Conditions: Secondary Hyperparathyroidism, Chronic Kidney Disease
Keywords: Chronic Kidney Disease, Dialysis, Secondary Hyperparathyroidism, Pediatric
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
The primary objective of this study was to characterize the long-term safety and tolerability of cinacalcet in pediatric patients with chronic kidney disease (CKD) receiving dialysis.

Detailed description:
This extension study was designed to characterize the long-term safety and tolerability of cinacalcet in pediatric patients from Amgen Studies 20130356 (NCT02138838) and 20110100 (NCT01439867) who either had completed the parent study or were ongoing at the time an administrative decision was made to end the parent study. After enrolling into this study participants were administered cinacalcet for 28 weeks or until the time of renal transplant or parathyroidectomy, whichever occurred first. The treatment period was followed by a 4-week safety follow-up period.

Arms:
arm 1: Participants received cinacalcet daily for 24 weeks in this extension study. For participants who received standard of care (SOC) in parent study 20130356, the starting dose was 0.20 mg/kg/day. For participants who received SOC and cinacalcet in parent study 20130356 or 20110100 the starting dose was either the same as the last dose received in the parent study or 0.20 mg/kg/day if the last dose of cinacalcet in the parent study was received \> 14 days before day 1 of this study.

Dose adjustments and withholding were based on weekly assessments of ionized calcium as well as plasma intact parathyroid hormone (iPTH) and corrected serum calcium levels assessed monthly.

Interventions: intervention 1: Cinacalcet
Intervention descriptions: intervention 1: Cinacalcet was provided as 5 mg capsules for sprinkling or as 30 mg film-coated tablets for swallowing. The protocol-specified doses were: 1, 2.5, 5, 7.5, 10, 15, 30, 60, 90, 120, and 180 mg.

Protocol document:
Prot_000.pdf: 
Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 1 
 
 
 
 
16.1.1 
Protocol and Amendments 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
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CONFIDENTIAL 
 
 
 
Product:  Cinacalcet HCl 
Protocol Number:  20140159 
Date:  01 June 2016 
Page 1 of 79 
 
 
Title: A Multicenter Single-arm Extension Study to Characterize the Long-term 
Safety of Cinacalcet Hydrochloride in the Treatment of Secondary 
Hyperparathyroidism in Pediatric Subjects With Chronic Kidney Disease on 
Dialysis 
 
 
Amgen Protocol Number (cinacalcet HCl) 20140159 
 
EudraCT number 2014-003563-38 
 
Clinical Study Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
 
Key Sponsor Contact(s): 
PPD  
 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park), Uxbridge, 
Middlesex, United Kingdom, UB8 1DH 
PPD 
 
 
Date: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Superseding 3: 
05 August 2014 
18 December 2014 
22 July 2015 
16 March 2016 
01 June2016 
 
 
Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries, please call the local toll-free Medical 
Information number or the US toll-free number (1-800-772-6346). Amgen’s general 
number in the US (1-805-447-1000). 
 
 
 
 
 
 
NCT Number: 2341417 
This NCT number has been applied to the document for purposes 
of posting on clinicaltrials.gov 


Product: Cinacalcet  hydrochloride 
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Protocol Number:  20140159 
Date:  01 June 2016 
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Investigator’s Agreement 
 
I have read the attached protocol entitled “A Multicenter Single-arm Extension Study to 
Characterize the Long-term Safety of Cinacalcet Hydrochloride in the Treatment of 
Secondary Hyperparathyroidism in Pediatric Subjects With Chronic Kidney Disease on 
Dialysis,” dated 01 June 2016, and agree to abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
 
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
 
 
Signature 
 
 
Name of Investigator 
Date (DD Month YYYY) 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
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Protocol Number:  20140159 
Date:  01 June 2016 
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Protocol Synopsis 
 
Title:  A Multicenter Single-arm Extension Study to Characterize the Long-term Safety of 
Cinacalcet Hydrochloride in the Treatment of Secondary Hyperparathyroidism in Pediatric 
Subjects With Chronic Kidney Disease on Dialysis 
Study Phase:  3 
Indication:  Management of secondary hyperparathyroidism in pediatric subjects with chronic 
kidney disease (CKD) receiving dialysis 
 
Primary Objective:  To characterize the long-term safety and tolerability of cinacalcet in pediatric 
subjects with CKD receiving dialysis 
Secondary Objective(s):  To characterize the long-term effect of cinacalcet in pediatric subjects 
receiving dialysis on laboratory parameters associated with chronic kidney disease-mineral bone 
disease (CKD-MBD) 
Exploratory Objective:  To characterize the long-term effect of cinacalcet in pediatric subjects 
on linear and pubertal growth 
Hypotheses:  A formal hypothesis does not apply for the study.  The long-term safety of 
cinacalcet in pediatric subjects will be characterized in this study. 
Primary Endpoint: 
• 
Incidence of treatment-emergent adverse events of interest 
 
Secondary Endpoints: 
Study 20140159 only 
• 
Achievement of ≥ 30% reduction from baseline to mean intact parathyroid hormone 
(iPTH) during weeks 11 and 15 (standard of care [SOC] arm of Study 20130356 only) 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during weeks 23 and 28 
(SOC arm of Study 20130356 only) 
• 
Percent change from baseline to mean iPTH during weeks 23 and 28 (SOC arm of 
Study 20130356 only) 
• 
Change in corrected total serum calcium from baseline to mean value during weeks 23 
and 28 
• 
Change in serum phosphorus from baseline to mean value during weeks 23 and 28 
• 
Achievement of a mean iPTH ≤ 300 pg/mL during weeks 23 and 28 
• 
Serum corrected calcium (cCa) at baseline, week 11, and week 28 
• 
Serum phosphorus at baseline, week 11, and week 28 
 
Combined Studies 20130356, 20110100, and 20140159 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to mean iPTH during 
weeks 11 and 15 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to mean iPTH during 
weeks 23 and 28 
• 
Percent change in iPTH over time from day 1 of cinacalcet treatment 
• 
Change in serum cCa over time from day 1 of cinacalcet treatment 
• 
Change in serum phosphorus over time from day 1 of cinacalcet treatment 
 
Exploratory Endpoints: 
Study 20140159 only 
• 
Growth velocity from baseline to end of study (EOS) 
• 
Change in Tanner stage from baseline to EOS 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
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Protocol Number:  20140159 
Date:  01 June 2016 
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Combined Studies 20130356, 20110100, and 20140159 
• 
Growth velocity from day 1 of cinacalcet treatment to EOS 
• 
Change in Tanner stage from day 1 of cinacalcet treatment to EOS 
 
Safety Endpoints: 
• 
Nature, frequency, and severity of all adverse events 
• 
Blood pressure, heart rate, and changes in laboratory parameters 
 
Study Design:  This is a phase 3, 32-week multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects.  Subjects will 
remain on cinacalcet treatment for 28 weeks after enrollment or until the time of renal transplant 
or parathyroidectomy, whichever occurs first.  The treatment period is followed by a 4-week 
safety follow-up period. 
 
Sample Size:  Up to 78 subjects may be enrolled 
Summary of Subject Eligibility Criteria:  Subjects who complete the 20-week treatment period 
or reach study termination in Study 20130356 or the week 26 End of Study visit or reach study 
termination in Study 20110100 will be eligible to receive 28 weeks of treatment with cinacalcet in 
this extension study, followed by a 4-week safety follow-up.  Subjects must also meet the 
inclusion and exclusion criteria for this extension study in order to be eligible.  Subjects must 
provide written informed consent (parents or guardian) and assent, where appropriate, according 
to local regulations specific to the procedures in this study. 
• 
Subjects enrolled in the SOC arm of Study 20130356 will be eligible for the extension 
study if the iPTH is ≥ 300 pg/mL and the cCa is ≥ 8.8 mg/mL within 7 days of day 1 in 
Study 20140159. 
• 
Eligible subjects from the cinacalcet arm of Study 20130356 will restart or continue 
cinacalcet treatment following the dosing rules described in Section 6.2.3.1.1. 
• 
Eligible subjects from Study 20110100 will restart or continue cinacalcet following the 
dosing rules as described in Section 6.2.3.1.2. 
 
Subjects will be excluded from this study if they have adverse events continuing from 
Study 20130356 or 20110100 that are considered related to investigational product (IP) and are 
≥ CTCAE grade 3 and/or considered clinically significant by the investigator.  For a full list of 
eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Cinacalcet is a calcimimetic 
agent which is synthesized as a hydrochloride salt.  Cinacalcet will be provided as 5 mg capsules 
for sprinkling or as film coated tablets for swallowing in a strength of 30 mg. 
The capsules provided must not be swallowed whole and must be opened and either sprinkled on 
soft food or suspended into a sucrose syrup to create a liquid suspension for administration. 
The protocol-specified doses (PSD) for use in this study are:  1, 2.5, 5, 7.5, 10, 15, 30, 60, 90, 
120, and 180 mg. 
Subjects will receive cinacalcet daily and all doses should be administered with food or shortly 
after a meal at the same time each day.  On study visit days where a blood sample is to be 
drawn, cinacalcet should not be administered until after the blood sample has been obtained. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  All subjects will 
receive standard of care treatment including vitamin D sterols, calcium supplementation, and 
phosphate binders at the discretion of the investigator. 
Procedures:  Informed consent, and assent where applicable, for this study should be presented 
during the Studies 20130356 or 20110100.  The informed consent, including assent as 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
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Protocol Number:  20140159 
Date:  01 June 2016 
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appropriate, will be obtained prior to execution of any study procedures for this extension study. 
Where the Screening and day 1 assessments for Study 20140159 overlap with visits in 
the 20130356 or 20110100 studies, these will be performed once at the site and applied to both 
study visits to minimize duplicate study assessments, eg, 20130356 end of investigational 
product (EOIP)  and 20140159 Screening. The subject visits and assessments for this study will 
occur from baseline through to the end of study.  Assessments during this study will include: 
• 
collection of blood samples for the evaluation of blood chemistry, hematology, calcium, 
iPTH, and bone biomarkers 
• 
physical assessments including vital signs (ie, blood pressure, heart rate) 
• 
12-lead electrocardiogram (ECG) at baseline and week 32 (if the subject ends the study 
prior to week 32, the 12-lead ECG will be performed at the last study visit) 
• 
assessments for symptoms of hypocalcemia 
• 
recording of adverse events, concomitant medications, and IP compliance 
 
Subjects from Study 20130356:  Subjects who complete the 20-week treatment period in 
study 20130356 or are still on study at the time of Study 20130356 termination, will be eligible to 
receive cinacalcet treatment in the current study. 
• 
Subjects from the SOC group in 20130356:  After confirming eligibility, subjects in the 
20130356 SOC group will receive the initial dose of cinacalcet based on the subject’s dry 
weight at day 1 in Study 20140159, 0.20 mg/kg/day, rounded down to the nearest PSD. 
Subjects from the 20130356 SOC group will follow the same cinacalcet titration schedule 
as subjects who received cinacalcet in Study 20130356. 
• 
Subjects from the cinacalcet group in 20130356:  After confirming eligibility, subjects 
from the cinacalcet group will continue to receive cinacalcet at the same dose as EOIP 
visit if there are ≤ 14 days between the last dose of cinacalcet treatment in 
Study 20130356 and day 1 of Study 20140159.  If the cinacalcet dose has been withheld 
or missed for > 14 days at the time of day 1 of Study 20140159, subjects will receive the 
initial dose of cinacalcet based on the subject’s dry weight at time of enrollment to 
20140159.  Subjects in this group will be eligible to receive dose titrations during the 
extension study if the maximum dose of 2.5 mg/kg (based on 20140159 day 1 dry 
weight), not exceeding 180 mg, has not been reached and they meet the titration criteria 
defined in Section 6. 
 
Subjects from Study 20110100:  Subjects who complete the week 26 End of Study visit or are 
still on study at the time of Study 20110100 termination, will be eligible to receive cinacalcet 
treatment in the current study.  After confirming eligibility, subjects will continue to receive 
cinacalcet at the same dose as EOIP visit if there are ≤ 14 days between the last dose of 
cinacalcet treatment in Study 20110100 and day 1 of Study 20140159.  If the cinacalcet dose has 
been withheld or missed for > 14 days at the time of day 1 of Study 20140159, subjects will 
receive the initial dose of cinacalcet based on the subject’s dry weight at time of enrollment to 
20140159 and age at time of enrollment to 20110100, 0.20 mg/kg/day, rounded down to the 
nearest PSD.  Subjects will follow the dose adjustments outlined in Section 6.2.3.1.2.  Subjects in 
this group will be eligible to receive dose titrations during the extension study if the maximum 
dose of 2.5 mg/kg (based on 20140159 day 1 dry weight), not exceeding 60 mg, has not been 
reached and they meet the titration criteria defined in Section 6. 
During the 20140159 study: 
Weekly monitoring of ionized calcium will be required for all subjects through the end of the 
treatment period, week 28. 
Cinacalcet doses will be calculated by the site staff and confirmed by the interactive voice 
response/interactive web response (IVR/IWR) system following the titration tables in Section 6. 
The titration tables are based on cCa and iPTH values from the central laboratory collected one 
week before dose titration.  Final dose assignment will be based on the ionized calcium obtained 


Product: Cinacalcet  hydrochloride 
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Date:  01 June 2016 
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on the day of titration.  An assessment of symptomatic hypocalcemia will also be performed on 
the day of titration.  Additional weekly dose adjustments for safety are permitted as described in 
Section 6.2.3.1.  The maximum dose assigned for all subjects will be 2.5 mg/kg/day (based on 
dry weight at day 1 in Study 20140159) not to exceed a dose of 180 mg/day for subjects from 
20130356 and 60 mg/day for subjects from 20110100. 
For all subjects, it is recommended that the vitamin D sterols, calcium supplementation, and 
phosphate binders be administered as appropriate per individual clinical practice.  The use of 
medications that may prolong the corrected QT (QTc) interval (eg, ondansetron, albuterol), 
CYP3A4 inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole), CYP2D6 
substrates (eg, flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine), 
and commercial cinacalcet during the course of the trial are prohibited while the subject is 
receiving investigational product. 
Serious adverse events will be collected from the date of the first dose through 30 days following 
the last dose of investigational product.  Adverse events will be collected from the date of the first 
dose through 30 days following the last dose of investigational product. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 4). 
Statistical Considerations:  There is no formal statistical testing for this study.  The analysis of 
the primary and secondary endpoints will be descriptive in nature. 
For categorical variables, the number and percentage of subjects in each category will be 
reported.  Descriptive statistics will be used to summarize data for continuous variables (including 
n, mean, standard deviation (SD) or standard error (SE), median, 25
th (Q1) and 75
th (Q3) 
percentiles, minimum and maximum values, where applicable).  All summary tables will be 
provided by study treatment group:  Study 20130356 (SOC, SOC + cinacalcet) and 
Study 20110100 and overall, unless otherwise specified. 
Graphical presentations may be provided for selected variables. 
All adverse events occurring during the study will be coded using the latest version of the 
MedDRA dictionary and the subject incidence will be tabulated. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version(s)/Date(s): 
 
 
Version (s) 4.0 
31 October 2013 


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Study Design and Treatment Schema 
 
 
Informed Consent 
 
Subject Assent (if applicable) 
 
Are collected within 7 days before day 1 of 
Study 20140159a 
 
 
 
 
 
 
 
 
Screening Period 
7 days before the 20140159 day 1 visita 
 
 
 
 
 
 
Eligible Subjects Enrolled 
 
Day 1 of Study 20140159 
 
 
 
 
 
 
 
Treatment Period
b
 
 
Day 1 – Week 28 
 
Cinacalcet QD 
 
 
 
 
 
 
End of Study 
 
Week 32 
 
 
a When it is not possible to perform a study visit at the specified time point, the visit may be performed within 
± 3 days. 
b The initial dose of cinacalcet assigned will be based on the dosing in the originating parent study. 
Refer to Section 6 of the protocol for additional details. 


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Study Glossary 
 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BALP 
Bone specific alkaline phosphatase 
Bazett's formula 
QT/√RR 
Ca 
serum calcium 
CaSR 
calcium sensing receptor 
CBC 
complete blood count 
cCa 
corrected calcium 
CKD 
chronic kidney disease 
CKD-MBD 
chronic kidney disease-mineral bone disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTx 
Type 1 collagen cross-linked telopeptide 
DHHS 
Department of Health and Human Services 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic patient diary 
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 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data 
End of Study for 
Individual Subject (EOS) 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
EOIP 
end of investigational product 
ERA-EDTA 
European Renal Association-European Dialysis and Transplant 
Association 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FGF 23 
fibroblast growth factor 23 
HD 
hemodialysis 
IB 
investigator brochure 
IEC 
independent ethics committee 
INR 
international normalized ratio 
Interactive Voice 
Response (IVR) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information. 


Product: Cinacalcet  hydrochloride 
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Abbreviation or Term 
Definition/Explanation 
Interactive Web 
Response (IWR) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information. 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
iPTH 
Intact parathyroid hormone 
IRB 
institutional review board 
LFT 
liver function test 
NAPRTCS 
North American Pediatric Renal Trials and Collaborative Services 
NASH 
nonalcoholic fatty liver disease including steatohepatitis 
NTx 
Cross-linked N-telopeptides of type 1 collagen 
Primary Completion 
the time when the last subject is assessed during the study (ie, 
week 32) 
P1NP 
Amino terminal propeptide of type 1 collagen 
PD 
peritoneal dialysis 
POC 
point of care 
PSD 
protocol specified dose 
PTH 
parathyroid hormone 
QTc 
corrected QT 
SD 
standard deviation 
SE 
standard error 
SHPT 
secondary hyperparathyroidism 
sNDA 
Supplemental New Drug Application 
SOC 
standard of care 
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 date that the initial dose of investigational product is 
administered 
TBL 
total bilirubin 
ULN 
upper limit of normal 
US 
United States 


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Table of Contents 
 
Protocol Synopsis .............................................................................................................  3 
 
Study Design and Treatment Schema .............................................................................. 7 
 
Study Glossary ..................................................................................................................  8 
 
1. 
OBJECTIVES .........................................................................................................  14 
1.1 
Primary ....................................................................................................... 14 
1.2 
Secondary .................................................................................................. 14 
1.3 
Exploratory ................................................................................................. 14 
 
2. 
BACKGROUND AND RATIONALE........................................................................ 14 
2.1 
Secondary Hyperparathyroidism in Pediatric Subjects............................... 14 
2.2 
Cinacalcet Background............................................................................... 15 
2.3 
Standard of Care Therapy .......................................................................... 15 
2.4 
Pediatric Risk Assessment ......................................................................... 15 
2.5 
Studies Eligible to Roll-over to 20140159................................................... 16 
2.5.1 
Amgen Study 20130356 ............................................................. 16 
2.5.2 
Amgen Study 20110100 ............................................................. 17 
2.6 
Rationale .................................................................................................... 17 
2.7 
Clinical Hypotheses .................................................................................... 17 
3. 
EXPERIMENTAL PLAN ......................................................................................... 18 
3.1 
Study Design .............................................................................................. 18 
3.1.1 
Subjects From Study 20130356 ................................................. 18 
3.1.2 
Subjects From Study 20110100 ................................................. 19 
3.2 
Number of Sites.......................................................................................... 19 
3.3 
Number of Subjects .................................................................................... 19 
3.4 
Replacement of Subjects............................................................................ 20 
3.5 
Estimated Study Duration ........................................................................... 20 
3.5.1 
Study Duration for Subjects........................................................ 20 
3.5.2 
End of Study ............................................................................... 20 
 
4. 
SUBJECT ELIGIBILITY.......................................................................................... 20 
4.1 
Inclusion and Exclusion Criteria ................................................................. 20 
4.1.1 
Inclusion Criteria......................................................................... 20 
4.1.2 
Exclusion Criteria........................................................................ 21 
 
5. 
SUBJECT ENROLLMENT ..................................................................................... 22 
5.1 
Screening ................................................................................................... 23 
5.2 
Enrollment .................................................................................................. 23 
 
6. 
TREATMENT PROCEDURES ............................................................................... 23 
6.1 
Standard of Care ........................................................................................ 23 


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6.2 
Cinacalcet................................................................................................... 24 
6.2.1 
Classification of Product ............................................................. 24 
6.2.2 
Investigational Product ............................................................... 24 
6.2.3 
Dosage, Administration, and Schedule ...................................... 24 
6.2.3.1 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 26 
6.2.3.2 
Measures of Compliance With Cinacalcet 
Administration .......................................................... 37 
6.2.3.3 
Overdose ................................................................. 37 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules........................................ 38 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 38 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 40 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity.............................................................. 40 
6.4 
Concomitant Therapy ................................................................................. 41 
6.5 
Product Complaints .................................................................................... 41 
6.6 
Excluded Treatments and/or Procedures During Study Period .................. 41 
 
7. 
STUDY PROCEDURES......................................................................................... 42 
7.1 
Schedule of Assessments .......................................................................... 42 
7.2 
General Study Procedures ......................................................................... 45 
7.2.1 
Screening and Enrollment .......................................................... 45 
7.2.2 
Day 1 .......................................................................................... 46 
7.2.3 
Treatment ................................................................................... 47 
7.2.4 
End of Investigational Product.................................................... 47 
7.2.5 
Early Termination ....................................................................... 48 
7.2.6 
End of Study Visit ....................................................................... 48 
7.3 
Description of General Study Procedures .................................................. 49 
7.3.1 
Informed Consent/Assent ........................................................... 49 
7.3.2 
Demographic Data...................................................................... 49 
7.3.3 
Medical and Surgical History ...................................................... 49 
7.3.4 
Physical Exam, Height, Tanner Stage, Dry Weight .................... 49 
7.3.5 
Blood Pressure and Heart Rate.................................................. 50 
7.3.6 
ECG............................................................................................ 50 
7.3.7 
Concomitant Medications ........................................................... 50 
7.3.8 
Electronic Patient Diary .............................................................. 51 
7.3.9 
Ionized Calcium .......................................................................... 51 
7.3.10 
Adverse Events .......................................................................... 52 
7.3.11 
Laboratory Assessments ............................................................ 52 


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7.3.12 
Home Healthcare........................................................................ 53 
7.4 
Biomarker Development ............................................................................. 53 
7.5 
Sample Storage and Destruction................................................................ 54 
 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 55 
8.1 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 55 
8.2 
Reasons for Removal From Study ............................................................. 56 
8.2.1 
Reasons for Removal From Treatment ...................................... 56 
8.2.2 
Reasons for Removal From Study ............................................. 56 
 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 56 
9.1 
Adverse Events .......................................................................................... 56 
9.1.1 
Definition of Adverse Events ...................................................... 56 
9.1.2 
Definition of Serious Adverse Events ......................................... 57 
9.2 
Reporting of Adverse Events ...................................................................... 57 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria.................................................................. 57 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 58 
9.3 
Pregnancy and Lactation Reporting ........................................................... 59 
 
10. STATISTICAL CONSIDERATIONS ....................................................................... 60 
10.1 
Study Endpoints, Analysis Sets, and Covariates........................................ 60 
10.1.1 
Study Endpoints ......................................................................... 60 
10.1.2 
Analysis Sets .............................................................................. 61 
10.1.3 
Covariates and Subgroups ......................................................... 61 
10.2 
Sample Size Considerations ...................................................................... 62 
10.3 
Planned Analyses....................................................................................... 62 
10.3.1 
Interim Analysis .......................................................................... 62 
10.3.2 
Primary Analysis......................................................................... 62 
10.4 
Planned Methods of Analysis ..................................................................... 62 
10.4.1 
General Considerations.............................................................. 62 
10.4.2 
Primary Endpoint ........................................................................ 62 
10.4.3 
Secondary Endpoints ................................................................. 63 
10.4.4 
Safety Endpoints ........................................................................ 64 
 
11. 
REGULATORY OBLIGATIONS ............................................................................. 65 
11.1 
Informed Consent ....................................................................................... 65 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 66 
11.3 
Subject Confidentiality ................................................................................ 66 
11.4 
Investigator Signatory Obligations.............................................................. 67 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS................................................... 67 
12.1 
Protocol Amendments and Study Termination ........................................... 67 
12.2 
Study Documentation and Archive ............................................................. 68 


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12.3 
Study Monitoring and Data Collection ........................................................ 68 
12.4 
Investigator Responsibilities for Data Collection ........................................ 70 
12.5 
Language....................................................................................................  70 
12.6 
Publication Policy ....................................................................................... 70 
12.7 
Compensation ............................................................................................ 71 
 
13. REFERENCES....................................................................................................... 72 
 
14. APPENDICES ........................................................................................................ 73 
 
List of Tables 
 
Table 1. Dose Adjustment Rules: Monthly, Weekly, and Withholding in 
Children 6-18 Years of age ...................................................................... 29 
 
Table 2. Dose Adjustment Rules: Monthly, Weekly, and Withholding in 
Subjects < 2 Years old ............................................................................. 33 
 
Table 3. Dose Adjustment Rules: Monthly, Weekly, and Withholding in 
Subjects ≥ 2 Years old in Study 20110100 .............................................. 36 
 
Table 4. Schedule of Assessments ................................................................................ 43 
 
Table 5. Analytes ...........................................................................................................  53 
 
List of Appendices 
 
Appendix A. Additional Safety Assessment Information ................................................ 74 
 
Appendix B. Sample Serious Adverse Event Report Form ............................................ 76 
 
Appendix C. Pregnancy and Lactation Notification Worksheets .................................... 78 


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1. 
OBJECTIVES 
 
1.1 
Primary 
 
To characterize the long-term safety and tolerability of cinacalcet in pediatric subjects 
with chronic kidney disease (CKD) receiving dialysis. 
 
1.2 
Secondary 
 
To characterize the long-term effect of cinacalcet in pediatric subjects receiving dialysis 
on laboratory parameters associated with chronic kidney disease – mineral and bone 
disease (CKD-MBD). 
 
1.3 
Exploratory 
 
To characterize the long-term effect of cinacalcet in pediatric subjects on linear and 
pubertal growth. 
 
2. 
BACKGROUND AND RATIONALE 
 
2.1 
Secondary Hyperparathyroidism in Pediatric Subjects 
 
Secondary hyperparathyroidism (SHPT) develops relatively early in the course of CKD, 
worsens with declining renal function, and is commonly associated with serious 
complications both in adults and in children on dialysis. CKD in children, as in adults, is 
a devastating illness. In children with CKD, growth retardation is a prominent finding and 
 
SHPT is an important contributor to this disorder (Kuizon et al, 1999). 
 
In both the United States (US) and Europe, there are few children with CKD on dialysis 
compared with the adult population. The rate of Stage 5 CKD in children was estimated 
at 15.2 per million population in the US over the 2007-2011 time period. This correlates 
with 6800 incident children with Stage 5 CKD reported during this same time period 
(USRDS, 2013). Data from the published 2011 European Renal Association-European 
Dialysis and Transplant Association (ERA-EDTA) registry, show 2115 prevalent pediatric 
patients with Stage 5 CKD receiving maintenance dialysis. Of these, 207 patients were 
0 to 4, 323 patients were 5 to 9, 566 patients were 10 to 14, and 1019 patients were 
 
15 to 19 years of age. 
 
Children on dialysis experience similar laboratory disturbances with regards to 
parathyroid hormone (PTH), serum calcium (Ca) and phosphorous as adults 
(Bacchetta et al, 2012). Traditional therapies for SHPT (eg, vitamin D sterols) are widely 
used in the pediatric dialysis population, but are sometimes insufficient to manage SHPT 
due to their potential to increase serum calcium and phosphorus. 


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A survey conducted among 18 sites belonging to North American Pediatric Renal Trials 
and Collaborative Services (NAPRTCS) (NAPRTCS, unpublished data), included data 
from 320 pediatric hemodialysis (HD) and peritoneal dialysis (PD) patients, between the 
ages of 2 to less than 18. The results show that overall, 49% of the pediatric dialysis 
population has intact parathyroid hormone (iPTH) levels above 300 pg/mL (31.8 pmol/L), 
the upper limit recommended by the NKF-K/DOQI™ guidelines for all pediatric age 
groups (NKF-KDOQI™, 2005). 
 
Published pediatric CKD-MBD guidelines markedly differ with respect to the 
recommended PTH target ranges. For children with stage 5 CKD, the guidelines 
recommend targets in the range between 120 and 540 pg/mL (Klaus et al, 2006; 
NKF KDOQI, 2005; KDIGO CKD-MBD Working Group, 2009). None of these 
recommendations has been validated in a large pediatric stage 5 CKD cohort. 
 
2.2 
Cinacalcet Background 
 
Cinacalcet is a first-in-class calcimimetic agent that acts as an allosteric modulator of the 
calcium sensing receptor (CaSR) located on the surface of the parathyroid chief cell, 
increasing the sensitivity of the CaSR to extracellular calcium. Cinacalcet has been 
shown to be safe and efficacious in simultaneously controlling PTH, calcium, and 
phosphorus in the adult dialysis population. Cinacalcet was initially approved in 2004 by 
the US Food and Drug Administration (FDA) for the treatment of SHPT in adult patients 
with CKD receiving dialysis. As of 28 February 2014, cinacalcet is approved for this 
indication in 67 countries. Cinacalcet is not approved for use in pediatric patients in any 
country. 
 
Refer to the Cinacalcet HCl Investigator’s Brochure (IB) for additional information related 
to the physical, chemical, and pharmaceutical properties and formulation(s). 
 
2.3 
Standard of Care Therapy 
 
Standard of care (SOC) in the treatment of children with CKD-MBD and SHPT consists 
of vitamin D sterols (eg, calcitriol, paricalcitol), calcium supplementation, and phosphate 
binders (calcium based and non-calcium based). 
 
2.4 
Pediatric Risk Assessment 
 
In the 4 interventional studies conducted by Amgen in the pediatric population to date, 
 
48 subjects between 1 to 17 years of age have been exposed to cinacalcet. The overall 
adverse event profile in children was similar to that seen in the adult population treated 
with cinacalcet. The most commonly observed adverse events were nausea, vomiting, 


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and hypocalcemia. One fatal adverse event was reported in a pediatric subject receiving 
cinacalcet in the double-blind interventional study in the presence of severe 
hypocalcemia. While the cause of death was multi-factoral, severe hypocalcemia was 
observed and a role of cinacalcet could not be excluded. 
 
Additional risk mitigation measures implemented in this trial include: 
 
• 
collection of real-time ionized calcium measurements, 
• 
weekly monitoring of calcium, 
• 
incorporation of local laboratory total calcium values into the dosing schema, 
• 
subject investigational product (IP) compliance measures, 
• 
dispensing limited quantities of IP to minimize the potential for overdosing 
• 
addition of exclusionary electrocardiogram (ECG) criteria 
 
A dosing strategy, using a weight-based starting dose of ≤ 0.2 mg/kg in pediatric 
subjects, which is approximately 50% below the adult starting dose, will be employed in 
this study. The dose of cinacalcet will be titrated based on iPTH, corrected calcium 
(cCa) levels, ionized calcium, and subject safety information. The maximum dose in this 
study will be 2.5 mg/kg/day based on day 1 dry weight, not to exceed a dose of 
 
• 
180 mg/day for subjects from 20130356 
• 
60 mg/day for subjects from 20110100 
 
Serum calcium will be monitored throughout the study. In the event a subject 
experiences protocol-defined hypocalcemia, an adverse event deemed related to IP or 
other adverse event that warrants IP dose withhold, the dose of cinacalcet will be 
reduced or discontinued as appropriate. Vitamin D sterols, calcium supplementation 
and/or calcium-based phosphate binders can be used to raise serum calcium levels and 
should be administered as appropriate per individual clinic practice. Training and 
informational tools will be provided to investigators for dissemination to care givers and 
subjects regarding the symptoms and risks of hypocalcemia. 
 
Volumes of blood withdrawn for analysis will be minimized as appropriate for this 
pediatric population based on dry weight. 
 
2.5 
Studies Eligible to Roll-over to 20140159 
 
2.5.1 
Amgen Study 20130356 
 
Amgen Study 20130356 is a phase 3 randomized, multicenter, open-label, controlled 
study. In Study 20130356, cinacalcet is being evaluated in pediatric subjects enrolled 
between the ages of 6 and < 18 years, with SHPT and CKD receiving either 


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hemodialysis or peritoneal dialysis. Approximately 48 subjects are planned to be 
randomized into the study to one of two treatment arms in a 1:1 allocation ratio; daily 
oral administration of cinacalcet in addition to SOC or SOC only. Once randomized, the 
expected treatment period in 20130356 is 20 weeks with a 4-week safety follow-up 
period. Subjects who are eligible for and enroll in the 20140159 extension study will do 
so at the completion of the 20-week treatment period in 20130356 or following 
Study 20130356 termination and within 7 days of day 1 of 20140159, unless there is an 
administrative delay. The end of study (EOS) procedures for an individual subject will 
occur at the same time as the end of investigational product (EOIP) visit for subjects 
enrolling in Study 20140159. The 4-week safety follow-up period in 20130356 will not 
apply for these subjects. 
 
2.5.2 
Amgen Study 20110100 
 
Amgen Study 20110100 is a phase 2, multicenter, open-label, single-arm study. In 
Study 20110100 cinacalcet is being evaluated in pediatric subjects enrolled between the 
ages of 28 days and < 6 years, with SHPT and CKD receiving either hemodialysis or 
peritoneal dialysis. The expected treatment period in 20110100 is 24 weeks of daily oral 
administration of cinacalcet in addition to SOC with a 2-week safety follow-up period. 
Subjects who are eligible for and enroll in the 20140159 extension study will do so at the 
completion of the week 26 End of Study visit or at Study 20110100 termination and 
within 7 days of day 1 of 20140159 unless there is an administrative delay. For subjects 
enrolled in the 20140159 extension study at the time of 20110100 study termination, the 
2-week safety follow-up period in 20110100 will not apply for these subjects and the 
EOS procedures for an individual subject will occur at the time as the EOIP visit for 
subjects enrolling in Study 20140159. 
 
2.6 
Rationale 
 
Cinacalcet has been shown to be safe and efficacious in treating adult CKD patients with 
SHPT by controlling iPTH, calcium, and phosphorus. The current study is an extension 
of Amgen studies 20130356 and 20110100 designed to assess the long-term safety and 
tolerability of cinacalcet in pediatric CKD subjects. 
 
2.7 
Clinical Hypotheses 
 
A formal hypothesis does not apply for the study. The long-term safety and tolerability of 
cinacalcet in pediatric subjects will be characterized in this study. 


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3. 
EXPERIMENTAL PLAN 
 
3.1 
Study Design 
 
This is a phase 3, 32-week, multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 
Subjects will remain on cinacalcet treatment for 28 weeks after enrollment or until the 
time of renal transplant or parathyroidectomy, whichever occurs first. The treatment 
period is followed by a 4-week safety follow-up period. 
 
The overall study design is described by a Study Design and Treatment Schema at 
the end of the protocol synopsis section. 
 
The study endpoints are defined in Section 10.1.1. 
 
3.1.1 
Subjects From Study 20130356 
 
Eligible subjects will complete the 20-week treatment period in Study 20130356, or reach 
Study 20130356 termination and either continue, restart, or start cinacalcet treatment in 
this study. Eligible subjects will not complete the safety follow-up period in Study 
20130356, beginning the extension study at the 20130356 EOIP study visit. The EOIP 
visit in Study 20130356 and day 1 in Study 20140159 will be the same visit unless there 
is an administrative delay. Eligible subjects will complete day 1 of 20140159 
assessments (Section 7.1) and confirm eligibility in the interactive voice response (IVR) 
system before dispensing IP on day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm in 
 
Study 20130356 will begin cinacalcet treatment on day 1 in Study 20140159 if their iPTH 
is ≥ 300 pg/mL and cCa is ≥ 8.8 mg/dL during screening in Study 20140159. Eligible 
subjects from the cinacalcet arm in 20130356 will continue cinacalcet treatment on day 1 
if their iPTH is ≥ 150 pg/mL and cCa is ≥ 8.4 mg/dL during screening in Study 20140159. 
If IP has been withheld or missed for > 14 days at the time of day 1 of Study 20140159, 
the subject will resume dosing at the starting dose level once all restart criteria are met. 
 
Cinacalcet dosing will follow the dose titration, dose withhold, and restarting rules 
defined in Section 6.2.3. 
 
Subjects will complete day 1 assessments (Section 7.1) and confirm eligibility in IVR 
 
system prior to dispensing IP on day 1. 
 
All subjects from 20130356 will be eligible to titrate the cinacalcet dose at monthly 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based on the 
subject’s dry weight at day 1 in Study 20140159, not to exceed a dose of 180 mg/day. 


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3.1.2 
Subjects From Study 20110100 
 
Eligible subjects will complete the End of Study visit or early termination visit for Study 
20110100 and continue or restart cinacalcet treatment in this study on day 1 based on 
dosing instructions outlined in Section 6.2.3. Eligible subjects completing the full 
treatment period in Study 20110100 will be screened during the safety follow-up period 
in Study 20110100 and will be required to have their 20140159 day 1 visit and 
their 20110100 week 26 End of Study visit at the same visit. Eligible subjects who reach 
Study 20110100 termination before week 26 will not complete the safety follow-up period 
in Study 20110100, beginning the 20140159 extension study at the 20110100 early 
termination visit. The early termination/EOS visit in Study 20110100 and day 1 in 
Study 20140159 will be the same visit unless there is an administrative delay. 
 
Subjects will complete day 1 assessments (Section 7.1) and confirm eligibility in IVR 
 
system before being dispensed IP on day 1. 
 
Eligible subjects will continue cinacalcet treatment on day 1 based on their dry weight at 
the time of enrollment in 20140159 study if their iPTH is ≥ 150 pg/mL and cCa 
is ≥ 8.8 mg/dL (age < 2 years of age) or cCa is ≥ 8.4 mg/dL (age is ≥ 2 years of age) 
during screening in Study 20140159. If IP has been withheld or missed for > 14 days at 
the time of day 1 of Study 20140159, the subject will resume dosing at the starting dose 
level based on dry weight at the time of enrollment once all restart criteria are met. 
Cinacalcet dosing will follow the dose titration, dose withhold, and restarting rules 
defined in Section 6.2.3.1.2. 
 
All subjects from 20110100 will be eligible to titrate the cinacalcet dose at monthly 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based on the 
subject’s dry weight at day 1 in Study 20140159, not to exceed a dose of 60 mg/day. 
 
3.2 
Number of Sites 
 
This study will be conducted at approximately 60 sites in North America, Europe, Russia, 
Latin America, and Australia. 
 
3.3 
Number of Subjects 
 
Participants in this clinical investigation shall be referred to as “subjects”. 
 
This study is open to subjects who complete the 20-week treatment period or reach 
study termination in Study 20130356 or the week 26 End of Study visit or reach study 
termination in Study 20110100. There may be up to 78 subjects enrolled in this study. 


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3.4 
Replacement of Subjects 
 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
 
3.5 
Estimated Study Duration 
 
3.5.1 
Study Duration for Subjects 
 
The total duration for this study is 32 weeks; a 28-week treatment period and 4-week 
safety follow-up period. 
 
3.5.2 
End of Study 
 
The end of study is the primary completion date. This is defined as the time when the 
last subject is assessed or receives an intervention for the purposes of final collection of 
data. 
 
4. 
SUBJECT ELIGIBILITY 
 
Before any study-specific activities/procedure, written informed consent must be 
obtained (see Section 11.1). In addition to written informed consent from a legally 
acceptable representative, the assent of the child also must be obtained, as appropriate 
and if requested by the institutional review board/independent ethics committee 
(IRB/IEC). 
 
Subjects from the cinacalcet arm of Study 20130356 or subjects in Study 20110100 who 
had their dose withheld at the EOIP visit, may enroll in this study if they meet eligibility 
criteria but will not restart dosing until the criteria for restarting dosing, defined in 
Section 6.2.3, are met. 
 
Subjects who were ≤ 18 years old at week 20 in the 20130356 study or at the time of 
study termination, are eligible to enter this Study 20140159 even if they have already 
turned 18 years of age or are due to turn 18 years of age during their planned 
participation in the 20140159 study. 
 
4.1 
Inclusion and Exclusion Criteria 
 
4.1.1 
Inclusion Criteria 
 
All Subjects 
 
101 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
Study 20140159 activities/procedures being initiated. 
 
102 
Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
All subjects with > 14 days between the last study visit in Study 20130356 or 
Study 20110100 and screening for Study 20140159 


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103 
Subjects on anti-convulsant medication must be on a stable dose 
 
All subjects from 20130356 
 
104 
Completed treatment through week 20 in the 20130356 study or on study at the 
time of Study 20130356 termination 
105 
Dry weight ≥ 12.5 kg at day 1 of Study 20140159 
 
Subjects Randomized to the 20130356 Standard of Care Arm Only 
 
106 
iPTH value ≥ 300 pg/mL (within 7 days of day 1 in Study 20140159) 
 
107 
Corrected calcium value ≥ 8.8 mg/dL within 7 days of day 1 in Study 20140159 
 
All Subjects from 20110100 
 
108 
Completed week 26 End of Study visit in the, 20110100 study or on study at the 
time of Study 20110100 termination 
109 
Dry weight ≥ 7 kg at day 1 of Study 20140159 
 
4.1.2 
Exclusion Criteria 
 
General 
 
Studies 20130356 or 20110100 
 
201 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(s), other than Amgen Studies 20130356 or 20110100. 
 
202 
Other investigational procedures while participating in this study are excluded. 
 
203 
Malignancy except non-melanoma skin cancers, cervical or breast ductal 
carcinoma in situ within the last 5 years. 
 
204 
Subject has known sensitivity to any of the products to be administered during 
dosing. 
 
205 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, electronic 
patient diary [ediary]) to the best of the subject and investigator’s knowledge 
206 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
 
207 
Subject previously has entered this study. 
 
208 
If sexually active, subject is not willing to use acceptable contraception during 
treatment and for at least 9 days after the end of treatment. 
 
209 
Subject is pregnant or breast feeding, or planning to become pregnant during the 
study or within 9 days after the end of treatment 
 
210 
History of congenital long QT syndrome, second or third degree heart block, 
ventricular tachyarrythmias, or other conditions associated with prolonged QT 
interval 


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211 
A new onset of seizures or worsening of pre-existing seizure disorder 
 
All Subjects with > 14 days between the last study visit in Study 20130356 or 
Study 20110100 and the screening visit in Study 20140159 will have the following 
exclusion criteria applied during screening and day 1: 
 
212 
Unstable chronic heart failure defined as worsening pulmonary edema or other 
signs and symptoms as per investigator assessment during screening 
213 
Received therapy with commercial cinacalcet after the last study visit in 
Study 20130356 or Study 20110100 before day 1 of Study 20140159 
 
214 
Scheduled date for kidney transplantation from a known living donor that makes 
completion of the study unlikely 
 
215 
Either new or recurrent cardiac ventricular arrhythmias requiring a change in 
treatment within 10 days prior to screening visit or day 1 of Study 20140159 
screening 
216 
Hepatic impairment indicated by elevated levels of hepatic transaminase or 
bilirubin (aspartate aminotransferase [AST] ≥ 1.5 × upper limit of normal [ULN] 
OR alanine aminotransferase [ALT] ≥ 1.5 × ULN OR total bilirubin ≥ 1 × ULN per 
institutional laboratory range) during screening 
 
All Subjects - Day 1 Study Visit 
 
217 
Subject has an ongoing adverse event from Studies 20130356 or 20110100 that 
is considered related to IP and: 
 
• 
Is ≥ CTCAE (v 4.0) grade 3, and/or 
• 
Considered clinically significant in the opinion of the investigator 
 
218 
Central laboratory values were not obtained/are not available at day 1 in 
Study 20140159 
 
219 
Corrected QT Interval (QTc) > 500 ms, using Bazett’s formula 
 
220 
QTc ≥ 450 to ≤ 500 ms, using Bazett’s formula, unless written permission to 
enroll is provided by the investigator after consultation with a pediatric 
cardiologist 
 
221 
Use of grapefruit juice, herbal medications, CYP3A4 inhibitors (eg, erythromycin, 
clarithromycin, ketoconazole, itraconazole), or CYP2D6 substrates 
(eg, flecainide, propafenone, metoprolol, desipramine, nortriptyline, 
clomipramine) 
222 
Use of concomitant medications that may prolong the QTc interval 
(eg, ondansetron, albuterol) 
 
5. 
SUBJECT ENROLLMENT 
 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written IRB/IEC approval of the protocol, informed consent 
form, and all other subject information and/or recruitment material, if applicable (see 
Section 11.2). Before commencement of study-specific activities/procedures the 
subject’s legally acceptable representative(s) must personally sign and date the 


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informed consent form, and the subject must personally sign and date the assent form 
as appropriate and if required by the IRB/IEC. 
 
Subjects will retain the unique subject identification number received in 
 
studies 20130356 or 20110100. 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. 
 
5.1 
Screening 
 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
The informed consent can be signed up to 7 days (± 3 days) prior to 20140159 day 1. 
 
For subjects who do not meet the eligibility criteria in Section 4, re-screening will not be 
considered in this study. 
 
5.2 
Enrollment 
 
Following confirmation that subjects met eligibility criteria in Section 4, the subject will be 
registered in the interactive voice response/interactive web response (IVR/IWR) system. 
The subject will be considered enrolled in the extension study: 
 
• 
20130356 subjects will be assigned a cinacalcet dose based on the treatment 
arm and/or last dose received in Study 20130356 following the dosing 
instructions in Section 6.2.3. 
• 
20110100 subjects will be assigned a cinacalcet dose based on the last dose 
received at the EOIP visit in Study 20110100 following the dosing instructions in 
Section 6.2.3. 
 
6. 
TREATMENT PROCEDURES 
 
6.1 
Standard of Care 
 
Standard of care therapy will include the use of vitamin D sterols, calcium 
supplementation, and phosphate binders. 
 
Standard of care therapy that is commercially available will not usually be provided or 
reimbursed by Amgen (except if required by local regulation). The Investigator will be 
responsible for obtaining supplies of these therapies unless they are provided by 
Amgen. 


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6.2 
Cinacalcet 
 
6.2.1 
Classification of Product 
 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, and 
administration of cinacalcet. 
 
6.2.2 
Investigational Product 
 
Cinacalcet will be manufactured and packaged by Amgen Inc., or designee, and 
distributed using Amgen clinical study drug distribution procedures. Cinacalcet will be 
provided as capsules or as film coated tablets and will be orally administered daily. For 
subjects unable to swallow, the dose of cinacalcet may be administered via their feeding 
tube using the liquid suspension. 
 
Capsules 
 
Each capsule will contain 5 mg of cinacalcet in addition to the following inactive 
excipients: microcrystalline cellulose, pregelatinized starch, povidone, crospovidone, 
and colloidal silicon dioxide. Cinacalcet capsules will be provided in bottles containing 
10 capsules each. The capsules provided must not be swallowed whole. Capsules 
must be opened and either sprinkled onto soft food (eg, applesauce) or suspended into 
a sucrose syrup to create a liquid suspension for administration. Once opened, the 
empty capsule shells should be discarded. 
 
Tablets 
 
Tablets will be provided in bottles containing 10 tablets of cinacalcet in a 
 
strength of 30 mg. Tablets of cinacalcet are to be swallowed whole and contain the 
following inactive excipients in addition to cinacalcet: microcrystalline cellulose, 
pregelatinized starch, povidone, crospovidone, colloidal silicon dioxide, and magnesium 
stearate. Each tablet is color-coated with Opadry II (green) and Opadry clear coatings 
then covered with carnauba wax. 
 
6.2.3 
Dosage, Administration, and Schedule 
 
Cinacalcet will be administered daily. All doses are to be taken orally and administered 
with food or shortly after a meal at the same time each day. For subjects unable to 
swallow, cinacalcet may be administered via their feeding tube using the liquid 
suspension. It is expected that for children under the age of 12 the daily administration 
of cinacalcet will be under the supervision of their parent(s) or legal guardian(s). On 


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study visit days where a blood sample is to be drawn, cinacalcet should not be 
administered until after the blood sample has been obtained. 
 
The protocol-specified doses (PSD) for use in this study are: 
 
• 
Subjects ≥ 6 years of age: 2.5, 5, 10, 15, 30, 60, 90, 120, and 180 mg. Subjects 
from Study 20130356 will either continue to receive cinacalcet at the same dose as 
at the EOIP visit if ≤ 14 days have passed between last dose of cinacalcet treatment 
in Study 20130356 and day 1 of Study 20140159. If > 14 days have passed, 
subjects will start cinacalcet in Study 20140159 at 0.20 mg/kg/day based on the 
subject’s dry weight at Study 20140159 day 1 time point and age at time of 
enrollment in Study 20130356, rounded down to the lowest PSD. 
− Subjects from 20130356 may receive capsules for any dose which is an exact 
multiple of 5 mg. Subjects who are assigned doses of 60 to 180 mg/day will 
require administration of two to six 30 mg tablets per dose. For those subjects 
unable to swallow tablets, capsules may be dispensed. 
 
− The maximum dose of cinacalcet that will be administered at any time during the 
study will be 2.5 mg/kg/day based on the subject’s day 1 dry weight in 
Study 20140159 or 180 mg daily, whichever is lower. 
• 
Subjects < 6 years of age: 1, 2.5, 5, 7.5, 10, 15, 30, and 60 mg. Subjects from 
Study 20110100 will either continue to receive cinacalcet at the same dose as at the 
EOIP visit if ≤ 14 days have passed between last dose of cinacalcet treatment in 
Study 20110100 and day 1 of Study 20140159. If > 14 days have passed, subjects 
will start cinacalcet in Study 20140159 at 0.20 mg/kg/day based on the subject’s dry 
weight at the 20140159 day 1 time point and age at time of enrollment in 
20110100 study, rounded down to the lowest PSD. 
− Subjects assigned a dose between 10 to 60 mg/day will require more than 
1 capsule per dose be sprinkled on soft food or used to create the liquid 
suspension for administration. 
− Subjects enrolling into 20140159 from 20110100 would have a maximum dose of 
2.5 mg/kg/day based on the subject’s 20140159 day 1 dry weight or 60 mg daily, 
whichever is lower. 
 
Subjects will be required to return all unused medication, including empty bottles, at 
each study visit. Site staff will confirm that the previously assigned medication bottle(s) 
have been returned prior to dispensing a new bottle(s) of IP. In the event unused 
medications or empty bottles have been permanently misplaced, contact Amgen prior to 
dispensing new bottle(s) of IP. 
 
If no ionized calcium values are available at the time of a study visit, a new bottle of IP 
will not be dispensed to the subject. Once the ionized calcium value has been obtained 
and in accessible range, IP may be dispensed as appropriate. 


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6.2.3.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Dosage adjustments, titrations, and withholding/restarting rules will be the same as the 
parent studies. 
 
6.2.3.1.1 
Subjects From Study 20130356 
 
On day 1 of Study 20140159, subjects from the SOC arm in 20130356 will receive the 
initial dose of cinacalcet as defined in Section 6.2.3.1.1.1 
 
Subjects from the cinacalcet arm with ≤ 14 days between last dose of cinacalcet 
treatment in Study 20130356 and Study 20140159 day 1 will continue at the same dose 
as the last dose at EOIP and will follow the dose adjustments outlined in Table 1 in 
Section 6.2.3.1.1.1. Dose titration cannot occur until week 4 per Table 1. If subjects 
from the cinacalcet arm in 20130356 are on a dose that was withheld or missed 
for > 14 days and ≤ 1 month at day 1 of Study 20140159, the iPTH and cCa restart 
values (iPTH > 150 pg/mL and cCa > 8.4 mg/dL) must be reached prior to resuming 
cinacalcet will receive the initial dose of cinacalcet in the current extension study outlined 
in Table 1 in Section 6.2.3.1.1.1. 
 
Subjects from the cinacalcet arm with > 1 month between the last dose of cinacalcet 
treatment in Study 20130356 and Study 20140159 day 1, will receive the initial dose of 
cinacalcet as defined in Section 6.2.3.1.1.1. To commence dosing, all subjects must 
have: 
 
• 
ionized calcium ≥ 1.05 mmol/L prior to initiation of treatment on day 1 in this 
study 
• 
iPTH value ≥ 300 pg/mL within 7 days of day 1 
• 
corrected calcium value ≥ 8.8 mg/dL within 7 days of day 1 
 
6.2.3.1.1.1 
Dosage Adjustments 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system. Subjects from the SOC arm will start at the initial 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1 of 
Study 20140159, rounded down to the lowest PSD. 
 
Subjects from the cinacalcet arm with ≤ 14 days between the last dose of cinacalcet 
treatment in Study 20130356 and day 1 of Study 20140159 will start cinacalcet dosing at 
the same dose they received at the completion of the EOIP visit and follow weekly dose 
adjustment based on the Table 1. For subjects from the cinacalcet arm with > 14 days 
between the last dose of cinacalcet treatment in Study 20130356 and day 1 of 


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Study 20140159, the initial dose of cinacalcet will be 0.20 mg/kg/day, based on the 
subject’s dry weight at day 1 of 20140159, rounded down to the lowest PSD, will be 
assigned. 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each weekly visit 
during the treatment period. The daily dose of cinacalcet may only be increased at 
monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be increased at any other 
time during the treatment period. At all weekly visits (including week 4, 8, 12, 16, 20, 
and 24), the dose may be maintained, reduced or withheld based upon the dose 
adjustment criteria in Table 1. 
 
If any of the criteria for dose withholding are met at any time during the trial, including 
between scheduled study visits (ie, unscheduled), the dose of cinacalcet is to be 
withheld until all of the following criteria are met: 
 
• 
central laboratory corrected calcium value is >8.4 mg/dL 
• 
iPTH is > 150 pg/mL 
• 
ionized calcium is >1.05mmol/L 
• 
subject has no symptoms of hypocalcemia 
 
• 
subject doesn’t have any ongoing adverse event(s) which warrant withholding of 
cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed weekly 
until an ionized calcium of ˃1.05 mmol/L is obtained, at which point, cCa and iPTH 
should be assessed by the central laboratory. 
 
Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received. Subjects receiving the lowest PSD (2.5 mg) who 
require a dose reduction will have their dose withheld until the criteria for maintaining or 
increasing the dose are met, at which time they will restart dosing at 2.5 mg/day. 
 
If subjects require temporary administration of concomitant medications that are known 
to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 substrates, the 
administration of IP is to be withheld. The dose may be restarted at one PSD below the 
previous dose once the treatment with the concomitant medication has completed and 
all of the restart criteria above are met. 
 
If IP has been withheld or missed for > 14 days, the subject will resume dosing at the 
starting dose level once (initial dose in parent Studies 20130356 or 20110100) all restart 
criteria are met based on dry weight at day 1 of Study 20140159. 


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If any of the criteria for dose decrease are met between scheduled study visits, the dose 
of cinacalcet is to be suspended until the next visit at which time the dose will be 
decreased per dose adjustment procedures of that visit. 


 
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Table 1.  Dose Adjustment Rules:  Monthly, Weekly, and Withholding in Children 6-18 Years of age 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16, 20, 24) 
Dose 
Withholding for 
Safety at Any 
Weekly Dose Adjustment Visit Rules 
Time 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
(Monthly, Weekly 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27) 
or Unscheduled) 
↑ one PSD 
Maintain Dose 
↓ one PSD** 
withhold* 
(if all criteria 
(if all criteria 
(if any criteria 
(if any criteria 
met) 
 
met) 
 
met) 
 
met) 
Maintain Dose 
↓ one PSD** 
withhold* 
withhold* 
(if all criteria 
(if any criteria 
(if any criteria 
(if any criteria 
met) 
 
met) 
 
met) 
 
met) 
Corrected Calcium 
(central laboratory) 
Ionized Calcium 
Total Calcium 
(local laboratory) 
iPTH 
Symptoms of 
Hypocalcemia 
Other AE that 
warrants IP dose 
withhold 
≥ 8.4 mg/dL 
≥ 8.4 mg/dL 
≥ 8.0 - 
< 8.0 mg/dL 
< 8.4 mg/dL 
(≥ 2.1 mmol/L)    (≥ 2.1 mmol/L) 
(≥ 2.0- 
(< 2.0 mmol/L) 
< 2.1 mmol/L) 
≥ 1.05 mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.00 mmol/L 
< 1.05 mmol/L 
N/A 
N/A 
N/A 
 < 8.0 mg/dL 
(< 2.0 mmol/L) 
≥ 300 pg/mL 
≥ 150 - 
≥ 100 - 
< 100 pg/mL 
< 300 pg/mL 
< 150 pg/mL 
(≥ 31.8 pmol/L) 
(≥ 15.9 - 
(≥ 10.6 - 
(< 10.6 pmol/L) 
< 31.8 pmol/L)    < 15.9 pmol/L) 
None 
None 
N/A 
Yes 
None 
None 
N/A 
Yes 
≥ 8.4 mg/dL 
≥ 8.0 - 
< 8.0 mg/dL 
< 8.0 mg/dL 
< 8.4 mg/dL 
(≥ 2.1 mmol/L) 
(≥ 2.0- 
(< 2.0 mmol/L) 
(< 2.0 mmol/L) 
< 2.1 mmol/L) 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.00 mmol/L 
< 1.00 mmol/L 
< 1.05 mmol/L 
N/A 
N/A 
 < 8.0 mg/dL 
  < 8.0 mg/dL 
(< 2.0 mmol/L) 
(< 2.0 mmol/L) 
≥ 150 pg/mL 
≥ 100 - 
< 100 pg/mL 
< 100 pg/mL 
< 150 pg/mL 
(≥ 15.9 pmol/L) 
(≥ 10.6 - 
(< 10.6 pmol/L) 
(< 10.6 pmol/L) 
< 15.9 pmol/L) 
None 
N/A 
Yes 
Yes 
None 
N/A 
Yes 
Yes 
* restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 150 pg/mL, ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
** if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, at which 
time the dose will be decreased per dose adjustment procedures of that visit. 
 
 
 
 
CONFIDENTIAL 


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6.2.3.1.2 
Subjects From Study 20110100 
 
For subjects where the last dose of cinacalcet treatment in Study 20110100 and day 1 of 
Study 20140159 occurs within 14 days, in order to commence dosing, subjects from 
Study 20110100 will follow the weekly dose adjustment criteria as outlined in Table 2 for 
age < 2 years and Table 3 for age ≥ 2 years. Dose titration cannot occur until week 4. 
 
For subjects with > 14 days and < 1 month between last dose of cinacalcet treatment in 
Study 20110100 and day 1 of Study 20140159, in order to commence dosing at the 
initial dose, all subjects from Study 20110100 must meet restart criteria per weekly dose 
adjustment criteria as outlined in Table 2 for age < 2 years and Table 3 for 
age ≥ 2 years. Dose titration cannot occur until week 4. 
 
• 
Additionally the phosphorus value within 7 days of day 1 should be: 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age is < 1 year 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age is ≥ 1 year 
 
For subjects with > 1 month between last dose of cinacalcet treatment in 
 
Study 20110100 and day 1 of Study 20140159, in order to commence dosing, subjects 
from Study 20110100 must have: 
 
• 
ionized calcium prior to initiation of treatment on day 1 in this study 
− ≥ 1.13 mmol/L if age is < 2 years 
− ≥ 1.05 mmol/L if age is ≥ 2 years 
 
• 
iPTH value ≥ 300 pg/mL within 7 days of day 1 
• 
corrected calcium value within 7 days of day 1 
− ≥ 9.4 mg/dL if age is < 2 years 
− ≥ 8.8 mg/dL if age is ≥ 2 years 
 
• 
phosphorus value within 7 days of day 1 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age is < 1 year 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age is ≥ 1 year 
 
6.2.3.1.2.1 
Subjects < 2 Years of Age 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system. 
 
For subjects with > 14 days since the last dose of cinacalcet treatment in 
 
Study 20110100 and day 1 of Study 20140159, subjects will start at the initial cinacalcet 
dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1, in the 
20140159 study rounded down to the lowest PSD. 


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For subjects with ≤ 14 days between the last dose of cinacalcet in Study 20110100 and 
Study 20140159 day 1, subjects will continue the same dose of cinacalcet they received 
at the completion EOIP visit or early termination visit at Study 20110100 termination and 
follow the weekly dose adjustments outlined in Table 2. Dose titration cannot occur until 
week 4. If subjects from the Study 20110100 are on a dose withhold at day 1 of 
Study 20140159, the iPTH and cCa restart values (iPTH > 150 pg/mL and 
 
cCa > 9.0 mg/dL) must be reached prior to resuming cinacalcet in the Study 20140159. 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each weekly visit 
during the treatment period. The daily dose of cinacalcet may only be increased at 
monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be increased at any other 
time during the treatment period. At all weekly visits (including week 4, 8, 12, 16, 20, 
and 24), the dose may be maintained, reduced or withheld based upon the criteria in 
Table 2. 
 
If any of the criteria for dose withholding are met at any time during the trial, including 
between scheduled study visits (ie, unscheduled), the dose of cinacalcet is to be 
withheld until all of the following criteria are met: 
 
• 
central laboratory corrected calcium value is >9.0 mg/dL 
• 
iPTH is >150 pg/mL 
• 
ionized calcium is >1.13 mmol/L 
• 
subject has no symptoms of hypocalcemia 
 
• 
subject doesn’t have any ongoing adverse event(s) which warrant withholding of 
cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed weekly 
until an ionized calcium of ˃1.13 mmol/L is obtained, at which point, cCa and iPTH 
should be assessed by the central laboratory. 
 
Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received. Subjects receiving the lowest PSD (1 mg) who 
require a dose reduction will have their dose withheld until the criteria for maintaining or 
increasing the dose are met, at which time they will restart dosing at 1 mg/day. 
 
If subjects require temporary administration of concomitant medications that are known 
to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 substrates, the 
administration of IP is to be withheld. The dose may be restarted at one PSD below the 
previous dose once the treatment with the concomitant medication has completed and 
all of the restart criteria above are met. 


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If IP has been withheld or missed for more than 14 days, the subject will resume dosing 
at the starting dose level (initial dose in parent Studies 20130356 or 20110100) once all 
restart criteria are met. 
 
If any of the criteria for dose decrease are met between scheduled study visits, the dose 
of cinacalcet is to be suspended until the next visit at which time the dose will be 
decreased per dose adjustment procedures of that visit. 


 
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Table 2.  Dose Adjustment Rules:  Monthly, Weekly, and Withholding in Subjects < 2 Years old 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16, 20, 24) 
Dose 
Withholding for 
Safety at 
Weekly Dose Adjustment Visit Rules  
Any Time 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
(Monthly, Weekly 
15, 17, 18, 19) 
or Unscheduled) 
↑ one PSD 
Maintain Dose 
↓ one PSD** 
withhold* 
(if all criteria  
(if all criteria 
(if any criteria  
(if any criteria 
met)  
 
met)  
 
met)  
 
met) 
Maintain Dose 
↓ one PSD** 
withhold*  
withhold* 
(if any criteria  
(if any criteria  
(if any criteria 
(if all criteria met)  
met)  
met)  
met) 
Corrected 
Calcium 
(central 
laboratory) 
Ionized 
Calcium 
Total Calcium 
(local 
laboratory) 
iPTH 
Symptoms of 
Hypocalcemia 
Other AE that 
warrants IP 
dose withhold 
≥ 9.0 mg/dL  
≥ 9.0 mg/dL  
≥ 8.6 - 
< 8.6 mg/dL 
< 9.0 mg/dL 
(≥ 2.25 mmol/L)     (≥ 2.25 mmol/L)  
(≥ 2.15 - 
(< 2.15 mmol/L) 
< 2.25 mmol/L) 
≥ 1.13 mmol/L  
≥ 1.13 mmol/L  
≥ 1.08 - 
< 1.08 mmol/L 
< 1.13 mmol/L 
Not Applicable  
< 8.6 mg/dL  
Not Applicable  
< 8.6 mg/dL 
(< 2.15 mmol/L)  
(< 2.15 mmol/L) 
≥ 300 pg/mL  
    ≥ 150 - 
   ≥ 100 - 
< 100 pg/mL (≥ 
31.8 pmol/L)  
 < 300 pg/mL  
< 150 pg/mL  
(< 10.6 pmol/L) 
(≥ 15.9 - 
(≥ 10.6 - 
< 31.8 pmol/L)  
< 15.9 pmol/L) 
None 
None 
N/A  
Yes 
None 
None 
N/A  
Yes 
≥ 9.0 mg/dL  
≥ 8.6 - 
< 8.6 mg/dL  
< 8.6 mg/dL 
< 9.0 mg/dL 
(≥ 2.25 mmol/L)  
(≥ 2.15 - 
(< 2.15 mmol/L)  
(< 2.15 mmol/L) 
< 2.25 mmol/L) 
≥ 1.13 mmol/L  
≥ 1.08 - 
< 1.08 mmol/L  
< 1.08 mmol/L 
< 1.13 mmol/L 
< 8.6 mg/dL  
Not Applicable  
< 8.6 mg/dL  
< 8.6 mg/dL 
(< 2.15 mmol/L)  
(< 2.15 mmol/L)  
(< 2.15 mmol/L) 
≥ 150 - 
≥ 100 - 
< 100 pg/mL  
< 100 pg/mL 
< 300 pg/mL  
< 150 pg/mL  
(< 10.6 pmol/L)  
(< 10.6 pmol/L) 
(≥ 15.9 - 
   (≥ 10.6 - 
< 31.8 pmol/L)  
< 15.9 pmol/L) 
None 
N/A  
Yes 
Yes 
None 
N/A  
Yes 
Yes 
* restart one PSD below last dose when cCa is > 9.0 mg/dL, iPTH is > 150 pg/mL, ionized calcium is > 1.13 mmol/L symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
** if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, at which 
time the dose will be decreased. 
 
 
 
 
 
CONFIDENTIAL 


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6.2.3.1.2.2 
Subjects ≥ 2 Years of Age 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system. 
 
For subjects with > 14 days since the last dose of cinacalcet in Study 20110100 and 
day 1 of Study 20140159, subjects will start at the initial cinacalcet dose of 
0.20 mg/kg/day, based on the subject’s dry weight at day 1 in Study 20140159, rounded 
down to the lowest PSD. 
 
For subjects with ≤ 14 days since the last dose of cinacalcet in Study 20110100 and 
day 1 of Study 20140159, subjects will continue cinacalcet based on the dose at the 
EOIP visit or early termination/EOS at study termination and follow the weekly dose 
adjustments outlined in Table 3. Dose titration cannot occur until week 4. If subjects 
from the Study 20110100 are on a dose that was withheld at day 1 of Study 20140159, 
the iPTH and cCa restart values (iPTH > 150 pg/mL and cCa > 8.4 mg/dL) must be 
reached before resuming cinacalcet in Study 20140159. 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each weekly visit 
during the treatment period. The daily dose of cinacalcet may only be increased at 
monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be increased at any other 
time during the treatment period. At all weekly visits (including week 4, 8, 12, 16, 20, 
and 24), the dose may be maintained, reduced or withheld based upon the criteria in 
Table 3. 
 
If any of the criteria for dose withholding are met at any time during the trial, including 
between scheduled study visits (ie, unscheduled), the dose of cinacalcet is to be 
withheld until all of the following criteria are met: 
 
• 
central laboratory corrected calcium value is >8.4 mg/dL 
• 
iPTH is >150 pg/mL 
• 
ionized calcium is >1.05 mmol/L 
• 
subject has no symptoms of hypocalcemia 
 
• 
subject doesn’t have any ongoing adverse event(s) which warrant withholding of 
cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed weekly 
until an ionized calcium of ˃1.05 mmol/L is obtained, at which point, cCa and iPTH 
should be assessed by the central laboratory. 


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Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received. Subjects receiving the lowest PSD (1 mg) who 
require a dose reduction will have their dose withheld until the criteria for maintaining or 
increasing the dose are met, at which time they will restart dosing at 1 mg/day. 
 
If subjects require temporary administration of concomitant medications that are known 
to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 substrates, the 
administration of IP is to be withheld. The dose may be restarted at one PSD below the 
previous dose once the treatment with the concomitant medication has completed and 
all of the restart criteria above are met. 
 
If IP has been withheld or missed for more than 14 days (initial dose in parent 
Studies 20130356 or 20110100), the subject will resume dosing at the starting dose 
level once all restart criteria are met. 
 
If any of the criteria for dose decrease are met between scheduled study visits, the dose 
of cinacalcet is to be suspended until the next visit at which time the dose will be 
decreased per dose adjustment procedures of that visit. 


 
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Table 3.  Dose Adjustment Rules:  Monthly, Weekly, and Withholding in Subjects ≥ 2 Years old in Study 20110100 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16, 20, 24) 
Dose Withholding 
for Safety at 
Weekly Dose Adjustment Visit Rules 
Any Time 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
(Monthly, Weekly 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27) 
or Unscheduled) 
↑ one PSD 
Maintain Dose 
↓ one PSD** 
withhold* 
(if all criteria 
(if all criteria 
(if any criteria 
(if any criteria 
met) 
 
met) 
 
met) 
 
met) 
Maintain Dose 
↓ one PSD** 
withhold* 
withhold* 
(if all criteria 
(if any criteria 
(if any criteria 
(if any criteria 
met) 
 
met) 
 
met) 
 
met) 
Corrected Calcium 
(central laboratory) 
Ionized Calcium 
Total Calcium 
(local laboratory) 
iPTH 
Symptoms of 
Hypocalcemia 
Other AE that 
warrants IP dose 
withhold 
≥ 8.4 mg/dL 
≥ 8.4 mg/dL 
≥ 8.0 - 
< 8.0 mg/dL 
< 8.4 mg/dL 
(≥ 2.1 mmol/L)    (≥ 2.1 mmol/L) 
(≥ 2.0- 
(< 2.0 mmol/L) 
< 2.1 mmol/L) 
≥ 1.05 mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.00 mmol/L 
< 1.05 mmol/L 
N/A 
N/A 
N/A 
 < 8.0 mg/dL 
(< 2.0 mmol/L) 
≥ 300 pg/mL 
≥ 150 - 
≥ 100 - 
< 100 pg/mL 
< 300 pg/mL 
< 150 pg/mL 
(≥ 31.8 pmol/L) 
(≥ 15.9 - 
(≥ 10.6 - 
(< 10.6 pmol/L) 
< 31.8 pmol/L)    < 15.9 pmol/L) 
None 
None 
N/A 
Yes 
None 
None 
N/A 
Yes 
≥ 8.4 mg/dL 
≥ 8.0 - 
< 8.0 mg/dL 
< 8.0 mg/dL 
< 8.4 mg/dL 
(≥ 2.1 mmol/L) 
(≥ 2.0- 
(< 2.0 mmol/L) 
(< 2.0 mmol/L) 
< 2.1 mmol/L) 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.00 mmol/L 
< 1.00 mmol/L 
< 1.05 mmol/L 
N/A 
N/A 
 < 8.0 mg/dL 
  < 8.0 mg/dL 
(< 2.0 mmol/L) 
(< 2.0 mmol/L) 
≥ 150 pg/mL 
≥ 100 - 
< 100 pg/mL 
< 100 pg/mL 
< 150 pg/mL 
(≥ 15.9 pmol/L) 
(≥ 10.6 - 
(< 10.6 
(< 10.6 pmol/L) 
< 15.9 pmol/L) 
pmol/L) 
None 
N/A 
Yes 
Yes 
None 
N/A 
Yes 
Yes 
* restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 150 pg/mL, ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
** if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, at which 
time the dose will be decreased per dose adjustment procedures of that visit. 
 
 
 
 
 
 
 
 
CONFIDENTIAL 


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6.2.3.1.3 
Missed Doses 
 
If a subject misses > 14 consecutive doses of cinacalcet for any reason, including 
temporary dose withholding due to the administration of concomitant medications as 
noted above, they will be restarted at their initial dose of cinacalcet (0.20 mg/kg/day 
based on dry weight at day 1 in Study 20140159) when administration of IP resumes per 
the dose titration guidelines outlined in Table 1, Table 2, and Table 3. 
 
6.2.3.2 
Measures of Compliance With Cinacalcet Administration 
 
Poor compliance and/or intermittent dosing or ingestion of cinacalcet may lead to 
changes (ie, increases or decreases) in iPTH and calcium concentrations that do not 
conform to those seen in clinical trials where subjects have consistently received daily 
doses of cinacalcet. Increases in iPTH can be interpreted to be a result of 
subtherapeutic dosing leading to increases in cinacalcet doses which may result in 
potentially severe hypocalcemia, particularly in the setting of intermittent ingestion of IP. 
 
Electronic patient diaries (eDiary) and IP accountability information will be reconciled 
and utilized in this study to document subject compliance with daily administration of 
cinacalcet therapy. The data entered into the eDiary will be available to the investigator 
and/or study coordinator on a daily basis to enable ongoing reviews of subject 
compliance. The eDiary and IP accountability data collected will be reviewed with the 
subject and/or their parent(s) or legal guardian(s) by the investigator and/or study 
coordinator during the weekly study visits. 
 
For this study non-compliance is defined as: 
 
• 
missing > 2 doses within any dosing week, or 
• 
≥ 2 documented overdoses within a dosing week 
• 
other indicators of non-compliance per physician judgment 
 
If a subject is considered to be non-compliant, the dose of cinacalcet should not be 
increased and additional counseling should be provided about the importance of taking 
the study medication as prescribed. It will also be documented on the eCRF. The 
additional counseling should be documented in the subject’s source documents. If the 
subject remains non-compliant, removal from IP dosing should be considered. 
 
6.2.3.3 
Overdose 
 
An overdose of cinacalcet will be defined as receiving any dose greater than the 
assigned daily dose. This can cause hypocalcemia. Hypocalcemia may cause anxiety, 
muscular cramping or stiffness, twitching, tingling, paresthesias around the mouth or 


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extremities, tetany, abdominal cramping, arrhythmias, hypotension, worsening of 
pre-existing chronic heart failure, convulsions, or death. 
 
If an overdose is suspected, the Amgen Study Manager, Amgen Medical Monitor, and/or 
Amgen Clinical Safety representative should be contacted within 24 hours of discovery. 
For subjects in whom an overdose is suspected, close monitoring for signs and 
symptoms of hypocalcemia and appropriate measures (eg, including intravenous 
calcium gluconate and more frequent monitoring of calcium levels) should be considered 
by the investigator in those with acute symptomatic hypocalcemia. 
 
Once hypocalcemia and any symptoms associated with the overdose have resolved, 
subjects resume cinacalcet administration dose. To resume dosing, the subject must 
meet the dosing restart criteria for his/her respective age group as specified in 
Sections 6.2.3.1.1, 6.2.3.1.2.1, and 6.2.3.1.2.2. 
 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen IP or other protocol-required therapies as specified in the Guidance for Industry 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009. 
 
Cinacalcet is metabolized by the liver. Subjects with moderate to severe hepatic 
impairment have the potential for 2- to 4-fold higher area under the curve (AUC) of 
cinacalcet concentration and may require additional follow-up. 
 
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
 
Cinacalcet should be discontinued permanently and the subject should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
Information) for possible drug-induced liver injury (DILI), if ALL of the criteria below are 
met: 
 
• 
TBL > 2 × upper limit of normal (ULN) or INR > 1.5 
• 
AND increased AST or ALT from the relevant day 1 value as specified below: 
 
 
Baseline AST or ALT value 
AST or ALT elevation 
 
< ULN 
> 3 × ULN 


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• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− Hepatobiliary tract disease 
 
− Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
− Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 
− Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms 
− Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− Alpha-one antitrypsin deficiency 
− Alcoholic hepatitis 
− Autoimmune hepatitis 
− Wilson’s disease and hemochromatosis 
− Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 
− Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if Amgen IP and other protocol-required therapies 
should be withheld (see section 6.3.2) or permanently discontinued, as deemed 
appropriate for the safety of the subject. 


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6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
normal transaminases and TBL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of Amgen IP and other protocol-required therapies: 
 
• 
Elevation of either AST or ALT according to the following schedule: 
 
Baseline AST or ALT value 
AST or ALT elevation 
 
Any 
> 8 × ULN at any time 
 
Any 
> 5 × ULN but < 8 × ULN for ≥ 2 weeks 
 
Any 
> 5 × ULN but < 8 × ULN and unable to adhere to 
enhanced monitoring schedule 
 
Any 
> 3 × ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice). 
 
• 
OR: TBL > 3 × ULN at any time 
• 
OR: ALP > 8 × ULN at any time 
 
Cinacalcet should be withheld pending investigation into alternative causes of DILI. If 
investigational product(s) is withheld, the subject is to be followed according to 
recommendations in Appendix A for possible DILI. Rechallenge may be considered if an 
alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is 
discovered and the laboratory abnormalities resolve to normal or baseline 
(Section 6.3.3). 
 
6.3.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject’s legally acceptable representative(s), investigator, and 
Amgen. 
 
If signs or symptoms recur with rechallenge, then cinacalcet should be permanently 
discontinued. Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.3.1) should never be rechallenged. 


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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 6.6. 
 
Vitamin D sterols, calcium supplementation, and/or phosphate binders should be 
administered as appropriate per individual clinic practice. 
 
Dialysate calcium concentrations should not be adjusted during the course of the trial, 
remaining at ≥ 2.5 mEq/L. 
 
All concomitant medications taken by a subject while on study are to be recorded on the 
eCRF. Refer to Section 7.3.7 for additional information regarding what is to be recorded. 
 
6.5 
Product Complaints 
 
A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of any investigational or non-investigational product(s) or device(s). 
 
Any product complaint(s) associated with an investigational product(s) or 
 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
 
6.6 
Excluded Treatments and/or Procedures During Study Period 
Subjects are prohibited from participating in other interventional studies (eg, studies 
which require medical device use or drug therapy or with protocol-required procedures) 
while participating in this study. 
 
Cinacalcet is not approved for use in children and the use of commercial cinacalcet while 
participating in this study is prohibited. Refer to Section 7.3.7 for additional information 
regarding the reporting of commercial cinacalcet use. 
 
Subjects should not receive any medications known to prolong the QT interval (eg, 
ondansetron, albuterol) while participating in this study. In addition, the use of grapefruit 
juice, herbal medications, CYP3A4 inhibitors (eg, erythromycin, clarithromycin, 
ketoconazole, itraconazole), or CYP2D6 substrates (eg, flecainide, propafenone, 
metoprolol, desipramine, nortriptyline, clomipramine) are excluded during the study. If 
subjects require these medications for temporary use, the administration of cinacalcet is 
to be withheld until the concomitant medication has been discontinued, at which time 


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cinacalcet administration can be resumed. Additional information may be found in the 
 
IPIM. 
 
7.                    STUDY PROCEDURES 
 
7.1                  Schedule of Assessments 
 
Screening assessments and study procedures required for each visit are outlined in this 
section and the Schedule of Assessments (Table 4). The informed consent, and assent 
if applicable, must be obtained prior to performing any screening or study procedures. 


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Screening 
Table 4.  Schedule of Assessments 
Treatment Period (Week) 
FU Period 
 
Week -1  
Day 1  
1    2     3     4     5     6     7     8     9    10   11   12   13   14   15   16   17   18   19   20   21   22   23   24   25   26    27 
EOIP 
W28 
ET/EOS 
W32 
GENERAL & SAFETY ASSESSMENTS 
Informed consent, 
Assent (if applicable)                 X 
Medical/Surgical History                              X 
12-lead ECG                                                X                                                                                                                                                                                                                     X            X 
Physical Exam                                             X
1                                                                                                                                                                                                                                                                                                                                                                                                       X 
Height, Tanner Stage                                  X
1                                                                                                                                                                                                                                                                                                                                                                                                       X 
Dry Weight                                                   X
1                                                                                                                                                                                                                                                                                                                                                                                                       X 
Dialysate Ca 
Concentration                                             X 
Blood Pressure, Heart  
1 
Rate  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant  
2 
Medications
2  
X 
 
Record Continuously  
X 
X 
Patient Diary Review                                  X
1            X    X    X    X    X     X    X    X    X    X     X    X     X     X     X    X    X     X    X    X    X    X    X     X    X    X     X         X 
Adverse events
2                                                                                                                                                                                                                          Record Continuously                                                                                                 X            X 
Serious Adverse events
2                                                                                                                                                                                                   Record Continuously                                                                                                 X            X 
LABORATORY ASSESSMENTS 
Ionized Ca                                                   X
1            X    X    X    X    X     X    X    X    X    X     X    X     X     X     X    X    X     X    X    X    X    X    X     X    X    X     X         X 
Liver Function Tests                  X
2                         X                                                                                 X                                                                                       X                                                       X 
Chemistry, hematology,  
2 
1 
25(OH)Vit D
3  
X 
X 
X 
X 
Ca, Albumin, cCa, P 
X
1 
X
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iPTH  
X
1 
X
1 
X 
X 
X 
X 
X 
X 
X 
X 
Total & Bioavail  
1 
Testosterone (male)  
X 
X 
Serum Pregnancy Test 
(females of child bearing  
X 
X 
potential) 
BIOMARKER ASSESSMENTS 
BALP, NTx, CTx, P1NP,  
1 
FGF 23
3  
X 
X 
DOSING 
Dispensing  
X 
X    X    X    X    X     X    X    X    X    X     X    X     X     X     X    X    X     X    X    X    X    X    X     X    X    X    X 
Cinacalcet Dose 
Titration  
X 
X 
X 
X 
X 
X 
X 
Footnotes defined on next page 


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Note:  When it is not possible to perform a study visit at the specified time point, the visit may be performed within ± 3 days. 
1 - Where the Screening and day 1 assessments for Study 20140159 overlap with visits in the Studies 20130356 or 20110100, these will be performed once at the site and applied to both 
study visits to minimize duplicate study assessments. 
2 - These procedures are required for Study 20140159 screening visit if > 14 days since last study visit in Studies 20130356 or 20110100 for subjects impacted by study termination. 
3 - Biomarker Assessments and 25 (OH) Vit D are not required for subjects previously enrolled in 20110100.  If baseline FGF23 is not collected at day 1, it must not be collected at 
week 28. 


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Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures. 
 
7.2 
General Study Procedures 
 
All on-study visits and dosing should be scheduled from day 1. Week 1 begins one 
week after the day 1 visit. It is important to perform study assessments and obtain 
samples at the time points outlined in the Schedule of Assessments in Section 7.1. 
 
The duplicate study assessments will be collected once for both studies as described in 
 
Section 7.2.2. 
 
When it is not possible to perform a study visit at the specified time point, the visit may 
 
be performed within ± 3 days. If a study visit is missed, subsequent visits should resume 
on the original visit schedule. Missed assessments at prior visits should not be 
duplicated at subsequent visits. 
 
With the exception of screening assessments, all study procedures for a visit must be 
completed on the same day. 
 
It is the responsibility of the investigator to ensure that all procedures are performed 
according to the protocol. 
 
Any blood or serum collected according to the Schedule of Assessments may be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
ensure subject safety. This includes testing to ensure analytical methods produce 
reliable and valid data throughout the course of the study. This may also include, but is 
not limited to, investigation of unexpected results, incurred sample reanalysis, and 
analyses for method transfer and comparability. 
 
Details regarding each type of procedure are provided in Section 7.3 
 
7.2.1 
Screening and Enrollment 
 
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Section 7.1, Table 4): 
 
• 
Confirmation that the Informed Consent Form and Assent Form (if applicable) 
have been signed 
• 
Registration of the subject in the IVR/IWR system 
• 
Serum pregnancy test 
• 
Serum calcium, serum albumin, and calculation of cCa, phosphorus 
• 
iPTH 


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7.2.2 
Day 1 
 
The following day 1 procedures are also required for the EOIP study visit for Amgen 
Study 20130356 and End of Study visit for Study 20110100 except where indicated. 
These procedures should not be duplicated and may be collected once where study 
visits overlap and entered onto the appropriate eCRF once eligibility for this study has 
been confirmed: 
 
• 
12-lead ECG 
• 
physical exam 
• 
dry weight 
• 
height/Tanner stage 
• 
dialysate calcium, type of dialysis 
• 
blood pressure, heart rate 
• 
ionized calcium 
• 
central laboratory assessments including the following 
o serum calcium, serum albumin, and calculation of cCa, phosphorus 
o iPTH 
o liver Function Tests (LFT) 
o chemistry panel 
o hematology panel 
o 25 (OH) Vitamin D (not required for subjects from 20110100) 
o total & bioavailable testosterone (male) 
o bone specific alkaline phosphatase (BALP), cross-linked N-telopeptides 
of type 1 collagen (NTx), type 1 collagen cross-linked telopeptide (CTx), 
amino terminal propeptide of type 1 collagen (P1NP), FGF23 (not 
required for subjects from 20110100). 
 
The following day 1 procedures will be recorded on the day 1 eCRF: 
 
• 
medical history (including ongoing AEs/SAEs from studies, 20130356 and 
20110100) 
• 
concomitant medications 
• 
adverse event reporting 
• 
serious adverse event (SAE) reporting 
• 
ediary provision and training (all subjects) 
 
Following completion of the day 1 visit assessments, eligibility, dry weight, and 
 
enrollment will be entered in the IVR/IWR system, as applicable. Following enrollment in 
the IVR/IWR system, IP will be dispensed and recorded on the day 1 eCRF. 


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7.2.3 
Treatment 
 
The following procedures will be completed during the 28-week treatment period at the 
times designated in the Schedule of Assessments (Table 4). Study visits will occur 
weekly ± 3 days. All blood samples for laboratory assessments for hemodialysis 
subjects are to be collected prior to initiating the dialysis session during the visit. 
Cinacalcet will be dispensed to subjects to take home for daily administration at the 
conclusion of the study visit weekly. 
 
The following procedures and assessments will be completed at the times designated in 
the Schedule of Assessment (Table 4, Section 7.1) and recorded on the eCRF: 
 
• 
concomitant medications 
• 
documentation of subject compliance with daily administration of cinacalcet 
o patient diary review 
o counts of returned bottles of tablets/capsules/suspension 
 
• 
adverse events, including signs and symptoms of hypocalcemia, seizures, and 
infections 
• 
serious adverse events 
• 
ionized calcium 
• 
central laboratory assessments including the following: 
o serum calcium, serum albumin, and calculation of cCa, phosphorous 
o iPTH 
o LFT (weeks 11 & 23) 
 
7.2.4 
End of Investigational Product 
 
The end of investigational product (EOIP) visit will occur at week 28. The procedures to 
be performed at this visit include the following: 
 
• 
12-lead ECG 
• 
blood pressure, heart rate 
• 
concomitant medications 
• 
documentation of subject compliance with daily administration of cinacalcet 
o patient diary review 
o counts of returned bottles of tablets/capsules/suspension 
 
• 
adverse events, including signs and symptoms of hypocalcemia, seizures, and 
infections 
• 
serious adverse events 


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• 
ionized calcium 
• 
central laboratory assessments including the following: 
 
o serum calcium, serum albumin, and calculation of cCa, phosphorus 
o chemistry panel 
o hematology 
o 25 (OH) Vitamin D (not required for subjects from 20110100) 
o iPTH 
o total and bioavailable testosterone (male) 
o BALP, NTx, CTx, P1NP, FGF23 (not required for subjects from 
20110100) 
7.2.5 
Early Termination 
Subjects who discontinue participation in the study prior to week 28 will be asked to 
complete an early termination visit and should have all EOIP and EOS evaluations 
performed as outlined in the Schedule of Assessments and in Sections 7.2.4 and 7.2.6. 
 
7.2.6 
End of Study Visit 
 
Subjects will complete an EOS visit at week 32 within +/- 3 days of the scheduled visit 
date or at early termination. The following evaluations apply to the EOS visit: 
 
• 
physical exam 
• 
dry weight 
• 
height/Tanner stage 
• 
12-lead ECG 
• 
blood pressure, heart rate 
• 
concomitant medications 
• 
adverse events, including signs and symptoms of hypocalcemia, seizures, and 
infections 
• 
serious adverse events 
• 
central laboratory assessments including the following: 
o serum calcium, serum albumin, and calculation of cCa, phosphorous 
o chemistry panel 
o CBC, LFTs 
o 25 (OH) Vitamin D (not required for subjects from 20110100) 
o iPTH 
o serum pregnancy test (female of child bearing potential) 


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7.3 
Description of General Study Procedures 
 
7.3.1 
Informed Consent/Assent 
 
All subjects must have a parent or legal representative sign and personally date the 
IRB/IEC approved informed consent form before any study specific procedures are 
performed. In addition, subjects must sign and personally date the assent form when 
applicable prior to the performance of any study specific procedures. See Section 11.1 
for further details. 
 
7.3.2 
Demographic Data 
 
Demographic data including sex, date of birth, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness. 
These data will be transferred from the studies 20130356 and 20110100. 
 
7.3.3 
Medical and Surgical History 
 
The subject’s complete medical and surgical history will be reviewed on day 1. The 
investigator or designee will collect a complete medical and surgical history for 
conditions that started within 5 years of the date of enrollment, including information on 
the subject’s concurrent conditions. Ongoing adverse events and serious adverse 
events in studies 20130356 and 20110100 will be entered as concurrent conditions on 
the medical history form. This information will be recorded on the medical history eCRF 
for subjects enrolled into the study. 
 
7.3.4 
Physical Exam, Height, Tanner Stage, Dry Weight 
 
A physical exam will be performed on day 1. Breast, genital, and rectal examinations 
are not required for any study visit unless specific evaluation is warranted. 
 
The physical examination at the EOS visit will consist of a follow-up examination to 
monitor for any changes from the day 1 physical examination. Any clinically significant 
changes in the physical examination per the investigator’s opinion should be recorded 
on the adverse event eCRF. 
 
Information regarding the subject’s residual urine output will be collected on day 1. 
 
Height will be collected on day 1 and at the EOS visit and should be measured with the 
subject’s shoes removed. 
 
Tanner stage will be determined on day 1 and at the EOS visit and recorded in the 
eCRF. 


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The subject’s dry weight should be collected at day 1 and at the EOS visit post-dialysis 
for hemodialysis subjects and at the study visit, while the peritoneal cavity is empty, for 
peritoneal dialysis subjects. For all subjects the weight is to be measured with the 
subject wearing light clothing and with his/her shoes removed. 
 
7.3.5 
Blood Pressure and Heart Rate 
 
The blood pressure should be taken with the subject’s arm supported at heart level using 
the appropriate sized cuff with the subject comfortably seated in a chair with his/her back 
supported and both feet on the ground. Subjects should be resting quietly for at least 
5 minutes before the blood pressure and heart rate are measured. For subjects receiving 
hemodialysis, blood pressure and heart rate are to be measured at the conclusion of the 
dialysis session. For subjects receiving peritoneal dialysis, blood pressure and heart rate 
are to be measured during the study visit. All measurements will be recorded in the 
eCRF. 
 
7.3.6 
ECG 
 
The subject must be in a supine position in a calm and resting state for at least 
 
5 minutes before the ECG assessment is conducted. If the subject is unable to be in a 
supine position, he/she should be in the most recumbent position possible. 
 
The ECG must include the following measurements: heart rate, QRS, QTc, and RR, QT 
intervals. For the purposes of this study, the QTc should be provided or calculated using 
Bazett’s formula (QT/√RR). For subjects receiving hemodialysis, the ECG is to be 
obtained prior to the initiation of the dialysis session. For subjects receiving peritoneal 
dialysis, the ECG is to be obtained during the study visit. All measurements will be 
recorded in the eCRF. 
 
The investigator will review, sign, and date all ECGs. Once signed the original ECG 
tracing will remain in the subject’s source documents. At the request of the sponsor, a 
copy of the original ECG will be made available to Amgen. 
 
7.3.7 
Concomitant Medications 
 
Concomitant medications will be collected beginning on day 1 through the end of study, 
and recorded in the eCRF for this study as described below. 
 
The administration of vitamin D sterols, calcium supplementation, bisphosphonates, and 
phosphate binders, including the name of the medication, dose, unit, route, frequency, 
and start and stop dates of administration, will be collected. 


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Commercial cinacalcet is an excluded medication during this study (Section 6.6). For 
subjects who receive commercial cinacalcet, this will be documented as a protocol 
deviation and the name of the medication, dose, unit, route, frequency, and start and 
stop dates of administration will be collected. 
 
Changes in dialysate calcium concentration during the course of the trial will be 
documented as a protocol deviation. For subjects in whom the dialysate calcium 
concentration changes during the course of the trial, the change in concentration and 
start date will be collected. 
 
For all other concomitant medications, including over the counter and herbal medicines, 
the name of the medication, start and stop dates of administration will be collected. 
 
7.3.8 
Electronic Patient Diary 
 
Subject compliance with daily administration of cinacalcet will be collected using a 
handheld eDiary. The eDiary will collect date, time and amount of cinacalcet taken each 
day. Subjects will use the eDiary daily beginning on day 1 and completing at their 
week 28 study visit. It is expected that children under the age of 12 will have their 
parent(s) or legal guardian(s) complete the eDiary daily. Children ≥ 12 years of age may 
either have their parent(s) or legal guardian(s) complete the eDiary daily or do this 
themselves under the supervision of their parent(s) or legal guardian(s). The subjects 
will be instructed to bring their eDiary with them to every study visit. The data entered 
into the eDiary will be available to the investigator and/or study coordinator on a daily 
basis to enable ongoing reviews of subject compliance. The data collected will be 
reviewed with the subject by the investigator and/or study coordinator during the weekly 
study visits. The investigator and/or study coordinator will also reconcile any 
discrepancies between the eDiary and the IP accountability data during the weekly study 
visits. Reasons for discrepancies will be documented and subjects and/or parents/legal 
guardians counseled on the importance of compliance with the administration of 
cinacalcet during the trial. The data collected will be captured in the study database. 
 
Refer to Section 6.2.3.2 for additional information regarding the measures of compliance 
for this study and the eDiary manual for additional details. 
 
7.3.9 
Ionized Calcium 
 
All ionized calcium values will be collected as specified in the Schedule of Assessments 
for identification of potential hypocalcemia. Ionized calcium values will be obtained 
either per routine practice at the clinical site or using a point of care device provided by 


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Amgen. The clinical site will document the method that is being used to obtain the 
ionized calcium for each subject enrolled at the site and ensure that this remains 
consistent for the duration of the trial. All measurements should occur on the day of the 
study visit prior to the administration of cinacalcet. For sites that use the point of care 
device provided by Amgen, refer to the device manual provided for further information. 
 
The measurements obtained will be entered into the IVR/IWR system at each study visit 
and entered into the eCRF. 
 
In addition, cCa values from the central laboratory will be collected as specified in the 
Schedule of Assessments. These cCa values will be utilized for monthly dose titration 
visits. 
 
7.3.10 
Adverse Events 
 
Adverse events will be collected in the eCRF for each subject at all study visits. 
Targeted questions regarding hypocalcemia, seizures and infections will be asked and 
data will be entered into the eCRF at each study visit. 
 
All clinically significant (according to the investigator’s judgment), laboratory 
abnormalities will be reported as adverse events. In assessing clinical significance of a 
low serum calcium value, the investigator should consider factors such as presence of 
clinical symptoms associated with hypocalcaemia, dose adjustment of cinacalcet or 
concomitant medications (eg, vitamin D, phosphate binders). In addition, the 
investigator should indicate on the eCRF whether hypocalcemia was symptomatic, and if 
so provide the accompanying symptoms. 
 
Serious adverse events that occur in a subject from the date of the first dose through 
 
30 days after the last dose of IP will be recorded in the adverse event eCRF. All 
adverse events that occur from the date of the first dose through 30 days after the last 
dose of IP will be recorded in the adverse event eCRF. Refer to Section 9 for additional 
information. 
 
7.3.11 
Laboratory Assessments 
 
All study laboratory samples, with the exception of the ionized calcium samples, will be 
processed and sent to the central laboratory for assessment. The central laboratory will 
provide a study manual that outlines handling, labeling, and shipping procedures for all 
blood samples. All blood samples will be obtained via venipuncture prior to the 
administration of IP. The date and time of the sample collection will be recorded in the 
source documents at the site. 


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Table 5 below outlines the specific analytes that will be assessed at the central 
laboratory: 
 
Table 5.  Analytes 
 
Serum Chemistry 
Hematology 
Bicarbonate 
Hemoglobin 
Blood Urea Nitrogen 
Hematocrit 
Chloride 
Platelets 
Creatinine 
White blood cell count 
Potassium 
Red blood cell count 
Sodium 
Liver Function Tests 
Total Protein 
ALT 
Total Bilirubin 
AST 
Phosphorus 
Alk Phos 
Other 
iPTH, Albumin, Calcium 
Serum Pregnancy (females of child bearing potential) 
Corrected Calcium
a
 
Total and bioavailable testosterone (male) 
BALP, NTx, CTx, P1NP, 25(OH) Vitamin D, FGF23 (not required for subjects from 20110100) 
a Corrected calcium will be determined by the central laboratory using the following formula, where 
4.0 represents the average albumin level.  No correction will be made if the 
serum albumin level is ≥ 4.0 g/dL. 
Corrected calcium (mg/dL) = Measured total serum calcium (mg/dL) + 0.8 (4.0-serum albumin [g/dL]) 
 
7.3.12 
Home Healthcare 
 
Subjects receiving peritoneal dialysis may not have to be seen routinely by the 
investigator at the clinical site on a weekly basis. These subjects will be required to be 
seen in the clinic every 2 weeks, including the week prior to the monthly dosing titration 
visit and those visits where central laboratory samples are collected, at a minimum 
during the trial. The investigator may utilize their site staff or a qualified home healthcare 
service provider to conduct the procedures required for remaining weekly study visits, 
subject to the investigator’s direction and oversight. 
 
7.4 
Biomarker Development 
 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity. 


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Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to cinacalcet. 
 
Blood Samples 
 
Blood samples are to be collected for biomarker development at the following time 
points: day 1 and EOIP visit (week 28). 
 
7.5 
Sample Storage and Destruction 
 
Any blood or biomarker sample collected according to the Schedule of Assessments 
(Table 4) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects. This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study. This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage. Samples will be tracked using a unique identifier that is assigned to 
the samples for the study. Results are stored in a secure database to ensure 
confidentiality. 
 
If permitted by local regulations and informed consent is provided by the subject’s legally 
acceptable representative(s), Amgen can do additional testing on remaining samples 
(ie, residual and back-up) to investigate and better understand the CKD and SHPT, the 
dose response and/or prediction of response to cinacalcet, 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 pharmacogenetic, biomarker development, or 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. 


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However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample). If a commercial product is developed from this 
research project, the sponsor owns the commercial product. The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample. See 
Section 11.3 for subject confidentiality. 
 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures at any time during the study but 
continue participation in the study. If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 4) and collection of data, including endpoints and adverse 
events. The investigator must document the change to the Schedule of Assessments 
(Table 4) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records). 
 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation. Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent. The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
 
8.1 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP, protocol 
procedures, or the study as a whole at any time prior to study completion. 


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Subjects may be eligible for continued treatment with Amgen IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
 
8.2 
Reasons for Removal From Study 
 
8.2.1 
Reasons for Removal From Treatment 
 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
• 
subject request 
• 
safety concern (eg, due to an adverse event, protocol deviation, non-compliance, 
requirement for alternative therapy, pregnancy) 
• 
protocol-specified criteria (eg, renal transplant, parathyroidectomy) 
• 
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 
Adverse Events 
 
9.1.1 
Definition of Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment. 
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
 
The definition of adverse events includes worsening of a pre-existing medical condition. 
Worsening indicates that the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome. A pre-existing condition that has not 
worsened during the study or involves an intervention such as elective cosmetic surgery 
or a medical procedure while on study is not considered an adverse event. 


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If the toxicity grade of an adverse event worsens from the date of onset to the date of 
resolution, record as a single event with the worst CTCAE grade on the Adverse Event 
Summary eCRF. 
 
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 6.3.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
 
9.1.2 
Definition of Serious Adverse Events 
 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay). 
 
If an investigator considers an event to be clinically important, but it does not meet any 
 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”. Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
 
9.2 
Reporting of Adverse Events 
 
Ongoing adverse events and serious adverse events in studies 20130356 or 20110100, 
will be entered as a concurrent condition on the Medical History eCRF. 
 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from the date of the first dose and up to 


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30 days after the last dose of IP, are reported using the applicable eCRF (eg, Adverse 
 
Event Summary). 
 
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), 
• 
toxicity, 
• 
assessment of relatedness toIP, and 
• 
action taken. 
 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE, v4.0). 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 IP. This relationship is indicated by a “yes” or “no” response to the question: Is 
there a reasonable possibility that the event may have been caused by the IP? 
 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values. In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events. However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events. Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
 
9.2.2 
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 from the date of the first dose 
through 30 days after the last day of the dosing interval of IP or end of study visit 
(whichever is later) are recorded in the subject’s medical record and are submitted to 
Amgen. All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the serious adverse event form. 
 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events. However, if the 


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investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours 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. 
 
See Appendix A for a sample of the Serious Adverse Event Worksheet. 
 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure. This relationship is indicated by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen. All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information. The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record. Information provided about the serious 
adverse event must be consistent with that recorded on the applicable eCRF 
(eg, Adverse Event Summary eCRF). 
 
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. 
 
9.3 
Pregnancy and Lactation Reporting 
 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapy, report the pregnancy to Amgen as specified 
below. 


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In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of cinacalcet through 90 days. 
 
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). Amgen Global Patient Safety will seek 
to follow the pregnant woman throughout her pregnancy and her baby up to 12 months 
after birth. 
 
If a lactation case occurs while the female subject is taking cinacalcet report the lactation 
case to Amgen as specified below. 
 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of cinacalcet through 90 days. 
 
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). 
 
10. 
STATISTICAL CONSIDERATIONS 
 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
 
10.1.1 
Study Endpoints 
 
Primary Endpoint: 
 
• 
Incidence of treatment emergent adverse events of interest 
 
Secondary Endpoints: 
 
20140159 study only 
 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during weeks 11 
and 15 (SOC arm of Study 20130356 only) 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during weeks 23 
and 28 (SOC arm of Study 20130356 only) 
• 
Percent change from baseline to mean iPTH during weeks 23 and 28 (SOC arm 
of Study 20130356 only) 
• 
Change in corrected total serum calcium from baseline to mean value during 
weeks 23 and 28 
• 
Change in serum phosphorus from baseline to mean value during weeks 23 and 
28 
• 
Achievement of a mean iPTH ≤ 300 pg/mL during weeks 23 and 28 
• 
Serum cCa at baseline, week 11, and week 28 
• 
Serum phosphorus at baseline, week 11, and week 28 


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Combined 20130356, 20110100, and 20140159 Studies 
 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to mean 
iPTH during weeks 11 and 15 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to mean 
iPTH during weeks 23 and 28 
• 
Percent change in iPTH over time from day 1 of cinacalcet treatment 
• 
Change in serum cCa over time from day 1 of cinacalcet treatment 
• 
Change in serum phosphorus over time from day 1 of cinacalcet treatment 
 
Exploratory Endpoints: 
Study 20140159 only 
• 
Growth velocity from baseline to EOS 
• 
Change in Tanner stage from baseline to EOS 
 
Combined Studies 20130356, 20110100, and 20140159 
 
• 
Growth velocity from day 1 of cinacalcet treatment to EOS 
• 
Change in Tanner stage from day 1 of cinacalcet treatment to EOS 
 
Safety Endpoints: 
 
• 
Nature, frequency, and severity of all adverse events 
 
• 
Blood pressure, heart rate, and changes in laboratory parameters, including 
clinical chemistry and hematology 
 
10.1.2 
Analysis Sets 
 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all enrolled subjects in Study 20140159. 
 
Safety Analysis Set 
 
The Safety Analysis Set includes all enrolled subjects who receive at least one dose of 
cinacalcet. 
 
Efficacy Analysis Set 
 
The Efficacy Analysis Set includes all enrolled subjects who received at least one 
dose of cinacalcet and have at least one assessment after day 1. 
 
10.1.3 
Covariates and Subgroups 
 
The primary, secondary, and safety endpoints may be summarized by baseline age 
group (6 to < 12 years and 12 to < 18 years for Study 20130356; 28 days to < 2 years 
and 2 to < 6 years for Study 20110100) as supportive analyses upon availability of data 
in each subgroup. 


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10.2 
Sample Size Considerations 
 
This is an extension study of Studies 20130356 and 20110100. The sample size may 
be up to 78 subjects. 
 
10.3 
Planned Analyses 
 
10.3.1 
Interim Analysis 
 
Several interim analyses may be conducted. The first interim analysis will be performed 
to support the Supplemental New Drug Application (sNDA) for pediatric indication. Its 
scope of analysis will be limited to the planned analysis using 20140159 study data only. 
The rest of interim analyses may be performed to support further request from 
regulatory. The scope of these analyses will be specified in a separate statistical 
analysis plan of interim analysis. There is no plan to conduct formal statistical testing. 
There are no plans to change the conduct of the study based on interim analysis results. 
 
10.3.2 
Primary Analysis 
 
The general approach is to provide estimates for the primary and secondary endpoints 
for the study population. 
 
The primary analysis of all endpoints will be conducted after all subjects have completed 
the week 32 EOS visit or terminated early from Study 20140159. 
 
The primary analysis of all endpoints will be conducted after all subjects have completed 
the week 32 EOS visit or terminated early from Study 20140159. 
 
10.4 
Planned Methods of Analysis 
 
10.4.1 
General Considerations 
 
There is no formal statistical testing for this study. The analysis for all endpoints will be 
descriptive in nature. Descriptive statistics will be used to summarize data for 
continuous variables (including n, mean, standard deviation (SD) or standard error (SE), 
median, 25th (Q1) and 75th (Q3) percentiles, and minimum and maximum values, where 
applicable). 
 
For categorical variables, the number and percentage of subjects in each category will 
be reported. Graphical presentations may be provided for selected variables. 
 
All summary tables will be provided by study treatment group: Study 20130356 (SOC, 
SOC + cinacalcet) and Study 20110100 and overall, unless otherwise specified. 
 
10.4.2 
Primary Endpoint 
 
The analysis of the primary endpoint will be based on the Safety Analysis Set. The 
primary analysis of the primary endpoint is subject incidence of events of interest (EOI; 


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eg, hypocalcemia, convulsions, hypotension, worsening of heart failure, hypersensitivity, 
ischemic heart disease, QT prolongation/ventricular tachyarrhythmias, fracture, acute 
pancreatitis, drug-related hepatic disorders, nervous system disorders [excluding 
seizures], neoplastic events, and infection) for data in the 20140159 study only. The 
secondary analysis of the primary endpoint is the incidence of events of interest adjusted 
by the amount of safety follow-up time for combined data from parent studies and data 
from the 20140159 study. The 95% confidence intervals (CI) of the overall incidence 
rates will be reported. 
 
10.4.3 
Secondary Endpoints 
 
The analysis of secondary endpoints will be based on Efficacy Analysis Set. The 
approach for handling the missing data will be described for each endpoint in the 
statistical analysis plan. 
 
20140159 study only 
 
The proportion of subjects who achieve a ≥ 30% reduction from baseline of 
 
Study 20140159 to mean iPTH at weeks 11 and 15 and to mean iPTH at weeks 23 and 
 
28 will be assessed for the SOC arm in Study 20130356 with a 95% CI. 
 
Summary statistics will be provided for the percent change in mean iPTH from baseline 
in Study 20140159 during weeks 23 and 28 for the SOC group in Study 20130356. 
 
Summary statistics will be provided for the change in corrected total serum calcium and 
change in serum phosphorus from baseline of Study 20140159 to mean value at 
weeks 23 and 28 by treatment group in the parent study. 
 
The proportion of subjects who achieve a mean iPTH value of ≤ 300 pg/mL during 
 
weeks 23 and 28 will be provided by treatment group in the parent study with a 95% CI. 
 
Summary statistics will be provided for serum cCa and phosphorus values at baseline to 
week 11 and week 28. 
 
Combined 20130356, 20110100, and 20140159 Studies 
 
The proportion of subjects who achieve a ≥ 30% reduction from day 1of cinacalcet 
treatment to mean iPTH at weeks 11 and 15 and to mean iPTH at weeks 23 and 28 will 
be provided by previous treatment group in the parent study with a 95% CI. 
 
The percent change in iPTH, change in corrected serum calcium, and change in serum 
phosphorus from day 1 of cinacalcet treatment at each measurement time point will be 
summarized overall. 


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10.4.4 
Safety Endpoints 
 
The safety analysis will be based on the safety analysis set. All safety endpoints in 
 
20140159 study only and combined with their parent studies will be summarized by 
treatment group in the parent studies and overall. 
 
Adverse Events 
 
All treatment-emergent adverse events occurring during the study will be coded using 
the latest version of the MedDRA dictionary. The subject incidence of all 
treatment-emergent adverse events, serious adverse events, treatment-related adverse 
events, and serious treatment-related adverse events will be tabulated by system organ 
class and preferred term in descending order of frequency. Tables of 
treatment-emergent adverse events, fatal adverse events, serious adverse events, and 
adverse events leading to withdrawal from investigational product or from study will be 
tabulated by preferred term. 
 
Laboratory Data, Blood Pressure, and Heart Rate 
 
Descriptive statistics for values, changes and percent changes of selected laboratory 
parameters from first dose of IP date will be presented at each measurement time point 
during the study. In addition, shift tables will summarize grades using CTCAE 
(version 3) by worst grades between baseline and any visit up to the end of the study for 
selected hematology and chemistry parameters. 
 
The incidence of hypocalcemia after the first dose of IP will be summarized using 
descriptive statistics. Hypocalcemia will be defined in two ways: with the subject 
incidence of corrected serum calcium of < 7.5 mg/dL, < 8.0 mg/dL, and < 8.4 mg/dL 
being summarized; and with subject incidence of ionized calcium value < 0.94 mmol/L, 
< 1.05 mmol/L, and < 1.00 mmol/L being summarized. Blood pressure (systolic and 
diastolic) and heart rate will be summarized at each time point. 
 
Medications of Interest 
 
Use of vitamin D sterols and phosphate binders during study. 
 
ECG 
 
The ECG measurements from this clinical study will be performed as per standard of 
care for routine safety monitoring, rather than for purposes of assessment of potential 
QTc effect. Since these evaluations may not necessarily be performed under the 
rigorous conditions expected to lead to meaningful evaluation of QTc data, summaries 


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and statistical analyses of ECG measurements are not planned, and these data would 
not be expected to be useful for meta-analysis with data from other trials. 
 
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 patient population. 
 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered. A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study. If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study. If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion. The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable representative. 
 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions. Thereafter, both the 


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subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood. 
 
In this study, obtaining assent from the child and consent from the parents or legally 
authorized representative, except if the child is very young, as defined by local law will 
apply. A child is defined as a person who has not attained the legal age for consent for 
treatments or procedures involved in clinical investigations, under the applicable law of 
the jurisdiction in which the clinical investigation will take place. The local IRB/IEC will 
determine the process for obtaining and documenting the assent process for pediatric 
subject, but should follow the guidelines established by the Department of Health and 
Human Services (DHHS) Office of Human Research Protections guidelines, which state 
an explanation of the procedures involved in the study should be made in a language 
appropriate to the child’s age, experience, maturity, and condition. 
 
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/IEC approval/renewal 
throughout the duration of the study. Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
 
11.3 
Subject Confidentiality 
 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
 
• 
Subjects are to be identified by a unique subject identification number. 
• 
Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations. 
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment. 


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• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by 
their unique subject identification number, initials (for faxed reports, in 
accordance with local laws and regulations), and date of birth (in accordance with 
local laws and regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
 
In compliance with Federal regulations/ICH GCP guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data. Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study. The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
 
11.4 
Investigator Signatory Obligations 
 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
• 
a recognized expert in the therapeutic area 
 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
12.1 
Protocol Amendments and Study Termination 
 
If Amgen amends the protocol, agreement from the Investigator must be obtained. The 
IRB/IEC must be informed of all amendments and give approval. The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
 
Amgen reserves the right to terminate the study at any time. Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract. The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen. 
 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism. 
However, Amgen reserves the unilateral right, at its sole discretion, to determine 


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whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are 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 should include: 
 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, IB, 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. 
 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
 
Retention of study documents will be governed by the Clinical Trial Agreement. 
 
12.3 
Study Monitoring and Data Collection 
 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
 
The Amgen clinical monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 


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research. The clinical monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees). Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
 
Data capture for this study is planned to be electronic: 
 
• 
All source documentation supporting entries into the CRFs must be maintained 
and readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen. During 
this review, subject data are checked for consistency, omissions, and any 
apparent discrepancies. In addition, the data are reviewed for adherence to the 
protocol and GCP. To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications are created in 
the EDC system database for site resolution and subsequently closed by the 
EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study. 
This signature indicates that the investigator inspected or reviewed the data on 
the CRF, the data queries, and the site notifications, and agrees with the content. 
 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan. Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination). Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout. 


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12.4 
Investigator Responsibilities for Data Collection 
 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study. For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 4), the investigator can search publically available 
records (where permitted) to ascertain survival status. This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible. 
 
12.5 
Language 
CRFs must be completed in English. TRADENAMES® (if used) for concomitant 
medications may be entered in the local language. 
 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
 
12.6 
Publication Policy 
 
To coordinate dissemination of data from this study, 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 International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, 
which states: 
 
• 
Authorship credit should be based on (1) substantial contributions to conception 
and design, acquisition of data, or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final 
approval of the version to be published and (4) agreement to be accountable for 
all aspects of the work in ensuring that questions related to the accuracy or 
integrity of any part of the work are appropriately investigated and resolved. 
Authors should meet conditions 1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group should 
identify the individuals who accept direct responsibility for the manuscript. These 
individuals should fully meet the criteria for authorship defined above. 


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• 
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. 
 
Additional information on the current guidelines for publications can be found at the 
following location: http://www.icmje.org/. 
 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review. The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
 
12.7 
Compensation 
 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
 
During the study, the subjects may be reimbursed for reasonable expenses associated 
with the study (eg, transportation), if permitted under applicable regional laws or 
regulatory guidelines. The subjects’ parents or legal representatives may be 
compensated for other inconveniences not associated with study-related injuries 
(eg, lost work time), if permitted under applicable regional laws or regulatory guidelines. 
These arrangements for compensation are described in the Informed Consent that is 
available as a separate document. 


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13. 
REFERENCES 
 
Bacchetta J, Harambat J, Cochat P, et al. The consequences of chronic kidney disease 
on bone metabolism and growth in children. Nephrol Dial Transplant. 2012;27(8): 
3063 3071 
Cinacalcet HCl Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
European Renal Association-European Dialysis Transplant Association Registry 
(ERA-EDTA) Annual Report 2011. 
 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2013. 
http://www.icmje.org/ 
Kidney Disease: Improving Global Outcomes (KDIGO) CKDMBD Work Group (2009) 
KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment 
of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. 
2009;76(Suppl 113):S121-S130 
 
Klaus G, Watson A, Edefonti A, et al. Prevention and treatment of renal osteodystrophy 
in children on chronic renal failure: European guidelines. Pediatr Nephrol.2006; 
21:151-159 
 
Kuizon BD, Salusky IB. Growth retardation in children with chronic renal failure. J Bone 
Miner Res. 1999;14:1680-1690 
 
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). 
KDOQI clinical practice guidelines for bone metabolism and disease in children with 
chronic kidney disease. National Kidney Foundation, Inc. 2005. 
http://www.kidney.org/professionals/kdoqi/guidelines_pedbone/index.htm 
 
North American Pediatric Renal Trials and Collaborative Services (NAPRTCS), 
unpublished data 
United States Renal Data System (USRDS). 2013. http://www.usrds.org 


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14. 
APPENDICES 


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Appendix A. Additional Safety Assessment Information 
 
Adverse Event Grading Scale 
 
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Drug-induced Liver Injury Reporting & Additional Assessments 
 
Reporting 
 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 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, Adverse 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 9.1.2. 
 
Additional Clinical Assessments and Observation 
 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.3.1 and 6.3.2 or who experience AST or ALT elevations > 3 x ULN are to 
undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels. Assessments that are to be performed during this period 
include: 
 
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 


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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or 
elevated TBL: 
− Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− Obtain serum acetaminophen (paracetamol) levels 
− Obtain a more detailed history of: 
 
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents 
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
− Obtain viral serologies 
− Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
− Perform appropriate liver imaging if clinically indicated 
 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected 
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with 
an hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all 
laboratory abnormalities return to baseline or normal. The “close observation 
period” is to continue for a minimum of 4 weeks after discontinuation of all 
investigational product(s) and protocol-required therapies. 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


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Appendix  B. Sample Serious Adverse Event Report Form 
 
 
 
Clinical TrialSerious Adverse Event Report Phase 1-4 
Notify Amgen Within 24 Hours of knowledge of the event 
 
 
1.SIT E INFORMATION 
SELECT OR TYPE IN A FAX# 
Site Numb er 
Investigator 
I I I I I 
c....., 
Date of Report 
I 
Ooy  
Month 
Voar
 
Reporter 
PAone NLmb e, 
FaxNul11tber 
)  
( 
) 
2.SUBJECT INFORMATION 
Subjeet10 Ntmber 
I  Initials 
I  I  I I I I I I 
I 
 
o., 
 
Da!Bof Birth 
SO< 
Raco 
Mooth 
Year 
OF   O M 
3.SE R OUS ADVERSE EVENT ·Information in this section must also be entered on the Serious Adverse Event Summary CRF 
Provide the date the lnvestiqatorbecame aware of this Serious Adverse Event Information: Oav_ 
Month      Year 
Serious Adverse Event Diagnosis or 
"""'   
frio- 
Outcome   """'.... 
If diagnosis i'5 unknown,Bllter Signs I 
""""""' 
Qt.;.    -....·
. 
po&$1b'l!y'll'ltl lh& 
teliiedlo 
- -
r= 
may h<r•ebeen "' "'""" =  
' ·""'"' 
Syndrome 
 
Symptoms 
When Fiul Oi01gnosis is known,enter u 
Adven:eEvent 
 
 
 
1tcome. 
Date Started 
Date Ended 
"" · 
diP 
sn...    lslhefe e 
lslha"t a reas<lflaUe         ofEwnl   1IMf\IJ$ 
code   pos:sbkytlalthe 
"'"' 
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""""""""" 
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• 
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st one event per line. If event is tatat 
""")  utuctioniO 
nferthe CauseofDeath. Entry of 
Doy       "''"'"' 
v... 
Day    Moo      Year 
v 
v.    rv,. 
"' 
Death" i$ not eptabb.as this is an 
• 
 
 
 
 
 
Serious 
01Fatal 
03 Required hos pitaHzatioo 
05 Persistent cw- siificant disability /Incapacity    07 0ttler 
Criter1a:       02 Immediately life-threatening 
04 Prolonged hospital zation  
06Congenitalanomaly I birth c;tefect 
siiflcant 
mecicalhazard 
4.HOSPITALIZATION 
 
Was subject hospitalized? 0No  DYes.If yes.please complete date(s): 
I 
5.INVESTIGATIONAL PRODUCT  IP 
 
Date Admitted  
Date Discharged 
Day      Month      Year 
Day      Montf1      v ... 
Initial Start Date 
Priorto, or at li-ne of Event 
Action Taken with 
Date of Dose 
llo< O 
Route       Frequency 
Product 
01 Stillbeillg 
<tninistered 
02 Po m ntntly 
discontinued 
 
C
inacalcet 


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CONFIDENTIAL 
 
 
"Open Label 
Dav 
Month      Year 
oav     Month      Year 
03 Wilhhold 
6.RELEVANT CONCOMITANT MEDICATIONS eg,chemolherapy) 
AllyRelevant Medications? 
0 
"" 
...,, ,... 
""  - '"'
  
No.I I y,.,  Nool      y..,t 
 
No./i.... 
Medication Name(s) 
Sta rt Date 
Stop Date 
Co-suspeet       Continuing 
Treatment 
Dose 
Routo 
freq. 
' 
i 
 
 
 
 
 
FORM-015482 v7.0  Effective daft!: 01-APR-2013 
Page 1of2 
SAER Crested: 16-JUN-2014 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 79 
CONFIDENTIAL 
 
 
I 
 
Product: Cinacalcet HCI 
ProtocolNumber:  20140159 
Date: 01June 2016 
Page 77 of79 
 
 
 
 
Clinical TrialSerious Adverse Event Report Phase 1-4 
Notify Amgen Within 24 Hours of knowledge of the event 
 
1'///////////////////1  
Site Number 
Subject 10 Number 
V//////////..1: 
I 
I  I I I  I  I  I I  I  I  I I  I 
7. RELEVANT MEDICAL HISTORY  include dates alleraies and anv relevant orior theraovJ 
 
 
 
 
 
8. RELEVANT LABORATORY VALUES (include baseline values) Any Relevant laboratoryvellues? 0 No 0 Yes,If yes, please complete: 
Test 
IUnit 
D•te 
""'    """  "" 
 
 
 
 
 
 
 
 
 
9. OTHER RELEVANT TESTS (diagnostics and procedures) 
My other  Relevant tests?   0 No   0 Yes. If yes-.please complete: 
o... 
AdditionalTests 
Results 
Units 
""'""""  
Vw
 
 
 
 
10.  CASE DESCRIPTION (Provide naffative details of events listed in section 3) For each eventin section 3, wnere 
relationshpi =Yes,pfease provide rationale. 
 
 
 
 
 
 
 
Signature of Investigator or Designee 
ITitle 
Date 
 
 
 
 
 
FORM-015482 v7.0 Effective daft!: 01-APR-2013 
Page 2 of2 
SAER Crested: 16-JUN-2014 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 80 
CONFIDENTIAL 
 
 
 
Product: Cinacalcet HCI 
ProtocolNumber: 20140159 
Date:  01June 2016 
Page 78 of 79 
 
 
 
Appendix  C. Pregnancy and Lactation Notification Worksheets 
 
ANI(;Bf Pregnancy Noti fica t on Worksheet 
Fax  Completed Form to the Country-respective Safety Fax Line 
SEL ECT OR TY PE N A.FAX# 
 
 
 
study Desi gn:D lnterventional     D Observational (If Observational:D Prospective D Retrospective) 
 
2. Contact Information 
Investi gator Name   
 
 
 
Si te #   
 
Phone l  
,j  
 
Faxl  
) , 
Email  
 
Institution   
 
Address 
 
 
SubjectID #  
Subject Gender: D Female    D Mael 
Subject DOB: mm  
/ dd  
/ yyyy  
 
 
4. Amgen Product Exposure 
Amgen Product 
Dose at time of 
conception 
Frequency 
Route 
Start Date 
mm 
ldd 
fyyyy  
 
Was the Amgen product (or study drug) discontinued?  D Yes    0No 
If yes,provide product (or study drug) stop dael: mm   
/dd  
lyyyy  
 
Did the subject Withdraw from the study? D Yes    D No 
5. Pregnancy Information 
Pregnant female's LMP  
mm  
/ dd  
I yyyy  
   D Unknown 
Estimated dale of delivery  mm  
/ dd  
/ yyyy  
   D Unknown    D N/A 
If N/A,date of tenninalion (actual or planned) mm  
/ dd  
/ yyyy  
 
Has the pregnant female already delivered?    D Yes    D No    D Unknown    D N/A 
If yes. provide da e of deilivery: mm   
/ dd  
/ yyyy  
 
wastheinfant healthy? 0 Yes     0 No     0 Unknown    0 NIA 
If any Adverse Event wasexperienced by theinfant. provide brief details:  
 
 
 
Form Completed by: 
Pri nt Name: --------------- 
Title:   
 
Signature:   
 
Date:   
 
 
 
 
 
 
 
Effective Date:March 27,2011 
Page 1 of 1 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 81 
CONFIDENTIAL 
 
 
 
Product: Cinacalcet HCI 
ProtocolNumber: 20140159 
Date:  01June 2016 
Page 79 of 79 
 
 
 
Ati'GEtf Lactat on Notifi cati on Worksheet 
Fax Completed Form to the Cou,ntry-respective Safety Fax Line 
SELECT OR TYPEIN A FAXJI e
!::lnl=e=r=fa=x=n=u=m=b=er   =====::! 
 
 
Protocol/Study Number: 
study Design: D lntervenuonal     D Observational (If Observational: D Prospective  D RetrospectiVe) 
 
2. Contact Information 
Invest gator Name   
 
 
Site #   
 
Phone l  
j,  
 
Fax l  
j  
 
Email  
 
Institution  
 
 
 
 
 
 
4. Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
mm  
/dd  
Jyyyy  
 
was the Amgen product (or study drug)discontinued?  0 Yes    0No 
If yes,provide product (or study drug) stop date: mm   
/dd  
lyyyy  
 
Did tile subject Withdraw from the study? 0 Yes    D No 
 
5. Breast Feeding Information 
 
Did the mother breastfeed or provide the infant with pumpedbreast mik while actively taking an Amgen product?  D Yes    0 No 
If No,provide stop date: mm  
/dd  
tyyyy  
 
Infant date of birth:mm  
/dd  
lyyyy  
 
Infant gender: 0 Female     D Male 
Is theinfant healthy?  0 Yes    D No     D Unknown   D N/A 
 
If any Adverse Event was experiencedby the mother or theinfant,provide brief details:  
 
 
 
 
 
 
Form Completed by: 
Print Name:   
 
 
Signature:   
 
 
Ti tle:   
 
D·ate:   
 
 
 
 
 
 
Effective Date: 03 April2012, version 2. 
Page 1 of 1 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 82 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 1 of 17 
 
 
Amendment 1 
 
Protocol Title:  A MulticenterSingle-arm Extension Study to Characterize the 
Long-term Safety of Cinacalcet Hydrochloride in the Treatment of Secondary 
Hyperparathyroidism in Pediatric Subjects With Chronic Kidney Disease on 
Dialysis 
 
Amgen Protocol Number (Cinacalcet HCl) 20140159 
 
Amendment Date: 
18 December 2014 
 
Rationale: 
 
The purpose of this amendment is to incorporate language regarding the transition of 
eligible subjects from the parent study (Amgen Study 20130356) to this open label 
extension.  The amendment also addresses updates made to language regarding study 
procedures for consistency within the cinacalcet pediatric program. 
 
Minor administrative changes and clarifications have also been incorporated. 
Additions are noted in bold text. 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 83 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 2 of 17 
 
Description of Changes: 
 
Section:  Global 
 
Replace date of protocol: 
 
5 August 2014 
 
With: 
 
18 December 2014 
 
Section:  Cover Page 
 
Replace: 
PPD  
, MS 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
PPD 
 
 
 
With: 
 
PPD 
 
PRA Health Services 
 
520 Virginia Drive 
 
Fort Washington, PA 19034 
PPD 
 
 
 
Cover: 
Replace: 
<<for all other countries, insert the local toll-free Medical Information number>> 
With: 
for all other countries, please call the local toll-free Medical Information number or 
the US toll-free number (1-800-772-6346). 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 84 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 3 of 17 
 
Section:  Protocol Synopsis, Page 3 
 
Replace: 
 
 
Blood pressure, heart rate, and changes in laboratory parameters, including 
clinical chemistry and hematology 
 
With: 
 
 
Blood pressure, heart rate, and changes in laboratory parameters 
 
Section:  Protocol Synopsis, Page 3 
 
Replace: 
 
Subjects who complete the 20-week treatment period in the parent study 20130356 will 
be eligible to receive 28 weeks of treatment with cinacalcet in this extension study. 
 
With: 
 
Subjects who complete the 20-week treatment period in the parent study 20130356 will 
be eligible to receive 28 weeks of treatment with cinacalcet in this extension study, 
followed by a 4-week safety follow-up. 
 
Section:  Protocol Synopsis, Page 4 
 
Replace: 
 
Weekly monitoring with a point of care (POC) device during this study will be required for 
these subjects through the end of the treatment period, week 28. 
 
With: 
 
Weekly monitoring of ionized calcium will be required for these subjects through the end 
of the treatment period, week 28. 
 
Section:  Protocol Synopsis, Page 4 
 
Replace: 
 
Subjects from the cinacalcet group who complete the 20-week treatment period in parent 
study 20130356, will continue in the extension study on the same dose of cinacalcet 
they received at the completion of the treatment period (week 20) in the parent study. 
With: 
Subjects from the cinacalcet group who complete the 20-week treatment period in the 
parent study 20130356, will continue in the extension study on cinacalcet at the 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 85 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 4 of 17 
 
completion of the treatment period (week 20) in the parent study following the dose 
titration rules outlined in Table 1 in Section 6.2.3.1.2. 
 
Section:  Protocol Synopsis, Page 4 
 
Replace: 
 
Cinacalcet doses will be assigned by the interactive voice response/interactive web 
response (IVR/IWR) system following the titration tables in Section 6. 
 
With: 
 
Cinacalcet doses will be calculated by the site staff and confirmed by the interactive 
voice response/interactive web response (IVR/IWR) system following the titration tables 
in Section 6. 
 
Section:  Protocol Synopsis, Page 4 
 
Replace: 
 
Final dose assignment will be based on the ionized calcium.  An assessment of 
symptomatic hypocalcemia will also be assessed on the day of titration. 
 
With: 
 
Final dose assignment will be based on the ionized calcium obtained on the day of 
titration.  An assessment of symptomatic hypocalcemia will also be performed on the 
day of titration.  Additional weekly dose adjustments for safety are permitted as 
described in Section 6.2.3.1.3. 
 
Section:  Protocol Synopsis, Page 5 
 
Replace: 
 
The use of medications that may prolong the corrected QT (QTc) interval (eg, 
ondansetron, albuteron), CYP3A4 inhibitors (eg, erythromycin, clarithromycin, 
ketoconazole, itraconazole), and commercial cinacalcet during the course of the trial are 
prohibited. 
 
Serious adverse events will be collected from study day 1 through 30 days following the 
last dose of investigational product. 
 
With: 
 
The use of medications that may prolong the corrected QT (QTC) interval (eg, 
ondansetron, albuterol), CYP3A4 inhibitors (eg, erythromycin, clarithromycin, 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 86 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 5 of 17 
 
ketoconazole, itraconazole), CYP2D6 substrates (eg, flecainide, propafenone, 
metoprolol, desipramine, nortryptiline, clomipramine), and commercial cinacalcet 
during the course of the trial are prohibited while the subject is receiving 
investigational product. 
 
Serious adverse events will be collected from the date of the first dose through 
 
30 days following the last dose of investigational product. 
Section:  Glossary, Page 8 
Replace: 
 
Study Day 1 
defined as the date that the day 1 laboratory assessments are 
performed 
 
With: 
 
Study Day 1 
defined as the date that the initial dose of investigational product 
is administered 
 
Section:  2.4 Pediatric Risk Assessment, Page 15 
 
Replace: 
 
Additional risk mitigation measures implemented in this trial include: 
 
 
use of a point of care (POC) device to provide real-time calcium measurements 
 
With: 
 
Additional risk mitigation measures implemented in this trial include: 
 
 
collection of real-time ionized calcium measurements 
 
Section:  2.5 Amgen Study 20130356, Page 16 
 
Add: 
 
Subjects who are eligible for and enroll in the 20140159 extension study will do so 
at the completion of the 20-week treatment period in 20130356.  The 4-week safety 
follow-up period in 20130356 will not apply for these subjects. 
 
Section:  3.1 Study Design, Page 17 
 
Replace: 
 
All subjects will be eligible to titrate the cinacalcet dose at monthly titration visits to a 
maximum dose of 2.5 mg/kg/day, not to exceed a dose of 180 mg/day. 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 87 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 6 of 17 
 
With: 
 
All subjects will be eligible to titrate the cinacalcet dose at monthly titration visits to a 
maximum dose of 2.5 mg/kg/day based on the subject’s dry weight at day 1, not to 
exceed a dose of 180 mg/day. 
 
Section:  3.2 Number of Sites, Page 17 
 
Replace: 
 
This study will be conducted at approximately 60 sites in North America, Europe, Russia, 
Latin America, and Australia. 
 
With: 
 
This study will be conducted at approximately 50 sites in North America, Europe, Russia, 
Latin America, and Australia. 
 
Section:  4.1.1 Inclusion Criteria, Page 18 
 
Replace: 
 
104  Dialysate calcium ≥ 2.5 mEq/L at day 1 
 
With: 
 
104  Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
Section:  4.1.2 Exclusion Criteria, Page 19 
 
Replace: 
 
215  Use of grapefruit juice, herbal medications or CYP3A4 inhibitors (eg, erythromycin, 
clarithromycin, ketoconazole, itraconazole) 
 
With: 
 
215  Use of grapefruit juice, herbal medications, CYP3A4 inhibitors (eg, erythromycin, 
clarithromycin, ketoconazole, itraconazole),or CYP2D6 substrates (eg, 
flecainide, propafenone, metoprolol, desipramine, nortriptyline, 
clomipramine) 
 
Section:  5.1 Screening, Page 19 
 
Replace: 
 
The informed consent can be signed up to 1 week prior to day 1 (eg, at week 19 in 
 
20130356). 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 88 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 7 of 17 
 
With: 
 
The informed consent can be signed up to 1 week (± 3 days) prior to day 1 (eg, at week 
 
19 in 20130356). 
 
Section:  6.2.3.1 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation, Page 22 
 
Replace: 
 
If subjects from the cinacalcet arm in 20130356 are on a dose withhold at day 1, the 
iPTH and cCa restart values (iPTH ≥ 150 pg/mL and cCa ≥ 8.4 mg/dL) must be reached 
prior to resuming cinacalcet in the current extension study. 
 
With: 
 
If subjects from the cinacalcet arm in 20130356 are on a dose withhold at day 1, the 
iPTH and cCa restart values (iPTH > 100 pg/mL and cCA > 8.4 mg/dL) must be reached 
prior to resuming cinacalcet in the current extension study. 
 
Section:  6.2.3.1.1 Dosage Adjustments, Page 22 
 
Replace: 
 
The initial dose of cinacalcet and all subsequent doses will be assigned by the IVR/IWR 
 
system. 
With: 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site 
staff and confirmed by the IVR/IWR system. 
 
Section:  6.2.3.1.2 Monthly Dose Titration, Page 22 
 
Replace: 
 
Cinacalcet doses will be titrated up or down one PSD or maintained monthly by the 
IVR/IWR system using the corrected serum calcium and iPTH values obtained from the 
central laboratory the week prior to the dose titration visit, as well as assessments of 
symptoms of hypocalcemia and ionized calcium values from the POC device obtained 
on the day of the titration visit, as outlined in Table 1 below. 
 
With: 
 
Cinacalcet doses will be titrated up or down one PSD or maintained monthly and 
confirmed by the IVR/IWR system using the corrected serum calcium and iPTH values 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 89 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 8 of 17 
 
obtained from the central laboratory the week prior to the dose titration visit, as well as 
assessments of symptoms of hypocalcemia and ionized calcium values obtained on the 
day of the titration visit, as outlined in Table 1 below. 
 
Section:  6.2.3.1.2 Monthly Dose Titration, Page 23 
 
Replace: 
 
If the central laboratory corrected calcium value is < 8.0 mg/dL at any time during the 
trial, the dose of cinacalcet is to be withheld until the central laboratory corrected calcium 
value is > 8.4 mg/dL, at which time the dose may be restarted at one PSD below the 
previous dose received, if the iPTH is > 100 pg/mL, the ionized calcium using the POC 
device is > 1.05 mmol/L, and the subject has no symptoms of hypocalcemia. 
 
With: 
 
If the central laboratory corrected calcium value is < 8.0 mg/dL at any time during the 
trial, the dose of cinacalcet is to be withheld until the central laboratory corrected calcium 
value is > 8.4 mg/dL, at which time the dose may be restarted at one PSD below the 
previous dose received, provided that the iPTH is > 100 pg/mL, the ionized is 
> 1.05 mmol/L, and the subject has no symptoms of hypocalcemia. 
Section:  6.2.3.1.3 Dose Adjustments for Safety, Page 23 
Replace: 
 
Administration of cinacalcet may be withheld at any time during the study based on the 
ionized calcium obtained using the POC device, local laboratory total corrected calcium 
values, and/or if the subject has signs/symptoms of hypocalcemia.  The dose may be 
decreased based on the ionized calcium obtained using the POC device, as described in 
Table 2 below. 
 
With: 
 
Administration of cinacalcet may be withheld at any time during the study based on the 
ionized calcium, local laboratory total calcium values, and/or if the subject has 
signs/symptoms of hypocalcemia.  The dose may be decreased based on the ionized 
calcium, as described in Table 2 below. 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 90 
CONFIDENTIAL 
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 9 of 17 
 
Section:  6.2.3.1.3 Dose Adjustments for Safety, Page 24 
 
Replace: 
 
If at any time the subject has a local total corrected calcium value of < 8.0 mg/dL, the 
dose of investigational product must be withheld until an ionized calcium of 
> 1.05 mmol/L or a central lab corrected calcium of > 8.4 mg/dL are obtained, at which 
time the dose may be resumed at one PSD below the previous dose. 
 
With: 
 
If at any time the subject has a local total calcium value of < 8.0 mg/dL, the dose of 
investigational product must  be withheld until an ionized calcium of > 1.05 mmol/L or a 
central lab corrected calcium of > 8.4 mg/dL are obtained, at which time the dose may 
be resumed at one PSD below the previous dose. 
 
Section:  6.2.3.1.3 Dose Adjustments for Safety, Page 24 
 
Replace: 
 
In addition, if subjects require temporaroy administration of concomitant medications that 
are known to prolong the QTc interval or are CYP 3A4 inhibitors, the administration of 
cinacalcet is to be withheld.  The dose may be restarted when an ionized calcium of 
> 1.05 mmol/L or a central lab corrected calcium of > 8.4 mg/dL are obtained, at which 
time the dose may be resumed either at one PSD below the previous dose or at the 
initial dose if the criteria in Section 6.2.3.1.4 are met. 
 
With: 
 
In addition, if subjects require temporaroy administration of concomitant medications that 
are known to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 
substrates, the administration of cinacalcet is to be withheld.  The dose may be 
restarted when treatment with the concomitant medication has completed and an 
ionized calcium of > 1.05 mmol/L or a central lab corrected calcium of > 8.4 mg/dL are 
obtained at which time the dose may be resumed either at one PSD below the previous 
dose or at the initial dose if the criteria in Section 6.2.3.1.4 are met. 
 
Section:  6.4 Concomitant Therapy, Page 28 
 
Replace: 
 
Dialysate calcium levels should not be adjusted during the course of the trial, remaining 
at ≥ 2.5 mEq/L. 


Product: Cinacalcet hydrochloride 
Clinical Study Report: 20140159 
Date:  21August 2017 
Page 91 
CONFIDENTIAL
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 10 of 17 
 
With: 
 
Dialysate calcium concentrations should not be adjusted during the course of the trial, 
remaining at ≥ 2.5 mEq/L. 
 
Section:  6.6 Excluded Treatments and/or Procedures During Study Period, Page 29 
 
Replace: 
 
In addition, the use of grapefruit juice, herbal medications, or CYP3A4 inhibitors (eg, 
erythromycin, clarithromycin, ketoconazole, itraconazole) are excluded during the study. 
 
With: 
 
In addition, the use of grapefruit juice, herbal medications, CYP3A4 inhibitors (eg, 
erythromycin, clarithromycin, ketoconazole, itraconazole), or CYP2D6 substrates (eg, 
flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine) are 
excluded during the study. 
 
Section:  Schedule of Assessments, Table 3, Page 30 


CONFIDENTIAL 
 
Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date: 21 August  2017 
Page 91 
 
 
 
 
 
 
Product:  Cinacalcet HCl 
Protocol Number:  20140159 
Date:  18 December 2014 
Page 11 of 17 
 
Replace: 
 
Screening 
Day 1 
Treatment Period (Week) 
FU Period 
Week -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 
27 
EoIP 
W28 
ET/EOS 
W32 
GENERAL & SAFETY ASSESSMENTS 
Height, Tanner Stage 
X
2
 
X 
Dry Weight 
X
2
 
X 
Dialysate Ca 
X 
LABORATORY ASSESSMENTS 
Ionized Ca 
X
2
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests 
X 
X 
X 
With: 
 
Screening 
Day 1 
Treatment Period (Week) 
FU Period 
Week -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 
27 
EoIP 
W28 
ET/EOS 
W32 
GENERAL & SAFETY ASSESSMENTS 
Height, Tanner Stage 
X
2
 
X 
Dry Weight 
X
2
 
X 
Dialysate Ca 
Concentration 
X 
LABORATORY ASSESSMENTS 
Ionized Ca 
X
2
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests 
X 
X 
X 
X 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 92 
CONFIDENTIAL
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 12 of 17 
 
Section:  7.2 General Study Procedures, Page 31 
 
Replace: 
 
The duplicate study assessments from the end of investigational product (EOIP) visit in 
the parent study, 20130356, and from the day 1 visit can be collected once for both 
studies as described in Section 7.2.2. 
 
With: 
 
The duplicate study assessments from the end of the investigation product (EOIP) visit 
in the parent study, 20130356, and from the day 1 visit will be collected once for both 
studies as described in Section 7.2.2. 
 
Section:  7.2.1 Screening and Enrollment, Page 31 
 
Add: 
 
 
Registration of the subject in the IVR/IWR system 
 
Section:  7.2.2 Day 1, Page 32 
 
Replace: 
 
 
Laboratory Assessments including the following: 
o Ionized calcium using a POC device 
o Serum calcium, serum albumin, and calculation of corrected calcium, 
phosphorus 
 
With: 
 
 
Ionized calcium 
 
Central laboratory assessments including the following 
o Serum calcium, serum albumin, and calculation of corrected calcium, 
phosphorus 
 
Section:  7.2.2 Day 1, Page 32 
 
Replace: 
 
Following completion of the day 1 visit assessments, eligibility, and enrollment will be 
entered into the IVR/IWR system, as applicable. 
 
With: 
 
Following completion of the day 1 visit assessments, eligibility, dry weight, and 
enrollment will be entered in the IVR/IWR system, as applicable. 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 93 
CONFIDENTIAL
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 13 of 17 
 
Section:  7.2.3 Treatment, Page 33 
 
Replace: 
 
Laboratory Assessments including the following 
 
 
Laboratory Assessments including the following: 
o Serum calcium, serum albumin, and calculation of corrected calcium, 
phosphorous 
o iPTH 
o LFT (Weeks 11 & 23) 
o Ionized calcium using the POC device 
Ionized calcium will be collected prior to IP dispensing. 
With: 
 
Ionized calcium 
 
Central laboratory assessments including the following: 
o Serum calcium, serum albumin, and calculation of corrected calcium, 
phosphorous 
o iPTH 
o LFT (Weeks 11 & 23) 
 
Section:  7.2.4 End of Investigational Product, Page 33 
 
Remove: 
 
 
Dry weight, Tanner stage 
 
Section:  7.2.4 End of Investigational Product, Page 33 
 
Replace: 
 
 
Laboratory assessments including the following: 
With: 
 
Ionized calcium 
 
Central laboratory assessments including the following: 
Section:  7.2.6 End of Study, Page 34 
Add: 
 
Dry weight 
 
Height/Tanner stage 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 94 
CONFIDENTIAL
 
 
 
 
Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 18 December 2014 
Page 14 of 17 
 
Section:  7.2.6  End of Study, Page 34 
 
Replace: 
 
 
Laboratory assessments including the following: 
With: 
 
 
Central laboratory assessments including the following: 
 
Section:  7.3.4 Physical Exam, Height, Tanner Stage, Dry Weight, Page 35 
 
Replace: 
 
Height will be collected on day 1 and at the EOIP visit… 
 
Tanner stage will be determined on day 1 and at the EOIP visit… 
 
The subject’s dry weight should be collected at day 1 and at the end of investigational 
product visit… 
 
With: 
 
Height will be collected on day 1 and at the EOS visit… 
Tanner stage will be determined on day 1 and the EOS visit… 
The subject’s dry weight should be collected at day 1 and at the EOS visit… 
Section:  7.3.9 Ionized Calcium, Page 37 
Replace: 
 
All ionized calcium values will be collected as specified in the Schedule of Assessments 
for identification of potential hypocalcemia.  Ionized calcium values will be obtained 
using a POC device provided by Amgen.  All measurements should occur on the day of 
the study visit prior to the administration of cinacalcet.  The blood sample to be used for 
ionized calcium measurements will be obtained by venipuncture.  The utilization of blood 
obtained by a finger or heel stick for ionized calcium evaluations will not be permitted. 
 
With: 
 
All ionized calcium values will be collected as specified in the Schedule of Assessments 
for identification of potential hypocalcemia.  Ionized calcium values will be obtained 
either per routinepractice at the clinical site or using a point of care device provided 
by Amgen.  The clinical site will document the method that is being used to obtain 
the ionized calcium for each subject enrolled at the site and ensure that this 


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remains consistent for the duration of the trial.  All measurements should occur on 
the day of the study visit prior to the administration of cinacalcet.  For sites that use the 
point of care device provided by Amgen, refer to the device manual provided for 
further information. 
 
Section:  7.3.10 Adverse Events, Page 38 
 
Replace: 
 
Serious adverse events that occur in a subject from study day 1 through 30 days after 
the last dose of investigational product will be recorded in the adverse event eCRF.  All 
adverse events that occur after enrollment through 30 days after the last dose of 
investigational product will be recorded in the adverse event eCRF. 
 
With: 
 
Serious adverse events that occur in a subject from the date of the first dose through 
 
30 days after the last dose of investigational product will be recorded in the adverse 
events eCRF.  All adverse events that occur from the date of the first dose through 
30 days after the last dose of investigational product will be recorded in the adverse 
event eCRF. 
 
Section:  7.3.12 Home Healthcare, Page 39 
 
Replace: 
 
These subjects will be required to be seen in the clinic every 2 weeks, including the 
monthly dosing titration visit, at a minimum during the trial. 
 
With: 
 
These subjects will be required to be seen in the clinic every 2 weeks, including the 
 
week prior to the monthly dosing titration visit, at a minimum during the trial. 
 
Section:  9.2.1 Reporting Procedures for Adverse events that do not meet Serious 
 
Criteria, Page 44 
 
Replace: 
 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after day 1 and up to 30 days after the 
last dose of IP, are reported using the applicable CRF (eg, Adverse Event Summary). 
 
With: 


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The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from the date of the first dose and up 
to 30 days after the last dose of IP, are reported using the applicable eCRF (eg, Adverse 
Event Summary). 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events, Page 45 
 
Replace: 
 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after day 1 through 30 days after 
the last day of the dosing interval of investigational product or end of study visit 
(whichever is later) are recorded in the subject’s medical record and are submitted to 
Amgen. 
 
With: 
 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur from the date of the first dose 
through 30 days after the last day of the dosing interval of investigational product or end 
of study visit (whichever is later) are recorded in the subject’s medical record and are 
submitted to Amgen. 
 
Section:  10.2 Sample Size Considerations, Page 47 
 
Replace: 
 
The sample size of 48 for the parent study will result in a maximum of 48 subjects. 
With: 
The sample size of approximately 48 for the parent study will result in a maximum of 
 
48 subjects. 
 
Section:  10.4.2 Primary Endpoint, Page 48 
 
Replace: 
 
The primary endpoint is subject incidence of events of interest (EOI; eg, symptomatic 
hypocalcemia, seizure, hypotension, worsening heart failure, hypersensitivity reactions, 
ventricular arrhythmia, fracture, pancreatitis, drug-related hepatic disorders, nervous 
system disorders, and infection. 


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With: 
 
The primary endpoint is subject incidence of events of interest (EOI; hypocalcemia, 
convulsions, hypotension, worsening of heart failure, hypersensitivity, ischemic heart 
disease, QT prolongation/ventricular tachyarrhytmias, fracture, acute pancreatitis, 
drug-related hepatic disorders, nervous system disorders [excluding seizures], 
neoplastic events, and infection). 
 
Section:  10.4.4 Safety Endpoints, Page 49 
 
Replace: 
 
All treatment-emergent adverse events occurring during the study will be coded using 
the latest version of the MedDRA dictionary and the subject incidence will be tabulated 
by system organ class and preferred term in descending order of frequency by parent 
study treatment group. 
 
With: 
 
All treatment-emergent adverse events occurring during the study will be coded using 
the latest version of the MedDRA dictionary.  The subject incidence of all 
treatment-emergent adverse events, serious adverse events, treatment-related 
adverse events, and serious treatment-related adverse events will be tabulated by 
system organ class and preferred term in descending order of frequency by parent study 
treatment group. 
 
Section:  10.4.4 Safety Endpoints, Page 49 
 
Replace: 
 
Descriptive statistics for values, changes and percent changes of laboratory parameters 
from first dose of IP date will be presented by parent study treatment group at each 
measurement time point during the study. 
 
With: 
 
Descriptive statistics for values, changes and percent changes of selected laboratory 
parameters from first dose of IP date will be presented by parent study treatment group 
at each measurement time point during the study. 


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Page 1 of 50 
 
 
 
Amendment 2 
 
A Multicenter Single-arm Extension Study to Characterize the Long-term Safety of 
Cinacalcet Hydrochloride in the Treatment of Secondary Hyperparathyroidism in 
Pediatric Subjects With Chronic Kidney Disease on Dialysis 
 
 
Cinacalcet HCl 
 
Amgen Protocol Number 20140159 
 
 
 
Amendment Date: 
22 July 2015 
 
 
Rationale: 
 
• 
Added inclusion of eligible subjects from 20110100 into this extension study. 
 
• 
Added investigational product (IP) holding for other adverse events that warrant IP 
dose withhold.  Original protocol only specified hold for corrected calcium (cCa), 
ionized calcium (iCa), intact parathyroid hormone (iPTH), and symptomatic 
hypocalcemia. 
• 
Made restart criteria consistent for all IP holds. 
 
• 
Revised the Dose Adjustments section for clarity. 
 
• 
Clarified the iCa value on Day 1 must be ≥ 1.05 mmol/L prior to initiation of treatment 
for all subjects enrolling from 20120356 study and only subjects who are ≥ 2 years of 
age in Study 20110100.  The iCa value on Day 1 for subjects who are < 2 years of 
age enrolling from Study 20110100 must be ≥ 1.13 mmol/L. 
• 
Updated Key Contact from PPD  
to PPD  
 
 
• 
Removed reference to serious adverse events being reported via the electronic case 
report form (eCRF).  For this open-label extension study, serious adverse events are 
reported via a paper form. 
• 
Clarified eligibility for the 20140159 study for those subjects who turn 18 years of age 
while participating in the 20130356 study. 
• 
Revised the wording to indicate that standard of care therapy that is commercially 
available will not usually be provided or reimbursed by Amgen (except if required by 
local regulation) as these will need to be provided to sites in Russia. 
• 
Updated study design and treatment schema to be consistent with the other changes 
in the protocol. 


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Description of Changes: 
 
Section:  Global 
 
Replace: 
 
18 December 2014 
 
With: 
 
22 July 2015 
 
 
 
Section:  Title Page 
 
Add: 
 
Amendment 2: 
22 July 2015 
 
 
 
Section:  Title Page 
Key Sponsor Contact 
Replace: 
PPD  
 
PRA Health Services 
520 Virginia Drive 
Fort Washington, PA 19034 
PPD 
 
 
 
With: 
PPD 
 
Amgen Limited 
1 Sanderson Road (Uxbridge Business Park), 
Uxbridge, Middlesex, United Kingdom, UB8 1DH 
PPD 


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Section:  Synopsis, Study Design 
 
Paragraph 1 
 
Replace: 
 
This is a phase 3, 32-week multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 
Eligible subjects will complete the 20-week treatment period in the parent 
Study 20130356 prior to enrollment in this trial. 
With: 
This is a phase 3, 32-week multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 
Subjects will remain on cinacalcet treatment for 28 weeks after enrollment or until 
the time of renal transplant or parathyroidectomy, whichever occurs first.  The 
treatment period is followed by a 4-week safety follow-up period. 
 
 
 
Section:  Synopsis, Sample Size 
 
Replace: 
 
Up to 48 subjects may be enrolled 
 
With: 
 
Up to 78 subjects may be enrolled 
 
 
 
Section:  Synopsis, Summary of Subject Eligibility Criteria 
 
Replace: 
 
Subjects who complete the 20-week treatment period in the parent Study 20130356 will 
be eligible to receive 28 weeks of treatment with cinacalcet in this extension study, 
followed by a 4-week safety follow-up.  Subjects must also meet the inclusion and 
exclusion criteria for this extension study in order to be eligible.  Subjects must provide 
written informed consent (parents or guardian) and assent, where appropriate, according 
to local regulations specific to the procedures in this study.  Subjects enrolled in the 
standard of care arm of Study 20130356 will be eligible for the extension study if the iPTH 
≥ 300 pg/mL and the cCa ≥ 8.8 mg/mL at the week 19 visit.  Eligible subjects from 


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the cinacalcet arm in Study 20130356 will continue cinacalcet treatment following the 
dosing rules described in Section 6.2.3.  Subjects will be excluded from this study if they 
have adverse events continuing from Study 20130356 that are considered related to 
investigational product (IP) and are ≥ CTCAE grade 3 and/or considered clinically 
significant by the investigator.  For a full list of eligibility criteria, please refer to Section 
4.1.1 through Section 4.1.2. 
With: 
Subjects who complete the 20-week treatment period in Study 20130356 or Week 26 
 
End of Study visit in Study 20110100 will be eligible to receive 28 weeks of treatment 
with cinacalcet in this extension study, followed by a 4-week safety follow-up.  Subjects 
must also meet the inclusion and exclusion criteria for this extension study in order to be 
eligible.  Subjects must provide written informed consent (parents or guardian) and 
assent, where appropriate, according to local regulations specific to the procedures in 
this study. 
 
• 
Subjects enrolled in the standard of care arm of Study 20130356 will be eligible 
for the extension study if the iPTH ≥ 300 pg/mL and the cCa ≥ 8.8 mg/mL at the 
week 19 visit.  Eligible subjects from the cinacalcet arm in Study 20130356 will 
continue cinacalcet treatment following the dosing rules described in 
Section 6.2.3. 
 
• 
Eligible subjects from 20110100 study will restart cinacalcet treatment as 
described in Section 6.2.3.1. 
 
Subjects will be excluded from this study if they have adverse events continuing from 
Study 20130356 or 20110100 study that are considered related to investigational 
product (IP) and are ≥ CTCAE grade 3 and/or considered clinically significant by the 
investigator.  For a full list of eligibility criteria, please refer to Section 4.1.1 through 
Section 4.1.2. 
 
 
 
Section:  Synopsis, Amgen Investigational Product Dosage and Administration 
 
Paragraph 3 
 
Replace: 
 
The protocol-specified doses (PSD) for use in this study are: 2.5, 5, 10, 15, 30, 60, 90, 
 
120 and 180 mg. 


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With: 
 
The protocol-specified doses (PSD) for use in this study are: 1, 2.5, 5, 7.5, 10, 15, 30, 
 
60, 90, 120 and 180 mg. 
 
 
 
Section:  Synopsis, Procedures 
 
Paragraphs 1, 2, 3, and 4 
 
Replace: 
 
Informed consent, and assent where applicable, for this study should be presented during 
the parent Study 20130356.  The informed consent, including assent as appropriate, will 
be obtained prior to execution of any study procedures for this extension study.  The 
study assessments from the parent study End of Investigational Product (EOIP) visit may 
be collapsed with the study assessments for the baseline visit in the current study to 
minimize duplicate study assessments.  The subject visits and assessments for this study 
will occur from baseline through to the end of study. Assessments during this study will 
include: 
 
• 
Collection of blood samples for the evaluation of blood chemistry, hematology, 
calcium, iPTH, and bone biomarkers 
• 
Physical assessments including vital signs (ie, blood pressure, heart rate) 
 
• 
12-lead electrocardiogram (ECG) at baseline and week 32 (if the subject ends 
the study prior to week 32, the 12-lead ECG will be performed at the last study 
visit) 
• 
Assessments for symptoms of hypocalcemia 
 
• 
Recording of adverse events, concomitant medications, and IP compliance 
 
Subjects who complete the 20-week treatment period in Study 20130356 will be eligible 
to receive cinacalcet treatment in the current study.  After confirming eligibility, subjects 
in the 20130356 Standard of Care (SOC) group will receive the initial dose of cinacalcet 
based on the subject’s dry weight at baseline, 0.20 mg/kg/day, rounded down to the 
nearest PSD.  Subjects from the 20130356 SOC group will follow the same cinacalcet 
titration schedule as subjects who received cinacalcet in the parent Study 20130356. 
Weekly monitoring of ionized calcium will be required for these subjects through the end 
of the treatment period, week 28. 
 
Subjects from the cinacalcet group who complete the 20-week treatment period in parent 
 
Study 20130356, will continue in the extension study on cinacalcet at the completion of 


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the treatment period (week 20) in the parent study following the dose titration rules 
outlined in Table 1 in Section 6.2.3.1.2.  Subjects in this group will be eligible to receive 
dose titrations during the extension study if the maximum dose of 2.5 mg/kg has not 
been reached and they meet the titration criteria defined in Section 6. 
 
Cinacalcet doses will be calculated by the site staff and confirmed by the interactive voice 
response/interactive web response (IVR/IWR) system following the titration tables in 
Section 6.  The titration tables are based on cCa and iPTH values from the central 
laboratory collected one week before dose titration.  Final dose assignment will be based 
on the ionized calcium obtained on the day of titration.  An assessment of symptomatic 
hypocalcemia will also be performed on the day of titration.  Additional weekly dose 
adjustments for safety are permitted as described in Section 6.2.3.1.3.  The maximum 
dose assigned for all subjects will be 2.5 mg/kg/day (based on dry weight at day 1) not to 
exceed a dose of 180 mg/day for any subject. 
 
With: 
 
Informed consent, and assent where applicable, for this study should be presented during 
the Studies 20130356 or 20110100.  The informed consent, including assent as 
appropriate, will be obtained prior to execution of any study procedures for this extension 
study.  Where the Screening and Day 1 assessments for Study 20140159 overlap 
with visits in the 20130356 or 20110100 studies, these will be performed once at 
the site and applied to both study visits to minimize duplicate study assessments, eg, 
20130356 week 19 and 20140159 Screening.  The subject visits and assessments for 
this study will occur from baseline through to the end of study.  Assessments during this 
study will include: 
 
• 
Collection of blood samples for the evaluation of blood chemistry, hematology, 
calcium, iPTH, and bone biomarkers 
• 
Physical assessments including vital signs (ie, blood pressure, heart rate) 
 
• 
12-lead electrocardiogram (ECG) at baseline and week 32 (if the subject ends 
the study prior to week 32, the 12-lead ECG will be performed at the last study 
visit) 
• 
Assessments for symptoms of hypocalcemia 
 
• 
Recording of adverse events, concomitant medications, and IP compliance 
 
Subjects from 20130356: Subjects who complete the 20-week treatment period in study 
 
20130356 will be eligible to receive cinacalcet treatment in the current study.  After 
confirming eligibility, subjects in the 20130356 Standard of Care (SOC) group will 


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receive the initial dose of cinacalcet based on the subject’s dry weight at baseline, 
 
0.20 mg/kg/day, rounded down to the nearest PSD.  Subjects from the 20130356 SOC 
group will follow the same cinacalcet titration schedule as subjects who received 
cinacalcet in study 20130356.   Subjects will continue in the extension study on 
cinacalcet at the completion of the treatment period (week 20) in 20130356 study 
following the dose adjustments outlined in Section 6.2.3.1.1.1.  Subjects in this group 
will be eligible to receive dose titrations during the extension study if the maximum dose 
of 2.5 mg/kg has not been reached and they meet the titration criteria defined in 
Section 6. 
 
Subjects from 20110100: Subjects who complete the Week 26 End of Study visit 
will be eligible to receive cinacalcet treatment in the current study.  After 
confirming eligibility, subjects will receive the initial dose of cinacalcet based on 
the subject’s dry weight at time of enrollment to 20140159 and age at time of 
enrollment to 20110100, 0.20 mg/kg/day, rounded down to the nearest PSD. 
Subjects will follow the dose adjustments outlined in Section 6.2.3.1.1.1.  Subjects 
in this group will be eligible to receive dose titrations during the extension study if 
the maximum dose of 2.5 mg/kg has not been reached and they meet the titration 
criteria defined in Section 6. 
 
Weekly monitoring of ionized calcium will be required for all subjects through the 
end of the treatment period, week 28. 
 
Cinacalcet doses will be calculated by the site staff and confirmed by the interactive voice 
response/interactive web response (IVR/IWR) system following the titration tables in 
Section 6.  The titration tables are based on cCa and iPTH values from the central 
laboratory collected one week before dose titration.  Final dose assignment will be based 
on the ionized calcium obtained on the day of titration.  An assessment of symptomatic 
hypocalcemia will also be performed on the day of titration.  Additional weekly dose 
adjustments for safety are permitted as described in Section 6.2.3.1.1.1.  The maximum 
dose assigned for all subjects will be 2.5 mg/kg/day (based on dry weight at day 1) not to 
exceed a dose of 180 mg/day for subjects from 20130356 and 60 mg/day for 
subjects from 20110100. 


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Section:  Synopsis, Statistical Considerations 
 
Paragraph 2 
 
Replace: 
 
For categorical variables, the number and percentage of subjects in each category will 
be reported.  Descriptive statistics will be used to summarize data for continuous 
variables (including n, mean, standard deviation (SD) or standard error (SE), median, 
25th  (Q1) and 75th  (Q3) percentiles, minimum and maximum values, where applicable). 
 
With: 
 
For categorical variables, the number and percentage of subjects in each category will 
be reported.  Descriptive statistics will be used to summarize data for continuous 
variables (including n, mean, standard deviation (SD) or standard error (SE), median, 
25th  (Q1) and 75th  (Q3) percentiles, minimum and maximum values, where applicable). 
 
All summaries will be provided by study treatment group: Study 20130356 (SOC, 
SOC + cinacalcet, overall) and Study 20110100. 
 
 
 
Section:  Study Design and Treatment Schema 
 
Updated study design and treatment schema 
 
 
 
Section:  2.4 Pediatric Risk Assessment 
 
Paragraph 2 
 
Replace: 
 
Additional risk mitigation measures implemented in this trial include: 
 
• 
collection of real-time ionized calcium measurements, 
 
• 
weekly monitoring of calcium, 
 
• 
incorporation of local laboratory total calcium values into the dosing schema, 
 
• 
subject investigational product (IP) compliance measures, 
 
• 
dispensing limited quantities of IP to minimize the potential for overdosing 
 
• 
addition of exclusionary electrocardiogram (ECG) criteria 
 
A dosing strategy, using a weight-based starting dose of ≤ 0.2 mg/kg in pediatric 
subjects, which is approximately 50% below the adult starting dose, will be employed in 


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this study.  The dose of cinacalcet will be titrated based on iPTH, corrected calcium 
levels, ionized calcium, and subject safety information.  The maximum dose in this study 
will be 2.5 mg/kg/day based on day 1 dry weight, not to exceed a dose of 180 mg/day for 
any subject. 
 
With: 
 
Additional risk mitigation measures implemented in this trial include: 
 
• 
collection of real-time ionized calcium measurements, 
 
• 
weekly monitoring of calcium, 
 
• 
incorporation of local laboratory total calcium values into the dosing schema, 
 
• 
subject investigational product (IP) compliance measures, 
 
• 
dispensing limited quantities of IP to minimize the potential for overdosing 
 
• 
addition of exclusionary electrocardiogram (ECG) criteria 
 
A dosing strategy, using a weight-based starting dose of ≤ 0.2 mg/kg in pediatric 
subjects, which is approximately 50% below the adult starting dose, will be employed in 
this study.  The dose of cinacalcet will be titrated based on iPTH, corrected calcium 
(cCa) levels, ionized calcium, and subject safety information.  The maximum dose in this 
study will be 2.5 mg/kg/day based on day 1 dry weight, not to exceed a dose of 
 
• 
180 mg/day for subjects from 20130356 
 
• 
60 mg/day for subjects from 20110100. 
 
 
 
Section:  2.4 Pediatric Risk Assessment 
 
Paragraph 3 
 
Replace: 
 
Serum calcium will be monitored throughout the study.  In the event a subject 
experiences protocol-defined hypocalcemia or an adverse event deemed related to IP, 
the dose of cinacalcet will be reduced or discontinued as appropriate.  Vitamin D sterols, 
calcium supplementation and/or calcium-based phosphate binders can be used to raise 
serum calcium levels and should be administered as appropriate per individual clinic 
practice.  Training and informational tools will be provided to investigators for 
dissemination to care givers and subjects regarding the symptoms and risks of 
hypocalcemia. 


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With: 
 
Serum calcium will be monitored throughout the study.  In the event a subject 
experiences protocol-defined hypocalcemia, an adverse event deemed related to IP or 
other adverse events that warrants IP dose withhold, the dose of cinacalcet will be 
reduced or discontinued as appropriate.  Vitamin D sterols, calcium supplementation 
and/or calcium-based phosphate binders can be used to raise serum calcium levels and 
should be administered as appropriate per individual clinic practice.  Training and 
informational tools will be provided to investigators for dissemination to care givers and 
subjects regarding the symptoms and risks of hypocalcemia. 
 
 
 
Section:  2.5 Studies Eligible to Roll-over to 20140159 
 
Heading 
 
Add: 
 
2.5 Studies Eligible to Roll-Over to 20140159 
 
 
 
Section:  2.5.1 Amgen Study 20130356 
 
Paragraph 1, sentence 1 and 2 
 
Replace: 
 
Amgen Study 20130356 (parent study) is a phase 3 randomized, multicenter, open- 
label, controlled study.  In Study 20130356, cinacalcet is being evaluated in pediatric 
subjects between the ages of 6 and < 18 years, with SHPT and CKD receiving either 
hemodialysis or peritoneal dialysis. 
 
With: 
 
Amgen Study 20130356 is a phase 3 randomized, multicenter, open-label, controlled 
study.  In Study 20130356, cinacalcet is being evaluated in pediatric subjects enrolled 
between the ages of 6 and < 18 years, with SHPT and CKD receiving either 
hemodialysis or peritoneal dialysis. 


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Section:  2.5.2 Amgen Study 20110100 
 
Heading 
 
Add: 
 
2.5.2 Amgen Study 20110100 
 
 
 
Section:  2.5.2 Amgen Study 20110100 
 
Paragraph 1 
 
Add: 
 
Amgen Study 20110100 is a phase 2, multicenter, open-label, single-arm study.  In 
Study 20110100 cinacalcet is being evaluated in pediatric subjects enrolled 
between the ages of 28 days and < 6 years, with SHPT and CKD receiving either 
hemodialysis or peritoneal dialysis.  The expected treatment period in 20110100 is 
24 weeks of daily oral administration of cinacalcet in addition to SOC with a 
 
2-week safety follow-up period.  Subjects who are eligible for and enroll in the 
 
20140159 extension study will do so at the completion of the Week 26 End of 
 
Study visit. 
 
 
 
Section:  2.6 Rationale 
 
Paragraph 1 
 
Replace: 
 
Cinacalcet has been shown to be safe and efficacious in treating adult CKD patients with 
SHPT by controlling iPTH, calcium, and phosphorus.  The current study is an extension 
of Amgen Study 20130356 designed to assess the long-term safety and tolerability of 
cinacalcet in pediatric CKD subjects. 
 
With: 
 
Cinacalcet has been shown to be safe and efficacious in treating adult CKD patients with 
SHPT by controlling iPTH, calcium, and phosphorus.  The current study is an extension 
of Amgen Studies 20130356 and 20110100 designed to assess the long-term safety 
and tolerability of cinacalcet in pediatric CKD subjects. 


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Section:  3.1 Study Design 
 
Section was reorganized to accommodate addition of heading for Section 3.1.1. 
 
 
 
Section:  3.1 Study Design 
 
Replace: 
 
This is a phase 3, 32-week, multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 
Eligible subjects will complete the 20-week treatment period in study 20130356 and 
either continue or start cinacalcet treatment in this study.  Eligible subjects will not 
complete the safety follow-up period in study 20130356, beginning the extension study 
at the week 20 end of investigational product (EOIP) study visit in the parent study. 
Week 20 in study 20130356 and day 1 in this study will be the same visit.  Eligible 
subjects will complete day 1 assessments (Section 7.1) and confirm eligibility in IVRS 
prior to dispensing IP on day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm will begin 
cinacalcet treatment on day 1 if their iPTH is ≥ 300 pg/mL and cCa is ≥ 8.8 mg/dL at 
week 19 of study 20130356.  Eligible subjects from the cinacalcet arm in 20130356 will 
continue cinacalcet treatment on day 1 if their iPTH is ≥ 150 pg/mL and cCa is 
≥ 8.4 mg/dL at week 19 of study 20130356.  Cinacalcet dosing will follow the dose 
titration, dose withhold, and restarting rules defined in Section 6.2.3. 
 
Subjects will remain on cinacalcet treatment for 28 weeks after enrollment or until the 
time of renal transplant, whichever occurs first.  The treatment period is followed by a 
4 week safety follow-up period.  All subjects will be eligible to titrate the cinacalcet dose 
at monthly titration visits to a maximum dose of 2.5 mg/kg/day, not to exceed a dose of 
180 mg/day. 
 
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. 
With: 
This is a phase 3, 32-week, multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 


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Subjects will remain on cinacalcet treatment for 28 weeks after enrollment or until the 
time of renal transplant or parathyroidectomy, whichever occurs first.  The treatment 
period is followed by a 4-week safety follow-up period. 
 
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. 
 
3.1.1    Subjects from Study 20130356 
 
Eligible subjects will complete the 20-week treatment period in study 20130356 and 
either continue or start cinacalcet treatment in this study.  Eligible subjects will not 
complete the safety follow-up period in Study 20130356, beginning the extension study 
at the week 20 end of investigational product (EOIP) study visit.  Week 20 in study 
20130356 and day 1 in Study 20140159 will be the same visit.  Eligible subjects will 
complete 20140159 day 1 assessments (Section 7.1) and confirm eligibility in IVRS prior 
to dispensing IP on day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm in Study 
 
20130356 will begin cinacalcet treatment on day 1 in Study 20140159 if their iPTH is ≥ 
 
300 pg/mL and cCa is ≥ 8.8 mg/dL at week 19 of study 20130356.  Eligible subjects from 
 
the cinacalcet arm in 20130356 will continue cinacalcet treatment on day 1 if their iPTH 
 
is ≥ 150 pg/mL and cCa is ≥ 8.4 mg/dL at week 19 of study 20130356.  Cinacalcet 
 
dosing will follow the dose titration, dose withhold, and restarting rules defined in Section 
 
6.2.3. 
 
All subjects from 20130356 will be eligible to titrate the cinacalcet dose at monthly 
titration visits to a maximum dose of 2.5 mg/kg/day based on the subject’s dry weight at 
day 1, not to exceed a dose of 180 mg/day. 
 
 
 
Section:  3.1.2 Subjects From Study 20110100 
 
Heading 
 
Add: 
 
3.1.2 Subjects from Study 20110100 


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Section:  3.1.2 Subjects From Study 20110100 
 
Add: 
 
Eligible subjects will complete the Week 26 End of Study visit for Study 20110100 
and restart cinacalcet treatment in this study on Day 1.  Eligible subjects will be 
screened during the safety follow-up period in Study 20110100, they will be 
required to have their 20140159 Day 1 visit and their 20110100 End of Study visit 
at the same time point.  Week 26 in Study 20110100 and day 1 in this study will be 
the same visit.  Subjects will complete day 1 assessments (Section 7.1) and 
confirm eligibility in IVRS prior to dispensing IP on day 1. 
 
Eligible subjects from 20110100 will restart cinacalcet treatment based on their 
dry weight at the time of enrollment in the 20140159 study and age at the time of 
enrollment in the 20110100 study. 
 
Cinacalcet dosing will follow the dose titration, dose withhold, and restarting rules 
defined in Section 6.2.3.1.2. 
 
All subjects from 20110100 will be eligible to titrate the cinacalcet dose at monthly 
titration visits to a maximum dose of 2.5 mg/kg/day based on the subject’s dry 
weight at day 1 in Study 20140159, not to exceed a dose of 60 mg/day. 
 
 
 
Section:  3.2 Number of Sites 
 
Paragraph 1 
 
Replace: 
 
This study will be conducted at approximately 50 sites in North America, Europe, Russia, 
Latin America, and Australia. 
 
With: 
 
This study will be conducted at approximately 60 sites in North America, Europe, Russia, 
Latin America, and Australia. 


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Section:  3.3 Number of Subjects 
 
Paragraph 2 
 
Replace: 
 
This study is open to subjects who complete the 20-week treatment period in study 
 
20130356.  There may be up to 48 subjects enrolled in this study. 
With: 
This study is open to subjects who complete the 20-week treatment period in study 
 
20130356 or the Week 26 End of Study visit in Study 20110100.  There may be up to 
 
78 subjects enrolled in this study. 
 
 
 
Section:  4. Study Eligibility 
 
Paragraph 2, sentence 2 
 
Add: 
 
Subjects who were ≤ 18 years old at week 20 in the 20130356 study are eligible to 
enter this Study 20140159 even if they have already turned 18 years of age or are 
due to turn 18 years of age during their planned participation in the 20140159 
study. 
 
 
 
Section:  4.1.1 Inclusion Criteria 
 
Replace: 
 
101 Subject’s legally acceptable representative has provided informed consent when the 
subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
day 1 study-specific activities/procedures being initiated. 
 
102 Completed treatment through week 20 in the parent study, 20130356 
 
103 Dry weight ≥ 12.5 kg at day 1 
 
104 Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
Subjects Randomized to the 20130356 Standard of Care Arm Only 
 
105 iPTH value ≥ 300 pg/mL (week 19 in 20130356) 


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106 Corrected calcium value ≥ 8.8 mg/dL (week 19 in 20130356) 
With: 
101 Subject’s legally acceptable representative has provided informed consent when the 
subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
day 1 study-specific activities/procedures being initiated. 
 
102 Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
All subjects from 20130356 
 
103 Completed treatment through week 20 in the 20130356 study 
 
104 Dry weight ≥ 12.5 kg at day 1 of Study 20140159 
 
Subjects Randomized to the 20130356 Standard of Care Arm Only 
 
105 iPTH value ≥ 300 pg/mL (week 19 in 20130356) 
 
106 Corrected calcium value ≥ 8.8 mg/dL (week 19 in 20130356) 
 
All Subjects from 20110100 
 
107 Completed Week 26 End of Study visit in the 20110100 study 
 
108 Dry weight ≥ 7 kg at day 1 of Study 20140159 
 
 
 
Section:  4.1.2 Exclusion Criteria 
 
First paragraph 
 
Replace: 
 
Study 20130356 
 
With: 
 
Studies 20130356 or 20110100 


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Section:  4.1.2 Exclusion Criteria 
 
Exclusion Criteria 201 
 
Replace: 
 
201 Currently receiving treatment in another investigational device or drug study, or less 
than 30 days since ending treatment on another investigational device or drug 
study(s), other than Amgen Study 20130356. 
 
With: 
 
201 Currently receiving treatment in another investigational device or drug study, or less 
than 30 days since ending treatment on another investigational device or drug 
study(s), other than Amgen Studies 20130356 or 20110100. 
 
 
 
Section:  4.1.2 Exclusion Criteria 
 
Exclusion Criteria 211 
 
Replace: 
211. Subject has an ongoing adverse event from Study 20130356 that is considered 
related to IP and: 
 
 
 
 
With: 
• 
Is  ≥ CTCAE (v 4.0)  grade 3, and/or 
 
• 
Considered clinically significant in the opinion of the investigator 
 
211. Subject has an ongoing adverse event from Studies 20130356 or 201101100 that 
is considered related to IP and: 
 
• 
Is  ≥ CTCAE (v 4.0)  grade 3, and/or 
 
• 
Considered clinically significant in the opinion of the investigator 
 
 
 
Section:  4.1.2 Exclusion Criteria 
 
Exclusion Criteria 212 
 
Replace: 
 
212 Central laboratory values (cCa, iPTH) were not obtained/are not available for week 
 
19 in the 20130356 study 


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With: 
 
212 Central laboratory values (cCa, iPTH) were not obtained/are not available for 
 
• 
20130356 week 19 or 
 
• 
20140159 Screening visit for subjects from 20110100 study 
 
 
 
Section:  4.1.2 Exclusion Criteria 
 
After exclusion criteria 216 
 
Replace: 
 
At Day 1 Study Visit-Subjects Randomized to the 20130356 Cinacalcet Arm Only 
 
With: 
 
At Day 1 Study Visit-Subjects Rolling Over from 20130356 Cinacalcet Arm or from 
 
20110100 Study 
 
 
 
Section:  4.1.2 Exclusion Criteria 
 
Exclusion Criteria 217 
 
Replace: 
 
217 Cinacalcet dose withheld > 1 month 
 
With: 
 
217 Cinacalcet dose withheld for ≥ last 4 weeks of treatment in studies 20130356 
and 201101100. 
 
 
 
Section:  5 Subject Enrollment 
 
Paragraph 2 
 
Replace: 
 
Subjects will retain the unique subject identification number received in the parent 
 
Study 20130356.  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. 


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With: 
 
Subjects will retain the unique subject identification number received in 
 
Studies 20130356 or 20110100.  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. 
 
 
 
Section:  5.1 Screening 
 
Paragraph 1 
 
Replace: 
 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
The informed consent can be signed up to (± 3 days) prior to day 1 (eg, at week 19 in 
20130356). 
With: 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
The informed consent can be signed up to 1 week (± 3 days) prior to 20140159 day 1. 
 
 
 
Section:  5.2 Enrollment 
 
Paragraph 1 
 
Replace: 
 
Following confirmation that subjects met eligibility criteria in Section 4, the subject will be 
registered in the interactive voice response/interactive web response (IVR/IWR) system. 
The subject will be considered enrolled in the extension study and assigned a cinacalcet 
dose based on the treatment arm and/or last dose received in Study 20130356. 


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With: 
 
Following confirmation that subjects met eligibility criteria in Section 4, the subject will be 
registered in the interactive voice response/interactive web response (IVR/IWR) system. 
The subject will be considered enrolled in the extension study: 
 
• 
20130356 subjects will be assigned a cinacalcet dose based on the treatment 
arm and/or last dose received in Study 20130356. 
• 
20110100 subjects will be assigned a cinacalcet dose based on their dry 
weight at the time of enrollment in the 20140159 study and age at time of 
enrollment in the 20110100 study. 
 
 
 
Section:  6.1 Standard of Care 
 
Paragraph 2 
 
Replace: 
 
Standard of care therapy that is commercially available will not be provided or 
reimbursed by Amgen (except if required by local regulation).  The Investigator will be 
responsible for obtaining supplies of these therapies. 
 
With: 
 
Standard of care therapy that is commercially available will not usually be provided or 
reimbursed by Amgen (except if required by local regulation).  The Investigator will be 
responsible for obtaining supplies of these therapies unless they are provided by 
Amgen. 
 
 
 
Section:  6.2.3 Dosage, Administration, and Schedule 
 
Paragraph 2 
 
Replace: 
 
The protocol-specified doses (PSD) for use in this study are:  2.5, 5, 10, 15, 30, 60, 90, 
 
120, and 180 mg.  Subjects who are assigned doses of 10 or 15 mg/day will require 
administration of 2 or 3 capsules respectively per dose.  Subjects who are assigned 
doses of 60 - 180 mg/day will require administration of 2 - 6 tablets per dose.  For those 
subjects unable to swallow tablets, capsules may be dispensed. 


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The maximum dose of cinacalcet that will be administered at any time during the study 
will be 2.5 mg/kg/day based on the subject’s day 1 dry weight or 180 mg daily, 
whichever is lower. 
 
With: 
 
The subject will be considered enrolled in the extension study: 
 
• 
Subjects ≥ 6 years of age:  2.5, 5, 10, 15, 30, 60, 90, 120, and 180 mg. 
 
− Subjects from 20130356 may receive capsules for any dose which is an 
exact multiple of 5 mg.  Subjects who are assigned doses of 60 - 180 mg/day 
will require administration of 2 - 6 tablets per dose.  For those subjects unable to 
swallow tablets, capsules may be dispensed. 
− The maximum dose of cinacalcet that will be administered at any time during the 
study will be 2.5 mg/kg/day based on the subject’s day 1 dry weight in Study 
20140159 or 180 mg daily, whichever is lower. 
 
• 
Subjects < 6 years of age:  1, 2.5, 5, 7.5, 10, 15, 30 and 60 mg.  Subjects from 
Study 20110100 will start cinacalcet in Study 20140159 at 0.20 mg/kg/day 
based on the subject’s dry weight at the 20140159 Day 1 timepoint and age at 
time of enrollment in 20110100 study, rounded down to the lowest PSD. 
− Subjects assigned dose of 10-60 mg/day will require that more than 1 
capsule per dose be sprinkled on soft food or used to create the liquid 
suspension for administration. 
− Subjects enrolling into 20140159 from 20110100 would have a maximum 
dose of 2.5 mg/kg/day based on the Day 1 dry weight or 60 mg daily, 
whichever is lower. 
 
 
 
Section:  6.2.3 Dosage, Administration, and Schedule 
 
Paragraphs 4 and 5 
 
Replace: 
 
Subjects will be required to return all unused medication, including empty bottles, at 
 
each study visit.  Site staff will confirm that the previously assigned medication bottle has 
been returned prior to dispensing a new bottle of IP. 
 
If no ionized calcium values are available at the time of a study visit, a new bottle of IP 
investigational product will not be dispensed to the subject.  Once the calcium value has 
been obtained, IP may be dispensed as appropriate. 
 
With: 
 
Subjects will be required to return all unused medication, including empty bottles, at 
each study visit.  Site staff will confirm that the previously assigned medication bottle(s) 


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have been returned prior to dispensing a new bottle(s) of IP.  In the event unused 
medications or empty bottles have been permanently misplaced, contact Amgen 
prior to dispensing new bottle(s) of IP. 
 
If no ionized calcium values are available at the time of a study visit, a new bottle of IP 
will not be dispensed to the subject.  Once the ionized calcium value has been obtained 
and in accessible range, IP may be dispensed as appropriate. 
 
 
 
Section:  6.2.3.1 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
 
Paragraph 1 
 
Replace: 
 
Dosage adjustments, titrations, and withholding/restarting rules will be the same as the 
parent Study 20130356. 
 
With: 
 
Dosage adjustments, titrations, and withholding/restarting rules will be the same as the 
parent studies. 
 
 
 
Section:  6.2.3.1 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
 
Heading 
 
Add: 
 
6.2.3.1.1 Subjects from Study 20130356 
 
 
 
Section:  6.2.3.1.1 Subjects from Study 20130356 
 
Replace: 
 
On day 1, subjects from the SOC arm in 20130356 will receive the initial dose of 
cinacalcet as defined in Section 6.2.3.1.1 
 
Subjects from the cinacalcet arm will follow the dose titration rules outlined in Table 1 in 
 
Section 6.2.3.1.2.  If subjects from the cinacalcet arm in 20130356 are on a dose 


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withhold at day 1, the iPTH and cCa restart values (iPTH > 100 pg/mL and 
 
cCa > 8.4 mg/dL) must be reached prior to resuming cinacalcet in the current extension 
study.  Subjects from the cinacalcet arm, who have had their dose withheld for 
> 1 month at the time of day 1 in this extension study will not be eligible for this study. 
With: 
On day 1 of Study 20140159, subjects from the SOC arm in 20130356 will receive the 
initial dose of cinacalcet as defined in Section 6.2.3.1.1.1 
 
Subjects from the cinacalcet arm will follow the dose adjustments outlined in Table 1 in 
Section 6.2.3.1.1.1.  If subjects from the cinacalcet arm in 20130356 are on a dose 
withhold at 20140159 day 1, the iPTH and cCa restart values (iPTH > 100 pg/mL and 
cCa > 8.4 mg/dL) must be reached prior to resuming cinacalcet in the current extension 
study.  Subjects from the cinacalcet arm, who have had their dose withheld for 
> 1 month at the time of 20140159 day 1 will not be eligible for this study. 
 
 
 
Section:  6.2.3.1.1.1 Dosage Adjustments 
 
Paragraph 1 
 
Replace: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects from the SOC arm will start at the initial 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1, rounded 
down to the lowest PSD.  Subjects from the cinacalcet arm will start cinacalcet dosing on 
day 1 at the same dose of cinacalcet they received at the completion of the treatment 
period (week 20) in the parent study or titrate based on the Table 1 in Section 6.2.3.1.2. 
The initial dose of cinacalcet will be assigned to subjects restarting cinacalcet after 
withholding the dose for more than 14 days during the study. 
 
With: 
 
On day 1, the subject’s ionized calcium must be at or above threshold (i.e. ≥ 1.13 
mmol/L for subjects less than 2 years of age, ≥ 1.05 mmol/L for subjects 2 years of 
age and above) prior to initiation of treatment.  The initial dose of cinacalcet and all 
subsequent doses will be calculated by the site staff and confirmed by the IVR/IWR 
system.  Subjects from the SOC arm will start at the initial cinacalcet dose of 
0.20 mg/kg/day, based on the subject’s dry weight at 20140159 day 1, rounded down to 


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the lowest PSD.  Subjects from the cinacalcet arm will start cinacalcet dosing on 
 
20140159 day 1 at the same dose of cinacalcet they received at the completion of the 
treatment period (week 20) in Study 20130356 or titrate based on the Table 1 in 
Section 6.2.3.1.1.1.  The initial dose of cinacalcet will be assigned to subjects restarting 
cinacalcet after withholding the dose for more than 14 days during the study. 
 
 
 
Section:  6.2.3.1.1.1 Dose Adjustments 
 
Replace: 
 
Monthly dose titrations will be assessed at Day 1, Weeks 4, 8, 12, etc as outlined in the 
Schedule of Assessments (Section 7.1).  Cinacalcet doses will be titrated up or down 
one PSD or maintained monthly and confirmed by the IVR/IWR system using the 
corrected serum calcium and iPTH values obtained from the central laboratory the week 
prior to the dose titration visit, as well as assessments of symptoms of hypocalcemia and 
ionized calcium values obtained on the day of the titration visit, as outlined in Table 1 
below. 
 
Dose increases can occur only once a month. 
 
Table 1.  Monthly Dose Titration Rules 
 
↑ one PSD 
(if all criteria 
met) 
Maintain Dose 
(if all criteria 
met) 
↓ one PSD 
(if any criteria 
met) 
withhold* 
(if any criteria 
met) 
Corrected 
≥ 8.4 mg/dL 
≥ 8.4 mg/dL 
≥ 8.0 - 
< 8.0 mg/dL 
Calcium 
(central 
laboratory) 
(≥ 2.1 mmol/L) 
(≥ 2.1 mmol/L) 
< 8.4 mg/dL 
(≥ 2.0 - 
< 2.1 mmol/L) 
(< 2.0 mmol/L) 
Ionized Calcium 
≥ 1.05 mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.00 mmol/L 
< 1.05 mmol/L 
iPTH 
≥ 300 pg/mL 
≥ 150 - 
≥ 100 - 
< 100 pg/mL 
(≥ 31.8 pmol/L) 
< 300 pg/mL 
< 150 pg/mL 
(< 10.6 pmol/L) 
(≥ 15.9 - 
(≥ 10.6 - 
< 31.8 pmol/L) 
< 15.9 pmol/L) 
Symptoms of 
None 
None 
Not Applicable 
Yes 
Hypocalcemia 
*restart one PSD below last dose when corrected calcium is > 8.4 mg/dL, iPTH is > 100 pg/mL, ionized 
calcium is > 1.05 mmol/L and symptoms of hypocalcemia have resolved. 
 
If the central laboratory corrected calcium value is < 8.0 mg/dL at any time during the 
trial, the dose of cinacalcet is to be withheld until the central laboratory corrected calcium 


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value is > 8.4 mg/dL, at which time the dose may be restarted at one PSD below the 
previous dose received, provided that the iPTH is > 100 pg/mL, the ionized calcium is 
> 1.05 mmol/L, and the subject has no symptoms of hypocalcemia.  Subjects receiving 
the lowest PSD (2.5 mg) who require a dose reduction will have their dose withheld until 
the criteria for maintaining or increasing the dose are met, at which time they will restart 
dosing at 2.5 mg/day. 
 
6.2.3.1.1.3 Dose Adjustments 
 
Administration of cinacalcet may be withheld at any time during the study based on the 
ionized calcium, local laboratory total calcium values, and/or if the subject has 
signs/symptoms of hypocalcemia.  The dose may be decreased based on the ionized 
calcium, as described in Table 2 below. 
 
 
Table 2:  Dose Adjustments for Safety 
 
↓ one PSD 
(if any criteria met) 
 
 
withhold* 
(if any criteria met) 
 
Total calcium (local laboratory) 
Not Applicable 
 < 8.0 mg/dL 
(< 2.0 mmol/L) 
Ionized Calcium 
≥ 1.00 - < 1.05 - mmol/L 
< 1.00 mmol/L 
Symptoms of Hypocalcemia 
 
Not Applicable 
 
Yes 
*restart one PSD below last dose when ionized calcium is > 1.05 mmol/L and symptoms of hypocalcemia 
have resolved. 
 
If at any time the subject has a local total calcium value of < 8.0 mg/dL, the dose of 
investigational product must be withheld until an ionized calcium of > 1.05 mmol/L or a 
central lab corrected calcium of > 8.4 mg/dL are obtained, at which time the dose may 
be resumed at one PSD below the previous dose.  If a local laboratory measurement is 
used it must be documented in the subject’s source record and recorded in the 
electronic case report form (eCRF). 
 
In addition, if subjects require temporary administration of concomitant medications that 
are known to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 
substrates, the administration of cinacalcet is to be withheld.  The dose may be restarted 
when treatment with the concomitant medication has completed and an ionized calcium 
of > 1.05 mmol/L or a central lab corrected calcium of > 8.4 mg/dL are obtained, at which 
time the dose may be resumed either at one PSD below the previous dose or at the 
initial dose if the criteria in Section 6.2.3.1.4 are met. 


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With: 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each 
weekly visit during the treatment period.  The daily dose of cinacalcet may only be 
increased at monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be 
increased at any other time during the treatment period.  At all weekly visits 
(including week 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, and 
27), the dose may be maintained, reduced or withheld based upon the criteria in 
 
Table 1. 
 
If any of the criteria for dose withholding are met at any time during the trial, 
including between scheduled study visits (ie, unscheduled), the dose of cinacalcet 
is to be withheld until all of the following criteria are met: 
 
• 
Central laboratory corrected calcium value is > 8.4 mg/dL 
 
• 
iPTH is > 100 pg/mL 
 
• 
Ionized calcium is > 1.05mmol/L 
 
• 
Subject has no symptoms of hypocalcemia 
 
• 
Subject doesn’t have any ongoing adverse event(s) which warrant withholding 
of cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed 
weekly until an ionized calcium of ˃ 1.05 mmol/L is obtained, at which point, cCa 
and iPTH should be assessed by the central laboratory. 
 
Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received.  Subjects receiving the lowest PSD (2.5 mg) who 
require a dose reduction will have their dose withheld until the criteria for 
maintaining or increasing the dose are met, at which time they will restart dosing 
at 2.5 mg/day. 
 
If subjects require temporary administration of concomitant medications that are known to 
prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 substrates, the 
administration of IP is to be withheld.  The dose may be restarted at one PSD below the 
previous dose once the treatment with the concomitant medication has completed and 
all of the restart criteria above are met. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume 
dosing at the starting dose level once all restart criteria are met. 


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If any of the criteria for dose decrease are met between scheduled study visits, the 
dose of cinacalcet is to be suspended until the next visit at which time the dose will 
be decreased per dose adjustment procedures of that visit. 


CONFIDENTIAL 
 
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Table 1.  Dose Adjustment Rules:  Monthly, Weekly and Withholding in Children 6-18 years of age 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16, 20, 24) 
Weekly Dose Adjustment Visit Rules 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27) 
Dose Withholding 
for Safety at 
Anytime 
(Monthly, Weekly 
or Unscheduled) 
withhold* 
(if any criteria 
met) 
↑ one PSD 
(if all criteria 
met) 
Maintain Dose 
(if all criteria 
met) 
↓ one PSD** 
(if any criteria 
met) 
withhold* 
(if any criteria 
met) 
Maintain 
Dose 
(if all criteria 
met) 
↓ one PSD** 
(if any criteria 
met) 
withhold* 
(if any criteria 
met) 
Corrected Calcium 
(central laboratory) 
≥ 8.4 mg/dL 
(≥ 2.1 mmol/L) 
≥ 8.4 mg/dL 
(≥ 2.1 
mmol/L) 
≥ 8.0 - 
< 8.4 mg/dL 
(≥ 2.0- 
< 2.1 mmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
≥ 8.4 mg/dL 
(≥ 2.1 
mmol/L) 
≥ 8.0 - 
< 8.4 mg/dL 
(≥ 2.0- 
< 2.1 mmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
Ionized Calcium 
≥ 1.05 mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.05 mmol/L 
< 1.00 mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.05 mmol/L 
< 1.00 mmol/L 
< 1.00 mmol/L 
Total Calcium 
(local laboratory) 
N/A 
N/A 
N/A 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
N/A 
N/A 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
iPTH 
≥ 300 pg/mL 
(≥ 31.8 
pmol/L) 
≥ 150 - 
< 300 pg/mL 
(≥ 15.9 - 
< 31.8 pmol/L) 
≥ 100 - 
< 150 pg/mL 
(≥ 10.6 - 
< 15.9 pmol/L) 
≥ 150 pg/mL 
(≥ 15.9 
pmol/L) 
≥ 100 - 
< 150 pg/mL 
(≥ 10.6 - 
< 15.9 pmol/L) 
Symptoms of 
Hypocalcemia 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
Other AE that 
warrants IP dose 
withhold 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
*restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 100 pg/mL, ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
**if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, 
at which time the dose will be decreased per dose adjustment procedures of that visit. 


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Protocol Number: 20140159 
Date: 22 July 2015 
Page 29 of 50 
 
Section:  6.2.3.1.2 Subjects From 20110100 
 
Heading: 
Add: 
6.2.3.1.2 Subjects from 20110100 
 
 
 
Section:  6.2.3.1.2 Subjects From 20110100 
 
Add: 
 
In order to start dosing, all subjects from Study 20110100 must have: 
 
• 
Ionized calcium prior to initiation of treatment on day 1 in this study 
 
− ≥ 1.13 mmol/L if age < 2 years 
 
− ≥ 1.05 mmol/L if ≥ 2 years 
 
• 
iPTH value ≥ 150 pg/mL within 7 days of day 1 
 
• 
Corrected calcium value within 7 days of day 1 
 
− ≥ 9.4 mg/dL if age < 2 years 
 
− ≥ 8.8 mg/dL if age ≥2 years 
 
• 
Phosphorus value within 7 days of day 1 
 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age < 1 year 
 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age ≥ 1 year 
 
 
 
Section:  6.2.3.1.2.1 Subjects < 2 Years of Age 
 
Heading 
 
Add: 
 
6.2.3.1.2.1 Subjects < 2 Years of Age 
 
 
 
Section:  6.2.3.1.2.1 Subjects < 2 Years of Age 
 
Paragraph 1 
 
Replace: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects from the SOC arm will start at the initial 


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Clinical  Study Report:  20140159 
Date:  21 August  2017 
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Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 22 July 2015 
Page 30 of 50 
 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1, rounded 
down to the lowest PSD. 
 
With: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects will start at the initial cinacalcet dose of 
0.20 mg/kg/day, based on the subject’s dry weight at day 1, in the 20140159 study 
 
rounded down to the lowest PSD. 
 
 
 
Section:  6.2.3.1.2.1 Subjects < 2 Years of Age 
 
After paragraph 1 
 
Add: 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each 
weekly visit during the treatment period.  The daily dose of cinacalcet may only be 
increased at monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be 
increased at any other time during the treatment period.  At all weekly visits 
(including week 4, 8, 12, 16, 20, and 24), the dose may be maintained, reduced or 
withheld based upon the criteria in Table 2. 
 
If any of the criteria for dose withholding are met at any time during the trial, 
including between scheduled study visits (ie, unscheduled), the dose of cinacalcet 
is to be withheld until all of the following criteria are met: 
 
• 
Central laboratory corrected calcium value is > 9.0 mg/dL 
 
• 
iPTH is > 150 pg/mL 
 
• 
Ionized calcium is > 1.13 mmol/L 
 
• 
Subject has no symptoms of hypocalcemia 
 
• 
Subject doesn’t have any ongoing adverse event(s) which warrant withholding 
of cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed 
weekly until an ionized calcium of ˃1.13 mmol/L is obtained, at which point, cCa 
and iPTH should be assessed by the central laboratory. 
 
Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received.  Subjects receiving the lowest PSD (1 mg) who 
require a dose reduction will have their dose withheld until the criteria for 


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Date: 22 July 2015 
Page 31 of 50 
 
maintaining or increasing the dose are met, at which time they will restart dosing 
at 1 mg/day. 
 
If subjects require temporary administration of concomitant medications that are 
known to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 
substrates, the administration of IP is to be withheld.  The dose may be restarted 
at one PSD below the previous dose once the treatment with the concomitant 
medication has completed and all of the restart criteria above are met. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume 
dosing at the starting dose level once all restart criteria are met. 
 
If any of the criteria for dose decrease are met between scheduled study visits, the 
dose of cinacalcet is to be suspended until the next visit at which time the dose will 
be decreased per dose adjustment procedures of that visit. 


CONFIDENTIAL 
 
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Date: 21 August  2017 
Page 129 
 
 
 
 
 
 
Product:  Cinacalcet HCl 
Protocol Number:  20140159 
Date:  22 July 2015 
Page 32 of 50 
 
Table 2.  Dose Adjustment Rules:  Monthly, Weekly and Withholding in Subjects < 2 Years Old 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16 20, 24) 
Weekly Dose Adjustment Visit Rules 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
15, 17, 18, 19) 
Dose 
Withholding for 
Safety at 
Anytime 
(Monthly, 
Weekly or 
Unscheduled) 
↑ one PSD 
(if all criteria 
met) 
Maintain 
Dose 
(if all 
criteria 
met) 
↓ one PSD** (if 
any criteria 
met) 
withhold* 
(if any 
criteria met) 
Maintain 
Dose 
(if all criteria 
met) 
↓ one PSD** (if 
any criteria 
met) 
withhold* 
(if any criteria 
met) 
withhold* 
(if any criteria 
met) 
Corrected 
Calcium 
(central 
laboratory) 
≥ 9.0 
mg/dL 
(≥ 2.25 
mmol/L) 
≥ 9.0 
mg/dL 
(≥ 2.25 
mmol/L) 
≥ 8.6 - < 
9.0 mg/dL 
(≥ 2.15 - 
< 2.25 mmol/L) 
< 8.6 mg/dL 
(< 2.15 
mmol/L) 
≥ 9.0 mg/dL 
(≥ 2.25 
mmol/L) 
≥ 8.6 - 
< 9.0 mg/dL 
(≥ 2.15 - 
< 2.25 mmol/L) 
< 8.6 mg/dL 
(< 2.15 mmol/L) 
< 8.6 mg/dL 
(< 2.15 mmol/L) 
Ionized Calcium 
≥ 1.13 
mmol/L 
≥ 1.13 
mmol/L 
≥ 1.08 - 
< 1.13 mmol/L 
< 1.08 
mmol/L 
≥ 1.13 
mmol/L 
≥ 1.08 - 
< 1.13 mmol/L 
< 1.08 mmol/L 
< 1.08 mmol/L 
Total Calcium 
(local 
laboratory) 
Not 
Applicable 
< 8.6 
mg/dL 
(< 2.15 
mmol/L) 
Not 
Applicable 
< 8.6 mg/dL 
(< 2.15 
mmol/L) 
< 8.6 
mg/dL 
(< 2.15 
mmol/L) 
Not 
Applicable 
< 8.6 mg/dL 
(< 2.15 mmol/L) 
< 8.6 mg/dL 
(< 2.15 mmol/L) 
iPTH 
≥ 300 
pg/mL 
(≥ 31.8 
pmol/L) 
≥ 150 - 
< 300 
pg/mL 
(≥ 15.9 - 
< 31.8 
pmol/L) 
≥ 100 - < 
150 pg/mL 
(≥ 10.6 - 
< 15.9 pmol/L) 
< 100 
pg/mL 
(< 10.6 
pmol/L) 
≥ 150 - < 
300 pg/mL 
(≥ 15.9 - 
< 31.8 
pmol/L) 
≥ 100 - < 150 
pg/mL 
(≥ 10.6 - < 15.9 
pmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
Symptoms of 
Hypocalcemia 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
Other AE that 
warrants IP 
dose withhold 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
*restart one PSD below last dose when cCa is > 9.0 mg/dL, iPTH is > 150 pg/mL, ionized calcium is > 1.13 mmol/L, symptoms of hypocalcemia and other AE 
that warrants IP dose withholding have resolved 
**if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, 
at which time the dose will be decreased. 


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Date:  21 August  2017 
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Protocol Number: 20140159 
Date: 22 July 2015 
Page 33 of 50 
 
Section:  6.2.3.1.2.2 Subjects ≥ 2 Years of Age 
 
Heading 
 
Add: 
 
Subjects ≥ 2 Years of Age 
 
 
 
Section:  6.2.3.1.2.2 Subjects ≥ 2 Years of Age 
 
Paragraph 1 
 
Replace: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects from the SOC arm will start at the initial 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1, rounded 
down to the lowest PSD. 
 
With: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects will start at the initial cinacalcet dose of 
0.20 mg/kg/day, based on the subject’s dry weight at day 1 in the 20140159 study, 
rounded down to the lowest PSD. 
 
 
 
Section:  6.2.3.1.2.2 Subjects ≥ 2 Years of Age 
 
After paragraph 1 
 
Add: 
 
Dose adjustments for subjects receiving cinacalcet will be assessed at each 
weekly visit during the treatment period.  The daily dose of cinacalcet may only be 
increased at monthly titration visits (week 4, 8, 12, 16, 20, and 24); it can’t be 
increased at any other time during the treatment period.  At all weekly visits 
(including week 4, 8, 12, 16, 20, and 24), the dose may be maintained, reduced or 
withheld based upon the criteria in Table 3. 
 
If any of the criteria for dose withholding are met at any time during the trial, 
including between scheduled study visits (ie, unscheduled), the dose of cinacalcet 
is to be withheld until all of the following criteria are met: 


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Protocol Number: 20140159 
Date: 22 July 2015 
Page 34 of 50 
 
 
• 
Central laboratory corrected calcium value is > 8.4 mg/dL 
 
• 
iPTH is > 150 pg/mL 
 
• 
Ionized calcium is > 1.05 mmol/L 
 
• 
Subject has no symptoms of hypocalcemia 
 
• 
Subject doesn’t have any ongoing adverse event(s) which warrant withholding 
of cinacalcet. 
 
If a subject dose is being withheld, ionized calcium levels should be assessed 
weekly until an ionized calcium of ˃1.05 mmol/L is obtained, at which point, cCa 
and iPTH should be assessed by the central laboratory. 
 
Once all the restart criteria above are met, cinacalcet may be restarted at one PSD 
below the previous dose received.  Subjects receiving the lowest PSD (1 mg) who 
require a dose reduction will have their dose withheld until the criteria for 
maintaining or increasing the dose are met, at which time they will restart dosing 
at 1 mg/day. 
 
If subjects require temporary administration of concomitant medications that are 
known to prolong the QTc interval, are CYP3A4 inhibitors, or are CYP2D6 
substrates, the administration of IP is to be withheld.  The dose may be restarted 
at one PSD below the previous dose once the treatment with the concomitant 
medication has completed and all of the restart criteria above are met. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume 
dosing at the starting dose level once all restart criteria are met. 
 
If any of the criteria for dose decrease are met between scheduled study visits, the 
dose of cinacalcet is to be suspended until the next visit at which time the dose will 
be decreased per dose adjustment procedures of that visit. 


CONFIDENTIAL 
 
Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date: 21 August  2017 
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Product:  Cinacalcet HCl 
Protocol Number:  20140159 
Date:  22 July 2015 
Page 35 of 50 
 
 
Table   .  Dose Adjustment Rules:  Monthly, Weekly and Withholding in Subjects ≥ 2 years old 
 
Monthly Dose Titration Visit Rules 
(Weeks 4, 8, 12, 16, 20, 24) 
Weekly Dose Adjustment Visit Rules 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27) 
Dose 
Withholding for 
Safety at 
Anytime 
(Monthly, 
Weekly or 
Unscheduled) 
withhold* 
(if any criteria 
met) 
↑ one PSD (if 
all criteria 
met) 
Maintain 
Dose 
(if all criteria 
met) 
↓ one PSD** (if 
any criteria 
met) 
withhold* 
(if any criteria 
met) 
Maintain 
Dose 
(if all criteria 
met) 
↓ one PSD** (if 
any criteria 
met) 
withhold* 
(if any criteria 
met) 
Corrected 
Calcium (central 
laboratory) 
≥ 8.4 mg/dL 
(≥ 2.1 
mmol/L) 
≥ 8.4 mg/dL 
(≥ 2.1 
mmol/L) 
≥ 8.0 - 
< 8.4 mg/dL 
(≥ 2.0- 
< 2.1 mmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
≥ 8.4 mg/dL 
(≥ 2.1 
mmol/L) 
≥ 8.0 - 
< 8.4 mg/dL 
(≥ 2.0- 
< 2.1 mmol/L) 
< 8.0 mg/dL 
(< 2.0 
mmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
Ionized Calcium 
≥ 1.05 
mmol/L 
≥ 1.05 mmol/L 
≥ 1.00 - 
< 1.05 mmol/L 
< 1.00 mmol/L 
≥ 1.05 
mmol/L 
≥ 1.00 - 
< 1.05 mmol/L 
< 1.00 mmol/L 
< 1.00 mmol/L 
Total Calcium 
(local laboratory) 
N/A 
N/A 
N/A 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
N/A 
N/A 
< 8.0 mg/dL 
(< 2.0 
mmol/L) 
< 100 pg/mL 
(< 10.6 
pmol/L) 
< 8.0 mg/dL 
(< 2.0 mmol/L) 
< 100 pg/mL 
(< 10.6 pmol/L) 
iPTH 
≥ 300 pg/mL 
(≥ 31.8 
pmol/L) 
≥ 150 - 
< 300 pg/mL 
(≥ 15.9 - 
< 31.8 pmol/L) 
≥ 100 - 
< 150 pg/mL 
(≥ 10.6 - 
< 15.9 pmol/L) 
≥ 150 pg/mL 
(≥ 15.9 
pmol/L) 
≥ 100 - 
< 150 pg/mL 
(≥ 10.6 - 
< 15.9 pmol/L) 
Symptoms of 
Hypocalcemia 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
Other AE that 
warrants IP dose 
withhold 
None 
None 
N/A 
Yes 
None 
N/A 
Yes 
Yes 
*restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 150 pg/mL, ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia, and other AE 
that warrants IP dose withholding have resolved. 
**if any lab values that warrant a dose decrease are received between regularly scheduled visits, the subject dose should be suspended until the next visit, at which time 
the dose will be decreased per dose adjustment procedures of that visit. 


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Date: 22 July 2015 
Page 36 of 50 
 
Section:  6.2.3.1.3 Missed Doses 
 
Paragraph 1 
 
Replace: 
 
If a subject misses > 14 consecutive doses of cinacalcet for any reason, including 
temporary dose withholding due to the administration of concomitant medications as 
noted above, they will be restarted at their initial dose of cinacalcet (0.20 mg/kg/day 
based on dry weight at day 1) when administration of IP resumes per the dose titration 
guidelines outlined in Table 1. 
 
With: 
 
If a subject misses > 14 consecutive doses of cinacalcet for any reason, including 
temporary dose withholding due to the administration of concomitant medications as 
noted above, they will be restarted at their initial dose of cinacalcet (0.20 mg/kg/day 
based on dry weight at day 1) when administration of IP resumes per the dose titration 
guidelines outlined in Table 1, Table 2, and Table 3. 
 
 
 
Section:  6.2.3.2 Measures of Compliance with Cinacalcet Administration 
 
Paragraph 2 
 
Replace: 
 
Electronic patient diaries (eDiary) and pill counts will be reconciled and utilized in this 
study to document subject compliance with daily administration of cinacalcet therapy. 
The data entered into the eDiary will be available to the investigator and/or study 
coordinator on a daily basis to enable ongoing reviews of subject compliance.  The 
eDiary and pill counts data collected will be reviewed with the subject and/or their 
parent(s) or legal guardian(s) by the investigator and/or study coordinator during the 
weekly study visits. 
 
With: 
 
Electronic patient diaries (eDiary) and IP accountability information will be reconciled 
and utilized in this study to document subject compliance with daily administration of 
cinacalcet therapy.  The data entered into the eDiary will be available to the investigator 
and/or study coordinator on a daily basis to enable ongoing reviews of subject 
compliance.  The eDiary and IP accountability data collected will be reviewed with the 


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Date:  21 August  2017 
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Date: 22 July 2015 
Page 37 of 50 
 
subject and/or their parent(s) or legal guardian(s) by the investigator and/or study 
coordinator during the weekly study visits. 
 
 
 
Section:  6.2.3.3 Overdose 
 
Paragraph 3 
 
Replace: 
 
Once hypocalcemia and any symptoms associated with the overdose have resolved, 
subjects may resume cinacalcet administration at their previously assigned dose. 
 
With: 
 
Once hypocalcemia and any symptoms associated with the overdose have resolved, 
subjects resume cinacalcet administration dose.  To resume dosing, the subject must 
meet the dosing restart criteria for his/her respective age group as specified in 
Sections 6.2.3.1.1, 6.2.3.1.2.1, and 6.2.3.1.2.2. 
 
 
 
Section:  6.3.1 Criteria for Permanent Discontinuation of Amgen IP and Other 
 
Protocol-required Therapies Due to Potential Hepatotoxicity 
 
Paragraph 2 
 
Replace: 
 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if Amgen IP and other protocol-required therapies 
should be withheld or permanently discontinued, as deemed appropriate for the safety of 
the subject. 
 
With: 
 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if Amgen IP and other protocol-required therapies 
should be withheld (see section 6.3.2) or permanently discontinued, as deemed 
appropriate for the safety of the subject. 


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Date:  21 August  2017 
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Date: 22 July 2015 
Page 38 of 50 
 
Section:  7.1 Schedule of Assessments 
Table 4. Schedule of Assessments 
Replace: 


CONFIDENTIAL 
 
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Date: 21 August  2017 
Page 136 
 
 
 
 
 
 
Product:  Cinacalcet HCl 
Protocol Number:  20140159 
Date:  22 July 2015 
Page 39 of 50 
 
Chemistry, hematology, 
25(OH)Vit D 
X
2
 
X 
X 
 
 
BALP, NTx, CTx, P1NP, 
FGF 23 
X
2
 
X 
 
 
With: 
 
Chemistry, hematology, 
25(OH)Vit D3 
X2 
X 
X 
 
 
BALP, NTx, CTx, P1NP, 
FGF 23
3
 
X2 
X 


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Date:  21 August  2017 
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Date: 22 July 2015 
Page 40 of 50 
 
Section:  7.1 Schedule of Assessments 
 
Table 4.  Schedule of Assessments, Footnotes 2 and 3 
 
Replace: 
 
2 - These procedures are required for the 20130356 EOIP visit and 20140159 day 1 
visit.  These procedures will be performed once at the site and applied to both study 
visits. 
 
With: 
 
2 - These procedures are required for the 20130356 EOIP and 20110100 EOS visit and 
 
20140159 day 1 visit.  These procedures will be performed once at the site and applied 
to both study visits. 
 
3 - Biomarker Assessments and 25 (OH) Vit D are not required for subjects 
previously enrolled in 20110100.  If baseline FGF23 is not collected at Day 1, it 
must not be collected at week 28. 
 
 
 
Section:  7.2 General Study Procedures 
 
Paragraph 2 
 
Replace: 
 
The duplicate study assessments from the end of investigational product (EOIP) visit in 
the parent study, 20130356, and from the day 1 visit will be collected once for both 
studies as described in Section 7.2.2. 
 
 
 
With: 
 
The duplicate study assessments will be collected once for both studies as described 
in Section 7.2.2. 


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Date:  21 August  2017 
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Date: 22 July 2015 
Page 41 of 50 
 
Section:  7.2.2 Day 1 
 
Paragraph 1 
 
Replace: 
 
The following day 1 procedures are also required for the EOIP study visit at week 20 for 
Amgen study 20130356.  These procedures should not be duplicated and may be 
collected once and entered onto the appropriate eCRF once eligibility for this study has 
been confirmed: 
 
With: 
 
The following day 1 procedures are also required for the EOIP study visit at week 20 for 
Amgen study 20130356 and Week 26 End of Study visit for Study 20110100 except 
where indicated.  These procedures should not be duplicated and may be collected 
once and entered onto the appropriate eCRF once eligibility for this study has been 
confirmed: 
 
 
 
Section:  7.2.2 Day 1 
 
Bullet 8, subbullet 6 
 
Replace: 
 
25 (OH) Vitamin D 
With: 
25 (OH) Vitamin D (not required for subjects from 20110100) 
 
 
 
Section:  7.2.2 Day 1 
 
Bullet 8, subbullet 8 
 
Replace: 
 
Bone specific alkaline phosphatase (BALP), cross-linked N-telopeptides of type 1 
collagen (NTx), type 1 collagen cross-linked telopeptide (CTx), amino terminal 
propeptide of type 1 collagen (P1NP), FGF23 


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Date:  21 August  2017 
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Date: 22 July 2015 
Page 42 of 50 
 
With: 
 
Bone specific alkaline phosphatase (BALP), cross-linked N-telopeptides of type 1 
collagen (NTx), type 1 collagen cross-linked telopeptide (CTx), amino terminal 
propeptide of type 1 collagen (P1NP), FGF23 (not required for subjects from 
20110100). 
 
 
 
Section:  7.2.2 Day 1 
 
Bullet 9 
 
Replace: 
 
Medical history (including ongoing AEs/SAEs from the parent study, 20130356) 
With: 
Medical history (including ongoing AEs/SAEs from Studies, 20130356 and 20110100) 
 
 
 
Section:  7.2.3 Treatment 
 
Bullet 2, subbullet 2 
 
Replace: 
Pill counts 
With: 
Counts of returned bottles of tablets/capsules/suspension 
 
 
 
Section:  7.2.4 End of Investigational Product 
 
Bullet 4, subbullet 2 
 
Replace: 
Pill counts 
With: 
Counts of returned bottles of tablets/capsules/suspension 


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Section:  7.2.4 End of Investigational Product 
 
Bullet 8, subbullet 4 
 
Replace: 
 
25 (OH) Vitamin D 
With: 
25 (OH) Vitamin D (not required for subjects from 20110100) 
 
 
 
Section:  7.2.4 End of Investigational Product 
 
Bullet 8, subbullet 7 
 
Replace: 
 
BALP, NTx, CTx, P1NP, FGF23 
 
With: 
 
BALP, NTx, CTx, P1NP, FGF23 (not required for subjects from 20110100) 
 
 
 
Section:  7.2.6 End of Study Visit 
 
Bullet 9, subbullet 4 
 
Replace: 
 
25 (OH) Vitamin D 
With: 
25 (OH) Vitamin D (not required for subjects from 20110100) 
 
 
 
Section:  7.3.2 Demographic Data 
 
Replace: 
 
Demographic data including sex, date of birth, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness. 
These data will be transferred from the parent Study 20130356. 


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With: 
 
Demographic data including sex, date of birth, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness. 
These data will be transferred from the Studies 20130356 and 20110100. 
 
 
 
Section:  7.3.3 Medical and Surgical History 
 
Replace: 
 
The subject’s complete medical and surgical history will be reviewed on day 1.  The 
investigator or designee will collect a complete medical and surgical history for 
conditions that started within 5 years of the date of enrollment, including information on 
the subject’s concurrent conditions.  Ongoing adverse events and serious adverse 
events in the parent Study 20130356 will be entered as concurrent conditions on the 
medical history form.  This information will be recorded on the medical history eCRF for 
subjects enrolled into the study. 
 
With: 
 
The subject’s complete medical and surgical history will be reviewed on day 1.  The 
investigator or designee will collect a complete medical and surgical history for 
conditions that started within 5 years of the date of enrollment, including information on 
the subject’s concurrent conditions.  Ongoing adverse events and serious adverse 
events in Studies 20130356 and 20110100 will be entered as concurrent conditions on 
the medical history form.  This information will be recorded on the medical history eCRF 
for subjects enrolled into the study. 
 
 
 
Section:  7.3.8 Electronic Patient Diary 
 
Paragraph 1, sentence 2 
 
Replace: 
 
The eDiary will collect date, time and number of capsules/tablets of cinacalcet taken 
each day. 
 
With: 
 
The eDiary will collect date, time and amount of cinacalcet taken each day. 


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Section:  7.3.8 Electronic Patient Diary 
 
Paragraph 1, Sentence 9 
 
Replace: 
 
The investigator and/or study coordinator will also reconcile any discrepancies between 
the eDiary and the pill count during the weekly study visits. 
 
With: 
 
The investigator and/or study coordinator will also reconcile any discrepancies between 
the eDiary and the IP accountability data during the weekly study visits. 
 
 
 
Section:  7.3.11 Laboratory Assessments 
Table 4 Analytes, last row of table 
Replace: 
BALP, NTx, CTx, P1NP, 25(OH) Vitamin D, FGF23 
 
With: 
 
BALP, NTx, CTx, P1NP, 25(OH) Vitamin D, FGF23 (not required for subjects from 
20110100) 
 
 
 
Section:  7.3.12 Home Healthcare 
 
Paragraph 1 
 
Replace: 
 
Subjects receiving peritoneal dialysis may not have to be seen routinely by the 
investigator at the clinical site on a weekly basis.  These subjects will be required to be 
seen in the clinic every 2 weeks, including the week prior to the monthly dosing titration 
visit at a minimum during the trial.  The investigator may utilize their site staff or a 
qualified home healthcare service provider to conduct the procedures required for 
remaining weekly study visits, subject to the investigator’s direction and oversight. 
 
With: 
 
Subjects receiving peritoneal dialysis may not have to be seen routinely by the 
investigator at the clinical site on a weekly basis.  These subjects will be required to be 


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Page 46 of 50 
 
seen in the clinic every 2 weeks, including the week prior to the monthly dosing titration 
visit and those visits where central laboratory samples are collected, at a minimum 
during the trial.  The investigator may utilize their site staff or a qualified home healthcare 
service provider to conduct the procedures required for remaining weekly study visits, 
subject to the investigator’s direction and oversight. 
 
 
 
Section:  9.2 Reporting of Adverse Events 
 
Paragraph 1 
 
Replace: 
 
Ongoing adverse events and serious adverse events in the parent Study 20130356, will 
be entered as a concurrent condition on the Medical History eCRF. 
 
With: 
 
Ongoing adverse events and serious adverse events in Studies 20130356 or 20110100, 
will be entered as a concurrent condition on the Medical History eCRF. 
 
 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
 
Paragraph 1 
 
Replace: 
 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur from the date of the first dose 
through 30 days after the last day of the dosing interval of IP or end of study visit 
(whichever is later) are recorded in the subject’s medical record and are submitted to 
Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the applicable eCRF. 
 
With: 
 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur from the date of the first dose 
through 30 days after the last day of the dosing interval of IP or end of study visit 
(whichever is later) are recorded in the subject’s medical record and are submitted to 
Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the serious adverse event form. 


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Section:  10.1.3 Covariates and Subgroups 
 
Replace: 
 
The primary, secondary, and safety endpoints will be summarized by parent study 
baseline age group (6 to < 12 years old and 12 to < 18 years old as supportive analyses. 
 
With: 
 
The primary, secondary, and safety endpoints will be summarized by baseline age group 
 
(6 to < 12 years and 12 to < 18 years for Study 20130356; 28 days to < 2 years and 
 
2 to < 6 years for Study 20110100) as supportive analyses. 
 
 
 
Section:  10.2 Sample Size Considerations 
 
Replace: 
 
This is an extension study of Study 20130356.  The sample size of approximately 48 for 
the parent study will result in a maximum of 48 subjects. 
 
With: 
 
This is an extension study of Studies 20130356 and 20110100.  The sample size may 
be up to 78 subjects. 
 
 
 
Section:  10.3.1 Interim Analysis 
 
Paragraph 1 
 
Replace: 
 
An interim analysis will be conducted.  The timing of the interim analysis will be 
dependent on the completion of the parent study.  There is no formal statistical testing. 
The analysis for all endpoints will be descriptive in nature. 
 
With: 
 
An interim analysis will be conducted.  The timing of the interim analysis will be 
dependent on the completion of the Study 20130356.  There is no formal statistical 
testing.  The analysis for all endpoints will be descriptive in nature.  There are no plans 
to change the conduct of the study based on interim analysis results. 


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Section:  10.4.1 General Considerations 
 
Paragraph 4 
 
Add: 
 
All summaries will be provided by study treatment group: Study 20130356 (SOC, 
SOC + cinacalcet, overall) and Study 20110100. 
 
 
 
Section:  10.4.2 Primary Endpoint 
 
Paragraph 1, sentence 3 
 
Delete: 
 
The incidence will be categorized and summarized by parent study treatment group and 
overall. 
 
 
 
Section:  10.4.3 Secondary Endpoints 
 
Paragraph 1, Sentence 4 
 
Replace: 
 
Summary statistics will be provided for serum cCa and phosphorus values at day 1 to 
week 11, and week 28 within the study population and within each age group by 
previous treatment group in the parent study and overall.  No imputation of missing data 
will be utilized. 
 
With: 
 
Summary statistics will be provided for serum cCa and phosphorus values at day 1 to 
week 11, and week 28.  No imputation of missing data will be utilized. 


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Section:  10.4.4 Safety Endpoints 
 
Paragraphs 2, 3, 4, and 5 
Replace: 
Adverse Events 
 
All treatment-emergent adverse events occurring during the study will be coded using 
the latest version of the MedDRA dictionary.  The subject incidence of all 
treatment-emergent adverse events, serious adverse events, treatment-related adverse 
events, and serious treatment-related adverse events will be tabulated by system organ 
class and preferred term in descending order of frequency by parent study treatment 
group.  Tables of treatment-emergent adverse events, fatal adverse events, serious 
adverse events, and adverse events leading to withdrawal from IP or from study will be 
tabulated by preferred term by parent study treatment group. 
 
Laboratory Data, Blood Pressure, and Heart Rate 
 
Descriptive statistics for values, changes and percent changes of selected laboratory 
parameters from first dose of IP date will be presented by parent study treatment group 
at each measurement time point during the study.  In addition, shift tables will 
summarize grades using CTCAE (version 4) by worst grades between baseline and any 
visit up to the end of the study for selected hematology and chemistry parameters. 
 
The incidence of hypocalcemia after the first dose of IP will be summarized using 
descriptive statistics by parent study treatment group.  Hypocalcemia will be defined in 
two ways, with the subject incidence of corrected serum calcium of < 7.5 mg/dL and 
< 8.4 mg/dL both being summarized.  Subject incidence of ionized calcium value 
 
< 1.05 mmol/L and <1.00 mmol/L will be summarized.  Blood pressure (systolic and 
diastolic) and  heart rate will be summarized at each time point. 
 
Medications of Interest 
 
Use of vitamin D sterols and phosphate binders during study will be tabulated by parent 
study treatment group. 
 
With: 
 
Adverse Events 
 
All treatment-emergent adverse events occurring during the study will be coded using 
the latest version of the MedDRA dictionary.  The subject incidence of all 


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treatment-emergent adverse events, serious adverse events, treatment-related adverse 
events, and serious treatment-related adverse events will be tabulated by system organ 
class and preferred term in descending order of frequency.  Tables of treatment- 
emergent adverse events, fatal adverse events, serious adverse events, and adverse 
events leading to withdrawal from IP or from study will be tabulated by preferred term. 
 
Laboratory Data, Blood Pressure, and Heart Rate 
 
Descriptive statistics for values, changes and percent changes of selected laboratory 
parameters from first dose of IP date will be presented at each measurement time point 
during the study.  In addition, shift tables will summarize grades using CTCAE 
(version 3) by worst grades between baseline and any visit up to the end of the study for 
selected hematology and chemistry parameters. 
 
The incidence of hypocalcemia after the first dose of IP will be summarized using 
descriptive statistics.  Hypocalcemia will be defined in two ways, with the subject 
incidence of corrected serum calcium of < 7.5 mg/dL and < 8.4 mg/dL both being 
summarized.  Subject incidence of ionized calcium value < 1.05 mmol/L and < 1.00 
mmol/L will be summarized.  Blood pressure (systolic and diastolic) and  heart rate will 
be summarized at each time point. 
 
Medications of Interest 
 
Use of vitamin D sterols and phosphate binders during study. 


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Page 1 of 42 
 
 
 
Amendment 3 
 
Protocol Title:  A Multicenter Single-arm Extension Study to Characterize the 
Long-term Safety of Cinacalcet Hydrochloride in the Treatment of Secondary 
Hyperparathyroidism in Pediatric Subjects With Chronic Kidney Disease on 
Dialysis 
 
 
 
Amgen Protocol Number (cinacalcet HCl) 20140159 
 
 
 
 
 
Amendment Date: 
16 March 2016 
 
Rationale: 
 
The protocol is being amended to allow not only subjects who complete the 20-week 
treatment period Study 20130356 or reach study termination or the week 26 End of 
Study visit in Study 20110100 or reach study termination to be eligible to receive 
28 weeks of treatment with cinacalcet in this single-arm extension study.  It is also being 
amended to include additional secondary efficacy and exploratory endpoints. 
Specifically: 
 
• 
Added subjects who are eligible for and enroll in the 20140159 extension study will 
do so at the completion of the 20-week treatment period in 20130356 or following 
Study 20130356 termination and within 1 week of day 1 of 20140159. 
• 
Clarified that subjects who are in Study 20130356 study, the end of study (EOS) 
procedures for an individual subject will occur at the same time as the end of 
investigational product (EOIP) visit for subjects enrolling in Study 20140159. 
• 
Clarified that for subjects enrolled in Study 20140159 at the time of 20110100 study 
termination, the 2-week safety follow-up period in 20110100 will not apply for these 
subjects and the EOS procedures for an individual subject will occur at the time as 
the EOIP visit for subjects enrolling in Study 20140159. 
• 
Added the EOIP visit in study 20130356 and day 1 in Study 20140159 will be the 
same visit unless there is an administrative delay.  Eligible subjects will complete 
day 1 of 20140159 assessments. 
• 
Clarified the initial dose of cinacalcet for eligible subjects from the cinacalcet arm in 
20130356 who meet eligibility on day 1 for Study 20140159. 
 
• 
Clarified the initial dose of cinacalcet for eligible subjects from Study 20110100 on 
day 1 of Study 20140159. 
• 
Added eligible subjects who reach Study 20110100 termination before week 26 will 
not complete the safety follow-up period in Study 20110100, beginning the 20140159 
extension study at the early termination visit.  The early termination/EOS visit in 
study 20110100 and Day 1 in Study 20140159 will be the same visit unless there is 


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an administrative delay and that eligible subjects will complete the End of Study visit 
or early termination visit for Study 20110100 and continue or restart cinacalcet 
treatment in this study on day 1 based on dosing instructions 
• 
Added inclusion criteria for all subjects with > 14 days between the last study visit in 
Study 20130356 or 20110100 and screening for Study 20140159 who are prescribed 
anti-convulsant medication must be on a stable dose 
• 
Added inclusion criteria for all subjects from 20130356 study.  Subjects must have 
completed treatment through week 20 in the 20130356 study or on study at time of 
Study 20130356 termination 
• 
Added inclusion criteria for subjects randomized to the 20130356 Standard of Care 
Arm Only must have an iPTH value ≥ 300 pg/mL (within 1 week of day 1 in 
Study 20140159) and corrected calcium value ≥ 8.8 mg/dL within 1 week of Day 1 in 
Study 20140159 
 
• 
Added inclusion criteria for all subjects from the 20110100 study.  Subjects must 
have completed Week 26 End of Study visit in the, 20110100 study or on study at 
time of Study 20110100 termination 
• 
Added exclusion criteria that subjects with a new onset of seizure or worsening of 
pre-existing seizure disorder would not be eligible to enroll in the study 
• 
Added exclusion criteria for all subjects with > 14 days between the last study visit in 
Study 20130356 or 20110100 and the screening visit in Study 20140159 
 
• 
Revised the Dose Adjustments sections for clarity. 
 
• 
Added secondary endpoints for the 20140159 study only 
 
• 
Added secondary endpoints for the combined 20130356, 20110100 and 20140159 
studies 
• 
Added exploratory endpoints for the 20140159 study only 
 
• 
Added exploratory endpoints for the combined 20130356, 20110100 and 20140159 
studies 
• 
Added the definition of Efficacy Analysis Set 
 
• 
Clarified the interim analyses that may be conducted 
 
• 
Clarified the primary analysis of all endpoints will be conducted after all subjects 
completed the week 32 End of Study visit or early terminated the study and clarified 
the secondary analysis of the primary endpoint 
• 
Clarified the analysis of the secondary endpoints 
 
• 
Clarified safety endpoints in 20140159 study only and combined 20130356, 
20110100, and 20140159 studies will be summarized by treatment group in parent 
studies and overall 
• 
Administration, typographical and formatting changes were made throughout the 
protocol.  Updates have been implemented to align with the current template. 


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Page 3 of 42 
 
 
Description of Changes: 
 
Section:  Global 
 
Change: 
 
Minor corrections throughout (eg, correcting typographical and formatting errors) 
Section:  Global 
Replace: 
 
22 July 2015 
 
With: 
 
16 March 2016 
 
Section:  Title Page 
 
Added: 
 
Amendment 3: 
16 March 2016 
 
Section:  Synopsis, Secondary Endpoints 
 
Replace: 
 
Secondary Endpoints: 
 
• 
Percent change from day 1 in intact parathyroid hormone (iPTH) to week 11 and 
week 28 
• 
Serum corrected calcium (cCa) values at day 1, week 11, and week 28 
 
• 
Serum phosphorus values at day 1, week 11, and week 28 
 
With: 
 
Secondary Endpoints: 
 
Study 20140159 only 
 
• 
Achievement of ≥ 30% reduction from baseline to mean intact parathyroid 
hormone (iPTH) during weeks 11 and 15 (standard of care [SOC] arm of 
Study 20130356 only) 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during 
weeks 23 and 28 (SOC arm of Study 20130356 only) 
• 
Percent change from baseline to mean iPTH during weeks 23 and 28 (SOC 
arm of Study 20130356 only) 
 
• 
Change in corrected total serum calcium from baseline to mean value 
during weeks 23 and 28 


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Page 4 of 42 
 
 
• 
Change in serum phosphorus from baseline to mean value during 
weeks 23 and 28 
• 
Achievement of a mean iPTH ≤ 300 pg/mL during weeks 23 and 28 
 
•   Percent change from day 1 in intact parathyroid hormone (iPTH) to week 11 and 
week 28 
• 
Serum corrected calcium (cCa) at baselinevalues at day 1, week 11, and 
week 28 
• 
Serum phosphorus at baselinevalues at day 1, week 11, and week 28 
 
Combined Studies 20130356, 20110100, and 20140159 
 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks 11 and 15 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks 23 and 28 
• 
Percent change in iPTH over time from day 1 of cinacalcet treatment 
 
• 
Change in serum cCa over time from day 1 of cinacalcet treatment 
 
• 
Change in serum phosphorus over time from day 1 of cinacalcet treatment 
 
Section:  Synopsis Exploratory Endpoints 
 
Replace: 
 
Exploratory Endpoint: 
 
• 
Growth velocity from day 1 to end of study 
 
• 
Change in Tanner stage from day 1 to end of study 
 
With: 
 
Exploratory Endpoints: 
Study 20140159 only 
• 
Growth velocity from baseline to end of study (EOS) 
 
• 
Change in Tanner stage from baseline to EOS 
 
Combined Studies 20130356, 20110100, and 20140159 
 
• 
Growth velocity from day 1 of cinacalcet treatment to EOS 
 
• 
Change in Tanner stage from day 1 of cinacalcet treatment to EOS 
 
•   Growth velocity from day 1 to end of study 
 
•   Change in Tanner stage from day 1 to end of study 


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Section:  Protocol Synopsis, Summary of Subject Eligibility Criteria 
 
Replace: 
 
Summary of Subject Eligibility Criteria:  Subjects who complete the 20-week 
treatment period in Study 20130356 or the week 26 End of Study visit in 
Study 20110100 will be eligible to receive 28 weeks of treatment with cinacalcet in this 
extension study, followed by a 4-week safety follow-up.  Subjects must also meet the 
inclusion and exclusion criteria for this extension study in order to be eligible.  Subjects 
must provide written informed consent (parents or guardian) and assent, where 
appropriate, according to local regulations specific to the procedures in this study. 
 
• 
Subjects enrolled in the standard of arm of Study 20130356 will be eligible for the 
extension study if the iPTH ≥ 300 pg/mL and the cCa ≥ 8.8 mg/mL at the 
week 19 visit.  Eligible subjects from the cinacalcet arm in Study 20130356 will 
continue cinacalcet treatment following the dosing rules described in 
Section 6.2.3. 
 
• 
Eligible subjects from 20110100 study will restart cinacalcet treatment as 
described in Section 6.2.3.1. 
 
With: 
 
Summary of Subject Eligibility Criteria:  Subjects who complete the 20-week 
treatment period in Study 20130356 or reach study termination in Study 20130356 or 
the week 26 End of Study visit in Study 20110100 or reach study termination in 
Study 20130356 will be eligible to receive 28 weeks of treatment with cinacalcet in this 
extension study, followed by a 4-week safety follow-up.  Subjects must also meet the 
inclusion and exclusion criteria for this extension study in order to be eligible.  Subjects 
must provide written informed consent (parents or guardian) and assent, where 
appropriate, according to local regulations specific to the procedures in this study. 
 
• 
Subjects enrolled in the standard of care SOC arm of Study 20130356 will be 
eligible for the extension study if the iPTH is ≥ 300 pg/mL and the cCa is 
≥ 8.8 mg/mL within 7 days of day 1 in Study 20140159  at the week 19 visit. 
 
• 
Eligible subjects from the cinacalcet arm of  in  Study 20130356 will restart or 
continue cinacalcet treatment following the dosing rules described in 
Section 6.2.3.1.1  6.2.3. 
 
• 
Eligible subjects from Study 20110100 study will restart or continue cinacalcet 
following the dosing rules  treatment as described in Section 6.2.3.1.2  6.2.3.1. 


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Page 6 of 42 
 
 
Section:  Protocol Synopsis, Procedures 
 
Replace: 
 
Procedures:  Informed consent, and assent where applicable, for this study should be 
presented during the studies 20130356 or 20110100.  The informed consent, including 
assent as appropriate, will be obtained prior to execution of any study procedures for this 
extension study.  Where the Screening and day 1 assessments for Study 20140159 
overlap with visits in the 20130356 or 20110100 studies, these will be performed once at 
the site and applied to both study visits to minimize duplicate study assessments, eg, 
20130356 week 19 and 20140159 Screening.  The subject visits and assessments for 
this study will occur from baseline through to the end of study.  Assessments during this 
study will include: 
 
• 
Collection of blood samples for the evaluation of blood chemistry, hematology, 
calcium, iPTH, and bone biomarkers 
• 
Physical assessments including vital signs (ie, blood pressure, heart rate) 
 
• 
12-lead electrocardiogram (ECG) at baseline and week 32 (if the subject ends 
the study prior to week 32, the 12-lead ECG will be performed at the last study 
visit) 
• 
Assessments for symptoms of hypocalcemia 
 
• 
Recording of adverse events, concomitant medications, and IP compliance 
 
Subjects from 20130356: Subjects who complete the 20-week treatment period in 
Study 20130356 will be eligible to receive cinacalcet treatment in the current study. 
After confirming eligibility, subjects in the 20130356 Standard of Care (SOC) group will 
receive the initial dose of cinacalcet based on the subject’s dry weight at baseline, 
0.20 mg/kg/day, rounded down to the nearest PSD.  Subjects from the 20130356 SOC 
group will follow the same cinacalcet titration schedule as subjects who received 
cinacalcet in Study 20130356.  Subjects will continue in the extension study on 
cinacalcet at the completion of the treatment period (week 20) in 20130356 study 
following the dose adjustments outlined in Section 6.2.3.1.1.1.  Subjects in this group will 
be eligible to receive dose titrations during the extension study if the maximum dose of 
2.5 mg/kg has not been reached and they meet the titration criteria defined in Section 6. 
 
Subjects from 20110100: Subjects who complete the Week 26 End of Study visit will be 
eligible to receive cinacalcet treatment in the current study.  After confirming eligibility, 
subjects will receive the initial dose of cinacalcet based on the subject’s dry weight at 
time of enrollment to 20140159 and age at time of enrollment to 20110100, 


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Page 7 of 42 
 
0.20 mg/kg/day, rounded down to the nearest PSD.  Subjects will follow the dose 
adjustments outlined in Section 6.2.3.1.1.1.  Subjects in this group will be eligible to 
receive dose titrations during the extension study if the maximum dose of 2.5 mg/kg has 
not been reached and they meet the titration criteria defined in Section 6. 
 
Weekly monitoring of ionized calcium will be required for all subjects through the end of 
the treatment period, week 28. 
 
Cinacalcet doses will be calculated by the site staff and confirmed by the interactive voice 
response/interactive web response (IVR/IWR) system following the titration tables in 
Section 6.  The titration tables are based on cCa and iPTH values from the central 
laboratory collected one week before dose titration.  Final dose assignment will be based 
on the ionized calcium obtained on the day of titration.  An assessment of symptomatic 
hypocalcemia will also be performed on the day of titration.  Additional weekly dose 
adjustments for safety are permitted as described in Section 6.2.3.1.1.1.  The maximum 
dose assigned for all subjects will be 2.5 mg/kg/day (based on dry weight at day 1) not to 
exceed a dose of 180 mg/day for subjects from 20130356 and 60 mg/day for subjects 
from 20110100. 
 
With: 
 
Procedures:  Informed consent, and assent where applicable, for this study should be 
presented during the Studies 20130356 or 20110100.  The informed consent, including 
assent as appropriate, will be obtained prior to execution of any study procedures for this 
extension study.  Where the Screening and day 1 assessments for Study 20140159 
overlap with visits in the 20130356 or 20110100 studies, these will be performed once at 
the site and applied to both study visits to minimize duplicate study assessments, eg, 
20130356 week 19 end of investigational product (EOIP) and 20140159 Screening. 
The subject visits and assessments for this study will occur from baseline through to the 
end of study.  Assessments during this study will include: 
 
• 
collection of blood samples for the evaluation of blood chemistry, hematology, 
calcium, iPTH, and bone biomarkers 
• 
physical assessments including vital signs (ie, blood pressure, heart rate) 
 
• 
12-lead electrocardiogram (ECG) at baseline and week 32 (if the subject ends 
the study prior to week 32, the 12-lead ECG will be performed at the last study 
visit) 
• 
assessments for symptoms of hypocalcemia 
 
• 
recording of adverse events, concomitant medications, and IP compliance 


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Subjects from Study 20130356:  Subjects who complete the 20-week treatment period 
in Study 20130356 or are still on study at the time of Study 20130356 termination, 
will be eligible to receive cinacalcet treatment in the current study. 
 
• 
Subjects from the SOC group in 20130356:  After confirming eligibility, 
subjects in the 20130356 SOC group will receive the initial dose of cinacalcet 
based on the subject’s dry weight at day 1  baseline in Study 20140159, 
0.20 mg/kg/day, rounded down to the nearest PSD.  Subjects from the 20130356 
SOC group will follow the same cinacalcet titration schedule as subjects who 
received cinacalcet in Study 20130356. 
• 
Subjects from the cinacalcet group in 20130356:  After confirming eligibility, 
subjects from the cinacalcet group will continue to receive cinacalcet at the 
same dose as EOIP visit if there are ≤ 14 days between the last dose of 
cinacalcet treatment in Study 20130356 and day 1 of Study 
20140159.  If the cinacalcet dose has been withheld or missed for > 14 days 
at the time of day 1 of Study 20140159, subjects will receive the initial dose 
of cinacalcet based on the subject’s dry weight at time of enrollment to 
20140159. Subjects will continue in the extension study on cinacalcet at the 
completion of the treatment period (week 20) in 20130356 study following the 
dose adjustments outlined in Section 6.2.3.1.1.1.  Subjects in this group will be 
eligible to receive dose titrations during the extension study if the maximum dose 
of 2.5 mg/kg (based on 20140159 day 1 dry weight), not exceeding 180 mg, 
has not been reached and they meet the titration criteria defined in Section 6. 
 
Subjects from 20110100:  Subjects who complete the week 26 End of Study visit or 
are still on study at the time of Study 20110100 termination, will be eligible to 
receive cinacalcet treatment in the current study.  After confirming eligibility, subjects will 
continue to receive cinacalcet at the same dose as EOIP visit if there are ≤ 14 days 
between the last dose of cinacalcet treatment in Study 20110100 and day 1 of 
Study 20140159.  If the cinacalcet dose has been withheld or missed for > 14 days 
at the time of day 1 of Study 20140159, subjects will receive the initial dose of 
cinacalcet based on the subject’s dry weight at time of enrollment to 20140159 and age 
at time of enrollment to 20110100, 0.20 mg/kg/day, rounded down to the nearest PSD. 
Subjects will follow the dose adjustments outlined in Section 6.2.3.1.1.  Subjects in this 
group will be eligible to receive dose titrations during the extension study if the maximum 
dose of 2.5 mg/kg (based on 20140159 day 1 dry weight), not exceeding 60 mg, has 
not been reached and they meet the titration criteria defined in Section 6. 
 
During the 20140159 study: 
 
Weekly monitoring of ionized calcium will be required for all subjects through the end of 
the treatment period, week 28. 


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Cinacalcet doses will be calculated by the site staff and confirmed by the interactive voice 
response/interactive web response (IVR/IWR) system following the titration tables in 
Section 6.  The titration tables are based on cCa and iPTH values from the central 
laboratory collected one week before dose titration.  Final dose assignment will be based 
on the ionized calcium obtained on the day of titration.  An assessment of symptomatic 
hypocalcemia will also be performed on the day of titration.  Additional weekly dose 
adjustments for safety are permitted as described in Section 6.2.3.1.  The maximum 
dose assigned for all subjects will be 2.5 mg/kg/day (based on dry weight at day 1 in 
 
Study 20140159) not to exceed a dose of 180 mg/day for subjects from 20130356 and 
 
60 mg/day for subjects from 20110100. 
 
 
Section:  Protocol Synopsis, Statistical Considerations 
 
Replace: 
 
Statistical Considerations:  There is no formal statistical testing for this study.  The 
analysis of the primary and secondary endpoints will be descriptive in nature. 
 
For categorical variables, the number and percentage of subjects in each category will 
be reported.  Descriptive statistics will be used to summarize data for continuous 
variables (including n, mean, standard deviation (SD) or standard error (SE), median, 
25th  (Q1) and 75th  (Q3) percentiles, minimum and maximum values, where applicable). 
 
All summaries will be provided by study treatment group:  Study 20130356 (SOC, 
SOC + cinacalcet, overall) and Study 20110100. 
 
With: 
 
Statistical Considerations:  There is no formal statistical testing for this study.  The 
analysis of the primary and secondary endpoints will be descriptive in nature. 
 
For categorical variables, the number and percentage of subjects in each category will 
be reported.  Descriptive statistics will be used to summarize data for continuous 
variables (including n, mean, standard deviation (SD) or standard error (SE), median, 
25th  (Q1) and 75th  (Q3) percentiles, minimum and maximum values, where applicable). 
 
All summaryies tables will be provided by study treatment group: Study 20130356 
(SOC, SOC + cinacalcet, overall) and Study 20110100 and overall, unless otherwise 
specified. 


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Section:  Study Design and Treatment Schema 
 
Replace: 
 
 
Study Design and Treatment Schema 
 
 
Informed Consent 
Subject Assent (if applicable) 
(Study 20130356 week 19; 
Study 20110100 week 26 – 7 days) 
 
 
 
 
 
Screening Period 
1 week 
 
 
 
 
 
Eligible Subjects Enrolled 
Day 1 
(Study 20130356 week 20/EOIP; 
Study 20110100 week 26/EOS) 
 
 
 
 
 
 
 
 
Treatment Period* 
Day 1 – Week 28 
Cinacalcet QD 
 
 
 
 
 
 
 
End of Study 
Week 32 
 
 
 
The initial dose of cinacalcet assigned will be based on the dosing in the originating parent study.  Refer 
to Section 6 of the protocol for additional details. 


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With: 
 
 
Study Design and Treatment Schema 
 
 
Informed Consent 
Subject Assent (if applicable) 
Are collected within 7 days before day 1 of 
Study 20140159
a 
 
 
 
 
 
 
 
Screening Period 
7 days before the 20140159 day 1 visita 
 
 
 
 
 
 
Eligible Subjects Enrolled 
 
Day 1 of Study 20140159 
 
 
 
 
 
 
 
Treatment Periodb 
Day 1 – Week 28 
Cinacalcet QD 
 
 
 
 
 
 
End of Study 
Week 32 
 
 
a When it is not possible to perform a study visit at the specified time point, the visit may be 
performed within ± 3 days. 
b The initial dose of cinacalcet assigned will be based on the dosing in the originating parent study.  Refer 
to Section 6 of the protocol for additional details. 


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Section:  List of Abbreviations 
 
Delete 
 
LSP 
Lactation Surveillance Program 
PSP 
Pregnancy Surveillance Program 
 
Add: 
 
sNDA 
Supplemental New Drug Application 
 
Section:  2.5.1 Amgen Study 20130356 
 
Replace: 
 
Amgen Study 20130356 is a phase 3 randomized, multicenter, open-label, controlled 
study.  In Study 20130356, cinacalcet is being evaluated in pediatric subjects enrolled 
between the ages of 6 and < 18 years, with SHPT and CKD receiving either 
hemodialysis or peritoneal dialysis.  Approximately 48 subjects are planned to be 
randomized into the study to one of two treatment arms in a 1:1 allocation ratio; daily 
oral administration of cinacalcet in addition to SOC or SOC.  Once randomized, the 
expected treatment period in 20130356 is 20 weeks with a 4-week safety follow-up 
period.  Subjects who are eligible for and enroll in the 20140159 extension study will do 
so at the completion of the 20-week treatment period in 20130356 or following 
Study 20130356 termination and within 1 week of day 1 of 20140159.  The 4-week 
safety follow-up period in 20130356 will not apply for these subjects. 
 
With: 
 
Amgen Study 20130356 is a phase 3 randomized, multicenter, open-label, controlled 
study.  In Study 20130356, cinacalcet is being evaluated in pediatric subjects enrolled 
between the ages of 6 and < 18 years, with SHPT and CKD receiving either 
hemodialysis or peritoneal dialysis.  Approximately 48 subjects are planned to be 
randomized into the study to one of two treatment arms in a 1:1 allocation ratio; daily 
oral administration of cinacalcet in addition to SOC or SOC only.  Once randomized, the 
expected treatment period in 20130356 is 20 weeks with a 4-week safety follow-up 
period.  Subjects who are eligible for and enroll in the 20140159 extension study will do 
so at the completion of the 20-week treatment period in 20130356 or following 
Study 20130356 termination and within 7 days of day 1 of 20140159 unless there is 
an administrative delay.  The end of study (EOS) procedures for an individual 
subject will occur at the same time as the end of investigational product (EOIP) 


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visit for subjects enrolling in Study 20140159.  The 4-week safety follow-up period in 
 
20130356 will not apply for these subjects. 
 
 
Section:  2.5.2 Amgen Study 20110100 
 
Replace: 
 
Amgen Study 20110100 is a phase 2, multicenter, open-label, single-arm study.  In Study 
20110100 cinacalcet is being evaluated in pediatric subjects enrolled between the ages 
of 28 days and < 6 years, with SHPT and CKD receiving either hemodialysis or peritoneal 
dialysis.  The expected treatment period in 20110100 is 24 weeks of daily oral 
administration of cinacalcet in addition to SOC with a 2-week safety follow-up period. 
Subjects who are eligible for and enroll in the 20140159 extension study will do so at the 
completion of the Week 26 End of Study visit. 
 
With: 
 
Amgen Study 20110100 is a phase 2, multicenter, open-label, single-arm study.  In Study 
20110100 cinacalcet is being evaluated in pediatric subjects enrolled between the ages 
of 28 days and < 6 years, with SHPT and CKD receiving either hemodialysis or peritoneal 
dialysis.  The expected treatment period in 20110100 is 24 weeks of daily oral 
administration of cinacalcet in addition to SOC with a 2-week safety follow-up period. 
Subjects who are eligible for and enroll in the 20140159 extension study will do so at the 
completion of the week 26 End of Study visit or at Study 20110100 termination and 
within 7 days of day 1 of 20140159 unless there is an administrative delay.  For 
subjects enrolled in the 20140159 extension study at the time of 20110100 study 
termination, the 2-week safety follow-up period in 20110100 will not apply for 
these subjects and EOS procedures for an individual subject will occur at the time 
as the EOIP visit for subjects enrolling in Study 20140159. 
 
Section:  3.1.1 Subjects from Study 20130356 
 
Replace: 
 
Eligible subjects will complete the 20-week treatment period in study 20130356 and 
either continue or start cinacalcet treatment in this study.  Eligible subjects will not 
complete the safety follow-up period in Study 20130356, beginning the extension study 
at the week 20 end of investigational product (EOIP) study visit.  Week 20 in 
Study 20130356 and day 1 in Study 20140159 will be the same visit.  Eligible subjects 


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will complete 20140159 day 1 assessments (Section 7.1) and confirm eligibility in IVRS 
 
prior to dispensing IP on day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm in 
 
Study 20130356 will begin cinacalcet treatment on day 1 in Study 20140159 if their iPTH 
is ≥ 300 pg/mL and cCa is ≥ 8.8 mg/dL at week 19 of Study 20130356.  Eligible subjects 
from the cinacalcet arm in 20130356 will continue cinacalcet treatment on day 1 if their 
iPTH is ≥ 150 pg/mL and cCa is ≥ 8.4 mg/dL at week 19 of Study 20130356.  Cinacalcet 
dosing will follow the dose titration, dose withhold, and restarting rules defined in 
Section 6.2.3. 
 
All subjects from 20130356 will be eligible to titrate the cinacalcet dose at monthly 
titration visits to a maximum dose of 2.5 mg/kg/day based on the subject’s dry weight at 
day 1, not to exceed a dose of 180 mg/day. 
 
With: 
 
Eligible subjects will complete the 20-week treatment period in Study 20130356, or 
reach Study 20130356 termination and either continue, restart, or start cinacalcet 
treatment in this study.  Eligible subjects will not complete the safety follow-up period in 
Study 20130356, beginning the extension study at the 20130356  week 20 end of 
investigational product (EOIP) study visit.  The EOIP visit  Week 20 in Study 20130356 
and day 1 in Study 20140159 will be the same visit unless there is an administrative 
delay.  Eligible subjects will complete day 1 of 20140159 day 1 assessments 
(Section 7.1) and confirm eligibility in the interactive voice response (IVR) system 
before  prior to dispensing IP on day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm in 
 
Study 20130356 will begin cinacalcet treatment on day 1 in Study 20140159 if their iPTH 
 
is ≥ 300 pg/mL and cCa is ≥ 8.8 mg/dL during screening in Study 20140159  at week 
 
19 of study 20130356.  Eligible subjects from the cinacalcet arm in 20130356 will 
continue cinacalcet treatment on day 1 if their iPTH is ≥ 150 pg/mL and cCa is 
≥ 8.4 mg/dL during screening in Study 20140159.  If IP has been withheld or missed 
for > 14 days at the time of day 1 of Study 20140159, the subject will resume 
dosing at the starting dose level once all restart criteria are met  at week 19 of study 
 
20130356. 
 
Cinacalcet dosing will follow the dose titration, dose withhold, and restarting rules 
defined in Section 6.2.3. 


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Subjects will complete day 1 assessments (Section 7.1) and confirm eligibility in 
 
IVR system prior to dispensing IP on day 1. 
 
All subjects from 20130356 will be eligible to titrate the cinacalcet dose at monthly 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based on the 
subject’s dry weight at day 1 in Study 20140159, not to exceed a dose of 180 mg/day. 
 
Section:  3.1.2 Subjects from Study 20110100 
 
Replace: 
 
Eligible subjects will complete the week 26 End of Study visit for Study 20110100 and 
restart cinacalcet treatment in this study on day 1.  Eligible subjects will be screened 
during the safety follow-up period in Study 20110100, they will be required to have their 
20140159 day 1 visit and their 20110100 End of Study visit at the same time point. 
Week 26 in Study 20110100 and day 1 in this study will be the same visit.  Subjects will 
complete day 1 assessments (Section 7.1) and confirm eligibility in IVRS prior to 
dispensing IP on day 1. 
 
Eligible subjects from 20110100 will restart cinacalcet treatment based on their dry 
weight at the time of enrollment in 20140159 study and age at the time of enrollment in 
the 20110100 study.  Cinacalcet dosing will follow the dose titration, dose withhold, and 
restarting rules defined in Section 6.2.3.1.2. 
 
All subjects from 20110100 will be eligible to titrate the cinacalcet dose at monthly 
titration visits to a maximum dose of 2.5 mg/kg/day based on the subject’s dry weight at 
day 1 in Study 20140159, not to exceed a dose of 60 mg/day. 
 
With: 
 
Eligible subjects will complete the Week 26 End of Study visit or early termination visit 
for Study 20110100 and continue or restart cinacalcet treatment in this study on day 1 
based on dosing instructions outlined in Section 6.2.3.  Eligible subjects 
completing the full treatment period in Study 20110100 will be screened during the 
safety follow-up period in Study 20110100 and  they will be required to have their 
20140159 day 1 visit and their 20110100 week 26 End of Study visit at the same visit 
time point.  Eligible subjects who reach Study 20110100 termination before week 26 
will not complete the safety follow-up period in Study 20110100, beginning the 
20140159 extension study at the 20110100 early termination visit.  The early 


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termination/EOS visit in Study 20110100 and day 1 in Study 20140159 will be the 
same visit unless there is an administrative delay. 
 
Subjects will complete day 1 assessments (Section 7.1) and confirm eligibility in IVR 
 
system before being dispensed IP on day 1. 
 
Eligible subjects will continue cinacalcet treatment on day 1 based on their dry 
weight at the time of enrollment in 20140159 study if their iPTH is ≥ 150 pg/mL and 
cCa is ≥ 8.8 mg/dL (age < 2 years of age) or cCa is ≥ 8.4 mg/dL (age is ≥ 2 years of 
age) during screening in Study 20140159.  If IP has been withheld or missed for 
> 14 days at the time of day 1 of Study 20140159, the subject will resume dosing at 
the starting dose level based on dry weight at the time of enrollment once all 
restart criteria are met.   Eligible subjects from 20110100 will restart cinacalcet 
treatment based on their dry weight at the time of enrollment in 20140159 study and age 
at the time of enrollment in the 20110100 study. 
 
All subjects from 20110100 will be eligible to titrate the cinacalcet dose at monthly 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based on the 
subject’s dry weight at day 1 in Study 20140159, not to exceed a dose of 60 mg/day. 
 
Section:  3.3 Number of Subjects 
 
Replace: 
 
This study is open to subjects who complete the 20-week treatment period in 
 
Study 20130356 or the Week 26 End of Study visit in Study 20110100.  There may be 
up to 78 subjects enrolled in this study. 
 
With: 
 
This study is open to subjects who complete the 20-week treatment period in Study 
 
20130356 or reach study termination in Study 20130356 or the week 26 End of Study 
visit in Study 20110100or reach study termination in Study 20110100.  There may be 
up to 78 subjects enrolled in this study. 
 
Section:  4 Subject Eligibility 
 
Replace: 
 
Subjects from the cinacalcet arm in Amgen Study 20130356, who are on a dose 
withhold at the completion of week 20 in Amgen Study 20130356, may enroll in this 


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study if they meet eligibility criteria but will not restart dosing until the criteria for 
restarting dosing, defined in Section 6.2.3, are met. 
 
Subjects who were ≤ 18 years old at week 20 in the 20130356 study are eligible to enter 
this Study 20140159 even if they have already turned 18 years of age or are due to turn 
18 years of age during their planned participation in the 20140159 study. 
With: 
Subjects from the cinacalcet arm in Amgen of Study 20130356 or subjects in 
 
Study 20110100 who had their are on a dose withheld at the completion of week 20 
 
EOIP visit in Amgen Study 20130356, may enroll in this study if they meet eligibility 
criteria but will not restart dosing until the criteria for restarting dosing, defined in 
Section 6.2.3, are met. 
 
Subjects who were ≤ 18 years old at week 20 in the 20130356 study or at the time of 
study termination, are eligible to enter this Study 20140159 even if they have already 
turned 18 years of age or are due to turn 18 years of age during their planned 
participation in the 20140159 study. 
 
Section:  4.1.1 Inclusion Criteria 
 
Replace: 
 
101 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
day 1 study-specific activities/procedures being initiated. 
102 
Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
All subjects from 20130356 
 
103 
Completed treatment through week 20 in the 20130356 study 
104 
Dry weight ≥ 12.5 kg at day 1 of Study 20140159 
 
Subjects Randomized to the 20130356 Standard of Care Arm Only 
 
105 
iPTH value ≥ 300 pg/mL (week 19 in 20130356) 
106 
Corrected calcium value ≥ 8.8 mg/dL (week 19 in 20130356) 
 
All Subjects from 20110100 
 
107 
Completed week 26 End of Study visit in the, 20110100 study 
108 
Dry weight ≥ 7 kg at day 1 of Study 20140159 


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With: 
 
All Subjects 
 
101 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
Study 20140159 day 1 study-specific activities/procedures being initiated. 
102 
Dialysate calcium concentration ≥ 2.5 mEq/L at day 1 
 
All subjects with > 14 days between the last study visit in Study 20130356 or 
 
Study 20110100 and screening for Study 20140159 
 
103 
Subjects on anti-convulsant medication must be on a stable dose 
 
All subjects from 20130356 
 
104 
Completed treatment through week 20 in the 20130356 study or on study at the 
time of Study 20130356 termination 
105 
Dry weight ≥ 12.5 kg at day 1 of Study 20140159 
 
Subjects Randomized to the 20130356 Standard of Care Arm Only 
 
106 
iPTH value ≥ 300 pg/mL (within 7 days of day 1 in Study 20140159) (week 19 
in20130356) 
107 
Corrected calcium value ≥ 8.8 mg/dL within 7 days of day 1 in Study 20140159 
(week 19 in20130356) 
 
All Subjects from 20110100 
 
108 
Completed week 26 End of Study visit in the, 20110100 study or on study at the 
time of Study 20110100 termination 
109 
Dry weight ≥ 7 kg at day 1 of Study 20140159 
 
Section:  4.1.2 Exclusion Criteria 
 
General 
 
Studies 20130356 or 20110100 
 
Added: 
 
Studies 20130356 or 20110100 
 
211 
A new onset of seizures or worsening of pre-existing seizure disorder All 
Subjects with > 14 days between the last study visit in Study 20130356 or Study 
20110100 and the screening visit in Study 20140159 will have the following 
exclusion criteria applied during screening and day 1: 


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212 
Unstable chronic heart failure defined as worsening pulmonary edema or 
other signs and symptoms as per investigator assessment during 
screening 
213 
Received therapy with commercial cinacalcet after the last study visit in 
Study 20130356 or Study 20110100 before day 1 of Study 20140159 
 
214 
Scheduled date for kidney transplantation from a known living donor that 
makes completion of the study unlikely 
 
215 
Either new or recurrent cardiac ventricular arrhythmias requiring a change 
in treatment within 10 days prior to screening visit or day 1 of 
Study 20140159 screening 
 
216 
Hepatic impairment indicated by elevated levels of hepatic transaminase or 
bilirubin (aspartate aminotransferase [AST] ≥ 1.5 × upper limit of normal 
[ULN] OR alanine aminotransferase [ALT] ≥ 1.5 × ULN OR total 
bilirubin ≥ 1 × ULN per institutional laboratory range) during screening 
 
Section:  4.1.2 Exclusion Criteria 
 
General 
 
Studies 20130356 or 20110100 
 
Replace: 
 
208 
If sexually active, subject is not willing to use highly effective contraception during 
treatment and for at least 9 days after the end of treatment. 
 
With: 
208 
If sexually active, subject is not willing to use acceptable  highly effective 
contraception during treatment and for at least 9 days after the end of treatment. 
 
At Day 1 Study Visit-All Subjects 
 
212 
Central laboratory values (cCa, iPTH) were not obtained/are not available for 
 
• 
20130356 week 19 or 
 
• 
20140159 Screening visit for subjects from 20110100 study 
 
With: 
 
All Subjects – At Day 1 Study Visit – All Subjects 
 
217 
Central laboratory values (cCa, iPTH) were not obtained/are not available at 
day 1 in Study 20140159 
•   20130356 week 19 or 
 
•   20140159 Screening visit for subjects from 20110100 study 
Delete: 
At Day 1 Study Visit-Subjects Rolling Over from 20130356 Cinacalcet Arm or from 
20110100 Study 


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217 
Cinacalcet dose withheld for ≥ last 4 weeks of treatment in studies 20130356 and 
201101100. 
 
218 
 If sexually active, subject is not willing to use highly effective contraception during 
treatment and for at least 9 days after the end of treatment. 
 
Section:  5.1 Screening 
 
Replace: 
 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
The informed consent can be signed up to (± 3 days) prior to 20140159 day 1. 
 
With: 
 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
The informed consent can be signed up to 7 days (± 3 days) prior to 20140159 day 1. 
 
Section:  5.2 Enrollment 
 
Replace: 
 
The subject will be considered enrolled in the extension study: 
 
• 
20130356 subjects will be assigned a cinacalcet dose based on the treatment arm 
and/or last dose received in Study 20130356. 
• 
20110100 subjects will be assigned a cinacalcet dose based on their dry weight at 
the time of enrollment in the 20140159 study and age at time of enrollment in the 
20110100 study. 
With: 
The subject will be considered enrolled in the extension study: 
 
• 
20130356 subjects will be assigned a cinacalcet dose based on the treatment 
arm and/or last dose received in Study 20130356 following the dosing 
instructions in Section 6.2.3 
• 
20110100 subjects will be assigned a cinacalcet dose based on enrollment  the 
last dose received at the EOIP visit in Study 20110100 study following the 
dosing instructions in Section 6.2.3  their dry weight at the time of enrollment in 
the 201401159 study and the age at the time of. 


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Section:  6.2.3 Dosage, Administration, and Schedule 
 
Replace: 
 
• 
Subjects ≥ 6 years of age:  2.5, 5, 10, 15, 30, 60, 90, 120, and 180 mg. 
 
− Subjects from 20130356 may receive capsules for any dose which is an exact 
multiple of 5 mg. Subjects who are assigned doses of 60 - 180 mg/day will 
require administration of 2 - 6 tablets per dose.  For those subjects unable to 
swallow tablets, capsules may be dispensed. 
• 
Subjects < 6 years of age:  1, 2.5, 5, 7.5, 10, 15, 30 and 60 mg. Subjects from 
Study 20110100 will start cinacalcet in Study 20140159 at 0.20 mg/kg/day based on 
the subject’s dry weight at the 20140159 day 1 timepoint and age at time of 
enrollment in 20110100 study, rounded down to the lowest PSD. 
- 
Subjects assigned dose of 10-60 mg/day will require that more than 1 capsule 
per dose be sprinkled on soft food or used to create the liquid suspension for 
administration. 
- 
Subjects enrolling into 20140159 from 20110100 would have a maximum dose of 
2.5 mg/kg/day based on the subject’s day 1 dry weight or 60 mg daily, whichever 
is lower. 
With: 
 
• 
Subjects ≥ 6 years of age:  2.5, 5, 10, 15, 30, 60, 90, 120, and 180 mg.  Subjects 
from Study 20130356 will either continue to receive cinacalcet at the same 
dose as at the EOIP visit if ≤ 14 days have passed between last dose of 
cinacalcet treatment in Study 20130356 and day 1 of Study 20140159.  If 
> 14 days have passed, subjects will start cinacalcet in Study 20140159 at 
0.20 mg/kg/day based on the subject’s dry weight at Study 20140159 day 1 time 
point and age at time of enrollment in Study 20130356, rounded down to the 
lowest PSD. 
• 
Subjects from Study 20130356 may receive capsules for any dose which is an exact 
multiple of 5 mg.  Subjects who are assigned doses of 60 to 180 mg/day will require 
administration of two to six 30 mg tablets per dose.  For those subjects unable to 
swallow tablets, capsules may be dispensed. 
• 
Subjects < 6 years of age:  1, 2.5, 5, 7.5, 10, 15, 30 and 60 mg. Subjects from 
Study 20110100 will either continue to receive cinacalcet at the same dose as at 
the EOIP visit if ≤ 14 days have passed between last dose of cinacalcet 
treatment in Study 20110100 and day 1 of Study 20140159.  If > 14 days have 
passed, subjects will start cinacalcet in Study 20140159 at 0.20 mg/kg/day based 
on the subject’s dry weight at the 20140159 day 1 time point and age at time of 
enrollment in 20110100 study, rounded down to the lowest PSD. 
- 
Subjects assigned a dose between 10 to 60 mg/day will require more than 
1 capsule per dose be sprinkled on soft food or used to create the liquid 
suspension for administration. 
- 
Subjects enrolling into 20140159 from 20110100 would have a maximum dose of 
2.5 mg/kg/day based on the subject’s 20140159 day 1 dry weight or 60 mg daily, 
whichever is lower. 


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Page 22 of 42 
 
 
Section:  6.2.3.1.1 Subjects From Study 20130356 
 
Replace: 
 
Subjects from the cinacalcet arm will follow the dose adjustments outlined in Table 1 in 
Section 6.2.3.1.1.1.  If subjects from the cinacalcet arm in 20130356 are on a dose 
withhold at 20140159 day 1, the iPTH and cCa restart values (iPTH > 100 pg/mL and 
cCa > 8.4 mg/dL) must be reached prior to resuming cinacalcet in the current extension 
study.  Subjects from the cinacalcet arm, who have had their dose withheld for 
> 1 month at the time of 20140159 day 1 will not be eligible for this study. 
With: 
Subjects from the cinacalcet arm with ≤ 14 days between last dose of cinacalcet 
treatment in Study 20130356 and Study 20140159 day 1 will continue at the same 
dose as the last dose at EOIP and will follow the dose adjustments outlined in Table 1 
in Section 6.2.3.1.1.1.  Dose titration cannot occur until the week 4 visit per Table 1. 
If subjects from the cinacalcet arm in 20130356 are on a dose that was withheld or 
missed for > 14 days and ≤ 1 month at day 1 of Study 20140159  day 1, the iPTH and 
cCa restart values (iPTH > 100 150 pg/mL and cCa > 8.4 mg/dL) must be reached prior 
to resuming cinacalcet will receive the initial dose of cinacalcet in the current 
extension study outlined in Table 1 in Section 6.2.3.1.1.1. 
 
Subjects from the cinacalcet arm with > 1 month between the last dose of cinacalcet 
treatment in Study 20130356 and Study 20140159 day 1, will receive the initial 
dose of cinacalcet as defined in Section 6.2.3.1.1.1.  To commence dosing, all 
subjects must have: who have had their dose withheld for > 1 month at the time of 
20140159 day 1 will not be eligible for this study 
 
• 
ionized calcium ≥ 1.05 mmol/L prior to initiation of treatment on day 1 in 
this study 
• 
iPTH value ≥ 300 pg/mL within 7 days of day 1 
 
• 
corrected calcium value ≥ 8.8 mg/dL within 7 days of day 1 
 
Section:  6.2.3.1.1.1 Dosage Adjustments 
 
Replace: 
 
On day 1, the subject’s ionized calcium must be at or above threshold (ie, ≥ 1.13 mmol/L 
for subjects less than 2 years of age, ≥ 1.05 mmol/L for subjects 2 years of age and 
above) prior to initiation of treatment.  The initial dose of cinacalcet and all subsequent 


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Page 23 of 42 
 
doses will be calculated by the site staff and confirmed by the IVR/IWR system. Subjects 
from the SOC arm will start at the initial cinacalcet dose of 0.20 mg/kg/day, based on the 
subject’s dry weight at 20140159 day 1, rounded down to the lowest PSD. Subjects from 
the cinacalcet arm will start cinacalcet dosing on 20140159 day 1 at the same dose of 
cinacalcet they received at the completion of the treatment period 
(week 20) in Study 20130356 or titrate based on the Table 1.  The initial dose of 
cinacalcet will be assigned to subjects restarting cinacalcet after withholding the dose for 
more than 14 days during the study. 
 
At all weekly visits (including week 4, 8, 12, 16, 20, and 24), the dose may be 
maintained, reduced or withheld based upon the criteria in Table 1. 
 
If any of the criteria for dose withholding are met at any time during the trial, including 
between scheduled study visits (ie, unscheduled), the dose of cinacalcet is to be 
withheld until all of the following criteria are met: 
 
• 
iPTH is > 100 pg/mL 
 
If IP has been withheld or missed for more than 14 days, the subject will resume dosing 
at the starting dose level once all restart criteria are met. 
 
With: 
 
On day 1, the subject’s ionized calcium must be at or above threshold (ie, ≥ 1.13 mmol/L 
for subjects less than 2 years of age, ≥ 1.05 mmol/L for subjects 2 years of age and 
above) prior to initiation of treatment.   The initial dose of cinacalcet and all subsequent 
doses will be calculated by the site staff and confirmed by the IVR/IWR system. 
Subjects from the SOC arm will start at the initial cinacalcet dose of 0.20 mg/kg/day, 
based on the subject’s dry weight at day 1 of Study 20140159 day 1, rounded down to 
the lowest PSD. 
 
Subjects from the cinacalcet arm will start cinacalcet dosing on with ≤ 14 days between 
the last dose of cinacalcet treatment in Study 20130356 and day 1 of 
Study 20140159 will start cinacalcet dosing at the same dose of cinacalcet they 
received at the completion of the EOIP visit treatment period (week 20) in Study 
20130356 or and  titrate follow weekly dose adjustment based on the Table 1.  For 
subjects from the cinacalcet arm with > 14 days between the last dose of 
cinacalcet treatment in Study 20130356 and day 1 of Study 20140159,  Tthe initial 
dose of cinacalcet will be assigned to subjects restarting cinacalcet after withholding the 
dose for more than 14 days 0.20 mg/kg/day, based on the subject’s dry weight at 


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Page 24 of 42 
 
day 1 of 20140159, rounded down to the lowest PSD, will be assigned  during the 
study. 
 
At all weekly visits (including week 4, 8, 12, 16, 20, and 24), the dose may be 
maintained, reduced or withheld based upon the dose adjustment criteria in Table 1. 
 
If any of the criteria for dose withholding are met at any time during the trial, including 
between scheduled study visits (ie, unscheduled), the dose of cinacalcet is to be 
withheld until all of the following criteria are met: 
 
• 
iPTH is > 150  100 pg/mL 
 
If IP has been withheld or missed for more than> 14 days, the subject will resume dosing 
at the starting dose level once (initial dose in parent Studies 20130356 or 20110100) 
all restart criteria are met based on dry weight at day 1 of Study 20140159. 
 
Section:  Table 1 Footnote * 
Replace: 
* restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 100 pg/mL, 
ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
 
With: 
 
* restart one PSD below last dose when cCa is > 8.4 mg/dL, iPTH is > 150  100 pg/mL, 
ionized calcium is > 1.05 mmol/L, symptoms of hypocalcemia and other AE that 
warrants IP dose withholding have resolved. 
 
Section:  6.2.3.1.2 Subjects from 20110100 
 
Replace: 
 
Subjects From 20110100 
 
In order to start dosing, all subjects from Study 20110100 must have: 
 
• 
Ionized calcium prior to initiation of treatment on day 1 in this study 
 
− ≥ 1.13 mmol/L if age < 2 years 
 
− ≥ 1.05 mmol/L if ≥ 2 years 
 
• 
iPTH value ≥ 150 pg/mL within 7 days of day 1 
 
• 
Corrected calcium value within 7 days of day 1 


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• 
Phosphorus value within 7 days of day 1 
 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age < 1 year 
 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age ≥ 1 year 
 
With: 
 
Subjects From Study 20110100 
 
For subjects where the last dose of cinacalcet treatment in Study 20110100 and 
day 1 of Study 20140159 occurs within 14 days, in order to commence dosing, 
subjects from Study 20110100 will follow weekly dose adjustment criteria as 
outlined in Table 2 for age < 2 years and Table 3 for age ≥ 2 years.  Dose titration 
cannot occur until week 4. 
 
For subjects with > 14 days and < 1 month between the last dose of cinacalcet 
treatment in Study 20110100 and day 1 of Study 20140159, in order to commence 
start dosing at the initial dose, all subjects from Study 20110100 must have meet 
restart criteria per weekly dose adjustment criteria as outlined in Table 2 for age 
< 2 years and Table 3 for age ≥ 2 years.  Dose titration cannot occur until week 4. 
 
• 
Additionally the phosphorus value within 7 days of day 1 should be: 
 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age is < 1 year 
 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age is ≥ 1 year 
 
For subjects with > 1 month between EOS visit in Study 20110100 and day 1 of 
Study 20140159, in order to commence dosing, all subjects from Study 20110100 
must have: 
 
• 
ionized calcium prior to initiation of treatment on day 1 in this study 
 
− ≥ 1.13 mmol/L if age is < 2 years 
 
− ≥ 1.05 mmol/L if age is ≥ 2 years 
 
• 
iPTH value ≥ 300 150pg/mL within 7 days of day 1 
 
• 
Corrected calcium value within 7 days of day 1 
 
• 
phosphorus value within 7 days of day 1 
 
− ≥ 5.0 mg/dL (1.25 mmol/L) if age is < 1 year 
 
− ≥ 4.5 mg/dL (1.13 mmol/L) if age is ≥ 1 year 
Section:  6.2.3.1.2.1 Subjects < 2 Years of Age 
Replace: 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects will start at the initial cinacalcet dose of 


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Page 26 of 42 
 
0.20 mg/kg/day, based on the subject’s dry weight at day 1, in the 20140159 study 
rounded down to the lowest PSD. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume dosing 
at the starting dose level once all restart criteria are met. 
 
With: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system. 
 
For subjects with > 14 days since the last dose of cinacalcet treatment in 
Study 20110100 and day 1 of Study 20140159,  S subjects will start at the initial 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1, in 
Study 20140159 rounded down to the lowest PSD. 
 
For subjects with ≤ 14 days between the last dose of cinacalcet in Study 20110100 
and Study 20140159 day 1, subjects will continue the same dose of cinacalcet they 
received at the completion EOIP visit or early termination visit at Study 20110100 
termination and follow the weekly dose adjustments outlined in Table 2.  Dose 
titration cannot occur until week 4.  If subjects from the Study 20110100 are on a 
dose withhold at day 1 of Study 20140159, the iPTH and cCa restart values 
(iPTH > 150 pg/mL and cCa > 9.0 mg/dL) must be reached prior to resuming 
cinacalcet in the Study 20140159. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume dosing 
at the starting dose level (initial dose in parent Studies 20130356 or 20110100) once 
all restart criteria are met. 
 
Section:  6.2.3.1.2.2 Subjects ≥ 2 Years of Age 
 
Replace: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system.  Subjects will start at the initial cinacalcet dose of 
0.20 mg/kg/day, based on the subject’s dry weight at day 1 in the 20140159 study, 
rounded down to the lowest PSD. 
 
If IP has been withheld or missed for more than 14 days, the subject will resume dosing 
at the starting dose level once all restart criteria are met. 


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Page 27 of 42 
 
With: 
 
The initial dose of cinacalcet and all subsequent doses will be calculated by the site staff 
and confirmed by the IVR/IWR system. 
 
For subjects with > 14 days since the last dose of cinacalcet treatment in 
Study 20110100 and day 1 of Study 20140159,  Ssubjects will start at the initial 
cinacalcet dose of 0.20 mg/kg/day, based on the subject’s dry weight at day 1 in 
Study 20140159, rounded down to the lowest PSD. 
 
For subjects with ≤ 14 days since the last dose of cinacalcet in Study 20110100 
and day 1 of Study 20140159, subjects will continue cinacalcet based on the dose 
at the EOIP visit or early termination/EOS at study termination and follow the 
weekly dose adjustments outlined in Table 3.  Dose titration cannot occur until 
week 4.  If subjects from the Study 20110100 are on a dose that was withheld at 
day 1 of Study 20140159, the iPTH and cCa restart values (iPTH > 150 pg/mL and 
cCa > 8.4 mg/dL) must be reached before resuming cinacalcet in Study 20140159. 
 
If IP has been withheld or missed for more than 14 days (initial dose in parent 
Studies 20130356 or 20110100), the subject will resume dosing at the starting dose 
level once all restart criteria are met. 
 
Section:  6.2.3.1.3 Missed Doses 
 
Replace: 
 
If a subject misses > 14 consecutive doses of cinacalcet for any reason, including 
temporary dose withholding due to the administration of concomitant medications as 
noted above, they will be restarted at their initial dose of cinacalcet (0.20 mg/kg/day 
based on dry weight at day 1) when administration of IP resumes per the dose titration 
guidelines outlined in Table 1, Table 2, and Table 3. 
 
With: 
 
If a subject misses > 14 consecutive doses of cinacalcet for any reason, including 
temporary dose withholding due to the administration of concomitant medications as 
noted above, they will be restarted at their initial dose of cinacalcet (0.20 mg/kg/day 
based on dry weight at day 1 in Study 20140159) when administration of IP resumes 
per the dose titration guidelines outlined in Table 1, Table 2, and Table 3. 


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Page 28 of 42 
 
Section:  Table 4 Schedule of Assessments 
 
Add: 
 
Requirement to collect concomitant medications, liver function tests, and chemistry, 
hematology, 25(OH) Vit D at Screening, Week -1. 
 
Note: When it is not possible to perform a study visit at the specified time point, the visit 
may be performed within ± 3 days 
 
. 


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Replace: 
 
Physical Exam 
X
2 
X 
Height, Tanner Stage 
X
2 
X 
Dry Weight 
X
2 
X 
 
Blood Pressure, Heart 
Rate 
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications2 
Record Continuously 
X 
X 
Patient Diary Review 
X
2 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X X 
X 
X 
 
Ionized Ca 
X
2 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests 
X 
X 
X 
X 
Chemistry, hematology, 
25(OH)Vit D3 
2 
X 
X 
X 
Ca, Albumin, cCa, P 
X
1 
X
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iPTH 
X
1 
X
2 
X 
X 
X 
X 
X 
X 
X 
X 
Total & Bioavail 
Testosterone (male) 
2 
X 
X 
 
BALP, NTx, CTx, P1NP, 
FGF 23
3
 
2 
X 
X 
1 - These procedures are required for the 20130356 week 19 visit and 20140159 screening visit.  These procedures will be performed once at the site and applied to both study visits. 
2 - These procedures are required for the 20130356 EOIP and 20110100 EOS visit and 20140159 day 1 visit.  These procedures will be performed once at the site and applied to both 
study visits. 


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With: 
 
Physical Exam 
X
1 
X 
Height, Tanner Stage 
X
1 
X 
Dry Weight 
X
1 
X 
 
Blood Pressure, Heart 
Rate 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications2 
2 
X 
Record Continuously 
X 
X 
Patient Diary Review 
X
1 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X X 
X 
X 
X 
X 
X 
 
Ionized Ca 
X
1 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X X 
X 
X 
X 
X 
X 
Liver Function Tests 
X
2 
X 
X 
X 
X 
Chemistry, 
hematology, 25(OH)Vit 
D3 
X
2 
X
1 
X 
X 
Ca, Albumin, cCa, P 
X
1 
X
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iPTH 
X
1 
X
1 
X 
X 
X 
X 
X 
X 
X 
X 
Total & Bioavail 
Testosterone (male) 
1 
X 
X 
 
BALP, NTx, CTx, 
P1NP, FGF 23
3
 
1 
X 
X 
Note:  When it is not possible to perform a study visit at the specified time point, the visit may be performed within ± 3 days. 
1 - Where the Screening and day 1 assessments  for Study 20140159 overlap with visits in the Studies 20130356 or 20110100, these will be performed once at the site and applied to both 
study visits to minimize duplicate study assessments.  These procedures are required for the 20130356 week 19 visit and 20140159 screening visit.  These procedures will be performed 
once at the site and applied to both study visits. 
2 - These procedures are required for Study 20140159 screening visit if > 14 days since last study visit in Studies 20130356 or 20110100 for subjects impacted by study termination.  These 
procedures are required for the 20130356 EOIP and 20110100 EOS visit and 20140159 day 1 visit.  These procedures will be performed once at the site and applied to both study visits 
. 


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Section:  7.2.2 Day 1 
 
Replace: 
 
The following day 1 procedures are also required for the EOIP study visit at week 20 for 
Amgen study 20130356 and Week 26 End of Study visit for Study 20110100 except 
where indicated.  These procedures should not be duplicated and may be collected once 
and entered onto the appropriate eCRF once eligibility for this study has been confirmed: 
 
With: 
 
The following day 1 procedures are also required for the EOIP study visit at week 20 for 
Amgen sStudy 20130356 and week 26End of Study visit for Study 20110100 except 
where indicated.  These procedures should not be duplicated and may be collected once 
where study visits overlap and entered onto the appropriate eCRF once eligibility for 
this study has been confirmed: 
 
Section:  9.3 Pregnancy and Lactation Reporting 
 
Replace: 
 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 30 days. 
 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
(PSP) within 24 hours of the investigator’s knowledge of the event of a pregnancy. 
Report a pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The PSP 
will seek to follow the pregnant woman throughout her pregnancy and her baby up to 
12 months after birth. 
 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below. 
 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through 
30 days. 
 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
 
(LSP) within 24 hours of the investigator’s knowledge of event. 


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With: 
 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of cinacalcet  protocol-required 
therapies through 90  30 days. 
 
The pregnancy should be reported to Amgen’s Global Patient Safety  global Pregnancy 
Surveillance Program (PSP) within 24 hours of the investigator’s knowledge of the event 
of a pregnancy.  Report a pregnancy on the Pregnancy Notification Worksheet 
(Appendix C).  Amgen Global Patient Safety  The PSP will seek to follow the pregnant 
woman throughout her pregnancy and her baby up to 12 months after birth. 
 
If a lactation case occurs while the female subject is taking cinacalcet  protocol-required 
therapies report the lactation case to Amgen as specified below. 
 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of cinacalcet  protocol-required therapies 
through 90  30 days. 
 
Any lactation case should be reported to Amgen’s Global Patient Safety global 
Lactation Surveillance Program (LSP) within 24 hours of the investigator’s knowledge of 
event. 
 
Section:  10.1.1 Study Endpoints 
 
Replace: 
 
Secondary Endpoints: 
 
• 
Percent change from day 1 in iPTH to week 11and week 28 
 
• 
Serum cCa values at day 1, week 11, and week 28 
 
• 
Serum phosphorus values at day 1, week 11, and week 28 
 
Exploratory Endpoint 
 
• 
Growth velocity from day 1 to end of study 
 
• 
Change in Tanner stage from day 1 to end of study 
 
With: 
 
Secondary Endpoints: 
 
20140159 Study Only 
 
•   Percent change from day 1 in iPTH to week 11and week 28 
 
•   Serum cCa values at day 1, week 11, and week 28 


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•   Serum phosphorus values at day 1, week 11, and week 28 
 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during 
weeks 11 and 15 (SOC arm of Study 20130356 only) 
• 
Achievement of ≥ 30% reduction from baseline to mean iPTH during 
weeks 23 and 28 (SOC arm of Study 20130356 only) 
• 
Percent change from baseline to mean iPTH during weeks 23 and 28 (SOC 
arm of Study 20130356 only) 
 
• 
Change in corrected total serum calcium from baseline to mean value 
during weeks 23 and 28 
• 
Change in serum phosphorus from baseline to mean value during weeks 23 
and 28 
• 
Achievement of a mean iPTH ≤ 300 pg/mL during weeks 23 and 28 
 
• 
Serum cCa at baseline day 1, week 11, and week 28 
 
• 
Serum phosphorus at baselineday 1, week 11, and week 28 
 
Combined 20130356, 20110100, and 20140159 Studies 
 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks 11 and 15 
• 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks 23 and 28 
• 
Percent change in iPTH over time from day 1 of cinacalcet treatment 
 
• 
Change in serum cCa over time from day 1 of cinacalcet treatment 
 
• 
Change in serum phosphorus over time from day 1 of cinacalcet treatment 
 
Exploratory Endpoints: 
 
Study 20140159 Only 
 
• 
Growth velocity from baseline to EOS 
 
• 
Change in Tanner stage from baseline to EOS 
 
Combined Studies 20130356, 20110100, and 20140159 
 
• 
Growth velocity from day 1 of cinacalcet treatment to EOS 
 
• 
Change in Tanner stage from day 1 of cinacalcet treatment to EOS 
Exploratory Endpoint 
•   Growth velocity from day 1 to end of study 
 
•   Change in Tanner stage from day 1 to end of study 


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Section:  10.1.2 Analysis Sets 
 
Replace: 
 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all enrolled subjects with at least one assessment 
 
after day 1. 
 
With: 
 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all enrolled subjects in Study 20140159  with at 
 
least one assessment after day 1. 
 
Added: 
 
Efficacy Analysis Set 
 
The Efficacy Analysis Set includes all enrolled subjects who received at least one 
 
dose of cinacalcet and have at least one assessment after day 1. 
 
Section:  10.1.3 Covariates and Subgroups 
 
Replace: 
 
The primary, secondary, and safety endpoints will be summarized by baseline age group 
 
(6 to < 12 years and 12 to < 18 years for Study 20130356; 28 days to < 2 years and 
 
2 to < 6 years for Study 20110100) as supportive analyses. 
With: 
The primary, secondary, and safety endpoints may will be summarized by baseline age 
group (6 to < 12 years and 12 to < 18 years for Study 20130356; 28 days to < 2 years 
and 2 to < 6 years for Study 20110100) as supportive analyses upon availability of 
data in each subgroup. 
 
Section: 10.3.1 Interim Analysis 
 
Replace: 
 
An interim analysis will be conducted.  The timing of the interim analysis will be 
dependent on the completion of the Study 20130356.  There is no formal statistical 
testing.  The analysis for all endpoints will be descriptive in nature. 


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Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 16 March 2016 
Page 35 of 42 
 
With: 
 
Several interim analyses may be conducted.  The first interim analysis will be 
performed to support the Supplemental New Drug Application (sNDA) for pediatric 
indication.  Its scope of analysis will be limited to the planned analysis using 
20140159 study data only.  The rest of interim analyses may be performed to 
support further request from regulatory.  The scope of these analyses will be 
specified in a separate statistical analysis plan of interim analysis.  There is no 
plan to conduct formal statistical testing.  An interim analysis will be conducted.  The 
timing of the interim analysis will be dependent on the completion of the Study 
20130356.  There is no formal statistical testing.  The analysis for all endpoints will be 
 
descriptive in nature. 
 
Section:  10.3.2 Primary Analysis 
 
Replace: 
 
The general approach is to provide estimates for the primary and secondary endpoints 
for the study population. 
 
The primary analysis of all endpoints will be conducted after the Primary Completion is 
achieved for this study. 
 
With: 
 
The general approach is to provide estimates for the primary and secondary endpoints 
for the study population. 
 
The primary analysis of all endpoints will be conducted after all subjects have 
completed the week 32 EOS visit or terminated early from Study 20140159. 
 
Section:  10.4.1 General Considerations 
 
Replace: 
 
There is no formal statistical testing for this study.  The analysis for all endpoints will be 
descriptive in nature.  No missing data imputation will be used. 
 
All summaries will be provided by study treatment group:  Study 20130356 (SOC, SOC + 
 
cinacalcet, overall) and Study 20110100. 
With: 
There is no formal statistical testing for this study.  The analysis for all endpoints will be 
descriptive in nature.  No missing data imputation will be used. 


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Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 16 March 2016 
Page 36 of 42 
 
All summaryies tables will be provided by study treatment group:  Study 20130356 
(SOC, SOC + cinacalcet, overall) and Study 20110100 and overall, unless otherwise 
specified. 
 
Section:  10.4.2 Primary Endpoint 
 
Replace: 
 
The primary analysis of the primary endpoint will be based on the Safety Analysis Set. 
The primary endpoint is subject incidence of events of interest (EOI; eg, hypocalcemia, 
convulsions, hypotension, worsening of heart failure, hypersensitivity, ischemic heart 
disease, QT prolongation/ventricular tachyarrhythmias, fracture, acute pancreatitis, 
drug-related hepatic disorders, nervous system disorders [excluding seizures], 
neoplastic events, and infection).  The exact 95% confidence intervals (CI) of the overall 
incidence rates will be reported. 
 
With: 
 
The primary analysis of the primary endpoint will be based on the Safety Analysis Set. 
The primary analysis of the primary endpoint is subject incidence of events of interest 
(EOI; eg, hypocalcemia, convulsions, hypotension, worsening of heart failure, 
hypersensitivity, ischemic heart disease, QT prolongation/ventricular tachyarrhythmias, 
fracture, acute pancreatitis, drug-related hepatic disorders, nervous system disorders 
[excluding seizures], neoplastic events, and infection) for data in the 20140159 study 
only.  The secondary analysis of the primary endpoint is the incidence of events 
of interest adjusted by the amount of safety follow-up time for combined data from 
parent studies and data from the 20140159 study.  The exact 95% confidence 
intervals (CI) of the overall incidence rates will be reported. 
 
Section:  10.4.3 Secondary Endpoints 
 
Replace: 
 
The primary analysis will be based on FAS for all secondary endpoints.  Summary 
statistics will be provided for percent change in iPTH, from day 1 to week 11 and 
week 28 within the study population and each age group by previous treatment group in 
the parent study and overall.  No missing data imputation will be used.  Summary 
statistics will be provided for serum cCa and phosphorus values at day 1 to week 11, 
and week 28.  No imputation of missing data will be utilized. 


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Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 16 March 2016 
Page 37 of 42 
 
With: 
 
The analysis of secondary endpoints will be based on the Efficacy Analysis Set. 
The approach for handling the missing data will be described for each endpoint in 
the statistical analysis planprimary analysis will be based on FAS for all secondary 
endpoints.  Summary statistics will be provided for percent change in iPTH, from day 1 
to week 11 and week 28 within the study population and each age group by previous 
treatment group in the parent study and overall.  No missing data imputation will be 
used.  Summary statistics will be provided for serum cCa and phosphorus values at day 
1 to week 11, and week 28.  No imputation of missing data will be utilized. 
 
20140159 study only 
 
The proportion of subjects who achieve a ≥ 30% reduction from baseline of 
Study 20140159 to mean iPTH at weeks 11 and 15 and to mean iPTH at weeks 23 
and 28 will be assessed for the SOC arm in Study 20130356 with a 95% CI. 
 
Summary statistics will be provided for the percent change in mean iPTH from 
baseline in Study 20140159 during weeks 23 and 28 for the SOC group in Study 
20130356. 
 
Summary statistics will be provided for the change in corrected total serum 
calcium and change in serum phosphorus from baseline of Study 20140159 to 
mean value at weeks 23 and 28 by treatment group in the parent study. 
 
The proportion of subjects who achieve a mean iPTH value of ≤ 300 pg/mL during 
weeks 23 and 28 will be provided by treatment group in the parent study with a 
95% CI. 
Summary statistics will be provided for serum cCa and phosphorus values at 
baseline to week 11 and week 28. 
 
Combined 20130356, 20110100, and 20140159 Studies 
 
The proportion of subjects who achieve a ≥ 30% reduction from day 1 of 
cinacalcet treatment to mean iPTH at weeks 11 and 15 and to mean iPTH at 
weeks 23 and 28 will be provided by previous treatment group in the parent study 
 
with a 95% CI. 
 
The percent change in iPTH, change in corrected serum calcium, and change in 
serum phosphorus from day 1 of cinacalcet treatment at each measurement time 
point will be summarized overall. 


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Product: Cinacalcet HCl 
Protocol Number: 20140159 
Date: 16 March 2016 
Page 38 of 42 
 
Section:  10.4.4 Safety Endpoints 
 
Added: 
 
All safety endpoints in 20140159 study only and combined with their parent 
studies, will be summarized by treatment group in the parent studies and overall. 
 
Replace: 
 
Laboratory Data, Blood Pressure, and Heart Rate 
 
The incidence of hypocalcemia after the first dose of IP will be summarized using 
descriptive statistics.  Hypocalcemia will be defined in two ways, with the subject 
incidence of corrected serum calcium of < 7.5 mg/dL and < 8.4 mg/dL both being 
summarized.  Subject incidence of ionized calcium value < 1.05 mmol/L 
and < 1.00 mmol/L will be summarized. 
 
With: 
 
Laboratory Data, Blood Pressure, and Heart Rate 
 
The incidence of hypocalcemia after the first dose of IP will be summarized using 
descriptive statistics.  Hypocalcemia will be defined in two ways, with the subject 
incidence of corrected serum calcium of < 7.5 mg/dL, 8.0 mg/dL, and < 8.4 mg/dL both 
being summarized.  Subject incidence of ionized calcium value < 
0.94 mmol/L, < 1.05 mmol/L, and < 1.00 mmol/L will be summarized. 
 
Section:  Appendix C Pregnancy and Lactation Notification Worksheets 
 
Replace: 
 
Footnotes on the Pregnancy and Lactation Notification Worksheets was removed. 


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Clinical Study Report:  20140159 
Date: 21 August 2017 
Page 186 
..... 
CONFIDENTIAL 
 
 
4. AmgenProd ct Exposure 
Amge:n Produet 
Dose at tmi  e of 
conception 
Frequency 
Route 
Start Date 
mm .... .J.., ....:.Jtyyyy_ 
W:tS lheen product (orstudy drug)discont nued? 
D Yes     0No 
If yes.provideproduct (orstudy drug) stop date: mm  /dd 
....:.Jyyyy_ 
Did lhe subject withdrawfrom the study? 0 Yes    0No 
5. Pregnancy I nformation 
Pregnant female's LMP       mm.     .1 
dd      ! yyyy  
 
0 Unknown 
Es6m.lted date oi delivery mm     -=..J I dd       -=..J,yyyy    0 Unknown   DNIA 
If NIA, date of termination (aCI:Ualor planned) mm      .....!..J I dd      / yyyy  
 
Has thpregnant female ateady deil vered?      0Yes     0 No    0 lklk.nown    0 N/A 
lfyes.provide dateof delivery: nvn  
/ dd 
I YYYY : 
Was tl'e inbnthea!thy? 0 Yes    0 No    0 Unknown  0 NIA 
H any AdYerse Ewnt was experienced by !he infant. prcwide brief details: 
 
 
Product: Cinacalcet HCI 
ProtocolNumber. 20140159 
Date: 16 March 2016 
Page39 ot42 
 
 
 
At.GEN• Pregnancy Notification Wor1<sheet 
Fax Completed For m to the Country-respective Safety Fax line 
8ElECTOf tTYP£1 N...FA» 
 
 
 
 
2. Contact Information 
lnvest;gator Name   
_ 
 
Site #   
_ 
P hone{_),  
_ 
Fax(       )  
_ Ei  
 
lnst bJi:on  
_ 
 
Addreis 
 
 
Subj4KtiOM 
Subject Gender: 0 Female    0 t.We     SubjeetOOB: mm  l dd 
f'f'IY'f  
 
 
u 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Form Completed bv: 
Pri nt Harne...==,------------- 
Signature: 
 
Trtle: --------------- 
Date: 
 
 
Amgenmalnt.ll n& a Pregnancy Sur.-emance Program thai OOI»<U &Ia aooutpregMnCy Of P Cmeno ruve oeen exposea to an Amgenp-ocluc:l ruectly 
or v.a mare &eiCUalpartner.ormation trom thl& progratn at1Cii from other &OI.JC E'& of rnronna-JOn. WI cootriDUte to lnCM'JeCiige' trutultrJ1al?,l)' col.£<1necp 
pa;»n:l ana tnerr Clioctor& In tne tLture rnne more ttronnea oecr510n& aoout  talnl g an Amgen <1.11ng pregNncy. 
 
 
Efte' ct!\e Date: Mate:h 27, 201l 
Page 1ot 1 


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Product: Cinacalcet HCI 
ProtocolNumber: 20140159 
Date:  16 March 2016  
Page40 of42 
 
 
 
AIIIGEH" Lactation NotificationWorksheet 
Fax Completed Form to the Country.respective Safety Fax Line 
SELECT OR TYPE IN A FAXJIlenter fax number 
 
Protocol/Study Number:  
 
Study Design: 0 lnterventional     0 Observational (It Observational:  0 Prospective 0 Retrospective) 
Print form 
 
2    Contact lnformatron 
 
 
 
Fax l  
j  
 
 
 
Site# 
Email   
 
 
 
 
 
 
4 Amgen Product Exposure 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
mm  
/dd_/yyyy_ 
Was the Amgen product (or study drug) discontinued? 0 Yes     0 No 
If yes,provide product {or study drug) stop date: rrm   
/dd  
/yyyy  
 
Did the subject Wthdraw from the study? 0 Yes     0 No 
5 Breast Feed;ng Inform
tion 
Did the mother breastfeed or provtde the infant with pumped breast mikl 'or'llhile actively taking an Amgen product?   0 Yes      0 No 
If No, provide stop date: rrm  
/dd  
lyyyy  
 
Infant date of birth:rrrn  
/dd  
/yyyy  
 
Infant gender: 0 Female    0 Male 
Is theinfant heatthy?  0 Yes    0 No     0 Unkno'Ml    0 NIA 
If any Adverse Event v.as exper enced by the mother or the infant,provide br ef details:. 
 
 
Form completed bY: 
PrintName:-------------------------------     Title:                                                                                
Sign ture; ----------------   D  e: ---------------- 
 
 
Amgen maintains 1!1  Lactation Surveillance Program  that collects dl!lta about  wanen who have been  exposed to a.n Amgen product  whiel breastfeeding. 
Information from thiS program and from d:her sources of  nformation willcontribute to knowledge that ultimatety  coo!d help patients: and their doctors in 
the future make more informeddecisions aboot taking an Amgen medlcalioo duringlactation. 
Effective Date:03 Apfit 2012.versioo 2.                                                                                                                                                          Page 1Of 1 


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AMGBf
CONFIDENTIAL 
 
 
Am gen Product 
Dose at ti me of 
conception 
Frequency 
Route 
Start Date 
mm 
ldd 
lyyyy  
 
 
 
Product: Cinacalcet HCI 
ProtocolNumber: 20140159 
Date: 16 March 2016 
Page 41 of 42 
 
 
With: 
 
AIII'I(;Eit" Pregnancy Notification Worksheet 
Fax Completed Form to the Country-respective Safety Fax Line 
SELECT OR TYPE  N A FAXi- 
 
 
 
 
2. Contact Information 
Investi gator Nam e   
 
 
Site#   
 
Phonel  
j,  
 
Fax l  
j  
 
Emali   
 
Institution  
 
Address 
 
 
Subjec t  D # 
Subject Gender: D Fem ale     D Male     Subject DOB: mm  
l dd  
/ yyyy  
 
 
4. Amgen Product Exposure 
Was the Amgenproduct (or study drug) discontinued?  D Yes     D No 
If yes,provide product (or study drug) stop date: mm   
/dd  
tyyyy  
 
Did the subject withdraw from the study? D Yes     D No 
5. Pregnancy Information 
Pregnant female's LMP 
mm  
/ dd  
l yyyy  
   D Unknown 
Estimated date of delivery  mm   
/ dd  
/ yyyy   
   DUnknown   D N/A 
If N/A,date of terminat on (actualor planned)mm  
/ dd  
/ yyyy  
 
Has the pregnant fem ale already delivered?    DYes    D No    D Unknown    DN/A 
If yes.provide date of delvery:  mm   
1dd  
/ yyyy  
 
Was theinfant healthy?  DYes    D No     DUnknown   D NIA 
If any Adverse Event was experienced by theinfant. provide brief detai ls:  
 
 
 
Form Com pleted by: 
Print Name:   
 
 
Ti tl e:   
 
 
Signature:   
 
 
Date:   
 
 
 
 
 
 
 
Effecttve Date:March 27.2011 
Page 1of 1 


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AMGBf
CONFIDENTIAL 
 
 
Am gen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
mm  
tdd  
IYYYV  
 
 
 
Product: Cinacalcet HCI 
ProtocolNumber: 20140159 
Date: 16 March 2016 
Page 42 of 42 
 
Allti(;Etf Lactation Notification Worksheet 
Fax Completed Form to the Country-respective Safety Fax Line 
SELECT OR TYPEIN A FAX# 
 
 
 
Study Design: D lnlervenijonal     D Observailonal  (If Observaional:  D Prospect ve  D Retrospective) 
 
2. Contact Information 
 
 
Fax L  
)  
 
 
Site # 
Email  
 
 
 
 
 
 
4. Amgen Product Exposure 
Was the Amgen product (or study drug) discontinued?  0 Yes     0 No 
If yes.provide product (or study drug) stop date: mm   
/dd  
tyyyy  
 
Did the subject IMihdraw from the study? 0 Yes   0 No 
5. Breast Feeding Information
Did the mother breastfeed or provide theinfant with pumpedbreast milk whiel acijvely laking an Amgen product?   D Yes     D No 
If No,provide stop date: mm  
/dd  
tyyyy  
 
Infant dale of birth:mm  
/dd  
tyyyy  
 
Infant gender: 0 Female     0 Male 
Is theinfant hea thy?   0 Yes     0 No     0 Unknown 0 N/A 
If any Adverse Event was expeliencedby the mother or theinfant,provide brief details.:  
 
 
 
Fonm Completed by: 
Print Name:  
 
 
Signature:   
 
 
Title:   
 
Date:    
  
 
 
 
 
 
Effecit ve Date:03April2012,verston 2. 
Page 1of 1 


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CONFIDENTIAL 
 
 
 
Product:  Cinacalcet HCI 
Protocol Number:  20140159 
Date:  01 June 2016 
Page 1 of 2 
 
 
 
Superseding Amendment 3 
 
Protocol Title: A Multicenter Single-arm Extension Study to Characterize the 
Long-term Safety of Cinacalcet Hydrochloride in the Treatment of Secondary 
Hyperparathyroidism in Pediatric Subjects With Chronic Kidney Disease on 
Dialysis 
 
 
Amgen Protocol Number (cinacalcet HCl) 20140159 
 
EudraCT number 2014-003563-38 
 
 
 
Superseding Amendment 3 
Date: 
01 June 2016 
 
 
Rationale: 
 
The purpose of the superseding protocol amendment is to correct administrative and 
typographical changes in Section 10.4.4 Safety Endpoints. 


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Product:  Cinacalcet HCI 
Protocol Number:  20140159 
Date:  01 June 2016 
Page 2 of 2 
 
Description of Changes: 
 
Section: Global 
 
Replace: 
 
16 March 2016 
 
With: 
 
01 June 2016 
 
Section: Title Page Date 
 
Added: 
 
Superseding 3.1: 01 June 2016 
 
Section: 10.4.4 Safety Endpoints 
 
Replace: 
 
Hypocalcemia will be defined in two ways, with the subject incidence of corrected serum 
calcium of < 7.5 mg/dL, 8.0 mg/dL, and < 8.4 mg/dL both being summarized. Subject 
incidence of ionized calcium value < 0.94 mmol/L, < 1.05 mmol/L, and < 1.00 mmol/L will 
be summarized. 
 
With: 
 
Hypocalcemia will be defined in two ways: with the subject incidence of corrected serum 
calcium of < 7.5 mg/dL, < 8.0 mg/dL, and < 8.4 mg/dL being summarized; and with 
subject incidence of ionized calcium value < 0.94 mmol/L, < 1.05 mmol/L, and 
< 1.00 mmol/L being summarized. 

SAP_001.pdf: 
Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 1 
 
 
 
 
16.1.9 
Documentation of Statistical Methods 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 2 
 
 
 
Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 1 of 36 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Multicenter Single-arm Extension Study to Characterize the Long-term Safety of 
Cinacalcet Hydrochloride in the Treatment of Secondary Hyperparathyroidism in 
Pediatric Subjects With Chronic Kidney Disease on Dialysis 
 
 
 
Protocol Number: 
20140159 
 
Version: 
2.0 
 
Date: 
24 May 2016 
 
Authors: 
 
PPD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT Number: 2341417 
This NCT number has been applied to the document for purposes 
of posting on clinicaltrials.gov 
 
 


Product: Cinacalcet  hydrochloride 
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Date:  21 August  2017 
Page 3 
 
 
 
Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 2 of 36 
 
 
 
Table of Contents 
 
Table of Abbreviations ...................................................................................................... 4 
 
1. 
Introduction .............................................................................................................. 5 
 
2. 
Objectives ................................................................................................................ 5 
2.1 
Primary ......................................................................................................... 5 
2.2 
Secondary .................................................................................................... 5 
2.3 
Exploratory ................................................................................................... 5 
 
3. 
Study Overview ........................................................................................................ 5 
3.1 
Study Design ................................................................................................ 5 
3.1.1 
Subjects From Study 20130356 ................................................... 5 
3.1.2 
Subjects From Study 20110100 ................................................... 6 
3.2 
Sample Size ................................................................................................. 7 
 
4. 
Study Endpoints ....................................................................................................... 7 
 
5. 
Hypotheses and/or Estimations................................................................................ 8 
 
6. 
Definitions ................................................................................................................ 8 
6.1 
Study Periods ............................................................................................... 8 
6.2 
Study Time points......................................................................................... 9 
6.3 
Demographics and Baseline Characteristics .............................................. 12 
6.4 
Study Endpoints ......................................................................................... 14 
6.5 
Derived Variables ....................................................................................... 16 
 
7. 
Analysis Subsets .................................................................................................... 16 
7.1 
Full Analysis Set ......................................................................................... 16 
7.2 
Safety Analysis Set..................................................................................... 16 
7.3 
Efficacy Analysis Set .................................................................................. 16 
7.4 
Study 20130356 SOC Set .......................................................................... 17 
7.5 
Per Protocol Set for Study 20140159 Only (for interim and final 
analyses) .................................................................................................... 17 
7.6 
Per Protocol Set for Combined 20130356, 20110100 and 
20140159 Studies (for final analysis only) .................................................. 17 
7.7 
Subgroup Analyses .................................................................................... 18 
 
8. 
Interim Analysis and Early Stopping Guidelines..................................................... 18 
 
9. 
Data Screening and Acceptance............................................................................ 18 
9.1 
General Principles ...................................................................................... 18 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 18 
9.3 
Handling of Missing and Incomplete Data .................................................. 18 
9.3.1 
Examination of the Missing Data ................................................ 18 
9.3.2 
Handling of Missing Data............................................................ 19 
 
 
 
 


Product: Cinacalcet  hydrochloride 
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Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 3 of 36 
 
 
9.3.2.1 
Missing Adverse Event date .................................... 19 
9.3.2.2 
Other Missing Dates ................................................ 20 
9.4 
Detection of Bias ........................................................................................ 20 
9.5 
Outliers ....................................................................................................... 21 
9.6 
Distributional Characteristics ...................................................................... 21 
9.7 
Validation of Statistical Analyses ................................................................ 21 
 
10. 
Statistical Methods of Analysis............................................................................... 21 
10.1 
General Principles ...................................................................................... 21 
10.2 
Subject Accountability ................................................................................ 22 
10.3 
Important Protocol Deviations .................................................................... 22 
10.4 
Demographic and Baseline Characteristics................................................ 22 
10.5 
Analysis of Primary Endpoint...................................................................... 22 
10.6 
Efficacy Analyses ....................................................................................... 23 
10.6.1 
Analyses of Secondary Endpoints .............................................. 23 
10.6.2 
Sensitivity Analysis of Secondary Endpoints .............................. 24 
10.6.3 
Analyses of Exploratory Endpoints ............................................. 29 
10.7 
Safety Analyses.......................................................................................... 30 
10.7.1 
Adverse Events .......................................................................... 30 
10.7.2 
Laboratory Test Results ............................................................. 31 
10.7.3 
Vital Signs................................................................................... 32 
10.7.4 
Electrocardiogram (ECG) ........................................................... 33 
10.7.5 
Exposure to Investigational Product ........................................... 33 
10.7.6 
Exposure to Concomitant Medication ......................................... 33 
 
11. 
Literature Citations / References............................................................................ 34 
 
12. 
Appendices ............................................................................................................ 35 
 
List of Appendices 
 
Appendix A.  Reference Values/Toxicity Grades ....................................................... 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
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Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 4 of 36 
 
 
Table of Abbreviations 
 
Refer to Study Glossary in the protocol. Additional abbreviations are below: 
 
Abbreviation/Acronym  
Definition 
 
25(OH)D 
25-hydroxyvitamin D 
CDM 
CSR 
EOI 
Clinical Data Management 
Clinical Study Report 
Events of Interest 
 
IV 
Intravenous 
 
QTcB 
Corrected QT using Bazett’s formula 
 
SAP 
Statistical Analysis Plan 
 
IPW 
Inverse Probability Weighting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 6 
 
 
 
Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 5 of 36 
 
 
1. 
Introduction 
 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 3 for cinacalcet 
Study 20140159 dated 16 March 2016.  The scope of this plan includes the planned 
interim and final analyses that are planned and will be executed by the Biostatistics 
department unless otherwise specified. 
 
2. 
Objectives 
 
2.1 
Primary 
 
To characterize the long-term safety and tolerability of cinacalcet in pediatric subjects 
with chronic kidney disease (CKD) receiving dialysis. 
 
2.2 
Secondary 
 
To characterize the long-term effect of cinacalcet in pediatric subjects receiving dialysis 
on laboratory parameters associated with chronic kidney disease – mineral and bone 
disease (CKD-MBD) 
 
2.3 
Exploratory 
 
To characterize the long-term effect of cinacalcet in pediatric subjects on linear and 
pubertal growth. 
 
3. 
Study Overview 
 
3.1 
Study Design 
 
This is a phase 3, 32-week, multicenter, single-arm, extension study designed to 
characterize the long-term safety and tolerability of cinacalcet in pediatric subjects. 
Subjects will remain on cinacalcet treatment for 28 weeks after enrollment from 
parent studies 20110100 or 20130356, or until the time of renal transplant or 
parathyroidectomy, whichever occurs first.  The treatment period is followed by 
a 4-week safety follow-up period. 
 
The overall study design is described by a study schema at the end of 
the protocol synopsis section. 
 
3.1.1 
Subjects From Study 20130356 
 
The screening period for Study 20140159 begins when the informed consent, and 
assent if applicable, is signed and concludes when the subject is either enrolled 
into the trial or screen failed. The informed consent can be signed up to 7 days 
(± 3 days) prior to Study 20140159 day 1. Eligible subjects who reach 
 
Study 20130356 termination or complete the 20-week treatment period in 
 
 
 


Product: Cinacalcet  hydrochloride 
Clinical  Study Report:  20140159 
Date:  21 August  2017 
Page 7 
 
 
 
Product:  Cinacalcet HCl 
Statistical Analysis Plan:  20140159 
Date:  24 May 2016 
Page 6 of 36 
 
 
study 20130356, will either continue, restart, or start cinacalcet treatment in this 
study, depending on their cinacalcet treatment status at the time of enrollment. 
Eligible subjects will begin procedures in Study 20140159 at the Study 20130356 
end of investigational product (EOIP) study visit, and will therefore not complete 
the safety follow-up period in Study 20130356; ie, the EOIP visit in 
Study 20130356 and Study Day 1 in Study 20140159 will be the same visit unless 
there is an administrative delay.  Eligible subjects will complete Study Day 1 of 
Study 20140159 assessments and confirm eligibility in IVR system prior to dispensing 
IP on study day 1. 
 
Eligible subjects from 20130356 who were randomized to the SOC arm in 
 
Study 20130356 will begin cinacalcet treatment on Study Day 1 in Study 20140159 if 
their iPTH is ≥ 300 pg/mL and cCa is ≥ 8.8 mg/dL during screening in 
Study 20140159.  Eligible subjects from the cinacalcet arm in 20130356 will continue 
cinacalcet treatment on Study Day 1 if their iPTH is ≥ 150 pg/mL and cCa is ≥ 8.4 mg/dL 
during screening in Study 20140159.  If IP has been withheld or missed for more 
than 14 days on Study Day 1, the subject will resume dosing at the starting dose 
level once all restart criteria are met. 
 
All subjects from 20130356 will be eligible to titrate the cinacalcet dose at monthly 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based on the 
subject’s dry weight at Study Day 1, not to exceed a dose of 180 mg/day. 
 
3.1.2 
Subjects From Study 20110100 
 
Eligible subjects will complete the End of Study visit or early termination visit for 
Study 20110100 and continue or restart cinacalcet treatment in this study on 
Study Day 1 depending on their cinacalcet treatment status at the time of 
enrollment, dry weight at the time of enrollment in 20140159 study and age at the 
time of enrollment in the 20110100 study. Subjects completing the 26-week 
treatment period in Study 20110100 will be screened during the safety follow-up 
period in Study 20110100; if eligible, these subjects will begin procedures in 
Study 20140159 at the Study 20110100 week 26 End of Study visit (Study Day 1 
in 20140159 will be the same as EOS in Study 20110100).  Subjects who reach 
Study 20110100 termination before week 26 will not complete the safety follow-up 
period in Study 20110100, beginning the 20140159 extension study at early 
termination visit. The early termination/EOS visit in study 20110100 and 
 
 
 
 
 


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Study Day 1 in Study 20140159 will be the same visit unless there is an 
administrative delay. 
 
Eligible subjects will complete Study Day 1 assessments and confirm eligibility in 
 
IVR system before being dispensed IP on Study Day 1. 
 
Eligible subjects will continue cinacalcet treatment on Study Day 1 based on their 
dry weight at the time of enrollment in 20140159 study if their iPTH is ≥ 150 pg/mL 
and cCa is ≥ 8.8 mg/dL (age < 2 years of age) or cCa is ≥ 8.4 mg/dL (age 
is ≥ 2 years of age) during screening in Study 20140159.  If IP has been withheld or 
missed for > 14 days at the time of Study Day 1 of Study 20140159, the subject will 
resume dosing at the starting dose level based on dry weight at the time of 
enrollment once all restart criteria are met. 
 
All subjects from 20110100 will be eligible to titrate the cinacalcet dose at monthly 
 
titration visits (beginning at week 4) to a maximum dose of 2.5 mg/kg/day based 
on the subject’s dry weight at Study Day 1 in Study 20140159, not to exceed a 
dose of 60 mg/day. 
 
Cinacalcet dosing will follow the dose titration, dose withhold, and restarting 
rules defined in protocol Section 6.2.3. 
 
3.2 
Sample Size 
 
This is an extension study for subjects from Study 20130356 and Study 20110100. 
The sample size of approximately 48 for the parent study 20130356 and 30 for the 
parent Study 20110100 will result in a planned sample size of 78 subjects in 
Study 20140159. 
 
4. 
Study Endpoints 
 
Primary Endpoint: 
 
Incidence of treatment emergent adverse events of interest 
 
Secondary Endpoints: 
 
20140159 study only (for interim and final analyses) 
 
Achievement of ≥30% reduction from baseline to mean iPTH during 
weeks 11 and 15 (SOC arm of Study 20130356 only) 
 
Achievement of ≥30% reduction from baseline to mean iPTH during 
weeks 23 and 28 (SOC arm of Study 20130356 only) 
 
Percent change from baseline to mean iPTH during weeks 23 and 28 (SOC 
arm of Study 20130356 only) 
 
 
 
 


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Change in corrected total serum calcium from baseline to mean value 
during week 23 and 28 
 
Change in serum phosphorus from baseline to mean value during week 23 
and 28 
 
Achievement of a mean iPTH value ≤300 pg/mL during week 23 and 28 
 
Serum cCa values at baseline, week 11, and week 28 
 
Serum phosphorus values at baseline, week 11, and week 28 
 
Combined 20130356, 20110100 and 20140159 studies (for final analysis only) 
 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks 11 and 15 
 
Achievement of ≥ 30% reduction from day 1 of cinacalcet treatment to 
mean iPTH during weeks  23 and 28 
 
Percent change in iPTH over time from day 1 of cinacalcet treatment 
 
Change in serum cCa over time from day 1 of cinacalcet treatment 
 
Change in serum phosphorus over time from day 1 of cinacalcet treatment 
 
Exploratory Endpoint 
 
20140159 study only (for final analysis only) 
 
Growth velocity from baseline to EOS 
 
Change in Tanner stage from baseline to EOS 
 
Combined 20130356, 20110100 and 20140159 Studies (for final analysis only) 
Growth velocity from day 1 of cinacalcet treatment to EOS 
Change in Tanner stage from day 1 of cinacalcet treatment to EOS 
 
Safety Endpoints: 
 
Nature, frequency, and severity of all adverse events 
 
Blood pressure, heart rate, and changes in laboratory parameters, including 
clinical chemistry and hematology 
 
5. 
Hypotheses and/or Estimations 
 
There is no formal statistical testing for this study. The proportions of subjects with 
treatment emergent adverse events of interest will be estimated. 
 
6. 
Definitions 
 
6.1 
Study Periods 
 
Screening 
 
The screening period begins when the informed consent, and assent if applicable, is 
signed and concludes when the subject is either enrolled into the trial or screen failed. 
 
 
 
 


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The informed consent can be signed up to 7 days (± 3 days) prior to Study Day 1 of 
 
Study 20140159. 
 
For subjects who do not meet the eligibility criteria in Section 4 of the protocol, 
re-screening will not be considered in this study. 
 
End of Dose titration phase 
 
The end of dose titration phase is Week 24 of Study 20140159. 
 
Time on study 
 
If the subject has ended study, time on study (in days) is defined as: time on 
 
study = end of study date – study Day 1 +1. 
 
Otherwise, time on study (in days) = data cutoff day – study Day1 +1, which is 
 
applicable for interim analysis only. 
 
Time of follow-up (in days; use for follow-up adjusted AE for the final analysis) 
 
End of study date – Day 1 of cinacalcet treatment +1 
 
6.2 
Study Time points 
 
Unless otherwise specified, these study time point definitions are for 
 
Study 20140159 only. 
 
Enrollment date 
 
The date the subject has met all eligibility criteria and eligibility has been completed in 
 
the IVR/IWR system. 
 
Study Day 1 
 
The date that the initial dose of IP is administered in Study 20140159. For subjects 
 
who didn’t take any IP throughout the study, leave as missing. 
 
Day 1 of cinacalcet treatment (combined studies 20130356, 20110100 and 
 
20140159) 
 
The date that the initial dose of cinacalcet treatment is administered in 
 
studies 20130356, 20110100 or 20140159. 
 
Study day 
 
For a given study visit, the study day is defined as: study day= (visit date - date of 
 
Study Day 1) +1. 
 
 
 
 


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Cinacalcet day (combined studies 20130356, 20110100 and 20140159) 
 
For a given study visit, the cinacalcet day is defined as: cinacalcet day = (visit 
 
date – date of Day 1 of cinacalcet treatment) +1. 
 
End of treatment 
 
For subject who completed treatment as of cutoff date, the end of treatment is 
defined as the date of the last dose of IP. If subject is ongoing as of cutoff date, 
leave as missing. 
 
End of study Date (for interim analysis only) 
 
For subjects who completed the study or early terminated from the study as of the 
data cut-off date, the end of study date is the date on the end of study form. For 
subjects who are ongoing as of cutoff date, leave the end of study date as missing. 
 
End of study Date (for final analysis only) 
 
Use the end of study date from the End of Study Form. 
 
Study Visit 
 
Since the actual visit for a subject may not exactly coincide with their scheduled 
 
visit date, the actual visit date is mapped to the study visit as follows. 
 
Analysis window for ionized calcium and cinacalcet dose: 
 
Analysis Visit 
Target Day 
Study Day 
Interval (days) 
Baseline (for ionized calcium) 
1 
<= 1 
N/A 
Day 1 (for cinacalcet dose) 
1 
1 
1 
Week 1 
8 
2 – 11 
9 
Week 2 
15 
12 – 18 
7 
Week 3 
22 
19 – 25 
7 
Week 4 
29 
26 – 32 
7 
Week 5 
36 
33 – 39 
7 
Week 6 
43 
40 – 46 
7 
Week 7 
50 
47 – 53 
7 
Week 8 
57 
54 – 60 
7 
Week 9 
64 
61 – 67 
7 
Week 10 
71 
68 – 74 
7 
Week 11 
78 
75 – 81 
7 
Week 12 
85 
82 – 88 
7 
Week 13 
92 
89 – 95 
7 


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Analysis window for ionized calcium and cinacalcet dose: 
 
Analysis Visit 
Target Day 
Study Day 
Interval (days) 
Week 14 
99 
96 – 102 
7 
Week 15 
106 
103 – 109 
7 
Week 16 
113 
110 - 116 
7 
Week 17 
120 
117 – 123 
7 
Week 18 
127 
124 – 130 
7 
Week 19 
134 
131 – 138 
7 
Week 20 
141 
139 – 144 
7 
Week 21 
148 
145 – 152 
7 
Week 22 
155 
153 – 158 
7 
Week 23 
162 
159 – 166 
7 
Week 24 
169 
167 – 173 
7 
Week 25 
176 
174 – 180 
7 
Week 26 
183 
181 – 187 
7 
Week 27 
190 
188 – 194 
7 
Week 28 
197 
≥195 
N/A 
Page 2 of 2 
 
Analysis window for iPTH 
 
Study Visit 
Target Day 
Study Day 
Interval (days) 
Baseline 
1 
<= 1 
N/A 
Week 3 
22 
2-36 
35 
Week 7 
50 
37-64 
28 
Week 11 
78 
65-92 
28 
Week 15 
106 
93-120 
28 
Week 19 
134 
121-148 
28 
Week 23 
162 
149-176 
28 
Week 28 
197 
177-211 
35 
Week 32 
225 
≥212 
N/A 
 
Analysis window for calcium, corrected total serum calcium, serum phosphorus, 
serum albumin, CaxP 
 
Study Visit 
Target Day 
Study Day 
Interval (days) 
Baseline 
1 
<= 1 
N/A 
Week 1 
8 
2-14 
13 
Week 3 
22 
15-36 
21 
Week 7 
50 
37-64 
28 
Week 11 
78 
65-92 
28 
Week 15 
106 
93-120 
28 


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Analysis window for calcium, corrected total serum calcium, serum phosphorus, 
serum albumin, CaxP 
 
Study Visit 
Target Day 
Study Day 
Interval (days) 
Week 19 
134 
121-148 
28 
Week 23 
162 
149-176 
28 
Week 28 
197 
177-211 
35 
Week 32 
225 
≥212 
N/A 
Page 2 of 2 
 
Analysis window for vital signs and all other labs. 
 
Study Visit 
Target Day 
Study Day 
Interval (days) 
Baseline 
1 
<= 1 
N/A 
Week 3 
22 
2-36 
35 
Week 7 
50 
37-64 
28 
Week 11 
78 
65-92 
28 
Week 15 
106 
93-120 
28 
Week 19 
134 
121-148 
28 
Week 23 
162 
149-176 
28 
Week 27 
190 
177 – 194 
18 
Week 28 
197 
195 – 211 
17 
Week 32 
225 
≥212 
N/A 
 
If there is more than one observation in a visit window, use the value collected 
closest to the target day. If multiple observations are equally close to the target 
day, use the later value. 
 
6.3 
Demographics and Baseline Characteristics 
 
Demographics 
 
Sex, ethnicity, race, age at enrollment of parent studies will be transferred from the 
parent studies 20130356 and 20110100. Study baseline age at Study Day 1 of 
Study 20140159 is defined as the subject’s age (in years) on the day of enrollment 
 
in study 20140159. 
 
Study Baseline Values 
 
Study Baseline at Study Day 1 of Study 20140159 
 
Study Baseline iPTH, corrected total serum calcium, and serum phosphorus values are 
defined as the mean values of samples collected during the screening period and Study 
Day 1 pre-dose. 
 
 
 
 
 
 


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Ca x P will be calculated at central lab COVANCE using corrected total serum calcium 
and serum phosphorus. Study Baseline value will be the mean of the values during the 
screening period and Study Day 1 pre-dose. 
 
Study Baseline dry weight is defined as the value collected at Study 20140159 Day 1 
visit. 
 
For all other variables, the study baseline value is defined as the last non-missing value 
collected prior to the first dose of IP, either during the screening phase or on Study 
Day 1. 
 
All study baseline values will be calculated to the same number of decimal places as the 
raw data. 
 
Study Baseline vitamin D use 
 
Vitamin D use at study baseline is defined as any use of nutritional vitamin D or 
 
vitamin D sterol within 7 days prior to Study Day 1. 
 
Study Baseline growth hormone use 
 
Growth hormone use at study baseline is defined as any use of growth hormone during 
 
the screening period prior to Study Day 1. 
 
Study Baseline phosphate binder use 
 
Phosphate binder use at study baseline is defined as any use of any phosphate binder 
 
the day prior to Study Day 1. 
 
Study Baseline calcium supplement use 
 
Calcium supplement use at study baseline is defined as any use of any calcium 
 
supplement the day prior to Study Day 1. 
 
Baseline at first cinacalcet dose (combined studies 20130356, 20110100 and 
20140159) 
For subjects who received SOC only in Study 20130356, baseline values at first 
cinacalcet dose are same as study baseline at Study Day 1 of Study 20140159. 
 
For other subjects, all baseline values at first cinacalcet dose will be transferred 
from the parent studies 20130356 and 20110100. 
 
 
 
 
 
 
 
 


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6.4 
Study Endpoints 
 
Treatment emergent adverse events 
 
20140159 study only 
 
Treatment-emergent adverse events are defined as adverse events that occurred on or 
 
after Study Day 1 in Study 20140159. 
 
Combined 20130356, 20110100 & 20140159 Studies 
 
Treatment-emergent adverse events are defined as adverse events that occurred 
on or after day 1 of cinacalcet treatment in the parent study (Studies 20140356 and 
20110100) or Study 20140159. 
 
Events of interest (EOI) 
 
The EOI names and search scopes (provided by Amgen Global Safety) are listed 
below: 
 
EOI Name 
Scope 
Acute pancreatitis (SMQ) 
Narrow 
Cardiac failure (SMQ) 
Narrow 
Convulsions (SMQ) 
Broad 
Drug related hepatic disorders - 
comprehensive search (SMQ) 
Narrow 
Fractures (Amgen MedDRA Search 
Strategy) 
Narrow 
Hypersensitivity (SMQ) 
Narrow 
Hypocalcemia (Amgen MedDRA 
Search Strategy) 
Narrow 
Hypotension (Amgen MedDRA Search 
Strategy) 
Narrow 
Ischaemic heart disease (SMQ) 
Narrow 
Malignant or unspecified tumors (SMQ) 
Narrow 
Medication errors (SMQ) 
Broad 
Product use issues (MedDRA HLGT) 
Broad 
Nervous system disorders excluding 
seizures (Amgen MedDRA Search 
Strategy) 
Broad 
Torsade de pointes/QT prolongation 
(SMQ) 
Narrow 
Ventricular tachyarrhythmias (SMQ) 
Narrow 
 
 
 
 


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Change from study baseline 
 
For each subject, change from study baseline for a given variable at a given time point 
 
or periods is defined as: 
 
(Value at the given time point or period – study baseline value) 
 
and will be calculated at the same number of decimal places as the raw data provided by 
laboratory where applicable. 
 
Percent change from study baseline 
 
For each subject, percent change from study baseline in a given variable at a given time 
 
point is defined as: 
 
100 x ((value at the given time point or period – study baseline value) / study baseline 
value) 
 
and will be calculated to one decimal place. 
 
Change from day 1 of cinacalcet treatment 
 
For each subject, change from baseline at first cinacalcet dose for a given variable 
 
at a given time point or period is defined as: 
 
(Value at the given time point or period – baseline at first cinacalcet dose) 
 
and will be calculated at the same number of decimal places as the raw data 
provided by laboratory where applicable. 
 
Percent change from day 1 of cinacalcet treatment 
 
For each subject, percent change from baseline at first cinacalcet dose in a given 
 
variable at a given time point or period is defined as: 
 
100 x ((value at the given time point or period – baseline at first cinacalcet dose) / 
 
baseline at first cinacalcet dose) 
 
and will be calculated to one decimal place. 
 
Growth velocity 
 
Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks 
between the two assessments. 
 
 
 
 
 
 
 


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6.5 
Derived Variables 
 
Corrected total serum calcium 
 
Corrected total serum calcium (mg/dL) = measured total serum calcium (mg/dL) + 0.8 
 
(4.0 – Serum albumin (g/dL)), or 
 
Corrected total calcium (mmol/L) = measured total serum calcium (mmol/L) + 0.02 
(40 – Serum albumin (g/L)). 
 
Total serum calcium will only be corrected using above formulae if the serum albumin is 
 
< 4 g/dL or 40 g/L. The correction will be done at the Covance central lab. 
 
IP compliance 
 
Daily subject compliance with administration of cinacalcet is documented on the IP 
 
administration eCRF. IP compliance (%) = 100 x (number of days of planned 
dosing – number of days dose is changed due to noncompliance) / number of days of 
planned dosing. 
 
Actual treatment 
 
Actual treatment of a subject in Study 20140159 is cinacalcet if the subject 
received at least one dose of IP, and is missing if the subject did not receive any 
IP throughout the study. 
 
7. 
Analysis Subsets 
 
7.1 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all Study 20140159 enrolled subjects. All 
subjects will be analyzed according to the actual treatment received in the parent 
studies and overall. 
 
7.2 
Safety Analysis Set 
 
The Safety Analysis Set will be used for primary and safety endpoints.  It includes all 
subjects who were enrolled in Study 20140159 and received at least one dose of 
investigational product. Subjects will be analyzed according to the treatment 
received in the parent studies and overall. 
 
7.3 
Efficacy Analysis Set 
 
The efficacy analysis set will be used for secondary endpoints. The efficacy 
analysis set includes all enrolled subjects in Study 20140159 who received at least 
one dose of cinacalcet during Study 20140159 and have at least one assessment 
 
 
 
 


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after Study Day 1. Subjects will be analyzed according to the treatment received in 
the parent studies and overall. 
 
7.4 
Study 20130356 SOC Set 
 
The Study 20130356 SOC set will be used for secondary endpoints that analyze 
subjects from Study 20130356 SOC arm only. The Study 20130356 SOC set 
includes all Study 20140159 enrolled subjects from Study 20130356 who did not 
receive cinacalcet prior to Study Day 1 of 20140159 and received at least one dose 
of cinacalcet in Study 20140159 and have at least one assessment after 
Study Day 1 of 20140159. 
 
7.5 
Per Protocol Set for Study 20140159 Only (for interim and final 
analyses) 
 
The Per Protocol Set for Study 20140159 only is defined as all enrolled subjects who 
do not have significant deviations from the protocol (as assess by IPD), or 
missing > 2 doses within any dosing week or ≥2 documented overdoses within a 
dosing week. 
 
For each secondary endpoint that requires sensitivity analysis using per protocol 
set, a subset of the Per Protocol Set for Study 20140159 only who has at least one 
desired lab measurement during the corresponding evaluation period will be 
used. 
 
7.6 
Per Protocol Set for Combined 20130356, 20110100 and 
20140159 Studies (for final analysis only) 
 
The Per Protocol Set for combined 20130356, 20110100 and 20140159 studies is 
defined as all Study 20140159 enrolled subjects who do not have significant 
deviations from the protocols of parent studies and Study 20140159 (as assessed 
by IPD) or non-compliance as defined for each study specifically. 
 
For each secondary endpoint that requires sensitivity analysis using per protocol 
set, a subset of the Per Protocol Set for Combined 20130356, 20110100 and 
20140159 Studies who has at least one corresponding lab measurement during 
the corresponding evaluation period will be used. 
 
 
 
 
 
 
 
 
 
 
 


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7.7 
Subgroup Analyses 
 
The following characteristics may be used in the subgroup analyses planned for the 
primary,  secondary and safety endpoints: 
 
baseline age group in parent studies (6 to < 12 years old and 12 to < 18 years 
old for Study 20130356; 28 days to < 2 years old and 2 to < 6 years for 
Study 20110100) 
gender (male and female) 
race (black, white and other). If any category has ≤ 4 subjects, the category 
will be pooled together with other category for summary purposes. 
Tanner stage (1 and >1) 
 
8. 
Interim Analysis and Early Stopping Guidelines 
 
An interim analysis will be performed to support the sNDA for the pediatric 
indication. The scope of this interim analysis will be specified in section 10 of this 
SAP. Additional interim analyses may be performed if necessary to support 
regulatory inquiries and the SAP may be amended to reflect the additional 
analyses.  There are no plans to change the conduct of the study based on the 
interim analysis results. 
 
There is no formal statistical testing. The analysis for all endpoints will be descriptive in 
nature. 
 
9. 
Data Screening and Acceptance 
 
9.1 
General Principles 
 
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
 
9.2 
Data Handling and Electronic Transfer of Data 
 
Amgen’s Clinical Data Management department will provide all data to be used in the 
planned analyses. This study will use the RAVE database and non-CTDB database. 
 
9.3 
Handling of Missing and Incomplete Data 
 
9.3.1 
Examination of the Missing Data 
Missing data frequency and pattern for any of the following key variables will be 
reviewed. The potential impact of these missing values on the planned analysis will be 
evaluated. 
 
1.  Subject Identification Data 
 
subject identification number 
date of birth 
 
 
 


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race 
ethnicity 
sex 
center/site number 
 
country 
 
2.  Dates and Times 
 
informed consent date 
enrollment date 
end of study date 
 
3.  Safety Data 
 
dates for onset of adverse events 
 
dates for resolution of adverse events (if not continuing at the end of the 
study) 
 
CTCAE v4 severity grading, relationship to treatment, seriousness, and 
action taken for adverse events 
 
4.  Efficacy Data 
 
iPTH, corrected total serum calcium values, ionized calcium values, 
phosphorus values and dates of assessment 
 
5.  Investigational Product Administration 
 
Daily planned IP (dose level, date, reason for dose change) 
 
Daily IP administration (dose level, date, reason for dose 
change/withheld) 
 
box ID numbers 
 
9.3.2 
Handling of Missing Data 
 
9.3.2.1 
Missing Adverse Event date 
 
For any listings, missing or incomplete dates will be listed as is. 
 
All missing dates (missing entirely or partially) of adverse events occurring after first 
dose of IP will be queried.  For adverse events with the question “Did event start 
before first dose of investigational product?” on the eCRF was answered as 
“Yes”, the missing adverse event start dates won’t be imputed. All other missing 
adverse event start dates will be handled as described below: 
When the adverse event start year is available and the start day and month are 
missing, if the start year is the same as the year of Study Day 1, the start 
date will be set to date of Study Day 1, otherwise set to the 1st of January of 
the onset year. 
 
 
 


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When the start year and month are available and the start day is missing, if the 
start year and month are the same as the year and month of Study Day 1, 
the start date will be set to date of Study Day 1, otherwise the 1st of the 
month of the onset year. 
 
If the entire start date is missing, it will be set to the date of Study Day 1 
 
9.3.2.2 
Other Missing Dates 
 
Partial/missing start dates for vitamin D, phosphate binders, calcium supplements, and 
growth hormone will be imputed using the following algorithm. 
 
If the start year is available and the start day and month are missing, the 
start date will be set to the 1st of January of the onset year. 
If the start year and month are available and the start day is missing, the 
start date will be set to the 1st of the month of the onset year. 
 
If the entire start date is missing, it will not be imputed. 
 
Partial/missing stop dates for the concomitant medications (not continuing at the end of 
the study) will be imputed using the following logic: 
 
If the stop year is available and stop month and day are missing, the stop date 
will be reset to 31st of December of the stop year. 
 
If the stop year and month are available and the stop day is missing, the stop 
date will be set to the last day of the month of the stop year. 
 
If the stop year and day are available and stop month is missing, the stop month 
will be set to December of the stop year. 
 
If the stop month and day are available and stop year is missing, the stop year 
will be reset to the year of the End of Study date. 
 
If the entire stop date is missing, it will not be imputed. 
 
9.4 
Detection of Bias 
 
This study is an open label, single arm study. Some factors that may bias the results of 
the study include: 
 
important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints 
IP dosing compliance 
 
the timing of and reasons for early withdrawal from treatment and from study 
 
The incidence of these factors as well as potential biases from the parent studies 
discussed in the parent studies SAPs will be assessed.  Important protocol deviations 
likely to impact the analysis and interpretation of the efficacy endpoints will be tabulated 
in the Clinical Study Report (CSR).  If necessary, the incidence of the other factors will 
be reported as well. 
 
 
 
 


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9.5 
Outliers 
 
This is a descriptive study, all outliers that are not known errors will be included in the 
relevant analysis. Outliers that are confirmed to be errors that are discovered before the 
database lock will be corrected in the database by CDM. Any erroneous values 
discovered after the database lock will be noted in the CSR. 
 
9.6 
Distributional Characteristics 
 
There is no distributional assumption being made due to the descriptive nature of the 
analysis. Both mean and median will be presented for continuous outcomes. 
 
9.7 
Validation of Statistical Analyses 
 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures. 
 
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
 
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.2 or later 
and Qualified R. 
 
10. 
Statistical Methods of Analysis 
 
10.1 
General Principles 
 
There is no formal statistical testing for this study. The analysis of all endpoints will be 
descriptive in nature. 
 
Descriptive statistics will be used to summarize data for continuous variables (including n, 
mean, standard deviation (SD), standard error (SE), median, 25th (Q1) and 75th (Q3) 
percentiles, minimum and maximum values, and corresponding 2-sided 95% CI, where 
applicable.)  For categorical variables, the number and percentage of subjects in each 
category,will be reported. Graphical presentation may be provided for selected variables. 
 
The laboratory data collected more than 7 days after the last dose of IP will be 
excluded for the efficacy analyses. 
 
For the interim analysis supporting pediatric sNDA, only data from the 
 
20140159 study before interim data cutoff date will be analyzed according to the 
actual treatment received from the parent study and overall. 
 
 
 
 
 
 
 


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Date:  24 May 2016 
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For the final analysis, final efficacy and safety data from Study 20140159 will be 
analyzed. In addition, cumulative data combining the parent studies (20130356 
and 20110100) and Study 20140159 will also be summarized. 
 
10.2 
Subject Accountability 
 
The number (and percent) of subjects who are enrolled, receive investigational product, 
and complete each study period will be summarized.  The number (and percentage) of 
subjects who withdraw from treatment and from study will be summarized. The time of 
withdrawal and reason for withdrawal from IP or study will be listed.  In addition, the 
number of subjects in each analysis set will be summarized. 
 
10.3 
Important Protocol Deviations 
 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes and 
descriptions will be used during the course of the study. The final IPD list is used to 
produce the Summary of IPDs table and the List of Subjects with IPDs. 
 
Eligibility deviations are defined in the protocol. Important inclusion/exclusion criteria 
deviations will be listed by subject. 
 
10.4 
Demographic and Baseline Characteristics 
 
The following demographic and baseline characteristics will be summarized based on 
FAS at Study 20140159 baseline and at baseline at first cinacalcet dose separately 
using descriptive statistics: 
 
Sex, age, dry weight, height, race group (white, black, other), ethnicity, dialysis status, 
Tanner stage, baseline iPTH, corrected total serum calcium, ionized calcium, serum 
phosphorous, Ca x P, and selected concomitant medication. 
 
10.5 
Analysis of Primary Endpoint 
 
The primary endpoint is incidence of treatment emergent adverse events of interest as 
defined in Section 6.4. The analysis will be based on Safety Analysis Set.  Subject 
incidence of EOIs will be summarized by EOI category and preferred term for data in 
Study 20140159 only for both the interim and final analyses. The 95% confidence 
intervals (CI) of the overall subject incidence rates will be reported. 
 
The secondary analysis of the primary endpoint is follow-up time adjusted 
incidence of EOIs for combined data from parent studies and data from the 
20140159 study for the final analysis. 
 
 
 


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Date:  24 May 2016 
Page 23 of 36 
 
 
10.6 
Efficacy Analyses 
 
10.6.1 
Analyses of Secondary Endpoints 
 
Analyses of secondary endpoints will be based on Efficacy Analysis Set or 20130356 
 
SOC Set per endpoint definitions unless otherwise specified. 
 
Study 20140159 only 
 
Proportion of subjects achieving the secondary endpoints of ≥30% reduction in 
iPTH from study baseline to mean value during weeks 11 and 15 will be reported 
with 95% CI based on 20130356 SOC Set. Subjects who have no iPTH values 
during weeks 11 or 15 will be considered non-responders. 
 
Proportion of subjects achieving the secondary endpoints of ≥30% reduction in 
iPTH from study baseline to mean value during weeks 23 and 28 will be reported 
with 95% CI based on 20130356 SOC Set. For subjects who do not have a iPTH 
value during weeks 23 and 28, the mean of the last two available post-baseline 
values in the dose-titration phase will be used. If only one post-baseline value is 
available, this single value will be used. If no post-baseline value is available, the 
subject is considered a non-responder. 
 
Summary statistics will be provided for percent change from study baseline to 
mean iPTH during weeks 23 and 28 based on 20130356 SOC Set, and change in 
corrected total calcium and change in serum phosphorus from study baseline to 
mean value during weeks 23 and 28 based on efficacy analysis set by treatment 
group in the parent studies. For subjects who are missing the efficacy 
measurement during weeks 23 to 28, the mean of the last two available 
post-baseline values in the dose titration phase will be used. If only one 
 
post-baseline value is available, this single value will be used. If no post-baseline 
value is available, the subject will be excluded from the analysis. 
 
Proportion of subjects who achieve a mean iPTH value ≤ 300 pg/mL during 
 
weeks 23 and 28 will be provided based on efficacy analysis set by the treatment 
group in parent study with 95% CI. For subjects who do not have an iPTH value 
during weeks 23 and 28, the mean of the last two available post-baseline values in 
the dose-titration phase will be used. If only one post-baseline value is available, 
this single value will be used. If no post-baseline value is available, the subject is 
considered a non-responder. 
 
 
 
 
 


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Summary statistics will be provided for serum cCa and phosphorus values at 
 
study baseline, week 11, and week 28 for all efficacy analysis set subjects. 
 
Combined 20130356, 20110100 & 20140159 studies 
Proportion of subjects achieving the secondary endpoints of ≥30% reduction in 
iPTH from day 1 of cinacalcet treatment to mean value during weeks 11 and 15 will 
be reported with 95% CI for all efficacy analysis set subjects. Subjects who have 
no weeks 11 or 15 iPTH values will be considered non-responders. 
 
Proportion of subjects achieving the secondary endpoints of ≥30% reduction in 
iPTH from day 1 of cinacalcet treatment to mean value during weeks 23 and 28 will 
be reported with 95% CI for all efficacy analysis set subjects. For subjects who do 
not have an iPTH value during weeks 23 and 28, the mean of the last two available 
post-baseline values collected at protocol-specified visits in the dose titration 
phase will be used. If only one post-baseline value is available, this single value 
will be used. If no post-baseline value is available, the subject is considered a 
non-responder. 
 
Summary statistics will be provided for percent change in iPTH, change in serum 
cCa and change in serum phosphorus over time from day 1 of cinacalcet 
treatment for all efficacy analysis set subjects. 
 
10.6.2 
Sensitivity Analysis of Secondary Endpoints 
 
Sensitivity Analysis of the effect of dose interruption (final analysis only) 
 
To study the effect of dose interruption, sensitivity analyses will be performed 
separately for subjects in the efficacy analysis set who have and do not have dose 
interruption of >14 days between EOIP of the parent study and Study Day 1 in 
study 20140159. Secondary endpoints of achievement of ≥ 30% reduction from 
day 1 of cinacalcet treatment to mean iPTH during weeks 11 and 15, and percent 
change in iPTH over time from day 1 of cinacalcet treatment will be analyzed using 
combined 20130356, 20110100 and 20140159 studies data. 
 
Sensitivity analyses to assess the effect of missing data or non-compliance 
 
 
 
 
 
 
 
 
 
 
 
 


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Secondary endpoints for Study 20140159 only 
 
Secondary endpoint 
Sensitivity Analyses 
Planned for Interim 
or Final analysis 
Achievement of 
≥30% reduction 
from baseline to 
mean iPTH 
during weeks 11 
and 15 (SOC 
arm of 
Study 20130356 
only) 
Inverse Probability Weighting (IPW) 
The missingness model will 
include study baseline iPTH, 
cCa, phosphorus, age group, 
sex, race, and AEs of nausea, 
vomiting and symptomatic 
hypocalcemia. Dialysis vintage, 
AE or IPD related to ending IP 
may be also included in the 
model depending on the EOIP 
reason observed in the study. 
The final weighted pooled 
logistic regression model will 
include study baseline iPTH, 
cCa, phosphorus and age 
group. This analysis will be 
performed using the 
Study 20130356 SOC set. 
Final analysis only 
Completer analysis: 
Only subjects completing 
15 weeks of study in the 
Study 20130356 SOC set will be 
included in the analysis. 
Subjects with no iPTH values 
during weeks 11 and 15 will be 
considered as nonresponders. 
Final analysis only 
Per protocol analysis: 
Subjects in per protocol set 
who did not receive cinacalcet 
in the parent study and have at 
least one iPTH value during 
weeks 11 and 15 will be used. 
Interim and Final 
analyses 
Nearest 2 imputation 
If no values are observed 
during weeks 11 and 15, the 
nearest two values at or after 
week 7 will be used, including 
unscheduled visit values, 
values prior to or after 
weeks 11 and 15. Subjects with 
no observed values at or after 
week 7 will be considered 
nonresponders. 
Final analysis only 
Page 1 of 3 
 
 
 
 
 
 
 


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Page 26 of 36 
 
 
Secondary endpoints for Study 20140159 only 
 
Secondary endpoint 
Sensitivity Analyses 
Planned for Interim 
or Final analysis 
Achievement of 
≥30% reduction 
from baseline to 
mean iPTH 
during weeks 23 
and 28 (SOC 
arm of 
Study 20130356 
only) 
Achievement of 
a mean iPTH 
value 
≤300 pg/mL 
during week 23 
and 28 (efficacy 
analysis set) 
IPW: 
The IPW method is same as 
specified for the sensitivity of 
binary endpoint “Achievement 
of ≥30% reduction from study 
baseline to mean iPTH during 
weeks 11 and 15”. 
Final analysis only 
Completer analysis: 
Only subjects with at least one 
iPTH value during week 23-28 
will be included in the analysis. 
Final analysis only 
Per protocol analysis: 
Subjects from in per protocol 
set for Study 20140159 only 
who did not receive cinacalcet 
in the parent study and have at 
least one iPTH value during 
weeks 23 and 28 will be used 
for the endpoint defined for 
SOC arm of Study 20130356 
only. 
Subjects from the per protocol 
set for Study 20140159 only 
and with at least one iPTH 
value during  weeks 23 and 28 
will be used for the other 
endpoint. 
Interim and Final 
analyses 
Page 2 of 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date:  24 May 2016 
Page 27 of 36 
 
 
Secondary endpoints for Study 20140159 only 
 
Secondary endpoint 
Sensitivity Analyses 
Planned for Interim 
or Final analysis 
Percent change 
from baseline to 
mean iPTH 
during weeks 23 
and 28 (SOC 
arm of 
Study 20130356 
only) 
Change in 
corrected total 
serum calcium 
from baseline to 
mean value 
during week 23 
and 28 (efficacy 
analysis set) 
Change in 
serum 
phosphorus 
from baseline to 
mean value 
during week 23 
and 28 (efficacy 
analysis set) 
Repeated measures mixed effect 
model: 
The repeated measures model 
will include treatment group, 
study baseline age group, 
scheduled visits, and 
interaction of treatment group 
and scheduled visits. An 
unstructured covariance will be 
used for the model. 
Final analysis only 
Completer analysis: 
Only subjects with at least one 
required lab value for the 
endpoint during week 23-28 will 
be included in the analysis. 
Final analysis only 
Per protocol analysis: 
Subjects in both the Study 
20130356 SOC set and per 
protocol set for Study 20140159 
only and with at least one iPTH 
value during weeks 23 and 28 
will be used for the endpoint 
defined for SOC arm of 
Study 20130356 only. 
Subjects from the per protocol 
set for Study 20140159 only 
and with at least one 
corresponding lab value during 
weeks 23 and 28 will be used 
for other endpoints. 
Interim and Final 
analyses 
Page 3 of 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date:  24 May 2016 
Page 28 of 36 
 
 
Secondary endpoints for combined 20130356, 20110100 and 20140159 studies 
 
Secondary endpoint 
Sensitivity Analyses 
Planned for Interim 
or Final analysis 
Achievement of 
≥ 30% reduction 
from day 1 of 
cinacalcet 
treatment to 
mean iPTH 
during weeks 11 
and 15 
IPW: 
The missingness model will 
include baseline iPTH, cCa, 
phosphorus, age group at first 
cinacalcet dose, sex, race, and 
AEs of nausea, vomiting and 
symptomatic hypocalcemia. 
Dialysis vintage, AE or IPD 
related to ending IP may be 
also included in the model 
depending on the EOIP reason 
observed in the study. 
The final weighted pooled 
logistic regression model will 
include baseline iPTH, cCa, 
phosphorus and age group at 
first cinacalcet dose.This 
analysis will be performed. 
Final analysis only 
Completer analysis: 
Only enrolled subjects who 
completed 15 weeks from Day 1 
of cinacalcet treatment will be 
included in the analysis. 
Subjects with no iPTH values 
during weeks 11 and 15 since 
Day 1 of cinacalcet treatment 
will be considered as 
nonresponders. 
Final analysis only 
Per protocol analysis: 
Subjects from the per protocol 
set for combined 20130356, 
20110100 and 20140159 studies 
and with at least one iPTH value 
during  weeks 11 and 15 will be 
used. 
Final analysis only 
Nearest 2 imputation 
If no values are observed 
during weeks 11 and 15 from 
Day 1 of cinacalcet treatment, 
the nearest two values at or 
after week 7 from Day 1 of 
cinacalcet treatment will be 
used, including unscheduled 
visit values, values prior to or 
after weeks 11 and 15. Subjects 
with no observed values at or 
after week 7 will be considered 
nonresponders. 
Final analysis only 
Page 1 of 2 
 
 
 
 


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Date:  24 May 2016 
Page 29 of 36 
 
 
Secondary endpoints for combined 20130356, 20110100 and 20140159 studies 
 
Secondary endpoint 
Sensitivity Analyses 
Planned for Interim 
or Final analysis 
Achievement of 
≥ 30% reduction 
from day 1 of 
cinacalcet 
treatment to 
mean iPTH 
during weeks 23 
and 28 
IPW: 
The IPW method is same as 
specified for the sensitivity of 
binary endpoint “Achievement 
of ≥ 30% reduction from day 1 
of cinacalcet treatment to mean 
iPTH during weeks 11 and 15 
Final analysis only 
Completer analysis: 
Only subjects with at least one 
iPTH value during week 23-28 
since Day 1 of cinacalcet 
treatment will be included in the 
analysis. 
Final analysis only 
Per protocol analysis: 
Subjects from the per protocol 
set for combined 20130356, 
20110100 and 20140159 studies 
and with at least one iPTH value 
during  weeks 23 and 28 will be 
used. 
Final analysis only 
Page 2 of 2 
 
10.6.3 
Analyses of Exploratory Endpoints 
 
20140159 study only 
 
Analyses of exploratory endpoints will be based on Efficacy Analysis Set. Growth 
velocity and change in Tanner stage from Study Day 1 in study 20140159 to end of 
study will be summarized using descriptive statistics. The analysis will only include 
subjects who have growth velocity values available or tanner stage assessments 
available at both Study Day 1 in study 20140159 and end of study; no imputation 
will be done for missing values. 
 
Actual values, change and percent change of  iPTH, serum cCa, serum 
phosphorus and CaxP values at scheduled visits from study baseline for all 
Efficacy Analysis Set subjects through last dose of IP+7 days will be summarized 
and presented graphically. 
 
20130356, 20140159 and 20110100 studies combined 
 
Summary statistics of the exploratory endpoints will also be presented from day 1 
of cinacalcet treatment through end of study of 20140159. 
 
 
 
 


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Date:  24 May 2016 
Page 30 of 36 
 
 
The analysis will only include subjects who have growth velocity values available 
and Tanner stage assessments available at both day 1 of cinacalcet treatment and 
end of study; no imputation will be done for missing values. 
 
Actual values, change and percent change of iPTH, serum cCa, serum 
phosphorus and CaxP values at scheduled visits from baseline at first cinacalcet 
dose for all Efficacy Analysis Set subjects through last dose of IP+7 days will be 
summarized and presented graphically. 
 
10.7 
Safety Analyses 
 
The Safety Analysis Set is used for all analyses specified in this section unless 
otherwise specified. 
 
10.7.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 17.0 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term.  All 
adverse event tables will be summarized. 
 
20140159 study only 
 
An overall summary of treatment-emergent adverse events, defined for 
 
study 20140159 only in section 6.4, by toxicity grade and type will be provided. 
 
Subject incidence of all treatment-emergent AEs, serious AEs, treatment-related, serious 
treatment-related AEs, AEs leading to withdrawal of investigational product, and fatal 
AEs will be tabulated by system organ class in alphabetical order and preferred term in 
descending order of frequency. 
 
Subject incidence of AEs will be summarized for all treatment-emergent AEs, serious 
 
AEs, and EOIs by preferred term in descending order of frequency. 
 
Subgroup analyses of age groups will be presented by system organ class in 
alphabetical order and preferred term in descending order of frequency if there are 
more than 4 subjects in each subgroup. 
 
Treatment-emergent AEs will be listed for subjects who experienced QTcB ≥ 500 msec 
 
on study. 
 
 
 
 
 
 
 
 
 
 


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Focused adverse events questionnaires were administered for events of hypocalcemia, 
 
seizure, and infection, of which subject incidence will also be summarized. 
 
Combined 20130356, 20140159 and 20110100 studies 
Subject follow-up time adjusted incidence of all treatment-emergent AEs and EOIs, 
defined for studies 20130356, 20140159 and 20110100 combined in section 6.4, 
will also be tabulated by preferred term in descending order of follow-up time 
 
adjusted incidence rates for all subjects. 
 
10.7.2 
Laboratory Test Results 
All laboratory test results in 20140159 study only and combined with parent 
studies will be summarized by treatment received in parent studies and overall. 
 
20140159 study only 
 
Descriptive statistics for actual values, changes, and percent changes from study 
baseline of selected laboratory parameters below will be presented at  scheduled visits 
during the study. In addition, shift tables will summarize toxicity grades using CTCAE 
(version 3) by worst increase and decrease between study baseline and any visit up to 
the end of the study for selected laboratory parameters below. 
 
Summary 
over time 
Shifts in grade from study baseline 
Serum Chemistry 
Albumin 
X 
one way shift (decreased) 
Bicarbonate 
x 
Blood Urea Nitrogen 
x 
Chloride 
x 
Creatinine 
x 
Potassium 
two-way shift 
Sodium 
two-way shift 
Total Protein 
Liver function test 
ALT 
one way shift (increase ) 
AST 
one way shift (increase ) 
Total Bilirubin 
one way shift (increase ) 
Alk Phos 
one way shift (increase ) 
Page 1 of 2 
 
 
 
 
 


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Summary 
over time 
Shifts in grade from study baseline 
Hematology 
Platelets 
one way shift (decrease ) 
Hemoglobin 
x 
one way shift (decrease ) 
White blood cell count 
one way shift (decrease ) 
Red blood cell count 
Other 
iPTH 
x 
Corrected Ca 
x 
two-way shift 
Ionized Ca 
x 
two-way shift 
Phosphorus 
x 
Ca x P 
x 
BALP, NTx, CTx, P1NP (For 
20140159 subjects from 
parent Study 20130356 only) 
x 
FGF 23 (For 20140159 
subjects from parent Study 
20130356 only) 
x 
25(OH)D (For 20140159 
subjects from parent Study 
20130356 only) 
x 
Total and bioavailable 
testosterone (male) 
x 
Page 2 of 2 
 
Subject incidence of corrected total serum calcium value < 8.4 mg/dL, <8.0 mg/dL, 
 
<7.5 mg/dL or ionized calcium value < 1.05 mmol/L, <1.00 mmol/L and <0.94 mmol/L 
 
respectively during study 20140159 will also be summarized. 
 
20130356, 20110100 and 20140159 studies combined 
Actual values, change and percent change of serum cCa, serum phosphorus and 
CaxP values at scheduled visits from baseline at first cinacalcet dose for all Safety 
Analysis Set subjects will be summarized. 
 
10.7.3 
Vital Signs 
 
Change from baseline in study 20140159 in systolic and diastolic blood pressure 
(post-dialysis blood pressure for hemodialysis), will be summarized at each protocol 
specified time point. 
 
Sitting heart rate will be summarized at each protocol-specified time point. 
 
 
 


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10.7.4 
Electrocardiogram (ECG) 
 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; only summaries 
statistics will be provided for QTcB, and these data would not be expected to be useful 
for meta-analysis with data from other trials. ECG data of subjects who had abnormal 
ECG results or experienced QTcB ≥ 500 msec on study will be listed. 
 
10.7.5 
Exposure to Investigational Product 
 
Descriptive statistics will be produced to describe the exposure to investigational product 
in study 20140159 and in study 20140159 combined with parent studies. The 
number of days on investigational product, the minimum and maximum daily dose, the 
cumulative total dose of cinacalcet, and the number and percentage of subjects 
receiving each dose level of investigational product will be summarized using descriptive 
statistics. In addition, starting and maximum weight-adjusted dose will also be 
summarized. Compliance to the investigational product regimen will be calculated for 
each subject and summarized using descriptive statistics. 
 
10.7.6 
Exposure to Concomitant Medication 
 
The number and proportion of subjects receiving vitamin D sterol, nutritional vitamin D 
supplement, phosphate binder, calcium containing phosphate binder or Ca supplement 
in study 20140159 will be summarized over time. Intravenous Paricalcitol-equivalent 
dose at scheduled visits will also be summarized in a table and graphically. IV 
Paricalcitol-equivalent dose is calculated using the following: 2µg Paricalcitol (IV) = 1 µg 
Doxercalciferol (IV) = 1 µg Alfacalcidol (IV) = 0.5 µg Calcitriol (IV) = 1 µg Paricalcitol 
(PO) = 0.8 µg Doxercalciferol (PO) = 0.5 µg Alfacalcidol (PO) = 0.25 µg Calcitriol (PO). 
 
The number and proportion of subjects receiving bisphosphonates and growth hormone 
 
in study 20140159 will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. 
Literature Citations / References 
 
Fleiss J.L., Tytun A., Ury S.H.K. "A simple approximation for calculating sample sizes for 
comparing independent proportions" Biometrics 36(1980) pp. 343-346 
 
Liu M, Wei L and Zhang J (2006). Review of guidelines and literature for handling 
missing data in longitudinal clinical trials with a case study. Pharmaceutical Statistics 
2006; 5: 7-18 
 
SAS/STAT 9.2 User’s Guide, Fourth Edition. Cary, NC: SAS Institute Inc.; 2009. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A.  Reference Values/Toxicity Grades 
 
For CTCAE grading system V3, please refer to: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf 
For CTCAE grading system V4, please refer to: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf