identified risk of embryo-fetal toxicity. and malformations.  In 
developmental and reproductive toxicology studies in rats and rabbits, oral 
administration of AMG 986 resulted in abortions, embryo-fetal toxicity and 
external, visceral and skeletal malformations.  AMG 986 caused embryo-fetal toxicity 
in nonclinical developmental and reproductive toxicology studies in 2 different species.  
Oral administration of AMG 986 resulted in abortions in rabbits and fetal skeletal and tail 
abnormalities in rats. Women of childbearing potential are not eligible to participate in 
this study, and male subjects must agree to practice an acceptable method of effective 
birth control and not donate sperm while on study and through 11 weeks after receiving 
the last dose of AMG 986.  These inclusion/exclusion criteria will prevent pregnancy and
mitigate the risk of embryo-fetal toxicity. 
AMG 986 has a potential risk of causing changes in blood pressure.  AMG 986 is 
expected to positively stimulate the endogenous apelin-dependent pathways, which 
include vasodilation.  Therefore, possible expected acute risks associated with AMG 986 
administration are of cardiovascular nature, such as hypotension. Studies have shown 
that the principal effect of the apelin/APJ system is to counterbalance the 
renin-angiotension-aldosterone system, and apelin affects vascular tone and 
blood pressure.  
AMG 986-related cardiovascular changes in the nonclinical program were limited 
to modest and reversible decreases in mean blood pressure at the highest IV dose 
in the rat and small dose-independent increases in mean blood pressure in the 
anesthesized dog.  Subjects will be closely monitored for changes in 
cardiovascular parameters, such as blood pressure, heart rate, and ECG 
measurements, and for signs and symptoms suggesting adverse events.
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The nonclinical (toxicology and safety pharmacology) package suggests a safe profile 
for the initiation of clinical trials with AMG 986.  Genetic toxicology and photosafety 
evaluations indicated that AMG 986 is not genotoxic or phototoxic.  No AMG 986-related 
toxicity was identified in the rat or dog toxicology studies that were conducted with oral 
(28 days studies6- and 9-months duration in rats and dogs, respectively) or 
IV (14-day studies) dose administration.  The AUC-based exposure margins based on 
NO(A)EL doses from the rat and dog toxicology studies support the planned oral and 
IV infusion clinical dose ranges.  Additionally, no AMG 986-related effects in the safety 
pharmacology studies were identified, including data indicating that QTc interval 
prolongation risk is low.  
As of 01 June 201814 March 2017, safety and tolerability data on clinical exposure to 
AMG 986 from FIH study 20150183 (a randomized, placebo-controlled, double-blind, 
single day ascending dose and multiple daily ascending dose study) were available and 
reviewed for 19 fully implemented cohorts of 8 to 9 healthy subjects each.  The subjects 
reviewed included those who received single oral doses of AMG 986 up to 650200 mg, 
oral doses of 5 mg of AMG 986 up to 650 mg for 7 consecutive days, IV-infused doses 
of AMG 986 over up to 24 hours (loading doses up to 260 mg over 1 hour followed by 
maintenance doses up to 360 120 mg over 23 hours), IV-infused doses of AMG 986 
over 4 days (loading dose up to 60 mg over 1 hour followed by maintenance doses 
up to 360 mg over 23 hours and subsequent maintenance doses and up to 376 mg 
over 24 hours for 3 additional days), and placebo.  
There was a total of 54116 subjects who received AMG 986 and 1838 subjects who 
received placebo.  Of these 72154 subjects, 15171 completed the investigational 
product, and 3 subjects withdrew after receiving investigational product due to 
subject request and not related to an adverse event.  One subject withdrew from the 
study after receiving IP.  This discontinuation of study was due to subject request and 
not related to an adverse event.
For these 15472 subjects there were, no serious adverse events and, no adverse 
events with fatal outcome, and no discontinuation of IP due to adverse events were 
reported.  There were no adverse events from the cardiac disorders system organ class.  
Twenty-three Twelve subjects (14.916.7%) were reported to have treatment emergent 
adverse events during double-blind treatment.  The most common event was headache, 
which occurred in 58 subjects (5.26.9%).  The event of headache was reported as a 
common terminology criteria for adverse events (CTCAE) severity grade 1 in 47 of the 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 10 of 15
CONFIDENTIAL
subjects, and CTCAE grade 2 in 1 subject.  The majority of the adverse events were 
CTCAE grade 1 events.  There were 74 CTCAE grade 2 events (the only grade 2 
event that occurred in more than 1 subject was toothache), and none grade 3 of the
events. occurred in more than 1 subject.  No events were CTCAE grade ≥3 events.  
One CTCAE grade 4 event was reported; this event (blood creatine phosphokinase 
increased as high as 9927 U/L) occurred in a 
-year-old 
 subject in the 
650 mg PO multiple dose cohort on study day 5, was nonserious, resulted in no 
action/change to the investigational product administration, was not associated 
with clinical symptoms (eg, myalgia) or worsening renal function tests, occurred 
concurrently with a CTCAE grade 2 event of aspartate aminotransferase increased 
and a grade 1 event of alanine aminotransferase increased, did not require 
any treatment, and was reported as resolved on study day 29 (22 days after the 
last dose of investigational product).
Overall, the prevalence of adverse events was comparable across all the cohorts 
and did not show higher incidence with increasing doses.  The adverse event terms 
represented a variety of system organ classes and did not suggest a trend or indicate a 
specific safety concern.
After each dose cohort completed and before any dose escalation, an aggregate 
evaluation of adverse events, vital signs, ECG and laboratory parameters was 
performed in unblinded DLRMs.  No clinically meaningful individual subject changes in 
vital signs (including blood pressure) were identified within or across any of the 
19 cohorts.  There was were no notable variations in vital signs with increasing doses of 
AMG 986 throughout the study.  Additionally, no trends in laboratory (including troponin 
1) or ECG abnormalities (eg- QTc interval) were detected.
Additionally, data from 12 heart failure subjects enrolled in study 20150183 were 
available and reviewed.  Eight subjects received oral doses of AMG 986 for 
21 days (consisting of consecutive doses of 10, 30, and 100 mg for 7 days each) 
and 4 subjects received placebo.  Four of the 12 subjects (33.3%) reported 
treatment-emergent adverse events during the double-blind treatment.  No serious 
or fatal adverse events were reported.  There was no discontinuation of 
investigational product due to an adverse event.  All the events were CTCAE 
grade 1 events.
Refer to the AMG 986 Investigator’s Brochure for further details on AMG 986 
clinical experience.
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 11 of 15
CONFIDENTIAL
Section 2.4.3, Overall Benefit/Risk Assessment
Added bolded items and deleted strikethroughs:
The nonclinical (toxicology and safety pharmacology) package suggests a safe profile 
for the initiation of clinical trials with AMG 986.  The AUC-based exposure margins 
based on NO(A)EL doses from the rat and dog toxicology studies support the planned 
dose ranges.  To date, the clinical experience accumulated with AMG 986 provides 
evidence that the administration of AMG 986 has an acceptable safety profile in all up to  
doses tested.
Section 2.7, Rationale
Added bolded items and deleted strikethroughs:
The proposed loading dose infusion is supported by the planned use of AMG 986 in 
acute clinical settings and its anticipated rapid onset of pharmacological response.  
Selection of a 1 hour loading dose infusion will allow rapid titration to therapeutic 
concentration levels.  Establishment of therapeutic concentrations early in the treatment
course would also take advantage of the rapid rate of pharmacological response 
anticipated for AMG 986.  Preliminary evidence in an isolated rat heart model 
demonstrated rapid increases in the rate of left ventricular pressure rise in early systole 
shortly after the start of AMG 986 infusion.  In addition, sSystemic apelin administration 
was shown within minutes to cause reductions in peripheral vascular resistance 
accompanied by increases in cardiac output in healthy subjects (Japp et al, 2010).
Section 2.7, IV Cohorts 1 to 5:
Added bolded items and deleted strikethroughs:
A clinical starting IV dose of 0.5 mg infused over 1 hour is not expected to elicit 
pharmacological activity based on observations in normal healthy dogs (Study 118965).  
In healthy subjects, an IV dose of 0.5 mg infused over 1 hour is predicted to achieve a 
maximum plasma concentration of 0.0501 g/mL (Table 1), approximately one-half the 
nonclinical target plasma concentration of 0.13510 g/mL (0.25810 /M) associated 
with a 10% increase in both ejection fraction and fractional shortening in the dog heart 
failure model.  Model predictions of human maximal exposures for the next IV cohort 
dose of 3 mg infused over 1 hour is anticipated to approximate the target concentration 
associated with cardiovascular function improvement in the dog model (Figure 1).
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 12 of 15
CONFIDENTIAL
Section 2.7, Rationale, Figure 1
Replaced:
With:
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 13 of 15
CONFIDENTIAL
Section 2.7, Rationale, Figure 2
Replaced:
With:
Section 2.7, Oral Cohorts 5 and 6
Added bolded items and deleted strikethroughs:
After confirmation of safety and tolerability of oral AMG 986 at doses that range from 5 to 
200 mg in Parts A and B, further escalations in dose are planned.  The proposed 
single oral dose regimen extended for Part A will be 400 and 650 mg.  Selection of the 
extended range of oral doses was based on the following: (1) acceptable safety and 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 14 of 15
CONFIDENTIAL
tolerability of oral does up to 200 mg, (2) observed AMG 986 PK results and 
(3) exposure margins projected for AUC exposures up to 650 mg relative to exposures 
observed at NOEL and NOAEL doses in GLP toxicology studies.  Although dose 
proportionality was not formally evaluated in the FIH study, increases in AUC and Cmax
exposures appeared to be linear and proportional to dose over the 5 to 200 mg oral dose 
range tested. Assuming dose proportional increases in AMG 986 exposure at 650 mg, 
estimates of AUC24h exposures in rats at the NOEL dose and dogs at the NOAEL dose 
were approximately 1.4 fold and 2.0 fold greater than the predicted human exposure at 
650 mg, respectively (Table 3). Estimates of AUC24h exposures in rats at the 
NOEL dose and dogs at the NOAEL dose were 2.2-fold and 3.2-fold greater than 
the observed human exposure at the 650 mg oral dose, respectively (Table 3).
Section 2.7, Rationale, Table 3 Heading
      Added bolded items and deleted strikethroughs:
Table 3.  Preliminary Observed and Predicted AMG 986 PK Estimates in Healthy 
Subjects after Single Oral Dose Administration and Exposure Margins  
Section 3.2, Number of Sites
Added bolded items and deleted strikethroughs:
This study will be conducted in 15 or more sites in the United States, Europe, Canada 
and Asia New Zealand, Australia, Sweden, Germany, France, Poland, Czech Republic,  
Bulgaria, Singapore and The Netherlands.    Additional sites and/or countries could be 
added as necessary to complete enrollment.
Section 3.4, Replacement of Subjects
Added bolded items and deleted strikethroughs:
Subjects who are withdrawn or removed from treatment or the study prior to receiving 
AMG 986 will be replaced at the discretion of the Amgen Medical Monitor and Principal 
Investigator by notifying the unblinded study pharmacist.  Subjects who are withdrawn 
or removed from treatment or the study may be replaced.  This decision will be 
made by the Amgen Medical Monitor in consultation with the Principal 
Investigator and the Amgen Global Safety Officer.
The new subject will receive the identical treatment as the replaced subject, but will be 
assigned a replacement randomization number associated with this new record.  The 
unblinded study pharmacist will retain the randomization list. 
Approved 
 
 


Product:  AMG 986
Protocol Number:  20150183
Date:  27 July 2018
Page 15 of 15
CONFIDENTIAL
Subjects who are withdrawn or removed from treatment or the study may be replaced.  
This decision will be made by the Amgen Medical Monitor in consultation with the 
Principal Investigator and the Amgen Global Safety Officer.
Section 5.2 Site Personnel Access to Individual Treatment Assignments
Added bolded items and deleted strikethroughs:
Treatment assignments will be unblinded after final database lock. After initial database 
lock and Upon receipt of written authorization from Amgen to unblind, the unblinded 
pharmacist will release the specified unblinded pharmacy records to site staff designated 
to enter the subject Package Lot Number (PLN) treatment into each subject’s
Unblinded Investigational Product Administration Case Report Form (CRF).
Section 6.2.1.3.3, Dose Stopping Rules
Added bolded items and deleted strikethroughs
The quantity, volume, start date/time, stop date/time, and the amount of IP used as 
applicable to prepare the dose on the individual subjects will be entered in each 
subject’s Investigational Product Administration CRF prior to receipt of unblinded 
authorization. Upon receipt of written authorization from Amgen to unblind, the 
unblinded pharmacist will release the specified unblinded pharmacy records to 
site staff designated to enter the subject PLN into each subject’s Investigational 
Product Administration CRF. blinded prior to initial database lock.  Following initial 
database lock, upon written authorization from Amgen, the unblinded package lot 
number(s) will be recorded on each subject’s unblinded IP administration CRF.
Section 13, References
Deleted:
Cuffe MS, Califf RM, Adams KF Jr, et al.  Short-term intravenous milrinone for acute 
exacerbation of chronic heart failure: a randomized controlled trial.  JAMA.  
2002;287:1541-1547.
Felker GM, Benza RL, Chandler AB, et al.  Heart failure etiology and response to 
milrinone in decompensated heart failure: results from the OPTIME-CHF study.  J Am 
Coll Cardiol.  2003;41:997-1003.
Hasenfuss G, Teerlink JR.  Cardiac inotropes: current agents and future directions.  Eur 
Heart J.  2011;32:1838-1845
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  14 March 2018 
Page 1 of 4 
CONFIDENTIAL 
 
 
Protocol Amendment 7 
Title:  A Phase I, Randomized, Double-blind, Placebo-controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients 
 
Amgen Protocol Number (AMG 986) 20150183 
IND Number 129185 
Eudra-CT 2017‐002940‐34 
 
Protocol Date: 
 14 March 2018 
Rationale: 
The following updates were made to the protocol, dated 31 October 2017: 
• 
Eligibility criterion for QTc threshold was extended from 450 msec to 500 msec.  
The rationale for this change is based on;  
Non clinical findings  
o Studies on the human ether-a-go-go related gene (hERG) current 
experiments showing no inhibition 
o 28 day oral dog toxicology studies showing no changes in QTc interval 
o 14 day IV dog toxicology findings showing no changes in QTc interval 
o Telemetry dog study showing no change in QTc interval 
Clinical findings in healthy volunteers administered AMG 986 as oral tablets 
or intravenous infusion 
o No evidence in Parts A and B of the study involving healthy volunteers 
that suggests AMG 986 affects the QTc interval 
o Consistency of findings, particularly across MAD cohorts in Part B where 
sustained concentration of drug was achieved 
• 
Inconsistency and typographical errors were corrected throughout protocol. 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  31 October 2017 
Page 1 of 6 
CONFIDENTIAL 
 
 
Protocol Amendment 6 
Title:  A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients 
 
Amgen Protocol Number (AMG 986) 20150183 
IND Number 129185 
Eudra-CT 2017‐002940‐34 
 
Protocol Date: 
31 October 2017 
Rationale: 
The following updates were made to the protocol, dated 15 May 2017: 
• 
Incorporate sections and sub-sections that clearly outline Risk/Benefit 
Assessment 
• 
Key Sponsor Contacts updated based on changes in staff 
• 
Provide further clarity on unblinding procedures 
• 
Inconsistency, typographical errors were corrected throughout protocol. 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  15 May 2017 
Page 1 of 42 
CONFIDENTIAL 
 
 
Amendment 5 
Protocol Title:  A Phase I, Randomized, Double-blind, Placebo Controlled, Single 
and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients 
Amgen Protocol Number AMG 986 20150183 
IND Number 129185 
Amendment Date: 
15 May 2017 
Rationale: 
The following changes were made to the protocol 20150183, dated 15 May 2017: 
 
Updating safety/toxicology and risk assessment information based on recently 
available pre-clinical embryo-fetal toxicology studies and safety information from 
earlier and completed portions of the study 
 
Updating predicted pharmacokinetic data with actual observed data from earlier 
and completed portions of the study 
 
Testing higher oral dose formulation ranges of single and multiple doses of 
400 mg and 650 mg in healthy volunteers to provide a better understanding of 
safety and tolerability of AMG 986 
 
Changing the duration of IP administration in Part C from 4 days per dose level 
(total of 12 days) to 7 days per dose level (total of 21 days) to provide an 
opportunity for insights on dose level on safety, tolerability, pharmacokinetics and 
pharmacodynamics 
 
Broadening the eligibility age for subjects in part C from 70 years of age to 
85 years to better reflect the target populationLowering the NTproBNP eligibility 
criterion for HFrEF subjects from ≥ 600 pg/ml to ≥ 250 pg/ml to permit patients 
with less severe heart failure to participate 
 
Clarifying the need for a negative pre-enrollment pregnancy test for any female 
study participants  
 
Distinguishing the blood pressure and renal function thresholds for enrolment of 
healthy volunteer subjects from those with heart failure  
 
Aligning the starting dose in part C with doses used in Parts A and B of the study 
to enable more meaningful comparisons between patients and healthy volunteer 
subjects 
 
Increasing the BMI upper limit from 32 to 35 kg/m2 to reflect the generally higher 
body weight of actual patients with HF compared to healthy volunteers.  
 
Broadening the geographic spread of study sites participating primarily in Part C 
of the study from just the United States to also include Canada, Australia, New 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  31 January 2017 
Page 1 of 32 
Amendment 4 
Protocol Title:  A Phase I, Randomized, Double-blind, Placebo Controlled, Single 
and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects and 
Heart Failure Patients 
 
Amgen Protocol Number AMG 986 20150183 
 
Amendment Date: 
31 January 2017 
Rationale: 
This protocol amendment is being made to include the study of AMG 986 in patients with 
heart failure with either preserved or reduced ejection fraction. The primary objective of 
this amendment is to determine the safety, tolerability, pharmacokinetics and possibly 
pharmacodynamic impact of AMG 986 in patients with heart failure.  
Specific changes are being made to  
1. Define the objectives and endpoints that would be applicable to investigation of 
patient subjects in the study 
2. Define the eligibility criteria for patients with heart failure that would qualify to 
participate in the study  
3. Define the starting dose, dose escalation, dose reduction and dose stopping 
rules that would be applied to patient subjects.  
4. Outline the schedule of assessments for patient subjects 
CONFIDENTIAL 
 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  15 May 2017 
Page 2 of 42 
CONFIDENTIAL 
 
 
Zealand, Sweden, Germany, France, Poland, Slovakia, Czech Republic, 
Bulgaria, Belgium, and The Netherlands. 
 
Administrative, grammatical and typographical corrections to enhance clarity of 
the protocol.  
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  06 December 2016 
Page 1 of 22 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase I, Randomized, Double-blind, Placebo Controlled, Single 
and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of AMG 986 in Healthy Subjects 
 
Amgen Protocol Number AMG 986 20150183 
 
Amendment Date: 
06 December 2016 
Rationale: 
This protocol amendment is being made in light of emerging data from the study. 
Specific changes are being made to: 
1. Change Part B PO dosing duration to 7 days from 14 days. The rationale for this 
is to reduce exposure to healthy volunteers as longer duration of treatment is 
unlikely to provide substantively important exposure or safety information.  
2. Allow earlier transition from ascending single day IV doses in Part A to ascending 
multiple daily IV doses in Part B starting with Cohort 1 IV (6 mg LD + 36 mg MD 
on Day 1 followed by 38 mg MD for Days 2-4). This will be done after 
confirmation of AMG 986 safety and tolerability in IV Cohort 4 (20 mg LD + 
120 mg MD) of Part A. The rationale for this is supported by the anticipated 
exposure, safety and tolerability of AMG 986 in IV Cohort 4 of Part A at 20 mg 
(LD) + 120 mg (MD). 
3. Allow earlier transition to the PO cohorts of Part B starting with Cohort 1 PO 
(5 mg QD for 7 days) upon a DLRM decision to proceed for the 30 mg PO single 
dose cohort in Part A. The rationale for this is supported by the observed 
exposure, safety and tolerability of AMG 986 in PO Cohort 2 Part A (30 mg 
PO single dose). 
4. Perform additional PK and echocardiographic assessments at later time points 
after dosing in Part B. The rationale for this is supported by observed exposure to 
date and reanalyzed predicted exposure. 
Minor administrative, typographical and grammatical changes were made.  
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150183 
Date:  27 October 2016 
Page 1 of 23 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase I, Randomized, Double-blind, Placebo Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 986 in Healthy Subjects 
 
Amgen Protocol Number AMG 986 20150183 
 
Amendment Date: 
27 October 2016 
Rationale: 
The primary objective of this protocol amendment is to: 
1. Clarify the intravenous dosing requirements for a loading dose and a 
maintenance dose.  
2. Update the restrictions for nicotine and caffeine use on the study. 
3. Remove cumulative PK urine collection outside of residency.  
Minor administrative, typographical, and grammatical changes were made. 
Approved 
 
 


Approved 
 
 
Product:  AMG 986 
Protocol Number:  20150183 
Date:  08 July 2016 
Page 1 of 38 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase I, Randomized, Double-blind, Placebo Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of AMG 986 in Healthy Subjects 
 
Amgen Protocol Number AMG 986 20150183 
 
Amendment Date: 
08 July 2016 
 
Rationale: 
The primary objective of this protocol amendment is to enhance safety assessments of 
subjects during the study:  
1. Include an unblinded medical monitor to review adverse events in real-time 
2. Add the collection of laboratory assessments at 24 hours and discharge 
3. Add the assessment of troponin levels at baseline prior to dosing, Days 2 and 5 
4. Add the requirement to evaluate AMG 986 exposure and dose predictions using 
available human PK data and include in the review of dose cohorts by DLRM 
members.  
5. Add a physical exam at 24 hours 
Minor administrative, typographical, and grammatical changes were made. 

SAP_001.pdf: 
Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Phase I, Randomized, Double-blind, Placebo Controlled, Single and Multiple 
Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of AMG 986 in Healthy Subjects and Heart Failure Patients 
Protocol Number: 
20150183 
Version: 
2.0 
Date: 
04 August 2016 
Amendment 1: 
Amendment 2: 
11 April 2018 
17 June 2019 
Authors: 
 
NCT Number: NCT03276728
This NCT number has been applied to the document for purposes of posting on 
Clinicaltrials.gov


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 2 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes, Including 
Rationale for Changes 
Original (v1.0) 
04 Aug 2016 
[Amendment 1 (v2.0)] 
11 Apr 2018 
The purpose of SAP amendment 1 was to 
provide details of the statistical analyses 
that have been outlined within the 
Protocol Amendment 7 dated 
14 March 2018. 
[Amendment 2 (v3.0)] 
17 Jun 2019 
The purpose of SAP amendment 2 is to 
align with the Protocol Amendment 8 
dated 27 July 2018 and also to limit the 
scope of analysis due to early 
discontinuation of the study as referenced 
in early discontinuation memo dated 
15 April 2019. The scope of the analysis 
is restricted to key endpoints/ parameters, 
for selected parts/ cohorts of the study in 
agreement with study team to be used for 
the purpose of abbreviated Clinical Study 
Report.  


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 3 
 
Table of Contents 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives ............................................................................................................... 7 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.1.1 
Study Design and Treatment Schema ....................................... 11 
3.2 
Sample Size .............................................................................................. 13 
4. 
Study Endpoints and Covariates ........................................................................... 13 
4.1 
Study Endpoints ........................................................................................ 13 
4.1.1 
Primary Endpoints ..................................................................... 13 
4.1.2 
Secondary Endpoints ................................................................ 14 
4.1.3 
Exploratory Endpoints ............................................................... 14 
4.2 
Planned Covariates ................................................................................... 14 
5. 
Hypotheses and/or Estimations ............................................................................ 14 
6. 
Definitions ............................................................................................................. 14 
7. 
Analysis Subsets .................................................................................................. 16 
7.1 
Primary Analysis Set ................................................................................. 16 
7.2 
Safety Analysis Set ................................................................................... 16 
7.3 
Pharmacokinetic (PK) Analysis Set ........................................................... 17 
7.4 
Pharmacodynamics (PD) Analysis Set ...................................................... 17 
7.5 
Subgroup Analyses ................................................................................... 17 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 17 
9. 
Data Screening and Acceptance ........................................................................... 18 
9.1 
General Principles ..................................................................................... 18 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 19 
9.2.1 
Echocardiography Data ............................................................. 19 
9.3 
Handling of Missing and Incomplete Data ................................................. 19 
9.4 
Detection of Bias ....................................................................................... 19 
9.5 
Outliers ..................................................................................................... 20 
9.6 
Distributional Characteristics ..................................................................... 20 
9.7 
Validation of Statistical Analyses ............................................................... 20 
10. 
Statistical Methods of Analysis.............................................................................. 20 
10.1 
General Principles ..................................................................................... 20 
10.2 
Subject Accountability ............................................................................... 21 
10.3 
Important Protocol Deviations ................................................................... 21 
10.4 
Demographic and Baseline Characteristics ............................................... 22 
10.5 
Safety Analyses (Primary Endpoints) ........................................................ 22 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 4 
 
10.5.1 
Adverse Events ......................................................................... 22 
10.5.2 
Laboratory Test Results ............................................................ 22 
10.5.3 
Vital Signs ................................................................................. 23 
10.5.4 
Physical Measurements ............................................................ 23 
10.5.5 
Electrocardiogram (ECG) .......................................................... 23 
10.5.6 
Exposure to Investigational Product .......................................... 23 
10.5.7 
Exposure to Concomitant Medications....................................... 23 
10.6 
Pharmacokinetic/Pharmacodynamic Analyses .......................................... 23 
10.6.1 
PK Parameters for AMG 986 ..................................................... 23 
10.6.2 
Echocardiographic Measures .................................................... 24 
10.7 
Exploratory Endpoints Analyses ................................................................ 24 
11. 
Changes From Protocol-specified Analyses.......................................................... 24 
12. 
Data Not Covered by This Plan............................................................................. 25 
13. 
Literature Citations / References ........................................................................... 26 
14. 
Appendices ........................................................................................................... 27 
List of Appendices 
Appendix A. Handling of Missing or Incomplete Dates for Adverse Events and 
Concomitant Medications ....................................................................... 28 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 5 
 
Table of Abbreviations 
Abbreviation or Term 
Definition/Explanation 
ADPC 
Analysis Dataset for PK Concentrations 
AE 
Adverse Events 
AUC 
Area Under The Concentration-Time Curve 
BMI 
Body Mass Index 
Cmax 
Maximum Observed Concentration  
CPMS 
Clinical Pharmacology Modelling And Simulation 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLRM  
Dose Level Review Meeting 
DLRT 
Dose Level Review Team 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOI 
Events of Interest 
EOS 
End of Study 
GCP 
Good Clinical Practice 
GSO-DM 
Global Study Operations-Data Management 
H 
Hour 
HDL 
High-Density Lipoprotein  
ICH  
International Conference on Harmonization 
IP 
Investigational Product 
IPD  
Important Protocol Deviation 
IV 
Intravenous  
LD 
IV Loading Dose 
LDL 
Low-Density Lipoprotein  
MD 
IV Maintenance Dose 
MDAD 
Multiple Daily Ascending Dose  
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
Oral Dose 
QD 
Once Daily Dosing 
QTcB 
Bazett-Corrected QT Interval 
QTcF 
Fridericia-Corrected QT Interval 
Page 1 of 2 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 6 
 
Abbreviation or Term 
Definition/Explanation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SDAD 
Single Day Ascending Dose 
SE 
Standard Error 
TEAE 
Treatment-Emergent Adverse Event  
tmax 
Time of Maximum Observed Concentration  
Page 2 of 2 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 7 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the Protocol Amendment 8 for Study 20150183 
AMG 986 dated 27 July 2018. The scope of this plan includes the primary analysis that 
is planned and will be executed by the Biostatistics department unless otherwise 
specified. The scope of the analysis is restricted post the discontinuation of the 
study earlier than planned and includes key analyses to be performed as 
identified by the study team. 
2. 
Objectives 
Primary Objective: 
To evaluate the safety and tolerability of ascending single (Part A) and ascending 
multiple (Part B) doses of AMG 986 in healthy subjects who received AMG 986 by 
constant intravenous (IV) infusion or oral (PO) administration and of ascending multiple 
PO doses of AMG 986 in heart failure patients (Part C). 
Secondary Objectives: 
• 
To characterize AMG 986 pharmacokinetics (PK) after IV infusion and oral 
administration in healthy subjects and heart failure patients. 
• 
To characterize the pharmacodynamic (PD) effects of AMG 986 in healthy 
subjects and in heart failure patients. 
Exploratory Objectives: 
• 
To characterize AMG 986 excretion in urine. 
• 
To characterize potential metabolite(s) of AMG 986 in plasma and urine (if 
appropriate). 
• 
To evaluate AMG 986 impact on heart failure prognostic markers in heart failure 
patients. 
• 
To evaluate AMG 986 impact on endothelial function markers including 
endothelin-1 (ET-1), angiotensin II (ANG II), and apelin. 
• 
To characterize the effect of AMG 986 administration on free water clearance by 
the kidney into the urine after multiple doses of AMG 986. 
• 
To evaluate the impact of AMG 986 administration on glucose and lipid 
metabolism.  
• 
To explore the relationship between changes in QTc and AMG 986 exposure. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 8 
 
3. 
Study Overview 
3.1 
Study Design 
This study is a randomized, placebo controlled, double-blind, single day ascending dose 
(SDAD) study (Part A), and multiple daily ascending dose (MDAD) study (Part B), in 
healthy subjects and of ascending multiple doses of AMG 986 in heart failure patients 
(Part C). In Parts A and B of the study, subjects will receive AMG 986 by constant IV 
infusion or by oral administration in a fasted state. The IV infusions starting with cohort 3 
will be divided into an initial loading dose (LD) for the first hour followed immediately by a 
maintenance dose (MD) for up to 24 hours and up to multiple days (Part B). In Part C of 
the study, patients with heart failure and either reduced (HFrEF) or preserved (HFpEF) 
ejection fraction will receive ascending doses of IP by once daily oral administration for 
21 days. 
Part A 
Part A is a randomized, parallel group, double-blind, single day ascending dose study 
consisting of 11cohorts (5 IV infusion dose cohorts and 6 oral dose cohorts). Within each 
cohort, a total of 8 subjects will be randomized to receive AMG 986 or placebo in a 
3:1 ratio. The randomization will follow a sentinel dosing paradigm. 
Starting doses of 0.5 mg by IV infusion lasting 1 hour and 5 mg given by oral 
administration are planned. The sequence of escalation for IV dosing and PO dosing will 
partially overlap to achieve step-wise increases in AMG 986 exposure, as shown in the 
treatment schema. Dose escalations in Part A will initially be sequential, with AMG 986 
dosing to begin at the starting IV dose of 0.5 mg infused over 1 hour, followed by 
escalation to IV Cohort 2 dosing at 3 mg infused over 1 hour. After the safety and 
tolerability of AMG 986 in IV Cohort 2 are demonstrated and reviewed at a DLRM, 
escalation to IV Cohort 3 (6 mg LD + 36 mg MD) and initiation of oral dosing at the 
proposed 5 mg starting dose will be permitted. Subsequent IV and oral dose cohort 
escalations and DLRM reviews will occur as shown in the treatment schema below. After 
the safety and tolerability of AMG 986 in IV Cohort 4 (20 mg LD + 120 mg MD) and PO 
Cohort 4 (200 mg) are demonstrated and reviewed at a DLRM, escalation to IV Cohort 5 
(60 mg LD + 360 mg MD) and PO Cohort 5 (400 mg) will be permitted. Enrollment for IV 
Cohorts will end after IV Cohort 5. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 9 
 
Part B 
Part B is a randomized, parallel group, double-blind, multiple day ascending dose study 
consisting of 6 cohorts (2 IV infusion dose cohorts and 4 oral dose cohorts). Within each 
cohort, a total of 8 subjects will be randomized to receive AMG 986 or placebo in a 
3:1 ratio. Prior to the transition from Part A to Part B, verification of PK model 
assumptions is planned as AMG 986 human PK data become available from individual 
IV and oral single dose cohort escalations in Part A. 
In the IV cohorts, AMG 986 will be dosed as a series of IV infusions, each with duration 
of 24 hours, for 4 consecutive days. On study Day 1, IV infusions will be divided into an 
initial loading dose infusion for 1 hour followed immediately by a maintenance dose with 
duration for 23 hours. On study days 2 to 4, maintenance doses will be administered as 
constant infusions with duration for 24 hours. The transition from ascending single day 
doses in Part A to ascending multiple daily doses in Part B is planned to occur 
sequentially for IV cohorts. Dose administration in Part B by the IV route will start after 
confirmation of AMG 986 safety and tolerability in IV Cohort 4 (20 mg LD + 120 mg MD) 
of Part A. The starting IV dose in Part B at 6 mg (LD) + 38 mg/24 hour (MD; 1.57 mg/h, 
36 mg/ 23 h on Day 1 and 38 mg/ 24 h on Days 2-4) infused over 4 days will have been 
previously evaluated over 24 hours in IV Cohort 3 (6 mg LD + 36 mg MD) of Part A. 
In the PO cohorts, AMG 986 will be dosed once daily for 7 consecutive days. Parts A 
and B will partially overlap for the oral dose cohorts. Transition to the first PO cohort of 
Part B (5 mg QD) is planned to occur upon a DLRM decision to proceed after the 30 mg 
PO single dose cohort in Part A has been made. Subsequent oral dose escalations to 
200 mg QD will occur in Part B as shown in the study schema. Escalation to 400 mg QD 
in Part B will be allowed after the safety and tolerability of AMG 986 at 400 and 650 mg 
in Part A (PO cohorts 5 and 6, respectively) are demonstrated and reviewed at each 
DLRM. Subsequent oral dose escalations to 400 mg and 650 mg QD will occur in Part B 
as shown in the study schema. 
The safety and tolerability of each dose level (including the last dose cohort) in Part B 
will be assessed at the DLRM once safety data through at least 4 days post dose 
become available for all subjects in a treatment cohort. Escalation to a higher dose 
within a cohort, between cohorts, and enrollment of Part B, will proceed only when the 
previous doses have been found to be tolerated. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 10 
 
The impact of AMG 986 on PD measures of cardiovascular function in study subjects will 
be determined using echocardiography and evaluated at each DLRM as data becomes 
available. 
Part C 
Part C is a randomized, parallel group, double-blind, multiple day ascending dose study 
consisting of 2 PO dose cohorts, one cohort for HFrEF patients and one cohort for 
HFpEF patients. Within each cohort, 20 subjects will be randomized to receive AMG 986 
or placebo in a 3:1 ratio. Subjects will receive once daily oral administration of IP at 
10 mg for the first 7 days, 30 mg for the next 7 days and 100 mg for the last 7 days. As 
this portion of the study will enroll patients with heart failure, key eligibility criteria 
have been amended to reflect the severity of their underlying disease, including 
maximum age of enrollment (maximum age < 85 years) as specified in the study 
protocol. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 11 
 
3.1.1 
Study Design and Treatment Schema 
 
Part A: Single Day Ascending 
Dose (SDAD) 
Cohort 2 
IV (Part A)  
LD: 3 mg 
for 1 h 
infusion 
[total 
infusion 
= 1 h] 
Cohort 3  
IV (Part A) 
LD: 6 mg 
for 1 h 
infusion 
MD: 36 mg 
for 23 h 
infusion 
[total 
infusion  
= 24 h] 
Cohort 1 
PO (Part A) 
5 mg 
Cohort 3  
PO (Part A) 
100 mg 
Cohort 2  
PO  
(Part A) 
30 mg 
Cohort 4  
PO (Part A) 
200 mg 
DLRM 
DLRM 
Cohort 4  
IV (Part A) 
LD: 20 mg 
for 1 h 
infusion 
MD: 120 mg 
for 23 h 
infusion 
[total 
infusion  
= 24 h] 
DLRM 
Cohort 1  
IV (Part A)  
LD: 0.5 
mg for 1 h 
infusion 
[total 
infusion 
= 1 h] 
DLRM 
Cohort 5 
IV (Part A) 
LD: 60 mg 
for 1 h 
infusion 
MD: 360 
mg for 23 h 
infusion 
[total 
infusion  
= 24 h] 
DLRM 
Cohort 
3 PO 
(Part B) 
100 mg 
QD for 7 
days 
DLRM 
Cohort 2 IV 
(Part B) 
LD: 60 mg / 
1 h 
MD: 360 mg 
/ 23h (Day 
1) 
MD: 376 mg 
/ 24h (Days 
2-4) [total 
infusion = 
96 h] 
Cohort 
4 PO 
(Part B) 
200 mg 
QD for 7 
days 
DLRM 
DLRM 
DLRM 
DLRM 
DLRM 
DLRM 
Cohort 5 
PO (Part A) 
400 mg 
Cohort 6 
PO (Part A) 
650 mg 
Part B: Multiple Daily Ascending 
Dose (MDAD)  
DLRM 
Cohort 6 
PO (Part B) 
650 mg QD 
for 7 days 
Cohort 5 
PO (Part B) 
400 mg QD 
for 7 days 
DLRM 
DLRM 
DLRM 
Cohort 1 
PO (Part B) 
5 mg QD for 
7 days 
Cohort 2 
PO (Part B) 
30 mg QD 
for 7 days 
Cohort 1 IV 
(Part B) 
LD: 6 mg / 1 
h 
MD: 36 mg / 
23h (Day 1) 
MD: 38 mg / 
24h (Days 2-
4) [total 
infusion = 96 
h] 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 12 
 
Study Design and Treatment Schema 
Part C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part C: HFrEF and HFpEF Cohorts 
(After completion of Parts A & B) 
HFrEF (PO) 
 50 mg QD  
for 4 days 
(Days 1-4) 
 
HFpEF (PO) 
 50 mg QD  
for 4 days 
(Days 1-4) 
 
HFrEF (PO) 
100 mg QD  
for 4 days 
(Days 5-8) 
HFpEF (PO) 
100 mg QD  
for 4 days 
(Days 5-8) 
 
Data 
Review 
Data 
Review 
HFrEF (PO) 
 200 mg QD 
 for 4 days 
(Days 9-12) 
 
HFpEF (PO) 
 200 mg QD 
 for 4 days 
(Days 9-12) 
 
1 day 
washout 
Abbreviations:   
DLRM = Dose Level Review Meeting                       LD = IV Loading Dose            
h = Hour                                                                    MD = IV Maintenance Dose 
IV = Intravenous                                                       PO = Oral Dose 
QD = Once Daily Dosing 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 13 
 
3.2 
Sample Size 
This is a Phase 1 study. No formal statistical hypothesis testing will be performed. The 
study is designed to characterize the safety, tolerability, and PK/PD following single and 
multiple administration of AMG 986 by descriptive summaries based on the observed 
data. The sample size for both Parts A and B of this study is based on practical 
considerations and is consistent with the number of subjects enrolled in similar studies. 
Approximately 152 healthy subjects (8 subjects per cohort in 11 cohorts for Part A and 
8 cohorts in Part B) are expected to be enrolled. Part C will enroll an additional 
40 patient subjects. For safety considerations, with up to 144 subjects receiving 
AMG 986 (114 healthy and 30 patients), there is a 99.94% chance of detecting an 
adverse event with a true incidence rate of 5% or greater and a 99.99 % chance of 
detecting a more common adverse event with a true incidence rate of 10%. A rare event 
with a true incidence rate of 1% will have a chance of 76.48% to being detected with the 
current total sample size receiving AMG986. For Part A, with 66 subjects receiving 
AMG 986, there is a 96.6% chance to detect an AE with a 5% incidence rate and for 
Part B, with 48 subjects receiving AMG 986, a 91.5% chance to detect and AE with the 
same 5% incidence. For Part C, with 30 subjects receiving AMG 986, there is a 78.5% 
chance of observing an AE with a 5% incidence rate and 95.7% chance of observing a 
more common AE with a 10% incidence rate. 
In summary: 
• 
Part A IV Dose Cohorts: 40 subjects (8 subjects per cohort) 
• 
Part A Oral Dose Cohorts: 48 subjects (8 subjects per cohort) 
• 
Part B IV Dose Cohorts: 16 subjects (8 subjects per cohort) 
• 
Part B Oral Dose Cohorts: 48 subjects (8 subjects per cohort) 
• 
Part C Oral Dose Cohorts: 40 subjects (20 subjects per cohort) 
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary Endpoints 
• 
Subject incidence of treatment-emergent adverse events. 
• 
Subject incidence of clinically significant changes in physical examinations, vital 
signs, laboratory safety tests, and electrocardiograms (ECGs). 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
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4.1.2 
Secondary Endpoints 
• 
AMG 986 PK parameters including, but not limited to, maximum observed 
concentration (Cmax), the time of maximum observed concentration (tmax), area 
under the concentration-time curve (AUC), and oral bioavailability. 
• 
Changes over time from baseline in echocardiographic parameters of left 
ventricular systolic and diastolic functions (left ventricular ejection fraction, 
fraction shortening, stroke volume, wall thickening, end-systolic and end-diastolic 
volumes and indexes, septal and lateral e’, E/A ratio, E/e’ ratio, E wave 
deceleration time, left atrial volume index and ventriculo-arterial coupling (Part C 
only)) in healthy subjects and in heart failure patients. 
4.1.3 
Exploratory Endpoints 
• 
AMG 986 excretion in urine. 
• 
Characterization of potential metabolites of AMG 986 in plasma and urine (if 
appropriate). 
• 
Change from baseline in free water clearance in the urine after multiple daily 
doses of AMG 986. (Part B) 
• 
Change from baseline in fasting glucose and fasting lipid profiles after AMG 986 
administration. 
• 
Change from baseline of heart failure prognostic markers, eg, NT-pro-BNP, 
Troponin, Galectin-3, soluble ST-2, and GDF-15 (Part C) 
• 
Change from baseline of endothelial functional markers eg, endothelin-1 and 
angiotensin II, apelin, ADMA and SDMA (Parts B and C) 
• 
Change from baseline in QTc and relationship to AMG 986 exposure 
4.2 
Planned Covariates 
Baseline values may be used as a covariate in analyses as needed.  
5. 
Hypotheses and/or Estimations 
This is a Phase 1 study and no formal statistical hypothesis testing will be performed. 
6. 
Definitions 
Age at Enrollment 
Subject age at enrollment will be collected in years in the clinical database. 
Baseline 
Unless otherwise specified, baseline will be defined as the scheduled assessment 
closest to but before first dose administration. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 15 
 
Baseline and Post-Baseline Electrocardiogram (ECG) Values in Triplicate 
For the three sets of triplicate pre-dose ECG, the mean of values in a triplicate should be 
calculated before taking the mean of the three sets of averages. 
For all post-baseline ECG, the mean value for measurements taken at the same 
assessment will be calculated and used in the analysis. 
When an ECG is missing within a triplicate, all available data will be averaged for that 
time point. 
Bazett-corrected QT Interval (QTcB) 
The Bazett correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec): QTcB=QT/(RR/1000)0.5 
Fridericia-corrected QT Interval (QTcF) 
The Fridericia correction will be calculated from the investigator reported QT (msec) and 
RR interval (msec): QTcF=QT/(RR/1000)0.33 
BMI 
Subject’s BMI will be derived in kg/m2 in the clinical database 
Change From Baseline 
Change from baseline is the arithmetic difference between post-baseline and baseline. 
End of Investigational Product Administration Date 
End of IP administration for each subject is defined as the date the decision was made 
to end IP as recorded on the End of IP eCRF page. 
End-of-Study for Individual Subject 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study eCRF page. 
Enrollment Date 
Enrollment Date is defined in the date collected on the eCRF. 
Randomization Date 
Randomization Date is defined as the date subject was allocated to a treatment group. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 16 
 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to AMG 986 or placebo. 
Last IP Dose Date 
Last IP Dose Date for each subject is defined as the latest date IP is administered 
Study Day 
Post study day 1: study day = (date – date of Study Day 1) + 1 
Pre study day 1: study day = (date – date of Study Day 1) 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Study Day -1. 
Treatment-Emergent Adverse Event (TEAE) 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by the flag indicating if the adverse event started 
prior to the first dose on the Events CRF and up to and including 30 days after the end of 
investigational product. 
Serious Adverse Events 
Serious adverse events (SAEs) are events categorized as AEs that are starting on or 
after first dose of investigational product as determined by the flag indicating if the 
adverse event started prior to the first dose on the Events CRF and up to and including 
30 days after the end of investigational product. 
7. 
Analysis Subsets 
For all analyses, subjects will be analyzed according to the dose and treatment they 
received, not the dose and treatment to which they were randomized. 
7.1 
Primary Analysis Set 
Since this is an Early Development Study, the Primary Set will be the same as the 
Safety Analysis Set. 
7.2 
Safety Analysis Set 
The safety analysis set will consist of all study subjects who receive at least one dose of 
AMG 986 or placebo. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 17 
 
7.3 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will consist of all study subjects who received AMG 986 for whom at 
least one PK parameter or endpoint can be reliably estimated. 
7.4 
Pharmacodynamics (PD) Analysis Set 
The PD analysis set will consist of all study subjects who received AMG 986 or placebo 
for whom at least one echocardiographic parameter can be reliably measured.  
7.5 
Subgroup Analyses 
No subgroup analyses are planned. Data from placebo-treated healthy subjects in each 
of Parts A and B will be pooled across the cohorts within each part for analysis. Subjects 
getting IV and oral dosing will be pooled separately for summary of treatment 
exposure. Data for placebo-treated subjects in Part C will not be pooled together.  
The presentation of each summary is detailed out in the respective sections under 
section 10 
8. 
Interim Analysis and Early Stopping Guidelines 
No formal interim analysis is planned. However, dose escalation will occur after a Dose 
Level Review Team (DLRT) makes recommendations relating to early closure/extension 
or alteration of the study based on ongoing monitoring of the study data 
(ICH GCP 5.5.2).  
All available study data including demographics, IP administration, medical history, 
concomitant medications, adverse events, ECG’s, vital signs, plasma PK and laboratory 
results will be reviewed. Pharmacokinetic data for other cohorts, if available, may be 
reviewed at the DLRM’s. The DLRM’s will be conducted in an unblinded manner and all 
members of the DLRT will be approved to see the treatment assignments following the 
appropriate Amgen standard procedure. All cohorts in Part A, Part B and Part C will 
enroll according to the sequence shown on the Study Design and Treatment Schema 
above and after review of safety data at the previous dose level and modality, as 
indicated in the schema. 
Based on these emerging safety and tolerability data and upon assessment by the 
Principal Investigator (PI), Medical Monitor and Global Safety Officer (DLRM members), 
cohorts may be removed or additional cohorts may be added. Subject numbers within 
each cohort may also be increased or decreased based on the decision from the DLRM.  


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 18 
 
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.  


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
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9.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database.  
Details of PK and external lab data transfers to the data base are provided in the 
corresponding study data transfer plans. See details of this section in the Data 
Management Plan (DMP). 
An Analysis Dataset for PK Concentrations (ADPC) will be provided to the appropriate 
CPMS representative from Global Biostatistical Sciences. 
9.2.1 
Echocardiography Data 
Echocardiographic data will be collected, tested for quality, and provided by ICON 
Imaging, Inc. to GSO-DM according to transfer protocols also described in the Data 
Management Plan. Due to concerns regarding quality of echocardiographic data 
from Parts A and B, an additional echo core lab, Brigham and Women’s Hospital 
Research Imaging Core (BWIC), was added to the study on 12th October 2017. 
While no clinically meaningful inconsistencies were noted upon review of data 
from both core labs, the precision of measurements from BWIC was noted to be 
superior and therefore, measurements from BWIC are reported for Part C in lieu of 
measurements from ICON Imaging while ICON Imaging measurements are 
reported for Part A and B. 
9.3 
Handling of Missing and Incomplete Data 
The following imputation for missing or incomplete data will be performed if required: 
• 
Incomplete adverse event and concomitant medication dates missing data will be 
imputed as described in Appendix A. If imputed dates are used, then they will be 
identified as such in the final study report. 
PK concentrations below the lower limit of quantification will be set to zero. 
9.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 20 
 
9.5 
Outliers 
All confirmed outlier data will be included in the analyses presented in this statistical 
analysis plan unless there is sufficient scientific justification (eg, important protocol 
deviation leading to invalid data) to exclude them. 
PK concentration data will be evaluated for outliers by visual inspection and decisions to 
re-assay individual samples will be made in accordance with standard CPMS practice. 
All excluded observations will be detailed by CPMS along with reasons for exclusion, in 
accordance with standard CPMS practices. 
9.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
9.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.2 or 
later. 
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The primary analysis will occur after the database lock following last subject last visit.  
Descriptive statistics will be provided for selected demographics, adverse events, vital 
signs, ECG, selected laboratory measurements, and selected echocardiographic 
measures. Descriptive statistics on continuous data will include means, medians, 
standard deviations (SD), first and third quartiles and ranges, while categorical data will 
be summarized using frequency counts and percentages. 
AMG 986 and Placebo-treated subjects in Part A and Part B will be combined to form 
composite AMG 986 and placebo groups, respectively for each Part, wherever 
appropriate. . Placebo-treated subjects in Part C will be separated per cohort (HFrEF 
versus HFpEF). Graphical summaries of the data may also be presented.  


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Statistical Analysis Plan:  20150183 
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Page 21 
 
When data are summarized by time, the values recorded against the scheduled time 
points (refer to protocol section 7.1) listed in the protocol will be used.  
Unless stated otherwise in this statistical analysis plan, the data analysis will be 
conducted using subjects in the safety analysis set. For statistical analyses comparing 
change from baseline, only subjects with both baseline and at least one post-baseline 
assessment will be included. 
10.2 
Subject Accountability 
The number and percent of subjects who were enrolled, randomized, received 
investigational product, completed investigational product, discontinued from 
investigational product (including reasons for discontinuing), completed study, 
discontinued the study (including reasons for discontinuing) will be summarized by 
pooled AMG 986 and pooled placebo treatment groups and all subjects for part A 
and part B of the study and by each treatment group for each cohort HFrEF and 
HFpEF and all subjects for part C of the study. Key study dates for the first subject 
enrolled and last subject’s end of study will be presented for all subjects in part A and 
part B and for all subjects in each cohort HFrEF and HFpEF for part C of the study.  
A subject listing and summary table noting inclusion in each analysis subset will be 
provided for all subjects enrolled by pooled AMG 986 and pooled placebo treatment 
groups and all subjects for part A and part B of the study and by each treatment 
group for each cohort HFrEF and HFpEF and all subjects for part C of the study. A 
subject listing noting duration of investigational product administration, reason for 
discontinuation of treatment, and reason for discontinuing the study will be provided. 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. The final IPD list is used to produce the summary of IPDs table and the 
List of Subjects with IPDs. The summary of IPDs will be provided by pooled 
AMG 986 and pooled placebo treatment groups and all subjects for part A and 
part B of the study and by each treatment group for each cohort HFrEF and HFpEF 
and all subjects for part C of the study. In addition, a separate listing of all inclusion 
and exclusion deviations may be provided. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 22 
 
10.4 
Demographic and Baseline Characteristics 
Demographic (ie, age, sex, race, ethnicity) and baseline characteristics (ie, height, 
weight, BMI) will be summarized using descriptive statistics by pooled AMG 986 and 
pooled placebo treatment groups and all subjects for part A and part B of the 
study and by each treatment group for each cohort HFrEF and HFpEF and all 
subjects for part C of the study. If multiple races have been reported for a subject, the 
subject will be categorized as multiple-race. 
Demographic and baseline characteristics will be presented and reviewed for each 
subject. Medical and surgical history will also be presented and reviewed for each 
subject. 
10.5 
Safety Analyses (Primary Endpoints) 
10.5.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19 or later will be 
used to code all adverse events (AEs) to a system organ class and a preferred term. 
Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of investigational product, fatal AEs will be tabulated by system organ class 
and preferred term in descending order of frequency. All adverse event tables will be 
summarized by pooled AMG 986 and pooled placebo treatment groups for part A 
and part B of the study and by each treatment group for each cohort HFrEF and 
HFpEF for part C of the study.  
Details of each adverse event will be presented and reviewed for each subject. Listings 
and/or narratives of any on-study deaths, serious and treatment-emergent adverse 
events, including early withdrawals due to adverse events, will also be provided should 
they occur. 
10.5.2 
Laboratory Test Results 
Laboratory analytes are provided in the protocol Table 13. Summary tables of selected 
chemistry and hematology data and changes from baseline over time will be provided for 
each protocol scheduled visit by pooled AMG 986 and pooled placebo treatment 
groups for part A and part B of the study and by each treatment group for each 
cohort HFrEF and HFpEF for part C of the study..  
Number and percentage of subjects of each troponin status “undetected”, “detected” and 
“elevated” at each scheduled assessment may be summarized in a similar way as 
laboratory summaries.. Summaries will also be presented treating troponin as a 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 23 
 
continuous variable in a similar way as laboratory summaries. Troponin values below 
or above quantifiable limits will be treated as equal to the limits.  
10.5.3 
Vital Signs 
Summary tables for all the vital signs parameter data including blood pressure, heart 
rate, respiratory rate, and body temperature and corresponding changes from 
baseline at each protocol scheduled study visit by pooled AMG 986 and pooled 
placebo treatment groups for part A and part B of the study and by each treatment 
group for each cohort HFrEF and HFpEF for part C of the study will be provided. 
10.5.4 
Physical Measurements 
Subject weight, height and BMI will be presented as part of baseline characteristics 
and reviewed for all subjects.  
10.5.5 
Electrocardiogram (ECG) 
Summaries of all ECG parameters and changes from baseline over time will be provided 
by pooled AMG 986 and pooled placebo treatment groups for part A and part B of 
the study and by each treatment group for each cohort HFrEF and HFpEF for part 
C of the study. Baseline will be defined as mentioned in section 6. The analysis of 
Fridericia’s (QTcF) QT correction and Bazett’s (QTcB) QT correction will be performed 
for subjects in Part A and Part B using the derived results as specified in section 6.  
10.5.6 
Exposure to Investigational Product 
A listing of unique manufacturing lot numbers, and a subject listing of manufacturing lot 
number will be provided. Additionally an exposure table will be provided with the 
summaries of number of doses, cumulative doses and average doses for each cohort 
and treatment group in Part B and Part C. 
10.5.7 
Exposure to Concomitant Medications  
Concomitant medications will not be summarized with the restricted scope of 
analysis post the discontinuation of the study earlier than planned.  
10.6 
Pharmacokinetic/Pharmacodynamic Analyses 
10.6.1 
PK Parameters for AMG 986  
The pharmacokinetic endpoints calculation and analyses will not be performed by the 
CPMS group with the restricted scope of analysis post the discontinuation of the 
study earlier than planned.  
Plasma samples will be analyzed for AMG 986 concentrations using a validated assay 
and a listing for individual concentration-time data will be provided by the CPMS 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 24 
 
group. Additionally, CPMS group will also provide plots to present 
exposure-response relationship for echocardiographic measures of stroke volume 
and ejection fraction. 
10.6.2 
Echocardiographic Measures 
Echocardiographic parameters of left ventricular systolic function including left 
ventricular ejection fraction, stroke volume by volumetric (MoD) and Doppler 
assessment (LVOT) will be summarized along with changes from baseline and 
relative (percent) changes from baseline for these parameters by treatment group for 
HFrEF cohort of Part C. Figures will be produced to plot mean and SE of left 
ventricular ejection fraction and to plot mean relative (percent) change from 
baseline in left ventricular ejection fraction and stroke volume by volumetric 
(MoD) and Doppler assessment (LVOT) by treatment group. The summary will be 
based on PD analysis set.  
For the purpose of study data tabulation model (SDTM), echocardiographic data 
collected from both vendors ICON and BWIC will be utilized for all parts of the 
study. For analysis data model (ADaM), ICON vendor data will be used for Part A 
and Part B of the study and BWIC vendor data will be used for Part C of the study. 
10.7 
Exploratory Endpoints Analyses 
Exploratory endpoints will not be analyzed with the restricted scope of analysis 
post the discontinuation of the study earlier than planned. However, bio-marker 
group will provide the mean plots by treatment group and a listing for NT-pro BNP 
data for HFrEF cohort for Part C of the study. 
11. 
Changes From Protocol-specified Analyses 
We have redefined some of the analyses to be by “treatment group” instead of by 
“cohort” to emphasize the role of the placebos. As decided by the study team post 
discontinuation of the study, most of the summaries (except exposure to 
investigational product) are not presented by cohort levels for each treatment 
group and are provided by pooled AMG 986 and pooled placebo groups. In other 
places we use the wording “study cohort” to emphasize the different dose levels.  


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 25 
 
To restrict the scope of analysis post the discontinuation of the study earlier than 
planned, following changes were made in the reporting of results from protocol-specified 
analysis: 
• 
Subject-level data listings will not be presented and reviewed for vital signs 
(protocol section 10.5.2.1.2) and ECG (protocol section 10.5.2.1.3),  
• 
Summary of maximum change from baseline in QTcF and QTcB and maximum 
post-baseline values in QTcF and QTcB as stated in protocol section 10.2.5.2.1.3 
will not be provided. 
• 
Analysis of pharmacokinetic endpoints as stated in protocol section 10.5.3.1 will 
not be performed by the CPMS group. 
• 
Analysis of echocardiographic measures as stated in protocol section 10.5.3.2 
will not be performed. The analysis is restricted to HFrEF cohort for Part C of the 
study for selected parameters of left ventricular systolic function including left 
ventricular ejection fraction, stroke volume by volumetric (MoD) and Doppler 
assessment (LVOT). The summary will be based on PD analysis set. 
Analysis of exploratory endpoints as stated in protocol section 10.5.4 will not be 
performed 
12. 
Data Not Covered by This Plan 
All data are covered by this plan and this section is no longer applicable post the 
discontinuation of the study earlier than planned.  


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
Page 26 
 
13. 
Literature Citations / References 
Nelson, CH, Wang L, Fang L, Weng W, Cheng F, Hepner, M, Lin J, Garnett C, and 
Ramanathan, S (2015) “A Quantitative Framework to Evaluate Proarrhythmic Risk in a 
First-in-Human Study to Support Waiver of a Thorough QT Study” Clinical Pharmacology 
and Therapeutics v. 98 (6) December, 2015. 
Murphy PJ, Yasuda S, Nakai K, Yoshinaga T, Hall N, Zhou M, Aluri J, Rege B, Moline M, 
Ferry J, Darpo B, “Concentration response modeling of ECG data from early phase 
clinical studies as an alternative clinical and regulatory approach to assessing QT  
risk - experience from the development program of lemborexant” J. Clinical 
Pharmacology ePub ahead of print, 24-Jun-2016. 
ICH E14 Questions & Answers (R3) December 10, 2015 http://www.ich.org/fileadmin/ 
Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf. 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
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14. 
Appendices 


Product:  AMG 986 
Statistical Analysis Plan:  20150183 
Date:  17 June 2019 
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Appendix A. Handling of Missing or Incomplete Dates for Adverse Events and 
Concomitant Medications 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year. If the stop date is entirely missing, assume 
the event or medication is ongoing. If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.  
Imputation Rules for Partial or Missing Start Dates 
 
Stop Date 
 
 
Complete: 
yyyymmdd 
Partial: yyyymm 
Partial: yyyy 
Missing 
Start Date 
 
< 1st 
Dose 
≥ 1st 
Dose 
< 1st Dose 
yyyymm 
≥ 1st Dose 
yyyymm 
< 1st 
Dose 
yyyy 
≥ 1st 
Dose 
yyyy 
Partial: 
yyyymm 
= 1st Dose 
yyyymm 
2 
1 
2 
1 
N/A 
1 
1 
≠ 1st Dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
= 1st Dose 
yyyy 
3 
1 
3 
1 
N/A 
1 
1 
≠ 1st Dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1 = Impute the date of first dose 
2 = Impute the first of the month 
3 = Impute January 1 of the year 
4 = Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month. 
Note: If the start date imputation leads to a start date that is after the stop date, then do 
not impute the start date.