Clinical trial NCT03283098
Conditions: Secondary Hyperparathyroidism
Keywords: Secondary hyperparathyroidism Chronic kidney disease CKD Intact parathyroid hormone iPTH Hemodialysis
Sponsor: Amgen
Start date: 2018-03-01; Completion date: 2019-02-04
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multiple-dose, double-blind, randomized, placebo-controlled study. Chinese subjects residing in Mainland China with chronic kidney disease (CKD) receiving hemodialysis were randomized in a 3:1 ratio to receive 5 mg intravenous (IV) of etelcalcetide or placebo 3 times a week (TIW) for approximately 4 weeks, with a subsequent follow up period of approximately 4 weeks.

Doses were given at the end of each scheduled hemodialysis session on study days 1 through day 27 and subject participation was complete after day 55 end-of-study (EOS) procedures were performed. Doses were administered TIW for 4 weeks, for a total of 12 doses.

Detailed description:

Arms: arm 1: Intravenous (IV) administration of placebo three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks. arm 2: 5 mg intravenous (IV) dose of etelcalcetide three times a week (TIW) for 4 weeks for a total of 12 doses. Participants were followed for an additional 4 weeks.
Interventions: intervention 1: Etelcalcetide intervention 2: Placebo
Intervention descriptions: intervention 1: Etelcalcetide was supplied as a sterile, preservative-free, aqueous solution in a single-use 3 mL glass vial. intervention 2: Placebo supplied to match active intervention.

Protocol documents:
Prot_001.pdf: 
Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 1 of 73
CONFIDENTIAL
Title:  A Phase 1, Multiple Dose, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate Pharmacokinetics, Safety and Tolerability of AMG 416
Administered Intravenously to Chinese Subjects With Chronic Kidney Disease on 
Hemodialysis
AMG 416
Amgen Protocol Number 20140197
Clinical Study Sponsor:
Amgen Inc*
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Tel: 805-447-1000
Key Sponsor Contacts:
, PhD
Principal Scientist, Clinical Pharmacology
Phone:
E-mail:
, MD
Medical Director, Medical Sciences
Phone:
E-mail:
Study Manager
Phone:
E-mail:
Date:
Amendment 1 Date
Amendment 2 Date
Amendment 3 Date
16 July 2014
08 March 2017
20 Sep 2017
25 May 2018
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; for all other countries, call the local toll-free Medical Information
number. Amgen’s general number in the US (1-805-447-1000).
*Effective July 5, 2012, KAI Pharmaceuticals, Inc. became a wholly owned subsidiary of Amgen Inc. In connection
with Amgen’s acquisition of KAI, Amgen Inc. will be managing the clinical study described in this protocol on
behalf of KAI.
NCT Number: NCT03283098
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 2 of 73
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled A Phase 1, Multiple Dose, Randomized, 
Double-blind, Placebo-controlled Study to Evaluate Pharmacokinetics, Safety and 
Tolerability of AMG 416 Administered Intravenously to Chinese Subjects with Chronic 
Kidney Disease on Hemodialysis, dated 25 May 2018, and agree to abide by all 
provisions set forth therein.
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by:

me (including, if applicable, my spouse [or legal partner] and dependent children)

my sub investigators (including, if applicable, their spouses [or legal partners] and
dependent children)
At the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
Signature
Name of Investigator
Date (DD Month YYYY)


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 3 of 73
CONFIDENTIAL
Protocol Synopsis
Title: A Phase 1, Multiple Dose, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
Pharmacokinetics, Safety and Tolerability of AMG 416 Administered Intravenously to Chinese 
Subjects with Chronic Kidney Disease on Hemodialysis
Study Phase:  Phase I
Indication:  Secondary Hyperparathyroidism
Primary Objective:  
To characterize the pharmacokinetics of AMG 416 following thrice weekly intravenous (IV) 
administration of 5 mg in Chinese subjects with chronic kidney disease receiving hemodialysis.
Secondary Objectives:
To characterize the safety and tolerability of AMG 416 following thrice weekly intravenous 
(IV) administration of 5 mg in Chinese subjects with chronic kidney disease receiving
hemodialysis.
Exploratory Objectives:
Hypotheses: This study will adequately characterize the pharmacokinetics profile of AMG 416 in 
Chinese subjects with chronic kidney disease receiving hemodialysis.
AMG 416 will be safe and well tolerated after multiple dose administration in Chinese subjects 
with chronic kidney disease on hemodialysis. 
Primary Endpoint:

Pharmacokinetic parameters of AMG 416 in plasma including maximum plasma
concentration (Cmax) and area under the plasma concentration-time curve (AUClast) over the
interdialytic interval following the first and last dose.
Secondary Endpoints:

Incidence of adverse events

Vital signs, laboratory safety tests including cCa, and ECGs

Incidence of anti-AMG 416 antibodies
Exploratory Endpoint(s):
Study Design:  This is a multiple-dose, double-blind, randomized, placebo-controlled clinical 
study conducted in Chinese subjects residing in Mainland China with chronic kidney disease 
receiving hemodialysis. The treatment duration will be approximately 4 weeks with a post 
treatment follow-up of 4 weeks. A dose will be given at each scheduled hemodialysis session
(Dose administered three times a week for 4 weeks, for a total of 12 doses).
Sample Size: Approximately 32 subjects will be randomized in a 3:1 ratio to receive 5 mg IV of 
AMG 416 or placebo three times a week (TIW) at the end of each regularly scheduled 
hemodialysis session for 4 weeks (12 doses). 
For PK parameter estimation, 2-sided 90% confidence intervals (CI) for geometric means (GM) of 
PK measurements can be expressed as (GM/θ, GM.θ) where θ is a measure of precision.  Based 
on AMG 416 study 20120330 (Cohort 3, 5 mg dose), between-subject CV% for AMG 416 AUClast
(hr·µg/L) and Cmax (µg/L) (on original scale) are approximately 50.5% and 52.7%, respectively, 
following the Day 27 dose.  Assuming the same variability for 24 subjects receiving AMG 416 in 
this study, it is estimated that the precision (θ) of 2-sided 90% CI of geometric mean will be 1.18 
and 1.19 for AUClast and Cmax, respectively.  


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 4 of 73
CONFIDENTIAL
For safety considerations, with 24 subjects receiving AMG 416, there will be a 21% chance of 
detecting an adverse event with a true incidence rate of 1% and 98% chance of detecting a more 
common adverse event with a true incidence rate of 15%.
Summary of Subject Eligibility Criteria:  
Male or female subjects ≥ 18 and ≤70 years of age at the time of screening, with end stage renal 
disease receiving hemodialysis with a body mass index between 18 and 35 kg/m2 that are 
residents in Mainland China and of Chinese ancestry, inclusive. Corrected calcium (calculated) 
level is ≥ 2.07 mmol/L (8.3 mg/dL) and iPTH level is between 31.8 – 127.2 pmol/L 
(300 - 1200 pg/mL), inclusive at enrollment and subject has not received cinacalcet within the 
30 days prior to informed consent. 
For a full list of eligibility criteria, please refer to Section 4.
Investigational Product  
Amgen Investigational Product Dosage and Administration:
Investigational product will be administered thrice weekly with each hemodialysis treatment for 
4 weeks (12 doses). The dose of investigational product is 5 mg. Each subject will receive 
AMG 416 or placebo administered by bolus injection into the venous line of the dialysis circuit at 
the end of each of 12 consecutive hemodialysis treatments, prior to or during rinse-back with 
each hemodialysis session (ie, 3 times per week).  At least 150 mL of rinse back volume should 
be administered after investigational product injection to ensure investigational product reaches 
the systemic circulation.  
For a complete description see Section 6.3.1.
Procedures: 
Screening: After providing written informed consent, subjects enter a screening period of 22 days,
during which all screening tests required to establish eligibility will be completed. Subjects who 
meet the eligibility criteria after completion of all screening, Day -2 and Day 1 predose
procedures, will be enrolled in the study. Day -2 assessments will be performed 2 days before 
investigational product administration.
Screening procedures are summarized in the Schedule of Assessments.
Baseline and Treatment: Subjects will return to the research facility for day -2 assessments.  
Eligible subjects should be randomized to investigational product in a 3:1 ratio to AMG 416 or 
placebo, and should then receive the first dose. On Day 1, enrolled subjects will receive the 
first 5 mg IV dose of AMG 416 given after hemodialysis.  Following completion of all study 
procedures on Day 1, subjects will be released with instructions to return to the research facility at 
specified time points for dosing, collection of blood samples for PK, PD and completion of safety 
assessments (including blood samples for antibody analysis) through the end of the study
according to the Schedule of Assessments.
IP will be administered at the end of dialysis on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 
27 (12 doses). Dialysis will continue thrice weekly without study drug administration with study 
visits for data collection on Study Days 29, 34, 41, 55 (EOS). Blood samples for the 
determination of PK parameters will be collected on Day 1 and 27 at predialysis, and at 10, 30, 60 
and 90 min postdose, as well as on Day 2 and 28 between 18 and 30 h after study drug 
administration, and at predialysis on Days 3, 8, 15, 22, 29, 34, 41, and 55 (EOS) and at 10 min 
postdose on Days 8, 15 and 22.  Subjects will have blood samples drawn for antibody 
determination prior to dosing on Day 1 and on days 29 and 55. Blood samples for exploratory
 Electrocardiograms (ECG) will be performed at screening, on Day -2, and on 
days 28 and 55.
The date and time of hemodialysis treatment will be recorded throughout the treatment period.  
When a visit corresponds to a dialysis day, study procedures should be completed prior to 
hemodialysis with the exception of dose administration and specified PK sample collection as 
described in the Schedule of Assessments.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 5 of 73
CONFIDENTIAL
Routine hematology and chemistry safety laboratory tests will be performed periodically.
Subjects will be followed for safety throughout the 4-week treatment period and for 4 weeks after 
the last dose of investigational product.  Dosing with investigational product may be suspended, 
for low predialysis iPTH or cCa, symptomatic hypocalcemia, or other drug-related adverse 
events. 
End of Study
Subjects will be followed through Day 55 (EOS).  Subject participation is complete once 
end-of-study (EOS) procedures are performed.  Subjects who test positive for neutralizing 
antibodies to AMG 416 at the Day 55 EOS visit will be asked to return for additional follow-up 
testing.  This testing should occur approximately every 3 months starting from when the site has 
been notified of the positive result, until: (1) neutralizing antibodies are no longer detectable or
(2) the subject has been followed for a period of at least 1 year (± 4 weeks).  More frequent 
testing (eg, every month), or testing for a longer period of time, may be requested in the event of 
safety-related concerns.  Subjects who test positive for binding antibodies and have clinical 
sequelae that are considered potentially related to an anti-AMG 416 antibody response may also 
be asked to return for additional follow-up testing.  
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 Day 55 EOS visit.  
If 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 1).
Statistical Considerations:
Demographics and safety data will be summarized by treatment groups. Unless otherwise 
stated, the data analysis will be conducted using subjects in the Safety Analysis Set. Descriptive 
statistics on continuous measurements will include means, medians, standard deviations, and 
ranges, while categorical data will be summarized using frequency counts and percentages.
Pharmacokinetic, vital sign, ECG, and clinical laboratory data will be summarized at each time
point when samples are collected.
The number and percent of subjects reporting any treatment-emergent adverse events and each 
adverse event will be tabulated by system organ class and preferred term and will be further 
classified by relationship to treatment. Subjects who experience clinically-significant changes in 
clinical laboratory test values, ECGs, or vital signs will be noted.
Individual and mean (SD) plasma concentration-time plots for AMG 416 will be presented.  The 
PK parameters (eg, interdialytic Cmax and AUClast on after the first and last dose on Study 
Days 1 and 27) will be estimated using noncompartmental methods. Nominal dose and actual 
sampling time data will be used for calculation of PK parameters. Summary statistics will be 
generated for each PK parameter.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:
Amgen Inc*
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Tel: 805-447-1000
Tel: 805-447-1000
*Effective July 5, 2012, KAI Pharmaceuticals, Inc. became a wholly owned subsidiary of Amgen 
Inc. In connection with Amgen’s acquisition of KAI, Amgen Inc. will be managing the clinical study 
described in this protocol on behalf of KAI.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 6 of 73
CONFIDENTIAL
Study Design and Treatment Schema
a TIW = Three times a week (12 doses)
b Last Dose Administration (Day 27)
c EOS = End of Study will occur on Day 55, PK washout and safety followup (Day 28-55)


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 7 of 73
CONFIDENTIAL
Study Glossary
Abbreviation or Term
Definition/Explanation
%CV
coefficient of variation
ADA
Anti-drug antibody assay
ADME
Absorption, distribution, metabolism, and excretion
ALP
alkaline phosphatase
ALT
alanine aminotransferase
API
Active pharmaceutical ingredient
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUClast
area under the concentration-time curve from time 0 to the time of the 
last quantifiable sample
BMI
Body Mass Index
CaSR
Calcium sensing receptor
Ca
Calcium
cCa
Total serum albumin corrected calcium concentration
cCa x P
Corrected calcium-phosphorus product
CHD
Coronary heart disease
CKD
Chronic kidney disease
CKD-MBD
Chronic kidney disease-mineral and bone disorder
CI
Confidence Interval
CK
Creatinine kinase
CL
Clearance
Cmax
Maximum observed concentration
Corrected Total Serum 
Calcium (for albumin 
levels < 4.0 g/dL)
Corrected calcium (mg/dL) = Total calcium (mg/dL) + 
(4 - albumin [g/dL])*0.8.  
CRF
Case report form (electronic or paper)
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DILI
Drug-induced liver injury
EDC
Electronic data capture
ECG
Electrocardiogram
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
Page 1 of 3


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 8 of 73
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
Enrollment Date
Same as Study Day 1
EOS
End of Study
eSAE
electronic Serious Adverse Event (form)
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
GM
Geometric mean
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HDL-C
high density lipoprotein cholesterol
hERG
human Ether-à-go-go-Related Gene
HepCAb
hepatitis C virus antibodies
HIV
human immunodeficiency virus
HR
heart rate
ICF
informed consent form
ICH
International Conference on Harmonisation
IFU
instructions for Use
INR
international normalized ratio
Interdialytic AUClast
area under the concentration-time curve measured from the time of
drug administration to the beginning of the next dialysis session
Interdialytic Cmax
maximum drug concentration measured between the time of drug 
administration to the beginning of the next dialysis session
IP
investigational product
IPIM
investigational product instruction manual
iPTH
Intact parathyroid hormone
IRB
Institutional Review Board
IV
Intravenous
IVR/IWR                           
KDIGO
Interactive Voice/Web Response System
Kidney Disease Improving Global Outcomes
K/DOQI
Kidney Disease Outcomes Quality Initiative
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
Page 2 of 3


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 9 of 73
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
MedDRA
Medical dictionary for regulatory activities
mL
Milliliter
mM
Millimolar
n
number of subjects or observations
NKF
National Kidney Foundation
P
Phosphorous
PD
Pharmacodynamic(s)
pg
Picograms
PR interval
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG
PTH
Parathyroid hormone
qhd
Every hemodialysis day
QRS interval
QRS interval 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
RI
renal impairment
RR
respiratory rate
SAE
severe adverse event
SHPT
Study Day 1
Secondary hyperparathyroidism
Defined as the first day that protocol specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject
TEMP
Temperature
T1/2
Terminal elimination phase half life
TBL
Total bilirubin
TIW
Thrice weekly
ULN
Upper limit of normal
URR
Urea reduction ratio
Vit D
Vitamin D
Page 3 of 3


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
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..............................................15
2.2.1
Nonclinical Experience ..............................................................15
2.2.1.1
Nonclinical Pharmacology .......................................15
2.2.1.2
Nonclinical Pharmacokinetics, Absorption, 
Distribution, Metabolism, and Excretion 
(ADME) ...................................................................16
2.2.1.3
Nonclinical Toxicology.............................................17
2.2.2
Clinical Experience....................................................................17
2.2.2.1
Clinical Pharmacokinetics .......................................18
2.3
Risk Assessment.......................................................................................19
2.4
Rationale...................................................................................................20
2.5
Clinical Hypotheses...................................................................................20
3.
EXPERIMENTAL PLAN........................................................................................21
3.1
Study Design.............................................................................................21
3.2
Number of Sites ........................................................................................21
3.3
Number of Subjects...................................................................................21
3.4
Replacement of Subjects ..........................................................................21
3.5
Estimated Study Duration..........................................................................22
3.5.1
Study Duration for Subjects.......................................................22
3.5.2
End of Study..............................................................................22
4.
SUBJECT ELIGIBILITY ........................................................................................22
4.1
Inclusion Criteria .......................................................................................22
4.2
Exclusion Criteria ......................................................................................23
5.
SUBJECT ENROLLMENT....................................................................................25
5.1
Randomization/Treatment Assignment......................................................25
5.2
Site Personnel Access to Individual Treatment Assignments ....................26
6.
TREATMENT PROCEDURES..............................................................................26
6.1
Classification of Product(s) and/or Medical Device(s)................................26


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 11 of 73
CONFIDENTIAL
6.2
Investigational Product..............................................................................26
6.3
Amgen Investigational Product AMG 416..................................................26
6.3.1
Dosage, Administration, and Schedule......................................27
6.3.1.1
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation........................................................28
6.4
Hepatotoxicity Stopping and Rechallenge Rules .......................................28
6.4.1
Criteria for Permanent Withholding of AMG 416 due to 
Potential Hepatotoxicity.............................................................28
6.5
Concomitant Therapy................................................................................29
6.6
Alcohol Restrictions...................................................................................29
6.7
Medical Devices........................................................................................30
6.8
Product Complaints...................................................................................30
6.9
Excluded Treatments and/or Procedures During Study Period..................30
6.10
Hemodialysis Treatment Procedures and Concomitant 
Medications...............................................................................................30
7.
STUDY PROCEDURES .......................................................................................31
7.1
Schedule of Assessments.........................................................................31
7.2
General Study Procedures ........................................................................37
7.2.1
Screening..................................................................................37
7.2.2
Day -2........................................................................................39
7.2.3
Treatment (Day 1-27) and Follow up Periods 
(Day 28-55)...............................................................................39
7.3
Description of Study Procedures...............................................................42
7.3.1
Informed Consent......................................................................42
7.3.2
Demographics ...........................................................................42
7.3.3
Subject Residency.....................................................................42
7.3.4
Medical History..........................................................................42
7.3.5
Physical Examination ................................................................42
7.3.6
Height........................................................................................43
7.3.7
Weight and Body Mass Index....................................................43
7.3.8
Vital Signs .................................................................................43
7.3.9
12-Lead Electrocardiograms......................................................43
7.3.10
Clinical Chemistry, Hematology.................................................43
7.3.11
Follicle Stimulating Hormone Test (Females Only) ....................44
7.3.12
Human Immunodeficiency Virus Antibodies, Hepatitis 
B Surface Antigen, and Hepatitis C Antibodies..........................45
7.3.13
25-hydroxy Vitamin D ................................................................45
7.3.14
Alcohol Screen ..........................................................................45
7.3.15
Intact Parathyroid Hormone.......................................................45
7.3.16
AMG 416 Plasma Concentrations..............................................45
7.3.17
Adverse Event Reporting...........................................................45
7.3.18
Concomitant Medications ..........................................................45


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 12 of 73
CONFIDENTIAL
7.3.19
Blood Volume............................................................................46
7.4
Antibody Testing Procedures ....................................................................46
7.5
Sample Storage and Destruction...............................................................47
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY..................48
8.1
Subjects’ Decision to Withdraw .................................................................48
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion......................................49
8.2.1
Reasons for Removal From Treatment......................................49
8.2.2
Reasons for Removal From Study.............................................49
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................50
9.1
Adverse Events.........................................................................................50
9.1.1
Definition of Adverse Events......................................................50
9.1.2
Definition of Serious Adverse Events.........................................50
9.2
Reporting of Adverse Events.....................................................................51
9.2.1
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria.................................................................51
9.2.2
Reporting Procedures for Serious Adverse Events....................52
9.3
Changes in Serum Calcium and Symptomatic Hypocalcemia ...................53
9.4
Pregnancy and Lactation Reporting ..........................................................54
10.
STATISTICAL CONSIDERATIONS......................................................................55
10.1
Study Endpoints, Analysis Sets, and Covariates .......................................55
10.1.1
Study Endpoints ........................................................................55
10.1.1.1
Primary Endpoints...................................................55
10.1.1.2
Secondary Endpoints ..............................................55
10.1.1.3
Exploratory Endpoints .............................................55
10.1.2
Analysis Sets.............................................................................55
10.1.2.1
Safety Analysis Set .................................................55
10.1.2.2
PK Concentration Analysis Set................................55
10.1.2.3
PK Parameter Analysis Set .....................................55
10.1.2.4
Covariates and Subgroups......................................55
10.2
Sample Size Considerations .....................................................................55
10.3
Access to Individual Subject Treatment Assignments by Amgen 
or Designees.............................................................................................56
10.4
Planned Analyses .....................................................................................56
10.4.1
Interim Analyses........................................................................56
10.4.2
Primary Analysis........................................................................57
10.5
Planned Methods of Analysis ....................................................................57
10.5.1
General Approach/Considerations.............................................57
10.5.2
Pharmacokinetic Endpoints .......................................................57
10.5.3
Adverse Events .........................................................................57
10.5.4
Vital Signs .................................................................................57


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 13 of 73
CONFIDENTIAL
10.5.5
Electrocardiograms....................................................................57
10.5.6
Clinical Laboratory Tests ...........................................................58
10.5.6.1
Anti-drug Antibodies................................................58
10.5.7
Exploratory Endpoints ...............................................................58
11.
REGULATORY OBLIGATIONS............................................................................58
11.1
Informed Consent......................................................................................58
11.2
Institutional Review Board/Independent Ethics Committee........................59
11.3
Subject Confidentiality...............................................................................59
11.4
Investigator Signatory Obligations.............................................................60
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..................................................60
12.1
Protocol Amendments and Study Termination ..........................................60
12.2
Study Documentation and Archive ............................................................61
12.3
Study Monitoring and Data Collection .......................................................61
12.4
Investigator Responsibilities for Data Collection........................................63
12.5
Language..................................................................................................63
12.6
Publication Policy......................................................................................63
12.7
Compensation...........................................................................................64
13.
REFERENCES.....................................................................................................65
14.
APPENDICES ......................................................................................................66
List of Tables 
Table 1.  Schedule of Assessments...............................................................................32
Table 2.  Chemistry, Hematology...................................................................................44
Table 3.  Estimated Blood Volume Collection ................................................................46
List of Appendices
Appendix A.  Additional Safety Assessment Information................................................67
Appendix B.  Sample Electronic Adverse Event Contingency Report Form ...................69
Appendix C.  Sample Pregnancy Notification Worksheet...............................................72
Appendix D.  Sample Lactation Notification Worksheet .................................................73


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 14 of 73
CONFIDENTIAL
1.
OBJECTIVES
1.1
Primary
To characterize the pharmacokinetics of AMG 416 following thrice weekly 
intravenous (IV) administration of 5 mg in Chinese subjects with chronic kidney disease 
receiving hemodialysis.
1.2
Secondary
To characterize the safety and tolerability of AMG 416 following thrice weekly 
intravenous (IV) administration of 5 mg in Chinese subjects with chronic kidney disease 
receiving hemodialysis.
1.3
Exploratory
2.
BACKGROUND AND RATIONALE
2.1
Disease
Secondary hyperparathyroidism occurs commonly among patients with chronic kidney 
disease (CKD), and it is an integral component of the syndrome of chronic kidney 
disease-mineral and bone disorder, or CKD-MBD. Persistently elevated levels of intact 
parathyroid hormone (iPTH) in serum or plasma are the cardinal biochemical feature of 
SHPT, affecting 40% to 50% of patients receiving dialysis regularly in the US 
(USRDS 2009). These biochemical changes are associated with abnormalities in bone 
histology, increased fracture risk, vascular and soft tissue calcifications, calciphylaxis, a 
variety of patient symptoms (eg, muscle weakness, fatigue, lethargy, bone and joint
pain), and increased mortality (USRDS, 2009; Moe, 2001; Diaz- Corte and 
Cannata-Andia, 2000; Alem et al, 2000; Block and Port, 2000; Bro and Olgaard, 1997; 
Salusky and Goodman, 1996; Slatopolsky et al, 1980).
Intact parathyroid hormone values not only serve as a useful index of disease severity, 
but also can be used to monitor evolution of the disorder over time and the response to 
treatment.  The importance of managing SHPT chronically is highlighted in clinical 
practice guidelines promulgated by the National Kidney Foundation Kidney Disease 
Outcomes Quality Initiative (NKF KDOQITM) and the International Society of Nephrology 
Kidney Disease Improving Global Outcomes (KDIGO®) (KDIGO, 2009; K/DOQI, 2003). 
A retrospective study of Chinese hemodialysis patients during 2006 showed that mineral 
metabolism control in China remains an unmet medical need (Kong, 2012). Treatment 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
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guidelines for SHPT cover several therapeutic strategies used to lower elevated serum
iPTH levels and to manage SHPT among patients with CKD (Saliba and El-Haddad, 
2009; KDIGO, 2009; Locatelli et al, 2008). Traditionally, most have employed treatment 
with vitamin D sterols such as calcitriol or other synthetic vitamin D analogues.  
Vitamin D therapies are only partially effective for controlling serum iPTH levels among 
patients with SHPT, and values often remain elevated despite ongoing treatment.  
An alternative approach is directed toward enhancing signal transduction through 
modulation of CaSR in parathyroid tissue, thereby suppressing iPTH.  These 
compounds are called calcimimetic agents, and they include cinacalcet, which is taken 
daily by mouth, and the investigational medication being evaluated in this study, 
AMG 416, which is administered intravenously three times per week (TIW) at the end of 
each hemodialysis treatment.  Calcimimetics reduce iPTH secretion from the parathyroid 
glands and consequently lower serum iPTH levels.  Reductions in serum calcium 
concentrations are also observed and are an expected physiological consequence of 
iPTH reduction.  As such, treatment is initiated with small doses that are subsequently 
titrated upwards as needed to achieve meaningful reductions in serum iPTH levels only 
if serum calcium concentrations remain unchanged or decrease only modestly.  Intact 
parathyroid hormone and corrected calcium (cCa) laboratory values are routinely drawn 
to measure the effectiveness of cinacalcet, and to titrate the dose as appropriate.  
Detailed descriptions of the clinical studies of AMG 416 are provided in the 
Investigator’s Brochure.
2.2
Amgen Investigational Product Background 
AMG 416 hydrochloride (formerly KAI-4169) is an 8-amino-acid peptide agonist of the 
calcium-sensing receptor (CaSR) being developed as an intravenous (IV) calcimimetic 
for the treatment of SHPT. The seven amino acids in the peptide backbone have an 
unnatural D-configuration which renders the peptide resistant to proteolysis.  AMG 416 is 
administered to patients receiving hemodialysis as a bolus intravenous dose at the end 
of hemodialysis.
Refer to the Investigator’s Brochure for additional information.
2.2.1
Nonclinical Experience
2.2.1.1
Nonclinical Pharmacology
AMG 416 has been shown in pharmacological studies to be a potent and selective 
allosteric activator of the CaSR, lowering the threshold of receptor activation by calcium, 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
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the natural ligand. As such, it inhibits PTH secretion by the parathyroid tissue. The 
CaSR was shown in cellular studies to be the molecular target of AMG 416.
Please refer to the Investigator’s Brochure for detailed descriptions of the nonclinical 
pharmacology of AMG 416.
2.2.1.2
Nonclinical Pharmacokinetics, Absorption, Distribution, Metabolism, 
and Excretion (ADME)
The intravenous administration of AMG 416 to rats and dogs with normal kidney function 
resulted in a dose-proportional plasma exposure with no evidence of significant 
accumulation. Renal elimination was the predominant in vivo clearance pathway in rats, 
with the administered dose excreted as intact AMG 416 or its biotransformed products. 
Significant biotransformation of AMG 416 occurred in whole blood, predominately via 
replacement of the L-cysteine moiety of AMG 416; the D-amino acid backbone of the 
molecule remained intact. A significant portion of administered AMG 416 was covalently 
bound via disulfide conjugation of the D-amino acid peptide backbone to serum albumin 
in rat and human plasma. Preliminary in vitro results indicate the covalent binding to 
serum albumin was reversible. The biotransformation of AMG 416 appeared to be the 
result of disulfide exchange rather than via conventional metabolism by enzymes such 
as cytochrome P450. This mechanism is in accord with the disposition of other thiol- or 
disulfide containing drugs, eg, captopril (Duchin et al, 1984, Narazaki et al, 1997) and 
E-2072 (Rais et al, 2012). AMG 416 neither inhibited nor induced human hepatic 
cytochrome P450. AMG 416 was neither a substrate nor an inhibitor of common drug 
transporters. 
Several low molecular weight disulfide biotransformation products formed by conjugation 
with endogenous thiols have been observed along with the albumin disulfide.  
Tris(2-carboxyethyl) phosphine (TCEP) is a chemical agent that reduces disulfide bonds.  
TCEP reduction of plasma obtained from in vitro or in vivo studies resulted in the 
conversion of AMG 416 and all detected biotransformed products into a single 
component, M11 (the free thiol of the D-amino acid peptide backbone).  Thus, 
M11 formed upon TCEP treatment of plasma is referred to as “Total M11” and is a 
measure of all AMG 416 related components with an intact D-amino acid peptide 
backbone.
Detailed descriptions of the pharmacokinetics (PK), distribution, metabolism, and
excretion of AMG 416 in nonclinical species are provided in the Investigator’s Brochure.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
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2.2.1.3
Nonclinical Toxicology
AMG 416 is pharmacologically active in rats and in dogs, and all of the adverse effects
observed in both species are related, either directly or indirectly, to the effect of
AMG 416 on lowering serum calcium levels. There were no anatomic pathology findings
or other effects that suggested off-target toxicity of AMG 416 unrelated to its mechanism
of action. Moderate (13 to 17%) prolongation of the QTc interval was observed and
related to peak reductions in serum calcium and not plasma drug concentrations. 
Results of the in vitro human Ether-à-go-go-Related Gene (hERG) assay suggest no 
direct effect of AMG 416 on the QT interval. The nonclinical data indicates that 
AMG 416 neither poses a genotoxic risk for humans nor affects fertility and embryo-fetal 
development.
For a complete list of completed safety studies and additional details about the results,
please see the Investigator’s Brochure.
2.2.2
Clinical Experience
Etelcalcetide has been studied in three 26-week phase 3 studies, 2 placebo-controlled 
trials (20120229 and 20120230), and 1 active-controlled trial (20120360).  In 
Study 20120229, 74% of etelcalcetide subjects achieved > 30% reduction from baseline 
in mean PTH during the efficacy assessment phase (EAP) versus 8.3% of placebo 
subjects (p < 0.001).  In Study 20120230, 75.3% of etelcalcetide subjects achieved this 
endpoint versus 9.6% of placebo subjects (p < 0.001).  Similarly, the proportion of 
etelcalcetide subjects who achieved mean predialysis PTH ≤ 300 pg/mL during the EAP 
was significantly higher in the etelcalcetide group than in the placebo group (p < 0.001) 
in both Studies 20120229 and 20120230.  In Study 20120229, 49.6% of subjects in the 
etelcalcetide group and 5.1% of subjects in the placebo group achieved this endpoint, 
and 53.3% of subjects in the etelcalcetide group and 4.6% of subjects in the placebo 
group achieved this endpoint in Study 20120230.  The events that occurred with a 
greater frequency among subjects in the etelcalcetide group compared with subjects in 
the placebo group (≥ 5% in the etelcalcetide group with ≥ 1% difference from placebo) 
were blood calcium decreased (63.8% etelcalcetide; 10.1% placebo), muscle spasms 
(11.5% etelcalcetide; 6.6% placebo), diarrhea (10.7% etelcalcetide; 8.6% placebo), 
nausea (10.7% etelcalcetide; 6.2% placebo), vomiting (8.9% etelcalcetide; 5.1% 
placebo), headache (7.6% etelcalcetide; 6.0% placebo), and hypocalcemia (7.0% 
etelcalcetide; 0.2% placebo).  An additional phase 3 study (20120360) was performed to 
compare the therapeutic efficacy of etelcalcetide and cinacalcet for lowering serum PTH 


Product:  AMG 416
Protocol Number:  20140197
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concentrations among subjects with CKD and SHPT receiving maintenance 
hemodialysis.  A higher observed percentage of subjects in the etelcalcetide group 
(77.9%) had a > 30% reduction from baseline in serum PTH during the EAP compared 
with the cinacalcet group (63.9%).  The estimated treatment difference 
(cinacalcet - etelcalcetide) was -10.48% (95% confidence interval [CI]: -17.45%,
-3.51%).  Because the upper bound of the 95% CI is < 12% (the prespecified margin for 
noninferiority), etelcalcetide is noninferior to cinacalcet in the proportion of subjects with 
a > 30% reduction from baseline in serum PTH during the EAP.  Additionally,
etelcalcetide was superior to cinacalcet on the proportion of subjects achieving a > 50% 
and a > 30% reduction from baseline in mean predialysis serum PTH during the EAP.  
There was no significant difference in the mean number of days of vomiting or nausea 
per week in the first 8 weeks of treatment, as measured by a patient-reported outcome 
instrument.  The most common (> 10% in either treatment group) adverse events 
(etelcalcetide, cinacalcet) were asymptomatic decreased blood calcium (68.9%, 59.8%), 
nausea (18.3%, 22.6%), vomiting (13.3%, 13.8%), and diarrhea (6.2%, 10.3%).  
Symptomatic hypocalcemia was reported for 17 subjects (5.0%) in the etelcalcetide 
group and 8 subjects (2.3%) in the cinacalcet group. Please refer to the Investigator’s 
Brochure for additional information.
2.2.2.1
Clinical Pharmacokinetics
After both single and repeat IV bolus administration in end stage renal disease (ESRD)
patients, plasma AMG 416 exhibited a multiple exponential decay, characterized by
rapid initial distribution followed by a prolonged log-linear elimination phase
(Studies 20130139 and 20120330, respectively). Exposure (as assessed by mean Cmax
and AUC parameters) increased in a dose-related fashion.
In Study 20120330, AMG 416 was given at a dose of 5 or 10 mg three times a week
(TIW) for 4 weeks (12 doses given IV at the end of dialysis to Cohorts 3 and 4). 
Repeated TIW dosing of AMG 416 was associated with modest accumulation as 
measured by plasma AMG 416 Cmax and AUClast ratios, mean Cmax and AUClast  after 
twelve 5 mg doses were approximately 2-fold higher (Cmax), and approximately 3-fold 
higher (AUClast), relative to corresponding values on Study Day 1.  
Population PK analysis was conducted using the PK data from patients receiving 
hemodialysis. A three-compartment PK model with non-specific linear elimination and 
linear dialysis elimination from the central compartment was deemed appropriate to 
describe the PK of AMG 416 after single and multiple IV administrations in subjects with 


Product:  AMG 416
Protocol Number:  20140197
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SHPT receiving hemodialysis. Within the dose range of 2.5 to 60 mg, no evidence of 
nonlinear elimination or time-dependent PK was observed. Dose-proportional increases 
in systemic exposures were observed.
Within the range of values evaluated, demographic factors (body weight, age, sex, race),
liver function biomarkers (aspartate aminotransferase, alanine aminotransferase, serum
albumin, total bilirubin), as well as baseline alkaline phosphatase, iPTH, cCa,
phosphorus, serum creatinine, smoking status, and calcium supplements had no 
discernible impact on AMG 416 PK parameters. Consequently, further dose 
adjustments on the basis of these covariates are not warranted in subjects with SHPT 
receiving hemodialysis.
Ono Pharmaceuticals (ONO) conducted a comparative ethnic sensitivity study of the PK
of AMG 416 in healthy Japanese and non-Asian subjects by comparing results at the
matching dose levels (2 mg and 5 mg) from Amgen’s Study 20130107 (n=12 non-Asian
subjects) and Study ONO-5163-01 (n=12 Japanese subjects). ONO also conducted a
comparative ethnic sensitivity study of the PK of AMG 416 in Japanese and non-Asian
subjects receiving hemodialysis by comparing results from Amgen’s Study 20130139
(n=11) and the ongoing Study ONO-5163-02 (n=12) at the matching dose levels (5 mg,
10 mg, and 20 mg). While these data are preliminary and do not represent full efficacy
and safety comparisons, preliminary analysis of the data in healthy subjects and
subjects with SHPT suggests that there are no significant differences in AMG 416 PK
parameters between Japanese and non-Asian subjects.
Metabolism, Distribution and Excretion
AMG 416 does not undergo conventional metabolism (see section 2.2.1.2). The PK, 
biotransformation, and excretion, and elimination by hemodialysis of [14C] AMG 416 is 
currently being assessed in human hemodialysis subjects in study 20130147.
2.3
Risk Assessment
Safety reporting for all subjects in open-label and blinded studies completed as of 
10 November 2017 and the investigators brochure have identified the following risks:
Important identified risks:

Hypocalcemia

Worsening heart failure

QT prolongation secondary to hypocalcemia


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Important potential risks:

Ventricular arrhythmias

Infusion and hypersensitivity reactions

Convulsions (seizures)

Adynamic bone

Co-administration of cinacalcet (HCl) and etelcalcetide
The important identified risk is hypocalcemia, which will be mitigated in the protocol by 
close monitoring, and treatment as required. Coadministration of cinacalcet and 
AMG 416 is contraindicated until further studies inform the safety of simultaneous 
administration of these agents. The likelihood of these risks occurring with the planned 
dose for this study is expected to be low. In this study, cinacalcet will be prohibited from 
30 days prior to informed consent and throughout the study.
Please refer to the Investigator’s Brochure, Section 7 for additional information for the 
investigator.
2.4
Rationale
The purpose of the current study is to characterize the PK, safety and tolerability of 
AMG 416 in Chinese subjects with chronic kidney disease receiving hemodialysis. This 
study will use a placebo-controlled dose of 5 mg AMG 416 administered IV at the end of 
dialysis thrice weekly for 4 weeks. Within the dose range of 2.5 to 60 mg, no evidence 
of nonlinear PK was observed.  This design is similar to multiple dose Study 20120330
Cohort 3, conducted in non-Asian hemodialysis subjects (n = 12 at the 5 mg dose). 
The 5 mg dose level, given thrice weekly for 4 weeks, was selected because it is the 
starting dose in the AMG 416 dose titration that is used in pivotal Phase 3 clinical trials, 
where dose may be adjusted every 4 weeks based on serum predialysis iPTH and cCa 
levels obtained in the prior week.  The 5 mg dose was safe and well‑tolerated in phase 2 
studies and demonstrated a clinically meaningful effect on iPTH with approximately 50% 
of subjects achieving > 30% reduction in iPTH from baseline after approximately 
4 weeks of dosing.
2.5
Clinical Hypotheses
This study will adequately characterize the PK profile of AMG 416 in Chinese subjects 
with chronic kidney disease receiving hemodialysis.
AMG 416 will be safe and well tolerated after multiple dose administration in Chinese 
subjects with chronic kidney disease receiving hemodialysis. 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
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3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a multiple dose, double-blind, randomized, placebo-controlled clinical study.  
Chinese subjects residing in Mainland China with chronic kidney disease receiving 
hemodialysis will be randomized in a 3:1 ratio to receive 5 mg IV of AMG 416 or placebo 
thrice weekly (TIW) for approximately 4 weeks, with a subsequent follow up period of 
approximately 4 weeks.
Subjects will participate in the study as outpatients on scheduled study Day 1 through 
Day 55 (EOS) while receiving hemodialysis three times a week. All subjects, regardless 
of treatment assignment, will receive standard of care with calcium supplements, active 
vitamin D sterols, and phosphate binders, as prescribed by each individual Investigator.  
The overall study design is described by a study schema at the end of the 
protocol synopsis section.
The study endpoints are defined in Section 10.1.1.
3.2
Number of Sites
This study will be conducted in Chinese subjects with chronic kidney disease receiving 
hemodialysis at multiple clinical sites in Mainland China.  
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
32 subjects are expected to participate in this study.  Approximately 24 subjects are 
expected to receive AMG 416, and approximately 8 are expected to receive placebo.
Refer to Section 10.2 for the rationale for the number of required subjects.
3.4
Replacement of Subjects
Randomized subjects who miss AMG 416 or matching placebo doses may be replaced
at the discretion of Amgen in consultation with the investigator or their designee.  
Subjects who drop out of the study may be replaced at the discretion of Amgen in
consultation with the investigator or their designee.
Replacement subjects will receive the identical treatment as the assigned treatment for
the subject to be replaced. All data from the replaced subjects will be captured and kept
in the clinical trial database and identified as such.


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3.5
Estimated Study Duration
3.5.1
Study Duration for Subjects
The estimated duration of study participation for each subject is approximately 77 days.  
This includes a 22-day screening period preceding a 55-day treatment and follow-up
period.  Subject participation may be adjusted based on treatment-emergent data. All
adjustments or modifications to the schedule will be agreed upon by the investigator in
consultation with Amgen. The institutional review board (IRB) will be informed via
written correspondence and the informed consent form (ICF) will be updated
accordingly.
3.5.2
End of Study
The end of the entire study for all subjects occurs at the primary completion time point.
Primary Completion: The time when the last subject is assessed or receives an
intervention for the purposes of final collection of data for the primary analysis.
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 procedure, the appropriate written informed
consent must be obtained (see Section 11.1).
4.1
Inclusion Criteria
4.1.1
Subject has provided informed consent prior to initiation of any 
study-specific activities/procedures
4.1.2
Resident in Mainland China and of Chinese ancestry
4.1.3
Male or female subject ≥ 18 and ≤ 70 years of age at the time of 
screening, with end stage renal disease receiving hemodialysis
4.1.4
Body mass index is between 18 and 35 kg/m2, inclusive
4.1.5
Subject must be receiving hemodialysis 3 times weekly for at least 
3 months through a functioning permanent dialysis access prior to Day -2 
and have adequate hemodialysis with a delivered Kt/V ≥ 1.2 or urea 
reduction ratio (URR) ≥ 65% within 4 weeks to screening or at screening.  
The subject’s routine hemodialysis session must be of 3-4.5 hours in 
duration, inclusive
4.1.6
Subject has stable dialysis prescription and this prescription is not 
anticipated to significantly change during the course of the study


Product:  AMG 416
Protocol Number:  20140197
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4.2
Exclusion Criteria
4.2.1
Corrected calcium (calculated) level is < 2.07 mmol/L (8.3 mg/dL), and/or 
intact PTH level is outside the range of 31.8 – 127.2 pmol/L (300 - 1200
pg/mL) at screening and Day -2 (Day -2 assessments are only required if 
screening visit performed greater than 7 days prior to Day 1)
4.2.2
Chemistry and all other laboratory tests are not within clinically 
acceptable range to the investigator and sponsor at screening
4.2.3
Female subjects who are pregnant lactating/breastfeeding, or who plan to
conceive, or breastfeed while on study through 3 months after receiving 
the dose of study drug
4.2.4
Female subject of reproductive potential not willing to use a(n) acceptable 
method(s) of effective birth control during treatment with AMG 416, and 
for an additional 3 months after the end of treatment with AMG 416. 
Female subjects who have had a hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, bilateral tubal ligation, or who are 
postmenopausal are not required to use contraception.  Postmenopausal 
is defined as:  

Age > 55 years with cessation of menses for 12 months or more

Age < 55 but no spontaneous menses for at least 2 years

Age < 55 years and spontaneous menses within the past 1 years, but 
currently amenorrheic, AND with postmenopausal gonadrotropin 
levels (luteinizing hormone and follicle-stimulating hormone levels 
> 40 IU/L) or postmenopausal estradiol levels (<5.3 pmol/L or 5 ng/dL) 
or according to the definition of “postmenopausal range” for the 
laboratory involved

Underwent a bilateral oophorectomy
4.2.5
Females of reproductive potential with a positive pregnancy test, unless 
medical follow-up confirms the subject is not pregnant
4.2.6
Positive for human immunodeficiency virus (HIV) at screening or known 
diagnosis of acquired immune deficiency syndrome (AIDS)
4.2.7
Positive Hepatitis B Surface Antigen (HepBsAg) at screening (indicative 
of chronic Hepatitis B)
4.2.8
Positive for Hepatitis C virus Ribonucleic acid (RNA) by Polymerase 
Chain Reaction (PCR) at screening (indicative of active
Hepatitis C – screening is generally done by Hepatitis C Antibody 
(HepCAb), followed by Hepatitis C virus RNA by PCR if HepCAb is 
positive)
4.2.9
Previous administration of AMG 416
4.2.10
Subject has received cinacalcet within the 30 days prior to informed 
consent (treatment with cinacalcet is prohibited during the study)
4.2.11
Subject has known sensitivity to any of the products or components to be 
administered during dosing


Product:  AMG 416
Protocol Number:  20140197
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4.2.12
Use of concomitant medication other than that used in the management 
of end stage renal disease and its expected comorbidities that could in 
the opinion of the investigator or Amgen medical monitor interfere with the 
safety of subjects or interpretation of study results
4.2.13
Use of any herbal medicine, vitamins, and supplements consumed by the 
subject within 30 days prior to the dose of investigational product and 
continued use, if appropriate, 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.
4.2.14
Positive result for alcohol at Day -2, known alcohol or illicit drug abuse 
within 12 months of screening, unwilling or unable to refrain from alcohol 
consumption 24 hours in advance of each study visit, unwilling or unable 
to limit alcohol consumption to up to 2 drinks per day for the duration of 
the study during (1 drink being equivalent to 12 ounces of regular beer, 8 
to 9 ounces of malt liquor, 5 ounces of wine, or 1.5 ounces of 80 proof 
distilled spirits).
4.2.15
Receiving or has received any investigational drug (or is currently using 
an investigational device) within the 30 days before receiving study drug, 
or at least 10 times the respective elimination half-life (whichever is 
longer)
4.2.16
Subject has lost 500 mL or more of blood or plasma within 8 weeks of 
study drug administration or during the study period
4.2.17
Anticipated or scheduled to have major surgical procedures during the 
study period such as kidney transplant or parathyroidectomy
4.2.18
Subject has an active infection at screening or Day -2, or a history of any 
illness that, in the opinion of the Investigator, might confound the results 
of the study or pose additional risk to the subject
4.2.19
History of malignancy within 5 years before Day -2 (except 
non-melanoma skin cancers, or cervical carcinoma in situ)
4.2.20
Subject’s 12-lead electrocardiogram (ECG) at screening suggests 
unstable arrhythmia or other cardiac abnormality that could place the 
subject at increased risk, based upon the Investigator’s opinion
4.2.21
Subject has current or history of cardiovascular conditions such as 
uncontrolled hypertension, symptomatic ventricular dysrhythmias, 
Torsades de Pointes, angina pectoris congestive heart failure (New York 
Heart Association Classification III or IV), myocardial infarction, coronary 
angioplasty, or coronary arterial bypass grafting within the past 6 months 
prior to screening
4.2.22
Subject is receiving treatment for a seizure disorder or has a history of a 
seizure within the last 12 months prior to screening
4.2.23
Subject has had major surgery (excluding hemodialysis access repair) 
within the last 8 weeks prior to screening
4.2.24
Subject likely to not be available to complete all protocol-required study 
visits or procedures, and/or to comply with all required study procedures 
to the best of the subject and Investigator’s knowledge


Product:  AMG 416
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4.2.25
History or evidence of any other clinically significant disorder, condition or 
disease 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
5.
SUBJECT ENROLLMENT
Before subjects may be entered into the study, Amgen requires a copy of the site’s
written IRB approval of the protocol, ICF, and all other subject information and/or
recruitment material, if applicable (see Section 11.2). All subjects must personally sign
and date the ICF before commencement of study-specific procedures. All subjects who 
enter into the screening period for the study (defined as the point at which the subject 
signs the ICF) will receive a unique subject identification number assigned manually 
before any study-related activities/procedures are performed. 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 may be rescreened at the discretion of 
the investigator in consultation with Amgen. A subject is considered enrolled when the 
investigator decides that the subject has met all eligibility criteria. The investigator is to 
document this decision and date in the subject’s medical record and in/on the enrollment 
case report form (CRF). 
The subject identification number must remain constant throughout the entire clinical
study; it must not be changed at the time of rescreening, enrollment, or randomization.
This number will not necessarily be the same as the randomization number assigned for
the study.
 
 
 
 
 
The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment CRF.
5.1
Randomization/Treatment Assignment
Subjects will be randomized by IVR/IWR in a 3:1 ratio to either TIW IV etelcalcetide or 
placebo in a double-blind manner prior to the Day 1 activities. The randomization 
number will be provided to the unblinded pharmacist by accessing the IVR/IWR and then 
the unblinded pharmacist will obtain the appropriate IP/Placebo box. Details for this 


Product:  AMG 416
Protocol Number:  20140197
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procedure will be provided in the IVR/IWR manual. In the event subjects are 
randomized, but are withdrawn before receiving study medication, a replacement subject 
may be enrolled in the subject’s place and assigned to receive the identical treatment as 
the replaced subject.
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
5.2
Site Personnel Access to Individual Treatment Assignments
An unblinded pharmacist at the research facility (and/or their qualified designee) will
have access to subjects’ treatment assignment and will be responsible for preparing the
appropriate treatment based on the randomized treatment provided by the IVR/IWR. 
Access to the randomization list or unblinded safety records will be limited to the 
unblinded pharmacist and/or their qualified designee. A subject’s treatment assignment 
should only be unblinded when knowledge of the treatment is essential for the further 
management of the subject or may potentially impact the safety of subjects currently 
enrolled or subjects enrolled in the future.
Unblinding at the research facility for any other reason will be considered a protocol
deviation. The investigator is strongly encouraged to contact the Amgen study manager 
before unblinding any subject’s treatment assignment, but must do so within 24 hours 
after the event.
6.
TREATMENT PROCEDURES
6.1
Classification of Product(s) and/or Medical Device(s)  
The Amgen Investigational Product and placebo used in this study are AMG 416, also 
known as KAI-4169, and placebo. The Investigational Product Instruction Manual 
(IPIM), a document external to this protocol, contains detailed information regarding the 
storage, preparation, and administration of AMG 416 and placebo.
6.2
Investigational Product
Investigational product will be administered at the research facility by a qualified staff 
member.  A physician, trained healthcare provider or qualified designee must be 
available at the time of administration of investigational product.
6.3
Amgen Investigational Product AMG 416
AMG 416 will be manufactured and packaged by Amgen Inc. or its designee, and
distributed using Amgen clinical investigational product distribution procedures.  The 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 27 of 73
CONFIDENTIAL
active pharmaceutical ingredient (API) in AMG 416 is an eight-amino acid synthetic
peptide prepared as a hydrochloride salt.
The AMG 416 investigational drug is supplied as a sterile, preservative-free, aqueous
solution containing 10 mg AMG 416 API, 
 mg sodium chloride and 
 mg succinic
acid, in a single-use 3 mL glass vial. The drug product vial contains 2 mL of clear,
colorless solution with AMG 416 concentration of 5 mg/mL. The solution is ready to
administer and has pH between 
 and 
. The recommended storage condition for
AMG 416 liquid drug product is between
°C to
°C.
Placebo will be presented in identical containers and stored/packaged in the same
manner as AMG 416. Placebo is supplied as a sterile, preservative-free, aqueous
solution containing 
 mg sodium chloride and 
 mg succinic acid, in a single-use
3 mL glass vial. The placebo vial contains 2 mL of clear, colorless solution. The
solution is ready to administer and has pH between 
 and 
. The recommended
storage condition for the placebo drug product is
°C to
°C.  Additional details 
regarding AMG 416 and placebo are provided in the IPIM.
6.3.1
Dosage, Administration, and Schedule
Each subject will receive twelve intravenous doses of 5 mg AMG 416 or placebo 
administered by bolus injection into the venous line of the dialysis circuit at the end of 
each of the 12 consecutive hemodialysis treatments, just prior to or during rinse-back 
with each hemodialysis session (ie, one dose per hemodialysis session,
see Section 7.2).  
The end of hemodialysis treatment is defined as the time at which the prescribed
hemodialysis treatment has been completed (ie, remaining time on dialysis is zero) or
when the arterial flow is stopped (eg, arterial line is clamped or disconnected to
discontinue treatment), whichever occurs first.
After investigational product (IP) administration has been completed by a qualified 
healthcare professional, subjects will be observed for at least 30 minutes. 
The date, time, package lot number, and quantity administered will be recorded on the 
individual subject’s Investigational Product Administration CRF prior to database lock.  
The effects of overdose of AMG 416 are not known.  All overdose occurrences must be 
documented and corresponding adverse events must be recorded on the appropriate 
CRF and in the source documents.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 28 of 73
CONFIDENTIAL
6.3.1.1
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Subjects will be treated with investigational product thrice weekly for 4 weeks. The dose 
of investigational product is 5 mg. Dosing will be stopped or modified by the investigator 
and Amgen Medical Monitor if suspected adverse drug reactions, changes in vital signs, 
physical examination, or clinical laboratory results are observed and these changes pose 
a significant health risk.  Clinically or medically significant suspected adverse drug 
reactions, and serious adverse events considered to be related to study procedures will 
be followed until resolved or considered stable.
The study may be terminated at any point in time at the discretion of the sponsor.
6.4
Hepatotoxicity Stopping and Rechallenge Rules
Subjects with abnormal hepatic laboratory values (ie, ALP, aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], total bilirubin [TBL]) and/or international 
normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) may 
meet the criteria for withholding or permanent discontinuation of Amgen investigational 
product or other protocol-required therapies as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009.
6.4.1
Criteria for Permanent Withholding of AMG 416 due to Potential 
Hepatotoxicity
AMG 416 should be discontinued permanently and the subject should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
Information) for possible drug-induced liver injury (DILI), if ALL of the criteria below are 
met: 

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

TBL > 2 X the 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 
TBL values include, but are not limited to:

Hepatobiliary tract disease (obstructive gall bladder or bile duct disease)


Product:  AMG 416  
Protocol Number:  20140197 
Date:  25 May 2018 
Page 29 of 73 
CONFIDENTIAL 
 
 
− 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
Right-sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia 
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms 
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation  
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis 
− 
Wilson’s disease and hemochromatosis 
− 
Non-alcoholic fatty liver disease including steatohepatitis 
− 
Non-hepatic causes (eg, rhabdomyolosis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on subject population and/or 
severity of the hepatotoxicity or event) if AMG 416 and other protocol-required therapies 
should be withheld or permanently discontinued, as deemed appropriate for the safety of 
the subject. 
6.5 
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 6.9. Concomitant therapies are to be collected from informed consent 
through the EOS.  Collect therapy name, indication, dose, unit, frequency and route, 
start date, and stop date. 
Details of all concomitant medications will be recorded in the subject’s source 
documents and on the CRF. 
6.6 
Alcohol Restrictions 
Subjects should not consume any alcohol within 24 hours prior to each visit (including 
screening). 
Subjects will be required to limit alcohol consumption throughout the course of the study. 
Alcohol is limited to no more than 2 drinks per day for the duration of the study. (1 drink 
being equivalent to 12 ounces (approximately 355 mL) of regular beer, 8 to 9 ounces 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 30 of 73
CONFIDENTIAL
(approximately 237 to 266 mL) of malt liquor, 5 ounces (approximately 148 mL) of wine, 
or 1.5 ounces (approximately 44 mL) of 80 proof distilled spirits). 
6.7
Medical Devices
Medical devices for the IV infusion of investigational product (eg, inline filters, 
IV administration set, infusion pump) will not be provided by Amgen, as routine
hemodialysis tubing should be utilized. The Investigator will be responsible for obtaining
supplies of these devices.
Medical devices (eg, syringes, sterile needles, alcohol prep pads), that are commercially
available are not usually provided or reimbursed by Amgen (except, for example, if
required by local regulation). The Investigator will be responsible for obtaining supplies
of these devices.
6.8
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 any investigational or non-investigational product(s) or device(s).
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.
6.9
Excluded Treatments and/or Procedures During Study Period
Treatment with cinacalcet is prohibited during the study through the last study visit
(ie, Day 55 (EOS)).  Treatment during the study with other medications known to be 
associated with hypocalcemia is strongly discouraged. Cinacalcet must not have been 
taken for at least 30 days prior to informed consent.
Subjects should not have a planned kidney transplant during this study.
Subject should not be allowed to donate blood and/or plasma during this study.
6.10
Hemodialysis Treatment Procedures and Concomitant Medications
Subjects should be on maintenance hemodialysis treatment with a prescription for
dialysis 3 times per week. Dialysis duration and membrane may be modified in order to
maintain adequate hemodialysis treatment (eg, Kt/V ≥ 1.2 or URR > 65%). If there is a 
change to the hemodialysis prescription the sponsor should be notified.  In the event of a 
significant permanent change to the hemodialysis prescription, the subject may be 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 31 of 73
CONFIDENTIAL
withdrawn from treatment with investigational product as deemed necessary by the 
sponsor. 
Intermittent additional hemodialysis treatment (eg, for ultrafiltration) or changes in
hemodialysis schedule (eg, missed/rescheduled treatments or shifts in schedule) are not
considered significant changes in hemodialysis treatment prescription.
Subjects must have a prescribed dialysate calcium concentration ≥ 2.25 mEq/L stable
for at least 4 weeks prior to screening laboratories, and the dialysate calcium
concentration must be maintained ≥ 2.25 mEq/L throughout the study.
Medications used to treat hemodialysis-related symptoms or comorbid conditions should
be reported as concomitant medications whenever administered to the subject.
Medications administered at each dialysis session (eg, heparin, diphenhydramine)
should be reported on the CRF with a frequency of every hemodialysis (qhd) unless a
change in dose or frequency occurs. The following medications used in the delivery of
hemodialysis should not be reported on the CRF as concomitant medication:

local anesthetic for cannulation

saline prime for the dialysis circuit

saline or hypertonic saline for management of intradialytic hypotension

oxygen
7.
STUDY PROCEDURES
7.1
Schedule of Assessments


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 32 of 73
CONFIDENTIAL
Table 1.  Schedule of Assessments
Table 1a.  Schedule of Non-laboratory Assessments 
Study Visit (Day)
Assessment
Screening
-2
1
(HD)
2
3
(HD)
6
(HD)
8
(HD)
10
(HD)
13
(HD)
15
(HD)
17
(HD)
20
(HD)
22
(HD)
24
(HD)
27
(HD)
28
29/ETa,h
(HD)
34
(HD)
41
(HD)
55
(HD)
Informed consent
X
Eligibility
X
Medical and surgical history
X
Demographicsi
X
Prior medications
X
X
Body Heightb
X
Body Weightb
X
X
X
X
X
Physical examb
X
X
X
X
X
Hemodialysis symptomsc
X
Investigational product 
administrationd
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (BP, HR, RR, 
TEMP)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead electrocardiogramf
X
X
X
X
Adverse Event Monitoringg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes displayed on the next page


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 33 of 73
CONFIDENTIAL
ET = early termination; HD = hemodialysis.  
a If a treated subject withdraws before completion of dosing, the investigator will make every effort to perform Day 29 assessments as close to 2 days after the last 
dose of investigational product as possible.
b A physical examination will be performed at screening.  Abbreviated physical examinations will be performed on day 1 (unless day 1 occurred more than 2 weeks 
after screening physical examination), Days 15, 29 and 55.  Height will be captured once at screening.  Weight will be recorded before dialysis.
c Common symptoms associated with hemodialysis will be captured at screening.  Any worsening of hemodialysis symptoms will be reported as an adverse event.
d Investigational product will be administered by intravenous (IV) injection over approximately 30 seconds into the venous line with dialysis rinse back at the end of the 
dialysis session.
e Subjects will remain seated for at least 10 minutes prior to measurement of predialysis heart rate and blood pressure.  Vital signs will include blood pressure, heart 
rate, respiratory rate, and oral or ear temperature.  Vital signs will be obtained pre-dialysis treatments on scheduled dialysis days, and at ET and on Day 55 (EOS).     
f Subjects will remain supine for at least 5 minutes prior to recording 12-lead electrocardiogram (ECG).  Screening 12-lead ECG will be recorded prior to hemodialysis.  
The Day -2 12-lead ECG will be recorded within 4 hours after hemodialysis rinse back.  After the last dose of investigational product on Day 27, 12-lead ECGs will be 
recorded between 18 and 30 hours (recorded on day 28) post-dose.  
g Adverse events will be monitored and recorded from the dose of investigational product (AMG 416) or placebo.  Serious adverse events will be monitored and 
recorded  from the time of informed consent through Day 55.
h After Day 28, hemodialysis will continue on study days 29, 31, 34, 36, 38, 41, 43, 45, 48, 50, 52 and 55; data collection and study procedures will only occur on 
hemodialysis days 29, 34, 41, and 55(EOS).
i Demographic information collected at screening includes sex, age, race, and ethnicity.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 34 of 73
CONFIDENTIAL
Table 1b.  Schedule of Laboratory Assessments
TTime
Assessment
Study Visit (Day)
Screening
-2
1
(HD)
2
3
(HD)
6
(HD)
8
(HD)
10
(HD)
13
(HD)
15
(HD)
17
(HD)
20
(HD)
22
(HD)
24
(HD)
27
(HD)
28
29/
ETa
(HD)
34
(HD)
41
(HD)
55
(HD)
Laboratory Assessments
Pre HDHematology, PT, 
aPTTc
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
Albumind
X
X b
X
X
X
X
X
X
X
X
X
X
Phosphorus
X
X b
X
X
X
X
X
X
X
X
Calcium (cCa)d
X
X b
X
X
X
X
X
X
X
X
X
Serum or Urine 
Pregnancy (females 
only)
X
X b
X
Serum FSHg (female 
only)
X
Breath Alcohol 
Screen
X
X
HIV, Hep C Ab, 
HBsAg
X
iPTH
X
X b
X
X
X
X
X
X
X
X
25(OH) vitamin D
X
Kt/V or URRe
X
Anti-drug antibodiesf
X
X
X
Footnotes displayed on the next page


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 35 of 73
CONFIDENTIAL
HD = hemodialysis; ET = early termination; cCa = albumin-corrected calcium; SDA = Study drug administration；Kt/V = measure of dialysis adequacy; 
URR = urea reduction ratio  
a If a treated subject withdraws from study before completion of dosing, the investigator will make every effort to obtain day 29 samples as close to 2 days after the last 
dose of investigational product as possible.
b If screening albumin, phosphorus, cCa, pregnancy, and iPTH tests occur within 7 days prior to start of IP, then Day -2 lab tests can be waived
c Blood sample for PT and aPTT will be drawn prior to heparin administration for dialysis.  Day 1 hematology and coagulation tests will be performed only if day 1 
occurs more than 2 weeks after the screening hematology and coagulation tests.
d Serum samples for albumin and calcium for screening and routine monitoring of predialysis cCa.  When albumin is less than 4.0 g/dL, the calcium level will be 
corrected according to the formula: cCa (mg/dL) = total Ca (mg/dL) + (4 – albumin (g/dL))*0.8.  Corrected calcium results will inform dosing/dose withholding at the 
next hemodialysis treatment.
e Perform Kt/V or URR assessment at screening unless a qualifying Kt/V or URR measurement from within 4 weeks prior to screening assessments is available.
f Serum samples for anti-drug antibodies will be collected predialysis on days 1, 29, and 55.  Any subjects with positive titers for antibodies to AMG 416 may be asked 
to return to the clinical research unit to provide additional serum samples.
g Luteinizing hormone and estradiol levels may additionally be collected if deemed necessary for confirmation of postmenopausal status as described in exclusion 
criteria section 4.2.4


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 36 of 73
CONFIDENTIAL
Table 1c.  Schedule of Pharmacokinetic Assessments
Time
Assessment
Study Visit (Day)
Screening
-2
1
(HD)
2
3
(HD)
6
(HD)
8
(HD)
10
(HD)
13
(HD)
15
(HD)
17
(HD)
20
(HD)
22
(HD)
24
(HD)
27
(HD)
28
29/
ETa
(HD)
34
(HD)
41
(HD)
55
(HD)
Central Laboratory
Pre HD
PK
X
X
X
X
X
X
X
X
X
X
SDA + 
10 min
PK
X
X
X
X
X
SDA + 
30 min
PK
X
X
SDA + 
60 min
PK
X
X
SDA + 
90 min
PK
X
X
SDA + 
18 to 
30 hr
PK
X
X
HD = hemodialysis; ET = early termination; SDA = Study drug administration.  


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 37 of 73
CONFIDENTIAL
7.2
General Study Procedures
Study tests and procedures will be performed only after written informed consent is 
obtained. All screening procedures must be completed within 22 days before 
investigational product administration (Day 1).  Eligible subjects will be admitted to the
clinical research facility on Day -2 at which time continued eligibility will be reconfirmed 
and baseline safety assessments will be performed.  Subjects will be administered
AMG 416 or placebo on Day 1 after completion of baseline assessments.
In the event that multiple post dose procedures are required to be conducted at the 
same nominal time point, the following order of precedence will be used to ensure 
certain post dose safety assessments will not be disturbed by blood draws:  
(1) electrocardiogram (ECG) recording; (2) vital signs assessment; (3) PK blood 
sampling; (4) clinical laboratory tests; and (5) physical examination and physical 
measurements.  Electrocardiograms and vital signs may be conducted up to 15 and 
10 minutes, respectively, prior to the nominal time so that PK samples will be collected 
as close to the nominal time point as possible.  The remaining postdose 
procedures/assessments may be conducted up to 30 minutes after the nominal time.
Every effort should be made to conduct study procedures as scheduled. Acceptable 
windows for the timing of PK are as follows:  

Plus or minus 2 mins for the 10 min sample

Plus or minus 5 mins for the 30 min sample

Plus or minus 10 mins for the 60 min sample

Plus or minus 15 mins for the 90 min sample

Plus or minus 4 hours for the 18-30 hour post dose samples
7.2.1
Screening 
Screening assessments will be completed after the informed consent form is signed, but
prior to initiating treatment with investigational product, in a 22 day screening period.
Screening assessments must be performed within these 22 days prior to the first dose of 
investigational product.  All inclusion and exclusion central laboratory requirements must 
be met during the 3 weeks prior to randomization.  Screening assessments may be 
repeated up to 2 times during the 3-week screening period, utilizing the same informed 
consent signature. A new informed consent form must be signed if it has been more 
than 22 days since the previous signature.  Subjects may re-sign a new informed 
consent form two additional times.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 38 of 73
CONFIDENTIAL
After informed consent is obtained the following procedures will be completed during the 
screening period according to the Schedule of Assessments: 

Non Laboratory Assessments: 

Confirmation of informed consent

Eligibility

Demographics (sex, age, race, ethnicity)

Medical and surgical history

Prior (from 4 weeks prior to informed consent) and concomitant medication

Body weight (before dialysis if on a dialysis day)

Height

Physical examination 

Hemodialysis symptoms

Vital signs (BP,HR,RR, TEMP)

12 lead ECG recording

Serious adverse event monitoring

B ultrasound to exclude ovarian cancer (Optional at PI’s discretion)

Laboratory assessments (all pre-hemodialysis samples)

Clinical hematology

Clinical chemistry

PT, aPTT

Albumin, Phosphorus, Calcium (cCa)

Serum or urine pregnancy test (women of child-bearing potential only; within 
7 days prior to first study drug administration)

Serum FSH (females only)

Breath alcohol screen

HIV, Hepatitis C Antibody, Hepatitis B surface antigen  

iPTH 

25(OH) vitamin D

Kt/V or URR
Subjects who meet the eligibility criteria after completion of all screening, Day -2 
procedures will be considered enrolled in the study. 
If screening albumin, phosphorus, cCa, pregnancy, and iPTH tests occur within 7 days 
prior to start of IP, then Day -2 lab tests can be waived.


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 39 of 73
CONFIDENTIAL
Day -2 assessments will be performed 2 days before investigational product 
administration. Day -2 assessments will include recording the date and time of the last 
hemodialysis treatment before investigational product administration.
Evaluations obtained as part of routine medical care may be performed prior to informed 
consent and may be used in place of the study specific evaluations, provided they are 
performed within 22 days prior to Day 1 and meet the time windows described above.
7.2.2
Day -2
Two days before dosing (day -2) the following baseline procedures will be performed
and confirmed to meet eligibility requirement :

Non Laboratory Assessments: 

Medication use over 4 weeks prior to informed consent 

Vital signs (BP, HR, RR, TEMP)

Body weight

12 lead electrocardiogram 

Serious adverse event monitoring

Concomitant medications

Laboratory assessments:

Albumin, Phosphorus, Calcium (cCa)

Serum or urine pregnancy test (women of child-bearing potential only)

Breath alcohol  screen 

iPTH
Eligible subjects will be randomized prior to dosing to receive either AMG 416 or placebo 
in a 3:1 ratio. 
7.2.3
Treatment (Day 1-27) and Follow up Periods (Day 28-55)
On day 1 the following predose activities will be conducted:

Non Laboratory Assessments: 

Body weight (before dialysis)

Physical examination

Vital signs (BP,HR,RR, TEMP)

Adverse event monitoring

Concomitant medications 

Laboratory assessments and predose collections (pre-hemodialysis samples):

Hematology, PT, aPTT

Clinical chemistry


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 40 of 73
CONFIDENTIAL

Calcium (cCa)

iPTH 

Albumin 

Anti-Drug Antibodies

Pre-hemodialysis PK sample

IP Administration, Dialysis and Pharmacokinetic Schedule
IP will be administered at the end of dialysis on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 
22, 24, 27 (12 doses).  Investigational product will be administered by bolus injection into 
the venous line of the dialysis circuit at the end of hemodialysis treatment, prior to or 
during rinse-back with each hemodialysis session (ie, 3 times per week). At least 
150 mL of rinse back volume should be administered after investigational product 
injection to ensure investigational product reaches the systemic circulation. If rinse-back 
is completed and investigational product was not administered, then investigational 
product may be administered intravenously followed by at least 10 mL saline flush 
volume. The end of hemodialysis treatment is defined as when the prescribed 
hemodialysis treatment time is completed (ie, remaining time on dialysis (RTD) is zero) 
or when the arterial flow is stopped (eg, arterial line is clamped or disconnected to 
discontinue treatment), whichever occurs first.  If a regularly scheduled hemodialysis 
session is missed and subsequently rescheduled, investigational product will not be
administered at the rescheduled hemodialysis session. For example, a subject on a 
Mon/Wed/Fri schedule who misses a Wed session will be dosed on Mon and Fri; if a 
make-up session is added on Thu and the subject maintains the regularly scheduled 
session on Fri, the subject will only be dosed on Mon and Fri and not on Thu.  If an 
additional hemodialysis treatment is needed intermittently (eg, fourth treatment during a 
week for ultrafiltration) then an additional dose of investigational product will not be 
administered during the extra dialysis session.  Additional details will be provided in 
IPIM. Investigational product must only be administered intravenously; it must not be 
administered via any other route.  Investigational product must not be administered 
concurrently with any other intravenous medications. If there is a significant permanent 
change to the hemodialysis prescription, then the sponsor will be notified and subject 
may be withdrawn from treatment with investigational product.
Blood samples for the determination of PK parameters will be collected on Day 1 and 27 
at predialysis, and at 10, 30, 60 and 90 min postdose and on Day 2 and 28 between 


Product:  AMG 416
Protocol Number:  20140197
Date:  25 May 2018
Page 41 of 73
CONFIDENTIAL
18 and 30 h after study drug administration, and at predialysis on Days 3, 8, 15, 22, 29, 
34, 41, and 55 and at 10 min postdose on Days 8, 15 and 22.  
The date and time of hemodialysis treatment will be recorded throughout the treatment 
period.  When a visit corresponds to a dialysis day, study procedures should be 
completed prior to hemodialysis.
Following completion of all study procedures on Day 1, subjects will be discharged with 
instructions to return to the research facility at specified time points for dosing, collection 
of blood samples for PK, PD and completion of safety assessments (including blood 
samples for antibody analysis) through the end of the study according to the schedule of 
assessments.

Other Predialysis Assessments after Day 1:

Body Weight (before dialysis) on Days 29 and 55 

Physical exam on Days 15, 29 and 55 

Vital signs (BP,HR,RR, TEMP) – all visits

12 lead Electrocardiograms (ECG) on Day 28 and Day 55 (EOS)

Adverse event monitoring (including serious adverse events 
and deaths) – all visits 

Concomitant medications – all visits

Pregnancy test on Day 34 

Hematology, PT, aPTT on Days 15, 29 and 55 

Clinical Chemistry on Days 15, 29 and 55 

Albumin on Days 3, 8,15, 22, 27, 29, 34, 41, 55

Phosphorus on Days 3, 8, 15, 22, 27, 34, 41, 55

Calcium (cCa) on Days 8, 15, 22, 27, 29, 34, 41, 55 

iPTH on Days 8, 15, 22, 27, 34, 41, and 55 

Anti-Drug Antibodies on Day 29 and 55 
Subjects will be followed for safety throughout the 4-week treatment period and for 
4 weeks after the last dose of investigational product to Day 55 (EOS).  Dosing with 
investigational product may be suspended, for low predialysis iPTH or cCa, symptomatic 
hypocalcemia, or other drug-related adverse events.
Subjects who test positive for antibodies to AMG 416 at the EOS visit will be asked to 
return for additional follow-up testing (see section 7.4)


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If 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.
Subject participation is complete once Day 55 end-of-study (EOS) procedures are 
performed.  
For a full list of study procedures, including the timing of each procedure, please refer to 
the Schedule of Assessments.
7.3
Description of Study Procedures
7.3.1
Informed Consent
Before any study-related screening or baseline procedure can be completed, a subject 
must sign and date the IRB-approved ICF.
7.3.2
Demographics
Demographic data, including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on pharmacokinetics of 
the protocol required therapy.
7.3.3
Subject Residency
There is no in-house residency period.  Subjects will be admitted to the research facility
on each scheduled day and they will remain until all assessments are completed.  
7.3.4
Medical History
A complete medical history will be obtained at screening by the investigator or qualified 
designee.  Medical history will include information on the subject’s current health, 
surgical history, and use of tobacco, alcohol, and prescription and non-prescription 
medication(s).  Relevant medical history findings will be recorded in the subject’s source 
and on the appropriate pages of the CRF.  
7.3.5
Physical Examination
Physical examinations will be performed by the investigator or designated physician at 
time points specified in the Schedule of Assessments. A complete physical examination
(excluding genital and rectal examination) will be performed at screening.  Abbreviated 
physical examinations will be performed on Day 1 (unless Day 1 occurred more than 
2 weeks after screening physical examination), Days 15, 29 and 55.  
The individual performing the physical examination will characterize their findings as 
either normal or abnormal.  Abnormal findings found during screening or Day 1 will be 


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reported on the medical history page of the CRF.  Abnormal findings found after the 
subject has received study medication will be reported on the Event CRF.
7.3.6
Height
Height measurement in centimeters and without shoes will be performed at screening.
7.3.7
Weight and Body Mass Index
Weight (in kg and without shoes) will be obtained at screening, 2 days prior to dosing 
(Day -2), Day 1, Day 29 and Day 55 (EOS).  On a hemodialysis day, weight will be 
recorded before dialysis.
Body mass index will be calculated for eligibility at screening using the screening height 
and weight measurements according to the following formula:
BMI (kg/m2) = weight (kg)/[height (cm)/100]2
7.3.8
Vital Signs
Vital signs, including heart rate, blood pressure, respiration rate and oral or ear 
temperature will be recorded by the investigator or qualified designee at screening,
Day -2, and time points specified in the Schedule of Assessments (Table 1).
Subjects must be seated position for at least 10 minutes prior to vital signs 
measurements.  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 drawn.
7.3.9
12-Lead Electrocardiograms
The subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.
The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR 
intervals.  
The investigator or qualified designee 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.
7.3.10
Clinical Chemistry, Hematology
Blood samples for clinical chemistry and hematology will be collected at screening, the 
day -2, and the time points specified in the Schedule of Assessments.


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The tests listed below in Table 2, will be conducted on samples collected and analyzed 
by standard laboratory procedures. 
Table 2.  Chemistry, Hematology 
Chemistry 
Hematology  
Other Labs 
Sodium 
Potassium 
Chloride 
Total protein 
Albumin 
Glucose (Random) 
Blood urea nitrogen 
Creatinine 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase (ALT)  
Aspartate aminotransferase 
(AST) 
Calcium 
Adjusted Calcium 
Creatinine phosphokinase 
Phosphorus 
Thyroid-stimulating hormone 
(TSH)a 
Red blood cells 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelets 
White blood cells 
Differential 
• 
Total neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Antidrug Antibodies 
Hep B surface antigen 
Hep C antibody 
HIV 
Pregnancy 
Intact PTH (iPTH) 
25-hydroxyvitamin D 
PK 
PT 
aPTT 
FSHb 
Luteinizing hormoneb 
Estradiolb 
Syphilisc 
Urea/BUNd 
a Only required at screening for subjects who have a history of hyper- or hypothyroidism and do not have 
available TSH results within 6 months prior to screening 
b Females only, and only collected if deemed necessary for confirmation of postmenopausal status as 
described in exclusion criteria section 4.2.4   
c Only collected at screening when investigator consider it is necessary  
d Urea/BUN measurement to be performed locally for Kt/V or URR assessment at screening, unless a 
qualifying Kt/V or URR measurement from within 4 weeks prior to screening assessments is available. 
All clinical chemistry and hematology tests must be reviewed, signed, and dated by the 
Investigator or qualified designee, and all abnormal values must have clinical 
significance assessed.  Additional safety laboratory assessments may be performed, if 
clinically indicated. 
7.3.11 
Follicle Stimulating Hormone Test (Females Only) 
To confirm postmenopausal status for eligibility, a blood sample for the determination of 
serum FSH will be collected at screening and analyzed by standard laboratory 
procedures.  To be eligible for this study, FSH results must be within or above the 
laboratory’s reference range for postmenopausal.  Serum FSH is required for subjects 
as described in exclusion criteria section 4.2.4 (age < 55 years and spontaneous 
menses within the past 1 years, but currently amenorrheic). 


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7.3.12
Human Immunodeficiency Virus Antibodies, Hepatitis B Surface 
Antigen, and Hepatitis C Antibodies
Human immunodeficiency virus 1 and 2 antibodies, HBsAg, and HepCAb titers will be 
assessed at screening.  Serology tests must be negative in order for a subject to be 
eligible for the study.
7.3.13
25-hydroxy Vitamin D
The 25-hydroxy vitamin D will be obtained at screening as a part of the clinical chemistry 
sample. Subjects with a 25-hydroxyvitamin D level < 20 ng/mL can be repeated at the 
Investigator’s discretion. Amgen will not provide or reimburse for vitamin D 
supplements.
7.3.14
Alcohol Screen
A breath screen for alcohol will be performed at screening and 2 days prior to dosing 
(Day -2), respectively.  Subjects with a positive screen for alcohol at screening will be 
allowed to retest at Day -2.  Subjects with a positive screen for alcohol at Day -2 will be 
excluded from participation in the study.
7.3.15
Intact Parathyroid Hormone 
Blood samples for the determination of intact parathyroid hormone (iPTH) will be 
collected at the following time points:  Screening , Day -2, and time points specified in 
the Schedule of Assessments (Table 1).
7.3.16
AMG 416 Plasma Concentrations
Blood samples for the determination of AMG 416 concentrations will be collected at the 
time points specified in the Schedule of Assessments (Table 1c).
7.3.17
Adverse Event Reporting
Adverse event and serious adverse event assessments will be made throughout the 
study and will be evaluated and recorded in the source documents and on the CRF for 
the duration of the study as specified in Section 9.1 and Section 9.2 of this protocol.  
Determination of the severity of all adverse events will be consistent with CTCAE 
Version 4.0 (Appendix A) unless specified otherwise.
7.3.18
Concomitant Medications
Subjects will be assessed for concomitant medication(s) usage at each visit.  Any
concomitant medication use reported throughout the study will be recorded in the source
documents and CRF.


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7.3.19
Blood Volume
Subjects enrolled in this study will agree to provide whole blood for safety, serology, PK, 
and other assessments during participation in this study.  The approximate volumes 
collected for each sample, and the approximate total blood volume are presented in 
Table 3.
Table 3.  Estimated Blood Volume Collection
Test
Average Volume 
(mL) per Collection
Number of 
Collections
Total Volume 
(mL)
Clinical chemistry (including FSH, 
when applicable)
6
5
30
Hematology
5
5
25
Serology (HIV, HBsAg, and 
HepCAb)
15
1
15
iPTH
5
10
50
AMG 416 plasma concentration
3
23
69
Antibody sampling
3
3
9
TOTAL
198
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.
7.4
Antibody Testing Procedures
Blood samples will be collected from all subjects for the measurement of anti-AMG 416
binding antibodies.  Samples testing positive for binding antibodies may also be tested 
for neutralizing antibodies and may be further characterized for quantity/titer, isotype, 
affinity, and presence of immune complexes.  Additional blood samples may be obtained 
to rule out anti-AMG 416 antibodies during the study.  
Subjects who test positive for neutralizing antibodies to AMG 416 at the final scheduled 
study visit will be asked to return for additional follow-up testing.  This testing should 
occur approximately every 12 weeks (± 4 weeks) starting from when the site has been 
notified of the positive result, until: (1) neutralizing antibodies are no longer detectable or 
(2) the subject has been followed for a period of at least one year (± 4 weeks) from the 
day of dosing.  More frequent testing (eg, every month), or testing for a longer period of 
time may be requested in the event of safety-related concerns.  Follow-up testing will not 
be required where it is established that the subject did not receive AMG 416.


Product:  AMG 416
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Subjects who test positive for binding antibodies and have clinical sequelae that are 
considered potentially related to an anti-AMG 416 antibody response may also be asked 
to return for additional follow-up testing.
7.5
Sample Storage and Destruction
Any blood, serum, plasma sample collected according to the Schedule of Assessments 
(Table 1) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of 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 
dose response and/or prediction of response to AMG 416 and characterize aspects of 
the molecule (eg, mechanism of action/target, metabolites).  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 exploratory studies are not placed in the subject’s 
medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed
consent.
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the Investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood, serum or plasma 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.


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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 
investigational product and/or other protocol required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 1) and 
collection of data, including endpoints and adverse events.  The Investigator must 
document the change to the Schedule of Assessments (Table 1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).  
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  


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8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.  
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.2.1
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, noncompliance, requirement for alternative therapy, pregnancy)

decision by sponsor (other than subject request, safety concern, lost to follow-up, 
missed doses and/or hemodialysis treatments)

death

lost to follow-up

protocol specific criteria

subject requires a significant permanent change in hemodialysis 
prescription to maintain adequate hemodialysis (see section 6.10)

subject receives a kidney transplant

subject undergoes a parathyroidectomy
8.2.2
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


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9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING
9.1
Adverse Events
9.1.1
Definition of 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 preexisting medical condition.  
Worsening indicates that the preexisting medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A preexisting condition that has not 
worsened 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.  
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.  
9.1.2
Definition of Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria:

fatal

life threatening (places the subject at immediate risk of death)

requires in patient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

congenital anomaly/birth defect

other medically important serious event
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
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 


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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
Reporting of Adverse Events
9.2.1
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 from the dose of investigational product 
(AMG 416) through the Day 55 EOS are reported using the applicable CRF
(eg, 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 AMG 416 or other therapies, 

action taken
The adverse event grading scale used will be the CTCAE version 4.  The grading scale 
used in this study is described in Appendix A.  The criteria for grade 4 in the CTCAE 
grading scale differs from the regulatory criteria for serious adverse events. It is left to 
the investigator’s judgment to report these grade 4 abnormalities as serious adverse 
events. 
The investigator must assess whether the adverse event is possibly related to the 
investigational product.  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?”  
The investigator must assess whether the adverse event is possibly related to any study 
mandated activity (eg, protocol-required procedure (including any screening 
procedure[s]).  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by a study 
activity, 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 


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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.
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 is expected to follow reported adverse events until stabilization or 
reversibility.
9.2.2
Reporting Procedures for Serious Adverse Events
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last dose of investigational product or Day 55 End of 
Study, whichever is later are recorded in the subject’s medical record and are submitted 
to Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the applicable CRF.
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours of the 
investigator’s knowledge of the event.  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. 
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 eSAE 
Contingency Report Form.  For EDC studies where the first notification of a serious 
adverse event is reported to Amgen via the eSAE 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.  This relationship is indicated by a “yes” or “no” response to 


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the question:  “Is there a reasonable possibility that the event may have been caused by 
the investigational product?”
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure?”
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Event
CRF).
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities. Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs in 
compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP). 
The investigator is to notify the appropriate IRB of serious adverse events occurring at 
the site and other adverse event reports received from Amgen, in accordance with local 
procedures and statutes.
9.3
Changes in Serum Calcium and Symptomatic Hypocalcemia
Investigators should assess subjects for the onset of signs and symptoms associated 
with low serum calcium (see Section 6.3.1.1) at each visit. When observed, 


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“hypocalcemia” should be reported as the adverse event, and the associated signs and 
symptoms will also be captured.
Any serum calcium (corrected) (cCa) ≥ 7.5 and < 8.3 mg/dL can be reported as low 
blood calcium; however,  low a calcium result does not need to be reported as an 
adverse event if no action is taken, and the value is not deemed clinically significant by 
the investigator. If the cCa is < 8.3 mg/dL and there are symptoms of hypocalcemia then 
the event is to be reported as hypocalcemia and considered a serious adverse event. 
The associated signs and symptoms should also be captured.
Also, any cCa level < 7.5 mg/dL is to be reported as a serious adverse event of low 
blood calcium if there are no associated signs and symptoms, but it is to be reported as 
hypocalcemia if there are associated symptoms. The associated signs and symptoms 
should also be captured.
9.4
Pregnancy and Lactation Reporting
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking AMG 416, report the pregnancy to Amgen as specified below.
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of AMG 416 through 3 months
after the last dose of study drug (for female subjects and female partners of male 
subjects). 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet Appendix C.  The Pregnancy 
Surveillance Program will seek to follow the pregnant woman throughout her pregnancy 
and her baby up to 12 months after birth.
If a lactation case occurs while the female subject is taking AMG 416, report the lactation 
case to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of AMG 416 through 3 months after the last 
dose of study drug.
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
within 24 hours of the investigator’s knowledge of event.  Report a lactation case on the 
Lactation Notification Worksheet (Appendix D).


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10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints, Analysis Sets, and Covariates
10.1.1
Study Endpoints
10.1.1.1
Primary Endpoints
The primary endpoint of this study is:

PK parameters of AMG 416 in plasma including maximum plasma concentration 
(Cmax) and area under the plasma concentration-time curve (AUClast) over the 
interdialytic interval following the first and last dose
10.1.1.2
Secondary Endpoints
The secondary endpoints of this study are:

Incidence of adverse events

Vital signs, laboratory safety tests including cCa, and ECGs

Incidence of anti-AMG 416 antibodies
10.1.1.3
Exploratory Endpoints
10.1.2
Analysis Sets
10.1.2.1
Safety Analysis Set
The Safety Analysis Set will consist of all subjects who received at least one dose of 
investigational product.
10.1.2.2
PK Concentration Analysis Set
The PK Concentration Analysis Set will contain all subjects who received at least 
one dose of AMG 416 and have at least one PK sample collected.
10.1.2.3
PK Parameter Analysis Set
The PK Parameter Analysis Set will contain all subjects who received at least one dose 
of AMG 416 and for whom at least one PK parameter can be adequately estimated.
10.1.2.4
Covariates and Subgroups
No covariate adjusted or subgroup analyses are planned.
10.2
Sample Size Considerations
Approximately 32 subjects will be randomized in a 3:1 ratio to receive 5 mg IV of 
AMG 416 or placebo three times a week (TIW) at the end of each regularly scheduled 
hemodialysis session for 4 weeks  (12 doses).  


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For PK parameter estimation, 2-sided 90% confidence intervals (CI) for geometric 
means (GM) of PK measurements can be expressed as (GM/θ, GM.θ) where θ is a 
measure of precision.  Based on AMG 416 study 20120330 (Cohort 3, 5 mg dose), 
between-subject CV% for AMG 416 AUClast (hr· µg/L) and Cmax (µg/L) (on original scale) 
are approximately 50.5% and 52.7%, respectively, following the Day 27 dose.  Assuming 
the same variability for 24 subjects receiving AMG 416 in this study, it is estimated that 
the precision (θ) of 2-sided 90% CI of geometric mean will be 1.18 and 1.19 for AUClast
and Cmax, respectively.  
For safety considerations, with 24 subjects receiving AMG 416, there will be a 21% 
chance of detecting an adverse event with a true incidence rate of 1% and 98% chance 
of detecting a more common adverse event with a true incidence rate of 15%.
10.3
Access to Individual Subject Treatment Assignments by Amgen or 
Designees
Treatment groups will be blinded to the investigator (other than unblinded pharmacist), 
subjects, and the Amgen study team (other than unblinded role, eg, unblinded CRA). 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded at the time of primary analysis snapshot except as specified in Section 5.2
and Section 9.2.2.
The staff associated with tracking, assaying, and analyzing the PK, PD, and
anti-AMG 416 antibody samples and data will not be blinded. Designated statistician(s)
may be unblinded for performing PK/PD analyses to inform future study designs with
AMG 416.
A subject’s treatment assignment should only be unblinded when knowledge of the
treatment is essential for the further management of the subject, or may impact the
safety of subjects currently enrolled, or subjects in subsequent cohorts. If deemed
necessary, unblinding will be performed according to Amgen standard practices.
10.4
Planned Analyses
10.4.1
Interim Analyses
No formal interim analysis is planned


Product:  AMG 416
Protocol Number:  20140197
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10.4.2
Primary Analysis
The primary analysis for this study will occur when all subjects have completed all 
planned study procedures up to and including the EOS visit, as outlined in the Schedule 
of Assessments, and any follow up of a clinically significant clinical or laboratory 
abnormality and following data base lock.
10.5
Planned Methods of Analysis
10.5.1
General Approach/Considerations 
Demographics and safety data will be summarized by treatment groups. Unless 
otherwise stated, the data analysis will be conducted using subjects in the Safety 
Analysis Set. Descriptive statistics on continuous measurements will include means, 
medians, standard deviations, and ranges, while categorical data will be summarized 
using frequency counts and percentages. 
10.5.2
Pharmacokinetic Endpoints
Plasma concentrations of AMG 416 will be determined using a validated 
assay. Individual and mean plasma concentration-time plots for AMG 416 will be 
presented.  The PK parameters (ie, Cmax, AUClast) will be estimated using 
noncompartmental methods. Nominal dose and actual sampling time data will be used 
for calculation of PK parameters. Summary statistics will be generated for each PK 
parameter.
The PK analysis set will be used in the analyses for the primary endpoint.  
10.5.3
Adverse Events
Subject incidence of all treatment-emergent adverse events, will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product and 
treatment-emergent hypocalcemia (depending on number of subject incidences) will be 
provided.  
10.5.4
Vital Signs
Vital signs will be listed and reviewed for each subject.  Depending on the size and 
scope of changes, summaries of vital sign data over time and/or changes from baseline 
over time by period may be provided.  
10.5.5
Electrocardiograms
The ECG measurements from this clinical study are to be performed per standard of
care for routine safety monitoring, rather than for purposes of assessment of potential 


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QTc effect.  Since these evaluations may not necessarily be performed under the 
rigorous conditions expected to lead to meaningful evaluation of QTc data, summaries 
and statistical analyses of ECG measurements are not planned.  These data would not 
be expected to be useful for meta-analysis with data from other trials.  Subject level 
listing will be provided for these measurements.
10.5.6
Clinical Laboratory Tests
Subject level data for all lab tests will be provided and reviewed for each subject.  Values 
outside the normal laboratory reference range will be flagged as high or low on the 
listings. Additionally serum albumin, iPTH, cCa and phosphorus measurements will be 
summarized by treatment group for all scheduled visits. Change and percent change 
from baseline may also be summarized for all post-baseline scheduled visits by 
treatment group, as applicable.
10.5.6.1
Anti-drug Antibodies
The incidence and percentage of subjects who develop anti-AMG 416 antibodies 
(binding) at any time will be tabulated.
10.5.7
Exploratory Endpoints
11.
REGULATORY OBLIGATIONS
11.1
Informed Consent
An initial sample ICF 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 Amgen Clinical Study Manager to the investigator.  The 
written ICF 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 


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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.
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 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  
11.2
Institutional Review Board/Independent Ethics Committee
A copy of the protocol, proposed ICF, 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 ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product.
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB of deviations from the protocol or serious adverse events 
occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures.
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).


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
Documents that are not submitted to Amgen (eg, signed ICFs) 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
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments and Study Termination
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB must be informed of all amendments and give approval.  The investigator must send 
a copy of the approval letter from the IRB to Amgen.
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product, and by what mechanism, after 
termination of the study and before it is available commercially.


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12.2
Study Documentation and Archive
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
Elements to include:

Subject files containing completed CRF, ICFs, and subject identification list

study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre study documentation, and all correspondence to and from the IRB and 
Amgen

investigational product-related correspondence including proof of receipts, 
investigational product accountability record(s), return of investigational product for 
destruction form(s), and final investigational product reconciliation statement, as 
applicable

non-investigational product and or medical device(s) documentation, 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 Amgen 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 


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research.  The clinical monitor is to have access to subject medical records and other 
study related records needed to verify the entries on the CRFs.
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory
requirements.
Data capture for this study is planned to be electronic:

All source documentation supporting entries into the 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 and/or site notifications 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 the site notifications and agrees with the 
content.
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study-specific Self-evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.


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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
CRFs must be completed in English.  TRADENAMES(if used) for concomitant
medications may be entered in the local 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, the investigator will solicit input and 
assistance from Amgen staff as appropriate.
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states:

Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3.

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.


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Protocol Number:  20140197
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12.7
Compensation
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.


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13.
REFERENCES
Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients
with end-stage renal disease. Kidney international. 2000;58(1):396-399.
AMG 416 Investigator’s Brochure, Edition 6.0. Thousand Oaks, CA. KAI
Pharmaceuticals, Inc., a wholly owned subsidiary of Amgen Inc.
Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and
hyperparathyroidism in dialysis patients: recommendations for a change in management.
Am J Kidney Dis. 2000;35(6):1226-1237.
Bro S, Olgaard K. Effects of excess PTH on nonclassical target organs. Am J Kidney
Dis. 1997;30(5):606-620.
Diaz-Corte C, Cannata-Andia JB. Management of secondary hyperparathyroidism: the
gap between diagnosis and treatment. The Renal Osteodystrophy Multicenter Enquiry.
The American journal of the medical sciences. 2000;320(2):107-111.
Duchin KL, Perides AM, Heald A, Singhvi SM, and Rommel AJ. Elimination kinetics of 
captopril in patients with renal failure. Kidney international 1984;25:942-947.
KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment
of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl.
2009;(113):S1-130.
K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney 
disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-201. 
Kong X, Zhang L, Zhang L, Chen N, Gu Y, Yu X, Liu W, Chen J, Peng L, Yuan W, Wu H, 
Chen W, Fan M, He L, Ding F, Chen X, Xiong Z, Zhang J, Jia Q, Shi W, Xing C, Tang X, 
Hou F, Shu G, Mei C, Wang L, Xu D, Ni Z, Zuo L, Wang M, Wang H. Mineral and bone 
disorder in Chinese dialysis patients: a multicenter study. BMC Nephrol. 2012 
Sep 21;13:116.
Locatelli F, Limardo M, Pontoriero G. New approaches to treatment of secondary
hyperparathyroidism. Curr Opin Investig Drugs. 2008;9(4):363-370.
Moe SM. Current issues in the management of secondary hyperparathyroidism and
bone disease. Perit Dial Int. 2001;21 Suppl 3:S241-S246.
Narazaki R, Harada K, Sugii A, Otagiri M. Kinetic analysis of the covalent binding of 
captopril to human serum albumin. J Pharm Sci. 1997 Feb;86(2):215-9.
Rais R, Hoover R, Wozniak K, Rudek MA, Tsukamoto T, Alt J, Rojas C, Slusher BS. 
Reversible disulfide formation of the glutamate carboxypeptidase II inhibitor E2072 
results in prolonged systemic exposures in vivo. Drug Metab Dispos. 2012 
Dec;40(12):2315-23.
Saliba W, El-Haddad B. Secondary hyperparathyroidism: pathophysiology and 
treatment. J Am Board Fam Med. 2009;22(5):574-581.
Salusky IB, Goodman WG. The management of renal osteodystrophy. Pediatric
nephrology (Berlin, Germany). 1996;10(5):651-653.
Slatopolsky E, Martin K, Hruska K. Parathyroid hormone metabolism and its potential as
a uremic toxin. The American journal of physiology. 1980;239(1):F1-12.
USRDS U.S. Renal Data System, USRDS 2009 Annual Data Report: Atlas of End-Stage 
Renal Disease in the United States, National Institutes of Health, National Institute of 
Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009.


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14.
APPENDICES


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Appendix A.  Additional Safety Assessment Information
Adverse Event Grading Scale
The Common Terminology Criteria for Adverse Events Version, version 4 (CTCAE V 4) 
is available at the following link:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf.
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 6.4.1 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.
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 6.4.1 and Appendix A or who experience AST or ALT elevations > 3 × ULN are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include: 

Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 

In cases of TBL > 2 × ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve

Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic.

Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL:

Obtain complete blood count with differential to assess for eosinophilia

Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 to assess for 
autoimmune hepatitis


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
Obtain serum acetaminophen (paracetamol) levels

Obtain a more detailed history of: 
o
Prior and/or concurrent diseases or illness
o
Exposure to environmental and/or industrial chemical agents 
o
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever
o
Prior and/or concurrent use of alcohol, recreational drugs and special diets
o
Concomitant use of medications (including nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms

Obtain viral serologies

Obtain CPK, haptoglobin, LDH, and peripheral blood smear

Perform appropriate liver imaging if clinically indicated

Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected 

Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist)

Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies.
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs.


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Appendix B. Sample Electronic Adverse Event Contingency Report Form 


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Appendix C. Sample Pregnancy Notification Worksheet


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Appendix D.  Sample Lactation Notification Worksheet


Product:  AMG416
Protocol Number:  20140197
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Amendment 3
Protocol Title:  A Phase 1, Multiple Dose, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate Pharmacokinetics, Safety and Tolerability of 
AMG 416 Administered Intravenously to Chinese Subjects with Chronic Kidney 
Disease on Hemodialysis 
AMG 416 
Amgen Protocol Number 20140197
Amendment 3 Date:
25 May 2018
Rationale:
The rationale for the major changes in the study is provided below:

Updated Study Contacts information

Administrative and formatting changes were made throughout the protocol

Updated the introduction of the drug product including Clinical Experience and Risk 
Assessment to reflect the most up to date information

Clarify that the assessment of Kt/V or URR can be performed at screening

Corrected the process of subject Identification Number assignment

Updated the time window of Day -2 12-lead ECG from 15 minutes after Hemodialysis 
rinse back to within 4 hours after Hemodialysis rinse back

Corrected AE collection time requirement in the table footnote

Moved Anti-drug antibodies test from Day -2 to Day 1 Pre HD

Added statement explaining that if screening albumin, phosphorus, cCa, pregnancy, 
iPTH tests occur within 7 days prior to start of IP, then Day -2 lab tests can be 
waived

Added acceptable windows for the timing of PK

Added clarification that evaluations obtained as part of routine medical care may be 
performed prior to informed consent and may be used in place of the study specific 
evaluations, provided they are performed within 22 days prior to Day 1 and meet the 
time windows described in the protocol schedule

Moved anti-drug antibody lab schedule from Day -2 to Day 1

Removed the informed consent process of primary care physician in order to meet 
China situation. No primary care physician in China.

Corrected the description of FSH test in section 7.3.11

Corrected the CRF language from local language to English


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Protocol Number:  20140197
Date:  25 May 2018
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Description of Changes：
Section:  Global
Change:  
correcting typographical and formatting errors
Section:  Header Date
Replace: 
Date：20 September 2017
With:
Date：25 May 2018
Section:  Title page
Delete:
EudraCT Number: 2012-002805-23
US IND number 109,773
Section:  Title page
Replace: 
Key Sponsor Contacts:
, MD, PhD
Clinical Pharmacologist
Phone:
E-mail: 
, MD, PhD
Medical Sciences Medical Director
Phone: 
E-mail: 
Study Manager
Phone:
E-mail:
With:
Key Sponsor Contacts:
, PhD
Principal Scientist, Clinical Pharmacology                                                               
Phone:
E-mail:
, MD
Medical Director, Medical Sciences
Phone:
E-mail:
Study Manager
Phone:
E-mail:


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Section:  Title page
Add: 
Amendment 3 Date  25 May 2018
Section:  Investigator’s Agreement
Replace: 
dated 08 Mar 2017
With:
dated 25 May 2018
Section:  Protocol Synopsis
Replace: 
Baseline and Treatment: Two days before dosing (Day -2) baseline procedures will be performed. 
Eligible subjects should be randomized to investigational product in a 3:1 ratio to AMG 416 or 
placebo, and should then receive the first dose. On the morning of Day 1, enrolled subjects will 
receive the first 5 mg IV dose of AMG 416 given after hemodialysis.  Following completion of all 
study procedures on Day 1, subjects will be released with instructions to return to the research 
facility at specified time points for dosing, collection of blood samples for PK, PD and completion 
of safety assessments (including blood samples for antibody analysis) through the end of the 
study according to the Schedule of Assessments.
IP will be administered at the end of dialysis on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 
27 (12 doses).  Dialysis will continue thrice weekly without study drug administration with study 
visits for data collection on Study Days 29, 34, 41, 55 (EOS). Blood samples for the 
determination of PK parameters will be collected on Day 1 and 27 at predialysis, and at 10, 30, 60 
and 90 min postdose, as well as on Day 2 and 28 between 18 and 30 h after study drug 
administration, and at predialysis on Days 3, 8, 15, 22, 27 (last dose), 29, 34, 41, and 55 (EOS)
and at 10 min postdose on Days 8, 15 and 22.  Subjects will have blood samples drawn for 
antibody determination on Day -2 and on days 29 and 55. Blood samples for exploratory
 
 Electrocardiograms (ECG) will be performed at screening, on Day -2, and on 
days 28 and 55.
With:
Baseline and Treatment: Subjects will return to the research facility for day -2 assessments.  
Eligible subjects should be randomized to investigational product in a 3:1 ratio to AMG 416 or 
placebo, and should then receive the first dose. On Day 1, enrolled subjects will receive the first 
5 mg IV dose of AMG 416 given after hemodialysis.  Following completion of all study procedures 
on Day 1, subjects will be released with instructions to return to the research facility at specified 
time points for dosing, collection of blood samples for PK, PD and completion of safety 
assessments (including blood samples for antibody analysis) through the end of the study 
according to the Schedule of Assessments.
IP will be administered at the end of dialysis on Study Days 1, 3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 
27 (12 doses).  Dialysis will continue thrice weekly without study drug administration with study 
visits for data collection on Study Days 29, 34, 41, 55 (EOS). Blood samples for the 
determination of PK parameters will be collected on Day 1 and 27 at predialysis, and at 10, 30, 60 
and 90 min postdose, as well as on Day 2 and 28 between 18 and 30 h after study drug 
administration, and at predialysis on Days 3, 8, 15, 22 , 29, 34, 41, and 55 (EOS) and at 10 min 
postdose on Days 8, 15 and 22.  Subjects will have blood samples drawn for antibody 
determination prior to dosing on Day 1 and on days 29 and 55. Blood samples for exploratory 


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 4 of 14
CONFIDENTIAL
 
  Electrocardiograms (ECG) will be performed at screening, on Day -2, and 
on days 28 and 55.
Section:  2.2.2 Clinical Experience
Replace: 
Five clinical studies have been completed to date.  The first 2 clinical trials (phase 1a 
and phase 1b) evaluated the safety, tolerability, PK and pharmacodynamics (PD) of 
single doses in healthy male subjects and in hemodialysis subjects with SHPT, 
respectively.  Most adverse events were mild or moderate in severity.  The incidence of 
nausea, vomiting, and diarrhea was similar in subjects given AMG 416 or placebo.  The 
administration of AMG 416 produced dose-dependent reductions in PTH in both healthy 
male subjects and in hemodialysis subjects with SHPT.  Antibodies to AMG 416 were 
not detected following single dose exposures.
The AMG 416 phase 2 clinical program included a 4-week, double-blind, randomized, 
placebo-controlled study (Study 20120330 also known as KAI-4169-003) and a 12-week, 
open-label, dose-titration study (Study 20120331 also known as KAI-4169-005); both 
were conducted in hemodialysis subjects with SHPT, and the results are summarized in 
the Investigator's Brochure.  Treatment with AMG 416 appeared to be generally safe and 
well-tolerated.  The incidences of nausea, vomiting, or diarrhea were low and similar in 
subjects receiving AMG 416 or placebo.  Serum iPTH levels decreased by 36.7% and 
76.9%, respectively, from baseline values at the end of treatment among subjects given 
5 or 10 mg doses of AMG 416.  The reductions were significantly different in both 
dosage cohorts compared with placebo (p < 0.01 for both).  Reductions in iPTH ≥ 30% 
from baseline occurred in 53.9% of subjects treated with 5 mg and in 76.2% of those 
treated with 10 mg of AMG 416, compared with 15.4% (p = 0.10) and 9.5% (p < 0.0001) 
of those given placebo.  Dose-dependent reductions in serum calcium also were 
observed.  There were no treatment-emergent (developing) antibody responses 
detected against AMG 416 following up to 4 weeks of dosing in hemodialysis subjects 
with SHPT.  Pre-existing antibodies against AMG 416 were detected in 1 subject not 
previously exposed to AMG 416.
In a 12-week, single-arm, open-label, dose titration phase 2 study among hemodialysis 
subjects with SHPT, 5 mg was given thrice weekly during hemodialysis with subsequent 
dose increases to 10 mg after 4 weeks of treatment, and up to 15 mg or 20 mg after 
8 weeks of treatment based upon serial measurements of iPTH and cCa the week 
before dose titration.  Doses were reduced for low iPTH or low cCa.  Thirty-seven 
subjects were enrolled in the study and 5 discontinued the study early.  Three 
treatment-emergent serious adverse events were reported, but none were considered to 
be related to study drug.  The final dose of AMG 416 ranged from 2.5 mg to 20 mg after 
12 weeks.  The mean reduction in iPTH at the end of the 12-week treatment period was 
53%; furthermore, 82% of the subjects achieved a reduction in iPTH ≥ 30% at 12 weeks.  
The decreases in serum cCa were well tolerated, but 35% of subjects had 1 or more 
values of serum cCa < 8.0 mg/dL, and 2 subjects (5%) had 1 or more values of 
cCa< 7.5 mg/dL during treatment.
Four subjects (9%) reported symptomatic hypocalcemia as an adverse event.  The 
incidences of treatment-emergent diarrhea (14%) and nausea (5%) were relatively low. 
The AMG 416 phase 3 program is designed to demonstrate the safety and efficacy of 
AMG 416 for the treatment of SHPT in CKD patients on hemodialysis.  It is comprised of 
two 26-week, randomized, double-blind, placebo-controlled pivotal studies 
(Study 20120229 and Study 20120230) in CKD patients on hemodialysis with SHPT 


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 5 of 14
CONFIDENTIAL
(iPTH > 400 pg/mL) and one 26-week randomized, active-controlled, double-blind, 
double-dummy, dose-titration study (Study 20120360) in CKD patients on hemodialysis 
with SHPT (iPTH > 500 pg/mL).  Safety will be evaluated in Studies 20120229, 
20120230, and 20120360, and long-term safety of AMG 416 will be evaluated in 
2 single-arm, open-label extension studies (Study 20120231 and Study 20120213).  The 
objectives of these studies are to evaluate the efficacy of AMG 416 compared with 
placebo in the treatment of SHPT in CKD subjects receiving hemodialysis as assessed 
by the change from baseline in serum iPTH, cCa, cCa x P and phosphorus.  
Investigational product will be administered thrice weekly at the end of hemodialysis and 
the dose will be titrated to achieve iPTH levels ≤ 300 pg/mL while maintaining serum 
calcium levels within an acceptable range.  Please refer to the Investigator’s Brochure
for additional information.
With:
Etelcalcetide has been studied in three 26-week phase 3 studies, 
2 placebo-controlled trials (20120229 and 20120230), and 1 active-controlled trial 
(20120360).  In Study 20120229, 74% of etelcalcetide subjects achieved > 30% 
reduction from baseline in mean PTH during the efficacy assessment phase (EAP) 
versus 8.3% of placebo subjects (p < 0.001).  In Study 20120230, 75.3% of 
etelcalcetide subjects achieved this endpoint versus 9.6% of placebo subjects 
(p < 0.001).  Similarly, the proportion of etelcalcetide subjects who achieved mean 
predialysis PTH ≤ 300 pg/mL during the EAP was significantly higher in the 
etelcalcetide group than in the placebo group (p < 0.001) in both Studies 20120229 
and 20120230.  In Study 20120229, 49.6% of subjects in the etelcalcetide group 
and 5.1% of subjects in the placebo group achieved this endpoint, and 53.3% of 
subjects in the etelcalcetide group and 4.6% of subjects in the placebo group 
achieved this endpoint in Study 20120230.  The events that occurred with a 
greater frequency among subjects in the etelcalcetide group compared with 
subjects in the placebo group (≥ 5% in the etelcalcetide group with ≥ 1% difference 
from placebo) were blood calcium decreased (63.8% etelcalcetide; 10.1% placebo), 
muscle spasms (11.5% etelcalcetide; 6.6% placebo), diarrhea (10.7% etelcalcetide; 
8.6% placebo), nausea (10.7% etelcalcetide; 6.2% placebo), vomiting (8.9% 
etelcalcetide; 5.1% placebo), headache (7.6% etelcalcetide; 6.0% placebo), and 
hypocalcemia (7.0% etelcalcetide; 0.2% placebo).  An additional phase 3 
study (20120360) was performed to compare the therapeutic efficacy of 
etelcalcetide and cinacalcet for lowering serum PTH concentrations among 
subjects with CKD and SHPT receiving maintenance hemodialysis.  A higher 
observed percentage of subjects in the etelcalcetide group (77.9%) had a > 30% 
reduction from baseline in serum PTH during the EAP compared with the 
cinacalcet group (63.9%).  The estimated treatment difference 
(cinacalcet - etelcalcetide) was -10.48% (95% confidence interval [CI]: -17.45%,
-3.51%).  Because the upper bound of the 95% CI is < 12% (the prespecified 
margin for noninferiority), etelcalcetide is noninferior to cinacalcet in the 
proportion of subjects with a > 30% reduction from baseline in serum PTH during 
the EAP.  Additionally, etelcalcetide was superior to cinacalcet on the proportion 
of subjects achieving a > 50% and a > 30% reduction from baseline in mean 
predialysis serum PTH during the EAP.  There was no significant difference in the 
mean number of days of vomiting or nausea per week in the first 8 weeks of 
treatment, as measured by a patient-reported outcome instrument.  The most 
common (> 10% in either treatment group) adverse events (etelcalcetide, 
cinacalcet) were asymptomatic decreased blood calcium (68.9%, 59.8%), nausea 
(18.3%, 22.6%), vomiting (13.3%, 13.8%), and diarrhea (6.2%, 10.3%).  Symptomatic 


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 6 of 14
CONFIDENTIAL
hypocalcemia was reported for 17 subjects (5.0%) in the etelcalcetide group and 
8 subjects (2.3%) in the cinacalcet group. Please refer to the Investigator’s 
Brochure for additional information.
Section: 2.2.2.1 Clinical Pharmacokinetics
Replace: 
Preliminary population PK analysis was conducted using the PK data from patients 
receiving hemodialysis.  The dataset consisted of 1775 plasma samples from 
143 subjects, with 96 subjects receiving IV doses ranging from 2.5 mg to 60 mg of 
AMG 416.
With:
Population PK analysis was conducted using the PK data from patients receiving 
hemodialysis.  The dataset consisted of 1775 plasma samples from 143 subjects, 
with 96 subjects receiving IV doses ranging from 2.5 mg to 60 mg of AMG 416.
Section: 2.2.2.1 Clinical Pharmacokinetics
Delete: 
The estimated non-specific linear clearance (CL) and the hemodialysis CL were 
0.564 L/h and 22.2 L/h, respectively. The distribution volumes of the central and 
the two peripheral compartments were 37.6, 105, and 482 L, respectively.  Inter-
individual variability in AMG 416 distribution and elimination were relatively 
moderate to high, with coefficient of variation in key PK parameters ranging from 
approximately 50% to 100%
Section: 2.3 Risk Assessment
Replace: 
Safety reporting for all subjects in open-label and blinded studies completed as of 
May 1st 2014 and the investigators brochure have identified the following risks: The 
important identified risk is hypocalcemia, which will be mitigated in the protocol by close 
monitoring, and treatment as required. Other important potential risks include 
1) injection and hypersensitivity reactions, 2) ventricular arrhythmias, 
3) hypophosphatemia, 4) convulsions, 5) adynamic bone, 6) worsening heart failure, and 
7) coadministration of cinalcalcet. Coadministration of cinacalcet and AMG 416 is 
contraindicated until further studies inform the safety of simultaneous administration of 
these agents. The likelihood of these risks occurring with the planned dose as planned 
for this study is expected to be low. In this study, cinacalcet will be prohibited from 
30 days prior to informed consent and throughout the study.
Please refer to the Investigator’s Brochure, Section 7 for a complete description of 
potential risks related to AMG 416.
With:
Safety reporting for all subjects in open-label and blinded studies completed as of 
10 November 2017and the investigators brochure have identified the following 
risks: 


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 7 of 14
CONFIDENTIAL
Important identified risks:

Hypocalcemia

Worsening heart failure

QT prolongation secondary to hypocalcemia
Important potential risks:

Ventricular arrhythmias

Infusion and hypersensitivity reactions

Convulsions (seizures)

Adynamic bone

Co-administration of cinacalcet (HCl) and etelcalcetide
The important identified risk is hypocalcemia, which will be mitigated in the 
protocol by close monitoring, and treatment as required.  Coadministration of 
cinacalcet and AMG 416 is contraindicated until further studies inform the safety 
of simultaneous administration of these agents. The likelihood of these risks 
occurring with the planned dose for this study is expected to be low.  In this 
study, cinacalcet will be prohibited from 30 days prior to informed consent and 
throughout the study.
Please refer to the Investigator’s Brochure, Section 7 for additional information for 
the investigator.
Section: 3.1 Study Design
Replace: 
Subjects will participate in the study as outpatients on scheduled study Day -2 through 
Day 55 (EOS) while receiving hemodialysis three times a week.
With:
Subjects will participate in the study as outpatients on scheduled study Day 1 through 
Day 55 (EOS) while receiving hemodialysis three times a week.
Section: 3.1 Study Design
Delete:
The overall study design is described by a study schema at the end of the 8 March 2017
protocol synopsis section.
Section: 4.1.5 Inclusion Criteria
Add:
Subject must be receiving hemodialysis 3 times weekly for at least 3 months through a 
functioning permanent dialysis access prior to Day -2 and have adequate hemodialysis 
with a delivered Kt/V ≥ 1.2 or urea reduction ratio (URR) ≥ 65% within 4 weeks to 
screening or at screening. The subject’s routine hemodialysis session must be of 3-4. 
5 hours in duration, inclusive


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 8 of 14
CONFIDENTIAL
Section: 4.2.1 Exclusion Criteria
Add: 
Corrected calcium (calculated) level is < 2.07 mmol/L (8.3 mg/dL), and/or intact PTH 
level is outside the range of 31.8 – 127.2 pmol/L (300 - 1200 pg/mL) at screening and 
Day -2 (Day -2 assessments are only required if screening visit performed greater 
than 7 days prior to Day 1)
Section 5 Subject Enrollment
Replace:
All subjects who enter into the screening period for the study (defined as the point at 
which the subject signs the ICF) will receive a unique subject identification number 
assigned by IVR/WR before any study-related activities/procedures are performed.
With:
All subjects who enter into the screening period for the study (defined as the point at 
which the subject signs the ICF) will receive a unique subject identification number 
assigned manually before any study-related activities/procedures are performed.
Section: 5.1 Randomization/Treatment Assignment
Replace:
Subjects will be randomized by IVR/IWR in a 3:1 ratio to either TIW IV etelcalcetide or 
placebo in a double-blind manner prior to the first dose of IP. Treatment groups will be 
blinded to the investigator (other than unblinded pharmacist), subjects, and the Amgen 
study team.
With:
Subjects will be randomized by IVR/IWR in a 3:1 ratio to either TIW IV etelcalcetide or 
placebo in a double-blind manner prior to the Day 1 activities.
Section: 7.1 Schedule of Assessments                                                                       
Table 1a Schedule of Non-Laboratory Assessments-Footnotes
Replace:
e Subjects will remain seated for at least 10 minutes prior to measurement of predialysis pulse rate and blood 
pressure.  Vital signs will include blood pressure, heart rate, respiratory rate, and oral or ear temperature.  Vital signs 
will be obtained pre-dialysis treatments on scheduled dialysis days, and at ET and on Day 55 (EOS).     
f Subjects will remain supine for at least 5 minutes prior to recording 12-lead electrocardiogram (ECG).  
Screening 12-lead ECG will be recorded prior to hemodialysis.  The Day -2 12-lead ECG will be recorded 15 minutes 
after hemodialysis rinse back.  After the last dose of investigational product on Day 27, 12-lead ECGs will be 
recorded between 18 and 30 hours (recorded on day 28) post-dose.  
g Adverse events including serious adverse events will be monitored and recorded from the time of informed consent 
through Day 55.
With:
e Subjects will remain seated for at least 10 minutes prior to measurement of predialysis heart rate and blood 
pressure.  Vital signs will include blood pressure, heart rate, respiratory rate, and oral or ear temperature.  Vital signs 
will be obtained pre-dialysis treatments on scheduled dialysis days, and at ET and on Day 55 (EOS).     
f Subjects will remain supine for at least 5 minutes prior to recording 12-lead electrocardiogram (ECG).  
Screening 12-lead ECG will be recorded prior to hemodialysis.  The Day -2 12-lead ECG will be recorded within 
4 hours after hemodialysis rinse back.  After the last dose of investigational product on Day 27, 12-lead ECGs will be 
recorded between 18 and 30 hours (recorded on day 28) post-dose.  
g Adverse events will be monitored and recorded from the dose of investigational product (AMG 416) or 
placebo. Serious adverse events will be monitored and recorded from the time of informed consent through Day 55.


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 9 of 14
CONFIDENTIAL
Section 7.1 Schedule of Assessments Table 1b Schedule of Laboratory Assessments
Add:
Table 1b. Schedule of Laboratory Assessments
Footnotes displayed on the next page
TTime
Assessment
Study Visit (Day)
Screening
-2
1
(HD)
2
3
(HD)
6
(HD)
8
(HD)
10
(HD)
13
(HD)
15
(HD)
17
(HD)
20
(HD)
22
(HD)
24
(HD)
27
(HD)
28
29/
ETa
(HD)
34
(HD)
41
(HD)
55
(HD)
Laboratory  Assessments
Pre HDHematology, PT, 
aPTTc
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
Albumind
X
X b
X
X
X
X
X
X
X
X
X
X
Phosphorus
X
X b
X
X
X
X
X
X
X
X
Calcium (cCa)d
X
X b
X
X
X
X
X
X
X
X
X
Serum  or Urine 
Pregnancy (females 
only)
X
X b
X
Serum FSHg (female 
only)
X
Breath Alcohol 
Screen
X
X
HIV, Hep C Ab, 
HBsAg
X
iPTH
X
X b
X
X
X
X
X
X
X
X
25(OH) vitamin D
X
Kt/V or URR e
X
Anti-drug antibodiesf
X
X
X


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 10 of 14
CONFIDENTIAL
HD = hemodialysis; ET = early termination; cCa = albumin-corrected calcium; SDA = Study drug administration；Kt/V = measure of dialysis adequacy; URR = urea 
reduction ratio  
a If a treated subject withdraws from study before completion of dosing, the investigator will make every effort to obtain day 29 samples as close to 2 days after the last 
dose of investigational product as possible.
b If screening albumin, phosphorus, cCa, pregnancy, and iPTH tests occur within 7 days prior to start of IP, then Day -2 lab tests can be waived. Pregnancy 
tests will be performed in women of child bearing potential within 7 days prior to start of investigational product.
c Blood sample for PT and aPTT will be drawn prior to heparin administration for dialysis.  Day 1 hematology and coagulation tests will be performed only if day 1 
occurs more than 2 weeks after the screening hematology and coagulation tests.
d Serum samples for albumin and calcium for screening and routine monitoring of predialysis cCa.  When albumin is less than 4.0 g/dL, the calcium level will be 
corrected according to the formula: cCa (mg/dL) = total Ca (mg/dL) + (4 – albumin (g/dL))*0.8.  Corrected calcium results will inform dosing/dose withholding at the 
next hemodialysis treatment.
e Perform Kt/V or URR assessment at screening unless a qualifying Kt/V or URR measurement from within 4 weeks prior to screening assessments is 
available. Baseline iPTH is the average of predialysis iPTH levels on day -2 (may be collected up to -4 if needed) and day 1.
f Serum samples for anti-drug antibodies will be collected predialysis on days 1, 29, and 55.  Any subjects with positive titers for antibodies to AMG 416 may be asked 
to return to the clinical research unit to provide additional serum samples.
g Luteinizing hormone and estradiol levels may additionally be collected if deemed necessary for confirmation of postmenopausal status as described in exclusion 
criteria section 4.2.4.


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 11 of 14
CONFIDENTIAL
Section: 7.2 General Study Procedures
Add:
Study tests and procedures will be performed only after written informed consent is 
obtained. All screening procedures must be completed within 22 days before 
investigational product administration (Day 1).  Eligible subjects will be admitted to the 
clinical research facility on Day -2 at which time continued eligibility will be reconfirmed 
and baseline safety assessments will be performed.  Subjects will be administered 
AMG 416 or placebo on Day 1 after completion of baseline assessments.
Section: 7.2 General Study Procedures
Add:
Every effort should be made to conduct study procedures as scheduled. 
Acceptable windows for the timing of PK are as follows:  

Plus or minus 2 mins for the 10 min sample

Plus or minus 5 mins for the 30 min sample

Plus or minus 10 mins for the 60 min sample

Plus or minus 15 mins for the 90 min sample

Plus or minus 4 hours for the 18-30 hour post dose samples
Section: 7.2.1 Screening 
Add:

Laboratory assessments (all pre-hemodialysis samples)

Clinical hematology

Clinical chemistry

PT, aPTT

Albumin, Phosphorus, Calcium (cCa)

Serum or urine pregnancy test (women of child-bearing potential only; within 
7 days prior to first study drug administration)

Serum FSH (females only)

Breath alcohol screen

HIV, Hepatitis C Antibody, Hepatitis B surface antigen  

iPTH 

25(OH) vitamin D

Kt/V or URR
Subjects who meet the eligibility criteria after completion of all screening, Day -2 
procedures will be considered enrolled in the study. 
If screening albumin, phosphorus, cCa, pregnancy, and iPTH tests occur within 
7 days prior to start of IP, then Day -2 lab tests can be waived.


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 12 of 14
CONFIDENTIAL
Day -2 assessments will be performed 2 days before investigational product 
administration.  Day -2 assessments will include recording the date and time of the last 
hemodialysis treatment before investigational product administration. 
Evaluations obtained as part of routine medical care may be performed prior to 
informed consent and may be used in place of the study specific evaluations, 
provided they are performed within 22 days prior to Day 1 and meet the time 
windows described above. 
Section: 7.2.2 Day -2
Add:
Two days before dosing (day -2) the following baseline procedures will be performed 
and confirmed to meet eligibility requirement:
Section: 7.2.2 Day -2
Delete:
iPTH (may be collected up to day -4 if needed)Anti-Drug Antibodies
Section: 7.2.3 Treatment (Day 1-27) and Follow up Periods (Day 28-55)
Delete:
On the morning of day 1 the following predose activities will be conducted:
Section: 7.2.3 Treatment (Day 1-27) and Follow up Periods (Day 28-55)
Add:

Laboratory assessments and predose collections (pre-hemodialysis samples):

Hematology, PT, aPTT

Clinical chemistry

Calcium (cCa)

iPTH 

Albumin 

Anti-Drug Antibodies

Pre-hemodialysis PK sample


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 13 of 14
CONFIDENTIAL
Section: 7.3.10 Table 2 Chemistry, Hematology
Add:
Chemistry
Hematology 
Other Labs
Sodium
Potassium
Chloride
Total protein
Albumin
Glucose (Random)
Blood urea nitrogen
Creatinine
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT) 
Aspartate aminotransferase 
(AST)
Calcium
Adjusted Calcium
Creatinine phosphokinase
Phosphorus
Thyroid-stimulating hormone
(TSH)a
Red blood cells
Hemoglobin
Hematocrit
Mean corpuscular volume
Platelets
White blood cells
Differential

Total neutrophils

Eosinophils

Basophils

Lymphocytes

Monocytes
Antidrug Antibodies
Hep B surface antigen
Hep C antibody
HIV
Pregnancy
Intact PTH (iPTH)
25-hydroxyvitamin D
PK
PT
aPTT
FSHb
Luteinizing hormoneb
Estradiolb
Syphilisc
Urea/BUNd
a Only required at screening for subjects who have a history of hyper- or hypothyroidism and do not have 
available TSH results within 6 months prior to screening
b Females only, and only collected if deemed necessary for confirmation of postmenopausal status as 
described in exclusion criteria section 4.2.4
c Only collected at screening when investigator consider it is necessary 
d Urea/BUN measurement to be performed locally for Kt/V or URR assessment at screening, unless a 
qualifying Kt/V or URR measurement from within 4 weeks prior to screening assessments is 
available.
Section: 7.3.11 Follicle Stimulating Hormone Test (Females Only)
Replace:
Serum FSH is not required for subjects who have had a hysterectomy, and/ or who are 
at least 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) as 
documented in medical history and verified with an operative note, if available.
With:
Serum FSH is required for subjects as described in exclusion criteria section 4.2.4 
(age < 55 years and spontaneous menses within the past 1 years, but currently 
amenorrheic).
Section 10.3 Access to Individual Subject Treatment Assignments by Amgen or 
Designees
Add: 
Treatment groups will be blinded to the investigator (other than unblinded 
pharmacist), subjects, and the Amgen study team (other than unblinded role, eg,
unblinded CRA)


Product:  AMG416
Protocol Number:  20140197
Date:  25 May 2018
Page 14 of 14
CONFIDENTIAL
Section 11.1 Informed Consent
Delete:
The investigator is also responsible for asking the subject if he/she 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 ICF 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 ICF is to be retained in 
accordance with institutional policy, and a copy of the signed ICF is to be 
provided to the subject or legally acceptable representative.
Section 12.5 Language
Replace:
CRFs must be completed in the local language.
With:
CRFs must be completed in English.


Product:  AMG 416 
Protocol Number:  20140197 
Date:  20 September 2017 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1, Multiple Dose, Randomized, Double-blind, Placebo-
controlled Study to Evaluate Pharmacokinetics, Safety and Tolerability of 
AMG 416 Administered Intravenously to Chinese Subjects with Chronic Kidney 
Disease on Hemodialysis 
 
Amgen Protocol Number AMG 416, 20140197 
 
Amendment Date: 
20 Sep 2017 
Rationale: 
The protocol is being amended to: 
1. Correct the typo of the range of intact PTH level. 
2. Move 25(OH) vitamin D testing from Day1 to screening because a vitamin D level 
taken within the screening window before Day 1 should be representative of Day 1 
as vitamin D level is not likely to change much in such a short time. 
3. Add Albumin testing on Day 1 and Day 29 because corrected Calcium is needed so 
albumin will be necessary. 
4. Add oral temperature as an additional alternative besides ear temperature. Ear 
temperature has been the general practice for most of the China sites. This will be 
more flexible for the investigators. 
5. Add syphilis, B ultrasound testing as the optional tests when the investigator 
consider it necessary. Syphilis testing is recommended to be done in screening for 
clinical trials and the subjects with chronic kidney disease on hemodialysis will 
perform syphilis testing twice a year so it’s optional. B ultrasound is recommended to 
be optional in the screening to exclude ovarian cancer. 
6. Remove ‘Bicarbonate’ from Chemistry. Some sites do not conduct this testing and it 
is not critical testing for this study. 
7. Add ‘urine pregnancy testing’ as an additional alternative besides serum pregnancy 
testing. Some sites prefer to use urine pregnancy testing instead of serum pregnancy 
testing. This will be more flexible for the investigators. 
8. Modify the language of the timing of randomization to ‘prior to dosing’ in order to 
accurately clarify when the randomization happens. 
9. Delete the ‘Monday’ to ‘Sunday’ in the schedule of assessments to make it more 
flexible for the investigators. 
10. Modify the collection date of baseline iPTH up to Day -4 if needed in order to get 
result prior to dosing. 


Product:  AMG 416  
Protocol Number:  20140197 
Date:  08 March 2017 
Page 1 of 18 
Amendment 1 
Protocol Title:  A Phase 1, Multiple Dose, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate Pharmacokinetics, Safety and Tolerability of 
AMG 416 Administered Intravenously to Chinese Subjects With Chronic Kidney 
Disease on Hemodialysis 
 
Amgen Protocol Number AMG 416, 20140197 
 
Amendment Date: 
08 March 2017 
 
Rationale: 
The protocol is being amended to: 
1. Add IVR/IWR for this study 
2. Align with the latest version of DES 
3. Simplify some study procedures, for example, weight, vital sign and ECG 
4. Make administrative, typographical and formatting changes throughout the protocol. 
Updates have been implemented to align with the current template. 
5. Delete all the relevant verbiage related to M11 throughout the protocol because the 
team considers M11 assay as too variable 
6. Delete the verbiage “ Day -2 assessments will be performed 2 days before IP 
administration and Day-2 and Day -1 are not HD days.” in order to provide the 
flexibility on the scheduling of HD prior to Day 1. 
7. Some deleted text has been involved in other section (for example, a paragraph in 
Section 7.2 has been already involved in Section 7.5) 
 
CONFIDENTIAL 
 
 

SAP_000.pdf: 
Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 1 of 20 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1, Multiple Dose, Randomized, 
Double-blind, Placebo-controlled Study to Evaluate 
Pharmacokinetics, Safety and Tolerability of 
AMG 416 Administered Intravenously to Chinese 
Subjects with Chronic Kidney Disease on 
Hemodialysis 
Short Protocol Title: 
NA 
Protocol Number: 
20140197 
Authors: 
Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Tel: 805-447-1000 
SAP Date: 
Document Version 
Date 
Version 2.0 
26 November 2018 
NCT Number: NCT03283098
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 2 of 20 
CONFIDENTIAL 
Table of Contents 
1.
Introduction .............................................................................................................. 5 
2.
Objectives, Endpoints and Hypotheses .................................................................... 5 
2.1 
Objectives and Endpoints ............................................................................. 5 
2.2 
Hypotheses and/or Estimations .................................................................... 5 
3.
Study Overview ........................................................................................................ 6 
3.1 
Study Design ................................................................................................ 6 
3.2 
Sample Size ................................................................................................. 6 
3.3 
Adaptive Design ........................................................................................... 6 
4.
Covariates and Subgroups ....................................................................................... 6 
4.1 
Planned Covariates ...................................................................................... 6 
4.2 
Subgroups .................................................................................................... 6 
5.
Definitions ................................................................................................................ 7 
5.1 
Study Time Points ........................................................................................ 7 
5.2 
PK/PD Parameters ....................................................................................... 8 
5.3 
Demographics and Baseline Related Definitions ......................................... 8 
5.4 
Other Study Related Definitions ................................................................. 10 
6.
Analysis Sets .......................................................................................................... 10 
6.1 
Safety Analysis Set ..................................................................................... 10 
6.2 
PK Concentration Analysis Set ................................................................... 11 
6.3 
PK Parameter Analysis Set ........................................................................ 11 
6.4 
Intent-to-treat Analysis Set ......................................................................... 11 
7.
Planned Analyses .................................................................................................. 11 
7.1 
Interim Analysis and Early Stopping Guidelines ......................................... 11 
7.2 
Primary Analysis ......................................................................................... 11 
7.3 
Final Analysis ............................................................................................. 11 
8.
Data Screening and Acceptance ............................................................................ 11 
8.1 
General Principles ...................................................................................... 11 
8.2 
Data Handling and Electronic Transfer of Data .......................................... 11 
8.3 
Handling of Missing and Incomplete Data .................................................. 12 
8.4 
Detection of Bias ........................................................................................ 13 
8.5 
Outliers ....................................................................................................... 13 
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 ................................................................................ 14 
9.3 
Important Protocol Deviations .................................................................... 14 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 3 of 20 
CONFIDENTIAL 
9.4 
Demographic and Baseline Characteristics ................................................ 14 
9.5 
Pharmacokinetic Endpoints ........................................................................ 14 
9.6 
Safety Analyses .......................................................................................... 15 
9.6.1 
Adverse Events .......................................................................... 15 
9.6.2 
Clinical Laboratory Test Results ................................................. 15 
9.6.3 
Vital Signs ................................................................................... 15 
9.6.4 
Physical Measurements ............................................................. 15 
9.6.5 
Electrocardiogram ...................................................................... 15 
9.6.6 
Anti-drug Antibodies ................................................................... 16 
9.6.7 
Exposure to Investigational Product ........................................... 16 
9.6.8 
Exposure to Other Protocol-specified Treatment ....................... 16 
9.6.9 
Exposure to Concomitant Medication ......................................... 16 
9.7 
Exploratory Endpoints ................................................................................ 16 
10.
Changes From Protocol-specified Analyses .......................................................... 16 
11.
Literature Citations / References ............................................................................ 17 
12.
Prioritization of Analyses ........................................................................................ 18 
13.
Data Not Covered by This Plan .............................................................................. 18 
14.
Appendices ............................................................................................................ 19 
Appendix A.  Reference Values/Toxicity Grades ................................................... 20 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 4 of 20 
CONFIDENTIAL 
 
 
List of Abbreviations 
Abbreviation 
Definition/Explanation 
AUC 
area under the concentration-time curve 
AUClast 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable sample 
BMI 
Body Mass Index 
Ca 
Calcium 
cCa 
Total serum albumin corrected calcium concentration 
cCa x P 
Corrected calcium-phosphorus product 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CRF 
Case report form (electronic or paper) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
EOS 
End of Study 
GM 
Geometric mean 
IP 
investigational product 
iPTH 
Intact parathyroid hormone 
IV 
Intravenous 
IVR/IWR 
Interactive Voice/Web Response System 
MedDRA 
Medical dictionary for regulatory activities 
P 
Phosphorous 
PK 
Pharmacokinetic(s) 
PTH 
Parathyroid hormone 
SAE 
severe adverse event 
SHPT 
Secondary hyperparathyroidism 
TEAE 
Treatment Emergent Adverse Events 
T1/2  
Terminal elimination phase half life 
TIW 
Thrice weekly 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 5 of 20 
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 20140197,  Etelcalcetide 
(AMG 416) dated 25 May 2018. The scope of this plan includes the primary analysis that 
is planned and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 

To characterize the pharmacokinetics
of AMG 416 (etelcalcetide) following
thrice weekly intravenous (IV)
administration of 5 mg in Chinese
subjects with chronic kidney disease
receiving hemodialysis

Pharmacokinetic (PK) parameters of
etelcalcetide in plasma including
maximum plasma concentration (Cmax)
and area under the plasma
concentration-time curve (AUClast)
over the interdialytic interval following
the first and last dose
Secondary 

To characterize the safety and
tolerability of etelcalcetide following
thrice weekly intravenous (IV)
administration of 5 mg in Chinese
subjects with chronic kidney disease
receiving hemodialysis

Incidence of adverse events

Vital signs, laboratory safety tests
including cCa, and ECGs

Incidence of anti-etelcalcetide
antibodies
Exploratory 
2.2 
Hypotheses and/or Estimations 
This study will adequately characterize the pharmacokinetics profile of etelcalcetide in 
Chinese subjects with chronic kidney disease receiving hemodialysis. 
Etelcalcetide will be safe and well tolerated after multiple dose administration in Chinese 
subjects with chronic kidney disease on hemodialysis. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 6 of 20 
CONFIDENTIAL 
 
 
3. 
Study Overview 
3.1 
Study Design 
This is a multiple dose, double-blind, randomized, placebo-controlled clinical study. 
Chinese subjects residing in Mainland China with chronic kidney disease receiving 
hemodialysis will be randomized in a 3:1 ratio to receive 5 mg IV of etelcalcetide or 
placebo thrice weekly (TIW) for approximately 4 weeks, with a subsequent follow up 
period of approximately 4 weeks. 
3.2 
Sample Size 
Approximately 32 subjects will be randomized in a 3:1 ratio to receive 5 mg IV of 
etelcalcetide or placebo three times a week (TIW) at the end of each regularly scheduled 
hemodialysis session for 4 weeks (12 doses).   
For PK parameter estimation, 2-sided 90% confidence intervals (CI) for geometric 
means (GM) of PK measurements can be expressed as (GM/θ, GM·θ) where θ is a 
measure of precision.  Based on etelcalcetide study 20120330 (Cohort 3, 5 mg dose), 
between-subject CV for etelcalcetide AUClast (hr· µg/L) and Cmax (µg/L) (on original scale) 
are approximately 50.5% and 52.7%, respectively, following the Day 27 dose.  Assuming 
the same variability for 24 subjects receiving etelcalcetide in this study, it is estimated 
that the precision (θ) of 2-sided 90% CI of geometric mean will be 1.18 and 1.19 for 
AUClast and Cmax, respectively.   
For safety considerations, with 24 subjects receiving etelcalcetide, there will be a 21% 
chance of detecting an adverse event with a true incidence rate of 1% and 98% chance 
of detecting a more common adverse event with a true incidence rate of 15%.  
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
No covariate adjusted analyses are planned. 
4.2 
Subgroups 
No subgroup analyses are planned. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 7 of 20 
CONFIDENTIAL 
 
 
5. 
Definitions 
5.1 
Study Time Points 
Informed Consent Date 
The informed consent date for each subject is the date the subject signs the original 
informed consent for this study. 
Screening Phase 
The period after a subject has provided written informed consent and prior to 
randomization. This period may last up to 22 days and it is during this period when 
eligibility is determined, based on all screening tests and procedures. 
Enrollment Date 
The date a subject is randomized to a treatment group by the interactive voice/web 
response system (IXRS) after they have satisfied all enrollment criteria.  
Randomization Date 
The randomization date is the same as the enrollment date. 
Study Week 
The 7-day periods beginning with Study Day 1. 
Study Day 1 
The first day that investigational product is administered to the subject. For subjects who 
did not receive any investigational product during the study, Study Day 1 will be the 
randomization day.  
Study Day 
For each subject and for a given study visit date, study day is defined as the number of 
days since Study Day1: 
Study day = (study visit date – Study Day 1 date) + 1 
If the date of interest is prior to study day 1, study day will be calculated as 
Study day = (study visit date – Study Day 1 date). 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 8 of 20 
CONFIDENTIAL 
 
 
Date of Last Dose IP Received  
For each subject, the last investigational product dose date is defined as the date when 
the last non-missing dose of investigational product is administered (zero dose is still 
counted). 
Primary Completion 
The time when the last subject is assessed or receives an intervention for the purposes 
of final collection of data for the primary analysis. 
Subject-level End of Study Date 
End of study for each subject is defined as the date of the subject last study assessment 
in the study. The date subject ended the study is recorded on the End of Study 
electronic case report form (CRF). 
Study-level End of Study Date 
End of study for the study is defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study following any additional parts in the 
study (ie, safety follow-up) as applicable. 
5.2 
PK/PD Parameters 
AUClast 
AUClast is specifically defined in this study as the area under the concentration time 
curve measured from the time of drug administration to the beginning of the next 
dialysis session, following the first and last dose.  
Cmax 
Cmax is defined as the maximum observed plasma drug concentration measured 
between the time of drug administration to the beginning of the next dialysis 
session. 
5.3 
Demographics and Baseline Related Definitions 
Age 
Age will be collected as the subject’s age in years at enrollment as recorded on the 
eCRF. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 9 of 20 
CONFIDENTIAL 
 
 
Body Mass Index (BMI) 
BMI equals a person's weight in kilograms divided by baseline height in meters squared 
(kg/m2). 
Baseline 
Unless otherwise specified, for parameters/assessments scheduled to be performed on 
the same day as the first administration of the investigational product, the baseline value 
is the last value measured before the first administration of the investigational product on 
that day. 
For parameters/assessments not scheduled to be performed (or scheduled but not 
performed) on the same day as the first administration of the investigational product, the 
baseline value is the value from the screening period measured closest to the day of first 
administration of the investigational product. 
In the event that multiple pre-dose assessments are done on the same day as the first 
administration of the investigational product and there is no time associated with the 
assessments, the value associated with the last clinically planned event (CPE) will be 
used as the baseline value. 
Baseline iPTH, serum albumin and cCa is the average of predialysis assessments on 
day -2 and Day 1. If screening lab tests occur within 7 days prior to start of IP, then 
day -2 lab tests can be waived. Then baseline iPTH, serum albumin and cCa is the 
average of predialysis assessments at screening and day 1. 
Change from Baseline 
The arithmetic difference between a post-baseline value and baseline for a given time 
point: 
Change from baseline = (post-baseline value – baseline value) 
Percent Change from Baseline 
The percent change from baseline for a given variable at a given time point is defined 
as: 
100% x [(value at a given time point – baseline value) / baseline value] 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 10 of 20 
CONFIDENTIAL 
 
 
5.4 
Other Study Related Definitions 
Corrected Total Serum Calcium (cCa) 
Corrected calcium (mg/dL) = Total calcium (mg/dL) + (4 – albumin [g/dL]) x 0.8 
Total serum calcium will be corrected using above formulae if the serum albumin is 
< 4 g/dL or 40 g/L, otherwise cCa equals total serum calcium. 
Low Calcium Based on Corrected Calcium Values  
cCa values will be used to identify cases of low calcium of different severities using the 
following three categories:  < 7.0 mg/dL, 7.0 - < 7.5 mg/dL, and 7.5 - < 8.3 mg/dL. 
Treatment Emergent Adverse Events (TEAE) 
Adverse events (AEs) starting on or after the first dose of IP as determined by the flag 
indicating if the adverse event started prior to the first dose of IP on the Adverse Events 
Summary CRF and up to 30 days after the last dose date or EOS date, whichever is 
earlier.   
Adverse Event Subject Incidence 
Defined as the number and percentage of subjects with a reported event(s). For subjects 
with multiple reports of the same event during the study, the subject will be counted only 
once. For adverse event tabulations involving severity, the highest severity of the 
particular adverse events will be used for each subject. 
Adverse Events of Interest (EOI) 
Adverse events of interest are defined by the most current standardized product-level 
event of interest list. Unless otherwise specified, the narrow search scope will be used 
for all EOIs. 
Concomitant Medications of Interest 
The selected medications of interest are: nutritional vitamin D (vitamin D supplement), 
vitamin D sterol (active vitamin D), calcium supplements, and phosphate binders, as 
identified in the concomitant medication CRFs. 
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who received at least one dose of 
investigational product. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 11 of 20 
CONFIDENTIAL 
 
 
6.2 
PK Concentration Analysis Set 
The PK Concentration Analysis Set will contain all subjects who received at least one 
dose of etelcalcetide and have at least one PK sample collected. 
6.3 
PK Parameter Analysis Set 
The PK Parameter Analysis Set will contain all subjects who received at least one dose 
of etelcalcetide and for whom at least one PK parameter can be adequately estimated. 
6.4 
Intent-to-treat Analysis Set  
The Intent-to-treat Analysis Set (ITT) includes all subjects randomized. Subjects will be 
analyzed by randomized treatment. ITT Analysis Set will be used for study disposition 
summary. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No formal interim analysis is planned. 
7.2 
Primary Analysis 
The primary analysis for this study will occur when all subjects have completed all 
planned study procedures up to and including the EOS visit, as outlined in the Schedule 
of Assessments, and any follow up of a clinically significant clinical or laboratory 
abnormality and following database lock. 
7.3 
Final Analysis 
Not applicable. 
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. 
Details of PK, antibody and external lab data transfers to the database are provided in 
the corresponding study data transfer plans. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 12 of 20 
CONFIDENTIAL 
 
 
8.3 
Handling of Missing and Incomplete Data 
Subjects may be missing specific data points for various reasons.  In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a data point at a particular point in time.  Sites will be queried for 
missing or non-conformant data that are required or considered critical.  All efforts will be 
made to capture complete critical data prior to the database lock. 
The following imputation rules will be implemented for critical data if the missing or 
incomplete data cannot be resolved after the query process:  
Only missing or partially missing dates for adverse events will be imputed with the 
exception of adverse events occurring prior to the first dose date. Stop dates for AEs will 
not be imputed. Adverse events with a partially missing start date that is conclusively 
prior to the date of first IP administered (as indicated by ‘Did event start before first dose 
of IP’ on the AE CRF page) will be considered pre-treatment adverse events and 
excluded from safety analyses.  All other partially missing adverse event start dates will 
be handled as described below, with the reference date being Study Day 1: 
 
If the year is available and the day and month are missing, the day and month 
will be set to the 1st of January of the onset year 
 
If the year and month are available and the day is missing, the day will be set to 
the 1st of the onset month  
 
If the day and month are available and the year is missing, the year will be set to 
the year of the reference date 
 
If the year and day are available and the month is missing, the month will be set 
to January of the onset year 
 
If the resulting date is prior to the reference date, the date will be reset to the 
reference date (this applies to AE start date imputation only) 
Partial/missing start dates for concomitant medications of interest will be imputed using 
the algorithm above with the reference date being Study Day 1. Partial/missing stop 
dates for these concomitant medications will be imputed using the following logic: 
 
If the medication stop date is completely missing, then the stop date is set as the 
end of the study date 
 
If the stop year is available and stop month and day are missing, the month and 
day will be reset to 31st of December of the stop year 
 
If the stop year and month are available and the stop day is missing, the stop day 
will be set to the last day of the month of the stop year  
 
If the stop year and day are available and stop month is missing, the stop month 
will be set to December of the stop year     


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 13 of 20 
CONFIDENTIAL 
 
 
 
If the stop month and day are available and stop year is missing, the stop year 
will be reset to the year of the start date  
 
If any of the resulting dates are prior to the start date, the stop date will be reset 
to the start date 
 
If any of the resulting dates are after the end of study (EOS) date, the stop date 
will be reset to the EOS date 
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. The clinical study 
team will identify and document the criteria for important protocol deviations. 
8.5 
Outliers 
 PK plasma concentration data will be evaluated for outliers by visual inspection, and 
decisions to re-assay individual samples will be made in accordance with PK evaluation 
practice. 
8.6 
Distributional Characteristics 
There are no distributional requirements for the planned analyses. Therefore no 
assessment will be made. 
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 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Demographics, baseline characteristics, and safety data will be summarized by 
treatment groups. Unless otherwise stated, the data analysis will be conducted using 
subjects in the Safety Analysis Set. Descriptive statistics on continuous measurements 
will include mean, median, standard deviation, and range, 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. Descriptive 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 14 of 20 
CONFIDENTIAL 
 
 
summaries will be provided to characterize all primary and secondary endpoints in this 
study. 
9.2 
Subject Accountability 
The number and percent of subjects who received investigational product, completed 
investigational product, discontinued from investigational product (including reasons for 
discontinuing), completed study, or discontinued the study (including reasons for 
discontinuing) will be summarized. The number of subjects included in and excluded 
from each analysis set will be summarized. Key study dates for the first subject enrolled, 
last subject enrolled and last subject’s EOS will be presented. 
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. 
9.4 
Demographic and Baseline Characteristics 
Demographics data including sex, age, race, ethnicity and BMI will be summarized for 
each treatment using descriptive statistics. The same analysis will be performed for 
baseline characteristics and medical history. 
9.5 
Pharmacokinetic Endpoints 
Plasma concentrations of etelcalcetide will be determined using a validated assay from 
PK Concentration Analysis Set. Individual and mean plasma concentration-time plots for 
etelcalcetide will be presented.  
The PK parameters (ie, Cmax, AUClast) will be estimated using noncompartmental 
methods. Nominal dose and actual sampling time data will be used for calculation of PK 
parameters. Summary statistics will be generated for each PK parameter. Due to the 
effect of hemodialysis on the plasma concentration of etelcalcetide, AUClast is specifically 
defined in this study, as the area under the concentration-time curve during the time 
interval between dose administration and the beginning of the subsequent hemodialysis 
treatment. 
The PK Parameter analysis set will be used in the analyses for the primary endpoint. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 15 of 20 
CONFIDENTIAL 
 
 
9.6 
Safety Analyses 
9.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0 or later. 
Subject incidence of all treatment-emergent adverse events, will be tabulated by system 
organ class and preferred term. Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product and 
treatment-emergent hypocalcemia (depending on number of subject incidences) and 
event of interest (EOI) will be provided. Besides, subject incidence of AEs will also be 
summarized for all treatment-related AEs, treatment-related serious AEs, 
treatment-related fatal AEs and treatment-related AEs leading to withdrawal of IP. 
9.6.2 
Clinical Laboratory Test Results 
Serum albumin, iPTH, cCa and phosphorus measurements will be summarized by 
treatment group for all scheduled visits. Change and percent change from baseline may 
also be summarized for all post-baseline scheduled visits by treatment group, as 
applicable. 
9.6.3 
Vital Signs 
Vital signs will be listed and reviewed for each subject. Depending on the size and scope 
of changes, summaries of vital sign data by treatment group at each protocol-specified 
time point  may be provided. 
9.6.4 
Physical Measurements 
Physical measurements will be summarized by treatment group at each 
protocol-specified time point. 
9.6.5 
Electrocardiogram 
The ECG measurements from this clinical study are to be performed per standard of 
care for routine safety monitoring, rather than for purposes of assessment of potential 
QTc effect. Since these evaluations may not necessarily be performed under the 
rigorous conditions expected to lead to meaningful evaluation of QTc data, summaries 
and statistical analyses of ECG measurements are not planned.  
Subject level listing will be provided for all on-study ECG measurements. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
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Page 16 of 20 
CONFIDENTIAL 
 
 
9.6.6 
Anti-drug Antibodies 
The incidence and percentage of subjects who develop anti-etelcalcetide antibodies 
(binding) at any time will be tabulated. 
9.6.7 
Exposure to Investigational Product 
Descriptive statistics will be calculated to describe the exposure to investigational 
product by treatment group. A listing of the unique manufacturing lot numbers, and a 
listing of the subjects administered each manufacturing lot number will be provided. 
Summary statistics will be provided for: number of days on IP, the minimum and 
maximum weekly dose, the cumulative total dose, average weekly dose during the 
treatment period, and the number and percentage of subjects receiving each dose level 
(0mg, 5 mg or missing for etelcalcetide) of IP at each visit during the study.  
9.6.8 
Exposure to Other Protocol-specified Treatment 
N/A  
9.6.9 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving the following selected medications:  
nutritional vitamin D (vitamin D supplement), vitamin D sterol (active vitamin D), calcium 
supplements, and phosphate binder, will be summarized by treatment group at baseline 
and during the study.  
9.7 
Exploratory Endpoints 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses.  


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Protocol Number:  20140197 
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CONFIDENTIAL 
 
 
11. 
Literature Citations / References 
Not applicable. 


Product:  Etelcalcetide (AMG 416) 
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CONFIDENTIAL 
 
 
12. 
Prioritization of Analyses 
Not applicable. 
13. 
Data Not Covered by This Plan 
Not applicable. 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 19 of 20 
CONFIDENTIAL 
 
 
14. 
Appendices 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20140197 
Date:  26 November 2018 
Page 20 of 20 
CONFIDENTIAL 
 
 
Appendix A.  Reference Values/Toxicity Grades 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 4.0, published: 
May 28, 2009 (v4.03: June 14, 2010) for AE and lab shift grading and information.  The 
CTCAE is available at the following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html