Clinical trial NCT03299244
Conditions: Secondary Hyperparathyroidism Chronic Kidney Disease
Sponsor: Amgen
Start date: 2018-05-15; Completion date: 2020-04-08
Enrollment: 637 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to demonstrate that treatment with etelcalcetide (AMG 416) is not inferior to treatment with cinacalcet for lowering serum intact parathyroid hormone (PTH) levels by \> 30% from baseline among participants with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) who require management with hemodialysis.

Detailed description:

Arms: arm 1: Participants were randomized to receive oral cinacalcet once daily and placebo intravenous (IV) bolus injection at the end of each hemodialysis session three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 25 mg daily and the dose may have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum parathyroid hormone (PTH) ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL. arm 2: Participants were randomized to receive etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and the dose may have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL.
Interventions: intervention 1: Etelcalcetide intervention 2: Cinacalcet
Intervention descriptions: intervention 1: Administered intravenously three times per week. intervention 2: Cinacalcet administered orally once a day.

Protocol documents:
Prot_000.pdf: 
Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 1 of 82 
CONFIDENTIAL 
 
 
A Multicenter, Multiple-dose, Active-controlled, Double-blind, Double-dummy 
Study to Compare the Therapeutic Efficacy and Safety of Oral Doses of Cinacalcet 
Hydrochloride With Intravenous Doses of Etelcalcetide (AMG 416) in Asian 
Hemodialysis Subjects With Secondary Hyperparathyroidism 
 
Etelcalcetide (AMG 416) 
 
Amgen Protocol Number 20150238 
NCT #: NCT03299244 
 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Tel: +1 (805) 447-1000 
Key Sponsor Contact(s): 
, MD 
One Amgen Center Drive 
Thousand Oaks, CA 91230-1799 
 
 
Amgen, 1 Uxbridge Business Park 
Sanderson Road 
Uxbridge, Middlesex, UB8 1DH 
United Kingdom 
Date: 
04 December 2015 
Amendment 1 
07 February 2017 
Amendment 2 
16 February 2018 
Amendment 3 
27 November 2018 
 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 2 of 82 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  United States (US) sites, 1- 800-77-AMGEN, 
Canadian sites, 1-866-50-AMGEN; <<for all other countries, insert the local toll-free 
Medical Information number>> Amgen’s general number in the US (1-805-447-
1000).  
Approved 
 
 


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Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 4 of 82 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, Multiple-dose, Active-controlled, Double-blind, Double-dummy, Study to 
Compare the Therapeutic Efficacy and Safety of Oral Doses of Cinacalcet Hydrochloride with 
Intravenous Doses of Etelcalcetide (AMG 416) in Asian Hemodialysis Subjects with Secondary 
Hyperparathyroidism 
Study Phase:  3 
Indication:  Hemodialysis Subjects with Secondary Hyperparathyroidism (SHPT) 
Primary Objective:  To demonstrate that treatment with etelcalcetide (AMG 416) is not inferior to 
treatment with cinacalcet for lowering serum intact parathyroid hormone (PTH) levels by 
> 30% from baseline among subjects with chronic kidney disease (CKD) and secondary 
hyperparathyroidism (SHPT) who require management with hemodialysis.  
Secondary Objective:  To assess whether treatment with etelcalcetide is superior to treatment 
with cinacalcet as measured by the proportion of subjects with > 50% decrease in serum PTH 
from baseline, proportion of subjects with > 30% decrease in serum PTH from baseline, percent 
change from baseline in mean predialysis albumin corrected calcium (cCa) measured at the 
central laboratory, and achievement of mean predialysis serum phosphorus (P) ≤ 4.5 mg/dl 
measured at the central laboratory during the efficacy assessment phase (EAP).  
Safety Objectives:  
 
Assess the safety and tolerability of etelcalcetide compared to cinacalcet 
 
Evaluation of antibody formation to etelcalcetide 
Hypotheses:  Treatment of SHPT with etelcalcetide is not inferior to treatment with cinacalcet as 
measured by the proportion of subjects with > 30% reduction in predialysis serum PTH levels 
from baseline.  
Treatment with etelcalcetide is superior to treatment with cinacalcet as measured by the 
proportion of subjects with > 50% decrease in predialysis serum PTH from baseline, and by the 
proportion of subjects with > 30% decrease in predialysis serum PTH from baseline. 
Primary Endpoint:  The primary endpoint of the study is achievement of a > 30% reduction from 
baseline in mean predialysis serum PTH level during the EAP of the study (EAP is defined as 
weeks 20 to 27, inclusive). 
Key Secondary Endpoint(s):   
 
Achievement of a > 50% reduction from baseline in mean predialysis serum PTH during the 
EAP (superiority) 
 
Achievement of a > 30% reduction from baseline in mean predialysis serum PTH during the 
EAP (superiority) 
Other Secondary Endpoints 
 
Percent change from baseline in mean predialysis serum cCa measured by the central 
laboratory during the EAP 
 
Achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
Safety Endpoints 
 
Incidence of cCa < 8.3 mg/dL measured by the central laboratory at any time during the 
study 
 
Incidence of cCa < 8.0 mg/dL measured by the central laboratory at any time during the 
study 
 
Incidence of cCa < 7.5 mg/dL measured by the central laboratory at any time during the 
study 
 
Incidence of treatment-emergent symptomatic hypocalcemia during the study 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 5 of 82 
CONFIDENTIAL 
 
 
 
Incidence of antibody formation to etelcalcetide 
 
Nature, frequency, severity, and relationship of treatment-emergent adverse events. 
Exploratory Endpoints 
Study Design:  This is a phase 3, multicenter, randomized, active-controlled, double-blind, 
double-dummy, dose-titration, 26-week treatment period comparison of etelcalcetide and 
cinacalcet. 
All subjects, regardless of treatment assignment, may receive standard of care as prescribed by 
the individual Investigator, with calcium supplements, phosphate binders, and nutritional vitamin 
D supplements.  If treatment with calcitriol or vitamin D analogs is ongoing when subjects are 
enrolled in the study, the doses of these agents should remain constant for the duration of the 
study, unless treatment with vitamin D is initiated, interrupted, or adjusted for reasons of safety. 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) 
(≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central laboratory, and country (China 
versus non-China), and be randomized 1:1 to receive etelcalcetide or cinacalcet. 
Sample Size:  Approximately 660 subjects will be randomized in this study (approximately 
330 subjects in each of the 2 treatment arms).   
Summary of Subject Eligibility Criteria:  The study seeks to enroll subjects (≥ 18 years of age 
at the time of signing the informed consent) who are receiving maintenance hemodialysis 3 times 
weekly for at least 3 months, with adequate hemodialysis with a delivered Kt/V ≥ 1.2 or urea 
reduction ratio (URR) ≥ 65% within 4 weeks prior to screening laboratory assessments.   
Subjects must have SHPT as defined by 1 central laboratory screening predialysis serum PTH 
value > 500 pg/mL (53.00 pmol/L) and one serum cCa value ≥ 8.3 mg/dL (2.07 mmol/L) within 
2 weeks prior to randomization.  Eligible subjects cannot have received cinacalcet during the 
3 months preceding the first screening laboratory assessment.  For subjects currently receiving 
vitamin D sterols, the vitamin D dose must have no more than a maximum dose change of 50% 
within the 4 weeks prior to screening laboratory assessments, maintain stable through 
randomization, and be expected to maintain stable doses for the duration of the study, except for 
adjustments allowed per protocol or for safety reasons.  Subjects receiving calcium supplements 
must have no more than a maximum dose change of 50% within 2 weeks before screening 
laboratory assessments are obtained, and the dose must remain unchanged through 
randomization.  Subjects receiving phosphate binders must have had no more than a maximum 
of 50% dose change within 2 weeks before screening laboratory assessments are obtained, and 
the dose must remain stable thereafter throughout the study except as noted in the protocol or for 
safety reasons. 
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.1.1. 
Investigational Product: The investigational products (IPs) used in this study will include 
etelcalcetide (Amgen IP), cinacalcet (non-Amgen IP), and placebo.  Placebo will be provided with 
either intravenous (IV) or oral tablets. 
Amgen Investigational Product Dosage and Administration:  Subjects who are randomized to 
treatment with etelcalcetide will be treated with IV IP 3 times weekly at the end of each dialysis 
session and oral placebo tablets daily for 26 weeks.  The starting dose of IV IP is 5 mg and will be 
titrated by the Interactive Voice Response (IVR)/Interactive Web Response (IWR) system to 
target predialysis 
 The minimum IV IP dose is 2.5 mg, 
Approved 
 
 


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Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 7 of 82 
CONFIDENTIAL 
 
 
EAP will be tested for superiority.  The other secondary endpoints that will formally tests if both 
key secondary endpoints are statistically significant.  To control for the family-wise error rate, the 
Hochberg procedure of adjustment for multiple comparisons will be used for the testing of the 
other secondary endpoints. 
The primary analysis will be conducted upon achieving the Primary Completion milestone.  At the 
time of the Primary Analysis, the study will be unblinded and all endpoints will be evaluated.  The 
primary analysis of all primary and secondary endpoints will be conducted on the Full Analysis 
Set (FAS).   
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 IP, and treatment-emergent adverse events of interest will also be 
provided.  Proportion of subjects (with 95% confidence interval) with the following will be 
provided: 
 
cCa < 8.3 mg/dL measured by the central laboratory 
 
cCa < 8.0 mg/dL measured by the central laboratory 
 
cCa < 7.5 mg/dL measured by the central laboratory 
 
treatment-emergent symptomatic hypocalcemia adverse events during the study will be 
presented by treatment group.  
Laboratory parameters (hematology, chemistry anti-drug antibodies), blood pressure, pulse rate, 
and weight will also be analyzed. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
 
Data Element Standards 
Version/Date:  
Version 5/20 March 2015   
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 8 of 82 
CONFIDENTIAL 
 
 
Figure 1.  Study Design and Treatment Schema 
 
 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 9 of 82 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADA 
antidrug antibody 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
CaR 
calcium-sensing receptor 
cCa 
corrected calcium 
CCAS 
cCa Completer Analysis Set 
CI 
confidence interval 
CKD 
chronic kidney disease 
CMH 
Cochran-Mantel-Haenszel 
Cmax 
maximum observed plasma concentration 
CYP 
Cytochrome P-450 system 
D2 
Ergocalciferol 
D3 
Cholecalciferol 
DILI 
drug induced liver injury  
EAP 
efficacy assessment phase 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic data capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
defined as the date when the last subject completes the last 
protocol-specified assessment in the study   
End of Study  
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study at the follow-up visit 
(30 days after last dose [± 3 days]) or the last assessment is 
collected for the primary endpoint, whichever is later  
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 
EOS 
end-of-study 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 10 of 82 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
eSAE 
electronic Serious Adverse Event 
ESRD 
end-stage renal disease 
ET 
Early termination 
Etelcalcetide 
AMG 416 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HIV  
Human Immunodeficiency Virus 
HPT 
Hyperparathyroidism 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
INR 
International Normalized Ratio 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
Interactive Web 
Response (IWR) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information.  
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IV 
Intravenous 
MBD 
Mineral and Bone Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mantel-Haenszel 
NASH 
Nonalcoholic Steatohepatitis 
NKF-K/DOQI 
National Kidney Foundation- Kidney Disease Outcomes Quality 
Initiative 
P 
phosphorus 
PCAS 
PTH Completer Analysis Set 
PK 
Pharmacokinetics 
PPAS 
Per Protocol Analysis Set 
PTH 
parathyroid hormone 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SHPT 
Secondary Hyperparathyroidism 
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Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
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Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical 
research.  The information may include, but is not limited to, clinical 
findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents (original records or certified copies).  
(ICH Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
TIW 
three times per week 
ULN 
Upper limit of normal 
URR 
urea reduction ratio 
US 
United States 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 4 
1. 
OBJECTIVES ......................................................................................................... 17 
1.1 
Primary ....................................................................................................... 17 
1.2 
Secondary .................................................................................................. 17 
1.3 
Safety ......................................................................................................... 17 
1.4 
Exploratory ................................................................................................. 17 
2. 
BACKGROUND AND RATIONALE ........................................................................ 17 
2.1 
Disease Background of SHPT .................................................................... 17 
2.2 
Amgen Investigational Product Background ............................................... 18 
2.2.1 
Etelcalcetide ............................................................................... 18 
2.3 
Non-Amgen Medicinal Product Background ............................................... 20 
2.3.1 
Cinacalcet ................................................................................... 20 
2.4 
Rationale .................................................................................................... 21 
2.5 
Clinical Hypotheses .................................................................................... 21 
3. 
EXPERIMENTAL PLAN ......................................................................................... 22 
3.1 
Study Design .............................................................................................. 22 
3.2 
Number of Sites .......................................................................................... 22 
3.3 
Number of Subjects .................................................................................... 22 
3.4 
Replacement of Subjects ............................................................................ 23 
3.5 
Estimated Study Duration ........................................................................... 23 
3.5.1 
Study Duration for Subjects ........................................................ 23 
3.5.2 
End of Study ............................................................................... 23 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 23 
4.1 
Inclusion and Exclusion Criteria ................................................................. 23 
4.1.1 
Inclusion Criteria ......................................................................... 23 
4.1.2 
Exclusion Criteria ........................................................................ 24 
5. 
SUBJECT ENROLLMENT ..................................................................................... 25 
5.1 
Randomization/Treatment Assignment ...................................................... 26 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 27 
6. 
TREATMENT PROCEDURES ............................................................................... 27 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 27 
6.2 
Investigational Product ............................................................................... 27 
6.2.1 
Amgen Investigational Product Etelcalcetide ............................. 27 
6.2.1.1 
Dosage, Administration, and Schedule .................... 28 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 28 
6.2.2 
Non-Amgen Investigational Product Cinacalcet ......................... 30 
6.2.2.1 
Dosage, Administration, and Schedule .................... 30 
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6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 30 
6.2.3 
Suspension and Reduction of Oral and Intravenous 
Investigational Product ............................................................... 31 
6.2.3.1 
Low Predialysis Serum PTH .................................... 32 
6.2.3.2 
Low Predialysis Serum Corrected Calcium .............. 33 
6.2.3.3 
Symptomatic Hypocalcemia ..................................... 34 
6.2.3.4 
Adverse Event .......................................................... 34 
6.2.4 
Resumption of Investigational Product After Repeated 
Missed Doses ............................................................................. 35 
6.2.5 
cCa measured by the local laboratory ........................................ 35 
6.3 
Other Protocol-required Therapies ............................................................. 35 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 36 
6.4.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 36 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 37 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 37 
6.5 
Concomitant Therapy ................................................................................. 37 
6.5.1 
Calcium Supplements ................................................................. 38 
6.5.2 
Phosphate Binders ..................................................................... 38 
6.5.3 
Active Vitamin D Sterols ............................................................. 38 
6.5.4 
Nutritional Vitamin D ................................................................... 39 
6.5.5 
Allowed Treatments and/or Procedures During a 
Study Period ............................................................................... 39 
6.5.6 
Management of Laboratory Values ............................................ 40 
6.5.6.1 
Management of Elevated Serum 
Corrected Calcium or Symptomatic 
Hypercalcemia ......................................................... 40 
6.5.6.2 
Management of Serum Phosphorous ...................... 40 
6.6 
Medical Devices ......................................................................................... 40 
6.7 
Product Complaints .................................................................................... 41 
6.8 
Any product complaint(s) associated with an IP(s) or non-IP(s) 
or device(s) supplied by Amgen are to be reported according to 
the instructions provided in the IPIM Excluded Treatments, 
Medical Devices, and/or Procedures During Study Period ......................... 41 
6.8.1 
Excluded Treatments and/or Procedures During Study 
Period ......................................................................................... 41 
6.9 
Pregnancy Prevention Requirements ......................................................... 41 
7. 
STUDY PROCEDURES ......................................................................................... 42 
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7.1 
Schedule of Assessments .......................................................................... 44 
7.2 
Study Procedures ....................................................................................... 48 
7.2.1 
Screening Enrollment and/or Randomization ............................. 48 
7.2.2 
Re-screening .............................................................................. 48 
7.2.3 
Treatment ................................................................................... 48 
7.2.4 
Follow-up Visit ............................................................................ 49 
7.2.5 
Early Termination of Investigational Product Visit ...................... 49 
7.3 
Description of Study Procedures ................................................................ 49 
7.3.1 
Informed Consent ....................................................................... 50 
7.3.2 
Medical History ........................................................................... 50 
7.3.3 
Demographics ............................................................................ 50 
7.3.4 
Physical Examination ................................................................. 50 
7.3.5 
Height and Weight ...................................................................... 50 
7.3.6 
Medication History ...................................................................... 50 
7.3.7 
Concomitant Medication ............................................................. 50 
7.3.8 
Vital Signs ................................................................................... 51 
7.3.9 
Electrocardiogram (ECG) ........................................................... 51 
7.3.10 
Adverse Events and Disease Related Events ............................ 51 
7.3.11 
Pill Count .................................................................................... 51 
7.3.12 
Vital Status ................................................................................. 52 
7.4 
Laboratory Assessments ............................................................................ 52 
7.4.1 
Hepatitis Testing ......................................................................... 53 
7.4.2 
Pharmacokinetic Sampling ......................................................... 54 
7.5 
Antibody Testing Procedures ..................................................................... 54 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 54 
8.1 
Subjects’ Decision to Withdraw .................................................................. 54 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 55 
8.3 
Reasons for Removal From Procedures, Treatment, or Study .................. 55 
8.3.1 
Reasons for Removal From Treatment ...................................... 55 
8.3.2 
Reasons for Removal From Study ............................................. 56 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 56 
9.1 
Definition of Safety Events ......................................................................... 56 
9.1.1 
Adverse Events .......................................................................... 56 
9.1.2 
Serious Adverse Events ............................................................. 57 
9.2 
Safety Event Reporting Procedures ........................................................... 57 
9.2.1 
Adverse Events .......................................................................... 57 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 57 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 58 
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9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 60 
9.2.2 
Adverse Events of Interest ......................................................... 60 
9.2.3 
Changes in Serum Calcium and Symptomatic 
Hypocalcemia ............................................................................. 60 
9.3 
Pregnancy and Lactation Reporting ........................................................... 61 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 62 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 62 
10.1.1 
Study Endpoints ......................................................................... 62 
10.1.1.1 
Primary Endpoint ..................................................... 62 
10.1.1.2 
Key Secondary Endpoints ........................................ 62 
10.1.1.3 
Other Secondary Endpoints ..................................... 62 
10.1.1.4 
Safety Endpoints ...................................................... 62 
10.1.1.5 
Exploratory Endpoints .............................................. 62 
10.1.2 
Analysis Sets .............................................................................. 63 
10.1.2.1 
Full Analysis Set ...................................................... 63 
10.1.2.2 
PTH Completer Analysis Set ................................... 63 
10.1.2.3 
cCa Completer Analysis Set .................................... 63 
10.1.2.4 
Safety Analysis Set .................................................. 63 
10.1.2.5 
Per Protocol Analysis Set ........................................ 63 
10.1.3 
Covariates and Subgroups ......................................................... 63 
10.2 
Sample Size Considerations ...................................................................... 64 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 65 
10.4 
Planned Analyses ....................................................................................... 65 
10.4.1 
Primary Analysis ......................................................................... 65 
10.5 
Planned Methods of Analysis ..................................................................... 65 
10.5.1 
General Considerations .............................................................. 65 
10.5.2 
Primary Efficacy Endpoint .......................................................... 66 
10.5.3 
Secondary Efficacy Endpoints .................................................... 66 
10.5.3.1 
Other Secondary Efficacy Endpoints ....................... 67 
10.5.4 
Safety Endpoints ........................................................................ 67 
11. 
REGULATORY OBLIGATIONS ............................................................................. 68 
11.1 
Informed Consent ....................................................................................... 68 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 69 
11.3 
Subject Confidentiality ................................................................................ 69 
11.4 
Investigator Signatory Obligations .............................................................. 70 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 70 
12.1 
Protocol Amendments and Study Termination ........................................... 70 
12.2 
Study Documentation and Archive ............................................................. 71 
12.3 
Study Monitoring and Data Collection ........................................................ 72 
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12.4 
Investigator Responsibilities for Data Collection ........................................ 73 
12.5 
Language.................................................................................................... 73 
12.6 
Publication Policy ....................................................................................... 73 
12.7 
Compensation ............................................................................................ 74 
13. 
REFERENCES ....................................................................................................... 75 
14. 
APPENDICES ........................................................................................................ 76 
List of Tables 
Table 1. Investigational Product Dosing Algorithm Based on PTH ................................. 29 
Table 2.  Schedule of Assessments ................................................................................ 44 
Table 3  Schedule of Assessments Continued ............................................................... 46 
Table 4.  Analytes Table ................................................................................................. 53 
List of Figures 
Figure 1.  Study Design and Treatment Schema .............................................................. 8 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 77 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 79 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 81 
 
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1. 
OBJECTIVES 
1.1 
Primary 
 
To demonstrate that treatment with etelcalcetide (AMG 416) is not inferior to 
treatment with cinacalcet for lowering serum intact parathyroid hormone (PTH) 
levels by > 30% from baseline among subjects with chronic kidney disease 
(CKD) and secondary hyperparathyroidism (SHPT) who require management 
with hemodialysis. 
1.2 
Secondary 
 
To assess whether treatment with etelcalcetide is superior to treatment with 
cinacalcet as measured by the proportion of subjects with > 50% decrease in 
serum PTH from baseline, proportion of subjects with > 30% decrease in serum 
PTH from baseline, percent change from baseline in mean predialysis albumin 
corrected calcium (cCa) measured by the central laboratory  and achievement 
of mean predialysis serum phosphorus (P) ≤ 4.5 mg/dL measured by the 
central laboratory during the efficacy assessment phase (EAP).  
1.3 
Safety 
 
Assess the safety and tolerability of etelcalcetide compared to cinacalcet 
 
Evaluation of antibody formation to etelcalcetide 
1.4 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease Background of SHPT 
SHPT occurs commonly among patients with CKD, and it is an integral component of the 
syndrome of CKD- Mineral and Bone Disorder (MBD).  Persistently elevated levels of 
PTH 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).  SHPT is 
associated with important disturbances in calcium and P metabolism including 
hyperphosphatemia, pathological changes in bone described collectively as renal 
osteodystrophy, soft-tissue and vascular calcification, left ventricular hypertrophy, and 
cardiovascular events (Alem et al, 2000; Block et al, 2000; Bro and Olgaard, 1997; 
Diaz-Corte and Cannata-Andia, 2000; Moe, 2001; Salusky and Goodman, 1996; 
Slatopolsky et al, 1980; USRDS, 2009).  PTH 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/KDOQI) and the International Society of 
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Nephrology Kidney Disease Improving Global Outcomes ([KDIGO] KDIGO, 2009; 
K/DOQI, 2003).  
Adoption of hemodialysis in Asia, particularly in China, has rapidly expanded, and recent 
data describe emerging hemodialysis practice patterns and outcomes.  Retrospective 
studies of Chinese hemodialysis patients showed that mineral metabolism control in 
China remains an unmet medical need (Bieber et al, 2014; Kong, 2012). 
Treatment guidelines for SHPT cover several therapeutic strategies used to lower 
elevated plasma PTH levels and to manage SHPT among patients with CKD 
(Locatelli et al, 2008; KDIGO, 2009; Saliba and El-Haddad, 2009).  Traditionally, most 
have employed treatment with vitamin D sterols such as calcitriol or synthetic vitamin D 
analogues.  Vitamin D therapies are only partially effective for controlling serum PTH 
levels among patients with SHPT, and values often remain elevated despite ongoing 
treatment. 
An alternative approach is directed toward enhancing signal transduction through the 
calcium-sensing receptor (CaR) in parathyroid tissue, thereby suppressing PTH.  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, 
etelcalcetide, which is administered intravenously three times per week (TIW) at the end 
of each hemodialysis treatment.  Calcimimetics reduce PTH secretion from the 
parathyroid glands and consequently lower serum PTH levels.  Reductions in serum 
calcium concentrations are also observed and are an expected physiological 
consequence of PTH reduction.  As such, treatment is initiated with small doses that are 
subsequently titrated upwards as needed to achieve meaningful reductions in serum 
PTH levels only if serum calcium concentrations remain unchanged or decrease 
modestly.  PTH and calcium laboratory values are routinely drawn to measure the 
effectiveness of cinacalcet, and to titrate the dose as appropriate. 
2.2 
Amgen Investigational Product Background 
2.2.1 
Etelcalcetide 
Etelcalcetide is a novel peptide that has been shown in pharmacological studies to be a 
potent and selective allosteric activator of the CaR, lowering the threshold of receptor 
activation by calcium, the natural ligand.  As such, it inhibits PTH secretion by the 
parathyroid tissue.  The CaR was shown in cellular studies to be the molecular target of 
etelcalcetide.  Pharmacological activity of etelcalcetide requires formation of a disulfide 
bond between cysteine 482 in the human CaR and the D-cysteine of etelcalcetide.  
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Disulfide exchange of the D-cysteine of etelcalcetide also leads to biotransformed 
products in the blood. 
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 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
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 
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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 etelcalcetide Amgen Investigator Brochure for additional detailed 
information about the chemistry, toxicology, preclinical pharmacology, pharmacokinetics 
(PK), safety, and clinical experience of etelcalcetide. 
2.3 
Non-Amgen Medicinal Product Background 
2.3.1 
Cinacalcet 
Cinacalcet is a first-in-class calcimimetic agent that functions as an allosteric modulator 
of the CaR on the surface of parathyroid cells, increasing the sensitivity of the CaR to 
extracellular calcium ions. 
Cinacalcet has been approved by the Food and Drug Administration in the United States 
for the treatment of SHPT in patients with CKD on dialysis, for the treatment of 
hypercalcemia in subjects with parathyroid carcinoma, and for the treatment of severe 
hypercalcemia in patients with primary HPT who are unable to undergo 
parathyroidectomy.  Cinacalcet also has received marketing authorization under the 
name of Sensipar, Mimpara, or Regpara, in 6 countries in Asia, Australia, Canada, 
multiple countries in Europe, parts of Latin America, several countries in the Middle East, 
New Zealand, and Russia.  As of 07 September 2012, cinacalcet has been approved in 
60 countries.  Please refer to the cinacalcet package insert for the exact approved 
indication(s) in each of these regions. 
In adult humans, the maximum observed plasma concentration (Cmax) of cinacalcet is 
achieved between 2 to 6 hours after oral doses, which corresponds temporally with the 
nadir in plasma PTH.  After absorption, cinacalcet concentrations in serum decrease in a 
biphasic fashion with a terminal half-life of 30 to 40 hours.  Steady-state drug levels are 
achieved within 7 days, and serum calcium concentrations remain constant over the 
24-hour dosing interval once stable serum drug levels are achieved in patients with CKD 
on hemodialysis.  Cinacalcet is metabolized extensively by multiple hepatic cytochrome 
P-450 (CYP) enzymes, and < 1% of the parent drug is excreted in the urine.  No unique 
metabolites of cinacalcet have been identified in humans (original NDA 21-688, 
Study 980233). 
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An extensive phase 3 program was completed by Amgen in adult non-transplant 
subjects with end-stage renal disease (ESRD), demonstrating that treatment with 
cinacalcet resulted in concurrent reductions in PTH, calcium, P, and Ca x P, among 
dialysis subjects with inadequately controlled SHPT as defined by baseline plasma 
PTH > 300 pg/mL (31.8 pmol/L).  The incidence of serious adverse events was 31% and 
29% among subjects assigned randomly to treatment with cinacalcet or placebo.  The 
most common adverse events were nausea (31% versus 19%) and vomiting 
(27% versus 15%) among subjects assigned to treatment with cinacalcet compared with 
placebo.  Post-hoc analyses of phase 3 clinical trial data demonstrated that treatment 
with cinacalcet enabled a significantly greater proportion of adult subjects on dialysis 
with SHPT to achieve National Kidney Foundation- Kidney Disease Outcomes Quality 
Initiative (NKF-K/DOQI)™ recommended targets for PTH, calcium, P, and Ca x P 
compared with treatment using traditional therapies for SHPT (Moe et al, 2005).  
Please refer to the Cinacalcet package insert for Sensipar/Mimpara/Regpara for 
additional detailed information about the chemistry, toxicology, preclinical pharmacology, 
PK, safety, and clinical experience of cinacalcet. 
2.4 
Rationale 
Sub-optimal adherence and compliance with oral medication regimens that include 
cinacalcet are common among patients managed with hemodialysis.  This is due in part 
to a high daily pill burden and gastrointestinal intolerance in such individuals, and the 
overall complexity of the drug treatment strategies used to manage them clinically. 
Etelcalcetide is administered intravenous (IV) at the end of each hemodialysis session, 
and thus provides the opportunity to circumvent the shortcomings of oral therapies and 
to achieve greater drug adherence/compliance for managing SHPT.  
This current study is designed to assess the efficacy and safety of a novel therapeutic 
agent, IV etelcalcetide, compared with the other calcimimetic agent (oral cinacalcet), for 
the treatment of SHPT in CKD subjects on hemodialysis.  The data from this study will 
be used to support registration of etelcalcetide in China and other countries. 
2.5 
Clinical Hypotheses 
Treatment of SHPT with etelcalcetide is not inferior to treatment with cinacalcet as 
measured by the proportion of subjects with > 30% reduction in predialysis serum PTH 
levels from baseline during EAP. 
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Treatment with etelcalcetide is superior to treatment with cinacalcet as measured by the 
proportion of subjects with > 50% decrease in predialysis serum PTH from baseline, and 
by the proportion of subjects with > 30% decrease in predialysis serum PTH from 
baseline during EAP. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3, multicenter, randomized, active-controlled, double-blind, 
double-dummy, dose-titration, 26-week treatment period comparison of etelcalcetide and 
cinacalcet.   
All subjects, regardless of treatment assignment, may receive standard of care as 
prescribed by the individual Investigator, with calcium supplements, phosphate binders, 
vitamin D sterols, and nutritional vitamin D supplements.  If treatment with calcitriol or 
vitamin D analogs is ongoing when subjects are enrolled in the study, the doses of these 
agents should remain constant for the duration of study, unless treatment with vitamin D 
is initiated, interrupted, or adjusted for reasons of safety. 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) 
(≥ 2.25 mmol/L, < 2.25mmol/L) measured by the central laboratory, and country 
(China versus non-China), and be randomized 1:1 to receive etelcalcetide or cinacalcet. 
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 
The study is planned to be conducted at approximately 120 centers in China mainland, 
Taiwan, South Korea, Hong Kong, Malaysia, and India.  Other countries and/or regions 
may be added as needed. 
Sites that do not enroll subjects within 3 months of site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.” 
Approximately 660 subjects will be randomized in this study (approximately 330 subjects 
in each of the 2 treatment arms).  Refer to Section 10.2 for sample size considerations. 
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3.4 
Replacement of Subjects 
Randomized subjects who subsequently withdraw from the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The maximum duration of study participation for a subject will be approximately 
9 months; which includes an 8-week screening period, a 26-week treatment period, and 
a 30-day follow-up safety visit that is considered the end-of-study (EOS) visit. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is when the last subject is assessed 
or receives an intervention for evaluation in the study at the follow-up visit (30 days after 
last dose [± 3 days]) or the last assessment is collected for the primary endpoint, 
whichever is later. 
End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up) as applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system.  
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 Subject has provided informed consent prior to performing any study-related 
activities/procedures. 
102 Male or female subjects ≥ 18 years of age or older at the time of signing informed 
consent. 
103 Subject must be receiving maintenance hemodialysis 3 times weekly for at least 
3 months, with adequate hemodialysis with a delivered Kt/V ≥ 1.2 or urea reduction 
ratio (URR) ≥ 65% within 4 weeks prior to screening laboratory assessments.  The 
Kt/V formula used for a subject must be the formula used during routine care prior 
to screening. 
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104 Dialysate calcium concentration must be ≥ 2.5 mEq/L (1.25 mmol/L) and stable for 
at least 4 weeks prior to screening laboratory assessments, and must remain 
≥ 2.5 mEq/L (1.25 mmol/L) for the duration of the study. 
105 Subject must have SHPT as defined by one central laboratory screening 
predialysis serum PTH value > 500 pg/mL (53.00 pmol/L), within 2 weeks prior to 
randomization. 
106 Subject currently receiving vitamin D sterols must have had no more than a 
maximum dose change of 50% within the 4 weeks prior to screening laboratory 
assessments, remain stable through randomization, and be expected to maintain 
stable doses for the duration of the study, except for adjustments allowed per 
protocol or for safety reasons. 
107 Subject must have 1 screening predialysis serum cCa laboratory value ≥ 8.3 mg/dL 
(2.07 mmol/L) measured within 2 weeks prior to randomization. 
108 A subject receiving calcium supplements must have had no more than a maximum 
dose change of 50% within 2 weeks prior to screening laboratory assessments and 
remain stable through randomization. 
109 A subject receiving phosphate binders must have had no more than a maximum 
dose change of 50% within the 2 weeks prior to screening laboratory assessments, 
remain stable through randomization, and be expected to maintain stable dose for 
the duration of the study, except for adjustments allowed per protocol or for safety 
reasons. 
4.1.2 
Exclusion Criteria  
201 Currently receiving treatment in another investigational device or drug study, or 
≤ 30 days since ending treatment on another investigational device or drug 
study(s).  Other investigational procedures while participating in this study are 
excluded. 
202 Subject has received etelcalcetide in a prior clinical trial of etelcalcetide.  
203 Subject has received cinacalcet during the 3 months prior to the first screening 
laboratory assessments. 
204 Subject has known sensitivity to any of the products or components of either 
cinacalcet or etelcalcetide to be administered during dosing. 
205 Subject has previously been randomized in this study. 
206 Anticipated or scheduled parathyroidectomy during the study period. 
207 Subject has received a parathyroidectomy within 6 months prior to dosing. 
208 Anticipated or scheduled kidney transplant during the study period. 
209 Subject has an unstable medical condition based on medical history, physical 
examination, and routine laboratory tests, or is otherwise unstable in the judgment 
of the Investigator. 
210 Malignancy within the last 5 years of screening (except non-melanoma skin 
cancers or cervical carcinoma in situ). 
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211 Subject is unwilling or unable to avoid consumption of grapefruit juice during the 
study period.  
212 Subject is pregnant or nursing, or planning to become pregnant or nurse during 
treatment or within 3 months after the last dose of etelcalcetide or 30 days after the 
last dose of cinacalcet. 
213 Female subject of childbearing potential who is unwilling to use an acceptable 
method of effective contraception during treatment with investigational product (IP) 
through 3 months after the last dose of IP.  Refer to Section 6.9 for additional 
information on pregnancy prevention and definition of woman of childbearing 
potential.  
214 Subject has a history of symptomatic ventricular dysrhythmias or Torsades de 
Pointes. 
215 Subject has a history of myocardial infarction, coronary angioplasty, or coronary 
arterial bypass grafting within the past 6 months prior to screening. 
216 Subject has clinically significant abnormalities on prestudy clinical examination or 
abnormalities on the most recent central laboratory tests during the screening 
period prior to randomization according to the Investigator including but not limited 
to the following: 
 
serum albumin < 3.0 g/dL (30 g/L) 
 
serum magnesium < 1.5 mg/dL (0.62 mmol/L) 
 
serum transaminase (alanine transaminase [ALT] or serum glutamic pyruvic 
transaminase [SGPT], aspartate aminotransferase [AST] or serum glutamic 
oxaloacetic transaminase [SGOT]) > 3 times the upper limit of normal 
(ULN) at screening 
Note:  if results of serum transaminases are not available, Amgen should 
be notified prior to randomization; serum transaminases may be 
measured at the local laboratory 
217 Subject likely not 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. 
218 History or evidence of any other clinically significant disorder, condition or disease 
(with the exception of those outlined above) that, in the opinion of the Investigator 
or Amgen physician, if consulted, would pose a risk to subject safety or interfere 
with the study evaluation, procedures or completion. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  Specify 
Approved 
 
 


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that all subjects or legally acceptable representatives must personally sign and date the 
informed consent form before commencement of study-specific activities/procedures. 
After signing the informed consent, subjects must be randomized within 8 weeks.  
Subjects screening laboratory assessments may be repeated up to 2 times beyond the 
initial screening assessments within the 8-week screening period.  If a subject fails to 
meet all eligibility criteria in the initial 8-week screening period (including 3 attempts at 
meeting laboratory criteria), the 8-week screening period may be repeated once. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria via the IVR/IWR system.  The investigator is to document this 
decision and date, in the subject’s medical record and in/on the enrollment electronic 
case report form (eCRF). 
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned using IVR/IWR.  This 
number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
5.1 
Randomization/Treatment Assignment 
Subjects will be randomized by IVR/IWR in a 1:1 ratio to either TIW IV etelcalcetide (and 
daily oral placebo tablets) or daily oral cinacalcet tablets (and TIW IV placebo) in a 
double-blind, double-dummy manner, and should receive the first dose of IP within 1 day 
of randomization.  Randomization will be stratified by screening PTH level (< 900 pg/mL, 
≥ 900 pg/mL) (< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, 
< 9.0 mg/dL) (≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central laboratory, 
and country (China versus non-China).  The total duration of treatment will be 26 weeks.  
IP will be dosed to achieve predialysis 
Treatment groups will be blinded to the investigator, subjects, and the Amgen study 
team. 
Randomization should occur on the same day as enrollment and the date is to be 
documented in the subject’s medical record and on the enrollment eCRF.  The 
randomization number will be provided to the Investigator (or designee) by accessing the 
Approved 
 
 


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IVR/IWR and receiving the IP assignment (box number).  Details for this procedure will 
be provided in the IVR/IWR manual. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment but must do so within 1 working 
day after the event. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen IP used in this study is etelcalcetide. 
The non-Amgen IP used in this study is cinacalcet. 
Note:  Ancillary device(s) (ie, medical device(s) not under study) are described in 
Section 6.6. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of etelcalcetide and cinacalcet.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Etelcalcetide 
Etelcalcetide will be manufactured and packaged by Amgen Inc. or its designee, and 
distributed using Amgen clinical IP distribution procedures.  The active pharmaceutical 
ingredient (API) in etelcalcetide is an 8-amino acid synthetic peptide prepared as a 
hydrochloride salt. 
Etelcalcetide investigational drug product is supplied as a sterile, preservative-free, 
aqueous solution containing 10 mg etelcalcetide free base, 
 sodium chloride and 
 succinic acid, in a single-use 3 mL glass vial.  The drug product vial contains 
2 mL of clear, colorless solution with etelcalcetide concentration of 5 mg/mL.  The 
solution is ready to administer and has pH between 3.0 and 3.6.  The recommended 
storage condition for etelcalcetide liquid drug product is 2°C to 8°C. 
Etelcalcetide placebo will be presented in identical containers and stored/packaged in 
the same manner as etelcalcetide. 
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6.2.1.1 
Dosage, Administration, and Schedule 
Intravenous IP will be administered by dialysis site staff by bolus injection into the 
venous line of the dialysis circuit at the end of each TIW hemodialysis session just prior 
to or during rinse-back.  At least 150 mL of rinse-back volume should be administered 
after injection of IP to ensure that IP reaches the systemic circulation. 
If rinse back is completed and IP was not administered, then IP may be administered 
intravenously followed by at least 10 mL saline flush volume. 
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) 
unless hemodialysis treatment is discontinued early; in this case the end of hemodialysis 
is 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, 
IV IP should be administered at the rescheduled hemodialysis session.  If an additional 
hemodialysis treatment is needed intermittently (eg, fourth treatment during a week for 
ultrafiltration) then an additional dose of IP will not be administered during the extra 
dialysis session.   
Intravenous IP must only be administered intravenously; it must not be administered via 
any other route. 
Intravenous IP must not be administered concurrently with any other IV medications. 
The quantity, IP administration date/time, and kit number of IV IP are to be recorded on 
each subject’s eCRF. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
from the central laboratory obtained during the prior or current week. 
Subjects will be treated with IV IP three times weekly at the end of hemodialysis, for 
26 weeks.  The starting dose of IV IP is 5 mg and will be titrated by the IVR/IWR to 
target predialysis 
 and maintain 
cCa ≥ 8.3 mg/dL(2.07 mmol/L).  The minimum IV IP dose is 2.5 mg, and the maximum 
dose is 15 mg.  
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Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1 unless any of 
the following criteria are met: 
o subject has missed 3 or more IV doses during the prior 3 weeks 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o most recent predialysis serum cCa < 8.3 mg/dL (2.07 mmol/L) during 
the prior or current week  
o most recent predialysis
during 
the prior or current week 
Table 1. Investigational Product Dosing Algorithm Based on PTH 
PTH (pg/mL) 
IV IP Dose If 
Current Dose 
< 10mg 
IV IP Dose If 
Current Dose 
10 mg 
IV IP Dose If 
Current Dose 
12.5 mg 
Oral IP Dose 
PTH > 450 
(47.70 pmol/L) 
Increase dose 
by 2.5 mg 
Increase dose 
by 5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 25 mg 
300 (31.80 pmol/L) 
< PTH ≤ 450 
(47.70 pmol/L) 
Increase dose 
by 2.5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 25 mg 
PTH ≤ 300 
(31.80 pmol/L) 
Maintain dose 
Maintain dose 
Maintain dose 
Maintain dose 
PTH < 100 
(10.60 pmol/L) 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
IP = investigational product; IV = intravenous; PTH = parathyroid hormone 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
Dosing of IP may occur if the cCa results from the central laboratory are not 
available (as described in Section 6.2.3); however, IV IP dose cannot be resumed 
or increased without an available cCa result from the central laboratory for the 
prior or current week. 
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If an overdose of the IV IP has been administered to/taken by the subject, subjects 
should be monitored for signs and symptoms of hypocalcemia and appropriate 
measures taken to correct serum cCa levels. 
See Section 6.2.3 and Section 6.2.4 for details on dose suspensions, reductions, and 
resumptions.  
6.2.2 
Non-Amgen Investigational Product Cinacalcet 
Cinacalcet tablets are manufactured by Kyowa Hakko Kirin Co., Ltd at strengths of 
25 mg and packaged by Amgen Inc. or its designee.  Cinacalcet placebo tablets will be 
presented in identical dosage form images (ie, will be presented in the same size and 
color of actives) and containers (eg, bottle size, color, and shape).  Additional details 
regarding cinacalcet and its placebo will be provided in the IPIM. 
6.2.2.1 
Dosage, Administration, and Schedule 
Oral IP should be taken by the subject with food, at approximately the same time on a 
daily basis during the 26-week duration of the study treatment period.  The oral IP 
should be taken by the subject at least 12 hours before the PTH laboratory assessment. 
If ≤ 7 consecutive daily doses of the oral IP were missed, because of reasons unrelated 
to those described in Section 6, the subject should be instructed to resume dosing at the 
IVR/IWR assigned dose.  The subject must not attempt to make up for any missed 
doses. 
The quantity, start date, stop date, and box number of oral IP are to be recorded on each 
subject’s eCRF.  When the oral IP is returned by the subject during a study visit (see Pill 
Count in Dose Schema in Figure 1) the investigator or responsible person will determine 
the level of compliance with the administration of the oral IP.  The subject’s IP 
accountability (eg, amount used/amount expected to be used in interval between visits) 
will be recorded on the compliance forms provided in the IPIM.  This may require the 
review of subject’s diaries (if used), subject interviews, or other methods. 
6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
obtained during the prior or current week. 
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Subjects will be treated with oral IP daily, for 26 weeks.  The starting dose of oral IP is 
25 mg and will be titrated by the IVR/IWR to target predialysis
and maintain cCa ≥ 8.3 mg/dL (2.07 mmol/L).  The minimum oral IP 
dose is 25 mg, and the maximum IP dose is 100 mg. 
Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1. unless any of 
the following criteria are met: 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o most recent predialysis serum cCa < 8.3 mg/dL (2.07 mmol/L) during the 
prior or current week 
o most recent predialysis 
during 
the prior or current week 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
Dosing of IP may occur if the cCa results from the central laboratory are not 
available (as described in Section 6.2.3), but oral IP dose cannot be resumed or 
increased without an available cCa result from the central laboratory from the 
prior or current week.  
If an overdose of the oral IP has been administered to/taken by the subject, subjects 
should be monitored for signs and symptoms of hypocalcemia and appropriate 
measures taken to correct serum cCa levels. 
See Section 6.2.3 and Section 6.2.4 for details on dose suspensions, reductions, and 
resumptions.  
6.2.3 
Suspension and Reduction of Oral and Intravenous Investigational 
Product 
Dosing with IP may be temporarily suspended by the Investigator or by the IVR/IWR at 
any time if ANY of the criteria below apply.  IP dosing may resume only after ALL criteria 
contributing to suspension of IP dosing are resolved. 
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 
two consecutive predialysis central laboratory PTH < 100 pg/mL (10.60 pmol/L) at 
least 1 week apart (see Section 6.2.3.1) 
 
cCa is < 7.5 mg/dL (1.87 mmol/L) (see Section 6.2.3.2  measured by either the 
central or local laboratory  
 
subject experiences symptomatic hypocalcemia (see Section 6.2.3.3)   
 
there is any other ongoing adverse event that, in the opinion of the Investigator, 
necessitates suspension of IP dosing 
The site will immediately enter the information in IVR/IWR and electronic data 
capture (EDC) system when a dose suspension rule is invoked and the reason for 
missed or suspended doses is recorded on the subject eCRF.  Even when dosing 
with IP is suspended per protocol, all scheduled assessments should be 
completed. 
During a hospitalization or when hemodialysis is provided in a location other than the 
Investigator’s site, both oral and IV IPs should be suspended When hemodialysis is 
provided in a location other than the Investigator’s site, the visit should not be 
registered in the IVR/IWR.  The reasons for missed doses should be recorded on 
the subject eCRF. 
6.2.3.1 
Low Predialysis Serum PTH 
If a subject has 2 consecutive central laboratory predialysis serum PTH results obtained 
at least 1 week apart that are both < 100 pg/mL (10.60 pmol/L), then the Investigator will 
be notified by the IVR/IWR that dosing of both the IV and oral IPs should be suspended. 
Intact PTH monitoring will continue per the protocol.  Once PTH is ≥ 150 pg/mL 
(15.90 pmol/L) and the central laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L), the 
Investigator will be notified by the IVR/IWR that dosing with the IV and oral IPs may 
resume at a 2.5 mg lower dose for the IV, and at a 25 mg lower dose for the oral. 
If a subject was receiving the 2.5 mg IV dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 2.5 mg dose level 
when PTH is > 300 pg/mL (31.80 pmol/L), and the most recent predialysis central 
laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L). 
If a subject was receiving the 25 mg oral dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 25 mg dose level when 
PTH is > 300 pg/mL (31.80 pmol/L), and the most recent predialysis central laboratory 
serum cCa ≥ 8.3 mg/dL (2.07 mmol/L).  
Approved 
 
 


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6.2.3.2 
Low Predialysis Serum Corrected Calcium 
Administration of etelcalcetide or ingestion of cinacalcet, both potent agonists of the 
CaR, may result in rapid and sustained suppression of PTH levels.   
Management of subjects with rapid and sustained reductions in PTH includes careful 
monitoring of serum calcium by the Investigator.  Supplementation with oral calcium 
and/or increasing the dialysate calcium concentration may be instituted by the 
Investigator if serum cCa is below the lower limit of the reference range or there is a 
rapid large reduction in serum calcium, especially in subjects with PTH > 700 pg/mL 
(74.20 pmo/L) and markedly elevated serum alkaline phosphatase (ALP) at baseline.  
Increased calcium supplementation may only be needed on a temporary basis until 
mineral balance is re-established at the reduced PTH level. 
The following guidance is provided for the management of serum cCa below the lower 
limit of the reference range with any change to therapy based on Investigator clinical 
judgment.  If the cCa measured by either the central or local laboratory is 
< 8.3 mg/dL (2.07 mmol/L), the following options may be taken by the Investigator: 
 
May increase oral calcium intake  
 
May increase dialysate calcium concentration 
 
May initiate or increase active vitamin D analogues if other therapies are ineffective 
If the cCa measured by either the central or local laboratory is < 7.5 mg/dL 
(1.87 mmol/L) or the subject experiences symptomatic hypocalcemia, in addition to 
the above actions, do the following: 
 
Suspend dosing with IP, and at the next hemodialysis session following 
notification of the low serum calcium result, draw a confirmatory predialysis 
serum cCa sample and send to the central laboratory. 
 
Obtain weekly predialysis central laboratory serum cCa.  Once predialysis 
serum cCa ≥ 8.3 mg/dL (2.07 mmol/L) and any hypocalcemic symptoms have 
resolved the IVR/IWR will provide instructions to resume dosing.  For the oral IP, 
the dose should be reduced by 25 mg or at the minimum dose of 25 mg, 
whichever is greater.  For the IV IP, the dose should be reduced by 5 mg or at 
the minimum dose of 2.5 mg, whichever is greater.  Resume routine laboratory 
monitoring per Table 2, the Schedule of Assessments.  Refer to Section 7.2 for 
central laboratory samples to be submitted. 
An unscheduled collection of cCa from the central laboratory can be done at 
any time for safety. A cCa collected and measured by the local laboratory can 
only be done for the management of safety concerns. If the cCa measured by 
the local laboratory is < 7.5 mg/dL (1.87 mmol/L), IP must be suspended and 
Approved 
 
 


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can only be resumed once the cCa measured by the central laboratory is 
≥ 8.3 mg/dL (2.07 mmol/L) (see Section 6.2.5).  
6.2.3.3 
Symptomatic Hypocalcemia 
The clinical signs and symptoms of hypocalcemia include increased neuromuscular 
excitability, manifested as paresthesias of the fingers, toes, and circumoral region.  In 
more extreme cases, there may be muscle cramping, carpopedal spasm, laryngospasm, 
and seizures.  Symptoms reflect not only the degree of hypocalcemia, but also the 
acuteness of the fall in serum calcium concentration.  Signs of latent tetany include 
Chvostek's sign (twitching of the upper lip after tapping on the facial nerve below the 
zygomatic arch) and Trousseau's sign (carpal spasm after inflating a cuff on the upper 
arm above systolic blood pressure for 2 to 3 minutes).  Various mental disturbances, 
such as irritability, depression, and even psychosis, have been attributed to 
hypocalcemia.  Cardiac effects of hypocalcemia include a prolonged QT interval and, 
rarely, ventricular tachyarrhythmia’s or congestive heart failure which may be fatal.   
Common symptoms of hypocalcemia include paresthesias (fingertips, toes, or perioral), 
fatigue, muscle cramps, irritability or anxiety, tetany (eg, carpopedal spasm, 
laryngospasm), Chvostek's sign, seizures, and prolonged QT interval. 
If symptomatic hypocalcemia is suspected, calcium levels should be closely monitored, 
and corrective measures should be undertaken by the Investigator.  Calcium 
supplementation can be provided by IV infusion (eg, a calcium gluconate) and/or oral 
calcium supplementation. 
Suppressed levels of serum magnesium can be associated with refractory 
hypocalcemia.  Serum magnesium should be closely monitored in subjects with 
hypocalcemia, and magnesium supplements should be provided as needed. 
If dosing with IP is suspended for symptomatic hypocalcemia, dosing may resume at a 
lower dose once symptomatic hypocalcemia has resolved when the central laboratory 
cCa ≥ 8.3 mg/dL (2.07 mmol/L), and once the Investigator has notified the IVR/IWR.  
6.2.3.4 
Adverse Event 
If the adverse event is deemed not related to IP by the Investigator, dosing with IP may 
resume at the same dose once the clinical adverse event, which led to suspension of 
dosing, has resolved or has stabilized. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 35 of 82 
CONFIDENTIAL 
 
 
If the adverse event was deemed to be IP related by the Investigator but not related to 
PTH < 100 pg/mL (10.60 pmol/L), cCa < 7.5 mg/dL (1.87 mmol/L) or symptomatic 
hypocalcemia, dosing with IP may resume once the adverse event has resolved or 
stabilized and the central laboratory serum cCa is ≥ 8.3 mg/dL (2.07 mmol/L) with 
the dose reduced.  For the oral product, the dose should be reduced by 25 mg (if the 
dose was already at 25 mg, the dose of 25 mg should be resumed).  For the IV product, 
the dose should be reduced by 5 mg or at the minimum dose of 2.5 mg, whichever is 
greater. 
During a hospitalization or when hemodialysis is provided in a location other than the 
Investigator’s site, both oral and IV IPs should be suspended. 
6.2.4 
Resumption of Investigational Product After Repeated Missed Doses 
If more than 14 consecutive days of IP are missed (eg, extended hospitalization for an 
adverse event unrelated to IP, vacation), a central laboratory cCa must be obtained prior 
to restarting IP.  Only after the central laboratory cCa is ≥ 8.3 mg/dL (2.07 mmol/L) 
should dosing with IP resume.  Intravenous IP dosing will be restarted by the IVR/IWR at 
5 mg and oral IP dose at 25 mg.  If the subject’s last IV dose was 2.5 mg, then the 
subject should resume IV dosing at the 2.5 mg dose level. 
6.2.5 
cCa measured by the local laboratory  
A cCa can only be collected and measured by the local laboratory for the 
management of safety concerns and/or suspension of IP.  All cCa results 
measured by the local laboratory  will be recorded on the eCRF. If the cCa is 
< 7.5 mg/dL (1.87 mmol/L) or the subject experiences symptomatic hypocalcemia, 
refer to Section 6.2.3.2for further management. The IP can only be resumed once 
the cCa measured by the central laboratory is ≥ 8.3 mg/dL (2.07 mmol/L). 
A local laboratory cCa and central laboratory cCa must not be collected at the 
same time. 
If the local laboratory cCa is < 7.5 mg/dL (1.87 mmol/L), suspend IP by registering 
a suspension in IVR/IWR with the reason of adverse event related to IP or 
symptomatic hypocalcemia depending on the clinical assessment. 
6.3 
Other Protocol-required Therapies 
Dialysate calcium must remain ≥ 2.5 mEq/L (1.25 mmol/L) for the duration of the study. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 36 of 82 
CONFIDENTIAL 
 
 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, 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 IP or other protocol-required therapies (as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009).  Note:  If the 
central laboratory is unable to perform the analysis of the hepatic laboratory tests 
(as discussed with Amgen during screening) then those tests should be measured 
by the local laboratory. 
6.4.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
IP should be discontinued permanently by the Investigator and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met. 
 
TBL > 2 x ULN or International Normalized Ratio (INR) > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
 
AND no other cause for the combination of laboratory abnormalities is 
immediately apparent; important potential causes for abnormal AST/ALT or 
TBL values include, but are not limited to: 
 
Obstructive gall bladder or bile duct disease 
 
Viral or alcoholic hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, etc) 
 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome); 
alpha-one antitrypsin deficiency 
 
Autoimmune hepatitis  
 
Nonalcoholic Steatohepatitis (NASH) or other “fatty liver disease” 
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 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 37 of 82 
CONFIDENTIAL 
 
 
severity of the hepatotoxicity or event) if Amgen IP and other protocol-required therapies 
should be withheld or permanently discontinued, as deemed appropriate for the safety of 
the subject. 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects that do not meet the criteria for permanent withholding of IP outlined above, 
IP should be withheld if ANY of the following criteria are met, and the subject should be 
evaluated for DILI: 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
> 8 x ULN at any time 
Any 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
Any 
> 5 x ULN but < 8 x ULN and unable to adhere to enhanced 
monitoring schedule 
AST = aspartate aminotransferase; ALT = alanine transaminase; ULN = upper limit of normal 
 
OR: TBL > 3x ULN at any time 
 
OR: ALP > 8x ULN at any time 
If IPs are withheld, the subject is to be followed according to recommendations in 
Appendix A for possible DILI.  Rechallenge may be considered if an alternative cause for 
impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the 
laboratory abnormalities resolve to normal or baseline (Section 6.4.3). 
6.4.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then IP should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.4.1) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care, including calcium 
supplements, phosphate binders, active vitamin D sterols, vitamin D supplements except 
for those listed in Section 6.8.  These medications will not be provided by Amgen. 
Approved 
 
 


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Protocol Number:  20150238 
Date:  27 November 2018 
Page 38 of 82 
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Medication use at screening and then at every study visit including Early Termination will 
be recorded and categorized by general, vitamin D supplement, active vitamin D sterol, 
calcimimetics, calcium supplements, or phosphate binder.  Dialysate calcium will be 
collected at screening and anytime there is a change.  For previous cinacalcet use, 
specific reasons for discontinuation will be captured. 
Concomitant therapies are to be collected in the eCRF from informed consent through 
the EOS.  Therapy name, indication, dose, unit, frequency, route, start date and stop 
date should be recorded. 
6.5.1 
Calcium Supplements 
Subjects receiving calcium supplements must have had no more than a maximum dose 
change of 50% within the 2 weeks prior to screening laboratory assessments and remain 
stable through randomization.  Except during the screening period, calcium supplement 
therapy may be adjusted as needed based on Investigator clinical judgment. 
6.5.2 
Phosphate Binders 
Subjects receiving phosphate binders must have had no more than a maximum dose 
change of 50% within the 2 weeks prior to screening laboratory assessments, remain 
stable through randomization, and be expected to maintain stable dose for the duration 
of the study except as defined in the protocol (see Section 6.5.6.2). 
Changing the type of phosphate binder is discouraged during the study and should only 
occur if unavoidable (eg, drug shortage).  Should a change in type of phosphate binder 
be required, equivalent doses should be prescribed to maintain stable clinical effects to 
the extent possible. 
6.5.3 
Active Vitamin D Sterols 
Subjects receiving an active vitamin D sterol must have had no more than a maximum 
dose change of 50% within the 4 weeks prior to screening laboratory assessments, 
remain stable through randomization, and be expected to maintain stable dose for the 
duration of the study, unless a change in dose is appropriate and consistent with the 
guidance in this protocol. 
However, changes to the dose of active vitamin D sterols are permitted by the 
Investigator for reasons of safety with respect to the management of increased or 
decreased cCa as defined in the protocol (see Section 6.2.3.2 and Section 6.5.6.1). 
Changing the type of active vitamin D sterol is emphatically discouraged during the study 
and should only be considered, if unavoidable under uncommon circumstances such as 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 39 of 82 
CONFIDENTIAL 
 
 
drug shortage or drug availability.  Should a change in type of active vitamin D sterol 
become necessary, equivalent doses should be prescribed to maintain consistent clinical 
and biochemical responses to the extent possible.  The doses provided should be 
regarded as approximately equivalent doses to guide conversion between type and/or 
dosage form. 
6.5.4 
Nutritional Vitamin D 
If prescribed by the individual Investigator, subjects may receive nutritional vitamin D 
(ergocalciferol [D2] or cholecalciferol [D3]) without restriction.  Examples of nutritional 
vitamin D compounds are provided below: 
 
cholecalciferol 
 
ergocalciferol 
 
renal multivitamins that contain D2 or D3 
6.5.5 
Allowed Treatments and/or Procedures During a Study Period 
 
Subjects should be on maintenance hemodialysis treatment with a prescription for 
dialysis 3 times per week.  Dialysis duration and membrane may be modified to 
maintain adequate hemodialysis treatment (eg, Kt/V ≥ 1.2 or URR > 65%).  If a 
subject requires a significant change in hemodialysis prescription to maintain 
adequate hemodialysis (eg, permanent change from TIW), then the subject will be 
discontinued from treatment with IP, and every effort will be made to continue to 
follow the subject through the duration of the study. 
 
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 ≥ 2.5 mEq/L 
(1.25 mmol/L) stable for at least 4 weeks prior to screening laboratories, and the 
dialysate calcium concentration must be maintained ≥ 2.5 mEq/L (1.25 mmol/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 eCRF with a frequency of 3 times per week unless a 
change in dose or frequency occurs.  The following medications used in the delivery 
of hemodialysis should not be reported on the eCRF as concomitant medication: 
o local anesthetic for cannulation 
o saline prime for the dialysis circuit 
o saline or hypertonic saline for management of intradialytic hypotension 
o oxygen 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 40 of 82 
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6.5.6 
Management of Laboratory Values 
6.5.6.1 
Management of Elevated Serum Corrected Calcium or Symptomatic 
Hypercalcemia 
The following guidance is provided for the management of serum cCa above the upper 
limit of the reference range.  If a subject has 2 consecutive central laboratory 
cCa > 10.6 mg/dL (2.64 mmol/L), then doses of active vitamin D sterol, oral calcium 
intake, and/or dialysate calcium concentration may be reduced based on Investigator 
clinical judgment; however, dialysate calcium concentration must remain ≥ 2.5 mEq/L 
(1.25 mmol/L), unless otherwise permitted by Amgen. 
If a subject has a central laboratory cCa > 11.0 mg/dL (2.74 mmol/L) or develops 
symptomatic hypercalcemia, then any active vitamin D sterol and oral calcium intake 
(including calcium-based phosphate binders) may be reduced or discontinued, and 
dialysate calcium concentration may be reduced based on Investigator clinical judgment; 
however, dialysate calcium concentration must remain ≥ 2.5 mEq/L (1.25 mmol/L).  
Common signs and symptoms of hypercalcemia include: nausea, vomiting or 
constipation, fatigue or weakness, musculoskeletal pain, hypertension, impaired 
concentration, confusion or lethargy. 
6.5.6.2 
Management of Serum Phosphorous 
Serum P will be monitored locally in accordance with the dialysis unit’s standard 
operating procedures during the study.  It is recommended that phosphate binder dose 
remain stable throughout the study.  At the Investigator’s clinical discretion and based on 
dialysis unit routine monitoring tests, phosphate binder dose may be adjusted consistent 
with the following guidance: 
 
If 2 consecutive local predialysis serum P values are > 5.5 mg/dL (1.78 mmol/L) and 
not amenable to modification via dietary counseling, then the dose of phosphate 
binder may be increased. 
 
If 2 consecutive local predialysis serum P values are < 3.0 mg/dL (0.97 mmol/L), 
then the dose of phosphate binder may be decreased. 
6.6 
Medical Devices 
The following medical devices for the IV infusion of IP (eg, inline filters, IV administration 
set, infusion pump) will not be provided by Amgen, as routine hemodialysis tubing 
should be used.  The Investigator will be responsible for obtaining supplies of these 
devices. 
Other medical devices, which are not considered test articles, may be used in the 
conduct of this study as part of standard care (eg, syringes, sterile needles, alcohol prep 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 41 of 82 
CONFIDENTIAL 
 
 
pads).  These devices 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. 
6.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s) or device(s) provisioned and/or repackaged /modified by 
Amgen.  Drug(s) or device(s) includes IP. 
6.8 
Any Product Complaint(s) Associated With an IP(s) or Non-IP(s) or 
Device(s) Supplied by Amgen are to be Reported According to the 
Instructions Provided in the IPIM Excluded Treatments, Medical 
Devices, and/or Procedures During Study Period 
6.8.1 
Excluded Treatments and/or Procedures During Study Period 
The following treatments will be prohibited during the study: 
 
Treatment with commercial cinacalcet is prohibited during the study through the last 
study visit (ie, the 30-day follow-up visit).  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 3 months prior to the first screening 
laboratory assessments. 
 
Use of grapefruit juice is prohibited during the study.  Changes in medications, 
including herbal medications, that are strong inhibitors or inducers of the enzymes 
CYP3A4 and CYP1A2 (eg, erythromycin, clarithromycin, ketoconazole, itraconazole) 
are permitted throughout the study at the Investigator’s discretion.  The investigator 
should monitor subject cCa closely if these medications are initiated, discontinued, or 
the dose is changed. 
 
Cinacalcet is a strong inhibitor of CYP2D6.  Therefore, subjects receiving 
concomitant therapy with medications that are predominantly metabolized by the 
enzyme CYP2D6 and have a narrow therapeutic index (eg, flecainide, vinblastine, 
thioridazine, and most tricyclic antidepressants) should be monitored closely during 
initiation and titration of the IP.  Please refer to the product insert for additional 
details.  
6.9 
Pregnancy Prevention Requirements 
Female subject of childbearing potential who is unwilling to use an acceptable method of 
effective contraception during treatment with IP through 3 months after the last dose of 
IP.  Acceptable methods of effective birth control include not having intercourse (true 
sexual abstinence, hormonal birth control methods (oral, intravaginal, transdermal, 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 42 of 82 
CONFIDENTIAL 
 
 
injectable, or implantable), intrauterine devices, intrauterine hormonal-releasing system, 
surgical contraceptive methods (vasectomized partner with medical assessment of the 
surgical success of this procedure or bilateral tubal ligation/occlusion), or 2 barrier 
methods (each partner must use one barrier method and the female partner must use 
spermicide with the barrier method.  The male partner must use a condom and the 
female partner must choose either a diaphragm, OR cervical cap, OR contraceptive 
sponge.  A female condom is not an option because there is a risk of tearing when both 
partners use a condom.  The two-barrier is acceptable in countries where spermicide is 
not available).  Females of non-childbearing potential: 
 
Female subjects not of childbearing potential are defined as any female who: 
 
Is post-menopausal by history, defined as: 
o Age ≥ 55 years with cessation of menses for 12 or more months, OR 
o Age < 55 years but no spontaneous menses for at least 2 years, OR 
o Age < 55 years and spontaneous menses within the past 1 year, but 
currently amenorrhoeic (eg, spontaneous or secondary to hysterectomy), 
AND with postmenopausal gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol 
levels (< 5 ng/dL) or according to the definition of "postmenopausal 
range" for the laboratory involved. 
OR 
 
Underwent bilateral oophorectomy OR 
 
Underwent hysterectomy OR 
 
Underwent bilateral salpingectomy 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 2 can 
only be performed after obtaining a signed informed consent.  This includes any 
discontinuation of the subject’s medication for the purpose of participation in this study. 
It is very important to attempt to perform study procedures and obtain samples at the 
precise timepoints stipulated below.  When it is not possible to perform the study visit at 
the exact timepoint, the visit may be performed within the acceptable visit window as 
defined in the visit-specific section below. 
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the eCRFs.  Subsequent study visits should resume on the original 
schedule.  Missed assessments at prior visits should not be duplicated at subsequent 
visits unless discussed with Amgen. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
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CONFIDENTIAL 
 
 
Dosing schema is provided in Figure 1 
Initial IP dosing must start with a Monday through Friday hemodialysis treatment; initial 
dosing may not start with a Saturday hemodialysis treatment.  Assessments during the 
treatment period should be performed during the designated study week on the same 
hemodialysis treatment day of the week as the day dosing was started, whenever 
possible. 
The start of hemodialysis treatment is defined as when arterial flow is started.  The end 
of hemodialysis treatment is defined as when the prescribed hemodialysis time is 
completed (ie, remaining time on dialysis is zero) unless hemodialysis treatment is 
discontinued early; in this case the end of hemodialysis is when the arterial flow is 
stopped (eg, arterial line is clamped or disconnected to discontinue treatment). 
Procedures performed prior to hemodialysis should occur prior to the start of 
hemodialysis.  Procedures performed after hemodialysis should be performed after the 
end of hemodialysis. 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 44 of 82 
CONFIDENTIAL 
 
 
7.1 
Schedule of Assessments 
Table 2.  Schedule of Assessments 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-
91 
92-
98 
99-
105 
106-
112 
113-
119 
IV investigational product 
administration 
 
Three times per week at the end of the hemodialysis session starting from day 1 
Dose titrationb 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Kt/V or URRjL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pill count 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TIW Admin of IV IP (by site staff 
at the end of hemodialysis)d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to dialysis 
ECGf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testg 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin, Ca i j  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Phosphorus 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PTH 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PKh 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
25(OH)D 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on the next page 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 45 of 82 
CONFIDENTIAL 
 
 
Schedule of Assessments 
Table 2.  Schedule of Assessments 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-91 
92-
98 
99-
105 
106-
112 
113-
119 
After dialysis 
Pulse and blood pressureik 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK (10-30 minutes postdose)h 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 2 of 2 
25(OH)D = 25-hydroxy vitamin D; ADA = antidrug antibody;
; cCa = correct calcium; Ca =calcium; 
; 
ECG = electrocardiogram; IP = investigational product; HIV = Human immunodeficiency virus,  IV = intravenous; Kt/V = measure of dialysis adequacy;  
PTH = parathyroid hormone, PK = pharmacokinetic;  
TIW = three times per week; URR = urea reduction ratio 
a Baseline assessments will be performed on the first day of dosing with IP (day 1).  Assessments during the Treatment Period should be performed during the 
designated study week on the same hemodialysis treatment day of the week as the day dosing was started whenever possible. 
b The dose of IP may be increased or decreased at any time.  The dose of either active IP will be titrated to target predialysis 
 
but maintaining cCa ≥ 8.3 mg/dL (2.07 mmol/L).  Doses of investigational product will be managed by IVR/IWR and will be based on regular measurements of serum 
PTH and cCa levels obtained the week before dose adjustment. 
c The first dose of IP should occur within 1 day after randomization. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL (1.87 mmol87mmol/L), a predialysis serum sample for albumin and calcium should be submitted to the 
central laboratory on the day dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is 
obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP. 
f Subjects should remain supine or sitting for at least 10 minutes prior to recording the screening ECG, and be supine during the ECG.  The screening predialysis ECG 
is a single recording.  
g Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
h PK assessments can be done at any hemodialysis session during the treatment week. Note:  Per Section 7.4.2 this will not be drawn in subjects with a known 
history of HIV. 
i To be measured by the central laboratory  
j Chemistry will also include albumin and calcium 
k Subjects must be in a supine position in a rested and calm state for at least 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as possible.  
jL 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. 
 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 46 of 82 
CONFIDENTIAL 
 
 
Table 3  Schedule of Assessments Continued 
 
 
 
 
Treatment Perioda 
Follow-up 
 
 
Study Week (Study Day) 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27b 
30 days after last 
dose ± 3 days 
Early Term 
Dose 
Suspension 
IV investigational product administration 
 
 
 
Three times per week at the end of the 
hemodialysis session ending at week 26 
 
 
 
 
Dose titrationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Pill count 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
TIW Admin of IV IP (by site staff at the end of 
hemodialysis)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital statusf 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Prior to dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGg 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Serum pregnancy testh 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Chemistry 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Albumin, Ca i,j 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Xd 
Phosphorus 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
PTH 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
PK.k 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
25(OH)D 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
After dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse and blood pressureL 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
PK (10-30 min post dose)ik 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on the next page 
 
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ADA = antidrug antibody; 
; cCa = correct calcium; Ca =calcium; 
; ECG = electrocardiogram;  
IP = investigational product; IV = intravenous; PTH = parathyroid hormone, PK = pharmacokinetic; TIW = three times per week 
a Assessments during the Treatment Period should be performed during the designated study week on the same hemodialysis treatment day of the week as the day 
dosing was started whenever possible. 
b Week 27 assessments should be performed on the day of the first hemodialysis treatment after the last dose of IP. 
c The dose of IP may be decreased at any time. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL (1.87 mmol87mmol/L), a predialysis serum sample for albumin and calcium should be submitted to the 
central laboratory on the day dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is 
obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP.  
f Vital status will only be appropriately ascertained by sites for subjects who early terminated the study. 
g Subjects should remain supine or sitting for at least 10 minutes prior and be supine during the ECG.  The predialysis ECG is a single recording. 
h Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
i o be measured by the central laboratory.  
j Chemistry will also include albumin and calcium 
k PK assessments can be done at any hemodialysis session during the treatment week. 
L Subjects must be in a supine position in a rested and calm state 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is unable to be in 
the supine position, the subject should be in most recumbent position as possible. 
 
 
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7.2 
Study Procedures 
After signing the informed consent form, potential subjects will be evaluated to determine 
whether they fulfill the entry requirements listed in Section 4.1.  At screening, the subject 
should be reminded that participation in the study is contingent upon his or her screening 
test results.  The screening period begins the day the subject signs the informed consent 
form, and ends when the subject is randomized to receive the first dose of IP or fails the 
enrollment criteria. 
The procedures performed at each study visit are outlined above in Table 2.  Details 
regarding each type of procedure are provided in subsequent sub-sections. 
Refer to the applicable supplemental central laboratory, IVR/IWR system, and study 
manuals for detailed collection and handling procedures. 
7.2.1 
Screening Enrollment and/or Randomization 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
informed consent, the site will register the subject in IVR/IWR and screen the subject in 
order to assess eligibility for participation. 
The screening period is up to 8 weeks.  If a subject has not met all eligibility criteria at 
the end of the 8-week window, the subject will be registered as a screen fail.  Screen fail 
subjects may be eligible for re-screening once as described in Section 7.2.2. 
7.2.2 
Re-screening 
Screening assessments may be repeated up to 2 times during the 8-week screening 
period.  Subjects who do not meet eligibility requirements during the screening period 
will be permitted to be re-screened once as described in Section 5. 
7.2.3 
Treatment  
Procedures will be completed during the 26-week treatment period at the times 
designated in the Schedule of Assessments (Table 2).  Prior to enrollment, subject 
eligibility must be confirmed with screening procedures.  Subjects satisfying eligibility 
requirements will be enrolled and randomized 1:1 to either etelcalcetide or cinacalcet 
into the 26 week treatment period and should receive the first dose of investigational 
product within 1 day of randomization.  Randomization will be stratified by screening 
PTH level (< 900 pg/mL, ≥ 900 pg/mL) (< 95.40 pmol/L, ≥ 95.40 pmol/L), screening 
central laboratory serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) (≥ 2.25 mmol/L, 
< 2.25 mmol/L) measured by the central laboratory, and country (China versus 
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non-China).  The date of the first dose of IP is defined as day 1.  Baseline assessments 
will be performed on the first day of dosing with IP (day 1).  All subsequent study visits 
will be scheduled based on the day 1 date. 
The IP is to be administered after all pre-dose assessments have been completed on 
day 1.  Administration of IV IP is to be administered 3 times per week at the end of each 
hemodialysis session as specified in Section 6.2.1.  Assessments during the Treatment 
Period should be performed during the designated study week on the same 
hemodialysis treatment day of the week as the day dosing was started whenever 
possible.  Oral IP should be taken by the subject with food at approximately the same 
time every day of the 26-week treatment period as described in Section 6.2.2.  Week 27 
assessments should be performed on the day of the first hemodialysis treatment after 
the last dose of IP.  Concomitant medications, adverse events, and serious adverse 
events must be collected at every study visit. 
7.2.4 
Follow-up Visit 
Subjects will complete the follow-up visit 30 days (± 3 days) after the last dose of IP.  If a 
subject early terminates from IP or the study, the follow-up visit should also occur within 
30 days (± 3 days) after the last dose of IP. 
7.2.5 
Early Termination of Investigational Product Visit 
Subjects discontinuing IP prior to week 26 should return to the site for an early 
termination (ET) visit (refer to Table 2 and Table 3 for ET assessments) at the first 
hemodialysis treatment after the last dose of IP if at all possible, or at the earliest 
possible hemodialysis treatment.  Additionally, every attempt should be made to 
complete a follow-up visit 30 days (± 3 days) from the last dose of IP. 
After discontinuing IP, the subject may continue to participate in the study with varying 
levels of follow-up (refer to Section 8.1). 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures listed in 
Section 7.1 and Section 7.2.  Details regarding the collection, recording and reporting of 
adverse events and serious adverse events and/or other safety findings are provided in 
Section 9. 
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7.3.1 
Informed Consent 
All subjects/legally acceptable representatives must sign and personally date the 
IRB/IEC approved informed consent form before any study specific procedures are 
performed. 
7.3.2 
Medical History 
Detailed medical history including parathyroidectomy and known human 
immunodeficiency syndrome (HIV) status (yes/no) will be obtained at screening. 
Specific details on cardiovascular history will also be collected 
7.3.3 
Demographics 
Demographic data including age, sex, race, and ethnicity will be collected. 
7.3.4 
Physical Examination 
A physical examination will be conducted post hemodialysis per standard of care.  Any 
clinically significant findings noted at screening are to be detailed in the Medical History 
eCRF using the clinical diagnosis where applicable.  Investigators are to check for any 
findings that would constitute study exclusion.  Clinically significant findings noted at the 
30-day safety follow-up or early termination visits should be entered on the events eCRF 
as appropriate. 
7.3.5 
Height and Weight 
Height and weight will be collected and should be measured without shoes post 
hemodialysis. 
7.3.6 
Medication History 
The subject’s medications at screening (signing informed consent) will be recorded on 
the eCRF.  If the subject is not taking any calcium supplements, phosphate binders, or 
vitamin D sterols at screening, then the last use should be recorded.  If there is previous 
use of cinacalcet, then the most recent use should be recorded. 
7.3.7 
Concomitant Medication 
All medications taken while on study should be recorded on the eCRF per Section 6.5. 
Medications used to treat hemodialysis-related symptoms or comorbid conditions should 
be reported as concomitant medications whenever administered to the subject.  The 
following medications used in the delivery of hemodialysis should not be reported on the 
eCRF as concomitant medication: 
 
local anesthetic for cannulation 
 
saline prime for the dialysis circuit 
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 
saline or hypertonic saline for management of intradialytic hypotension 
 
oxygen 
7.3.8 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, and 
heart rate will be measured after hemodialysis. 
Subject must be in a supine position in a rested and calm state for at least 5 minutes 
before blood pressure and pulse rate assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as 
possible.  The position selected for a subject should be the same that is used throughout 
the study and documented on the vital sign eCRF. 
Record all measurements on the vital signs eCRF. 
7.3.9 
Electrocardiogram (ECG) 
Pre-hemodialysis ECGs will be obtained using ECG equipment available at the site.  
Subject must be in supine position in a rested and calm state for at least 10 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.  ECG 
abnormalities will be recorded in the Electrocardiogram eCRF. 
The Primary Investigator or designated site physician will review all ECGs.  Once 
signed, the original ECG tracing will be retained with the subject’s source documents.  At 
the request of the sponsor, a copy of the original ECG will be made available to Amgen. 
7.3.10 
Adverse Events and Disease Related Events 
Serious adverse events that occur in a subject after signing the informed consent form 
through 30 days after the last dose of IP will be recorded in the eCRF.  Non-serious 
adverse events will be recorded in the eCRF only if occurring after first dose of IP and 
through 30 days after the last dose of IP. 
7.3.11 
Pill Count 
Subjects should bring the bottle(s) of cinacalcet/placebo for a pill count approximately 
2 weeks after the dispensing visit, and then return the bottles(s) at the next dispensing 
visit approximately 2 weeks later for a final pill count for the dispensed bottles(s).  The 
first pill count will occur at week 3.  A pill count should also occur at an Early Termination 
visit. 
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7.3.12 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
should be obtained.  
For any subject who terminates early, study sites will be expected to attempt to collect 
survival status at week 26, if appropriate based on the applicable local regulations.  
7.4 
Laboratory Assessments 
All screening (except URR) and on-study laboratory samples will be processed and sent 
to the central laboratory.  If screening samples for URR or Kt/V are required, they will be 
processed at the site’s local laboratory.  When dosing with IP is suspended for 
cCa < 7.5 mg/dL (1.87 mmol/L), a predialysis serum sample for albumin and calcium 
should be submitted to the central laboratory on the day dosing is suspended.  Dose 
suspension samples do not need to be collected if a routine, local chemistry or 
albumin/calcium/phosphorous sample is obtained on the same day.  The results of this 
testing will be maintained in the source documents at the site.  The central laboratory will 
provide a study manual that outlines handling, labeling, and shipping procedures for all 
samples.  Please refer to the central laboratory manual for the complete listing of 
analytes run by the central laboratory.  Blood samples will be obtained before IP 
administration (except for the post-dialysis PK samples).  The date and time of sample 
collection will be recorded in the source documents at the site.   
Table 4. outlines the specific analytes for serum chemistry, hematology, urinalysis, and 
other testing to be conducted on blood and urine samples by central, local, or core 
laboratories. 
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Table 4.  Analytes Table 
Chemistry 
Hematologyc 
Other 
Sodium 
Hemoglobin 
Antibodiesa 
Potassium 
Hematocrit 
Pregnancy test 
Chloride 
Platelets 
Intact PTH 
Bicarbonate 
WBC  
25-hydroxyvitamin D 
Total protein 
RBC 
Albumin 
 
Calcium 
Ureab 
Corrected calcium 
(calculated) 
 
Magnesium 
Phosphorus 
Glucose 
Total bilirubinc 
Direct bilirubinc 
ALP 
LDH 
AST (SGOT)c 
ALT (SGPT)c 
ALP = serum alkaline phosphatase; ALT = alanine aminotransaminase; AST = aspartate transaminase; 
; LDH = lactate dehydrogenase; 
PTH = parathyroid hormone; RBC = red blood cells; SGOT = Serum glutamic oxaloacetic transaminase; 
SGPT = Serum glutamic pyruvic transaminase; WBC = white blood cells 
a These assays may be performed at a specialty laboratory 
b Urea 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. 
c If the central laboratory result is not available, local laboratory values may be used to determine 
eligibility, but Amgen must be contacted prior to randomization. 
When albumin is < 4.0 g/dL (40g/L), the calcium level will be corrected according to the 
following formula: 
cCa (mg/dL) = total Ca (mg/dL) + (4 - albumin [g/dL]) x 0.8. 
7.4.1 
Hepatitis Testing 
Baseline hepatitis testing may be conducted if there is a clinically relevant increase in 
liver function tests of unknown etiology during the study or the increase meets the 
criteria for permanent discontinuation or conditional withholding of Amgen IP because of 
potential hepatotoxicity.  For this purpose, a baseline sample will not be specifically 
stored for hepatitis testing but will be taken from the back-up baseline sample for 
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antibody testing.  If needed, a hepatitis-screening panel (for hepatitis A, B, and C) will be 
performed. 
7.4.2 
Pharmacokinetic Sampling 
Blood samples will be collected and assayed for etelcalcetide serum concentration.  The 
PK samples will be analyzed only for those subjects assigned to etelcalcetide.  PK 
assessments can be done at any hemodialysis session during the treatment week.  
Subjects with a known history of HIV will not have samples drawn for PK analysis. 
Predialysis samples will be collected at weeks 4, 12, 26, and at the 30-day Safety 
Follow-up visit.  Post-dialysis (10 to 30 minutes post-dose) blood samples will be 
collected at weeks 4,12, and 26. 
7.5 
Antibody Testing Procedures 
Blood samples for antibody testing for the measurement of anti-etelcalcetide antibodies 
will be collected.  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-etelcalcetide antibodies during the study. 
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 with a known history of HIV will not have samples drawn for antibody 
testing.  
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 IP 
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 IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 2) and collection of data, including endpoints and adverse 
events.  The investigator must document the change to the Schedule of Assessments 
(Table 2) and the level of follow-up that is agreed to by the subject (eg, in person, by 
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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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP 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 IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
8.3 
Reasons for Removal From Procedures, Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
Protocol Specified Criteria 
 
subject requires a significant permanent change in hemodialysis prescription to 
maintain adequate hemodialysis 
 
subject receives a kidney transplant 
 
subject undergoes a parathyroidectomy 
 
Ineligibility determined 
 
Protocol deviation 
 
Noncompliance 
 
Subject request   
 
Adverse event 
 
Death 
 
Lost to follow-up 
 
Decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
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Subjects who are removed from protocol-required IP(s) will be approached by 
investigators to determine the amount of follow-up assessments but at a minimum for 
vital status at the week 26. 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical study 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event. 
For the purpose of this study any asymptomatic reductions in serum cCa below 
7.5 mg/dL (1.87 mmol/L) measured by either the central laboratory or the local 
laboratory or asymptomatic reductions in serum cCa between 7.5 mg/dL (1.87 mmol/L) 
and < 8.3 mg/dL (2.07 mmol/L), measured by either the central laboratory or the 
local laboratory, that the investigator deems clinically significant (eg, required medical 
management) should be reported on the eCRF as “blood calcium decreased.”  
Symptomatic reductions in serum cCa < 8.3 mg/dL (2.07 mmol/L) measured by either 
the central laboratory or the local laboratory should be reported as “hypocalcemia”, 
and the associated signs and symptoms should also be captured. 
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The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment because of an adverse event.  In the event a subject, or 
subject’s legally acceptable representative requests to withdraw from protocol-required 
therapies or the study because of an adverse event, refer to Section 8 for additional 
instructions on the procedures recommended for safe withdrawal from protocol-required 
therapies or the study. 
9.1.2 
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 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of IP(s)/study 
treatment/protocol-required therapies through 30 days after the last dose of IP are 
reported using the Event CRF. 
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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 (mild, moderate, severe), 
 
Assessment of relatedness to IP or other protocol-required therapies, and 
 
Action taken 
The adverse event grading scale used will be the following: 
 
Mild:  Aware of sign or symptom, but easily tolerated 
 
Moderate:  Discomfort enough to cause interference with usual activity 
 
Severe:  Incapacitating with inability to work or do usual activity 
The grading scale used in this study is described in Appendix A.  The investigator must 
assess whether the adverse event is possibly related to IP.  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 IP? 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing the informed consent 
form through 30 days after the last day of the dosing interval of IP are recorded in the 
subject’s medical record and are submitted to Amgen.  All serious adverse events must 
be submitted to Amgen within 24 hours following the investigator’s knowledge of the 
event via the Event CRF. 
If the 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 
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Contingency Report Form within 24 hours of the investigator’s knowledge of the event.  
See Appendix B. for a sample of the Serious Adverse Event Worksheet/electronic 
Serious Adverse Event Contingency Report Form.  For EDC studies where the first 
notification of a Serious Adverse Event is reported to Amgen via the electronic Serious 
Adverse Event Contingency Report Form, the data must be entered into the EDC 
system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and GCP.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
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9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting. 
9.2.2 
Adverse Events of Interest 
Based on the mechanism of action, pharmacological profile of etelcalcetide, potential 
class effects of etelcalcetide as a CaR agonist, and observations made during the 
nonclinical and clinical program, certain safety events were considered of special 
interest as follows: cardiac failure, Torsade de pointes-QT prolongation and ventricular 
arrhythmia, convulsions, hypersensitivity, hypocalcemia, a dynamic bone, 
hypophosphatemia, and infusion reactions. 
9.2.3 
Changes in Serum Calcium and Symptomatic Hypocalcemia 
Serum cCa levels will be analyzed by the central laboratory throughout the study, and 
these results will be incorporated in the clinical database. The cCa measured by the 
local laboratory and collected for the management of safety concerns will also be 
incorporated in the clinical database. Per Section 6.2.3.2 dosing with IP will be 
suspended if a predialysis serum cCa < 7.5 mg/dL (1.87 mmol/L) value from either the 
central or local laboratory is observed.  A repeat central laboratory serum cCa will be 
obtained prior to hemodialysis at the next hemodialysis session, to allow verification of 
the low serum cCa level.  Central laboratory serum cCa will continue to be monitored 
per protocol if IP dosing is suspended for low serum cCa. Dosing may subsequently 
resume when central laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L) and any 
hypocalcemic symptoms have resolved with the dose (1) reduced by 5 mg, or at the 
minimum dose of 2.5 mg, whichever is greater for IV IP, or (2) reduced by 25 mg, or at 
the minimum dose of 25 mg, whichever is greater for oral IP. 
Investigators should assess subjects for the onset of signs and symptoms associated 
with low serum calcium (see Section 6.2.3.3) at each visit.  Any asymptomatic 
reductions in serum cCa below 7.5 mg/dL (1.87 mmol/L) from either the central or 
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local laboratory or asymptomatic reductions in serum cCa between 7.5 mg/dL 
(1.87 mmol/L) and < 8.3 mg/dL (2.07 mmol/L) from either the central or local 
laboratory that the investigator deems clinically significant (eg, required medical 
management) should be reported on the eCRF as “blood calcium decreased.”   
When signs and symptoms associated with low serum calcium are observed, 
“hypocalcemia” should be reported as the adverse event and the associated signs and 
symptoms should also be captured. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen Global 
Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of protocol-required therapies through 
3 months after the last dose of IP. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet Appendix C.).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
3 months after the last dose of IP.  Any lactation case should be reported to Amgen 
Global Patient Safety within 24 hours of the investigator’s knowledge of event.  Report a 
lactation case on the Lactation Notification Worksheet (Appendix C.).  Amgen Global 
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Patient Safety will follow-up with the investigator regarding additional information that 
may be requested. 
If a male subject’s female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
The primary endpoint of the study is achievement of a > 30% reduction from baseline in 
mean predialysis serum PTH level from baseline during the EAP of the study (EAP is 
defined as weeks 20 to 27, inclusive). 
10.1.1.2 
Key Secondary Endpoints 
 
Achievement of a > 50% reduction from baseline in mean predialysis serum PTH 
during the EAP (superiority) 
 
Achievement of a > 30% reduction from baseline in mean predialysis serum PTH 
during the EAP (superiority) 
10.1.1.3 
Other Secondary Endpoints 
 
Percent change from baseline in mean predialysis measured by the central 
laboratory serum cCa during the EAP 
 
Achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
10.1.1.4 
Safety Endpoints 
 
Incidence of cCa < 8.3 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 8.0 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 7.5 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of treatment-emergent symptomatic hypocalcemia during the study 
 
Incidence of antibody formation to etelcalcetide 
 
Nature, frequency, severity, and relationship of treatment-emergent adverse events.  
10.1.1.5 
Exploratory Endpoints 
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10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects.  Subjects will be analyzed 
according to randomized treatment group.  Primary analysis for the primary and key 
secondary endpoints will be performed using the FAS. 
10.1.2.2 
PTH Completer Analysis Set 
The PTH Completer Analysis Set (PCAS) includes all randomized subjects with at least 
one predialysis PTH value during the EAP.  Subjects will be analyzed according to 
randomized treatment group. 
10.1.2.3 
cCa Completer Analysis Set 
The cCa Completer Analysis Set (CCAS) includes all randomized subjects with at least 
one predialysis cCa value, measured by the central laboratory, during the EAP.  
Subjects will be analyzed according to randomized treatment group. 
10.1.2.4 
Safety Analysis Set 
The Safety Analysis Set consists of all randomized subjects who receive at least one 
dose of IP.  Subjects will be analyzed according to randomized treatment unless the 
incorrect treatment is administered throughout the study period.  Safety analyses will be 
performed using the Safety Analysis Set. 
10.1.2.5 
Per Protocol Analysis Set 
The Per Protocol Analysis Set (PPAS) is defined as all randomized subjects who have 
no major protocol violations and have at least one post-dose PTH value and had at least 
16 weeks exposure of IP.  Subjects in the PPAS will be analyzed according to 
randomized treatment assignment.   
10.1.3 
Covariates and Subgroups 
All analyses of primary and key secondary endpoints will be adjusted for the effect of the 
stratification factors of screening PTH level (< 900 pg/mL, ≥ 900 pg/mL) (95.40 pmol/L, 
≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) (≥ 2.25 mmol/L, 
< 2.25 mmol/L) measured by the central laboratory, and country (China versus 
non-China).  The primary and key secondary endpoints will be analyzed in the 
subgroups defined by the stratification factors. 
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10.2 
Sample Size Considerations 
The sample size calculations are based on the results of the global head-to-head 
study (20120360) and take into consideration sufficient power for both the primary and 
secondary endpoints.  The non-inferiority margin is defined based on an Amgen 
EVOLVE trial (Study 20050182), which was a randomized, placebo-controlled trial.  
Using a similar subject population in the EVOLVE trial as intended to be recruited in this 
study, rates of 25% and 60% in the placebo and cinacalcet arms, respectively, were 
derived and the two-sided 95% CI for the treatment difference based on the large 
sample normal approximation is (31%, 39%).  Half of the lower limit of the CI for the 
treatment difference (compared to placebo) is 15.5%.  Taking a conservative approach, 
the non-inferiority margin is defined as 12%. 
Based on the global head-to-head study comparing etelcalcetide with cinacalcet 
(20120360), 58% of subjects randomized to cinacalcet and 68% of subjects randomized 
to etelcalcetide achieved a > 30% reduction from baseline in mean predialysis PTH 
during the EAP.  Using this data, 300 subjects per treatment arm will provide over 99% 
power to demonstrate non-inferiority using a margin of 12% for the upper bound of the 
95% 2-sided CI for the treatment difference between cinacalcet and etelcalcetide 
(cinacalcet - etelcalcetide).  
For the key secondary endpoint of achievement of >50% reduction from baseline in 
mean predialysis PTH during the EAP, 300 subjects per treatment group will provide 
approximately 84% power to detect a statistically significant difference between the 
treatment groups at the 5% significance level (two-sided), assuming a 52% and 
40% response rate in subjects randomized to etelcalcetide and cinacalcet, respectively.  
For the key secondary endpoint of achievement of >30% reduction from baseline in 
mean predialysis PTH during the EAP (superiority analysis), 300 subjects per treatment 
group will provide about 72% power to detect a statistically significant difference 
between the treatment groups at the 5% significance level (two-sided), assuming a 68% 
and 58% response rate in subjects randomized to etelcalcetide and cinacalcet, 
respectively. 
Considering the 10% dropout rate, the estimated sample size in each group is 
330 subjects. 
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10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (Section 5.2 and Section 9.2.1.2).  
Amgen staff or designees from departments such as Biological Sample Management or 
Clinical Immunology who are responsible for tracking, assaying or analyzing biological 
samples during the conduct of study are considered unblinded to the treatment 
assignments in the study.  These individuals will not have access to subject level clinical 
data. 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The primary analysis will be conducted upon achieving the Primary Completion 
milestone.  At the time of the Primary Analysis, the study will be unblinded and all 
endpoints will be evaluated.  
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
This is a phase 3 study to evaluate the efficacy of etelcalcetide as compared to 
cinacalcet.  The primary objective is to determine if etelcalcetide is non-inferior to 
cinacalcet on achievement of a >30% reduction from baseline in mean predialysis serum 
PTH during the EAP.  Etelcalcetide will be considered non-inferior if the upper bound of 
the two-sided 95% CI of the treatment difference (cinacalcet – etelcalcetide) is smaller 
than 12%.  If this criterion is met, the 2 key secondary endpoints will be tested 
sequentially.  The testing for the endpoint of achievement of a > 50% reduction from 
baseline in mean predialysis serum PTH during the EAP will be carried out first.  Only if 
the result achieves statistical significance, the secondary endpoint of achievement of a 
> 30% reduction from baseline in mean predialysis serum PTH during the EAP will be 
tested.  The other secondary endpoints will be formally tested if both key secondary 
endpoints are statistically significant.  To control for the family-wise error rate, the 
Hochberg procedure of adjustment for multiple comparisons will be used for testing of 
the other secondary endpoints.  The primary analysis of all primary and secondary 
endpoints will be conducted on the FAS. 
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For the efficacy endpoints using laboratory results measured by the central laboratory 
(predialysis PTH, cCa, and P), values based on averaging over the EAP will be used in 
the analyses where applicable. 
Baseline values for PTH, cCa, and P will be based on the mean of the screening value 
and the day 1 value. 
Descriptive statistics include number of observations, mean, median, standard deviation 
or standard error, minimum and maximum for continuous variables, and number and 
percent for categorical variables. 
Descriptive statistics of plasma etelcalcetide at week 4 collected prior to dialysis will be 
summarized.  The PK data collected may be pooled with other study data for further 
evaluation. 
10.5.2 
Primary Efficacy Endpoint 
A Mantel-Haenszel (MH) method with adjustment for the 3 randomization stratification 
factors will be used to compute the 2-sided 95% CI for the difference between proportion 
of subjects who achieve > 30% reduction from baseline in mean predialysis serum PTH 
during the EAP between the cinacalcet and etelcalcetide groups.  In the primary 
analysis, an imputation under the non-inferiority null method (Koch, 2008) will be applied 
to subjects who do not have PTH data during the EAP. 
The following sensitivity analysis for the primary analysis on FAS will be conducted: 
 
For subjects without PTH data during the EAP, the mean of the last 2 predialysis 
PTH values obtained after day 1 will be carried forward.  If only one value is 
available, this single value will be carried forward to the EAP.  A similar 
imputation approach as the primary analysis will be applied to subjects without a 
post-baseline PTH value. 
In addition, supplementary analyses will be performed for primary endpoint using 
PCAS and PPAS. 
10.5.3 
Secondary Efficacy Endpoints 
Sequential testing of the following 2 key secondary efficacy endpoints will be performed 
if non-inferiority is demonstrated on the primary endpoint. 
 
achievement of > 50% reduction in mean predialysis serum PTH from baseline 
during the EAP (superiority) 
 
achievement of > 30% reduction in mean predialysis serum PTH from baseline 
during the EAP (superiority) 
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The endpoint of achievement of > 50% and > 30% reduction in mean predialysis serum 
PTH from baseline during the EAP will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test stratified by the randomization stratification factors.  In these analyses, 
subjects will be considered as not achieving the endpoint if they do not have PTH data 
during the EAP (ie, nonresponder imputation).  Sensitivity analysis will be conducted 
using multiple imputation method for both endpoints. 
10.5.3.1 
Other Secondary Efficacy Endpoints 
The following secondary endpoints will be formally tested if both key secondary 
endpoints are statistically significant.  To control the family-wise error rate, the Hochberg 
procedure of adjustment for multiple comparisons will be used: 
 
percent change from baseline in mean predialysis central laboratory serum cCa 
during the EAP 
 
achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
A repeated measures mixed effects model will be used to compare the percent change 
from baseline in serum cCa levels during the EAP, and will include the randomization 
stratification factors.  The difference between treatment groups will be presented with 
95% CI.  The analysis will be performed on the FAS and supplementary analysis will be 
performed using the cCa completer analysis set.  The achievement of mean predialysis 
serum P ≤ 4.5 mg/dL during the EAP will be analyzed by using CMH test stratified by the 
randomization stratification factors.  The difference between treatments will be estimated 
and presented with a 95% confidence interval.  These analyses will be performed on the 
FAS using the nonresponder imputation for those subjects without laboratory values 
during the EAP. 
10.5.4 
Safety Endpoints 
All reported adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, high-level group term, and preferred term.  Tables of fatal adverse events, 
serious adverse events, adverse events leading to withdrawal from IP, and 
treatment-emergent adverse events of interest will also be provided. 
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Proportion of subjects (with 95% confidence interval) with the following will be presented 
by treatment group: 
 
cCa < 8.3 mg/dL measured by the central laboratory 
 
cCa < 8.0 mg/dL measured by the central laboratory cCa < 7.5 mg/dL 
measured by the central laboratory 
 
treatment-emergent symptomatic hypocalcemia adverse event during the study 
will be presented by treatment group.  
No formal statistical testing will be performed. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any IP(s) 
is/are administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
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retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  Refer to ICH GCP guideline, Section 4.8.9. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen IP. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC 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/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
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 eCRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment. 
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
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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/IEC 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 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/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC 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/IEC in writing of the 
study’s completion or ET and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen IP(s) 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 IP(s) and by what mechanism, after termination of the study and before the 
product(s) is/are 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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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. 
In this study, the IVR/IWR system captures the following data points and these are 
considered source data: 
 
Planned IP dose 
 
Treatment assignment 
 
Box ID/Kit number 
eCRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data). 
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 eCRF, informed consent forms, and 
subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s 
Brochure, copies of prestudy documentation, and all correspondence to 
and from the IRB/IEC and Amgen 
 
IP-related correspondence including Proof of Receipts, IP Accountability 
Record(s), Return of IP for Destruction Form(s), Final IP Reconciliation 
Statement, as applicable. 
 
Non-IP(s) documentation, as applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
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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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
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 eCRFs, 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 eCRFs must be maintained and 
readily available. 
 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail.” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the eCRF, the data queries, and agrees with the 
content. 
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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. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subject’s 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 (Table 2), the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible. 
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
12.6 
Publication Policy 
To coordinate dissemination of data from this study, the investigator will solicit input and 
assistance from Amgen staff as appropriate. 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
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the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, 3, and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
Approved 
 
 


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13. 
REFERENCES 
Amgen. Investigator Brochure.  Edition 8. 
Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients 
with end-stage renal disease. Kidney Int. 2000;58(1):396-399. 
Bieber B, Qian J, Anand S, et al. Two-times weekly hemodialysis in China: frequency, 
associated patient and treatment characteristics and Quality of Life in the China Dialysis 
Outcomes and Practice Patterns study. Nephrol Dial Transplant. 2014;29:1770–1777. 
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. 
Cinacalcet package insert. Kyowa Hakko Kirin Co., Ltd. 
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. 
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. 
Koch G.G. Comments on ‘current issues in non-inferiority trials’ by Thomas R. Fleming, 
Statistics in Medicine, 2008; 27, 333-342. 
Kong X, Zhang L, Zhang L, et al. Mineral and bone disorder in Chinese dialysis patients: 
a multicenter study. BMC Nephrology. 2012; 13:116-122. 
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. 
Moe SM, Reslerova M, Ketteler M., et al. Role of calcification inhibitors in the 
pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int. 
2005;67(6):2295-2304. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
Work in Medical Journals 2013: http://www.icmje.org/ 
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. 
Approved 
 
 


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14. 
APPENDICES 
Approved 
 
 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of a serious adverse event, NOT when it is rated as severesevere 
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 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 eCRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.2.. 
Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) because of potential DILI as specified in Sections 6.4.1 
and 6.4.2 or who experience AST or ALT elevations > 3 x ULN are to undergo a period 
of “close observation” until abnormalities return to normal or to the subject’s baseline 
levels.  Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. Note:  Bilirubin (total and direct), ALT, and AST should be 
Approved 
 
 


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measured by the local laboratory if the central laboratory is unable to perform the 
analysis. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
 
Obtain plasma or serum acetaminophen (paracetamol) levels 
 
Obtain a more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Obtain viral serologies 
 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
 
Perform appropriate liver imaging if clinically indicated 
 
Obtain appropriate blood sampling for PK 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 IP(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 eCRFs. 
Approved 
 
 


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Appendix B.  Sample Serious Adverse Event Report Form 
 
 
 
Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
 
Approved 
 
 


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Approved 
 
 


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Amendment 3 
Protocol Title:  A Multicenter, Multiple-dose, Active-controlled, Double-blind, 
Double-dummy Study to Compare the Therapeutic Efficacy and Safety of Oral 
Doses of Cinacalcet Hydrochloride With Intravenous Doses of Etelcalcetide 
(AMG 416) in Asian Hemodialysis Subjects With Secondary Hyperparathyroidism 
 
Amgen Protocol Number (Etelcalcetide) 20150238 
 
Amendment 3 Date: 
27 November 2018 
 
Rationale: 
The rationale for the major changes in the study design is provided below: 
• 
Language clarifying the use of central and local laboratory results has been inserted 
throughout the protocol to ensure that all laboratory analyses are processed at the 
appropriate laboratory. 
Other changes to the protocol: 
• 
Laboratory values have been updated to include the International System of Units 
(SI) units. 
• 
Language on use of local hepatic laboratory results for eligibility and treatment of 
hepatic toxicities if central hepatic laboratory results are not available due to sample 
out of stability caused by shipping times has been included. 
• 
Medical History has been revised to include that subjects will be asked their human 
immunodeficiency virus (HIV) status to enable compliance with local restrictions 
regarding laboratory analysis where appropriate. 
• 
A PK sample has been added post-dose on week 26 
• 
Adverse Event (AE) descriptions have been made consistent throughout the protocol 
• 
The section on Drug Induced Liver Injury has been revised. 
• 
Definitions for primary completion date and end of treatment criteria have been 
clarified. 
• 
Study Efficacy endpoint analyses have been updated per ICH E9R1 
Approved 
 
 


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Description of Changes: 
Section:  Header date 
Replace: 
Date:  16 February 2018 
With: 
Date: 27 November 2018 
Section:  Title page 
Add: 
NCT #:  NCT03299244 
Date:   
 
04 December 2015 
Amendment 1   
07 February 2017 
Amendment 2   
16 February 2018 
Amendment 3 
27 November 2018 
Replace: 
 
Amgen, 1 Uxbridge Business Park 
Sanderson Road 
Uxbridge, Middlesex, UB8 1DH 
United Kingdom 
 
With: 
 
Amgen, 1 Uxbridge Business Park 
Sanderson Road 
Uxbridge, Middlesex, UB8 1DH 
United Kingdom 
 
 
Approved 
 
 


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Section:  Investigator’s Agreement 
Replace: 
I have read the attached protocol entitled:  A Multicenter, Multiple-dose, 
Active-controlled, Double-blind, Double-dummy Study to Compare the Therapeutic 
Efficacy and Safety of Oral Doses of Cinacalcet Hydrochloride with Intravenous Doses of 
Etelcalcetide (AMG 416) in Asian Hemodialysis Subjects with Secondary 
Hyperparathyroidism, dated 16 February 2018, and agree to abide by all provisions set 
forth therein. 
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 subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
With: 
I have read the attached protocol entitled:  A Multicenter, Multiple-dose, 
Active-controlled, Double-blind, Double-dummy Study to Compare the Therapeutic 
Efficacy and Safety of Oral Doses of Cinacalcet Hydrochloride with Intravenous Doses of 
Etelcalcetide (AMG 416) in Asian Hemodialysis Subjects with Secondary 
Hyperparathyroidism, dated 27 November 2018, and agree to abide by all provisions set 
forth therein. 
Section:  Protocol Synopsis 
Subsection: Secondary Objective 
Replace: 
Secondary Objective:  To assess whether treatment with etelcalcetide is superior to treatment 
with cinacalcet as measured by the proportion of subjects with > 50% decrease in serum PTH 
from baseline, proportion of subjects with > 30% decrease in serum PTH from baseline, percent 
change from baseline in mean predialysis albumin corrected calcium (cCa) and achievement of 
mean predialysis serum phosphorus (P) ≤ 4.5 mg/dl during the efficacy assessment phase (EAP). 
With: 
Secondary Objective:  To assess whether treatment with etelcalcetide is superior to treatment 
with cinacalcet as measured by the proportion of subjects with > 50% decrease in serum PTH 
Approved 
 
 


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from baseline, proportion of subjects with > 30% decrease in serum PTH from baseline, percent 
change from baseline in mean predialysis albumin corrected calcium (cCa) measured at the 
central laboratory, and achievement of mean predialysis serum phosphorus (P) ≤ 4.5 mg/dl 
measured at the central laboratory during the efficacy assessment phase (EAP). 
Subsection:  Other Secondary Endpoints 
Replace 
 
Percent change from baseline in mean predialysis serum cCa during the EAP 
 
Achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
With: 
 
Percent change from baseline in mean predialysis serum cCa measured by the 
central laboratory during the EAP 
 
Achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
Subsection: Safety Endpoints 
Replace: 
 
Incidence of cCa < 8.3 mg/dL at any time during the study 
 
Incidence of cCa < 8.0 mg/dL at any time during the study 
 
Incidence of cCa < 7.5 mg/dL at any time during the study 
 
Incidence of treatment-emergent symptomatic hypocalcemia during the study 
With 
 
Incidence of cCa < 8.3 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 8.0 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 7.5 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of treatment-emergent symptomatic hypocalcemia during the study 
Subsection:  Exploratory Endpoints 
Replace:  
Approved 
 
 


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Subsection:  Study Design 
Replace: 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL), screening 
serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL), and country (China versus non-China), and be 
randomized 1:1 to receive etelcalcetide or cinacalcet. 
With: 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) 
(≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central lab, and country (China versus 
non-China), and be randomized 1:1 to receive etelcalcetide or cinacalcet. 
Subsection:  Summary of Subject Eligibility Criteria 
Replace  
Subjects must have SHPT as defined by 1 central laboratory screening predialysis serum PTH 
value > 500 pg/mL (and one serum cCa value ≥ 8.3 mg/dL within 2 weeks prior to randomization.   
With: 
Subjects must have SHPT as defined by 1 central laboratory screening predialysis serum PTH 
value > 500 pg/mL (53.00 pmol/L) and one serum cCa value ≥ 8.3 mg/dL (2.07 mmol/L) within 
2 weeks prior to randomization.   
Subsection:  Amgen Investigational Product Dosage and Administration 
Replace:  
The starting dose of IV IP is 5 mg and will be titrated by the Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system to target predialysis
The 
minimum IV IP dose is 2.5 mg, and the maximum dose is 15 mg.  The dose of the IV IP may be 
increased in increments of 2.5 mg or 5 mg at weeks 5, 9, 13, and 17, if PTH values remain 
> 300 pg/mL and cCa values remain ≥ 8.3 mg/dL based on results obtained the previous week. 
With: 
The starting dose of IV IP is 5 mg and will be titrated by the Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system to target predialysis 
 
 
  The minimum IV IP dose is 2.5 mg, and the maximum dose is 15 mg.  The dose 
of the IV IP may be increased in increments of 2.5 mg or 5 mg at weeks 5, 9, 13, and 17, if PTH 
values remain > 300 pg/mL (31.80 pmol/L) and cCa values remain ≥ 8.3 mg/dL (2.07 mmol/L) 
based on results measured by the central laboratory obtained the previous or current week. 
Approved 
 
 


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Subsection:  Non-Amgen Investigational Product Dosage and Administration 
Replace: 
The starting dose of oral IP is 25 mg and will be titrated by the IVR/IWR to target predialysis 
  The minimum oral IP dose is 25 mg, and the maximum dose is 
100 mg.  The dose of oral IP may be increased in increments of 25 mg at weeks 5, 9, 13, and 17, 
if PTH values remain > 300 pg/mL and cCa values remain ≥ 8.3 mg/dL based on results obtained 
the previous week. 
With: 
The starting dose of oral IP is 25 mg and will be titrated by the IVR/IWR to target predialysis 
  The minimum oral IP dose is 25 mg, and the maximum 
dose is 100 mg.  The dose of oral IP may be increased in increments of 25 mg at weeks 5, 9, 13, 
and 17, if PTH values remain > 300 pg/mL (31.80 pmol/L) and cCa values remain ≥ 8.3 mg/dL 
(2.07 mmol/L) based on results measured by the central laboratory obtained the previous or 
current week. 
Subsection:  Procedures 
Replace: 
Randomization will be stratified by PTH level (< 900 pg/mL, ≥ 900 pg/mL), screening serum cCa 
(≥9.0 mg/dL, < 9.0 mg/dL), and country (China versus non-China).  Assessments during the 
treatment period should be performed during the designated study week on the same 
hemodialysis treatment day of the week as the day dosing was started and will be scheduled 
based on the day 1 date.  Subjects will complete the study at the follow-up visit 30 days 
(± 3 days) after the last dose of IP.  IP will be dosed to achieve predialysis 
 
 but maintaining cCa ≥ 8.3 mg/dL.  Doses of IP will be managed by IVR/IWR and will 
be based on regular measurements of serum PTH and cCa levels obtained the week before dose 
adjustment.  Dosing with IP may be suspended, and dosing resumed at a lower dose according 
to protocol-defined rules for low predialysis PTH (based on central laboratory values) or cCa 
values, for symptomatic hypocalcemia, or for other drug-related adverse events. 
With 
Randomization will be stratified by PTH level (< 900 pg/mL, ≥ 900 pg/mL) (< 95.40 pmol/L, 
≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) (≥ 2.25 mmol/L, 
< 2.25 mmol/L),  ), both measured by the central laboratory, and country (China versus non-
China).  Assessments during the treatment period should be performed during the designated 
study week on the same hemodialysis treatment day of the week as the day dosing was started 
and will be scheduled based on the day 1 date.  Subjects will complete the study at the follow-up 
visit 30 days (± 3 days) after the last dose of IP.  IP will be dosed to achieve predialysis 
 
Approved 
 
 


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 but maintaining cCa ≥ 8.3 mg/dL (2.07 mmol/L).  Doses of IP 
will be managed by IVR/IWR and will be based on regular measurements of serum PTH and cCa 
levels obtained the week before or week of dose adjustment.  Dosing of IP may occur if the 
cCa results from the central laboratory are not available (as described in Section 6.2.3); 
however, IV IP dose cannot be resumed or increased without an available cCa result from 
the central laboratory for the prior or current week. Dosing with IP may be suspended, and 
dosing resumed at a lower dose according to protocol-defined rules for low predialysis PTH 
(based on central laboratory values) or cCa values, for symptomatic hypocalcemia, or for other 
drug-related adverse events.  Corrected Calcium results from the local laboratory can only 
be used for the management of safety concerns and for suspension of IP; results must not 
be used for resumption or titration of IP.  A local cCa and central laboratory cCa, must not 
be collected at the same time. 
Subsection:  Statistical Considerations 
Replace: 
Proportion of subjects (with 95% confidence interval) with the following will be provided: 
• 
cCa < 8.3 mg/dL 
• 
cCa < 8.0 mg/dL 
• 
cCa < 7.5 mg/dL 
• 
treatment-emergent symptomatic hypocalcemia adverse events during the study 
will be presented by treatment group.  
With: 
Proportion of subjects (with 95% confidence interval) with the following will be provided: 
• 
cCa < 8.3 mg/dL measured by the central laboratory 
• 
cCa < 8.0 mg/dL measured by the central laboratory 
• 
cCa < 7.5 mg/dL measured by the central laboratory 
Subsection Study Design and Treatment Schema 
Replace: 
Study Design and Treatment Schema 
With 
Figure 1 Study Design and Treatment Schema 
Approved 
 
 


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Section:  Study Glossary 
Replace: 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint(s) 
With: 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for evaluation in the study at the follow-up visit 
(30 days after last dose [± 3 days]) or the last assessment is 
collected for the primary endpoint, whichever is later  
Add: 
HIV  
Human Immunodeficiency Virus 
Remove: 
SECs 
self-evident corrections 
Section:  1.2 Secondary Objectives 
Replace:  
 
To assess whether treatment with etelcalcetide is superior to treatment with 
cinacalcet as measured by the proportion of subjects with > 50% decrease in 
serum PTH from baseline, proportion of subjects with > 30% decrease in serum 
PTH from baseline, percent change from baseline in mean predialysis albumin 
corrected calcium (cCa) and achievement of mean predialysis serum phosphorus 
(P) ≤ 4.5 mg/dL during the efficacy assessment phase (EAP).  
Add: 
 
To assess whether treatment with etelcalcetide is superior to treatment with 
cinacalcet as measured by the proportion of subjects with > 50% decrease in 
serum PTH from baseline, proportion of subjects with > 30% decrease in serum 
PTH from baseline, percent change from baseline in mean predialysis albumin 
corrected calcium (cCa) measured by the central laboratory  and achievement 
of mean predialysis serum phosphorus (P) ≤ 4.5 mg/dL measured by the 
central laboratory during the efficacy assessment phase (EAP).  
Approved 
 
 


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Section:  2.2.1 Etelcalcetide 
Replace: 
Please refer to the etelcalcetide Amgen Investigator Brochure Edition 8 for additional 
detailed information about the chemistry, toxicology, preclinical pharmacology, 
pharmacokinetics (PK), safety, and clinical experience of etelcalcetide. 
With: 
Please refer to the etelcalcetide Amgen Investigator Brochure for additional detailed 
information about the chemistry, toxicology, preclinical pharmacology, pharmacokinetics 
(PK), safety, and clinical experience of etelcalcetide. 
Section:  3.1 Study Design 
Replace: 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) and country (China versus non-China) 
and be randomized 1:1 to receive etelcalcetide or cinacalcet. 
With: 
Subjects will be stratified by screening serum PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) 
(≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central laboratory, and country 
(China versus non-China), and be randomized 1:1 to receive etelcalcetide or cinacalcet. 
Section:  3.2 Number of Sites 
Replace: 
The study is planned to be conducted at approximately 120 centers in China, Taiwan, 
South Korea, Hong Kong, Malaysia, and India.  Other countries may be added as 
needed. 
With: 
The study is planned to be conducted at approximately 120 centers in China mainland, 
Taiwan, South Korea, Hong Kong, Malaysia, and India.  Other countries and/or regions 
may be added as needed. 
Approved 
 
 


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Section:  4.1.1 Inclusion Criteria 
Replace: 
105 
 Subject must have SHPT as defined by one central laboratory screening 
predialysis serum PTH value > 500 pg/mL, within 2 weeks prior to randomization. 
107  
Subject must have 1 screening predialysis serum cCa laboratory value 
≥ 8.3 mg/dL measured within 2 weeks prior to randomization. 
With: 
105 
 Subject must have SHPT as defined by one central laboratory screening 
predialysis serum PTH value > 500 pg/mL (53.00 pmol/L), within 2 weeks prior 
to randomization. 
107 Subject must have 1 screening predialysis serum cCa laboratory value ≥ 8.3 mg/dL 
(2.07 mmol/L) measured within 2 weeks prior to randomization. 
Section:  4.1.2 Exclusion Criteria 
Replace: 
216 Subject has clinically significant abnormalities on prestudy clinical examination or 
abnormalities on the most recent central laboratory tests during the screening 
period prior to randomization according to the Investigator including but not limited 
to the following: 
 
serum albumin < 3.0 g/dL  
 
serum magnesium < 1.5 mg/dL 
serum transaminase (alanine transaminase [ALT] or glutamic pyruvic transaminase 
[SGPT], aspartate aminotransferase [AST] or serum glutamic oxaloacetic transaminase 
[SGOT]) > 3 times the upper limit of normal (ULN) at screening 
Approved 
 
 


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With: 
216 
Subject has clinically significant abnormalities on prestudy clinical examination or 
abnormalities on the most recent central laboratory tests during the screening 
period prior to randomization according to the Investigator including but not 
limited to the following: 
 
serum albumin < 3.0 g/dL (30 g/L) 
 
serum magnesium < 1.5 mg/dL (0.62 mmol/L) 
 
serum transaminase (alanine transaminase [ALT] or serum glutamic pyruvic 
transaminase [SGPT], aspartate aminotransferase [AST] or serum glutamic 
oxaloacetic transaminase [SGOT]) > 3 times the upper limit of normal 
(ULN) at screening 
Note:  if results of serum transaminases are not available, Amgen 
should be notified prior to randomization; serum transaminases may 
be measured at the local laboratory 
Section:  5.1 Randomization/ Treatment Assignment 
Replace: 
Subjects will be randomized by IVR/IWR in a 1:1 ratio to either TIW IV etelcalcetide (and 
daily oral placebo tablets) or daily oral cinacalcet tablets (and TIW IV placebo) in a 
double-blind, double-dummy manner, and should receive the first dose of IP within 1 day 
of randomization.  Randomization will be stratified by screening PTH level (< 900 pg/mL, 
≥ 900 pg/mL) screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL and country (China 
versus non-China).  The total duration of treatment will be 26 weeks.  IP will be dosed to 
achieve predialysis
Treatment groups will be blinded to the 
investigator, subjects, and the Amgen study team. 
With: 
Randomization will be stratified by screening PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) 
(≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central laboratory, and country 
(China versus non-China). The total duration of treatment will be 26 weeks.  IP will be 
dosed to achieve predialysis
Treatment 
groups will be blinded to the investigator, subjects, and the Amgen study team. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 12 of 48 
CONFIDENTIAL 
 
 
Section:  6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Replace: 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
obtained during the prior week. 
Subjects will be treated with IV IP three times weekly at the end of hemodialysis, for 
26 weeks.  The starting dose of IV IP is 5 mg and will be titrated by the IVR/IWR to 
target predialysis 
 and maintain cCa ≥ 8.3 mg/dL.  The minimum 
IV IP dose is 2.5 mg, and the maximum dose is 15 mg.  
Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1 unless any of 
the following criteria are met: 
o subject has missed 3 or more IV doses during the prior 3 weeks 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o predialysis serum cCa < 8.3 mg/dL during the prior week 
o predialysis
during the prior week 
Table 1. Investigational Product Dosing Algorithm Based on PTH 
PTH 
(pg/mL) 
IV IP Dose If Current 
Dose < 10mg 
IV IP Dose If Current 
Dose 10 mg 
Oral IP Dose 
PTH > 450 
Increase dose by 
2.5 mg 
Increase dose by 5 mg 
Increase dose by 25 mg 
300 < PTH 
≤ 450 
Increase dose by 
2.5 mg 
Increase dose by 
2.5 mg 
Increase dose by 25 mg 
PTH ≤ 300 
Maintain dose 
Maintain dose 
Maintain dose 
PTH < 100 
If 2 consecutive values 
at least 1 week apart, 
suspend dose 
If 2 consecutive values 
at least 1 week apart, 
suspend dose 
If 2 consecutive values at 
least 1 week apart, suspend 
dose 
IP = investigational product; IV = intravenous; PTH = parathyroid hormone 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 13 of 48 
CONFIDENTIAL 
 
 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
With: 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
from the central laboratory obtained during the prior or current week. 
Subjects will be treated with IV IP three times weekly at the end of hemodialysis, for 
26 weeks.  The starting dose of IV IP is 5 mg and will be titrated by the IVR/IWR to 
target predialysis 
and maintain cCa 
≥ 8.3 mg/dL (2.07 mmol/L).  The minimum IV IP dose is 2.5 mg, and the maximum dose 
is 15 mg.  
Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1 unless any of 
the following criteria are met: 
o subject has missed 3 or more IV doses during the prior 3 weeks 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o most recent predialysis serum cCa < 8.3 mg/dL (2.07 mmol/L) during 
the prior or current week  
o most recent predialysis
during 
the prior or current week 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 14 of 48 
CONFIDENTIAL 
 
 
Table 1. Investigational Product Dosing Algorithm Based on PTH 
PTH (pg/mL) 
IV IP Dose If 
Current Dose 
< 10mg 
IV IP Dose If 
Current Dose 
10 mg 
IV IP Dose If 
Current Dose 
12.5 mg 
Oral IP Dose 
PTH > 450 
(47.70 pmol/L) 
Increase dose 
by 2.5 mg 
Increase dose 
by 5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 25 mg 
300 (31.80 pmol/L) 
< PTH ≤ 450 
(47.70 pmol/L) 
Increase dose 
by 2.5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 2.5 mg 
Increase dose 
by 25 mg 
PTH ≤ 300 
(31.80 pmol/L) 
Maintain dose 
Maintain dose 
Maintain dose 
Maintain dose 
PTH < 100 
(10.60 pmol/L) 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
If 2 consecutive 
values at least 
1 week apart, 
suspend dose 
IP = investigational product; IV = intravenous; PTH = parathyroid hormone 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
Dosing of IP may occur if the cCa results from the central laboratory are not 
available (as described in Section 6.2.3); however, IV IP dose cannot be resumed 
or increased without an available cCa result from the central laboratory for the 
prior or current week. 
Section 6.2.2.1 Dosage, Administration, and Schedule: 
Replace: 
Oral IP should be taken by the subject with food, at approximately the same time on a 
daily basis during the 26-week duration of the study treatment period.  The oral IP 
should be taken by the subject at least 12 hours before the PTH assessment. 
If ≤ 7 consecutive daily doses of the oral IP were missed, because of reasons unrelated 
to those described in Section 6, the subject should be instructed to resume dosing at the 
IVR/IWR assigned dose.  The subject must not attempt to make up for any missed 
doses. 
The quantity, start date, stop date, and box number of oral IP are to be recorded on each 
subject’s eCRF.  When the oral IP is returned by the subject during a study visit (see Pill 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 15 of 48 
CONFIDENTIAL 
 
 
Count in Dose Schema in Table 3) the investigator or responsible person will determine 
the level of compliance with the administration of the oral IP.   
With: 
Oral IP should be taken by the subject with food, at approximately the same time on a 
daily basis during the 26-week duration of the study treatment period.  The oral IP 
should be taken by the subject at least 12 hours before the PTH laboratory 
assessment. 
If ≤ 7 consecutive daily doses of the oral IP were missed, because of reasons unrelated 
to those described in Section 6, the subject should be instructed to resume dosing at the 
IVR/IWR assigned dose.  The subject must not attempt to make up for any missed 
doses. 
The quantity, start date, stop date, and box number of oral IP are to be recorded on each 
subject’s eCRF.  When the oral IP is returned by the subject during a study visit (see Pill 
Count in Dose Schema in Figure 1) the investigator or responsible person will determine 
the level of compliance with the administration of the oral IP.   
Section:  6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Replace: 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
obtained during the prior week. 
Subjects will be treated with oral IP daily, for 26 weeks.  The starting dose of oral IP is 
25 mg and will be titrated by the IVR/IWR to target predialysis 
and maintain cCa ≥ 8.3 mg/dL. The minimum oral IP dose is 25 mg, and the maximum 
IP dose is 100 mg. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 16 of 48 
CONFIDENTIAL 
 
 
Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1 unless any of 
the following criteria are met: 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o predialysis serum cCa < 8.3 mg/dL during the prior week 
o predialysis
during the prior week 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
With: 
Sites and subjects will be blinded to central laboratory serum PTH values.  Routine local 
PTH monitoring during the study should be suspended.  IP dose titration will be 
managed by an IVR/IWR and will be based on predialysis serum PTH and cCa results 
obtained during the prior or current week. 
Subjects will be treated with oral IP daily, for 26 weeks.  The starting dose of oral IP is 
25 mg and will be titrated by the IVR/IWR to target predialysis 
and maintain cCa ≥ 8.3 mg/dL (2.07 mmol/L).  The minimum oral IP 
dose is 25 mg, and the maximum IP dose is 100 mg. 
Each subject’s predialysis central laboratory serum PTH and cCa result will be evaluated 
by the IVR/IWR to determine if the dose of IP should be increased.  The dose of IP may 
be increased by the IVR/IWR during weeks 5, 9, 13, and 17 per Table 1 unless any of 
the following criteria are met: 
o the dose of IP was reduced within the prior 3 weeks 
o there is an ongoing adverse event, including symptomatic hypocalcemia 
that precludes a dose increase 
o most recent predialysis serum cCa < 8.3 mg/dL (2.07 mmol/L) during the 
prior or current week 
o most recent predialysis
during 
the prior or current week 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 17 of 48 
CONFIDENTIAL 
 
 
To maintain the blind, the IVR/IWR will adjust (increase/decrease/suspend) the placebo 
IP dose in the same subject, if adjustment is required.  Any adjustments made by the 
Investigator independent of the IVR/IWR should follow the same process, with the 
reason for dose change recoded on the subject eCRF. 
Dosing of IP may occur if the cCa results from the central laboratory are not 
available (as described in Section 6.2.3), but oral IP dose cannot be resumed or 
increased without an available cCa result from the central laboratory from the 
prior or current week.  
Section:  6.2.3 Suspension and Reduction of Oral and Intravenous Investigational 
Product 
Replace: 
Dosing with IP may be suspended by the Investigator or by the IVR/IWR at any time if 
ANY of the criteria below apply.  IP dosing may resume only after ALL criteria 
contributing to suspension of IP dosing are resolved. 
 
two consecutive predialysis central laboratory PTH < 100 pg/mL at least 1 week 
apart (see Section 6.2.3.1) 
 
cCa is < 7.5 mg/dL (see Section 6.2.3.2   
 
subject experiences symptomatic hypocalcemia (see Section 6.2.3.3)   
 
there is any other ongoing adverse event that, in the opinion of the Investigator, 
necessitates suspension of IP dosing 
During a hospitalization or when hemodialysis is provided in a location other than the 
Investigator’s site, both oral and IV IPs should be suspended. 
The site will immediately enter the information in IVR/IWR and electronic data capture 
(EDC) system when a dose suspension rule is invoked and the reason for missed or 
suspended doses recoded on the subject eCRF.  Even when dosing with IP is 
suspended per protocol, all scheduled assessments should be completed. 
With: 
Dosing with IP may be suspended by the Investigator or by the IVR/IWR at any time if 
ANY of the criteria below apply.  IP dosing may resume only after ALL criteria 
contributing to suspension of IP dosing are resolved. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 18 of 48 
CONFIDENTIAL 
 
 
 
two consecutive predialysis central laboratory PTH < 100 pg/mL (10.60 pmol/L) at 
least 1 week apart (see Section 6.2.3.1) 
 
cCa is < 7.5 mg/dL (1.87 mmol/L) (see Section 6.2.3.2) measured by either the 
central or local laboratory 
 
subject experiences symptomatic hypocalcemia (see Section 6.2.3.3)  
 
there is any other ongoing adverse event that, in the opinion of the Investigator, 
necessitates suspension of IP dosing 
Moved from the third paragraph in the section to the second paragraph in the section: 
The site will immediately enter the information in IVR/IWR and electronic data 
capture (EDC) system when a dose suspension rule is invoked and the reason for 
missed or suspended doses is recorded on the subject eCRF.  Even when dosing 
with IP is suspended per protocol, all scheduled assessments should be 
completed. 
During a hospitalization or when hemodialysis is provided in a location other than the 
Investigator’s site, both oral and IV IPs should be suspended.  When hemodialysis is 
provided in a location other than the Investigator’s site, the visit should not be 
registered in the IVR/IWR.  The reasons for missed doses should be recorded on 
the subject eCRF. 
Section: 6.2.3.1 
Low Predialysis Serum PTH 
Replace: 
If a subject has 2 consecutive central laboratory predialysis serum PTH results obtained 
at least 1 week apart that are both < 100 pg/mL then the Investigator will be notified by 
the IVR/IWR that dosing of both the IV and oral IPs should be suspended. 
Intact PTH monitoring will continue per the protocol.  Once PTH is ≥ 150 pg/mL serum 
cCa ≥ 8.3 mg/dL, the Investigator will be notified by the IVR/IWR that dosing with the IV 
and oral IPs may resume at a 2.5 mg lower dose for the IV, and at a 25 mg lower dose 
for the oral. 
If a subject was receiving the 2.5 mg IV dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 2.5 mg dose level 
when PTH is > 300 pg/mL and the most recent predialysis. serum cCa ≥ 8.3 mg/dL. 
If a subject was receiving the 25 mg oral dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 25 mg dose level when 
PTH is > 300 pg/mL, and the most recent predialysis serum cCa ≥ 8.3 mg/dL.  
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 19 of 48 
CONFIDENTIAL 
 
 
With: 
If a subject has 2 consecutive central laboratory predialysis serum PTH results obtained 
at least 1 week apart that are both < 100 pg/mL (10.60 pmol/L), then the Investigator will 
be notified by the IVR/IWR that dosing of both the IV and oral IPs should be suspended. 
Intact PTH monitoring will continue per the protocol.  Once PTH is ≥ 150 pg/mL 
(15.90 pmol/L) and the central laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L), the 
Investigator will be notified by the IVR/IWR that dosing with the IV and oral IPs may 
resume at a 2.5 mg lower dose for the IV, and at a 25 mg lower dose for the oral. 
If a subject was receiving the 2.5 mg IV dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 2.5 mg dose level 
when PTH is > 300 pg/mL (31.80 pmol/L), and the most recent predialysis central 
laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L). 
If a subject was receiving the 25 mg oral dose of IP when dosing was suspended for low 
PTH, then dosing with IP may be resumed by the IVR/IWR at the 25 mg dose level when 
PTH is > 300 pg/mL (31.80 pmol/L), and the most recent predialysis central laboratory 
serum cCa ≥ 8.3 mg/dL (2.07 mmol/L).  
Section: 6.2.3.2 
Low Predialysis Serum Corrected Calcium 
Replace: 
Supplementation with oral calcium and/or increasing the dialysate calcium concentration 
may be instituted by the Investigator if serum cCa is below the lower limit of the 
reference range or there is a rapid large reduction in serum calcium, especially in 
subjects with PTH > 700 pg/mL and markedly elevated serum alkaline phosphatase 
(ALP) at baseline.  Increased calcium supplementation may only be needed on a 
temporary basis until mineral balance is re-established at the reduced PTH level. 
The following guidance is provided for the management of serum cCa below the lower 
limit of the reference range with any change to therapy based on Investigator clinical 
judgment.  If cCa < 8.3 mg/dL, the following options may be taken by the Investigator: 
 
May increase oral calcium intake  
 
May increase dialysate calcium concentration 
 
May initiate or increase active vitamin D analogues if other therapies are ineffective 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 20 of 48 
CONFIDENTIAL 
 
 
If is < 7.5 mg/dL or the subject experiences symptomatic hypocalcemia: 
 
Suspend dosing with IP, and at the next hemodialysis session following 
notification of the low serum calcium result, draw a confirmatory predialysis 
serum cCa sample. 
 
Obtain weekly predialysis serum cCa.  Once predialysis serum cCa ≥ 8.3 mg/dL 
and any hypocalcemic symptoms have resolved the IVR/IWR will provide 
instructions to resume dosing.  For the oral IP, the dose should be reduced by 
25 mg or at the minimum dose of 25 mg, whichever is greater.  For the IV IP, the 
dose should be reduced by 5 mg or at the minimum dose of 2.5 mg, whichever is 
greater.  Resume routine laboratory monitoring per Table 2, the Schedule of 
Assessments.  Refer to Section 7.2 for central laboratory samples to be 
submitted. 
With: 
Supplementation with oral calcium and/or increasing the dialysate calcium concentration 
may be instituted by the Investigator if serum cCa is below the lower limit of the 
reference range or there is a rapid large reduction in serum calcium, especially in 
subjects with PTH > 700 pg/mL (74.20 pmol/L) and markedly elevated serum alkaline 
phosphatase (ALP) at baseline.  Increased calcium supplementation may only be 
needed on a temporary basis until mineral balance is re-established at the reduced PTH 
level. 
The following guidance is provided for the management of serum cCa below the lower 
limit of the reference range with any change to therapy based on Investigator clinical 
judgment.  If the cCa measured by either the central or local laboratory is 
< 8.3 mg/dL (2.07 mmol/L), the following options may be taken by the Investigator: 
 
May increase oral calcium intake  
 
May increase dialysate calcium concentration 
 
May initiate or increase active vitamin D analogues if other therapies are ineffective 
If the cCa measured by either the central or local laboratory is < 7.5 mg/dL 
(1.87 mmol/L) or the subject experiences symptomatic hypocalcemia, in addition to the 
above actions, do the following: 
 
Suspend dosing with IP, and at the next hemodialysis session following 
notification of the low serum calcium result, draw a confirmatory predialysis 
serum cCa sample and send to the central laboratory. 
 
Obtain weekly predialysis central laboratory serum cCa.  Once predialysis 
serum cCa ≥ 8.3 mg/dL (2.07 mmol/L) and any hypocalcemic symptoms have 
resolved the IVR/IWR will provide instructions to resume dosing.  For the oral IP, 
the dose should be reduced by 25 mg or at the minimum dose of 25 mg, 
whichever is greater.  For the IV IP, the dose should be reduced by 5 mg or at 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 21 of 48 
CONFIDENTIAL 
 
 
the minimum dose of 2.5 mg, whichever is greater.  Resume routine laboratory 
monitoring per Table 2, the Schedule of Assessments.  Refer to Section 7.2 for 
central laboratory samples to be submitted. 
An unscheduled collection of cCa from the central laboratory can be done at any 
time for safety. A cCa collected and measured by the local laboratory can only be 
done for the management of safety concerns.  If the cCa measured by the local 
laboratory is < 7.5 mg/dL (1.87 mmol/L), IP must be suspended and can only be 
resumed once the cCa measured by the central laboratory is ≥ 8.3 mg/dL 
(2.07 mmol/L) (see Section 6.2.5). 
Section:  6.2.3.3 
Symptomatic Hypocalcemia 
Replace  
If dosing with IP is suspended for symptomatic hypocalcemia, dosing may resume at a 
lower dose once symptomatic hypocalcemia has resolved when the central laboratory 
cCa ≥ 8.3 mg/dL, and once the Investigator has notified the IVR/IWR.  
With: 
If dosing with IP is suspended for symptomatic hypocalcemia, dosing may resume at a 
lower dose once symptomatic hypocalcemia has resolved when the central laboratory 
cCa ≥ 8.3 mg/dL (2.07 mmol/L), and once the Investigator has notified the IVR/IWR.  
Section:  6.2.3.4 
Adverse Event 
Replace: 
If the adverse event was deemed to be IP related by the Investigator but not related to 
PTH < 100 pg/mL, cCa < 7.5 mg/dL or symptomatic hypocalcemia, dosing with IP may 
resume once the adverse event has resolved or stabilized with the dose reduced.  
With 
If the adverse event was deemed to be IP related by the Investigator but not related to 
PTH < 100 pg/mL (10.60 pmol/L), cCa < 7.5 mg/dL (1.87 mmol/L) or symptomatic 
hypocalcemia, dosing with IP may resume once the adverse event has resolved or 
stabilized and the central laboratory serum cCa is ≥ 8.3 mg/dL (2.07 mmol/L) with 
the dose reduced. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 22 of 48 
CONFIDENTIAL 
 
 
Section:  6.2.4 Resumption of Investigational Product After Repeated Missed Doses 
Replace: 
If more than 14 consecutive days of IP are missed (eg, extended hospitalization for an 
adverse event unrelated to IP, vacation), a central laboratory cCa must be obtained prior 
to restarting IP.  Only after the cCa is ≥ 8.3 mg/dL should dosing with IP resume.   
With: 
If more than 14 consecutive days of IP are missed (eg, extended hospitalization for an 
adverse event unrelated to IP, vacation), a central laboratory cCa must be obtained prior 
to restarting IP.  Only after the central laboratory cCa is ≥ 8.3 mg/dL (2.07 mmol/L) 
should dosing with IP resume. 
Section:  6.2.5 cCa performed at the local laboratory 
New section added: 
A cCa can only be collected and measured by the local laboratory for the 
management of safety concerns and/or suspension of IP.  All cCa results 
measured by the local laboratory will be recorded on the eCRF.  If the cCa is 
< 7.5 mg/dL (1.87 mmol/L) or the subject experiences symptomatic hypocalcemia, 
refer to Section 6.2.3.2 for further management. The IP can only be resumed once 
the cCa measured by the central laboratory is ≥ 8.3 mg/dL (2.07 mmol/L). 
A local laboratory cCa and central laboratory cCa, must not be collected at the 
same time. 
If the local laboratory cCa is < 7.5 mg/dL (1.87 mmol/L), suspend IP by registering 
a suspension in IVR/IWR with the reason of adverse event related to IP or 
symptomatic hypocalcemia depending on the clinical assessment. 
Section:  6.4 Hepatotoxicity Stopping and Rechallenge Rules 
Replace: 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, 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 IP or other protocol-required therapies (as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009). 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 23 of 48 
CONFIDENTIAL 
 
 
With: 
Subjects with abnormal hepatic laboratory values (ie, ALP, AST, 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 IP or other protocol-required therapies (as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009).Note:  If the 
central laboratory is unable to perform the analysis of the hepatic laboratory tests 
(as discussed with Amgen during screening) then those tests should be measured 
by the local laboratory. 
Section:  6.4.1 Criteria for Permanent Discontinuation of Amgen Investigational Product 
and Other Protocol-required Therapies due to Potential Hepatotoxicity 
Replace: 
IP should be discontinued permanently by the Investigator and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met. 
 
TBL > 2 x ULN or International Normalized Ratio (INR) > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
 
Obstructive gall bladder or bile duct disease 
 
Viral or alcoholic hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, etc) 
 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome); 
alpha-one antitrypsin deficiency 
 
Autoimmune hepatitis  
 
Nonalcoholic Steatohepatitis (NASH) or other “fatty liver disease” 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 24 of 48 
CONFIDENTIAL 
 
 
With: 
IP should be discontinued permanently by the Investigator and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met. 
 
TBL > 2 x ULN or International Normalized Ratio (INR) > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
 
AND no other cause for the combination of laboratory abnormalities is 
immediately apparent; important potential causes for abnormal AST/ALT or 
TBL values include, but are not limited to: 
 
Obstructive gall bladder or bile duct disease 
 
Viral or alcoholic hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, etc) 
 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome); 
alpha-one antitrypsin deficiency 
 
Autoimmune hepatitis  
 
Nonalcoholic Steatohepatitis (NASH) or other “fatty liver disease” 
Section:  6.5.6.1 
Management of Elevated Serum Corrected Calcium or 
Symptomatic Hypercalcemia 
Replace: 
If a subject has 2 consecutive central laboratory cCa > 10.6 mg/dL, then doses of active 
vitamin D sterol, oral calcium intake, and/or dialysate calcium concentration may be 
reduced based on Investigator clinical judgment; however, dialysate calcium 
concentration must remain ≥ 2.5 mEq/L (1.25 mmol/L), unless otherwise permitted by 
Amgen. 
If a subject has a central laboratory cCa > 11.0 mg/dL, or develops symptomatic 
hypercalcemia, then any active vitamin D sterol and oral calcium intake (including 
calcium-based phosphate binders) may be reduced or discontinued, and dialysate 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 25 of 48 
CONFIDENTIAL 
 
 
calcium concentration may be reduced based on Investigator clinical judgment; however, 
dialysate calcium concentration must remain ≥ 2.5 mEq/L (1.25 mmol/L).   
With: 
If a subject has 2 consecutive central laboratory cCa > 10.6 mg/dL (2.64 mmol/L), then 
doses of active vitamin D sterol, oral calcium intake, and/or dialysate calcium 
concentration may be reduced based on Investigator clinical judgment; however, 
dialysate calcium concentration must remain ≥ 2.5 mEq/L (1.25 mmol/L), unless 
otherwise permitted by Amgen. 
If a subject has a central laboratory cCa > 11.0 mg/dL (2.74 mmol/L) or develops 
symptomatic hypercalcemia. then any active vitamin D sterol and oral calcium intake 
(including calcium-based phosphate binders) may be reduced or discontinued, and 
dialysate calcium concentration may be reduced based on Investigator clinical judgment; 
however, dialysate calcium concentration must remain ≥ 2.5 mEq/L (1.25 mmol/L).   
Section: 6.5.6.2 
Management of Serum Phosphorous 
Replace: 
 
If 2 consecutive local predialysis serum P values are > 5.5 mg/dL and not amenable 
to modification via dietary counseling, then the dose of phosphate binder may be 
increased. 
 
If 2 consecutive local predialysis serum P values are < 3.0 mg/dL, then the dose of 
phosphate binder may be decreased. 
With: 
 
If 2 consecutive local predialysis serum P values are > 5.5 mg/dL (1.78 mmol/L) and 
not amenable to modification via dietary counseling, then the dose of phosphate 
binder may be increased. 
 
If 2 consecutive local predialysis serum P values are < 3.0 mg/dL (0.97 mmol/L), 
then the dose of phosphate binder may be decreased. 
Section: 7 
STUDY PROCEDURES 
Replace: 
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the eCRFs.  Subsequent study visits should resume on the original 
schedule.  Missed assessments at prior visits should not be duplicated at subsequent 
visits. 
Dosing schema is provided in Table 3 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 26 of 48 
CONFIDENTIAL 
 
 
With: 
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the eCRFs.  Subsequent study visits should resume on the original 
schedule.  Missed assessments at prior visits should not be duplicated at subsequent 
visits unless discussed with Amgen.  
Dosing schema is provided in Figure 1 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 27 of 48 
CONFIDENTIAL 
 
 
Section 7.1 
Schedule of Assessments 
Replace: 
Table 2. Schedule of Assessments and Dosing Schema 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-
91 
92-
98 
99-
105 
106-
112 
113-
119 
IV investigational product 
administration 
 
Three times per week at the end of the hemodialysis session starting from day 1 
Dose titrationb 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Kt/V or URRj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pill count 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TIW Admin of IV IP (by site staff 
at the end of hemodialysis)d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to dialysis 
ECGf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testg 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin, Ca 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Phosphorus 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PTH 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PKh 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
25(OH)D 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on the next page 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 28 of 48 
CONFIDENTIAL 
 
 
Table 2. Schedule of Assessments and Dosing Schema 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-91 
92-
98 
99-
105 
106-
112 
113-
119 
After dialysis 
Pulse and blood pressurei 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK (10-30 minutes postdose)h 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 2 of 2 
25(OH)D = 25-hydroxy vitamin D; ADA = antidrug antibody; 
; cCa = correct calcium; Ca =calcium; 
; 
ECG = electrocardiogram; IP = investigational product; IV = intravenous; Kt/V = measure of dialysis adequacy; PTH = parathyroid hormone, PK = pharmacokinetic;  
TIW = three times per week; URR = urea reduction ratio 
a Baseline assessments will be performed on the first day of dosing with IP (day 1).  Assessments during the Treatment Period should be performed during the 
designated study week on the same hemodialysis treatment day of the week as the day dosing was started whenever possible. 
b The dose of IP may be increased or decreased at any time.  The dose of either active IP will be titrated to target predialysis 
 but maintaining 
cCa ≥ 8.3 mg/dL.  Doses of investigational product will be managed by IVR/IWR and will be based on regular measurements of serum PTH and cCa levels obtained 
the week before dose adjustment. 
c The first dose of IP should occur within 1 day after randomization. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL, a predialysis serum sample for albumin and calcium should be submitted to the central laboratory on the day 
dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP. 
f Subjects should remain supine or sitting for at least 10 minutes prior to recording the screening ECG, and be supine during the ECG.  The screening predialysis ECG 
is a single recording.  
g Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
h PK assessments can be done at any hemodialysis session during the treatment week. 
i Subjects must be in a supine position in a rested and calm state for at least 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as possible. 
j 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. 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 29 of 48 
CONFIDENTIAL 
 
 
With: 
Table 2.  Schedule of Assessments 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-
91 
92-
98 
99-
105 
106-
112 
113-
119 
IV investigational product 
administration 
 
Three times per week at the end of the hemodialysis session starting from day 1 
Dose titrationb 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Kt/V or URRL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pill count 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
TIW Admin of IV IP (by site staff 
at the end of hemodialysis)d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior to dialysis 
ECGf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testg 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin, Ca i j  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Phosphorus 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PTH 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PKh 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
25(OH)D 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on the next page 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 30 of 48 
CONFIDENTIAL 
 
 
Table 2.  Schedule of Assessments 
 
 
Treatment Perioda 
Study Week 
Screening 
Day 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Day 
Day -56 to -1 
Day 1 
8-
14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-84 
85-91 
92-
98 
99-
105 
106-
112 
113-
119 
After dialysis 
Pulse and blood pressureik 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK (10-30 minutes postdose)h 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Page 2 of 2 
25(OH)D = 25-hydroxy vitamin D; ADA = antidrug antibody;
; cCa = correct calcium; Ca =calcium; 
; 
ECG = electrocardiogram; IP = investigational product; HIV = Human immunodeficiency virus,  IV = intravenous; Kt/V = measure of dialysis adequacy;  
PTH = parathyroid hormone, PK = pharmacokinetic; TIW = three times per week; URR = urea reduction ratio 
a Baseline assessments will be performed on the first day of dosing with IP (day 1).  Assessments during the Treatment Period should be performed during the 
designated study week on the same hemodialysis treatment day of the week as the day dosing was started whenever possible. 
b The dose of IP may be increased or decreased at any time.  The dose of either active IP will be titrated to target predialysis 
 
but maintaining cCa ≥ 8.3 mg/dL (2.07 mmol/L).  Doses of investigational product will be managed by IVR/IWR and will be based on regular measurements of serum 
PTH and cCa levels obtained the week before dose adjustment. 
c The first dose of IP should occur within 1 day after randomization. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL (1.87 mmol87mmol/L), a predialysis serum sample for albumin and calcium should be submitted to the 
central laboratory on the day dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is 
obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP. 
f Subjects should remain supine or sitting for at least 10 minutes prior to recording the screening ECG, and be supine during the ECG.  The screening predialysis ECG 
is a single recording.  
g Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
h PK assessments can be done at any hemodialysis session during the treatment week. Note:  Per Section 7.4.2 this will not be drawn in subjects with a known 
history of HIV. 
i To be measured by the central laboratory  
jChemistry will also include albumin and calcium 
k Subjects must be in a supine position in a rested and calm state for at least 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as possible. 
L 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. 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 31 of 48 
CONFIDENTIAL 
 
 
Replace: 
Table 3.  Schedule of Assessments 
 
 
 
 
Treatment Perioda 
Follow-up 
 
 
Study Week (Study Day) 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27b 
30 days after last 
dose ± 3 days 
Early Term 
Dose 
Suspension 
IV investigational product administration 
 
 
 
Three times per week at the end of the 
hemodialysis session ending at week 26 
 
 
 
 
Dose titrationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Pill count 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
TIW Admin of IV IP (by site staff at the end of 
hemodialysis)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital statusf 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Prior to dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGg 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Serum pregnancy testh 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Chemistry 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Albumin, Ca 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Xd 
Phosphorus 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
PTH 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
PKi 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
25(OH)D 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
After dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse and blood pressurej 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
PK (10-30 min post dose)i 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes defined on the next page 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 32 of 48 
CONFIDENTIAL 
 
 
ADA = antidrug antibody; 
; cCa = correct calcium; Ca =calcium; 
; ECG = electrocardiogram;  
IP = investigational product; IV = intravenous; PTH = parathyroid hormone, PK = pharmacokinetic; TIW = three times per week 
a Assessments during the Treatment Period should be performed during the designated study week on the same hemodialysis treatment day of the week as the day 
dosing was started whenever possible. 
b Week 27 assessments should be performed on the day of the first hemodialysis treatment after the last dose of IP. 
c The dose of IP may be decreased at any time. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL, a predialysis serum sample for albumin and calcium should be submitted to the central laboratory on the day 
dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP.  
f Vital status will only be appropriately ascertained by sites for subjects who early terminated the study. 
g Subjects should remain supine or sitting for at least 10 minutes prior and be supine during the ECG.  The predialysis ECG is a single recording. 
h Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
I PK assessments can be done at any hemodialysis session during the treatment week. 
j Subjects must be in a supine position in a rested and calm state 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is unable to be in 
the supine position, the subject should be in most recumbent position as possible. 
 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 33 of 48 
CONFIDENTIAL 
 
 
With: 
Table 3  Schedule of Assessments Continued 
 
 
 
 
Treatment Perioda 
Follow-up 
 
 
Study Week (Study Day) 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27b 
30 days after last 
dose ± 3 days 
Early Term 
Dose 
Suspension 
IV investigational product administration 
 
 
 
Three times per week at the end of the 
hemodialysis session ending at week 26 
 
 
 
 
Dose titrationc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of oral IP bottle 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Pill count 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
TIW Admin of IV IP (by site staff at the end of 
hemodialysis)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital statusf 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Prior to dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGg 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Serum pregnancy testh 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Chemistry 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Albumin, Ca i,j 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Xd 
Phosphorus 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
PTH 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
PK.k 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
25(OH)D 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
After dialysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse and blood pressureL 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
PK (10-30 min post dose)ik 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on the next page 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 34 of 48 
CONFIDENTIAL 
 
 
ADA = antidrug antibody; 
; cCa = correct calcium; Ca =calcium; 
; ECG = electrocardiogram; IP = 
investigational product; IV = intravenous; PTH = parathyroid hormone, PK = pharmacokinetic; TIW = three times per week 
a Assessments during the Treatment Period should be performed during the designated study week on the same hemodialysis treatment day of the week as the day 
dosing was started whenever possible. 
b Week 27 assessments should be performed on the day of the first hemodialysis treatment after the last dose of IP. 
c The dose of IP may be decreased at any time. 
d When dosing with IP is suspended for cCa < 7.5 mg/dL (1.87 mmol87mmol/L), a predialysis serum sample for albumin and calcium should be submitted to the 
central laboratory on the day dosing is suspended.  Dose suspension samples do not need to be collected if a routine, local chemistry or albumin/calcium/P sample is 
obtained on the same day. 
e After informed consent and before first dose of IP, only serious adverse events are to be reported.  Subjects will be followed for both adverse events and serious 
adverse events for 30 days after the last dose of IP.  
f Vital status will only be appropriately ascertained by sites for subjects who early terminated the study. 
g Subjects should remain supine or sitting for at least 10 minutes prior and be supine during the ECG.  The predialysis ECG is a single recording. 
h Additional pregnancy tests may be performed at the discretion of the investigator or per local regulatory requirements. 
i o be measured by the central laboratory.  
j Chemistry will also include albumin and calcium 
k PK assessments can be done at any hemodialysis session during the treatment week. 
L Subjects must be in a supine position in a rested and calm state 5 minutes prior to all measurements of pulse rate and blood pressure.  If the subject is unable to be in 
the supine position, the subject should be in most recumbent position as possible. 
 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 35 of 48 
CONFIDENTIAL 
 
 
Section:  7.2.2 Re-screening 
Replace: 
Screening assessments may be repeated up to 2 times during the 8-week screening 
period.  Subjects who do not meet eligibility requirements during the screening period 
will be permitted to be re-screened once.  Screen failures more than 8 weeks after 
informed consent form completion require re-consent and repeat of all screening 
assessments.  If a subject fails to meet eligibility criteria after re-screening within 
8 weeks, that subject may not re-screen again and will be considered ineligible for the 
study. 
With: 
Screening assessments may be repeated up to 2 times during the 8-week screening 
period.  Subjects who do not meet eligibility requirements during the screening period 
will be permitted to be re-screened once as described in Section 5. 
Section:  7.2.3 Treatment 
Replace: 
Randomization will be stratified by screening PTH level (< 900 pg/mL, ≥ 900 pg/mL), 
screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) and country (China versus non-China).  
The date of the first dose of IP is defined as day 1.   
With: 
Randomization will be stratified by screening PTH level (< 900 pg/mL, ≥ 900 pg/mL) 
(< 95.40 pmol/L, ≥ 95.40 pmol/L), screening central laboratory serum cCa  
(≥ 9.0 mg/dL, < 9.0 mg/dL) (≥ 2.25 mmol/L, < 2.25 mmol/L) measured by the central 
laboratory, and country (China versus non-China).  The date of the first dose of IP is 
defined as day 1.   
Section:  7.3.2 Medical History 
Replace: 
Detailed medical history including parathyroidectomy will be obtained at screening. 
Specific details on cardiovascular history will also be collected 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 36 of 48 
CONFIDENTIAL 
 
 
With: 
Detailed medical history including parathyroidectomy and known human 
immunodeficiency syndrome (HIV) Status (yes/no) will be obtained at screening.  
Specific details on cardiovascular history will also be collected. 
Section:  7.4 Laboratory Assessments 
Replace: 
When dosing with IP is suspended for cCa < 7.5 mg/dL, a predialysis serum sample for 
albumin and calcium should be submitted to the central laboratory on the day dosing is 
suspended.   
With: 
When dosing with IP is suspended for cCa < 7.5 mg/dL (1.87 mmol/L), a predialysis 
serum sample for albumin and calcium should be submitted to the central laboratory on 
the day dosing is suspended.   
Table 4.  Analytes Table 
Replace: 
Chemistry 
Hematology 
Other 
Sodium 
Hemoglobin 
Antibodiesa 
Potassium 
Hematocrit 
Pregnancy test 
Chloride 
Platelets 
Intact PTH 
Bicarbonate 
WBC  
25-hydroxyvitamin D 
Total protein 
RBC 
Albumin 
 
Calcium 
Ureab 
Corrected calcium 
(calculated) 
 
Magnesium 
Phosphorus 
Glucose 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Footnotes defined on next page 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 37 of 48 
CONFIDENTIAL 
 
 
ALP = serum alkaline phosphatase; ALT = alanine aminotransaminase; AST = aspartate transaminase; 
; LDH = lactate dehydrogenase; 
PTH = parathyroid hormone; RBC = red blood cells; SGOT = Serum glutamic oxaloacetic transaminase; 
SGPT = Serum glutamic pyruvic transaminase; WBC = white blood cells 
a These assays may be performed at a specialty laboratory. 
b Urea 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. 
When albumin is < 4.0 g/dL, the calcium level will be corrected according to the following 
formula: 
cCa (mg/dL) = total Ca (mg/dL) + (4 - albumin [g/dL]) x 0.8. 
With: 
Chemistry 
Hematologyc 
Other 
Sodium 
Hemoglobin 
Antibodiesa 
Potassium 
Hematocrit 
Pregnancy test 
Chloride 
Platelets 
Intact PTH 
Bicarbonate 
WBC  
25-hydroxyvitamin D 
Total protein 
RBC 
Albumin 
 
Calcium 
Ureab 
Corrected calcium 
(calculated) 
 
Magnesium 
Phosphorus 
Glucose 
Total bilirubinc 
Direct bilirubinc 
ALP 
LDH 
AST (SGOT)c 
ALT (SGPT)c 
ALP = serum alkaline phosphatase; ALT = alanine aminotransaminase; AST = aspartate transaminase; 
LDH = lactate dehydrogenase; 
PTH = parathyroid hormone; RBC = red blood cells; SGOT = Serum glutamic oxaloacetic transaminase; 
SGPT = Serum glutamic pyruvic transaminase; WBC = white blood cells 
a These assays may be performed at a specialty laboratory. 
b Urea 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. 
c If the central laboratory result is not available, local laboratory values may be used to determine 
eligibility, but Amgen must be contacted prior to randomization. 
When albumin is < 4.0 g/dL (40g/L), the calcium level will be corrected according to the 
following formula: 
cCa (mg/dL) = total Ca (mg/dL) + (4 - albumin [g/dL]) x 0.8. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 38 of 48 
CONFIDENTIAL 
 
 
Section:  7.4.2 Pharmacokinetic Sampling 
Replace: 
Blood samples will be collected and assayed for etelcalcetide serum concentration.  The 
PK samples will be analyzed only for those subjects assigned to etelcalcetide.  PK 
assessments can be done at any hemodialysis session during the treatment week.   
Predialysis samples will be collected at weeks 4, 12, 26, and at the 30-day Safety 
Follow-up visit.  Post-dialysis (10 to 30 minutes post-dose) blood samples will be 
collected at weeks 4, and 12. 
With: 
Blood samples will be collected and assayed for etelcalcetide serum concentration.  The 
PK samples will be analyzed only for those subjects assigned to etelcalcetide.  PK 
Subjects with a known history of HIV will not have labs drawn for PK sampling. 
Predialysis samples will be collected at weeks 4, 12, 26, and at the 30-day Safety 
Follow-up visit.  Post-dialysis (10 to 30 minutes post-dose) blood samples will be 
collected at weeks 4, 12, and 26. 
Section:  7.5 Antibody Testing Procedures 
Add:  
Subjects with a known history of HIV will not have labs drawn for antibody testing. 
Section:  8.3.1 Reasons for Removal From Treatment 
Replace:  
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
Protocol Specified Criteria 
 
safety concern (eg, because of an adverse event, failure to follow contraception, 
breast feeding, and/or protocol requirements) 
 
subject requires a significant permanent change in hemodialysis prescription to 
maintain adequate hemodialysis 
 
subject receives a kidney transplant 
 
subject undergoes a parathyroidectomy 
 
Subject request 
 
Death 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 39 of 48 
CONFIDENTIAL 
 
 
 
Lost to follow-up 
 
Decision by Sponsor (other than subject request, safety concern, lost to 
follow-up) 
With: 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
Protocol Specified Criteria 
 
subject requires a significant permanent change in hemodialysis prescription to 
maintain adequate hemodialysis 
 
subject receives a kidney transplant 
 
subject undergoes a parathyroidectomy 
 
Ineligibility determined 
 
Protocol deviation 
 
Noncompliance 
 
Subject request 
 
Adverse event 
 
Death 
 
Lost to follow-up 
 
Decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
Section:  9.1.1 Adverse Events 
Replace: 
For the purpose of this study asymptomatic reductions in serum cCa below 7.5 mg/dL or 
asymptomatic reductions in serum cCa between 7.5 mg/dL and < 8.3 mg/dL, that the 
investigator deems clinically significant (eg, required medical management) should be 
reported on the eCRF as “blood calcium decreased.”  Symptomatic reductions in serum 
cCa < 8.3 mg/dL should be reported as “hypocalcemia”, and the associated signs and 
symptoms should also be captured. 
With:  
For the purpose of this study any asymptomatic reductions in serum cCa below 
7.5 mg/dL (1.87 mmol/L) measured by either the central laboratory or the local 
laboratory or asymptomatic reductions in serum cCa between 7.5 mg/dL (1.87 mmol/L) 
and < 8.3 mg/dL (2.07 mmol/L), measured by either the central laboratory or the 
local laboratory, that the investigator deems clinically significant (eg, required medical 
management) should be reported on the eCRF as “blood calcium decreased.”  
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 40 of 48 
CONFIDENTIAL 
 
 
Symptomatic reductions in serum cCa < 8.3 mg/dL (2.07 mmol/L) measured by either 
the central laboratory or the local laboratory should be reported as “hypocalcemia”, 
and the associated signs and symptoms should also be captured. 
Section:  9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet 
Serious Criteria 
Replace: 
The adverse event grading scale used will be the following: 
 
Mild:  Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
 
Moderate:  Mild to moderate limitation in activity-some assistance may be needed; 
no or minimal medical intervention/therapy required 
 
Severe:  Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations or prolongation of current 
hospitalization possible 
 
Maximal/Life-threatening:  Extreme limitation in activity, significant assistance 
required, significant medical intervention/therapy required, hospitalization or 
prolongation of current hospitalization or hospice care probable 
With: 
 
Mild:  Aware of sign or symptom, but easily tolerated 
 
Moderate:  Discomfort enough to cause interference with usual activity 
 
Severe:  Incapacitating with inability to work or do usual activity 
Section:  9.2.3 Changes in Serum Calcium and Symptomatic Hypocalcemia 
Replace: 
Serum cCa levels will be analyzed by the central laboratory throughout the study, and 
these results will be incorporated in the clinical database. Per Section 6.2.3.2 dosing 
with IP will be suspended if a predialysis serum cCa < 7.5 mg/dL value is observed.  A 
repeat serum cCa will be obtained prior to hemodialysis at the next hemodialysis 
session, to allow verification of the low serum cCa level.  Serum cCa will continue to be 
monitored per protocol if IP dosing is suspended for low serum cCa. Dosing may 
subsequently resume when serum cCa ≥ 8.3 mg/dL and any hypocalcemic symptoms 
have resolved with the dose (1) reduced by 5 mg, or at the minimum dose of 2.5 mg, 
whichever is greater for IV IP, or (2) reduced by 25 mg, or at the minimum dose of 
25 mg, whichever is greater for oral IP. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 41 of 48 
CONFIDENTIAL 
 
 
Investigators should assess subjects for the onset of signs and symptoms associated 
with low serum calcium (see Section 6.2.3.3) at each visit. Asymptomatic reductions in 
serum cCa below 7.5 mg/dL or asymptomatic reductions in serum cCa between 
7.5 mg/dL (and < 8.3 mg/dL that the investigator deems clinically significant (eg, required 
medical management) should be reported on the eCRF as “blood calcium decreased.”   
With 
Serum cCa levels will be analyzed by the central laboratory throughout the study, and 
these results will be incorporated in the clinical database.  The cCa measured by the 
local laboratory and collected for the management of safety concerns will also be 
incorporated in the clinical database.  Per Section 6.2.3.2 dosing with IP will be 
suspended if a predialysis serum cCa < 7.5 mg/dL (1.87 mmol/L) value from either the 
central or local laboratory is observed.  A repeat central laboratory serum cCa will be 
obtained prior to hemodialysis at the next hemodialysis session, to allow verification of 
the low serum cCa level.  Central laboratory serum cCa will continue to be monitored 
per protocol if IP dosing is suspended for low serum cCa.  Dosing may subsequently 
resume when central laboratory serum cCa ≥ 8.3 mg/dL (2.07 mmol/L) and any 
hypocalcemic symptoms have resolved with the dose (1) reduced by 5 mg, or at the 
minimum dose of 2.5 mg, whichever is greater for IV IP, or (2) reduced by 25 mg, or at 
the minimum dose of 25 mg, whichever is greater for oral IP. 
Investigators should assess subjects for the onset of signs and symptoms associated 
with low serum calcium (see Section 6.2.3.3) at each visit.  Any asymptomatic 
reductions in serum cCa below 7.5 mg/dL (1.87 mmol/L) from either the central or 
local laboratory or asymptomatic reductions in serum cCa between 7.5 mg/dL (1.87 
mmol/L) and < 8.3 mg/dL (2.07 mmol/L) from either the central or local laboratory 
that the investigator deems clinically significant (eg, required medical management) 
should be reported on the eCRF as “blood calcium decreased.”   
Section:  10.1.1.3 
Other Secondary Endpoints 
Replace: 
 
Percent change from baseline in mean predialysis serum cCa during the EAP 
With: 
 
Percent change from baseline in mean predialysis central laboratory serum cCa 
during the EAP 
 
Achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 42 of 48 
CONFIDENTIAL 
 
 
Section:  10.1.1.4 
Safety Endpoints 
Replace: 
 
Incidence of cCa < 8.3 mg/dL at any time during the study 
 
Incidence of cCa < 8.0 mg/dL at any time during the study 
 
Incidence of cCa < 7.5 mg/dL at any time during the study 
With: 
 
Incidence of cCa < 8.3 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 8.0 mg/dL measured by the central laboratory at any time 
during the study 
 
Incidence of cCa < 7.5 mg/dL measured by the central laboratory at any time 
during the study 
Section:  10.1.1.5 
Exploratory Endpoints 
Replace: 
Section:  10.1.2.3 
cCa Completer Analysis Set 
Replace: 
The cCa Completer Analysis Set (CCAS) includes all randomized subjects with at least 
one predialysis cCa value, during the EAP.  Subjects will be analyzed according to 
randomized treatment group 
With: 
The cCa Completer Analysis Set (CCAS) includes all randomized subjects with at least 
one predialysis cCa value, measured by the central laboratory, during the EAP.  
Subjects will be analyzed according to randomized treatment group. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 43 of 48 
CONFIDENTIAL 
 
 
Section:  10.1.2.5 
Per Protocol Analysis Set 
Replace: 
The Per Protocol Analysis Set (PPAS) is defined as all randomized subjects who have 
no major protocol violations and have at least one post-dose PTH value and had at least 
16 weeks exposure of IP.  Subjects in the PPAS will be analyzed according to 
randomized treatment assignment.  PPAS will be used in the sensitivity analysis of the 
primary endpoint.  Removed according to ICH E9R1. 
With: 
The Per Protocol Analysis Set (PPAS) is defined as all randomized subjects who have 
no major protocol violations and have at least one post-dose PTH value and had at least 
16 weeks exposure of IP.  Subjects in the PPAS will be analyzed according to 
randomized treatment assignment.   
Section:  10.1.3 
Covariates and Subgroups 
Replace: 
All analyses of primary and key secondary endpoints will be adjusted for the effect of the 
stratification factors of screening PTH level (< 900 pg/mL, ≥ 900 pg/mL), screening 
serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL), and country (China versus non-China).   
With:   
All analyses of primary and key secondary endpoints will be adjusted for the effect of the 
stratification factors of screening PTH level (< 900 pg/mL, ≥ 900 pg/mL) (95.40 pmol/L, 
≥ 95.40 pmol/L), screening serum cCa (≥ 9.0 mg/dL, < 9.0 mg/dL) (≥ 2.25 mmol/L, 
< 2.25 mmol/L) measured by the central laboratory, and country (China versus non 
China).   
Section 10.5.1 General Considerations 
Replace: 
For the efficacy endpoints using laboratory measurements (predialysis PTH, cCa, and 
P), values based on averaging over the EAP will be used in the analyses where 
applicable. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 44 of 48 
CONFIDENTIAL 
 
 
With: 
For the efficacy endpoints using laboratory measurements measured by the central 
laboratory (predialysis PTH, cCa, and P), values based on averaging over the EAP will 
be used in the analyses where applicable. 
Section:  10.5.2 
Primary Efficacy Endpoint 
Replace: 
The following 2 sensitivity analyses for the primary analysis on FAS will be conducted: 
 
PCAS:  Only subjects with PTH data during the EAP are included. 
 
For subjects without PTH data during the EAP, the mean of the last 2 predialysis 
PTH values obtained after day 1 will be carried forward.  If only one value is 
available, this single value will be carried forward to the EAP.  A similar 
imputation approach as the primary analysis will be applied to subjects without a 
post-baseline PTH value. 
In addition, a sensitivity analysis using PPAS will also be conducted using the 
non-inferiority null imputation method. 
With:  
The following sensitivity analysis for the primary analysis on FAS will be conducted: 
 
For subjects without PTH data during the EAP, the mean of the last 2 predialysis 
PTH values obtained after day 1 will be carried forward.  If only one value is 
available, this single value will be carried forward to the EAP.  A similar 
imputation approach as the primary analysis will be applied to subjects without a 
post-baseline PTH value. 
In addition, supplementary analyses will be performed for primary endpoint using 
PCAS and PPAS. 
Section:  10.5.3.1 
Other Secondary Efficacy Endpoints 
Replace: 
The following secondary endpoints will be formally tested if both key secondary 
endpoints are statistically significant.  To control the family-wise error rate, the Hochberg 
procedure of adjustment for multiple comparisons will be used: 
 
percent change from baseline in mean predialysis serum cCa during the EAP 
 
achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
A repeated measures mixed effects model will be used to compare the percent change 
from baseline in serum cCa levels during the EAP and will include the randomization 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 45 of 48 
CONFIDENTIAL 
 
 
stratification factors.  The difference between treatment groups will be presented with 
95% CI.  The analysis will be performed on the FAS and sensitivity analysis will be 
performed using the cCa completer analysis set.   
With: 
The following secondary endpoints will be formally tested if both key secondary 
endpoints are statistically significant.  To control the family-wise error rate, the Hochberg 
procedure of adjustment for multiple comparisons will be used: 
 
percent change from baseline in mean predialysis central laboratory serum cCa 
during the EAP 
 
achievement of mean predialysis serum P ≤ 4.5 mg/dL during the EAP 
A repeated measures mixed effects model will be used to compare the percent change 
from baseline in serum cCa levels during the EAP, and will include the randomization 
stratification factors.  The difference between treatment groups will be presented with 
95% CI.  The analysis will be performed on the FAS and supplementary analysis will be 
performed using the cCa completer analysis set.   
Section:  10.5.4 
Safety Endpoints 
Replace: 
Proportion of subjects (with 95% confidence interval) with the following will be presented 
by treatment group: 
 
cCa < 8.3 mg/dL  
 
cCa < 8.0 mg/dL  
 
Ca < 7.5 mg/dL treatment-emergent symptomatic hypocalcemia adverse event 
during the study.  
With: 
Proportion of subjects (with 95% confidence interval) with the following will be presented 
by treatment group: 
 
cCa < 8.3 mg/dL measured by the central laboratory 
 
cCa < 8.0 mg/dL measured by the central laboratory  
 
cCa < 7.5 mg/dL measured by the central laboratory 
 
treatment-emergent symptomatic hypocalcemia adverse event during the study 
will be presented by treatment group.  
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 46 of 48 
CONFIDENTIAL 
 
 
Section:  12.2 Study Monitoring and Data Collection 
Remove: 
• 
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. 
Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Replace: 
Grade 
Amgen Standard Adverse Event Grading Scale 
1 
MILD:  Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
2 
MODERATE:  Mild to moderate limitation in activity-some assistance may be 
needed; no or minimal medical intervention/therapy required 
3 
SEVERE:  Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations or prolongation of current 
hospitalization possible 
4 
MAXIMAL/LIFE-THREATENING:  Extreme limitation in activity, significant assistance 
required, significant medical intervention/therapy required, hospitalization or 
prolongation of current hospitalization or hospice care probable. 
With: 
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of a serious adverse event, NOT when it is rated as severe. 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 47 of 48 
CONFIDENTIAL 
 
 
Additional Clinical Assessments and Observation 
Replace: 
 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND 
the subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
 
Obtain serum acetaminophen (paracetamol) levels 
 
Obtain a more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
Add: 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. Note: Bilirubin (total and direct), ALT, and AST should be 
measured by the local laboratory if the central laboratory is unable to perform the 
analysis. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
 
Obtain plasma or serum acetaminophen (paracetamol) levels 
 
Obtain a more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  27 November 2018 
Page 48 of 48 
CONFIDENTIAL 
 
 
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Approved 
 
 


Product:  Etelcalcetide (AMG 416) 
Protocol Number:  20150238 
Date:  16 February 2018 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Multicenter, Multiple-dose, Active-controlled, Double-blind, 
Double-dummy Study to Compare the Therapeutic Efficacy and Safety of Oral 
Doses of Cinacalcet Hydrochloride With Intravenous Doses of Etelcalcetide 
(AMG 416) in Asian Hemodialysis Subjects With Secondary Hyperparathyroidism 
 
Amgen Protocol Number (Etelcalcetide) 20150238 
 
Amendment 2 Date: 
16 February 2018 
 
Rationale: 
The rationale for the major changes in the study design is provided below: 
• 
An assessment of Kt/V or URR at screening has been added to the Schedule of 
Assessments to facilitate enrollment. 
• 
Protocol language has been added indicating that Kt/V or URR is to be processed 
at the site’s local laboratory and urea has been added to the analyte table for local 
Kt/V or URR assessment at screening, if necessary. 
Other changes to the protocol: 
• 
Exclusion criterion number 211 has been amended for specificity and consistency 
with exclusion criteria format. 
• 
The location of the study sites has been updated to accurately reflect sites of 
subject enrollment. 
• 
The description of the drug product has been updated to correctly reflect the form of 
etelcalcetide as a free base and to correct the pH of the drug solution. 
• 
Clarification language has been added to indicate that both sites and subjects are to 
be blinded to PTH values.   
• 
Clarification language has been added to indicate that “initial” IP dosing must start 
with a Monday through Friday hemodialysis treatment. 
• 
Administrative and formatting changes were made throughout the protocol. 
Approved 
 
 


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