Clinical trial NCT03318809
Conditions: Heart Failure
Keywords: Cardiovascular Diseases Renal Impairment Heart Diseases
Sponsor: Amgen
Start date: 2017-12-12; Completion date: 2018-04-05
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to assess the safety, tolerability, and pharmacokinetics of AMG 986 given orally as a single dose to healthy participants and participants with severely impaired kidney function.

Detailed description:

Arms: arm 1: Participants with severely impaired renal function (estimated glomerular filtration rate \[eGFR\] 15 to 29 mL/min/1.73 m\^2) receive a single oral dose of 200 mg AMG 986. arm 2: Participants with normal renal function (eGFR \>= 90 mL/min/1.73 m\^2 or above) receive a single oral dose of 200 mg AMG 986.
Interventions: intervention 1: AMG 986
Intervention descriptions: intervention 1: tablets for oral administration

Protocol documents:
Prot_000.pdf: 
Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 1 of 73 
CONFIDENTIAL 
Title:  A Phase 1, Open-label, Single-dose Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of AMG 986 Administered Orally to Healthy 
Volunteers and Subjects With Severely Impaired Renal Function 
Amgen Protocol Number (AMG 986) 20150186 
IND number BB-IND 129185 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: 805-447-1000 
Key Sponsor 
Contact(s): 
 MD, MSc 
Medical Sciences Medical Director 
Phone: 
Email:
, PhD 
Clinical Pharmacologist 
Phone: 
Email:
 
Study Manager 
Phone:
Email:
 
Date: 
15 August 2017 
Amendment 1 Date: 
28 September 2017 
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, Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US (1-805-447-1000).
Approved
NCT Number: NCT03318809
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 2 of 73 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 1, Open-label, Single-Dose Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics of AMG 986 Administered Orally 
to Healthy Volunteers and Subjects with Severely Impaired Renal Function, dated 
28 September 2017, 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 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:  20150186 
Date:  28 September 2017 
Page 3 of 73 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 1, Open-label, Single-Dose Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of AMG 986 Administered Orally to Healthy Volunteers and Subjects with 
Severely Impaired Renal Function    
Study Phase:  1   
Indication:  Heart Failure 
Primary Objective:   
• 
To evaluate the pharmacokinetics (PK) of AMG 986 following the administration of a 
single oral 200 mg dose to healthy volunteers and subjects with severely impaired renal 
function. 
Secondary Objective:   
• 
To evaluate the safety and tolerability of AMG 986 following single oral dose 
administration to subjects with severely impaired renal function relative to heathy 
matched control subjects.  
Exploratory Objectives:  
• 
To determine unbound concentrations of AMG 986 in plasma. 
• 
To determine AMG 986 metabolite concentrations in plasma.  
Hypothesis:   
• 
Clinically significant changes in AMG 986 PK that would require dose adjustment are not 
expected in subjects with severe renal impairment when compared to subjects with 
normal renal function. 
Primary Endpoints:   
• 
AMG 986 PK parameters including area under the plasma concentration time curve from 
time 0 to the time of the last quantifiable sample (AUC0-t) and maximum observed plasma 
concentration after dosing (Cmax).  Additional AMG 986 PK parameters may include but 
not limited to terminal phase half-life (t1/2); time of maximum AMG 986 plasma 
concentration (tmax); and AUC from time 0 to infinity (AUCinf). 
Secondary Endpoint:   
• 
Subject incidence of adverse events and clinically significant changes in vital signs, 
physical examinations, clinical laboratory tests and ECGs 
Exploratory Endpoints:   
• 
Plasma protein binding of AMG 986  
• 
AMG 986 metabolite concentrations in plasma 
Study Design:   
This is a phase 1, multicenter, open-label, single-dose study conducted in subjects with severely 
impaired renal function as determined by the modification of diet in renal disease (MDRD) 
equation for estimated glomerular filtration rate (eGFR).  Approximately 12 subjects will be 
assigned to the two treatment groups in the study. Approximately 6 subjects with severely 
impaired renal function (eGFR 15 to 29 ml/min/1.73 m2) will be assigned to group 1; 
approximately 6 subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) will be assigned 
to the control group 2.  All subjects in each group will receive a single oral dose of 200 mg 
AMG 986. 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 4 of 73 
CONFIDENTIAL 
 
 
An attempt will be made to match the control group of healthy males and females with normal 
renal function (group 2) to the group of subjects with severely impaired renal function (group 1) by 
age range, body weight range, gender (proportion of male and female subjects), and race.  
Enrollment of subjects in the control group will be initiated after all subjects in the renal 
impairment (RI) group have been enrolled.  The mean age ± 5 years and mean body weight 
± 10% of the subjects in the RI group will be used to help match the subjects in the control group.  
The priority for matching subject characteristics of the two groups will be: age range, body weight 
range, gender, then race.  
Sample Size:  The sample size, approximately 12 subjects in 2 groups of 6 subjects each, is 
based on practical and is consistent with the number of subjects enrolled in similar studies. 
Summary of Subject Eligibility Criteria:   
Males or females ≥ 18 and ≤ 65 years of age, with a BMI of ≥ 18 and ≤ 38 kg/m2 at screening. 
• 
Subjects enrolled in group 1 will have severe RI (eGFR 15 to 29 mL/min/1.73m2). It will 
be anticipated that these subjects will not require hemodialysis or renal transplantation, 
and will have renal function appropriate to severe RI for the duration of the study.  
• 
Subjects enrolled in group 2 will be subjects with normal renal function 
(eGFR ≥ 90 mL/min/1.73m2).   
For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2. 
Investigational Product   
Amgen Investigational Product Dosage and Administration:   
AMG 986 for oral administration will be provided as 25 mg tablets in 15-count bottles. All subjects 
will receive a single oral dose of 200 mg AMG 986. 
Procedures:   
Screening 
After informed consent has been obtained, all screening procedures and tests to establish 
eligibility will be performed within 28 days prior to the administration of AMG 986.  Subjects who 
meet the eligibility criteria after completion of all screening, day -1 and day 1 pre-dose procedures 
will be enrolled in the study.  Screening procedures are summarized in the Schedule of 
Assessments.  Day -1 assessments will be performed 1 day before investigational product 
administration.  Subjects will be admitted to the research facility on day -1 for residency.  
Treatment 
On the morning of day 1, enrolled subjects will receive IP by oral administration as a single 
200 mg dose on an empty stomach (no food or liquids, except water, for at least 8 hours prior to 
dose administration).  Subjects will remain in a fasted state (no food or liquids, except water) for 
at least 2 hours after dose administration.  Subjects will reside at the research facility until 
day 2 procedures have been completed, according to the Schedule of Assessments. Subjects will 
be discharged and will be provided with instructions to return to the research facility at specified 
time points to complete procedures through the end of the study (according to the Schedule of 
Assessments).   
All adverse events, including serious adverse events, and use of concomitant medication will be 
collected for the duration of the study. 
End of Study 
Subjects will be followed through day 30.  Subject participation is complete once end-of-study 
(EOS) procedures are performed.   
All adverse events (including serious adverse events and deaths) and use of concomitant 
medication will be collected for the duration of the study up to and including the EOS visit.  If 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
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CONFIDENTIAL 
 
 
there is a clinically significant clinical or laboratory abnormality that requires monitoring, subjects 
will be followed until resolution of the abnormality or until it is considered stable. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2). 
Statistical Considerations:   
PK parameters of total AMG 986 in plasma will be calculated using non-compartmental methods.  
Descriptive statistics will be provided for all endpoints and will include selected demographics, 
adverse events, vital signs, ECG, PK, and selected laboratory measurements. Descriptive 
statistics on continuous data will include means, medians, standard deviations, and ranges, while 
categorical data will be summarized using frequency counts and percentages. PK parameters 
and clinical lab data will be summarized at each time point when samples are collected.  
Additionally, 90% confidence intervals will be calculated for the mean group difference ie, the 
geometric mean ratio (GMR) after back-transforming. These 90% CIs will be tabulated and 
presented for all PK parameters compared.  Assuming 20% for the intra-subject standard 
deviation for AMG 986 log–transformed PK parameters (AUC0-t and Cmax) and assuming that it is 
the same in the 2 groups, the current sample size of 6 would provide a CI for the GMR of 
(0.81, 1.23). The number and percentage of subjects reporting any treatment-emergent adverse 
event will be tabulated by system organ, preferred term, and renal function group. With 
12 subjects receiving AMG 986, there is a 46% chance of seeing an AE with a 5% incidence rate.  
Clinically significant changes in vital signs, ECGs, and clinical laboratory tests will be noted. For a 
full description of statistical analysis methods, please refer to Section 10. 
Sponsor:   
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 6 of 73 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
D -28 
D -28 
Screening
Screening 
Treatment 
Treatment 
Severe RI 
Group 1 
Normal 
Control 
Group 2 
D 1 
D 30 
EOS 
D 30 
EOS 
D 1 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
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CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADHERE 
US Acute Decompensated Heart Failure National Registry 
AE 
adverse event 
ALT 
alanine aminotransferase 
APJ 
apelin receptor 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf  
area under the concentration-time curve from time 0 to infinity 
AUC0-t 
area under the concentration-time curve from time 0 to the time of 
the last quantifiable sample 
BMI 
body mass index 
BP 
blood pressure 
Cmax 
maximum observed concentration 
CRF 
electronic case report form 
CTCAE 
common terminology criteria for adverse events 
DILI 
drug induced liver injury 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a study 
End of Study  
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, long-term follow-up), 
as applicable  
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 
Enrollment 
when the investigator decides that the subject has met all eligibility 
criteria 
GCP 
good clinical practice 
GMR 
geometric mean ratio 
HBcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
hERG 
human Ether-a-go-go-Related Gene 
HepCab 
hepatitis C antibody 
HF 
heart failure 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 8 of 73 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
HFpEF 
heart failure with preserved ejection fraction 
HFrEF 
heart failure with reduced ejection fraction 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
international conference on harmonization 
IP 
investigational product 
IPIM 
investigational product instruction manual 
IUD 
intrauterine device 
IV 
Intravenous 
MDRD 
modification of diet in renal disease 
NOAEL 
no-observed-adverse-effect-level 
NOEL 
no-observed-effect-level 
P-gp 
P glycoprotein 
PK 
Pharmacokinetics 
PR Interval 
pr interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the hearts electrical cycle as 
measured by ECG 
Primary Completion 
defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), 
for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early  
QRS Interval 
qrs interval is the interval between the Q wave and the S wave in the 
heart’s electrical cycle as measured by ECG; represents the time it 
takes for the depolarization of the ventricles 
QT interval 
qt interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart’s electrical cycle as measured 
by ECG 
QTc interval 
qt interval corrected for heart rate using accepted methodology 
QTcF 
qt interval corrected for heart rate using Fridericia’s formula 
RI 
renal impairment 
RR 
respiratory rate 
SAE 
serious adverse event 
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. 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 9 of 73 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Study Day 1 
 
defined as the first day that protocol specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
TEMP 
Temperature 
tmax 
time to max plasma concentration 
ULN 
upper limit of normal 
Vss 
steady-state volume of distribution 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 10 of 73 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ................................................................................................................3 
Study Design and Treatment Schema ................................................................................6 
Study Glossary .....................................................................................................................7 
1. 
OBJECTIVES ............................................................................................................14 
1.1 
Primary ..........................................................................................................14 
1.2 
Secondary .....................................................................................................14 
1.3 
Exploratory ....................................................................................................14 
2. 
BACKGROUND AND RATIONALE ..........................................................................14 
2.1 
Disease .........................................................................................................14 
2.2 
Amgen Investigational Product Background ................................................16 
2.2.1 
Pharmacology...............................................................................16 
2.2.2 
Pharmacokinetics .........................................................................17 
2.2.3 
Toxicology.....................................................................................19 
2.3 
Risk Assessment ..........................................................................................20 
2.4 
Rationale .......................................................................................................21 
2.5 
Clinical Hypothesis........................................................................................22 
3. 
EXPERIMENTAL PLAN............................................................................................22 
3.1 
Study Design .................................................................................................22 
3.2 
Number of Sites ............................................................................................23 
3.3 
Number of Subjects ......................................................................................23 
3.4 
Replacement of Subjects ..............................................................................23 
3.5 
Estimated Study Duration .............................................................................23 
3.5.1 
Study Duration for Subjects .........................................................23 
3.5.2 
End of Study .................................................................................23 
4. 
SUBJECT ELIGIBILITY ............................................................................................24 
4.1 
Inclusion Criteria ...........................................................................................24 
4.2 
Exclusion Criteria ..........................................................................................25 
5. 
SUBJECT ENROLLMENT ........................................................................................27 
5.1 
Treatment Assignment..................................................................................28 
6. 
TREATMENT PROCEDURES .................................................................................29 
6.1 
Classification of Product(s) ...........................................................................29 
6.2 
Investigational Product..................................................................................29 
6.2.1 
Amgen Investigational Product:  AMG 986 ..................................29 
6.2.1.1 
Dosage, Administration, and Schedule.....................29 
6.3 
Criteria for Additional Safety Assessment due to Potential 
Hepatotoxicity................................................................................................30 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
Date:  28 September 2017 
Page 11 of 73 
CONFIDENTIAL 
 
 
6.4 
Concomitant Therapy....................................................................................31 
6.5 
Alcohol and Tobacco Restrictions ................................................................31 
6.6 
Product Complaints.......................................................................................32 
6.7 
Excluded Treatments, Medical Device use, and/or Procedures 
During Study Period ......................................................................................32 
7. 
STUDY PROCEDURES ...........................................................................................33 
7.1 
Schedule of Assessments ............................................................................33 
7.2 
General Study Procedures ...........................................................................36 
7.2.1 
Screening......................................................................................37 
7.2.2 
Day -1 ...........................................................................................38 
7.2.3 
Treatment .....................................................................................38 
7.2.4 
End of Study Visit .........................................................................39 
7.2.5 
Demographics ..............................................................................40 
7.2.6 
Subject Residency........................................................................40 
7.2.7 
Medical History .............................................................................40 
7.2.8 
Physical Examination ...................................................................40 
7.2.9 
Physical Measurements ...............................................................40 
7.2.10 
Vital Signs .....................................................................................40 
7.2.11 
Pregnancy Test (Females Only) ..................................................41 
7.2.12 
Serum Follicle-stimulating Hormone Test (Females 
Only) .............................................................................................41 
7.2.13 
Drug, Alcohol, and Cotinine Screening ........................................42 
7.2.14 
Electrocardiogram (ECG) .............................................................42 
7.2.15 
Clinical Chemistry .........................................................................43 
7.2.16 
Hematology...................................................................................44 
7.2.17 
Plasma AMG 986 Concentrations................................................45 
7.2.18 
Estimated Glomerular Filtration Rate ...........................................45 
7.2.19 
Hepatitis B Surface Antigen and Core Antibody, 
Hepatitis C Antibody and HIV Status ...........................................45 
7.2.20 
Concomitant Medications and Adverse Event 
Reporting ......................................................................................45 
7.3 
Approximate Phlebotomy Volume ................................................................45 
7.4 
Sample Storage and Destruction..................................................................46 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ...................47 
8.1 
Subjects’ Decision to Withdraw ....................................................................47 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion........................................48 
8.3 
Reasons for Removal From Treatment or Study .........................................48 
8.3.1 
Reasons for Removal From Treatment........................................48 
8.3.2 
Reasons for Removal From Study ...............................................48 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ........................49 
9.1 
Definition of Safety Events............................................................................49 
Approved 
 
 


Product:  AMG 986 
Protocol Number:  20150186 
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CONFIDENTIAL 
 
 
9.1.1 
Disease Related Events ...............................................................49 
9.1.2 
Adverse Events ............................................................................49 
9.1.3 
Serious Adverse Events ...............................................................49 
9.2 
Safety Event Reporting Procedures .............................................................50 
9.2.1 
Adverse Events ............................................................................50 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria .............................50 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ........................................................................51 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ....................52 
9.3 
Pregnancy and Lactation Reporting .............................................................53 
10. 
STATISTICAL CONSIDERATIONS .........................................................................54 
10.1 
Study Endpoints, Analysis Sets, and Covariates .........................................54 
10.1.1 
Study Endpoints ...........................................................................54 
10.1.1.1 
Primary Endpoints .....................................................54 
10.1.1.2 
Secondary Endpoint ..................................................54 
10.1.1.3 
Exploratory Endpoints ...............................................54 
10.1.2 
Analysis Sets ................................................................................54 
10.1.2.1 
Safety Analysis Set....................................................54 
10.1.2.2 
Pharmacokinetic (PK) Analysis Set ..........................54 
10.1.3 
Covariates and Subgroups...........................................................54 
10.1.4 
Handling of Missing and Incomplete Data ...................................55 
10.2 
Sample Size Considerations.........................................................................55 
10.3 
Planned Analyses .........................................................................................55 
10.3.1 
Data Review Team Meeting .........................................................55 
10.3.2 
Primary Analysis ...........................................................................55 
10.3.3 
Final Analysis ...............................................................................56 
10.4 
Planned Methods of Analysis .......................................................................56 
10.4.1 
General Considerations................................................................56 
10.4.2 
Primary Endpoints ........................................................................56 
10.4.2.1 
Pharmacokinetic Analysis .........................................56 
10.4.3 
Secondary Endpoints ...................................................................56 
10.4.3.1 
Safety Endpoints .......................................................56 
10.4.4 
Exploratory Endpoints ..................................................................57 
10.4.4.1 
Plasma Protein Binding of AMG 986 ........................57 
10.4.4.2 
AMG 986 Metabolites ................................................57 
11. 
REGULATORY OBLIGATIONS ...............................................................................57 
11.1 
Informed Consent .........................................................................................57 
11.2 
Institutional Review Board/Independent Ethics Committee .........................58 
11.3 
Subject Confidentiality ..................................................................................59 
11.4 
Investigator Signatory Obligations ................................................................59 
Approved 
 
 


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Protocol Number:  20150186 
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CONFIDENTIAL 
 
 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................60 
12.1 
Protocol Amendments and Study Termination.............................................60 
12.2 
Study Documentation and Archive ...............................................................60 
12.3 
Study Monitoring and Data Collection ..........................................................61 
12.4 
Investigator Responsibilities for Data Collection ..........................................62 
12.5 
Language ......................................................................................................62 
12.6 
Publication Policy ..........................................................................................62 
12.7 
Compensation ...............................................................................................63 
13. 
REFERENCES..........................................................................................................64 
14. 
APPENDICES ...........................................................................................................66 
List of Tables  
Table 1.  Preliminary AMG 986 PK Estimates in Healthy Subjects After Single 
Oral Dose Administration and Exposure Margins (Study 
20150183) ..................................................................................................18 
Table 2.  Schedule of Assessments ..................................................................................34 
Table 3.  List of Analytes ...................................................................................................44 
Table 4.  Approximate Blood Volume Collection ...............................................................46 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ..................................................67 
Appendix B.  Sample eSerious Event Contingency Report Form ....................................69 
Appendix C.  Pregnancy and Lactation Notification Worksheets .....................................72 
Approved 
 
 


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CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the pharmacokinetics (PK) of AMG 986 following the administration of a 
single oral 200 mg dose to healthy volunteers and subjects with severely impaired renal 
function.  
1.2 
Secondary 
• 
To evaluate the safety and tolerability of AMG 986 following single oral dose 
administration to subjects with severely impaired renal function relative to heathy 
matched control subjects. 
1.3 
Exploratory 
• 
To determine unbound concentrations of AMG 986 in plasma. 
• 
To determine AMG 986 metabolite concentrations in plasma.  
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 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.  
2.1 
 Disease  
Heart failure (HF) 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.  It 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).  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 is a progressive disorder with a natural history punctuated by 
Approved 
 
 


Product:  AMG 986 
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Date:  28 September 2017 
Page 15 of 73 
CONFIDENTIAL 
 
 
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. 
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 
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. 
Non-cardiac comorbidities including chronic kidney disease (CKD) are extremely 
common in HF patients.  In a meta analysis of the published literature that included 
57 studies that evaluated CKD in HF patients, the pooled prevalence of CKD was 
reported as 32% in all HF patients, 53% in acute HF patients, and 42% in chronic HF 
patients (Damman et al, 2014). In the same publication, the pooled rate of worsening 
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renal function was reported as 23% in all HF patients, 23% in acute HF patients, and 
25% in chronic HF patients. In the US, the Acute Decompensated Heart Failure National 
Registry (ADHERE) Cohort showed that the prevalence of moderate (Stage III), severe 
without dialysis (Stage IV), and severe with dialysis (Stage V) renal dysfunction was 
41.2%, 11.5%, and 6.6%, respectively for males, and 45.7%, 14.8%, and 7.3%, 
respectively for females (Heywood et al, 2007). In the same meta-analysis 
(Damman et al, 2014) the mortality rate was also estimated: at baseline, the pooled 
mortality rate was 16% in HF patients with CKD and 11% in HF patients without CKD, 
after a mean follow-up of 681 days. The pooled unadjusted odds ratio (OR) of all-cause 
mortality in HF patients with CKD vs HF patients without CKD was 
2.34 (95% confidence interval [CI], 2.2-2.5). Furthermore, worsening renal failure during 
the course of disease was also correlated to mortality when compared with patients 
without worsening renal failure (pooled unadjusted OR = 1.81 [95% CI, 1.55-2.12]). The 
use of some HF therapies, such as ACE inhibitors and loop diuretics, can result in acute 
renal failure or acute worsening of pre-existing chronic kidney dysfunction. Acute 
worsening of cardiac output can also lead to decreases in renal function 
(Ezzat et al, 2015; Tariq and Aronow, 2015; McMurray et al, 2012; Schoolwerth et al, 
2001). Therefore, the knowledge of the safety and pharmacokinetic behavior of AMG 
986, being developed as a promising therapy for heart failure patients, in subjects with 
renal dysfunction is extremely relevant. 
2.2 
Amgen Investigational Product Background  
AMG 986 is a small-molecule agonist that binds to the APJ receptor and activates Gαi 
and arrestin pathways. 
Refer to the specific section of the IB for additional information related to the physical, 
chemical, and pharmaceutical properties and formulation(s). 
2.2.1 
Pharmacology 
Nonclinical Pharmacology 
AMG 986 increased cardiac contraction and relaxation in isolated perfused rat hearts.  
This increase in load-independent contractility without change in calcium transients was 
also observed in adult rat cardiomyocytes.  The contractile effects of AMG 986 appeared 
to be specific through APJ receptor, since the compound has no impact on 
phosphodiesterase inhibition.  The cardiovascular effects of AMG 986 in vivo were 
studied in both rodent and canine models.  In a rat model of systolic heart failure 
(induced by myocardial infarction), AMG 986 increased cardiac output, reduced systemic 
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vascular resistance, and improved ventriculo-arterial coupling.  In that same model, 
AMG 986 had beneficial effects on cardiac function that were additive to those of the 
reference drug captopril.  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 two 
canine heart failure models (microembolism and tachypacing), AMG 986 improved left 
ventricular contractile function without negative impact on heart rate and/or myocardial 
oxygen consumption.  Details of AMG 986 nonclinical pharmacology are summarized in 
the Investigators 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. 
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Human Pharmacokinetics 
Preliminary PK analyses were conducted in 54 healthy subjects who had received 
AMG 986 by intravenous infusion or by oral tablet administration in Study 20150183.  A 
total of 4 oral dose cohorts (24 subjects) and 5 intravenous (IV) dose cohorts 
(30 subjects) have been studied.   
After single oral dose administration at 5 mg, 30 mg, 100 mg and 200 mg, mean 
estimates of terminal half-life ranged from 13.2 to 18.0 hours, absorption was rapid with 
median estimates of Tmax that ranged from 1.0 to 2.0 hours and oral bioavailability 
ranged from 61% to 80% (Table 1). 
Pharmacokinetic dose proportionality was not assessed formally; however, exposure to 
AMG 986 generally increased with increased oral AMG 986 doses. 
The excretion of unchanged AMG 986 in urine was low in subjects who received 
AMG 986 by single IV infusion at 0.5 mg/1 hour or 3 mg/1 hour.  In IV cohorts 1 and 2, 
approximately 4% of dose was excreted unchanged within 12 hours following IV dosing 
and minimal additional excretion of dose occurred between 12 and 48 hours after IV 
administration. 
Table 1.  Preliminary AMG 986 PK Estimates in Healthy Subjects After Single Oral 
Dose Administration and Exposure Margins (Study 20150183) 
Dose 
(mg) 
Obs/ 
Pred 
F 
(%) 
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 
75 
334 (22) 
2460 (34) 
422X 
150X 
293X 
219X 
30 
Obs 
61 
1850 
(33) 
12600 (25) 
76X 
29X 
53X 
43X 
100 
Obs 
64 
5760 
(24) 
34100 (5) 
24X 
11X 
17X 
16X 
200 
Obs 
80 
12200 
(34) 
85600 (33) 
12X 
4X 
8X 
6X 
1 Ratio of mean observed Cmax and AUC24h exposure at NOAEL 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 Cmax and AUCinf 
exposures. 
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 Cmax 
and AUCinf exposures.  
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; F= oral bioavailability; 
Obs = observed 
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2.2.3 
Toxicology 
Nonclinical Toxicology 
The nonclinical toxicology package for AMG 986 includes repeat dose toxicology studies 
with both oral (28-day studies in rat and dog) and IV (14-day studies in rat and dog) dose 
routes, developmental and reproductive toxicology studies in rats and rabbits (oral 
dosing), as well as genetic toxicology, phototoxicity and safety pharmacology studies.  
Repeat Dose Toxicology Studies: 
In the 28-day oral toxicology studies, estimates of AUC24h exposures in rats and dogs at 
the no-observed-(adverse)-effect-level (NO[A]EL) doses were 4-fold and 6-fold greater 
than the human exposure at 200 mg, respectively (Table 1).  These margins from the 
toxicology studies support the planned oral dose of 200 mg. 
In developmental and reproductive toxicology studies in rats and rabbits, oral 
administration of AMG 986 resulted in embryo-fetal toxicity 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, and 
decreases in embryo-fetal survival.   
AMG 986 was negative in both in vitro and in vivo genetic toxicology studies and in an in 
vitro phototoxicity assay. 
Safety Pharmacology: 
The NOEL for effects on neurobehavioral and respiratory function in rats was 
1000 mg/kg (single oral dose).  In an anesthetized IV dog cardiovascular (CV) study, 
AMG 986 related CV effects were limited to small 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) after single oral doses up to 300 mg/kg.  No effects 
on QT/QTc interval were observed in the anesthetized or conscious dog safety 
pharmacology studies and there were no changes in QTc interval in the 28-day oral or 
14-day IV dog toxicology studies. 
The IC50 value for inhibitory effect of AMG 986 on hERG current (IKr current) was 
estimated to be > 300 µM (157 µg/mL, unbound concentration), more than 3000-fold 
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higher than the human unbound concentration at the oral dose of 200 mg.  Details of 
AMG 986 nonclinical package are summarized in the Investigators Brochure.   
2.3 
Risk Assessment 
AMG 986 has an identified risk of embryo-fetal toxicity.  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 refrain from sperm donation 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, expected acute risks associated with AMG 986 are of a 
cardiovascular nature, such as hypotension, although other effects, such as tachycardia 
or even hypertension cannot be excluded.  
Overall, the nonclinical (toxicology and safety pharmacology) package suggests a safe 
profile at the doses planned in 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-day studies) or IV (14-day studies) dose administration.  The 
AUC exposure margins based on NO(A)EL doses from the rat and dog toxicology 
studies support the planned clinical dose range.  Additionally, no AMG 986-related 
effects in the safety pharmacology studies were identified, and data indicate that QTc 
interval prolongation risk is low. 
Developmental and reproductive toxicology studies identified a risk for embryo-fetal 
toxicity as described above. 
As of 14 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 9 fully implemented cohorts of 8 healthy subjects each.  The subjects reviewed 
included those who received single oral doses of AMG 986 up to 200 mg, oral doses of 
5 mg of AMG 986 for 7 consecutive days, as well as IV doses of AMG 986 over 24 hours 
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(loading doses up to 20 mg over 1 hour followed by maintenance doses up to 120 mg 
over 23 hours) and placebo.  There was a total of 54 subjects who received AMG 986 
and 18 subjects who received placebo.  Of these 72 subjects, 71 completed the 
investigational product.  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 72 subjects, no serious adverse events, 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.  Twelve subjects (16.7%) 
were reported to have treatment emergent adverse events during double-blind 
treatment.  The most common event was headache, which occurred in 5 subjects 
(6.9%).  The event of headache was reported as a common terminology criteria for 
adverse events (CTCAE) severity grade 1 in 4 of the subjects, and CTCAE grade 2 in 
1 subject.  Most of the adverse events were CTCAE grade 1 events.  There were 
4 CTCAE grade 2 events, and none of the events occurred in more than 1 subject.  No 
events were CTCAE grade ≥3 events.   
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 meaningful individual subject changes in vital signs 
(including blood pressure) were identified within or across any of the 9 cohorts.  There 
was no notable variation in the vital signs with the increasing doses of AMG 986 
throughout the study.  Additionally, no laboratory (including troponin I) or ECG 
abnormalities were detected. 
In summary, the clinical experience accumulated with AMG 986 suggests that the 
administration of AMG 986 was well tolerated. 
Taken together, the non-clinical data and clinical experience accumulated with AMG 986 
suggest that the administration of AMG 986 at the proposed clinical dose is safe.  All 
doses tested thus far were well tolerated and an acceptable safety profile was observed.  
Pregnant women should not take AMG 986. 
2.4 
Rationale 
This study will evaluate the safety, tolerability, and PK of AMG 986 in male and/or 
female subjects with severely impaired renal function relative to heathy matched control 
subjects.  All subjects will receive IP in a fasted state as a single 200 mg dose by the 
oral route.  Healthy subjects with normal renal function will serve as a control group to 
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subjects with severely impaired renal function.  The dose selected for this study is based 
on model predictions of human exposure from preclinical studies and the First-In-Human 
study in healthy subjects, the safety and tolerability profile for the selected dose in 
healthy human subjects and the potential clinical doses to be investigated in patients 
with heart failure who may also have renal impairment.    
While clinical doses have not been selected for study in a pivotal trial of AMG 986 in 
patients with heart failure, a single dose of 200 mg was selected for this study.  Selection 
of the 200 mg oral dose level for evaluation was based on the following: (1) observed 
AMG 986 PK results in healthy subjects (2) acceptable safety and tolerability of a single 
oral dose up to 400 mg in study 20150183 (3) acceptable safety and tolerability of 
multiple daily oral dose of 200 mg.  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.     
Evaluation of AMG 986 PK in subjects with renal impairment at the planned dose will 
allow the conclusions of this study to be applied to subsequent studies where a dose as 
high as 200 mg could be tested. 
2.5 
Clinical Hypothesis 
Clinically significant changes in AMG 986 PK that would require dose adjustment are not 
expected in subjects with severe renal impairment when compared to subjects with 
normal renal function. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1, multicenter, open-label, single-dose study conducted in subjects with 
severely impaired renal function as determined by estimated glomerular filtration rate 
(eGFR).  The eGFR is estimated using the 4-Parameter Modification of Diet in Renal 
Disease (MDRD) equation (Levey et al, 2009). Approximately 12 subjects will be 
assigned to 1 of 2 treatment groups.  Approximately 6 subjects with severely impaired 
renal function (eGFR 15 to 29 ml/min/1.73 m2) will be assigned to group 1; 
approximately 6 subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) will be 
assigned to the control group 2.  All subjects will be assigned to receive a single 
oral dose of 200 mg AMG 986. 
An attempt will be made to match the control group of healthy males and females with 
normal renal function (group 2) to the group of subjects with severely impaired renal 
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function (group 1) by age range, body weight range, gender (proportion of male and 
female subjects), and race.  The mean age ± 5 years and mean body weight ± 10% of 
the subjects in the severely renal impaired group will be used to help match the subjects 
in the control group.  The priority for matching subject characteristics of the two groups 
will be: age range, body weight range, gender, then race. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
This study will be conducted at approximately 3 clinical research facilities in the United 
States.  Sites that do not enroll subjects within 1 month of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
12 subjects in 2 groups of 6 subjects each will be enrolled in the study. The sample size 
justification for subjects enrolled in this study is provided in Section 10.2.   
3.4 
Replacement of Subjects 
Enrolled subjects who do not receive AMG 986 or do not receive the full dose of 
AMG 986 may be replaced.  Subjects who drop out of the study for reasons other than 
adverse events or serious adverse events after receiving investigational product may be 
replaced at the discretion of Amgen in consultation with the investigator or their 
designee.   
All data from any replaced subjects will be captured and kept in the clinical trial database 
and identified as such.   
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Subject participation will last up to approximately 58 days, including a 28-day screening 
period prior to administration of AMG 986 and an on-study period lasting up to 30 days.   
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.   
The primary completion date is the date when the last subject has completed 
assessments for pharmacokinetics. 
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If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101. 
Male or female subjects, who are ≥ 18 and ≤ 65 years of age at the time of 
screening  
102. Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
103. 
Women must be of non-reproductive potential   
o Postmenopausal defined as:   
 
Age of ≥ 55 years with no menses for at least 12 months;  OR  
 
Age of < 55 years with no menses for at least 12 months AND with a 
follicle-stimulating hormone level > 40 IU/L) or according to the 
definition of “postmenopausal range” for the laboratory involved; OR 
o History of hysterectomy; OR  
o History of bilateral oophorectomy. 
104. 
Women must have negative results for both the screening (serum) and day -1 
(serum or urine) pregnancy tests 
105. 
Men must agree to practice an acceptable method of effective birth control while 
on study through 11 weeks after receiving the dose of study drug.  Acceptable 
methods of effective birth control include sexual abstinence; vasectomy and 
testing shows there is 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 IUD (women). 
106. 
Men must be willing to abstain from sperm donation while on study through 
11 weeks after receiving the dose of study drug  
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107. 
Body mass index (BMI) ≥ 18 and ≤ 38 kg/m2 at screening. 
108. 
Laboratory test values (clinical chemistry and hematology) within normal limits for 
subjects with normal renal function or consistent with the underlying condition for 
subjects with renal impairment, or clinically acceptable to the investigator for both 
normal renal function and subjects with renal impairment. 
109. 
Physical examination and 12-lead electrocardiograms (ECGs) are clinically 
acceptable to the investigator. 
110. 
Non-hypertensive subjects or subjects with treated, stable hypertension as 
defined by blood pressure not exceeding 170/100 mm Hg as an average during 
screening and day -1; for subjects with renal impairment, no change in dosage 
and medication for ≥ 4 weeks prior to screening, and expected to remain on this 
dose and medication for the entire duration of the study  
111. 
Willing to maintain current general diet and physical activity regimen 
112. 
Renal function in 1 of the following 2 categories at the time of screening for: 
• 
Group 1: Severe RI (eGFR 15 to 29 ml/min/1.73 m2) and not 
anticipated to require hemodialysis or renal transplantation, and 
anticipated to have renal function appropriate to severe RI for the 
duration of the study  
• 
Group 2: Normal renal function (eGFR ≥ 90 ml/min/1.73m2) 
4.2 
Exclusion Criteria 
Exclusion Criteria for All Subjects: 
201. 
Subjects whose second MDRD eGFR result on day -1 is not within 15% of the 
first eGFR result performed during the screening period. Healthy volunteers who 
have normal renal function, but show a difference greater than 15% in eGFR 
based on MDRD during the screening period, will be included in the trial at the 
discretion of the investigator and the sponsor after a 24-hour creatinine clearance 
has been performed that meets eligibility criteria. 
202. 
Subjects who are the recipient of a renal transplant and/or are on 
immunosupressants. 
203. 
Subjects with a history of hospitalization for heart disease or angina within 
4 months of screening.  
204. 
Current or prior malignancy within 5 years of enrollment 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.   
205. 
Positive for human immunodeficiency virus (HIV antibodies), hepatitis B surface 
antigen (HBsAg) or hepatitis C virus antibodies (HepCAb) at screening 
206. 
Subject has known sensitivity to any of the products or components to be 
administered during dosing.  
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207. 
Subject likely to not be available to complete all protocol-required study visits or 
procedures (including the research facility residency period), and/or to comply 
with all required study procedures to the best of the subject and investigator’s 
knowledge. 
208. 
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. 
209. 
Subject previously has entered this study or has been previously exposed to 
AMG 986. 
210. 
Women who are lactating/breastfeeding or who plan to breastfeed while on study 
through 11 weeks after receiving the dose of study drug. 
211. 
Men with partners who are pregnant or planning to become pregnant while the 
subject is on study through 11 weeks after receiving the dose of study drug. 
212. 
QTc Interval: 
• 
Group 1 (Severe Renal Impairment): QTc > 470 msec or history/evidence 
of long QT syndrome. 
• 
Group 2 (Normal Renal Function): QTc > 450 msec or history/evidence of 
long QT syndrome. 
213. 
Planned elective surgery within 30 days of study completion or before return of 
red blood cell parameters to normal values. 
214. 
Blood donation ≥ 500 mL within 60 days of day 1. 
215. 
Heart rate ≥ 100 beats per minute after 5 minutes of rest or an untreated 
symptomatic bradyarrhythmia within 1 month prior to enrollment. 
216. 
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. 
217. 
Unwilling or unable to abstain from alcohol consumption from 24 hours prior to 
admission to the research facility (day -1) and throughout the duration of the 
study. 
218. 
Known history of drug or alcohol abuse within last 12 months. 
219. 
Subjects with a positive drug and alcohol screen at screening or day -1  
220. 
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 dose of 
investigational product (AMG 986). 
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221. 
Concurrent use of any medications (over-the-counter or prescription) within 
14 days or 5 half-lives (whichever is longer) prior to dose of AMG 986, except 
acetaminophen (up to 2 g per day) for analgesia, hormone replacement therapy 
(eg, estrogen, thyroid),  and medications used to treat CKD and other chronic 
comorbidities in subjects with severe renal impairment.  Continued use if 
applicable, will be reviewed by the Principal Investigator and the Amgen Medical 
Monitor. Written documentation of this review and Amgen acknowledgment is 
required for subject participation. 
222. 
Concurrent or prior use of strong CYP3A4 inhibitors within 14 days or 5 half-lives 
(whichever is longer) of study day 1, including (not limited to): macrolide 
antibiotics (eg, clarithromycin, telithromycin), antifungals (eg, itraconazole, 
voriconazole), antivirals (eg, ritonavir, saquinavir, indinavir, nelfinavir), 
nefazodone. 
223. 
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. 
224. 
Concurrent or prior use of strong CYP3A4 inducers within 30 days or 5 half-lives 
(whichever is longer) of study day 1, Including (not limited to): phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital.  Subjects should 
also not take St. John’s Wort. 
225. 
Concurrent or prior use of strong P-glycoprotein inhibitors within 28 days of study 
day 1, including (not limited to): elacridar and valspodar. 
226. 
Concurrent or prior use of Phosphodiesterase 5 (PDE5) inhibitors within 28 days 
of study day 1, including (not limited to) avanafil, sildenafil, tadalafil, vardenafil. 
227. 
Concurrent use or prior use of vasodilators within 28 days of study day 1, that 
could in the opinion of the investigator potentially lead to a drop in blood pressure 
in combination with investigational product (AMG 986). 
228. 
Current use or prior use of all herbal medicines, vitamins, and supplements 
consumed by the subject within the 30 days prior to receiving the first dose of 
AMG 986. 
229. 
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. 
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 and/or legally acceptable 
representatives must personally sign and date the informed consent form before 
commencement of study-specific activities/procedures.  A subject is considered enrolled 
when the investigator decides that the subject has met all eligibility criteria. 
Approved 
 
 


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The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment CRF. 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the Informed Consent Form (ICF)) receives a unique subject 
identification number before any study procedures are performed.  The subject 
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.  Subjects who fail screening may be rescreened once at the 
discretion of the investigator and with approval in consultation with Amgen.   
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.   
 
 
 
 
 
5.1 
Treatment Assignment 
This is a phase 1, open-label, non-randomized study conducted in subjects with severely 
impaired renal function as determined by the modification of diet in renal disease 
(MDRD) equation for estimated glomerular filtration rate (eGFR).  Subjects who meet 
eligibility requirements (Section 4) will be assigned into one of 2 treatment groups: 
severe RI (eGFR 15 to 29 mL/min/1.73 m2) or normal renal function 
(eGFR ≥ 90 mL/min/1.73 m2 or above). 
Subjects with severely impaired renal function (eGFR 15 to 29 ml/min/1.73 m2) will be 
assigned to group 1.  Subjects with normal renal function will be assigned to the control 
group 2.  Enrollment of subjects in the control group will be initiated after all subjects in 
the RI group have been enrolled.   
 An attempt will be made to match the control group of healthy males and females with 
normal renal function (group 2) to the group of subjects with severely impaired renal 
function (group 1) by age range, body weight range, gender (proportion of male and 
female subjects), and race.  The mean age ± 5 years and mean body weight ± 10% of 
the subjects in the severely renal impaired group will be used to help match the subjects 
Approved 
 
 


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in the control group.  The priority for matching subject characteristics of the two groups 
will be: age range, body weight range, gender, then race.  After review of the 
characteristics of the subjects enrolled in the RI group, Amgen will decide on the 
acceptability of eligible subjects in the control group to match the RI group, and be 
enrolled in the study. 
All subjects in each group will receive a single oral dose of 200 mg AMG 986 on day 1.  
Subjects will be assigned an identification number in the order in which they were 
qualified.   
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) 
The Amgen Investigational Product (except if required by local regulation) used in this 
study include: AMG 986. The dose of AMG 986 that is planned is a single 200 mg dose 
administered orally.   
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.  
6.2 
Investigational Product 
All investigational product will be administered at the research facility by a qualified staff 
member.  
A physician must be available at the time of administration of Investigational Product 
(AMG 986). 
6.2.1 
Amgen Investigational Product:  AMG 986 
AMG 986 for oral administration will be manufactured and packaged by Amgen, Inc. and 
distributed using Amgen clinical investigational product distribution procedures. 
AMG 986 for oral administration will be provided to the site as 25 mg tablets available in 
15-count bottles.  
6.2.1.1 
Dosage, Administration, and Schedule 
Subjects will be admitted to the study clinic on day -1 and will remain resident until 
completion of all study procedures 24 hours after dosing until day 2.  
On day 1, enrolled subjects will receive IP (200 mg AMG 986) by oral administration on 
an empty stomach (no food or liquids, except water, for at least 8 hours prior to dose 
administration) on study day 1.  Subjects will remain in a fasted state (no food or liquids, 
Approved 
 
 


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except water) for at least 2 hours after dose administration.  Fasting instructions will 
apply to both treatment groups.  Following completion of all study procedures on day 2 
(see Schedule of Assessments), subjects will be discharged from the clinic with 
instructions to return to the research facility at specified time points for collection of blood 
samples for PK assessments and completion of safety assessments through the end of 
the study.   
Emesis and diarrhea will be documented in the subject source and on the Event CRF, 
with time and severity of the event noted. Any subject who experiences emesis within 
4 hours of dosing may be excluded from the pharmacokinetic analysis. Any subject who 
experiences diarrhea within 24 hours of dosing may be excluded from the 
pharmacokinetic analysis. 
The effects of overdose of this product are not known. 
6.3 
Criteria for Additional Safety Assessment due to Potential 
Hepatotoxicity 
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:  
• 
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   
• 
TBIL > 2x upper limit of normal (ULN) or INR > 1.5 
AND 
• 
No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
elevated TBIL values include, but are not limited to: 
• 
Hepatobilliary tract disease  
• 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, Cytomegalovirus, 
Herpes Simplex Virus, Varicella, Toxoplasmosis, and Parvovirus) 
• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia  
• 
Exposure to hepatotoxic agents/drugs including herbal and dietary supplements, 
plants, and mushrooms,  
Approved 
 
 


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• 
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, rhabdomyolysis, hemolysis) 
6.4 
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 6.7.  Subjects with impaired renal function may continue to use 
established therapies necessary for the treatment of renal disease (and conditions 
secondary to renal disease). 
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 (up to 2 g per day) for analgesia and hormone replacement therapy 
(eg, estrogen, thyroid) will be allowed.  All herbal medicines, vitamins, and supplements 
consumed by the subject within the 30 days prior to receiving the first dose of AMG 986, 
and continuing use if applicable, will be reviewed by the Principal Investigator and the 
Amgen Medical Monitor.  Written documentation of this review and Amgen 
acknowledgment is 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. 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
6.5 
Alcohol and Tobacco Restrictions 
Subjects will be required to abstain from alcohol consumption throughout the course of 
the study. Alcohol consumption is prohibited 24 hours prior to admission to the research 
facility (day -1) and throughout the duration of the study.   
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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. 
6.6 
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. 
6.7 
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, rifapentine, phenobarbital.  
Subjects should not take St. John’s Wort. 
During the study period, use of strong P-gycoprotein 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. 
Approved 
 
 


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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. 
Medications excluded in the eligibility criteria (Section 4.2) are excluded for the duration 
of the study.  Any exceptions (eg, medication given for the treatment of an adverse 
event) should be first discussed with Amgen. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
Approved 
 
 


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CONFIDENTIAL  
 
 
Table 2.  Schedule of Assessments 
 Activity 
Screening 
Treatment Period 
EOS 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
8 
11 
15 
22 
30 
Time (in hours)1 
  
 
Pre 
0 
1 
2 
4    
6 
8 
12 
24 
48 
72 
96 
120 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
Residency2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 X 
  
  
  
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
Body Weight 
 X 
 X 
  
  
  
 
 
  
  
  
  
  
  
  
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 X 
  
  
  
 
 
  
  
  
  
  
 
  
 
 
 
 
 
X 
Vital signs (BP, HR, RR, Temp) 
X3 
X3 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
12-Lead ECG4 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
Adverse events5  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serious Adverse Events6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medications Recording 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
IP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry and Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Troponin I 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Serum FSH (female only)7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine pregnancy 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV, HepCAb, HBsAg, HBcAb 
X 
  
  
  
  
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
Drug, Alcohol, & Cotinine Screen8 
X 
 X 
  
  
  
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
AMG 986 Plasma PK Collection 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Footnotes defined on follow ing page 
 
Approved 
 
 


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1 Time in hours relative to the time of administration of study drug on day 1 
2 Residency – Subjects w ill remain in-house from day -1 through the completion of all assessments on day 2, as designated in the Schedule of Assessments. 
3 Vital Signs – At screening and day -1, blood pressure will be measured on 2 occasions separated by at least 5 minutes, and an average of the blood pressures will be taken to confirm 
eligibility. 
4 ECGs – At screening a single ECG w ill be performed.  At pre-dose (day 1), ECGs w ill be performed on 3 occasions separated by at least 30 minutes all in triplicate for a total of 9 ECGs (3 
sets of triplicates).  At all other time points, ECGs w ill be performed in a standardized method, in triplicate, and approximately 30 seconds apart. 
5 AEs – All adverse events observed by the investigator or reported by the subject that occurs after the dose of AMG 986 through EOS. 
6 SAEs – All serious adverse events observed by the investigator or reported by the subject that occur after the informed consent through 30 days after the last dose of AMG 986 or EOS, 
w hichever is later. 
7 Only if required to ensure menopause in a female subject 
8 An alcohol breath test may also be used at day -1 should the saliva drug screen not include alcohol as an analyte  
 
 
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7.2 
General Study Procedures 
A signed and dated IRB-approved ICF must be obtained before any study-specific 
procedures are performed.  Screening procedures will be performed within 28 days prior 
to AMG 986 administration. 
During the study, every effort should be made to perform study procedures as indicated 
in the Schedule of Assessments.  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. 
In the event that multiple procedures are required to be conducted at the same time, the 
following order of precedence will be used to ensure that certain safety assessments are 
not disturbed by blood draws: (1) ECG recording; (2) vital sign assessment; (3) PK blood 
sampling; (4) clinical laboratory tests; and (5) physical examination and physical 
measurements.  Pharmacokinetic samples will be collected as close to the nominal time 
point as possible. 
Acceptable deviation windows (including PKs) are as follows: 
• 
± 10 minutes on days 1-2 
• 
± 1 hour on days 3-6 
Any missed visits, tests not done, and examinations not conducted must be reported as 
such on the CRFs. 
Laboratory samples will be analyzed as follows: 
• 
Hematology, chemistry, troponin I, serum FSH (if required), serum/urine 
pregnancy test, serology (HBsAg, HBcAb, and HepCAb), HIV, urine/serum 
drug/alcohol/cotinine testing will be analyzed at local laboratories   
• 
Pharmacokinetic samples will be sent to Amgen for analysis 
Refer to the provided Amgen manual for detailed collection, processing, and shipping 
procedures. 
Meal Restrictions 
Subjects will be required to fast at least 8 hours prior to IP administration (no food or 
liquid, except water) and refrain from food and liquid (except water) intake for at least 
2 hours after IP administration on study day 1.  Subjects are required to refrain from food 
and drinks (except water) 8 hours prior to each blood sample collection for clinical 
laboratory assessment.  
Approved 
 
 


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During in-house residency period, subjects will receive standardized meals provided by 
the clinical site.  
Subjects should maintain their current diet regimen throughout the study.  This 
information will be verified at each visit, and recorded in the subjects’ source documents. 
Consumption of grapefruit, grapefruit juice, and grapefruit-containing products is 
prohibited and must be avoided throughout the study. 
Exercise Restrictions 
Subjects should maintain their current exercise regimen.  Subjects will be required to 
refrain from strenuous exercise 48 hours prior to each visit, and during the in-house 
residency.  This information will be verified at each visit, and recorded in the subject 
source document. 
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. 
7.2.1 
Screening  
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments.   
• 
Confirmation that the Informed Consent Form has been signed  
• 
Medical/Surgical History 
• 
Physical Examination   
• 
Height and Weight 
• 
eGFR 
• 
Vital signs (eg, blood pressure, heart rate, respiratory rate, oral temperature) 
• 
12-lead ECG 
• 
Serious Adverse Event assessment/reporting 
• 
Documentation of concomitant medications 
• 
Laboratory Assessments: clinical chemistry, hematology, troponin I, serum/urine 
pregnancy test or serum FSH (if required to ensure menopause in a female subject), 
drug, alcohol and cotinine screening  
• 
HIV, Hepatitis B, and Hepatitis C testing 
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, and urine or serum drug screen) may be repeated during screening.  The 
Approved 
 
 


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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 
Day -1 
The following procedures are to be completed during day -1 designated in the Schedule 
of Assessments. 
• 
Medical History 
• 
Physical examination 
• 
Body Weight 
• 
eGFR 
• 
Vital Signs (blood pressure, heart rate, respiratory rate, and oral temperature) 
• 
Serious Adverse Event assessment/reporting 
• 
Documentation of concomitant medications 
• 
Laboratory Assessments: clinical chemistry, hematology, serum/urine pregnancy 
test, drug, alcohol, and cotinine screening. 
• 
In-house residency per Schedule of Assessments 
7.2.3 
Treatment 
Treatment begins when the first dose of protocol-required therapies is administered to a 
subject.    
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments.  The dose of AMG 986 is to be 
administered upon completion of all predose procedures on the day of dosing (day 1); 
subjects will receive a single 200 mg oral dose of AMG 986.   
Predose on Day 1: 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and oral temperature) 
• 
12-lead ECG 
• 
Serious adverse event assessment/reporting 
• 
Documentation of concomitant medications 
• 
Troponin I 
• 
AMG 986 PK sampling as per Schedule of Assessments 
• 
In-house residency per Schedule of Assessments  
Approved 
 
 


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Dosing at Day 1 (hour 0) 
• 
IP administration 
• 
Adverse event assessment/reporting 
• 
Serious adverse event assessment/reporting 
• 
Documentation of concomitant medications 
• 
In-house residency per Schedule of Assessments 
Postdose at Specified Timepoints on Day 1 through Day 22: 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and oral temperature) 
• 
12-lead ECG (day 1 to day 6) 
• 
AMG 986 PK sampling as per Schedule of Assessments (day 1 to day 6) 
• 
Laboratory Assessments: clinical chemistry and hematology  
• 
Troponin I (day 1 and day 6) 
• 
Serious Adverse Event assessment/reporting 
• 
Adverse Event assessment/reporting 
• 
Documentation of concomitant medications 
• 
In-house residency per Schedule of Assessments 
If the 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.   
7.2.4 
End of Study Visit 
Subjects will return to the clinic for follow-up visits in accordance to the Schedule of 
Assessments and be followed through the completion of the End of Study (EOS) 
procedures on study 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.   
The following procedures are to be completed during the End of study visit as 
designated in the Schedule of Assessments: 
• 
Body weight 
• 
Physical examination 
• 
Vital signs (blood pressure, heart rate, respiratory rate, oral temperature) 
• 
12-lead ECG 
• 
Laboratory Assessments: clinical chemistry, hematology, serum/urine pregnancy test 
Approved 
 
 


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CONFIDENTIAL 
 
 
• 
Serious Adverse Event assessment/reporting 
• 
Adverse Event assessment/reporting 
• 
Documentation of concomitant medications 
7.2.5 
Demographics 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and association to AMG 986. 
7.2.6 
Subject Residency 
Eligible subjects will be checked into the clinical site on day -1 and will be discharged 
after all assessments and procedures are completed at the end of day 2. 
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 the Schedule of Assessments.  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. 
7.2.8 
Physical Examination 
The investigator or qualified designee will perform a complete physical examination 
(excluding breast, genital, and rectal examination) at the time points indicated in the 
Schedule of Assessments.  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 the Schedule of Assessments. 
The following measurements must be performed:  systolic/diastolic blood pressure (BP), 
heart rate (HR), respiratory rate, and oral temperature. 
Approved 
 
 


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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.  If the subject is unable to be in the Fowler position, the subject 
should be in the most recumbent position possible.  The upper arm should be 
bare without constrictive clothing and supported at heart level.  For group 1 
ensure to use arm on non-dominant or non-access side.  The position selected 
for a subject should be the same that is used throughout the study and 
documented on the vital sign CRF. 
• 
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. 
• 
At screening and day -1, blood pressure will be measured on 2 occasions 
separated by at least 5 minutes, and an average of the blood pressures will be 
taken to confirm eligibility. 
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. 
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 are collected. 
7.2.11 
Pregnancy Test (Females Only) 
A serum pregnancy test will be performed on all female subjects at screening.  A serum 
or urine pregnancy test will be collected on all female subjects at day -1 and EOS as 
specified in the Schedule of Assessments.  The screening (serum) and day -1 (serum or 
urine) pregnancy test must be confirmed negative for the subject to be eligible for this 
study.   
Females who become pregnant during the study will be followed for safety until end of 
study.  A Pregnancy Notification Worksheet (Appendix C) will be completed for subjects 
with a positive test result at any point after providing informed consent. 
7.2.12 
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 – defined as:  age of 
≥ 55 years with no menses for at least 12 months; OR age of < 55 years with no menses 
Approved 
 
 


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for at least 12 months AND with a follicle-stimulating hormone level > 40 IU/L or 
according to the definition of “postmenopausal range” for the laboratory involved; OR 
history of hysterectomy; OR history of bilateral oophorectomy).  
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. 
7.2.13 
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. Drug screening includes 
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 drugs, alcohol, or cotinine will not qualify for 
AMG 986 administration and will be withdrawn from study participation. 
An alcohol breath test may also be used at day -1 should the saliva drug screen not 
include alcohol as an analyte.  Due to limitations with saliva test, certain parameters may 
not be assessed on day -1 (eg, barbiturates). 
7.2.14 
Electrocardiogram (ECG) 
Electrocardiograms (henceforth referred to as electrocardiogram or ECG) will be 
performed using a standard electrocardiogram machine at the times shown in the 
Schedule of Assessments. 
ECGs will be collected as follows: 
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 predose (day 1), 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. 
Approved 
 
 


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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 must include the following measurements:  PR, RR, QRS, and 
QTc intervals. 
The Principal Investigator or designated site physician will review all ECGs. Once 
signed, the original ECG tracing will be retained with the subject’s source documents.  At 
the request of the sponsor, a copy of the original ECG will be made available to Amgen. 
7.2.15 
Clinical Chemistry 
Blood samples for clinical chemistry will be collected at the time points specified in the 
Schedule of Assessments.   
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additionally safety laboratory assessments may be performed for subject 
safety. 
The tests listed in Table 3 will be conducted and analyzed by standard laboratory 
procedures. 
Approved 
 
 


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Table 3.  List of Analytes 
Local Laboratory Chemistry 
Local Laboratory Hematology 
Other  
Sodium 
Potassium 
Calcium 
Chloride 
Bicarbonate (HCO3) or Carbon 
Dioxide (CO2) 
Total protein 
Albumin 
Glucose 
Blood urea nitrogen (BUN) or 
Urea 
Creatinine 
Total creatine kinase 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Troponin I 
Lipid Profile 
• 
Total Cholesterol 
• 
HDL 
• 
LDL 
• 
Triglycerides 
Magnesium 
Phosphorous or Phosphate 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelets 
Red Blood Cells 
White blood cell  
Differential 
• 
Total neutrophils (OR 
segmented neutrophils and 
band cells) 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Local Laboratory: 
Hepatitis B surface 
antigen Hepatitis B core 
antibody 
Hepatitis C antibody 
HIV 
Serum FSH 
Serum or Urine 
Pregnancy 
Drug, Alcohol, and 
Cotinine Screening 
(Serum, Urine, Saliva, 
or Breath test (alcohol 
screen only)) 
 
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 
the Schedule of Assessments.  All laboratory tests must be reviewed and signed by the 
principal investigator or qualified designee.  Additionally safety laboratory assessments 
may be performed for subject safety. 
The tests listed in Table 3 will be conducted and analyzed by standard laboratory 
procedures. 
Approved 
 
 


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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 
Plasma AMG 986 Concentrations 
Blood samples for PK assessments will be collected at the time points as specified in the 
Schedule of Assessments.   
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. 
eGFR in mL/min per 1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if patient is 
black) x 0.742 (if female) 
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 assess 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 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 during each 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 document and on the CRF 
when reported or observed. 
7.3 
Approximate Phlebotomy Volume 
Subjects enrolled in this study will agree to provide whole blood for safety, and PK 
assessments during their participation in this study as noted in Table 4 below: 
Approved 
 
 


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Table 4.  Approximate Blood Volume Collection 
Test 
Volume per 
Collection, 
mL 
Number of 
Collections 
Total Volume, 
mL 
Clinical Chemistry 
5 
5 
25 
Troponin I 
5 
4 
20 
Clinical Hematology 
5 
5 
25 
Serum pregnancy test (females only) 
5 
1 
5 
HIV/Hepatitis B, C Panel 
15 
1 
15 
Serum FSH (females only) 
5 
1 
5 
AMG 986 PK plasma concentration  
5 
12 
60 
TOTAL (All Groups) 
 
 
155 
7.4 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments 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 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 on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
aspects of AMG 986 (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. 
Approved 
 
 


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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. 
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 
AMG 986 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 AMG 986, device or 
other protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments including different options of follow-up 
(eg, in person, by phone/mail, through family/friends, in correspondence/communication 
with other treating physicians, from the review of medical records) and collection of data, 
including endpoints, adverse events.  Subjects who have discontinued AMG 986 and/or 
protocol required therapies or procedures should not be automatically removed from the 
study.  Whenever safe and feasible it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data.  The investigator must 
document the level of follow-up that is agreed to by the subject.    
Approved 
 
 


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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, medical device(s), 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.  
8.3 
Reasons for Removal From 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) 
• 
disease flare  
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 
Approved 
 
 


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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Not applicable  
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.   
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 
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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
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 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after dose of investigational product 
through the Safety Follow-Up Visit/End of Study Visit 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 investigational product (AMG 986), and/or any 
study-mandated activity/procedure(s), and  
• 
Action taken 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.  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).  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?  Relatedness means that there are facts or 
reasons to support a relationship between investigational product and the event. 
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:  
Approved 
 
 


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“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 
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.  
9.2.1.2 
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 dose of Investigational product (AMG 986) or the 
Safety Follow-Up Visit/End of Study Visit, 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 Event CRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form. 
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product (AMG 986). This relationship is indicated by a “yes” or “no” 
response to the question: Is there a reasonable possibility that the event may have been 
Approved 
 
 


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caused by the investigational product?  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.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
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.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.1.3 
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.  
Approved 
 
 


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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.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking Amgen Investigational Product (AMG 986) 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 dose of Amgen Investigational 
Product (AMG 986). 
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 breastfeeds while taking protocol-required therapies 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 dose of protocol-required therapies 
(AMG 986).  
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. 
Approved 
 
 


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Men whose partners become pregnant while the subject is on study through 11 weeks 
after receiving the dose of study drug must practice sexual abstinence or use a condom 
for 11 weeks after receiving the dose of study drug, and will be followed for safety until 
the end-of-study visit. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
• 
AMG 986 PK parameters including area under the plasma concentration time 
curve from time 0 to the time of the last quantifiable sample (AUC0-t) and 
maximum observed plasma concentration after dosing (Cmax).  Additional 
AMG 986 PK parameters may include but not limited to terminal phase 
half-life (t1/2); time of maximum AMG 986 plasma concentration (tmax); and AUC 
from time 0 to infinity (AUCinf). 
10.1.1.2 
Secondary Endpoint   
• 
Subject incidence of adverse events and clinically significant changes in vital 
signs, physical examinations, clinical laboratory tests, and ECGs 
10.1.1.3 
Exploratory Endpoints 
• 
Plasma protein binding of AMG 986 
• 
AMG 986 metabolite concentrations in plasma  
10.1.2 
Analysis Sets 
For all analyses, subjects will be analyzed according to the group they were assigned.  
10.1.2.1 
Safety Analysis Set 
The safety analysis set will consist of all study subjects who receive at least one dose of 
AMG 986.  Subjects withdrawing prior to AMG 986 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. 
10.1.3 
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. 
Approved 
 
 


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Group 1 will be the group formed with subjects with severely impaired renal function. 
Group 2, the group formed with subjects with normal renal function, will be considered 
the control group.  An effort will be made to match the subjects in group 2, the normal 
renal function group to the subjects in group 1, by age range, body weight, gender, and 
race.  The mean age ± 5 years and mean body weight ± 10% of the subjects in the 
severely renal impaired group will be used to help match the subjects in the 
control group.  No subgroup analyses are planned. 
10.1.4 
Handling of Missing and Incomplete Data  
Incomplete data in the Primary Endpoints will be excluded from analysis.  The number 
and frequency of missing values will be reported in the final study report. 
Imputation for missing or incomplete dates will be performed, if required.  If imputed 
dates are used, they will be identified as such in the final study report. 
PK concentrations below the lower limit of quantification will be set to zero.  
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 AMG 986 PK and safety plus tolerability, following 
a single oral administration of a 200-mg dose by descriptive summaries based on the 
observed data.  The sample size of this study is based on practical considerations and is 
consistent with the number of subjects enrolled in similar studies.  Approximately 
12 subjects (6 subjects with severe RI and 6 subjects with normal renal function) will be 
enrolled for the study. Assuming 20% for the intra-subject standard deviation for 
AMG986 log-transformed PK parameters (AUC0-t and Cmax) and assuming that it is the 
same in the 2 groups, the current sample size of 6 would provide a Confidence Interval 
for the Geometric Mean Ratio of the parameters of (0.81, 1.23).  For safety 
considerations, with a total of 12 subjects receiving AMG 986, there is a 46% chance of 
detecting an adverse event with a true incidence of 5% and a 72% chance of detecting a 
more common adverse event with a true incidence rate of 10%.  
10.3 
Planned Analyses 
10.3.1 
Data Review Team Meeting 
A data review team meeting is not planned.   
10.3.2 
Primary Analysis 
The primary analysis will occur after the database locks following the last subject’s last 
visit. 
Approved 
 
 


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10.3.3 
Final Analysis 
The primary analysis will be the final analysis.  
10.4 
Planned Methods of Analysis 
10.4.1 
General Considerations 
Descriptive statistics will be provided all endpoints and will include selected 
demographics, adverse events, vital signs, ECG, PK, and selected laboratory 
measurements.  Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using 
frequency counts and percentages.  
10.4.2 
Primary Endpoints 
10.4.2.1 
Pharmacokinetic Analysis 
The PK parameters for each subject will be estimated using non-compartmental 
methods. All plasma concentrations below the limit of quantification of the assay will be 
considered as zero for all analyses unless explicitly noted otherwise. 
Summary statistics will be provided for each renal function group for AMG 986 PK 
parameters.  These parameters will include AUC0-inf, AUC0-t, Cmax, tmax, t1/2 as appropriate.  
Binding of AMG 986 to plasma proteins will be determined to calculate select unbound 
PK parameters, if appropriate, and summary statistics will be provided.  Graphs of 
AMG 986 plasma concentration-time profiles for individual subjects and for means for 
each function group may be provided.  The mean difference for the 2 groups will be back 
transformed to produce the geometric mean ratio.  Lower and upper limits of the 
90% confidence interval for these ratios of the PK parameters will also be reported.    
10.4.3 
Secondary Endpoints 
10.4.3.1 
Safety Endpoints 
10.4.3.1.1 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term according to the medical dictionary for regulatory 
activities (MedDRA) terminology.  Tables of events, fatal adverse events, serious 
adverse events, adverse events leading to withdrawal from investigational product, and 
significant treatment emergent adverse events will also be provided if observed. 
10.4.3.1.2 
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 
Approved 
 
 


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visit) by group.  Depending on the size and scope of changes, summaries of changes 
from baseline over time may be provided. 
10.4.3.1.3 
Electrocardiogram 
All on-study ECG data will be reviewed 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.  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). 
10.4.3.1.4 
Clinical Laboratory 
Analyses of laboratory values will include summary statistics over time (for each protocol 
scheduled visit) by group.  Additional summaries may include descriptive statistics of 
changes from baseline over time.  
10.4.4 
Exploratory Endpoints 
The statistical analyses in this section are considered exploratory in nature and will be 
performed only when deemed appropriate. 
10.4.4.1 
Plasma Protein Binding of AMG 986  
Pharmacokinetic parameters of unbound AMG 986, such as AUC, tmax, and Cmax, will be 
assessed and summarized, if appropriate. 
10.4.4.2 
AMG 986 Metabolites 
AMG 986 Metabolite concentrations in plasma will be measured and summarized, if data 
allows and team deems appropriate. 
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 form 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 
Approved 
 
 


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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 
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 
Approved 
 
 


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occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures. 
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 
Approved 
 
 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB and amended protocol Investigator’s Signature page to 
Amgen prior to implementation of the protocol amendment at their site. 
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 Clinical Trial Agreement.  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.   
Approved 
 
 


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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 prestudy 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. 
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. 
Approved 
 
 


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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. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
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 with different visit, [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, 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 may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
Approved 
 
 


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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. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, 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; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 
1, 2, and 3 and 4. 
• 
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. 
Approved 
 
 


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13. 
REFERENCES 
AMG 986 Investigator’s Brochure (always refer to the most current edition).  Thousand 
Oaks, CA:  Amgen Inc. 
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. 
Damman K, Valente M, Voors A, et al.  Renal impairment, worsening renal function, and 
outcome in patients with heart failure : an updated meta-analysis.  Eur Heart J.  2014; 
35 (7): 455-469. 
Ezzat V, Lee V, Ahsan S, et al.  A systemic review of ICD complications in randomised 
controlled trials versus registries: is our ‘real-word’ data an underestimation?                  
Open Heart.  2015;2:e000198. 
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. 
Heywood J, Fonarow G, Costanzo M, et al.  High prevalence of renal dysfunction and its 
impact on outcome in 118,465 patients hospitalized with acute decompensated heart 
failure: a report from the ADHERE database.  J Card Fail.  2007;13(6):422-430. 
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/. 
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. 
Levey AS, Stevens LA, Schmid CH, et al.  A new equation to estimate glomerular 
filtration rate. Ann Intern Med.  2009 May 5;150(9):604-12. 
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 J, Adamopoulos S, Anker S, 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(14):803-869;1787-1847. 
McMurray JJ, Pfeffer MA.  Heart Failure. Lancet.  2005;365:1877-1889. 
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. 
Approved 
 
 


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Schoolwerth A, Sica D, Ballermann B, et al.  Renal considerations in angiotensin 
converting enzyme inhibitor therapy: a statement for healthcare professionals from the 
Council on the Kidney in Cardiovascular Disease and the Council for High Blood 
Pressure Research of the American Heart Association.  Circulation.  
2001;104(16):1985-1991. 
Tariq S, Aronow W.  Use of Inotropic Agents in Treatment of Systolic Heart Failure.      
Int. J. Mol. Sci.  2015;16:29060-29068. 
Approved 
 
 


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14. 
APPENDICES 
Approved 
 
 


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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:   
https://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 6.3 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 9.2.1.2. 
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 6.3 or who experience AST or ALT elevations > 3 x ULN or 2-fold increase 
above baseline values for subjects with evaluated values before drug 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.  The following are to be considered depending on the clinical situation: 
− Complete blood count (CBC) with differential to assess for eosinophilia 
− Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
Approved 
 
 


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− Serum acetaminophen (paracetamol) levels 
− 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 
− Viral serologies 
− CPK, haptoglobin, LDH, and peripheral blood smear 
− Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
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 or considered stable by the investigator.  
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. 
Approved 
 
 


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Appendix B.  Sample eSerious Event Contingency Report Form 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
 
 
Approved 
 
 


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Approved 
 
 


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SAP_001.pdf: 
Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 1 of 17
CONFIDENTIAL
Statistical Analysis Plan
Protocol Title:
A Phase 1, Open-label, Single-Dose Study to 
Evaluate the Safety, Tolerability and 
Pharmacokinetics of AMG 986 Administered Orally to 
Healthy Volunteers and Subjects with Severely 
Impaired Renal Function
Short Protocol Title:
AMG 986
Protocol Number:
20150186
Authors:
Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
SAP Date:
Document Version
Date
Original (v 1.0)
12 January 2018
NCT Number: NCT03318809
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 2 of 17
CONFIDENTIAL
Table of Contents
Table of Contents ...................................................................................................2
1.
Introduction.............................................................................................................7
2.
Objectives, Endpoints and Hypotheses...................................................................7
2.1
Objectives and Endpoints............................................................................7
2.2
Clinical Hypotheses.....................................................................................8
3.
Study Overview ......................................................................................................8
3.1
Study Design...............................................................................................8
3.2
Sample Size................................................................................................8
4.
Covariates and Subgroups .....................................................................................9
4.1
Planned Covariates.....................................................................................9
4.2
Subgroups...................................................................................................9
5.
Definitions...............................................................................................................9
6.
Analysis Sets........................................................................................................11
6.1
Safety Analysis Set ...................................................................................11
6.2
Pharmacokinetic (PK) Analyses Set..........................................................11
7.
Planned Analyses.................................................................................................12
7.1
Interim Analysis and Early Stopping Guidelines ........................................12
7.2
Primary Analysis .......................................................................................12
7.3
Final Analysis............................................................................................12
8.
Data Screening and Acceptance...........................................................................12
8.1
General Principles.....................................................................................12
8.2
Data Handling and Electronic Transfer of Data .........................................12
8.3
Handling of Missing and Incomplete Data .................................................12
8.4
Detection of Bias.......................................................................................12
8.5
Outliers .....................................................................................................12
8.6
Distributional Characteristics.....................................................................13
8.7
Validation of Statistical Analyses...............................................................13
9.
Statistical Methods of Analysis..............................................................................13
9.1
General Considerations.............................................................................13
9.2
Subject Accountability ...............................................................................13
9.3
Important Protocol Deviations ...................................................................14
9.4
Demographic and Baseline Characteristics...............................................14
9.5
Efficacy Analyses......................................................................................14
9.6
Safety Analyses ........................................................................................14
9.6.1
Adverse Events .........................................................................14
9.6.2
Laboratory Test Results ............................................................15
9.6.3
Vital Signs .................................................................................15


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 3 of 17
CONFIDENTIAL
9.6.4
Electrocardiogram .....................................................................15
9.6.5
Exposure to Concomitant Medication ........................................15
9.7
Other Analyses .........................................................................................15
9.7.1
Analyses of Pharmacokinetic Endpoints....................................15
9.7.2
Analyses of Exploratory Endpoints ............................................16
10.
Changes From Protocol-specified Analyses..........................................................16
11.
Literature Citations / References...........................................................................16
12.
Prioritization of Analyses.......................................................................................16
13.
Data Not Covered by This Plan.............................................................................16
14.
Appendices...........................................................................................................17
Appendix A.  Imputation Rules for Partial or Missing Stop Dates ..........................17


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 4 of 17
CONFIDENTIAL
List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition/Explanation
ADHERE
US Acute Decompensated Heart Failure National Registry
AE
Adverse Event
ALT
Alanine aminotransferase
APJ
Apelin receptor
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUCinf
Area under the concentration-time curve from time 0 to infinity
AUC0-t
Area under the concentration-time curve from time 0 to the time 
of the last quantifiable sample
BMI
Body Mass Index
BP
Blood pressure
Cmax
Maximum observed concentration
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
Electronic Source Data
Source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a study
End of Study
Defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (i.e. last 
subject last visit), following any additional parts in the study 
(eg, long-term follow-up), as applicable
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
Enrollment
When the investigator decides that the subject has met all 
eligibility criteria
GCP
Good clinical practice
GMR
HBcAb
HBcAg
hERG
HepCab
HF
Geometric mean ratio
Hepatitis B core antibody
Hepatitis B surface antigen
Human Ether-a-go-go-Related Gene
Hepatitis C antibody
Heart failure


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 5 of 17
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
HFpEF
HFrEF
HIV
HR
ICF
IP
IPIM
IUD
IV
MDRD
NOAEL
NOEL
P-gp
PK
PR Interval
Primary Completion
QRS Interval
QT interval
QTc interval
QTcF
RI
RR
SAE
Source Data
Heart failure with preserved ejection fraction
Heart failure with reduced ejection fraction
Human immunodeficiency virus
Heart rate
Informed consent form
Investigational Product
Investigational Product Instruction Manual
Intrauterine device
Intravenous
Modification of diet in renal disease
No-observed-adverse-effect-level
No-observed-effect-level
P glycoprotein
Pharmacokinetics
PR interval is measured from the beginning of the P wave to the
beginning of the QRS complex in the hearts electrical cycle as 
measured by ECG
Defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early
QRS interval is the interval between the Q wave and the S wave 
in the heart’s electrical cycle as measured by ECG; represents 
the time it takes for the depolarization of the ventricles
QT interval is a measure of the time between the start of the Q 
wave and the end of the T wave in the heart’s electrical cycle as 
measured by ECG
QT interval corrected for heart rate using accepted methodology
QT interval corrected for heart rate using Fridericia’s formula
Renal impairment
Respiratory rate
Serious adverse event
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.


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 6 of 17
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
Study Day 1
TBL
TEMP
tmax
ULN
Vss
Defined as the first day that protocol specified investigational
product(s)/protocol-required therapies is/are administered to the
subject
Total bilirubin
Temperature
Time to max plasma concentration
Upper limit of normal
Steady-state volume of distribution


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 7 of 17
CONFIDENTIAL
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 for study 20150186 of product 
AMG 986 dated 28 September 2017. The scope of this plan includes the primary 
analysis that is planned and will be executed by the Amgen Global Bio-statistical 
Science department unless otherwise specified. The primary analysis will be considered 
as final analysis.
The clinical study report (CSR) will be written based on the results based on the primary 
analysis. Data collected and analyzed in Amgen-owned databases and systems will 
adhere to approved Data Element Standards and International Case Report Form (CRF) 
Standards established by Biomedical Data Stewardship Governance (BDSG).
2.
Objectives, Endpoints and Hypotheses
2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the pharmacokinetics 
(PK) of AMG 986 following the 
administration of a single oral 200 mg 
dose to healthy volunteers and 
subjects with severely impaired renal 
function

AMG 986 PK parameters including 
area under the plasma concentration 
time curve from time 0 to the time of 
the last quantifiable sample (AUC0-t) 
and maximum observed plasma 
concentration after dosing (Cmax). 

Additional AMG 986 PK parameters 
may include but not limited to terminal 
phase half-life (t1/2); time of maximum 
AMG 986 plasma concentration (tmax); 
and AUC from time 0 to infinity 
(AUCinf)
Secondary

To evaluate the safety and tolerability 
of AMG 986 following single oral dose 
administration to subjects with 
severely impaired renal function 
relative to healthy matched control 
subjects

Subject incidence of adverse events 
and clinically significant changes in 
vital signs, physical examinations, 
clinical laboratory tests, and ECGs
Exploratory

To determine unbound concentrations 
of AMG 986 in plasma

Plasma protein binding of AMG 986

To determine AMG 986 metabolite 
concentrations in plasma

AMG 986 metabolite concentrations in 
plasma


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 8 of 17
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2.2
Clinical Hypotheses
Clinically significant changes in AMG 986 PK that would require dose adjustment are not
expected in subjects with severe renal impairment when compared to subjects with
normal renal function.
3.
Study Overview
3.1
Study Design
This is a phase 1, multicenter, open-label, single-dose study conducted in subjects with 
severely impaired renal function as determined by the modification of diet in renal 
disease (MDRD) equation for estimated glomerular filtration rate (eGFR). Approximately 
12 subjects will be assigned to the two groups in the study. Approximately 6 subjects 
with severely impaired renal function (eGFR 15 to 29 ml/min/1.73 m2) will be assigned to 
group 1; approximately 6 subjects with normal renal function 
(eGFR ≥90 mL/min/1.73 m2) will be assigned to the control group 2. All subjects in each 
group will receive a single oral dose of 200 mg AMG 986.
An attempt will be made to match the control group of healthy males and females with 
normal renal function (group 2) to the group of subjects with severely impaired renal 
function (group 1) by age range, body weight range, gender (proportion of male and 
female subjects), and race. Enrollment of subjects in the control group will be initiated 
after all subjects in the renal impairment (RI) group have been enrolled. The mean age 
± 5 years and mean body weight ± 10% of the subjects in the RI group will be used to 
help match the subjects in the control group. The priority for matching subject 
characteristics of the two groups will be: age range, body weight range, gender, then 
race.
3.2
Sample Size
This is a Phase 1 study and no formal statistical hypothesis testing will be performed.
The study is designed to characterize AMG 986 PK and safety plus tolerability, following
a single oral administration of a 200-mg dose by descriptive summaries based on the
observed data. The sample size of this study is based on practical considerations and is
consistent with the number of subjects enrolled in similar studies. Approximately
12 subjects (6 subjects with severe RI and 6 subjects with normal renal function) will be
enrolled for the study. Assuming 20% for the intra-subject standard deviation for
AMG 986 log-transformed PK parameters (AUC0-t and Cmax) and assuming that it is the
same in the 2 groups, the current sample size of 6 would provide a Confidence Interval
for the Geometric Mean Ratio of the parameters of (0.81, 1.23). For safety


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 9 of 17
CONFIDENTIAL
considerations, with a total of 12 subjects receiving AMG 986, there is a 46% chance of
detecting an adverse event with a true incidence of 5% and a 72% chance of detecting a
more common adverse event with a true incidence rate of 10%.
4.
Covariates and Subgroups
4.1
Planned Covariates
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.
Group 1 will be the group formed with subjects with severely impaired renal function.
Group 2, the group formed with subjects with normal renal function, will be considered
the control group. An effort will be made to match the subjects in group 2, the normal
renal function group to the subjects in group 1, by age range, body weight, gender, and
race. The mean age ± 5 years and mean body weight ± 10% of the subjects in the
severely renal impaired group will be used to help match the subjects in the control 
group. 
4.2
Subgroups
No subgroup analyses are planned for this study.
5.
Definitions
Age at Enrollment 
Subject age at enrollment will be collected in years in the clinical database. 
AUC
Area under the plasma AMG 986 concentration-time curve.
AUC0-24 
Area under the concentration-time curve from time 0 extrapolated to 24 hours. 
AUCinf
Area under the concentration-time curve from time 0 extrapolated to infinity.
Baseline
Baseline is defined as the last assessment taken prior to the first administration of 
AMG 986.


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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Cmax
Maximum observed plasma AMG 986 concentration.
Baseline ECG recording
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).
Body Mass Index
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
End of Study
The end of study date is defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (i.e. last subject last visit), following 
any additional parts in the study (e.g. long-term follow-up), as applicable.
End of Study for Individual subject
The end of study for individual subject is defined as the last day that protocol-specified 
procedures are conducted for an individual subject.
End of Study Visit
Subjects will return to the clinic for follow-up visits in accordance to the Schedule of
Assessments and be followed through the completion of the End of Study (EOS)
procedures on study 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.
End of Treatment
The end of treatment is defined as the last assessment for the protocol specified 
treatment phase of the study for an individual subject.
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. The Glomerular Filtration Rate (GFR) will be estimated as


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 11 of 17
CONFIDENTIAL
eGFR in mL/min per 1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if patient is
black) x 0.742 (if female).
Investigational Product
Investigational product refers to AMG 986 in this study.
Primary Completion
The primary completion is defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the primary endpoint(s), for the 
purposes of conducting the primary analysis, whether the study concluded as planned in 
the protocol or was terminated early.
Study Day 1
The study day 1 is defined as the first day that protocol specified investigational
product(s) /protocol-required therapies is/are administered to the subject.
Half-life (t1/2)
The time required for the observed concentration of a drug to be reduced by one-half.
Tmax
The time of maximum observed plasma AMG 986 concentration.
Treatment-Emergent Adverse Event
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 or the End of Study date, whichever is earlier.
6.
Analysis Sets
For all analyses, subjects will be analyzed according to the group they were assigned.
6.1
Safety Analysis Set
The safety analysis set will consist of all study subjects who receive at least one dose of
AMG 986. Subjects withdrawing prior to AMG 986 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.
6.2
Pharmacokinetic (PK) Analyses Set
The PK analysis set will consist of all subjects for whom at least one PK parameter or
endpoint can be estimated.


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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7.
Planned Analyses
7.1
Interim Analysis and Early Stopping Guidelines
No formal interim safety analysis is planned for this study (Refer to 
protocol section 10.3.1).
7.2
Primary Analysis
The primary analysis will occur after the database lock following the last subject’s last
visit.
7.3
Final Analysis
The primary analysis will be the final analysis.
8.
Data Screening and Acceptance
8.1
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.
8.2
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. The database will be subject to edit checks outlined in the Clinical Data 
Management Plan (DMP). See details of this section in the DMP.
8.3
Handling of Missing and Incomplete Data
Incomplete data in the Primary Endpoints will be excluded from analysis. The number 
and frequency of missing values will be reported in the final study report. Imputation for 
missing or incomplete dates will be performed, if required. If imputed dates are used, 
they will be identified as such in the final study report. PK concentrations below the lower 
limit of quantification will be set to zero. Details of the imputation algorithm are provided 
in Appendix A.
8.4
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 group. 
The clinical study team will identify and document the criteria for important protocol 
deviations.
8.5
Outliers
All confirmed outlier data will be included in the analyses presented in this statistical 
analysis plan unless there is sufficient scientific justification to exclude them. 


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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Pharmacokinetic (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 pharmacokinetic evaluation practice.
8.6
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.
8.7
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 9.3 or 
later.
9.
Statistical Methods of Analysis
9.1
General Considerations
Descriptive statistics will be provided for selected demographics, adverse events, vital 
signs, ECG, PK, and laboratory measurements. Descriptive statistics on continuous data 
will include means, medians, standard deviations, and ranges, while categorical data will 
be summarized using frequency counts and percentages. 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. All data analysis will be conducted using 
subjects in the safety analysis set except for pharmacokinetic analysis, which will be 
conducted using PK analysis set. For statistical analyses comparing change from 
baseline, only subjects with both baseline and at least one post-baseline assessment will 
be included. The primary analysis will occur after the database lock following last subject 
last visit.
9.2
Subject Accountability
The number and percent of subjects who were enrolled, received investigational product,  
completed study, discontinued the study (including reasons for discontinuing) will be 


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
Page 14 of 17
CONFIDENTIAL
summarized by group. Key study dates for the first subject enrolled and last subject’s 
end of study will be presented. A subject listing and summary noting inclusion in each 
analysis subset will be reviewed for all subjects enrolled. A subject listing noting reason 
for discontinuing the study and a list of subjects screened but not enrolled (screen 
failures) will be reviewed.
9.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. Eligibility deviations that are defined as IPDs will be summarized in both 
the IPD and Eligibility Deviation table and IPD and Eligibility Deviation listings.
9.4
Demographic and Baseline Characteristics
Summary statistics of the demographic and baseline characteristics will be tabulated 
using the Safety Analysis Set for both the study groups. The demographic 
characteristics include age, sex (male versus female), race and ethnicity. The baseline 
characteristics will be vital signs (blood pressure, heart rate, respiratory rate, and oral 
temperature), physical examinations (height, weight, BMI), ECG parameters, and 
selected laboratory parameters. 
9.5
Efficacy Analyses
No efficacy analysis is applicable for this study.
9.6
Safety Analyses
9.6.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 will be used to 
code all events categorized as adverse events (AE) to a system organ class and a 
preferred term. The CTCAE version 4.0 will be used to grade severity of adverse events 
unless specified otherwise. Treatment-emergent adverse events are events with an 
onset after the administration of the first dose of investigational product. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, and fatal adverse events.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product, and fatal adverse events 
will be tabulated by system organ class and preferred term in alphabetical order.  


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term. Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade.
9.6.2
Laboratory Test Results
Analyses of laboratory values will include summary statistics over time (for each protocol
scheduled visit) for selected laboratory analytes in Table 3 of the protocol by group. 
Additional summaries may include descriptive statistics of changes from baseline over 
time, change from baseline to the post dose maximum, time to post-dose maximum, 
change from baseline to the post-dose minimum and the time to the post-dose minimum.
Shift tables based on CTCAE grading may be provided for select analytes.
9.6.3
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 group. Depending on the size and scope of changes, summaries of changes
from baseline over time may be provided.
9.6.4
Electrocardiogram
All on-study ECG data will be reviewed and may be plotted. Summaries over time and/or 
changes from baseline over time will be provided for all ECG parameters (e.g., 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. 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).
9.6.5
Exposure to Concomitant Medication
All medication will be coded using the WHO drug dictionary. All prior and concomitant 
medications will be presented and reviewed.
9.7
Other Analyses
9.7.1
Analyses of Pharmacokinetic Endpoints
The PK parameters for each subject will be estimated using non-compartmental
methods and will be performed by the Clinical Pharmacology, Modeling & Simulation 
group (CPMS). Actual dosing and sampling times will be used for calculation of PK 


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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CONFIDENTIAL
parameters. All plasma concentrations below the limit of quantification of the assay will 
be considered as zero for all analyses unless explicitly noted otherwise.
Summary statistics will be provided for each renal function group for AMG 986 PK
parameters. These parameters will include AUC0-inf, AUC0-t, Cmax, tmax, t1/2 as appropriate.
Graphs of AMG 986 plasma concentration-time profiles for individual subjects and for 
means for each function group may be provided. 
Geometric means and 90% CI for the ratio of the geometric means (group 1/ group 2) 
will be estimated using ANOVA model.  The model will use the log-transformed PK 
parameters as the dependent variable (or response) and renal function group as 
independent variable. The mean difference for the 2 groups will be back transformed to 
produce the geometric mean ratio. Lower and upper limits of the 90% confidence interval 
for these ratios of the PK parameters will also be reported.
9.7.2
Analyses of Exploratory Endpoints
The statistical analyses in this section are considered exploratory in nature and will be 
performed only when deemed appropriate.
If data allows, plasma protein binding of AMG 986 will be determined and summarized.
If data allows, AMG 986 metabolite concentration in plasma will be measured and 
summarized.
10.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses. 
11.
Literature Citations / References
Not applicable.
12.
Prioritization of Analyses
Tables to precede listings.
13.
Data Not Covered by This Plan
None.


Product:  AMG 986
Protocol Number:  20150186
Date:  12 January 2018
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14.
Appendices
Appendix A.  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.