Conditions: Chronic Kidney Disease, Secondary Hyperparathyroidism
Keywords: Secondary Hyperparathyroidism, chronic kidney disease, hemodialysis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is a study to evaluate the safety and pharmacokinetics in pediatric patients with secondary hyperparathyroidism receiving a single dose of etelcalcetide at the end of hemodialysis.

Detailed description:

Arms:
arm 1: Participants received a single, intravenous (IV) bolus administration of 0.035 mg/kg etelcalcetide at the end of hemodialysis on study day 1.

Interventions: intervention 1: Etelcalcetide
Intervention descriptions: intervention 1: A single IV-bolus dose of 0.035 mg/kg etelcalcetide into the venous line of the dialysis circuit at the end of a hemodialysis session.

Protocol document:
Prot_000.pdf: 
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Product:  Etelcalcetide 
Protocol Number: 20140336 
Date:  18 February 2016 
Page 6 of 64 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
 
Baseline 
Day -2 
   Screening 
Day -14 to Day -3 
Treatment - Day 1 
Etelcalcetide - IV Admin 
Bolus Dose* 
0.035 mg/kg  
  
EOS 
Day 30 
Follow up  
Day 3 - 10 
Cohort 1 → At least 
5 subjects age 12 to      
< 18 years age  
* IV bolus dose to be administered after haemodialysis during rinse back 
Data Review: 
 
Data from 2 subjects 
enrolled in Cohort 1 will be 
reviewed prior to enrolling 
subjects in Cohort 2
Cohort 2 → At least 
5 subjects age 2 to       
< 12 years 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 7 of 64 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
Term: 
 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
end of study for individual 
subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
end of treatment 
defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject 
end of study (primary 
completion) 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint(s).   
end of study (end of trial) 
defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts 
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 
 
 
Abbreviation: 
 
ANC 
absolute neutrophil count 
API 
Active pharmaceutical agent 
ALT 
alanine aminotransferase 
AUC 
area under the curve for plasma etelcalcetide 
CaSR 
calcium sensing receptor 
cCa 
albumin-corrected calcium 
CKD 
chronic kidney disease 
Cmax 
maximum plasma etelcalcetide concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury 
EAP 
efficacy assessment phase 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 8 of 64 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
ESRD 
end stage renal disease 
EU 
European Union 
iCa 
ionized calcium 
ICF 
informed consent form 
IUD 
intrauterine device 
LAR 
legally authorized representative 
IV 
intravenous 
NAPRTS 
North American Pediatric Renal Trials and Collaborative Studies 
group 
PD 
pharmacodynamic 
PDCO 
Paediatric Committee 
PIP 
Paediatric Investigation Plan 
PK 
pharmacokinetic 
PK/PD 
pharmacokinetic/pharmacodynamic 
PTH 
parathyroid hormone 
QTc 
corrected QT interval 
QTb 
Bazett corrected QT interval 
sHPT 
secondary hyperparathyroidism 
t1/2 
half-life of plasma etelcalcetide 
TBIL 
total bilirubin 
TIW 
three times a week 
Tmax 
time to Cmax 
USRDS 
United States Renal Data System 
 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 9 of 64 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 6 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 13 
1.1 
Primary ....................................................................................................... 13 
1.2 
Secondary .................................................................................................. 13 
2. 
BACKGROUND AND RATIONALE ........................................................................ 13 
2.1 
Disease ....................................................................................................... 13 
2.2 
Amgen Investigational Product Background ............................................... 15 
2.2.1 
Clinical Experience ..................................................................... 15 
2.2.2 
Clinical Pharmacokinetics ........................................................... 16 
2.3 
Paediatric Risk Assessment ....................................................................... 17 
2.4 
Rationale .................................................................................................... 17 
2.5 
Clinical Hypotheses .................................................................................... 18 
3. 
EXPERIMENTAL PLAN ......................................................................................... 18 
3.1 
Study Design .............................................................................................. 18 
3.2 
Number of Sites .......................................................................................... 18 
3.3 
Number of Subjects .................................................................................... 18 
3.4 
Replacement of Subjects ............................................................................ 19 
3.5 
Estimated Study Duration ........................................................................... 19 
3.5.1 
Study Duration for Subjects ........................................................ 19 
3.5.2 
End of Study ............................................................................... 19 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 19 
4.1 
Inclusion Criteria ......................................................................................... 19 
4.2 
Exclusion Criteria ........................................................................................ 20 
5. 
SUBJECT ENROLLMENT ..................................................................................... 21 
6. 
TREATMENT PROCEDURES ............................................................................... 22 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 22 
6.2 
Investigational Product ............................................................................... 22 
6.2.1 
Amgen Investigational Product Etelcalcetide 
(AMG 416) .................................................................................. 22 
6.2.1.1 
Dosage, Administration, and Schedule .................... 23 
6.2.1.2 
Safety Monitoring and Data Review ......................... 23 
6.2.2 
Cohort Stopping Rules ............................................................... 24 
6.3 
Criteria for Additional Safety Assessment due to Potential 
Hepatotoxicity ............................................................................................. 25 
6.4 
Concomitant Therapy ................................................................................. 26 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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6.5 
Other Treatment Procedures - Haemodialysis ........................................... 26 
6.6 
Product Complaints .................................................................................... 26 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period ................................................................................... 26 
7. 
STUDY PROCEDURES ......................................................................................... 27 
7.1 
Schedule of Assessments .......................................................................... 27 
7.2 
General Study Procedures ......................................................................... 30 
7.2.1 
Informed Consent ....................................................................... 30 
7.2.2 
Screening ................................................................................... 30 
7.2.3 
Baseline ...................................................................................... 31 
7.2.4 
Treatment ................................................................................... 31 
7.2.5 
Safety Follow-up Visit(s) ............................................................. 31 
7.2.6 
End of Study Visit ....................................................................... 32 
7.2.7 
Medical History ........................................................................... 32 
7.2.8 
Vital Signs ................................................................................... 32 
7.2.9 
Physical Examination ................................................................. 33 
7.2.10 
Electrocardiograms ..................................................................... 33 
7.2.11 
Clinical Laboratory Safety Assessments .................................... 33 
7.2.12 
Pharmacodynamic Measurements ............................................. 34 
7.2.13 
Pharmacokinetic Measurements ................................................ 34 
7.2.14 
Anticipated Blood Collection Volumes ........................................ 35 
7.3 
Antibody Testing Procedures ..................................................................... 36 
7.4 
Sample Storage and Destruction ................................................................ 36 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 38 
8.1 
Subjects’ Decision to Withdraw .................................................................. 38 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 38 
8.2.1 
Reasons for Removal From Treatment ...................................... 39 
8.2.2 
Reasons for Removal From Study ............................................. 39 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 39 
9.1 
Definition of Safety Events ......................................................................... 39 
9.1.1 
Adverse Events .......................................................................... 39 
9.1.2 
Serious Adverse Events ............................................................. 40 
9.2 
Safety Event Reporting Procedures - Adverse Events ............................... 40 
9.2.1 
Reporting Procedures for Adverse Events That Do Not 
Meet Serious Criteria .................................................................. 40 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 41 
9.2.2.1 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 42 
9.2.2.2 
Reporting of Reductions in Serum Calcium ............. 43 
9.3 
Pregnancy and Lactation Reporting ........................................................... 43 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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10. 
STATISTICAL CONSIDERATIONS ....................................................................... 44 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 44 
10.1.1 
Study Endpoints ......................................................................... 44 
10.1.1.1 
Primary Endpoints .................................................... 44 
10.1.1.2 
Secondary Endpoints ............................................... 44 
10.1.2 
Analysis Sets .............................................................................. 44 
10.2 
Sample Size Considerations ...................................................................... 44 
10.3 
Planned Analysis ........................................................................................ 44 
10.3.1 
Primary Analysis ......................................................................... 44 
10.4 
Planned Methods of Analysis ..................................................................... 44 
10.4.1 
General Considerations .............................................................. 44 
10.4.2 
Primary Endpoints ...................................................................... 45 
10.4.2.1 
Common Treatment-emergent Adverse 
Events ...................................................................... 45 
10.4.2.2 
Clinical Laboratory Tests, ECG and Vital 
Signs ........................................................................ 45 
10.4.3 
Secondary Endpoint(s) ............................................................... 45 
10.4.3.1 
Pharmacokinetic Endpoints ..................................... 45 
10.4.3.2 
Pharmacodynamic Endpoints .................................. 45 
10.4.3.3 
Antibody ................................................................... 46 
10.4.3.4 
Treatment-emergent Adverse Events ...................... 46 
10.4.4 
Additional Analyses .................................................................... 46 
10.4.4.1 
Subject Accountability .............................................. 46 
11. 
REGULATORY OBLIGATIONS ............................................................................. 46 
11.1 
Informed Consent ....................................................................................... 46 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 47 
11.3 
Subject Confidentiality ................................................................................ 48 
11.4 
Investigator Signatory Obligations .............................................................. 48 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 48 
12.1 
Protocol Amendments and Study Termination ........................................... 48 
12.2 
Study Documentation and Archive ............................................................. 49 
12.3 
Study Monitoring and Data Collection ........................................................ 50 
12.4 
Investigator Responsibilities for Data Collection ........................................ 50 
12.5 
Language.................................................................................................... 51 
12.6 
Publication Policy ....................................................................................... 51 
12.7 
Compensation ............................................................................................ 52 
13. 
REFERENCES ....................................................................................................... 53 
14. 
APPENDICES ........................................................................................................ 55 
 


 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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List of Tables  
Table 1.  Schedule of Assessments
 
 ................................................................................ 28
Table 2.  List of Analytes
 
 ................................................................................................. 34
Table 3.  Approximate Blood Draw Volume
 
 .................................................................... 36
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 56
Appendix B.  Sample Serious Adverse Event Form
 
 ........................................................ 58
Appendix C.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 63
 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the safety and tolerability of etelcalcetide after single dose administration to 
paediatric subjects aged 2 to less than 18 years old with secondary hyperparathyroidism 
(sHPT) receiving maintenance haemodialysis. 
1.2 
Secondary 
To evaluate the pharmacokinetic profile of plasma etelcalcetide, serum PTH and serum 
calcium (total calcium, ionized calcium and albumin corrected calcium) levels following a 
single intravenous (IV) administration of etelcalcetide.  
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Data from the United States Renal Data System (USRDS) reveals that in 2007, there 
were approximately 1,000 incident and 2,000 prevalent paediatric (0 to 19 years old) 
patients in the United States with chronic kidney disease (CKD) requiring maintenance 
dialysis, including haemodialysis and peritoneal dialysis (USRDS, 2009). The mortality 
rate in children receiving dialysis is 30 to 150 times greater than that of the general 
paediatric population (USRDS, 2009; McDonald, 2004).  
Secondary hyperparathyroidism (sHPT) develops relatively early in the course of CKD 
as a corrective response to metabolic disturbances resulting from declining kidney 
function. These disturbances include hypocalcemia, reduced renal synthesis of 
1,25-dihydroxy vitamin D, phosphate retention and skeletal resistance to the calcemic 
action of iPTH  (Martinez, 1997). The prevalence and severity of secondary HPT 
increases as CKD progresses toward end stage and is ubiquitous among patients 
receiving dialysis therapy. The disordered mineral metabolism that characterizes 
established secondary HPT is caused not only by renal failure itself but also exacerbated 
by parathyroid gland hyperplasia and by therapies directed toward treatment of 
secondary HPT. 
Once on dialysis, traditional therapies for secondary HPT (vitamin D [1,25(OH)2D3 and 
analogs] and phosphate binders) may be inadequate for disease control.  While vitamin 
D derivatives reduce iPTH concentrations, these agents can lead to hyperphosphatemia 
and relative hypercalcemia due to enhanced gastrointestinal absorption of these divalent 
ions. Unfortunately, the limitations of traditional therapy for secondary HPT appear to 
manifest in the paediatric as well as the adult dialysis population. A recent survey 
conducted among 18 sites belonging to the North American Paediatric Renal Trials and 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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CONFIDENTIAL 
 
 
Collaborative Studies group (NAPRTCS, unpublished data), included data from 
320 paediatric haemodialysis and peritoneal dialysis patients, between the ages of 2 to 
less than 18. The results show that overall, 49% of the paediatric dialysis population has 
iPTH levels above 300 pg/mL, the upper limit recommended by the National Kidney 
Foundation NKF K/DOQI guidelines for all paediatric age groups (NKF K/DOQI, 2005). 
In addition, similar to what is observed in the adult population, this survey revealed 
inadequate control of other biochemical parameters of secondary HPT in the paediatric 
dialysis population, including Ca x P. Specifically, 18% of paediatric dialysis patients 
between the ages of 2 to less than 18 years old display Ca x P above the NK -K/DOQI 
guidelines (NKF K/DOQI, 2005) recommended target for that age group of < 65 mg2/dL2. 
The prevalence of elevated Ca x P appears to increase with increasing age, as shown 
by the survey results, where 22% of children between the ages of 6 to less than 12 years 
old, and 44% of the population from 12 years to less than 18 years old were above the 
NKF K/DOQI recommended age-group specific target for Ca x P of < 65 and  
< 55 mg2/dL2, respectively. Finally, simultaneous achievement of target concentrations 
for the 2 biochemical parameters (iPTH and Ca x P) recommended by the NKF K/DOQI 
(NKF K/DOQI, 2005) guidelines was infrequent across all age groups: 5% for 2 years to 
less than 6 years old, 16% for 6 years to less than 12 years old, and 9% for 12 years to 
less than 18 years old. 
Failure to achieve NKF K/DOQI biochemical targets for the treatment of secondary HPT 
is associated with substantial adverse clinical consequence. The clinical outcome most 
frequently associated with secondary HPT is the development of high-turnover bone 
disease which results in reduced bone mass and increases the risk of bone deformities 
and fractures in adults and children with advanced CKD (Cundy, 1985; Spasovski, 2003; 
Coen, 1996; Sanchez, 2003; Salusky, 1987; Slatopolsky, 1999). In addition, secondary 
HPT may contribute to growth retardation, which has been linked to uncontrolled SHPT 
(Chesney, 2006) and also to over-suppression of iPTH with vitamin D in children with 
CKD, particularly those on dialysis (Kuizon, 1999). It has been suggested that normal 
growth velocity in this population can be promoted by minimizing renal osteodystrophy 
through the optimal control of iPTH levels (Waller, 2003), and by treatment with 
recombinant human growth hormone in an effort to correct disturbances in pulsatile 
secretion of growth hormone as well as to overcome peripheral growth hormone 
resistance (Kari, 2005; Tonshoff, 2005). Beyond the classical skeletal complications of 
secondary HPT, epidemiological data demonstrate that secondary HPT is a risk factor 
for mortality and cardiovascular morbidity (Moe, 2006; Melamed, 2006). This may be 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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due to promotion of vascular calcification by disordered mineral metabolism which in turn 
may lead to increased arterial stiffness and left ventricular hypertrophy 
(Abdelfatah, 2001; Klassen, 2002). While most available data describing the mortality 
and cardiovascular morbidity risk associated with secondary HPT are derived from the 
adult ESRD population, studies have shown that young adults with ESRD and 
childhood-onset CKD also display a high incidence of cardiovascular complications 
(Cheung et al, 2000; Oh et al, 2002). Indeed the youngest members of the adult dialysis 
population (between the ages of 25 and 34 years), many of whom began dialysis as 
children, have an annual cardiovascular mortality risk that is similar to that of the oldest 
members of the general population (above 75 years of age) (Foley et al, 1998). 
It is currently estimated that 60% to 80% of the paediatric dialysis population receives 
treatment for secondary HPT with vitamin D (USRDS, 2009; NAPRTCS, 2006). The 
burden of complications of secondary HPT in the paediatric dialysis population and 
limitations of current therapy underscore the need for better treatments for secondary 
HPT in these patients, with a goal of simultaneously improving serum iPTH, calcium, 
phosphorus, and Ca x P concentration.   
2.2 
Amgen Investigational Product Background  
Etelcalcetide (AMG 416, formerly KAI 4169) is a synthetic peptide with a molecular 
weight of 1048 Da, comprised of 7 D-amino-acid backbone and one L-cysteine.   It is an 
allosteric activator of the calcium sensing receptor (CaSR) intended for the treatment of 
secondary HPT in CKD patients receiving haemodialysis.  Etelcalcetide is the only 
calcimimetic formulated for IV administration and is administered TIW (three times a 
week) as a bolus dose at the end of the haemodialysis treatment during rinse back such 
that no additional invasive injection is needed.  In the context of expected clinical use, 
dose levels of etelcalcetide are adjusted individually based on PTH and serum calcium 
levels. 
Refer to the Etelcalcetide Investigator’s Brochure for additional information. 
2.2.1 
Clinical Experience 
In total, more than 1700 adult subjects from 14 clinical studies have received 
etelcalcetide.  Etelcalcetide has been studied in two phase 3 placebo-controlled studies 
(Studies 20120229 and 20120230) in adult populations.  In Study 20120229, 74.0% of 
etelcalcetide treated subjects achieved the primary endpoint of at least 30% reduction 
from baseline in mean PTH during Efficacy Assessment Phase (EAP) versus 8.3% of 
placebo subjects (p < 0.001).  In Study 20120230, 75.3% of etelcalcetide treated 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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subjects achieved this endpoint versus 9.6% of placebo subjects (p < 0.001). Consistent 
with the primary endpoint, all secondary endpoints (proportion of subjects with 
predialysis mean PTH ≤ 300 pg/mL during the EAP, percent change from baseline in 
predialysis PTH, cCa, cCaXP, and P during the EAP) evaluated in Studies 20120229 
and 20120230 achieved statistical significance after adjusting for multiplicity.  The 
primary and secondary endpoints collectively demonstrated the efficacy of etelcalcetide.  
Refer to the Etelcalcetide Investigator’s Brochure for additional information. 
In a head-to-head phase 3 study with cinacalcet (Study 20120360), etelcalcetide was 
demonstrated to be non-inferior to cinacalcet for achievement of > 30% reduction from 
baseline in mean PTH during the efficacy assessment phase (EAP). Etelcalcetide was 
also superior to cinacalcet for this endpoint (68.2% AMG 416 versus 57.7% cinacalcet, 
p = 0.004). A greater proportion of subjects randomized to the etelcalcetide group 
achieved > 50% reduction from baseline in mean PTH during the EAP compared with 
subjects in the cinacalcet group (52.4% etelcalcetide versus 40.2% cinacalcet; 
p = 0.001).  
Etelcalcetide was generally well-tolerated. Most of the risks characterized for 
etelcalcetide are related to its mechanism of action as a calcimimetic and are consistent 
with the known safety profile of cinacalcet. The most important risk of etelcalcetide is 
hypocalcemia and associated events that may occur secondary to reductions in serum 
calcium. 
2.2.2 
Clinical Pharmacokinetics 
In the adult population, the pharmacokinetics of etelcalcetide are linear and does not 
change over time following single (5 to 60 mg) and multiple IV doses (2.5 to 20 mg) in 
CKD patients with secondary HPT requiring haemodialysis.  Etelcalcetide exhibited 
tri-exponential decay following IV administration.  Following three times a week IV 
dosing at the end of each 3 to 4 hour haemodialysis session in adult CKD patients, 
etelcalcetide plasma levels reached near steady-state after 4 weeks of dosing with an 
observed accumulation ratio of 2- to 3-fold, and the effective half-life was 3 to 5 days 
when dosed three times a week following hemodialysis.  Etelcalcetide is rapidly cleared 
in patients with normal renal function, while haemodialysis is the predominant elimination 
pathway in CKD patients requiring haemodialysis.  
Etelcalcetide is not metabolized by CYP450 enzymes.  Etelcalcetide is predominately 
bound to plasma albumin by reversible covalent binding.  In adult CKD patients requiring 
haemodialysis, etelcalcetide was predominantly eliminated by haemodialysis. 


 
 
 
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Protocol Number:  20140336 
Date:  18 February 2016 
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2.3 
Paediatric Risk Assessment 
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic and 
pharmacodynamics of a single dose IV administration of etelcalcetide in paediatric 
subjects receiving haemodialysis.  A dose of 0.035 mg/kg etelcalcetide will be given IV in 
paediatric subjects aged 2 to less than 18 years old. This weight based dose 
corresponds to a 2.5 mg dose for a 70 kg individual which is half of the 5 mg starting 
dose given to adult subjects. The 2.5 mg dose was the lowest dose studied in adult 
subjects on haemodialysis.  
Amgen anticipates minimal risk with no prospect of direct benefit to the paediatric 
subject after a single dose. The study is likely to yield generalizable knowledge about 
safety, PK and PD characteristics of etelcalcetide in paediatric subjects with sHPT 
receiving maintenance haemodialysis.  Although no previous studies have been 
conducted in paediatric patients, a favorable risk-benefit profile of etelcalcetide was 
demonstrated during a clinical development program in the adult population where more 
than 1700 subjects received at least one dose of the drug with approximately 
499 patients having received etelcalcetide for > 12 months.  In clinical studies, 
administration of etelcalcetide resulted in statistically significant and clinically relevant 
reductions in PTH, including in difficult to manage subgroups of patients, such as those 
with baseline PTH > 1000 pg/mL. Reductions in serum calcium and serum phosphorus 
secondary to PTH reduction were also observed, consistent with the pharmacologic 
action of a calcimimetic.  The most important risk of etelcalcetide is hypocalcemia and 
associated events that can occur secondary to reductions in serum calcium (such as 
QTc prolongation, ventricular arrhythmia and convulsions).  
Please refer to the Etelcalcetide Investigator’s Brochure, section 7 for a description of 
known and additional potential risks based on experience with etelcalcetide in the adult 
population.   
2.4 
Rationale 
This study is being carried out to fulfill Amgen’s commitment to the etelcalcetide 
Paediatric Investigation Plan (PIP) agreed with the European Medicines Agency (EMA) 
Paediatric Committee (PDCO) in accordance with the Paediatric Regulation (Regulation 
(EC) No 1901/2006) in the EU (EMEA-001554-PIP01-13, decision dated 01 Oct 2014). 
This phase 1 study is intended to investigate the safety, tolerability, PK and PD 
characteristics of etelcalcetide after a single dose administration in paediatric population 
that may represent a safe starting dose for this titratable drug.  The dose of 0.035 mg/kg 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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selected for this study corresponds to a 2.5 mg dose for a 70 kg individual which is half 
of the 5 mg starting dose given to adult subjects. The 2.5 mg dose was the lowest dose 
studied in adult subjects on haemodialysis.   
2.5 
Clinical Hypotheses 
Etelcalcetide will be safe and well tolerated after a single IV dose administration in 
paediatric subjects with sHPT on maintenance haemodialysis.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a single arm, open-label, single-dose safety, pharmacokinetic (PK) and 
pharmacodynamic (PD) study in paediatric subjects with sHPT receiving maintenance 
haemodialysis.  The study considers haemodiafitration and haemodialysis procedures 
interchangeable.  Subjects will receive a single IV administration of 0.035 mg/kg 
etelcalcetide at the end of haemodialysis.  Intensive PK and PD samples will be 
collected on Day 1 at 10 min and 4 hours after etelcalcetide administration and for 
10 days post dose with a safety follow-up period up to 30 days post dose.   
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 
Subjects will be enrolled at approximately 15 sites.  Recruitment will be competitive 
across sites.   
3.3 
Number of Subjects 
At least 10 children and adolescents (male and female) with ages ranging from 2 to less 
than 18 years with sHPT receiving maintenance haemodialysis will be enrolled. The 
sample size is based on practical consideration. No formal sample size calculations 
have been performed.  
At least 5 subjects should be 2 to less than 12 years old and at least 5 subjects should 
be 12 to less than 18 years old.  These cohorts are consistent with the age categories 
defined by ICH guidelines for studying paediatric patients. 
Participants in this clinical investigation shall be referred to as “subjects”. 


 
 
 
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Date:  18 February 2016 
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3.4 
Replacement of Subjects 
Subjects who are withdrawn from the study may be replaced at the discretion of the 
investigator in consultation with Amgen. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The estimated study duration is 6 weeks, which includes up to a 14 day screening period 
and 30 days on study.   
3.5.2 
End of Study 
Primary Completion
4. 
SUBJECT ELIGIBILITY 
:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis. Subjects 
with clinically significant adverse events at the end of study will be followed until 
resolution of the adverse event or until it is considered clinically stable.  
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained from the subject’s legally acceptable representative (LAR) (see 
Section 11.1).   
In addition to written informed consent from a legally acceptable representative, the 
assent of the child must also be obtained as appropriate to the age of the subject and/or 
based on local regulations. 
4.1 
Inclusion Criteria 
101 
Subject’s legally acceptable representative has provided informed consent and 
the subject has provided written assent based on local regulations and/or 
guidelines prior to any study-specific activities/procedures being initiated. 
102 
Male or female subjects (aged 2 to less than 18 years) diagnosed with CKD and 
sHPT and receiving maintenance haemodialysis or haemodiafiltration for 
> 30 days prior to screening. 
103 
Subject must be on a dialysate calcium concentration of ≥ 2.5 mEq/L 
(1.25 mmol/L) for at least 1 month prior to enrollment and throughout the duration 
of the study. 
104 
Screening and Baseline serum PTH level > 200 pg/mL (21 pmol/L).  
105 
Subject must weigh ≥ 7 kg at Baseline (Day -2). 
106 
Screening and Baseline serum corrected calcium from the local laboratory  
≥ 9 mg/dL (2.25 mmol/L).  


 
 
 
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107 
Subjects on anti-convulsant medication must be on a stable dose for 3 months.  
108 
Free of any disease or condition other than those diseases or conditions related 
to their renal disease that, in the opinion of the investigator, would impact the 
subject’s safety or the integrity of the study data. 
 
4.2 
Exclusion Criteria 
201 
Currently receiving or has received any investigational drug (or is currently using 
an investigational device) within the 30 days or 5 half-lives (whichever is longer), 
prior to receiving the first dose of etelcalcetide. Other investigational procedures 
while participating in this study are excluded. 
202 
Subject previously has entered this study or previously exposed to etelcalcetide. 
203 
All herbal medicines (eg, St. John’s wort), vitamins, and supplements consumed 
by the subject within the 30 days prior to receiving the first dose of etelcalcetide, 
and continuing use if applicable, will be reviewed by the Principal Investigator 
and the Amgen Medical Monitor. Written documentation of this review and 
Amgen acknowledgment is required for subject participation. 
204 
Use of any over-the-counter or prescription medications within the 14 days or 
5 half-lives (whichever is longer) prior to receiving the first dose of etelcalcetide 
that are not established therapies for subjects with renal disease or other 
conditions secondary to renal disease will be reviewed by the Principal 
Investigator and the Amgen Medical Monitor.  Written documentation of this 
review and Amgen acknowledgment is required for subject participation. 
Paracetamol (up to 2 g per day) for analgesia will be allowed. 
205 
Malignancy except non-melanoma skin cancers,within the last 5 years.   
206 
History of hypersensitivity or allergic reaction to any of the excipients listed in 
Section 6.2.1. 
207 
Subject received cinacalcet therapy within less than 30 days prior to etelcalcetide 
dosing. 
208 
A new onset of seizure or worsening of a pre-existing seizure disorder within 
2 months prior to etelcalcetide administration.  
209 
Subject’s screening 12-lead ECG suggests unstable arrhythmia or other cardiac 
abnormality that could place the subject at increased risk, based upon the 
Investigator’s opinion. 
210 
History of prolongation of the QT interval  (eg, congenital long QT interval, 
second or third degree heart block or other conditions which prolong the QT 
interval) or history of ventricular arrhythmias. 
211 
Concurrent or within 28 days prior to enrollment use of medications that prolong 
QT interval (eg, sotalol, amiodarone, erythromycin, or clarithromycin).  Please 
refer to the complete QT prolongation medication list at 
http://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf  
212 
Subjects with a corrected QT Interval (QTc) > 500 ms during screening, using 
Bazett’s formula. 
213 
Subject has a history of symptomatic ventricular dysrhythmias or Torsades de 
Pointes.  


 
 
 
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214 
Subject has a screening ALT or AST from the local lab ≥ 1.5 times the upper limit 
of normal (ULN). 
215 
Female subjects of childbearing potential who are unwilling to practice true 
sexual abstinence or use an acceptable method(s) of effective birth control 
during treatment through 3 months after receiving the etelcalcetide. Female 
subjects are considered of childbearing potential following menarche.  Female 
subjects who have reached puberty must receive pregnancy prevention (sexual) 
counseling and be advised of the risk to the fetus if  they become pregnant 
during treatment and for an additional 3 months after receiving the study drug.   
Acceptable methods of effective birth control include True sexual abstinence  
(The reliability of sexual abstinence must be evaluated by the investigator and be 
the preferred and usual lifestyle of the subject.); Hormonal (Combined estrogen 
and progestogen or progesterone-only hormonal contraception given via oral, 
intravaginal, transdermal, injectable, or implantable route); Intrauterine device 
(IUD); Intrauterine hormonal-releasing system (IUS);  Two barrier methods (one 
by each partner) and the female partner must use spermicide with the barrier 
method [the male must use a condom (latex or other synthetic material) and the 
female may select either a diaphragm, 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.      
216 
Post-menarchal subject who is pregnant or breastfeeding, or is planning to 
become pregnant or breastfeed during treatment and for an additional 3 months 
after etelcalcetide administration. Female subjects with a positive pregnancy test 
at screening. 
217 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
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).  The 
subject’s legally acceptable representatives (LAR) must personally sign and date the 
informed consent form before commencement of study-specific activities/procedures.   
Adverse Events are to be collected for a subject once they have received the dose of 
investigational product (IP).  A subject is considered enrolled once they have met all 
eligibility criteria based on screening and Day -2 (Baseline Visit) assessments.  
Provided all eligibility criteria have been met, subjects will be asked to return to the 
research facility for admission on Day -2 (Baseline Visit) where additional assessments 
will be performed to confirm that the subject remains eligible for the study. If subject 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 22 of 64 
CONFIDENTIAL 
 
 
eligibility is confirmed, the subject will be assigned to Cohort 1 or Cohort 2 based on the 
subject’s age at screening: 
• 
Cohort 1 → At least 5 subjects age 12 to < 18 years  
• 
Cohort 2 → At least 5 subjects age 2 to < 12 years 
Cumulative data from 2 subjects enrolled in Cohort 1 will be reviewed prior to enrolling 
subjects in Cohort 2 (see section 6.2.1). 
The investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment CRF. 
Each subject who enters into the screening period for the study (defined as when the 
LAR signs the informed consent) receives a unique subject identification number before 
any study procedures are performed.  The subject identification number will be assigned 
manually.  This number will be used to identify the subject throughout the clinical study 
and must be used on all study documentation related to that subject.  Subjects may be 
rescreened at the discretion of the investigator in consultation with the Amgen Medical 
Monitor.   
 
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.   
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s)   
The Amgen Investigational Product(s) used in this study include: Etelcalcetide. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of etelcalcetide.  
6.2 
Investigational Product 
All investigational product(s) will be administered at the research facility by a qualified 
staff member.  
A physician must be available at the time of administration of Investigational Product. 
6.2.1 
Amgen Investigational Product Etelcalcetide (AMG 416) 
Etelcalcetide drug product will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical study drug distribution procedures.  The active 


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Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 24 of 64 
CONFIDENTIAL 
 
 
beyond end of study. The Amgen Medical Monitor and Amgen Global Safety Officer 
(GSO) or designee will review each subject’s cumulative safety data through end of 
study on an ongoing basis. 
Additionally, after end of study visits have been completed for 2 subjects enrolled in 
Cohort 1, cumulative study data will be reviewed by a team composed of the 
Investigator(s), Amgen Medical Monitor, Amgen Global Safety Officer (GSO) or 
designee and additional members as needed (eg, Amgen Clinical Research Study 
Manager (CRSM), Biostatistician, PK Scientist, etc.).  The voting members include the 
Principal Investigator or designee, Amgen Medical Monitor, and Amgen Global Safety 
Officer or designee. All available study data, including demographics, IP administration, 
medical history, concomitant medications, adverse events, ECGs, vital signs, laboratory 
and PK results will be reviewed. Data review will not require that all queries be resolved 
or source verified. Cohort 2 will open for enrollment when the dose has been found to be 
reasonably tolerated based on available study data for at least 2 subjects enrolled in 
Cohort 1 and upon unanimous decision by the review committee. Based on emerging 
safety and PK data, the review committee may make other decisions (eg,. lower the 
dose level, enroll additional subjects in Cohort 1, etc.). All decisions will be documented 
in meeting minutes. 
6.2.2 
Cohort Stopping Rules 
Dosing within the cohort will be stopped if suspected treatment-related AEs or changes 
in vital signs, ECGs or clinical laboratory results are observed and pose a significant 
health risk to the subject. In addition, dosing within the cohort will be stopped for any 
occurrence of the following: 
• 
suspected treatment-related Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0 Grade 2 adverse events in 2 or more subjects; or 
• 
2 separate, suspected treatment-related CTCAE v4.0 Grade 2 adverse events in 
a single subject; 
or 
• 
suspected treatment-related CTCAE v4.0 Grade 3 or greater adverse event in a 
single subject or 
• 
suspected treatment-related serious adverse event (SAE) in a single subject 
The review team will be convened, and the event and all relevant safety data will be 
reviewed for evidence of relationship to treatment and clinical or medical significance. 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 25 of 64 
CONFIDENTIAL 
 
 
Dosing of additional subjects in the cohort may only be resumed upon unanimous vote 
by the Investigator(s), Amgen Medical Monitor, and Amgen GSO. 
The review of safety data and dosing decisions will be documented in meeting minutes. 
Amgen will issue a written notification of the dosing decision to the Investigator(s). 
6.3 
Criteria for Additional Safety Assessment due to Potential 
Hepatotoxicity 
Subjects should be followed according to the recommendations in Appendix B 
(Additional Safety Assessment Information) for possible drug-induced liver injury (DILI), 
if ALL of the criteria below are met:  
• 
Increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
AND   
• 
TBIL > 2x upper limit of normal (ULN) or INR > 1.5 
AND  
 
• 
No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT 
and/or elevated TBIL values include, but are not limited to: 
o Hepatobilliary tract disease  
o Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
Cytomegalovirus, Herpes Simplex Virus, Varicella, Toxoplasmosis, and 
Parvovirus) 
o Right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia  
o Exposure to hepatotoxic agents/drugs including herbal and dietary 
supplements, plants, and mushrooms  
o Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
syndrome, Crigler-Najjar syndrome ) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir)  
o Alpha-one antitrypsin deficiency 
o Alcoholic hepatitis 
o Autoimmune hepatitis 
o Wilson’s disease and hemochromatosis 
o Non-alcoholic Fatty Liver Disease including Steatohepatitis (NASH) 
o Non-hepatic causes (e.g. rhabdomyolisis, hemolysis) 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 26 of 64 
CONFIDENTIAL 
 
 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
An attempt should be made not to change the subjects’ treatment during the course of 
the study as long as, in the judgment of the investigator, the subjects’ safety is not 
jeopardized. All use of concomitant medications and supplements will be recorded on 
the applicable CRF.  Concomitant therapies are to be collected from informed consent 
through the end of safety follow-up period.  Collect therapy name, indication, dose, unit, 
frequency, route, and start date and stop date. 
In cases of symptomatic hypocalcemia or if the serum calcium level is less than 
7.5 mg/dL (1.875 mmol/L), oral or IV calcium will be administered as necessary. 
All herbal supplements, vitamins, and nutritional supplements taken within the last 
30 days prior to dosing on Day 1 (and continued use, if appropriate) must be reviewed 
and approved by the Principal Investigator and Amgen Medical Monitor. 
6.5 
Other Treatment Procedures - Haemodialysis 
Haemodialysis information - including date(s), mode of dialysis, start and stop times - 
and the dialysate (amount of calcium and potassium) must be captured in the subject’s 
chart and reported on the appropriate case report form. 
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) provisioned and/or repackaged 
/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with etelcalcetide supplied by Amgen are to be 
reported according to the instructions provided in the IPIM. 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period  
Treatment with cinacalcet is prohibited within 30 days prior to receiving etelcalcetide and 
for the duration of the study. Use of any medications that prolong QT interval (eg, 
sotalol, amiodarone, erythromycin, or clarithromycin) within 28 days prior to receiving 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 27 of 64 
CONFIDENTIAL 
 
 
etelcalcetide and for the duration of the study is prohibited.  Please refer to the complete 
QT prolongation medication list at 
http://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf.  These excluded therapies 
and procedures will not be allowed during the study unless necessitated in order to 
maintain subject safety. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 


 
 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 28 of 64 
CONFIDENTIAL  
 
 
Table 1.  Schedule of Assessments 
 
Screening 
Baseline 
 
Treatment 
Follow up 
EOS 
Study Day 
-14 to -3 
-2 
 
1 
3 
5a 
8 
10 
30 
Study Time 
 
 
0 
10 min 
4 hour 
 
 
 
 
 
General and Safety Assessments 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
 
 
 
 
 
 
 
X 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
Vital signs (BP, HR, Temp) 
X 
X 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
X 
Serious adverse events 
X-------------------------------------------------------------------------------------X 
Adverse Events 
 
 
 
X-----------------------------------------------------X 
Concomitant medications 
X---------------------------------------------------------------------------------------X 
Dosing 
 
 
 
Etelcalcetide administrationb 
 
 
X 
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
Clinical chemistry 
X 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
X 
Ionized Ca, Serum albumin, Serum cCac, d 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Serum PTHc 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Serum pregnancy test  
(females of child bearing potential only)e 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinetic and Other Blood Samples 
 
 
 
 
Etelcalcetide PK plasma collectionc, f 
 
 
 
X 
X 
Xf 
X 
X 
X 
X 
Antibody sample collectiong 
 
X 
 
 
 
 
 
 
 
X 
Footnotes defined on next page of table 


 
 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 29 of 64 
CONFIDENTIAL  
 
 
cCa = albumin-corrected calcium; EOS = End of Study; iCa = ionized calcium; HD = haemodialysis; IV = intravenous 
 
a. Subjects will continue to receive HD per their regular schedule (Day -2, 1, 3, 5 [or Day 6 depending on the day of the week the study begins], 8 and 10). 
b. On Day 1, etelcalcetide will be administered as an IV bolus dose after HD during rinse back. 
c. All procedures (except those scheduled on Day 1 at time 0, 10 min and 4 hour and Day 3 post-HD) will be performed prior to HD on the respective study day. 
d. Serum samples for albumin and calcium for screening and routine monitoring of pre-HD cCa. When albumin is less than 4.0 mg/dL, the calcium level will be corrected 
according to the formula: cCa (mg/dL) = total Ca (mg/dL) + (4 – albumin (g/dL))*0.8. 
e. Pregnancy tests will be performed in female subjects of child-bearing potential within 7 days prior to start of investigational product. 
f. PK plasma collection pre-HD and post-HD on Day 3 
g. Subjects with positive titers for antibodies to etelcalcetide at EOS may be asked to return to the clinical research unit to provide additional serum samples. 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 30 of 64 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
During the study, every effort should be made to perform the study procedures as 
indicated in the Schedule of Assessments (Table 1, Section 7.1). Study visits should 
coincide with the subject’s haemodialysis (HD) schedule. Unless otherwise noted all 
procedures should be performed prior to HD (pre-HD). Depending on the day of the 
week that each subject begins the study (Day 1), Day 5 assessments may be performed 
on Day 6 to align with the subject’s HD schedule.  
Throughout the study, the permitted time windows for scheduled assessments will be as 
follows: 
• 
± 15 minutes for events on Day 1 
• 
± 30 minutes for Day 3 through 10 
• 
+1 day for Day 5 
• 
+ 3 days for Day 30 (EOS) 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
Key assessments are described in the subsections below. 
7.2.1 
Informed Consent 
Before any study-specific procedure, the appropriate written informed consent must be 
obtained from the subject’s legally acceptable representative. 
7.2.2 
Screening 
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 1) (Section 7.1). 
• 
Confirmation that the Informed Consent Form and Assent form (as applicable) have 
been signed  
• 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety  
• 
Physical Examination as per standard of care (including medical/surgical history)  
• 
Height and Weight 
• 
Vital signs (eg, blood pressure, heart rate, temperature) (pre-HD) 
• 
12-Lead ECG (pre-HD) 
• 
Laboratory assessments (pre-HD) 
• 
Serious Adverse Event reporting 
• 
Documentation of concomitant medications 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 31 of 64 
CONFIDENTIAL 
 
 
If a subject is rescreened, a new informed consent form must be signed unless it has 
been < 30 days since the previous ICF signature was obtained. 
7.2.3 
Baseline 
Two days before dosing (Day -2) eligible subjects will return to the research center for 
testing to confirm final eligibility and to establish baseline assessments prior to dosing. 
The following procedures will be completed at baseline and at time points designated in 
the Schedule of Assessments (Table 1) (Section 7.1). 
• 
Weight 
• 
Vital signs (eg, blood pressure, heart rate, temperature) (pre-HD) 
• 
12-Lead ECG (pre-HD) 
• 
Laboratory assessments  (pre-HD) 
• 
Anti-etelcalcetide antibody collection (pre-HD) 
• 
Serious Adverse Event reporting 
• 
Documentation of concomitant medications 
After the investigator has confirmed eligibility based on screening and Day -2 
assessments, the subject will be enrolled to Cohort 1 or Cohort 2 based on the subject’s 
age.  
7.2.4 
Treatment 
The following procedures will be completed during the treatment period at the times 
designated in the Schedule of Assessments (Table 1).  On Day 1 etelcalcetide is to be 
administered after the completion of all required pre-dose assessments and after HD, 
during rinse back. Subjects will remain in the clinical research unit for observation until 
the 4 hour PK sample is collected. 
• 
Etelcalcetide administration 
• 
PK (10 min and 4 hour post dose) 
• 
Laboratory assessments  (pre-HD) 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.2.5 
Safety Follow-up Visit(s) 
Safety follow up visits will occur on Day 3, 5 or 6 (depending on study start day), 8 and 
10. The following procedures will be completed at the safety follow-up visits according to 
the Schedule of Assessments (Table 1). 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 32 of 64 
CONFIDENTIAL 
 
 
• 
PK assessments (pre-HD and post-HD on Day 3; pre-HD on Day 5 or 6, Day 8 & 
Day 10) 
• 
Laboratory Assessments (pre-HD) 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.2.6 
End of Study Visit 
The end of study visit will occur on Day 30. The following procedures will be completed 
at the safety follow-up visits according to the Schedule of Assessments (Table 1). 
• 
Physical Examination as per standard of care  
• 
Weight 
• 
Vital signs (eg, blood pressure, heart rate, temperature) (pre-HD) 
• 
12-Lead ECG (pre-HD) 
• 
PK assessments (pre-HD) 
• 
Laboratory Assessments  (pre-HD) 
• 
Anti-etelcalcetide antibody collection (pre-HD) 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Documentation of concomitant medications 
7.2.7 
Medical History 
The investigator or qualified designee will obtain a complete medical history at screening 
and within 14 days prior to enrollment of a study subject.  Medical history will include the 
subject’s history of chronic kidney disease and secondary hyperparathyroidism.  
Relevant medical history findings will be recorded in the subject’s source document and 
on the appropriate CRF.  Any unresolved medical history will be graded according to 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix A). 
7.2.8 
Vital Signs 
Vital signs, including systolic/diastolic blood pressure, heart rate, and temperature will be 
recorded by the investigator or qualified designee at the time points specified in the 
Schedule of Assessments (Table 1). All measurements will be obtained prior to 
hemodialysis.  
Subjects must be in a supine position for at least 5 minutes prior to vital signs 
measurements.  Abnormal measurements may be repeated (upon investigator 
discretion) and must be reported on the CRF.  When vital signs and blood sample 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 33 of 64 
CONFIDENTIAL 
 
 
collection occur at the same time, vital signs should be performed before blood samples 
are drawn.  The position selected for a subject should be the same that is used 
throughout the study and documented on the vital sign CRF.  The temperature location 
selected for a subject should be the same that is used throughout the study.   
Record all measurements on the vital signs CRF. 
7.2.9 
Physical Examination 
A physical examination will be performed by the investigator or designated physician at 
the time points specified in the Schedule of Assessments. 
Abnormal findings found during screening will be reported on the medical history page of 
the CRF.  Any abnormal findings or worsening findings found after the subject has 
received etelcalcetide will be reported on the Event CRF. 
7.2.10 
Electrocardiograms 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted. If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. All 
measurements will be obtained prior to hemodialysis. 
A single 12-lead ECG will be performed at timepoints designated in the Schedule of 
Assessments (Table 1). Data will be reported on the CRF.  The ECG must include the 
following measurements: Heart Rate, QRS, QTc, and PR intervals. 
The PI will review all ECGs.  Once signed, the original ECG tracing will be retained with 
the subject’s source documents. At the request of the sponsor, a copy of the original 
ECG will be made available to Amgen. 
7.2.11 
Clinical Laboratory Safety Assessments 
Blood sampling (not to exceed 5.6 mL) for safety laboratory testing will be conducted at 
time points designated in the Schedule of Assessments.  Results will be reported on the 
CRF.  Table 2 below outlines the panel of analytes required for safety laboratory testing. 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
Page 34 of 64 
CONFIDENTIAL 
 
 
Table 2.  List of Analytes 
Chemistry 
Hematology 
Sodium 
Potassium 
Chloride 
Bicarbonate (HCO3) 
Total protein 
Albumin 
Calciuma 
PTH 
Magnesium 
Phosphorus 
Blood urea nitrogen (BUN) 
Creatinine 
Uric Acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) (SGPT) 
Aspartate aminotransferase (AST) (SGOT) 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelets 
White blood cell differentials 
• 
Total neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
 
aTo include total calcium, albumin-corrected calcium, and ionized calcium 
 
7.2.12 
Pharmacodynamic Measurements  
Measurements of serum calcium (total calcium, albumin corrected calcium and ionized 
calcium) and PTH determinations will be collected at time points designated in the 
Schedule of Assessments (Table 1). 
The calcium level determinations described in this section are derived from the samples 
drawn as part of the Clinical Laboratory Safety Assessments described in 
Section 7.2.11. Results will be reported in the CRF. Approximate blood draw volumes 
are shown in Table 3.  
7.2.13 
Pharmacokinetic Measurements  
Blood samples (0.15 mL) for the determination of etelcalcetide PK parameters will be 
collected at time points designated in the Schedule of Assessments. Study site staff will 
complete a shipping log that will include subject identification information and the time 
and date of collection of each sample. Detailed instructions on sample collection, 
storage and shipment to the central laboratory are provided in a separate Sample 
Collection Notebook. 


 
 
 
Product:  Etelcalcetide 
Protocol Number:  20140336 
Date:  18 February 2016 
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7.2.14 
Anticipated Blood Collection Volumes 
It is anticipated that subjects enrolled in this study with weights greater than 12 kg will be 
asked to donate approximately 28.8 mL of blood over the course of the study period 
(see Table 3 for estimated volumes).  At screening approximately 5.6 mL of blood will be 
drawn for safety laboratory assessments (including Baseline PD endpoints). Females of 
child bearing potential will have an additional blood sample (0.5 mL) obtained for serum 
pregnancy testing at screening. On Day -2 (Baseline) approximately 3.6 mL of blood will 
be drawn for antibody (0.45 mL) and safety lab/PD endpoints (3.1 mL). On Day 1 and at 
each safety follow up visit (Day 3, 5 (or 6), 8 and 10), approximately 0.15 to 3.3 mL will 
be drawn. Approximately 6.2 mL of blood will be drawn for antibody (0.45 mL),  
PK (0.15 mL) and safety laboratory assessments (5.6 mL) at the end of study visit.  
Subjects that weigh 7 to 12 kg will be asked to donate smaller amounts of blood, 
approximately 16.7 mL. At screening approximately 2.8 mL of blood will be drawn for 
safety laboratory assessments (including Baseline PD endpoints). Female subjects 
weighing 12 kg or less are not anticipated to be of child bearing potential and therefore 
will not require a serum pregnancy test.  On Day -2 (Baseline) approximately 2.3 mL of 
blood will be drawn for antibody (0.45 mL) and safety lab/PD endpoints (1.8 mL). On 
Day 1 and at each safety follow up visit (Day 3, 5 (or 6), 8 and 10), approximately 0.15 to  
2.1 mL will be drawn. Approximately 3.4 mL of blood will be drawn for antibody 
(0.45 mL) safety laboratory assessments (2.8 mL) at the end of study visit.  
Specified blood volumes are approximate and may vary, however, per individual, the 
study-related blood loss (including any losses in the maneuver) will not exceed 3% of the 
total blood volume during a period of four weeks and will not exceed 1% at any single 
time per regulatory guidance on paediatric clinical trials. 


 
 
 
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Table 3.  Approximate Blood Draw Volume 
Sample 
Volume 
(mL) 
Volume 
(mL) 
No of 
Samples 
Total 
Volume 
(mL) 
Total 
Volume 
(mL) 
Subject 
Weight  
> 12 kg 
Subject 
Weight  
7-12 kg 
All 
Subjects 
Subject 
Weight  
> 12 kg 
Subject 
Weight  
7 – 12 kg 
Safety Lab Tests  
(including Calcium, PTH) 
5.6 
2.8 
2 
11.2 
5.6 
cCA, albumin, PTH 
3.1 
1.8 
5 
15.5 
9 
 
 
 
 
 
 
PK 
0.15 
0.15 
8 
1.2 
1.2 
 
 
 
 
 
 
Antibody 
0.45 
0.45 
2 
0.9 
0.9 
  
 
 
 
 
 
Total 
 
 
 
28.8 
16.7 
7.3 
Antibody Testing Procedures 
Blood sample(s) for Antibody testing are to be collected at Baseline (Day -2) and at EOS 
(Schedule of Assessments, Table 1) for the measurement of anti-etelcalcetide binding 
antibodies.  Samples testing positive for binding antibodies may also be tested for 
neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity 
and presence of immune complexes.  Additional blood samples may be obtained to rule 
out anti-etelcalcetide antibodies during the study.  
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-etelcalcetide antibody 
response may also be asked to return for additional follow-up testing.   
Refer to the Schedule of Assessments (Table 1), as applicable, for specific time points 
and the laboratory manual for detailed collection and handling instructions. 
7.4 
Sample Storage and Destruction 
Any blood PK or antibody sample collected according to the Schedule of Assessments 
(Table 1) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  


 
 
 
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All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject’s LAR, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
secondary hyperparathyroidism due to chronic kidney disease,  the dose response 
and/or prediction of response to etelcalcetide, characterize antibody response, and 
characterize aspects of the molecule (eg, mechanism of action/target, metabolites).  
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of other exploratory studies are not placed in the subject’s 
medical record and are not to be made available to the subject, members of the family, 
the personal physician, or other third parties, except as specified in the informed 
consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the Investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.   
See Section 11.3 for subject confidentiality. 


 
 
 
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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative (LAR)) can decline to continue receiving 
investigational product and/or other protocol required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 1) and 
collection of data, including endpoints and adverse events.  The Investigator must 
document the change to the Schedule of Assessments (Table 1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject (or a LAR) does not wish to 
receive further protocol-required therapies or procedures, and the subject (or a LAR) 
does not wish to or is unable to continue further study participation.  Subject data up to 
withdrawal of consent will be included in the analysis of the study, and where permitted, 
publically available data can be included after withdrawal of consent.  The investigator is 
to discuss with the subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  


 
 
 
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8.2.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria (list criteria), pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
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 trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease has 
increased in severity, frequency, and/or duration more than expected by the 
investigator’s assessment.  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.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 


 
 
 
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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, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures - Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of study are reported using the Event CRF. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity, 
• 
Assessment of relatedness to etelcalcetide,  
• 
Action taken. 


 
 
 
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The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  The grading scale used in this study is described 
in Appendix A.   
The investigator must assess whether the adverse event is possibly related to the 
investigational product.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational product?  
The investigator must assess whether the adverse event is possibly related to other 
protocol-required therapies.   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 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. If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after etelcalcetide administration are recorded in the subject’s 
medical record and are submitted to Amgen.  All serious adverse events must be 
submitted to Amgen within 24 hours following the investigator’s knowledge of the event 
via the Event CRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event. See Appendix B for a sample of the Serious 


 
 
 
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Adverse Event Worksheet /electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
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. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.1 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 


 
 
 
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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.  
9.2.2.2 
Reporting of Reductions in Serum Calcium 
Asymptomatic reductions in calcium below 7.5 mg/dL or asymptomatic reductions in 
serum corrected calcium between 7.5 and < 8.3 mg/dL that required medical 
management or that the investigator deemed clinically significant should be reported as 
adverse events of “blood calcium decreased”.  Symptomatic reductions in serum 
corrected calcium < 8.3 mg/dL should be reported as adverse events of “hypocalcemia”, 
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 etelcalcetide, report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after etelcalcetide administration through 3 months 
after etelcalcetide administration. 
The pregnancy should be reported to Amgen’s 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).   
If a lactation case occurs while the female subject is taking etelcalcetide, 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 etelcalcetide administration through 3 months after 
etelcalcetide administration. 
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 


 
 
 
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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints   
• 
Common treatment-emergent adverse events [including changes in physical 
examinations] 
• 
Changes in key laboratory safety tests [albumin corrected calcium (cCalcium), 
phosphorus, potassium, parathyroid hormone (PTH)], ECGs and vital signs 
10.1.1.2 
Secondary Endpoints   
• 
Pharmacokinetic parameters (AUC, Cmax, tmax, t1/2) of etelcalcetide in plasma 
• 
Pharmacodynamics: concentration of parathyroid hormone (PTH), serum calcium 
[total calcium, ionized calcium and albumin corrected calcium] over time 
• 
Anti-etelcalcetide antibodies 
• 
Incidence of treatment-emergent adverse events 
10.1.2 
Analysis Sets 
The analysis of all endpoints, unless noted otherwise, will be conducted on the Safety 
Analysis Set defined as all subjects that are enrolled and receive a dose of etelcalcetide. 
10.2 
Sample Size Considerations 
The sample size is based on practical consideration. No formal sample size calculations 
have been performed.  
10.3 
Planned Analysis 
10.3.1 
Primary Analysis 
The objective of the primary analysis is to assess safety, tolerability, PK, and PD of a 
single dose of etelcalcetide in this patient population. The primary analysis will be 
performed upon achieving the Primary Completion milestone described in section 3.5.2. 
10.4 
Planned Methods of Analysis 
10.4.1 
General Considerations 
Descriptive statistics will be provided for selected demographics, safety data, PK and PD 
data for all subjects by cohort where appropriate. Descriptive statistics on continuous 
measurements will include number of observations, means, medians, first and third 
quartiles, standard deviations or standard error, minimum and maximum, while 
categorical data will be summarized using frequency counts and percentages.  
No formal statistical testing will be performed. 


 
 
 
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10.4.2 
Primary Endpoints 
10.4.2.1 
Common Treatment-emergent Adverse Events 
All reported adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Determination of the severity of all adverse events (AE) will be 
consistent with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
unless specified otherwise. 
Common adverse events include those with occurrence in 2 or more subjects. Subject 
incidence of all common treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.   
10.4.2.2 
Clinical Laboratory Tests, ECG and Vital Signs 
Summaries of key laboratory [albumin corrected calcium (cCalcium), phosphorus, 
potassium, parathyroid hormone (PTH)], ECG and vital sign data over time and changes 
from baseline over time will also be provided at each time point when samples are 
collected. Subject Incidence of low calcium (<7.5 mg/dL, <8.0 mg/dL and <8.3 mg/dL) 
post-baseline will be provided. 
10.4.3 
Secondary Endpoint(s) 
10.4.3.1 
Pharmacokinetic Endpoints 
Etelcalcetide concentration-time data in plasma will be used to determine the PK 
parameters using non-compartmental methods. Plasma etelcalcetide concentrations 
below the lower limit of quantifications will be set to zero for the estimation of the 
pharmacokinetic parameters for each subject and for the calculation of the summary 
statistic for each time point. Actual dosing and sampling time will be used for all 
calculations. The reasons for excluding any sample from the analyses will be provided. 
Individual and mean (SE) plasma concentration-time data for etelcalcetide will be 
presented graphically. PK parameters will be summarized for all subjects using 
descriptive statistics. 
10.4.3.2 
Pharmacodynamic Endpoints 
For concentrations of serum PTH and serum calcium (total calcium, albumin corrected 
calcium, and ionized calcium) over time, individual and mean (SE) of the absolute value 
and change from baseline at each post-baseline time point will be plotted and descriptive 
statistics will be tabulated. 


 
 
 
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10.4.3.3 
Antibody 
A table summarizing the evaluation of antibody formation to etelcalcetide will be 
provided. 
10.4.3.4 
Treatment-emergent Adverse Events 
In addition to the common treatment-emergent adverse events analyzed in the primary 
endpoints, all treatment emergent adverse events will be included as secondary 
endpoints. Subject incidence of all treatment emergent adverse events will be tabulated 
by system organ class and preferred term.  Tables of all treatment-related adverse 
events, fatal adverse events, serious adverse events, treatment emergent adverse 
events of interest will also be provided. 
10.4.4 
Additional Analyses 
10.4.4.1 
Subject Accountability 
The number of subjects who receive etelcalcetide and complete the study will be 
summarized. In addition, significant known protocol deviations will be noted for individual 
subjects. 
Age, race, sex, height, weight and selected baseline characteristics will be summarized 
for all the subjects receiving etelcalcetide using descriptive statistics. 
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’s legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential risks 
of the study and before any protocol specific screening procedures or any investigational 
product(s) is/ are administered.  A legally acceptable representative is an individual or 
other body authorized under applicable law to consent, on behalf of a prospective 
subject, to the subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 


 
 
 
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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’s legally acceptable representative and by 
the person who conducted the informed consent discussion.  The original signed 
informed consent form is to be retained in accordance with institutional policy, and a 
copy of the signed consent form is to be provided to the subject’s legally acceptable 
representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/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 investigational product. 
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 approval and renewal for IRBs 
and IECs throughout the duration of the study.  Copies of the investigator’s reports and 
the IRB/IEC continuance of approval must be sent to Amgen. 


 
 
 
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11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment.   
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/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 named such individuals to have access to 
his/her study related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multi-
center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/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. 


 
 
 
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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 early termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 


 
 
 
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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, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
Amgen (or designee) will perform self-evident corrections (SECs) to obvious data errors 
in the clinical trial database. SECs will be documented in the Standard Self Evident 
Corrections document and the eCRF Specific Instructions, both of these will be available 
through the EDC system. Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date but different visits eg, week 4 and early termination) and 
updating a specific response if the confirming datum is provided in the “other, specify” 
field (eg, for race, reason for ending study). 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 


 
 
 
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records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 


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


 
 
 
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13. 
REFERENCES 
Abdelfatah A, Motte G, Ducloux D, Chalopin J. Determinants of mean arterial pressure 
and pulse pressure in chronic haemodialysis patients. J Hum Hypertens. 
2001;15(11):775-779. 
Chesney RW, Brewer E, Moxey-Mims M, Watkins S, et al. Report of an NIH task force 
on research priorities in chronic kidney disease in children. Pediatr Nephrol. 
2006;21:14-25. 
Cheung AK, Sarnak MJ, Yan G, et al. Atherosclerotic cardiovascular disease risks in 
chronic haemodialysis patients. Kidney Int. 2000;58(1):353-62. 
Coen G, Mazzaferro S, Ballanti P, et al. Renal bone disease in 76 patients with varying 
degrees of predialysis chronic renal failure: a cross-sectional study. Nephrol Dial 
Transplant. 1996;11:813-819. 
Cundy T, Hand DJ, Oliver DO, et al. Who gets renal bone disease before beginning 
dialysis? Br Med J (Clin Res Ed). 1985;290:271-275. 
Etelcalcetide Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 05 Oct 2015 
EMEA-001554-PIP01-13, decision dated 01 Oct 2014 
Foley R, Parfrey P, Sarnak M. Clinical epidemiology of cardiovascular disease in chronic 
renal disease. Am J Kidney Dis. 1998;32(5 Suppl 3):112-119. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2006. http://www.icmje.org/ 
Kari JA, Rees L. Growth hormone for children with chronic renal failure and on dialysis. 
Pediatr Nephrol. 2005;20:618–621. 
Klassen S, Edmund G, et al. Association between pulse pressure and mortality in 
patients undergoing maintenance haemodialysis. JAMA. 2002;287:1548-1555. 
Kuizon BD, Salusky IB. Growth retardation in children with chronic renal failure. J Bone 
Miner Res. 1999;14:1680–1690. 
Martinez I, Saracho R, Montenegro J, et al. The importance of dietary calcium and 
phosphorous in the secondary hyperparathyroidism of patients with early renal failure. 
Am J Kidney Dis. 1997;29:496-502. 
McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. 
NEJM. 2004;350(26):2654-2662. 
Melamed M, Eustace J, et al. Changes in serum calcium, phosphate, and PTH and the 
risk of death in incident dialysis patients: A longitudinal study. Kidney Int. 
2006;70:351-357. 
Moe S, Drϋeke T, et al. Definition, evaluation, and classification of renal osteodystrophy: 
A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). 
Kidney Int. 2006;69:1945-1953. 
NKF K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children 
with Chronic Kidney Disease Am J of Kidney Disease 2005;46, 4.   
North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), 2006 
Annual Report, In:  https://web.emmes.com/study/ped/annlrept/annlrept.html 


 
 
 
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Oh J, Wunsch R, Turzer M, et al. Advanced Coronary and Carotid Arteriopathy in Young 
Adults With Childhood-Onset Chronic Renal Failure Circulation. 2002;106:100-105. 
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of Official 
Journal of the European Union 12 December 2006. 
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf 
Sanchez CP. Secondary hyperparathyroidism in children with chronic renal failure: 
pathogenesis and treatment. Paediatr Drugs. 2003;5(11):763-776. 
Salusky IB, Fine RN, Kangarloo H, et al. "High-dose" calcitriol for control of renal 
osteodystrophy in children on CAPD. Kidney Int. 1987;32(1):89-95. 
Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. 
Kidney Int Suppl. 1999;73:S14-S19. 
Spasovski GB, Bervoets AR, Behets GJ, et al. Spectrum of renal bone disease in 
end-stage renal failure patients not yet on dialysis. Nephrol Dial Transplant. 
2003;18:1159-1166. 
Tonshoff B, Kiepe D, Ciarmatori S. Growth hormone/insulin-like growth factor system in 
children with chronic renal failure. Pediatr Nephrol. 2005;20:279–289. 
US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States. National Institutes of 
Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, 
Maryland, 2009. 
Waller S, Ledermann S, Trompeter R, van't Hoff W, Ridout D, Rees L. Catch-up growth 
with normal parathyroid hormone levels in chronic renal failure. Pediatr Nephrol. 
2003;18(12):1236-1241. 
 


 
 
 
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14. 
APPENDICES 


 
 
 
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Appendix A.  Additional Safety Assessment Information 
The common Terminology Criteria for Adverse Evens Version 4.0 is available at 
the following link: 
Adverse Event Grading Scale 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Drug-induced Liver Injury Reporting & Additional Assessments  
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 
Reporting 
6.3 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2. 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 
Additional Clinical Assessments and Observation 
6.3 or who experience AST or ALT elevations > 3 x ULN are to undergo a period 
of “close observation” until abnormalities return to normal or to the subject’s baseline 
levels.  Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
• 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 


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


 
 
 
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Appendix B.  Sample Serious Adverse Event Form 
 


 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


 
 
 
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SAP_001.pdf: 
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