A Phase 1, Open-label, Randomized, Cross-over Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of a Single Dose of rhPTH(1-84) Administered Subcutaneously in Japanese Healthy Subjects Compared With Matched Non-Hispanic, Caucasian Healthy Adult Subjects and to Assess Dose Proportionality of 3 Doses of rhPTH(1-84) in the Japanese Subjects
Phase: PHASE1
Conditions: Hypoparathyroidism
Sponsor: Shire



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will only be assessed at the first screening visit.
Reason for Change:
Increase of BMI from 25 to 28 kg/m² to facilitate enrollment in 
a target population which includes the upper BMI of 28 kg/m².
Section 4.1 Inclusion Criteria
A clinical safety laboratory parameter of hemoglobin greater 
than 11.7g/dL (females) or 13.1g/dL (males) and less than 
16g/dL (females) or 17.4g/dL (males) or, if out of this range,
deemed not clinically significant by the principal 
investigator.
Reason for Change:
To allow the investigator to determine if the hemoglobin 
parameter is not clinically significant if it is out of normal 
laboratory range.
Synopsis: Inclusion Criteria
Section 4.1Inclusion Criteria
Dose proportionality of PK parameters will also be examined 
for the Japanese subjects. Dose proportionality will be 
assessed for Cmax and AUC (AUClast) using the power model. 
The power model assumes a linear relationship between the 
natural log transformed parameter and the natural log 
transformed dose.
ln (Parameter) = α + β × ln (Dose) + Random error
Where α is the intercept, β is the slope, and Random error is a 
random residual error. Dose proportionality implies that slope 
= 1 and will be assessed by estimating mean slope with the 
corresponding two-sided 9590% confidence interval (CI) from 
the power model.
Reason for Change:
The text “implies that slope -1 and” was removed to provide 
clarification that it is not required that H0 Slope =1 for testing. 
The confidence interval was changed from 90% to 95% since 
the interval is for the slope and not the pharmacokinetic 
parameter.
Synopsis: Statistical 
Methodology for 
Pharmacokinetic Endpoint(s), 
Section 9.8.1.1 Statistical 
Analysis of Pharmacokinetic 
Parameters
Treatment-emergent AEs (TEAEs) are defined as AEs with 
start dates between the time of the first exposure to study drug 
and the last dose of the study drug. whose onset occurs, 
severity worsens, or intensity increases after receiving the 
study medication of this study to the follow up visit.
Reason for Change:
Synopsis: Statistical 
Methodology for Safety 
Endpoints, 
Section 9.9.2 Statistical 
Methodology for Safety
Endpoints

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Clarification made on the definition of TEAEs
An “X” was added on Day 1 and Day 5 for “Biochemistry, 
hematology, and urinalysis”
Reason for Change:
An X was added on Day 1 to be consistent with Table 2 and 
Table 3. An X was added on Day 5 to be consistent with Table 
3.
Table 1 Schedule of 
Assessments
Tables 2 and 3, Footnote e
These assessments should be performed within 30 minutes 
prior to dose administration. The urine collection may be the 
first void of the day [providing that it is predose] but may 
be outside the 30 minute window if necessary.
Reason for Change:
It may be difficult to have the subject void in a specified 
window if they voided upon waking that morning. The 
window for the predose urine collection was removed and a 
statement was added stating that the first void of the day is 
acceptable, providing that it is predose.
Table 2 Detailed Schedule of 
Assessments (non-Hispanic, 
Caucasian Subjects)
Table 3 Detailed Schedule of 
Assessments (Subjects of 
Japanese Descent)
Figure 1
This is an open-label study to evaluate the PKs, PDs, safety, 
and tolerability of single doses of rhPTH(1-84) in healthy adult 
subjects of Japanese descent and matched, non-Hispanic, 
healthy, adult Non-Hispanic, Caucasian subjects. Group A 
and Group B need not be dosed at the same time.
Reason for Change:
Clarification that Group A and Group B do not need to be 
enrolled/dosed on the same study days.
Section 3.1 Study Design and 
Flowchart
In Table 4, the number of samples for Biochemistry increased 
from 4 to 5 for the Caucasian subjects.  This resulted in a 
change in blood volume of the Biochemistry from 34 to 42.5.  
The number of samples for the Hematology increased from 4 
to 5 for the Caucasian subjects. This resulted in a change in 
blood volume of the Hematology from 16 to 20. Due to these 
changes, the total blood volume for Caucasian subjects 
increased from 170.5 to 183 mL.
In Table 4, the number of samples for Biochemistry increased 
Section 7.2.6 Volume of Blood 
to be Drawn from Each Subject

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from 7 to 9 for the Japanese subjects.  This resulted in a 
change in blood volume of the Biochemistry from 59.5 to 76.5.  
The number of samples for the Hematology increased from 7 
to 9 for the Japanese subjects. This resulted in a change in 
blood volume of the Hematology from 28 to 36. Due to these 
changes, the total blood volume for Japanese subjects 
increased from 412 to 437 mL.
During this study, it is expected that approximately 412
437mL of blood will be drawn from all subjects of Japanese 
descent, regardless of sex. For the non-Hispanic, Caucasian 
volunteers it is expected that 170.5 183mL of blood will be 
drawn, regardless of sex.
Note: The amount of blood to be drawn for each assessment is 
an estimate. The amount of blood to be drawn may vary 
according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total 
volume drawn over the course of the study should be 
approximately 170.5 183mL (non-Hispanic, Caucasian 
subjects) or 412 437mL (subjects of Japanese descent). When 
more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the 
assessments may be combined.
Reason for Change:
The blood volume was previously calculated incorrectly
See Appendix 1 for protocol history, including all 
amendments.

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E M E R G E N C Y  C O N TA C T I N F O R M ATI O N
I n t he e ve nt of a seri o us a d verse e ve nt ( S A E), t he i n vesti gat or m ust fa x or e- mail t he S hire 
Cli nical St u d y  Seri o us A d verse E ve nt a n d N o n-seri o us A Es Re q uire d b y t he Pr ot oc ol F or m 
wit hi n 2 4 h o urs t o t he S hire Gl o bal Dr u g Safet y De part me nt. A p p lica ble fa x n u m bers a n d e-mail 
a d dress ca n be f o u n d o n t he f or m (se nt u n der se parate c o ver). A c o p y of t his f or m m ust als o be 
se nt t o t he c o ntract researc h or ga nizati o n ( C R O)/ S hire me dical m o nit or b y e mail usi n g t he 
details bel o w.
E- mail:
F or pr ot oc ol - or s afet y -rel ate d iss ues, t he i n vesti g at or m ust c o nt act t he S hire Me dic al 
M o nit or:
P P D
 D D S, P h. D.
Tele p h o ne:
 ( b usi ness h o urs)
 ( 2 4-h o ur c o vera ge)
P P D
P P D
P P D

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A D DI TI O N A L  C O N TA C T I N F O R M A TI O N
I n c ase of a n y ot her iss ues, i ncl u di n g n o n- s afet y rel ate d iss ues or if t he me dic al m o nit or is 
u n a ble t o be re ac he d, t he i n vesti g at or m ust c o nt act t he S hire St u d y M a n a ger:
P P D
St u d y  Ma na ger
Tele p h o ne:
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E mail:
If u na vaila ble, please c o ntact:
Cli nical P har mac ol o g y  Gr o u p Lea d
Tele p h o ne:
 ( b usi ness h o urs)
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E mail:
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P P D
P P D
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P R O D U C T Q U A LI T Y  C O M PL AI N T S
I n vesti gat ors are re q uire d t o re p ort i n vesti gati o nal pr o d uct q ualit y  co m plai nts t o S hire wit hi n 2 4 
h o urs. T his i ncl u des a n y insta nces w herei n t he q ualit y  or perf or ma nce of a S hire pr o d uct 
( mar kete d or i n vesti gati o nal) d oes n ot meet e x pectati o ns (e g, i na de q uate or fa ult y cl os ure, 
pr o d uct c o nta mi nati o n) or t hat t he pr o d uct di d n ot meet t he s pecificati o ns defi ne d i n t he 
a p plicati o n f or t he pr o d uct (e g, wr o n g pr o d uct s uc h t hat t he la bel a n d c o nte nts are differe nt 
pr o d ucts). F or i nstr ucti o ns o n re p orti n g A Es relate d t o p r o d uct c o m plai nts, see Secti o n 8 .
Please use t he i nf or mati o n bel o w as a p plica ble t o re p ort t he Pr o d uct Q ualit y C o m plai nt:
Ori gi n of Pr o d uct Q u alit y C o m pl ai nt
E -m ail A d dress
N ort h a n d S o ut h A merica
E ur o pea n U ni o n a n d Rest of W orl d
P P D
Tele p h o ne n u m bers ( pr o vi de d f or refere nce if nee de d):
S hire, Le xi n gt o n, M A ( U S A)
P P D
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................7
ADDITIONAL CONTACT INFORMATION................................................................................8
PRODUCT QUALITY COMPLAINTS..........................................................................................9
LIST OF TABLES.........................................................................................................................15
LIST OF FIGURES .......................................................................................................................15
LIST OF APPENDICES................................................................................................................15
ABBREVIATIONS .......................................................................................................................16
STUDY SYNOPSIS ......................................................................................................................18
STUDY SCHEDULE(S) ...............................................................................................................25
1.
BACKGROUND INFORMATION.......................................................................................30
1.1
Indication and Current Treatment Options...............................................................31
1.2
Product Background.................................................................................................31
1.2.1
Preclinical Information ..........................................................................................31
1.2.2
Clinical Information...............................................................................................32
1.3
Risk/Benefit and Ethical Assessment.......................................................................33
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................34
2.1
Rationale for the Study.............................................................................................34
2.2
Study Objectives ......................................................................................................35
2.2.1
Primary Objective..................................................................................................35
2.2.2
Secondary Objectives.............................................................................................35
2.2.3
Exploratory Objective............................................................................................35
3.
STUDY DESIGN ...................................................................................................................35
3.1
Study Design and Flow Chart ..................................................................................35
3.2
Rationale for Dose Selection and Study Design Elements ......................................39
3.3
Duration and Study Completion Definition .............................................................39
3.4
Sites and Regions .....................................................................................................40
4.
STUDY POPULATION.........................................................................................................40
4.1
Inclusion Criteria......................................................................................................40
4.2
Exclusion Criteria.....................................................................................................41
4.3
Restrictions...............................................................................................................42
4.4
Reproductive Potential .............................................................................................43
4.4.1
Female Contraception............................................................................................43
4.4.2
Male Contraception................................................................................................44

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4.5
Discontinuation of Subjects .....................................................................................44
4.5.1
Reasons for Discontinuation..................................................................................45
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................45
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................45
5.1
Prior Treatment ........................................................................................................45
5.2
Concomitant Treatment............................................................................................45
5.2.1
Permitted Treatment...............................................................................................45
6.
INVESTIGATIONAL PRODUCT ........................................................................................46
6.1
Identity of Investigational Product...........................................................................46
6.1.1
Blinding the Treatment Assignment......................................................................46
6.2
Administration of Investigational Product(s)...........................................................46
6.2.1
Allocation of Subjects to Treatment ......................................................................46
6.2.2
Dosing....................................................................................................................47
6.2.3
Unblinding the Treatment Assignment..................................................................47
6.3
Labeling, Packaging, Storage, and Handling ...........................................................47
6.3.1
Labeling .................................................................................................................47
6.3.2
Packaging...............................................................................................................48
6.3.3
Storage ...................................................................................................................48
6.4
Drug Accountability.................................................................................................49
6.5
Subject Compliance..................................................................................................50
6.6
Retention of Bioavailability and Bioequivalence Testing Samples.........................50
7.
STUDY PROCEDURES........................................................................................................50
7.1
Study Schedule.........................................................................................................50
7.1.1
Screening Period....................................................................................................50
7.1.1.1
Screening Failure....................................................................................51
7.1.1.2
Rescreening of Subjects .........................................................................51
7.1.2
Treatment Period....................................................................................................51
7.1.2.1
Days 1 to 8..............................................................................................51
7.1.2.2
Final Visit...............................................................................................51
7.1.3
Follow-up Period ...................................................................................................51
7.1.4
Additional Care of Subjects after the Study ..........................................................51
7.2
Study Evaluations and Procedures ...........................................................................52
7.2.1
Demographic and Other Baseline Characteristics .................................................52
7.2.1.1
Demographics.........................................................................................52
7.2.2
Safety .....................................................................................................................52
7.2.2.1
Medical and Medication History............................................................52
7.2.2.2
Physical Examination (Including Height and Weight) ..........................53
7.2.2.3
Adverse Event Collection.......................................................................53

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7.2.2.4
Vital Signs..............................................................................................53
7.2.2.5
Clinical Laboratory Evaluations.............................................................55
7.2.2.6
Pregnancy Test .......................................................................................57
7.2.2.7
Drug and Alcohol Screen .......................................................................57
7.2.2.8
Serology Screen......................................................................................57
7.2.2.9
Electrocardiogram ..................................................................................58
7.2.3
Pharmacokinetic Procedures..................................................................................59
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures.............59
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples .....................................59
7.2.3.3
Plasma Drug Assay Methodology..........................................................60
7.2.4
Pharmacodynamic Assessments ............................................................................60
7.2.4.1
Pharmacodynamic Sample Collection and Handling Procedures..........60
7.2.4.2
Shipment of Serum Pharmacodynamic Samples ...................................61
7.2.4.3
Serum Pharmacodynamic Assay Methodology .....................................61
7.2.5
Immunogenicity Testing for Anti-Parathyroid Hormone Antibodies....................61
7.2.5.1
Sample Collection and Handling Procedures for Immunogenicity 
Testing for Anti-Parathyroid Hormone Antibodies................................61
7.2.5.2
Anti-Parathyroid Hormone Antibody Assay Methodology ...................62
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................62
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................63
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................63
8.1.1
Severity Categorization..........................................................................................63
8.1.2
Relationship Categorization...................................................................................64
8.1.3
Outcome Categorization ........................................................................................64
8.1.4
Clinical Laboratory and Other Safety Evaluations................................................65
8.1.5
Pregnancy...............................................................................................................65
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................66
8.2
Serious Adverse Event Procedures ..........................................................................66
8.2.1
Reference Safety Information................................................................................66
8.2.2
Reporting Procedures.............................................................................................67
8.2.3
Serious Adverse Event Definition .........................................................................67
8.2.4
Serious Adverse Event Collection Time Frame.....................................................68
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................68
8.2.6
Fatal Outcome........................................................................................................68
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................68
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................69

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9.1
Data Collection.........................................................................................................69
9.2
Clinical Data Management.......................................................................................69
9.3
Data Handling Considerations..................................................................................69
9.4
Statistical Analysis Process......................................................................................69
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......69
9.6
Sample Size Calculation and Power Considerations................................................70
9.7
Study Population ......................................................................................................70
9.8
Pharmacokinetic and Pharmacodynamic Analyses..................................................70
9.8.1
Pharmacokinetic Analysis......................................................................................70
9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters ..............................71
9.8.2
Pharmacodynamic Analysis...................................................................................71
9.8.3
Statistical Analysis of Pharmacodynamic Values..................................................72
9.9
Safety Analyses........................................................................................................72
9.9.1
Safety Endpoint(s) .................................................................................................72
9.9.2
Statistical Methodology for Safety Endpoint(s) ....................................................72
9.10
Other Analyses .........................................................................................................73
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................73
10.1
Sponsor’s Responsibilities .......................................................................................73
10.1.1 Good Clinical Practice Compliance.......................................................................73
10.1.2 Indemnity/Liability and Insurance.........................................................................73
10.1.3 Public Posting of Study Information......................................................................73
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................74
10.1.5 Study Suspension, Termination, and Completion..................................................74
10.2
Investigator’s Responsibilities .................................................................................74
10.2.1 Good Clinical Practice Compliance.......................................................................74
10.2.2 Protocol Adherence and Investigator Agreement..................................................74
10.2.3 Documentation and Retention of Records.............................................................75
10.2.3.1
Case Report Forms.................................................................................75
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................75
10.2.3.3
Audit/Inspection.....................................................................................76
10.2.3.4
Financial Disclosure...............................................................................76
10.3
Ethical Considerations..............................................................................................76
10.3.1 Informed Consent...................................................................................................76
10.3.2 Institutional Review Board or Ethics Committee..................................................77
10.4
Privacy and Confidentiality......................................................................................77
10.5
Study Results/Publication Policy .............................................................................78

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11. REFERENCES .......................................................................................................................80
12. APPENDICES ........................................................................................................................81

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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................25
Table 2
Detailed Schedule of Assessments (non-Hispanic, Caucasian Subjects)......28
Table 3
Detailed Schedule of Assessments (Subjects of Japanese Descent) .............29
Table 4
Volume of Blood to Be Drawn from Each Subject.......................................62
LIST OF FIGURES
Figure 1
Study Design Flow Chart ..............................................................................38
Figure 2
Procedures for Screening Vital Signs (Blood Pressure – Pulse) ...................55
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................82

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ABBREVIATIONS
z
first order rate constant associated with the terminal (log linear) portion of 
the curve
%CV
percent coefficient of geometric mean
AE
adverse event
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CaSR
calcium-sensing receptor
CI
confidence interval
CL/F
apparent clearance
Cmax
maximum concentration occurring at tmax
CO2
carbon dioxide
CRC
clinical research center
CRF
case report form
CRO
contract research organization
CV%
coefficient of variation
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
EMA
European Medicines Agency
Emax
maximum effect
EU
European Union
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board

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MHLW
Ministry of Health, Labor and Welfare
PD
pharmacodynamic
pH
potentia hydrogenii (measure of acidity/alkalinity)
PK
pharmacokinetic
PMDA
Pharmaceuticals Medical Devices Agency
PR
time elapsed from P wave to R wave in an electrocardiogram
PTH
parathyroid hormone
QTcB
measure of time between the start of the Q wave and the end of the T wave 
using Bazett’s formula in an electrocardiogram
QD
quaque die (once a day)
QRS
measure of time for the 3 main deflections in an electrocardiogram
QT
measure of time between the start of the Q wave and the end of the T wave 
in an electrocardiogram
QTcF
measure of time between the start of the Q wave and the end of the T wave 
using Fridericia’s formula in an electrocardiogram
rhPTH
recombinant human parathyroid hormone
RR
the time between heart beats in an electrocardiogram
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis software
SC
subcutaneous
SD
standard deviation
t½
terminal half-life
T3
triiodothyronine
T4
thyroxine
TEAE
treatment emergent adverse event
TEmax
time to maximum effect
tmax
time of maximum observed concentration sampled during a dosing 
interval
TSH
thyroid stimulating hormone
UK
United Kingdom
US
United States
Vdz/F
apparent volume of distribution

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S T U D Y  S Y N O P SI S
Pr ot oc ol n u m ber:
S H P 6 3 4 -1 0 2
Dr u g:
Rec o m bi na nt H u ma n Parat h yr oi d H or m o ne (r h P T H[ 1 -8 4])
Title of t he st u d y:
A P hase 1, O pe n -la bel, Ra n d o mize d, Cr oss-o ver St u d y t o E val uate t he P har mac o ki netics, Safet y, a n d T olera bilit y of 
a Si n gle D ose of r h P T H( 1 -8 4) A d mi nistere d S u bc uta ne o usl y i n Ja pa nese Healt h y S u bjects C o m pare d w it h Matc he d 
N o n -His pa nic, Ca ucasia n  Healt h y A d ult S u bjects a n d t o Assess D ose Pr o p orti o nalit y of 3 D oses of r h P T H( 1 -8 4) i n 
t he Ja pa nese S u bjects
N u m ber of s u bjects (t ot al a n d f or e ac h tre at m e nt ar m):
A t otal of 2 4 healt h y, a d ult, male a n d/ or fe male s u bjects will be e nr olle d i nt o t he st u d y, c o m prisi n g 1 2 s u bjects of 
Ja pa nese desce nt a n d 1 2 matc he d, n o n-His pa nic, Ca ucasia n s u bjects. St u d y s u bjects w h o wit h dra w or disc o nti n ue 
earl y ma y be re place d at t he discreti o n of t he s p o ns or. N o n -His pa nic, Ca ucasia n s u bjects will be matc he d t o s u bjects 
of Ja pa nese desce nt base d o n se x ( 1: 1 male: fe male), a ge ( 7 years), a n d b o d y mass i n de x ( 1 5 %)

T he s u bjects of Ja pa nese desce nt will be e x p ose d t o 3, ra n d o mize d, cr oss-o ver si n gle d oses of 
r h P T H( 1-8 4) at 2 5 µ g, 5 0 µ g , a n d 1 0 0 µ g. 

Matc he d, n o n -His pa nic, Ca ucasia n  s u bjects will be e x p ose d t o a si n gle d ose of r h P T H( 1 -8 4) at 
1 0 0 µ g.
I n vesti g at or(s):
, M D
Site(s) a n d Re gi o n(s): 
P A R E X E L
Gle n dale A d ve ntist Me dical Ce nter
1 5 6 0 E. C he v y C hase Dri ve
S uite 1 4 0
Gle n dale, C A, 9 1 2 0 6, U S A
St u d y peri o d ( pl a n ne d):
M a y  2 0 1 7-J u ne 2 0 1 7
Cli nic al p h ase:
1
O bjecti ves:
Pri m ar y:

T o c o m pare t he p har mac o ki netic ( P K) pr ofile of rec o m bi na nt h u ma n parat h yr oi d h or m o ne 
(r h P T H[ 1-8 4]), a d mi nistere d as a si n gle s u bc uta ne o us ( S C) d ose of 1 0 0 μ g, bet w ee n healt h y a d ult 
v ol u nteer s u bjects of Ja pa nese desce nt a n d matc he d, n o n -His pa nic, healt h y, a d ult Ca ucasia n  
s u bjects.
Sec o n d ar y:

T o assess t he d ose pr o p orti o nalit y of t h e P Ks of r h P T H( 1 -8 4) i n healt h y a d ult v ol u nteer s u bjects 
of Ja pa nese desce nt w he n e x p ose d t o si n gle S C d oses of r h P T H( 1 -8 4) at 2 5 µ g, 5 0 µ g , a n d 1 0 0 µ g.

T o c o m pare t he p har mac o d y na mic ( P D) pr ofile (ser u m calci u m a n d p h os p hate le vels) of a 1 0 0 μ g 
S C i njecti o n o f r h P T H( 1-8 4) i n healt h y a d ult v ol u nteer s u bjects of Ja pa nese desce nt a n d matc he d, 
n o n- His pa nic, healt h y, a d ult Ca ucasia n s u bjects.

T o assess t he P D pr ofile (ser u m calci u m a n d p h os p hate le vels) of a 2 5 μ g a n d 5 0 µ g S C i njecti o n of 
P P D

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rhPTH(1-84) in healthy adult volunteer subjects of Japanese descent.

To assess the safety and tolerability of single SC doses of 25µg, 50µg, and 100µg of rhPTH(1-84) 
in healthy adult volunteer subjects of Japanese descent.

To evaluate the safety and tolerability of a single 100µg SC injection of rhPTH(1-84) in matched, 
non-Hispanic, healthy, adult volunteer Caucasian subjects.
Exploratory:

To evaluate the PK similarity of rhPTH[1-84] administered as a single subcutaneous (SC) dose at 
25μg and 50μg between healthy adult volunteer subjects of Japanese descent and matched, non-
Hispanic, healthy, adult Caucasian subjects using dose-normalized PK data.
Rationale:
This study is being conducted to evaluate the PK, PD, safety and tolerability of rhPTH(1-84) after single-dose SC 
administration in adult healthy volunteers of Japanese descent in comparison with adult, healthy, non-Hispanic, 
Caucasian volunteers. In addition, this study will assess the PK dose-proportionality and similarity of rhPTH(1-84) 
in healthy volunteers of Japanese descent as compared with historical data obtained in non-Japanese healthy 
volunteers.
The Japanese regulatory agencies, Pharmaceuticals Medical Devices Agency (PMDA) and the Ministry of Health, 
Labor and Welfare (MHLW) require evidence that current data in non-Japanese subjects can be extrapolated to the 
Japanese population.
This study can be conducted in a facility that is located outside of the country of Japan as long as steps are taken to 
ensure that the subjects will be viewed as Japanese (or of direct Japanese descent).
The results from this study will be utilized to guide dose selection for a future Phase 3 study in Japanese patients 
with hypoparathyroidism.
Investigational product, dose, and mode of administration: The investigational product (rhPTH[1-84]) is a 
lyophilized powder form of recombinant human parathyroid hormone produced from genetically modified 
Escherichia coli and contained within a glass cartridge that includes sterile diluent as well. The investigational 
product is reconstituted within the glass cartridge and administered from an injector pen (Haselmeier) as a SC 
injection at doses of 25µg, 50µg, and 100µg into the mid-thigh (100µg only in non-Hispanic, Caucasian subjects). 
The volume of reconstituted drug administered at 1 dose is 71.4µL.This study is open-label and does not require the 
use of a placebo.
Methodology:
This is a Phase 1, open-label, randomized, cross-over, single-center study to evaluate the PK and PD profiles and 
safety and tolerability of rhPTH(1-84) administered in healthy adult volunteer subjects of Japanese descent and 
matched non-Hispanic, Caucasian healthy adult volunteer subjects. The non-Hispanic, Caucasian volunteers will 
receive a single dose of 100µg rhPTH(1-84). The Japanese subjects will receive 3 single doses of rhPTH(1-84). On 
Day 1 the subjects of Japanese descent will receive a single SC injection of 100µg. On Days 4 and 7 the subjects of 
Japanese descent will be randomized to receive a single SC injection of either 25µg or 50µg. such that all of these 
subjects are exposed to the 3 dose strengths over a 7 day period to further characterize the PK profile in that group. 
A total of 24 subjects will be enrolled: 12 non-Hispanic, Caucasian subjects and 12 subjects of Japanese descent (1:1 
male: female). Non-Hispanic, Caucasian subjects will be matched to Japanese subjects based on sex, age (years), 
and body mass index (15%). 
All subjects will receive a single dose of 100μg rhPTH(1-84) administered by SC injection in the mid-thigh with the 
Haselmeier injector pen on Day 1. In addition, the subjects of Japanese descent will also receive single dose 
injections of 25µg and 50µg rhPTH(1-84) administered by SC injection in the mid-thigh to characterize the PK 
profile over a range of doses. There will be a minimum of 72 hours (maximum 73 hours) washout from single dose 
to single dose for the volunteers of Japanese descent. The study duration will comprise of a 28-day screening period, 
1 treatment period for the non-Hispanic, Caucasian group (Days 1 and 2); 1 treatment period for the volunteers of 

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Japanese descent (Days 1-8), and a follow-up visit (30±2 days) after the last dose of investigation drug is 
administered for each subject. The total number of nights subjects will be expected to stay at the clinical research 
center (CRC) is 2 for the non-Hispanic, Caucasian group and 8 for the volunteers of Japanese descent. The maximal 
total duration of study participation for a non-Hispanic, Caucasian subject is 62 days and 68 days for the volunteers 
of Japanese descent, if the maximum screening, treatment and follow-up visit durations are used.
Screening will occur within 28 days of the first dose. Subjects will be admitted to the CRC on Day -1.
Treatment Periods:

On Day 1, all study subjects will receive rhPTH(1-84) as a single 100μg SC injection in the mid-thigh.

On Day 4, and Day 7, all subjects of Japanese descent will receive rhPTH(1-84) as a single SC injection in 
the mid-thigh of either 25µg or 50µg depending upon randomization assignment. Administration of 
rhPTH(1-84) in subjects of Japanese descent in the mid-thigh should be randomized locally so that an equal 
number of subjects receive the first dose in the right thigh and an equal number in the left thigh. 
Subsequent doses should be administered in the opposing thigh to the last dose.
Assessments

Serial blood samples for PK analysis will be collected on Day 1 (and Day 4 and Day 7 for the 
subjects of Japanese descent) for the determination of parathyroid hormone (PTH) concentrations 
(original and baseline-adjusted) at pre-dose and up to 24 hours post dose. These blood samples 
will be collected according to the Schedule of Assessments.

Serial blood samples for PD analysis will be collected on Day 1 (and Day 4 and Day 7 for the 
subjects of Japanese descent) at pre-dose and up to 24 hours post dose for the determination of 
serum calcium, phosphate, and albumin concentrations.

Safety and tolerability will be determined through assessment of treatment-emergent adverse 
events (TEAEs) from Day 1 time of dose up to the follow up visit and vital signs, 
electrocardiogram (ECG) findings, and clinical laboratory evaluations on Day 1 pre-dose and up to 
24 hours post dose for the non-Hispanic, Caucasian subjects and Day 1 pre-dose and up to 24 
hours post last dose (Day 8) for the subjects of Japanese descent.

Additional blood samples for safety purposes will be collected for assessment of anti-PTH 
antibodies.
Follow-up
A post treatment follow-up visit will be completed 30 (± 2) days after the last dose of investigational product for 
each subject.
Inclusion and exclusion criteria:
Inclusion Criteria:
1. Ability to voluntarily provide written, signed, and dated informed consent as applicable to participate in the 
study.
2. An understanding, ability, and willingness to fully comply with study procedures and restrictions.
3. Age 18-65, inclusive, at the time of consent. The date of signature of the informed consent is defined as the 
beginning of the screening period. This inclusion criterion will only be assessed at the first screening visit.
4. Subjects must be either:
a)
A subject of Japanese descent born in Japan, who has resided outside of Japan for no longer than 5 
years and is of Japanese parentage, defined as having 2 Japanese parents, and 4 Japanese 
grandparents, all born in Japan.
b)
A non-Hispanic, Caucasian subject who has 2 non-Hispanic, Caucasian parents and 4 
non-Hispanic, Caucasian grandparents.

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5. Male or nonpregnant, nonlactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of nonchildbearing potential.
6. Considered “healthy” by the investigator.  Healthy status is defined by absence of evidence of any active or 
chronic disease following a detailed medical and surgical history, a complete physical examination 
including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis.
7. Body mass index between 18.5 and28 kg/m², inclusive, with a body weight ≥45 kg (99lbs). This inclusion 
criterion will only be assessed at the first screening visit.
8. Willing and able to consume standardized meals during the confinement period of the study. All participants 
will be required to consume the identical meals on study days when serial PK and PD blood samples are 
collected.
9.
A clinical safety laboratory parameter of hemoglobin greater than 11.7g/dL (females) or 13.1g/dL (males) 
and less than 16g/dl (females) or 17.4g/dL (males) or, if out of this range, deemed not clinically significant 
by the principal investigator.
10. Total serum calcium within laboratory normal limits.
11. Serum parathyroid hormone (PTH) levels within laboratory normal limits.
Exclusion Criteria:
1. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric disease, 
gall bladder removal, or current or recurrent disease that could affect the action, absorption, or disposition 
of the investigational product, or clinical or laboratory assessments.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment 
or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the 
investigational product or procedures.
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related 
compounds, or any of the stated ingredients.
4. Significant illness, as judged by the investigator, within 2 weeks of the first dose of investigational product.
5. Known history of alcohol or other substance abuse within the last year.
6. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first dose 
of investigational product.
7. Use of the following prior to administration of investigational product within:

30 days – loop diuretics, lithium, antacids, systemic corticosteroids (medical judgment is required 
by the investigator. Primarily high doses of systemic corticosteroids [eg, prednisone] should be 
excluded. Stable doses of hydrocortisone [eg, as treatment for Addison’s disease] may be 
acceptable).

3 months – calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or N-terminal PTH 
or PTH-related peptide fragments or analogs

For females: changes in hormone replacement therapy within 3 months are excluded. Stable (≥ 3 
months) hormone replacement therapy is acceptable.

6 months – fluoride tablets, oral bisphosphonates, methotrexate, growth hormone, digoxin, 
raloxifene or similar selective estrogen receptor modulators (SERMs)

12 months – intravenous bisphosphonates, drug or alcohol abuse, as determined by the 
investigator
8. Confirmed systolic blood pressure (BP) >139mmHg or <89mmHg, and diastolic BP >89mmHg or 
<49mmHg.
9. Twelve-lead ECG demonstrating measure of time between the start of the Q wave and the end of the T wave 
using Fridericia’s formula in an electrocardiogram (QTcF) >450msec at screening.  If QTcF exceeds 

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450msec, the ECG should be repeated 2 more times and the average of the 3 QTcF values should be used to 
determine the subject’s eligibility.
10. Positive screen for drugs of abuse at screening or drugs of abuse or alcohol on Day -1.
11. Male subjects who consume more than 21 units of alcohol per week or 3 units per day.  Female subjects 
who consume more than 14 units of alcohol per week or 2 units per day.  (1 alcohol unit=1 beer or 1 wine 
(5oz/150 mL) or 1 liquor (1.5oz/40 mL) or 0.75 oz alcohol).
12. Positive human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus 
(HCV) antibody screen.
13. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form 
(eg, gum, patch).  Ex-users must report that they have stopped using tobacco for at least 30 days prior to 
receiving the first dose of investigational product.
14. Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine 
withdrawal headaches.  (1 caffeine unit is contained in the following items: one 6 oz (180 mL) cup of 
coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, three 1 oz (85 g) chocolate bars.  
Decaffeinated coffee, tea, or cola are not considered to contain caffeine).
15. Prior screen failure, randomization, participation, or enrollment in this study or prior exposure to any 
exogenous PTH, PTH fragments or analogs.
16. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations; with the 
exception of hormonal replacement therapy or hormonal contraceptives and occasional use of ibuprofen 
and acetaminophen). Current use is defined as use within 14 days of the first dose of investigational 
product.
17. History of abnormalities of calcium homeostasis including hyperparathyroidism, hypoparathyroidism, 
hyperthyroidism, osteoporosis, Cushing’s syndrome, hypercalcemia, hypocalcemia, or any other calcium 
disorder.
Maximum duration of subject involvement in the study:
Subjects will be screened within 28 days prior to the dose of the investigational product.

There will be 1 treatment period for the non-Hispanic, Caucasian group consisting of one SC 
injection of rhPTH(1-84) and 1 treatment period for the subjects of Japanese descent consisting of 
3, randomized (only two of the doses will be randomized), SC injections of rhPTH(1-84); each 
subject will check in to the unit on Day -1 and remain in the unit until discharge (Day 2 for the 
non-Hispanic, Caucasian subjects and Day 8 for the subjects of Japanese descent). Non-Hispanic, 
Caucasian subjects will be dosed on Day 1 only and will spend 3 days and 2 nights in the unit. 
Volunteers of Japanese descent will be dosed on Days 1, 4 and 7 and will spend 9 days and 8 
nights in the unit.

There will be a follow-up clinic visit 30 ± 2 days after the last dose of the investigational product 
for each subject.

The total number of nights non-Hispanic, Caucasian subjects will be expected to stay at the 
clinical research center (CRC) is 2. The total number of nights subjects of Japanese descent will be 
expected to stay at the clinical research center (CRC) is 8. The maximal total duration of study 
participation for any subject is 68 days, if the maximum screening, treatment and follow-up visit 
durations are used.
Endpoints and statistical analysis:
No formal calculations were performed to determine sample size for this study. The sample size is based on 
feasibility and is similar to that of comparable studies.
Subject Populations:

The safety population includes subjects who have received at least 1 dose of rhPTH(1-84).

The PK population consists of subjects who receive at least 1 dose of rhPTH(1-84) and have at 

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least 1 evaluable post dose PK concentration value.

The PD population consists of subjects who receive at least 1 dose of rhPTH(1-84) and have at 
least 1 evaluable post dose PD concentration value.
Pharmacokinetic Endpoint(s):
A PK evaluation of PTH concentrations and baseline-adjusted PTH concentrations will be performed following the 
administration of rhPTH(1-84) on Day 1 for non-Hispanic, Caucasian subjects and Days 1, 4 and 7 for subjects of 
Japanese descent.
Pharmacokinetic parameters will be calculated from original and baseline-adjusted plasma concentration-time data 
using non-compartmental methods and all calculations will be based on actual sampling times. Baseline is defined as 
the average Day 1 pre-dose concentration for all subjects (and the Day 4 and Day 7 average pre-dose concentration 
for the subjects of Japanese descent for those respective dosing intervals). PK parameters will be estimated based on 
non-compartmental analysis and will include, but not be limited to, the following:

Cmax:
Maximum concentration occurring at tmax

tmax:
Time of maximum observed concentration sampled during a dosing interval

AUClast:
Area under the curve from the time of dosing to the last measurable concentration

z:
First order rate constant associated with the terminal (log linear) portion of the curve

t½:
Terminal half-life

CL/F:
Apparent clearance

Vdz/F:
Apparent volume of distribution
Non-body weight adjusted and body weight-adjusted AUClast, Cmax, CL/F, and Vdz/F will be estimated. In addition, 
dose-normalized baseline-adjusted AUClast and Cmax will be calculated. 
Statistical Methodology for Pharmacokinetic Endpoint(s):
Individual concentrations (original and baseline-adjusted) and PK parameters (original, baseline-adjusted, body 
weight-adjusted, and dose-normalized-baseline-adjusted) of rhPTH(1-84) will be listed and summarized with 
descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient of variation [CV%], median, 
minimum, maximum, geometric mean, and %CV of geometric mean. The 95% confidence intervals of the geometric 
means of PK parameters will be presented as well. Figures of individual and mean (±SD) concentration-time profiles 
of the original and baseline-adjusted plasma rhPTH(1-84) will be generated on linear and semi-log scales. The mean 
plots will be generated by overlaying the Japanese cohort and Non-Japanese cohort. Figures of baseline-adjusted PK 
parameters and dose-normalized baseline-adjusted PK parameters vs dose in Japanese subjects will be generated. 
Box-Whisker plots for selected PK parameter will be generated with Japanese cohort and Non-Japanese side by side. 
Forest plots of geometric mean ratios for selected PK parameters between Japanese cohort vs Non-Japanese cohort 
will be generated.
Dose proportionality of PK parameters will also be examined for the Japanese subjects. Dose proportionality will be 
assessed for Cmax and AUC (AUClast) using the power model. The power model assumes a linear relationship 
between the natural log transformed parameter and the natural log transformed dose.
ln (Parameter) = α + β × ln (Dose) + Random error
Where α is the intercept, β is the slope, and Random error is a random residual error. Dose proportionality will be 
assessed by estimating mean slope with the corresponding two-sided 95% confidence interval (CI) from the power 
model.
In order to compare the PKs of rhPTH(1-84) between subjects of Japanese descent and matched non-Hispanic, 
Caucasian subjects, the differences of log-transformed PK parameters from the rhPTH 100ug dose will be examined 
between groups using an analysis of variance model. The geometric mean ratio and its 90% confidence interval (CI) 

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will be provided from the model. Baseline-adjusted PK parameters will be the primary PK endpoints, and other PK 
parameters will be the secondary PK endpoints. In addition, the difference of log-transformed dose-normalized 
baseline-adjusted AUClast and Cmax will be examined between the Japanese cohort estimated at the 50ug dose and the 
Non-Japanese cohort estimated at 100ug dose, as well as between the Japanese cohort estimated at the 25ug dose 
and the Non-Japanese cohort estimated at 100ug dose using an analysis of variance model. The geometric mean 
ratio and its 90% CI will be provided from the model.
Pharmacodynamic Endpoint(s):
Pharmacodynamic parameters will be computed from individual post dose values of serum calcium (uncorrected and 
corrected for serum albumin levels and both unadjusted and baseline-adjusted) and phosphate using non-
compartmental methods. Pharmacodynamic parameters will be estimated based on both original and baseline-
adjusted values of serum calcium and phosphate. The calcium-phosphate product will be computed. Baseline is 
defined as the pre-dose value on Day 1 for all subjects and, additionally, also on Day 4 and Day 7 for the subjects of 
Japanese descent. All calculations will be based on actual sampling times. Pharmacodynamic parameters will be 
estimated based on non-compartmental analyses and will include, but not be limited to, the following:

AUClast: Area under the curve from the time of dosing to the last measurable concentration

tmax:
Time of maximum observed concentration sampled during a dosing interval

Emax:
Maximum effect

TEmax:
Time to maximum effect
Statistical Methodology for Pharmacodynamic Endpoint(s):
Individual values (original and baseline-adjusted) and PD parameters (original and baseline-adjusted) of serum total 
calcium, albumin-corrected calcium, phosphate and the calcium-phosphate (albumin-corrected calcium) product will 
be summarized with descriptive statistics (number, arithmetic mean, SD, CV%, median, minimum, maximum, 
geometric mean, and geometric CV%). Figures of individual and mean (±SD) concentration-time profiles of the 
original and baseline-adjusted PD markers, serum calcium (total and corrected for serum albumin) and phosphate, 
will be generated. Mean plots will be overlaid for the Japanese cohort and the Non-Japanese cohort. Box-Whisker 
plots for selected PD parameters will be prepared with the Japanese cohort and Non-Japanese cohort side by side.
Safety Endpoint(s):
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group and visit as indicated 
below:

Number, severity, seriousness and causality of treatment-emergent adverse events

Anti-PTH antibodies

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and 
urinalysis) from baseline to post baseline time points
Statistical Methodology for Safety Endpoint(s)
Safety data, including TEAEs, laboratory tests, anti-PTH antibodies, and vital signs, will be summarized. 
Descriptive statistics will be calculated for quantitative safety data as well as for the difference from baseline, if 
applicable. Frequency counts will be compiled for classification of qualitative safety data. Direct safety comparisons 
between the two ethnic groups will be presented from the rhPTH(1-84) 100µg dosing data. All other safety data 
from the 25µg and 50µg in the subjects of Japanese descent will be summarized and listed. Treatment-emergent AEs 
(TEAEs) are defined as AEs whose onset occurs, severity worsens, or intensity increases after receiving the study 
medication of this study and to the follow up visit.

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STUDY SCHEDULE(S)
Table 1
Schedule of Assessments
Visit
Screening
Predose 
assessments
Treatment Period
Follow-uph
Study Day
–28 to -02
-1
1
2
3
4
5
6
7
8
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demography and 
medical/medication 
history
X
Physical examinationa
X
X
X
Vital signs (BP, 
temperature and 
pulse)a,b,g
X
X
X
X
Xj
Xj
Xj
Xj
X
Height and weightc
X
X
Serum PTH
X
X
Triplicate 
Electrocardiogram (12-
lead)a,g
X
X
X
X j
Xj
Xj
Xj
X
Biochemistry, 
hematology, and 
urinalysisa
X
X
X
X
Xj
Xj
Xj
Xj
X
HIV, HBsAg, and HCV 
antibodies
X

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Table 1
Schedule of Assessments
Visit
Screening
Predose 
assessments
Treatment Period
Follow-uph
Study Day
–28 to -02
-1
1
2
3
4
5
6
7
8
Pregnancy test (females 
only)a,d
X
X
X
Xj
X
Urine drug and alcohol 
screeninge
X
X
Randomization
Xj
Investigational drug 
administrationk
X
Xj
Xj
Pharmacodynamic blood 
samplingf,g
X
X
Xj
X j
X j
X j
Anti-PTH antibody 
samplingg
X
Xa
Pharmacokinetic blood 
samplingg
X
X
Xj
Xj
Xj
Xj
Check-in to the CRC
X
Discharge from the CRC
Xi
Xj
Adverse events/serious 
adverse eventsa
X
X
X
X
Xj
Xj
Xj
Xj
Xj
Xj
Xl
Concomitant medicationa
X
X
X
X
Xj
Xj
Xj
Xj
Xj
Xj
X
BP=blood pressure; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; PTH=parathyroid hormone
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Vital signs will be obtained while subject is supine on study days noted. Temperature will only be taken at screening and predose on Day 1.
c Height will be recorded at the screening visit only.
d FSH (follicle stimulating hormone) is required at screening for all females. Serum β-hCG testing at timepoints indicated for all female subjects.
e Drugs of abuse at screening and drugs of abuse and alcohol on Day -1.

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Table 1
Schedule of Assessments
Visit
Screening
Predose 
assessments
Treatment Period
Follow-uph
Study Day
–28 to -02
-1
1
2
3
4
5
6
7
8
f  Pharmacodynamic blood sampling assessments will include serum calcium and phosphate.
g See Table 2 and Table 3 for detailed collection time points.
h There will be a follow-up visit approximately 30 ±2 days following the last dose of investigational product.
i Non-Hispanic, Caucasian subjects only.
j Subjects of Japanese descent only.
k There must be a minimum washout period of 72 hours (maximum 73 hours) from dose to dose for the volunteers of Japanese descent.
l SAEs will be followed to resolution (see Section 7.1.3)

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Table 2
Detailed Schedule of Assessments (non-Hispanic, Caucasian Subjects)
Study Day
Day 1
Day
2
Hour (relative to dosing 
time)
Pre
Dose 
1
Pre
Dose 
2
0
10m
20m
30m
45m
1h
1.25h
1.5h
2h
2.5h
3h
4h
6h
8h
12h
16h
24h
Physical examinationa
X
Vital signs (BP, 
temperature and pulse)a,b
Xe
X
X
X
X
Triplicate 
Electrocardiogram 
(12-lead)a,c
Xe
X
Biochemistry, hematology, 
and urinalysisa
Xe
X
Serum β-hCG  Pregnancy 
test (females only)a
X
Investigational drug 
administration
X
Pharmacodynamic blood 
samplingd
Xe
X
X
X
X
Anti-PTH antibody 
sampling
Xe
Pharmacokinetic blood 
sampling
Xf
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BP=blood pressure; ECG=electrocardiogram; PK=pharmacokinetic, PTH=parathyroid hormone
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Vital signs will be obtained while subject is supine at times noted. Temperature only to be obtained at screening and at predose on Day 1.
c Electrocardiograms will be performed in triplicate at each timepoint. 
d Pharmacodynamic blood sampling assessments will include serum calcium and phosphate and must be drawn before PK samples at the same timepoint.
e These assessments should be performed within 30 minutes prior to dose administration. The urine collection may be the first void of the day [providing that it is predose] but may 
be outside the 30 minute window if necessary.
f These assessments should be performed within 90 (±30) minutes prior to dose administration.

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Table 3
Detailed Schedule of Assessments (Subjects of Japanese Descent)
Study Day
Days 1, 4 and 7
Days
2, 5 
and 
8
Hour (relative to dosing 
time)
Pre-
dose 
1
Pre-
dose
2
0
10m
20m
30m
45m
1h
1.25h
1.5h
2h
2.5h
3h
4h
6h
8h
12h
16h
24h
Physical examinationa
X h
Vital signs (BP, 
temperature and pulse)a,b
Xe
X
X
X
X
Triplicate 
Electrocardiogram 
(12-lead)a,c
Xe
X
Biochemistry, hematology, 
and urinalysisa
Xe
X
Serum β-hCG  Pregnancy 
test (females only)a
Xh
Investigational drug 
administration
X
Pharmacodynamic blood 
samplingd
Xe
X
X
X
X
Anti-PTH antibody 
sampling
Xe
Pharmacokinetic blood 
sampling
Xf
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BP=blood pressure; ECG=electrocardiogram; PK=pharmacokinetic, PTH=parathyroid hormone
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Vital signs will be obtained while subject is supine at times noted. Temperature only to be obtained at screening and at predose on Day 1.
c Electrocardiograms will be performed in triplicate at each timepoint.
d Pharmacodynamic blood sampling assessments will include serum calcium and phosphate and must be drawn before PK samples at the same timepoint.
e These assessments should be performed within 30 minutes prior to dose administration. The urine collection may be the first void of the day [providing that it is predose] but may 
be outside the 30 minute window if necessary.
f These assessments should be performed within 90 (±30) minutes prior to dose administration.
h Serum β-hCG  Pregnancy test (females only) and physical exam on Day 8 at discharge only.

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1.
BACKGROUND INFORMATION
Hypoparathyroidism is a rare disorder characterized by hypocalcemia in the presence of 
inappropriately low or undetectable levels of circulating parathyroid hormone (PTH) 
(Avioli 1974; Haussler and Cordy 1982; Shoback 2008). The most frequent cause of 
hypoparathyroidism is resection of, or damage to, parathyroid glands during neck surgery (eg, 
thyroidectomy), although multiple other genetic, metabolic and congenital etiologies exist. 
Hypoparathyroidism occurs in about 0.9% to 6.6% of thyroidectomies, with higher rates 
associated with more complicated interventions (Shoback 2008; Thomusch et al. 2003; Zarnegar 
et al. 2003; Page and Strunski 2007).
Parathyroid hormone is an 84-amino acid protein that is secreted by the parathyroid glands. PTH 
has a variety of important physiological functions that are outlined below to explain the effects 
of absent or deficient PTH levels. Parathyroid hormone functions to help regulate bone 
metabolism and serum levels of calcium and phosphate. In general, if serum calcium 
concentrations decrease, the parathyroid glands consequently increase PTH secretion, and, if 
serum calcium concentrations increase, the parathyroid glands consequently reduce PTH 
secretion. The parathyroid glands sense the level of extracellular calcium at the surface of the 
parathyroid cell and adjust the synthesis and secretion of PTH accordingly. The relationship 
between ionized extracellular calcium and PTH secretion is a steep sigmoidal curve where small 
variations in calcium level lead to significant changes in PTH secretion. Calcium sensing is 
initiated by the binding of calcium to a calcium sensing receptor (CaSR) that is present at high 
levels on the plasma membrane of the parathyroid cells. The CaSR, a member of the G-protein 
coupled receptor superfamily, is activated by calcium binding to it that, in turn, induces 
intracellular signals and, through largely unknown mechanisms, regulates the synthesis and 
secretion of PTH. The net physiological effects are an increase in circulating PTH levels when 
the extracellular calcium decreases and a decrease in PTH levels when the extracellular calcium 
increases (Bilezikian et al. 2011).
Acute symptoms of hypoparathyroidism, linked mainly to the hypocalcemia, are generally 
reversible. The key symptoms associated with hypocalcemia involve mainly the neuromuscular 
system: numbness, paresthesias, twitching, and tetany. More serious and potentially life 
threatening effects of hypocalcemia such as seizures, cardiac arrhythmias, cardiomyopathy and 
laryngeal spasm are also recognized in hypoparathyroidism (Behaghel and Donal 2011). Other 
symptomatology includes difficulty in concentrating described by many subjects as “brain fog” 
(Bilezikian et al. 2011). Hypoparathyroidism has also been linked to effects on mood and 
ideation (Arlt et al. 2002; Velasco et al. 1999).
The kidneys are especially vulnerable in subjects with hypoparathyroidism. Circulating PTH 
promotes renal calcium reabsorption, especially at the level of the distal convoluted tubule 
(Blaine et al. 2015). In patients with hypoparathyroidism, this additional fraction of calcium is 
instead excreted through the kidneys (Shoback 2008), leading to hypercalciuria which, together 
with a high-calcium-phosphate product, can potentially can lead to nephrocalcinosis and kidney
stones and, ultimately, to renal impairment (Blaine et al. 2015).
For further details see the current rhPTH(1-84) investigator brochure.

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1.1
Indication and Current Treatment Options 
Prior to 2015, in the absence of an approved PTH replacement therapy, management of 
hypoparathyroidism consisted of supplemental oral calcium and active vitamin D in 
pharmacological doses sufficient to maintain the serum calcium level without the disabling 
symptoms of hypocalcemia. In order to improve the absorption of calcium from the 
gastrointestinal tract, pharmacological supplementation with active forms of vitamin D (eg, 
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], calcitriol, 1,25-dihydroxycholecalciferol or α-calcidol 
[1(OH)D3]) is also required. Since PTH also functions in the kidney to stimulate the conversion 
of 25(OH)D3, the major circulating form of vitamin D, to the active vitamin D hormone 
(1,25[OH]2D3), the relative lack of circulating PTH results in a reduction of the production of 
active vitamin D. Thus, exogenous active vitamin D overcomes the synthetic block in 
endogenous production of the active vitamin D hormone in hypoparathyroidism. Together, 
supplemental oral calcium and active vitamin D have formed the mainstay of current treatment 
of subjects with hypoparathyroidism. As noted above, the additional calcium load that results 
from supplementation with exogenous calcium and active vitamin D may contribute to the 
hypercalciuria and renal risks often noted in patients with hypoparathyroidism.
In an effort to limit the extent and effect of hypercalciuria, thiazide diuretics can be helpful since 
they promote renal calcium reabsorption. However, thiazides are associated with their own 
adverse events including hypokalemia and, more importantly, have no proven long-term effect to 
reduce hypercalciuria or kidney damage or improve the safety profile in this patient population 
(Shoback 2008). Although an accepted adjunct to the use of calcium and active vitamin D in 
hypoparathyroidism, thiazides are prescribed to only a minority of hypoparathyroid patients.
The investigational product (rhPTH[1-84]) is a recombinant human PTH that is identical in 
structure to endogenous human PTH, a single-chain polypeptide consisting of 84 amino acid 
residues and is manufactured using a strain of Escherichia coli modified by recombinant DNA 
technology. rhPTH(1-84) was approved for marketing in the United States on 23 January 2015 
under the brand name NATPARA® as a once-daily injectable dose as an adjunct to calcium and 
vitamin D to control hypocalcemia in patients with hypoparathyroidism.
1.2
Product Background
1.2.1
Preclinical Information
A total of 46 in vivo studies in mouse, rat, rabbit, dog, and rhesus and cynomolgus monkeys 
have evaluated the PKs, PDs and toxicology of rhPTH(1-84) at doses ranging from 0.1 to 10,000 
μg/kg given as single doses or as daily doses for up to 2 years. In the vast majority of studies, 
rhPTH(1-84) was administered by subcutaneous (SC) injection, the intended route of 
administration of rhPTH(1-84) in humans. A total of 7 in vitro pharmacology and toxicology 
studies have been performed.
In male and female rats, the administration of PTH was associated with an increase in the 
incidence of osteosarcoma. The occurrence of osteosarcoma was dependent on parathyroid 
hormone dose and treatment duration. This effect was observed at parathyroid hormone exposure 
levels ranging from 3 to 71 times the exposure levels in humans receiving a 100μg dose of 

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rhPTH(1-84). These data were interpreted as an increased risk for osteosarcoma in the clinic. 
Therefore, administration of rhPTH(1-84) should be avoided in subjects who are considered to 
be at increased risk for osteosarcoma (including those with Paget’s disease of bone or 
unexplained elevations of alkaline phosphatase, subjects with hereditary disorders predisposing 
to osteosarcoma or subjects with a history of prior external beam or implant radiation therapy 
involving the skeleton). Currently available results from animal reproductive toxicology studies 
suggest that rhPTH(1-84) is not associated with significant fetal or neonatal toxicity; however 
the safety of rhPTH(1-84) in pregnant or nursing women is not established.
For full details see the rhPTH(1-84) investigator brochure.
1.2.2
Clinical Information
Few studies of PTH use have been performed in the setting of hypoparathyroidism. Study 
CL1-11-040 (REPLACE) was a double-blind, placebo controlled study of once daily (QD) 
administration of 50μg, 75μg, or 100μg of rhPTH(1-84) which resulted in 54.8% of the 
rhPTH(1-84) subjects meeting a 3-tiered primary endpoint vs 2.5% of the placebo subjects 
(p<0.001). Long-term, open-label studies have supported these findings with subjects 
maintaining the physiologic benefit derived from rhPTH(1-84) treatment. One study, PAR-C10-
008 (RACE), is ongoing with subjects receiving treatment for more than 5 years.
In clinical trials, rhPTH(1-84) significantly reduced the calcium-phosphate product. In these 
studies hypercalciuria was defined as an excretion of calcium in the urine greater than 300mg per 
24 hours. Data from the REPLACE Study and the long-term open label study, RACE, show that 
rhPTH(1-84) has a calcium-sparing effect, consistent with the reduction of calcium excretion 
seen in a previous PK/PD study (C09-002) of single dose administration of rhPTH(1-84) in 
patients with hypoparathyroidism in comparison with calcitriol administration.
The Phase 3 clinical study, REPLACE, was the largest, randomized, placebo controlled clinical 
study conducted in hypoparathyroidism population and was the pivotal study demonstrating that 
rhPTH(1-84) is effective in maintaining serum calcium levels and enabling significant decreases 
in active vitamin D and oral calcium doses. REPLACE also established the rhPTH(1-84) dose 
and dose titration and evaluated the physiologic effects of PTH replacement on serum calcium, 
serum phosphate, urinary calcium excretion, and bone turnover markers. Eighty-four subjects 
were evaluated in the active treatment group and 40 subjects received placebo. Subjects received 
50μg, 75μg, or 100μg SC in the thigh once daily for 6 months. The study met the primary 
efficacy triple endpoint, with a statistically higher responder rate (54.8%) versus placebo (2.5%). 
To meet the primary endpoint a subject had to fulfill all 3 conditions as follows: a 50% or greater 
reduction in oral calcium requirement, a 50% or greater reduction in active vitamin D therapy 
and an albumin corrected serum calcium (ACSC) concentration that was maintained within a 
range of 7.5 to 10.6 mg/dL.
A review of safety data across the hypoparathryoidism program indicated that rhPTH(1-84) 
administered as 25μg, 50μg, 75μg, or 100μg SC QD is safe for use for the treatment of 
hypoparathyroidism. Very common adverse reactions (ie, reported in at least 1 in every 10 
subjects) included hypocalcemia, hypercalcemia, headaches, diarrhea, vomiting, and 
hypercalciuria. Common adverse reactions (ie, reported in at least 1 in every 100 subjects, but 

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less than 1 in every 10 subjects) included hypomagnesemia, anxiety symptoms, palpitations, 
flushing, coughing and associated symptoms, neck pain, pollakiuria, chest pain, thirst, blood 
25-hydroxycholecalciferol decreased, and blood alkaline phosphatase increased.
There was no suggestion that rhPTH(1-84) causes drug-induced liver injury in humans. There 
were no renal-related adverse events (AEs) or abnormalities in renal function tests or urinalysis 
tests in clinical studies apart from changes expected from the mechanism of action of rhPTH(1-
84). Despite significant increases in total serum calcium levels and improved calcium 
homeostasis, treatment with rhPTH(1-84) did not result in worsening of hypercalciuria.
Potential risks include those effects which are extensions of the pharmacologic actions of PTH 
including hypercalcemia. Post-treatment hypocalcemia following the abrupt withdrawal of 
rhPTH(1-84) can be particularly problematic. Following sustained withdrawal of rhPTH(1-84), 
serum calcium levels must be carefully monitored with reinstatement of appropriate dosages of 
oral calcium and active vitamin D. No on-treatment events of hypocalcemia occurred following 
incidental missed doses of rhPTH(1-84) during any of the clinical studies; patients should be 
advised, however, to take their rhPTH(1-84) dose as soon possible following a missed dose and 
to take oral calcium.
The investigational product (rhPTH[1-84]) has been developed for the treatment of 
hypoparathyroidism. In the United States the drug is currently marketed under the brand name 
NATPARA as a once a day injectable treatment, indicated as an adjunct to calcium and vitamin D 
to control hypocalcemia in patients with hypoparathyroidism. However, because of the potential 
risk of osteosarcoma, NATPARA is recommended only for patients who cannot be well-controlled 
on calcium supplements and active forms of vitamin D alone.
Always refer to the latest version of the rhPTH(1-84) investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, PKs, efficacy, and safety of rhPTH(1-84).
1.3
Risk/Benefit and Ethical Assessment
There is no anticipated benefit from taking part in this study.
Risks for subject exposure to rhPTH(1-84) are listed in the current investigator brochure and 
include, but are not limited to, the following:

Osteosarcoma: In male and female rats, parathyroid hormone caused an increase in the 
incidence of osteosarcoma (a malignant bone tumor). The occurrence of osteosarcoma was 
dependent on parathyroid hormone dose and treatment duration. This effect was observed at 
parathyroid hormone exposure levels ranging from 3 to 71 times the exposure levels in 
humans receiving a 100μg dose of rhPTH(1-84). These data could not exclude a risk to 
humans. Because of a potential risk of osteosarcoma, it is recommended to use rhPTH(1-84) 
only in subjects with hypoparathyroidism who cannot be well-controlled on calcium and 
active forms of vitamin D alone and for whom the potential benefits are considered to 
outweigh this potential risk. Use of rhPTH(1-84) is to be avoided in subjects who are at 

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increased baseline risk for osteosarcoma such as subjects with Paget’s disease of bone or 
unexplained elevations of alkaline phosphatase, pediatric and young adult subjects with open 
epiphyses, subjects with hereditary disorders predisposing to osteosarcoma or subjects with a 
prior history of external beam or implant radiation therapy involving the skeleton.

Hypercalcemia during initiation of rhPTH(1-84) administration: In previous efficacy and 
safety studies in hypoparathyroidism, 29 of 121 (24.0%) rhPTH(1-84)-treated subjects 
experienced an on-treatment event of hypercalcemia. Monitoring of serum calcium during 
the treatment process can mitigate the risk, along with appropriate medical treatment.

Hypocalcemia with abrupt withdrawal of rhPTH(1-84) therapy: In previous efficacy and 
safety studies in hypoparathyroidism, 24 of 121 (19.8%) subjects experienced a post-
treatment event of hypocalcemia. Monitoring of serum calcium during the treatment process 
and after withdrawal can mitigate the risk, along with appropriate medical treatment.

The safety of rhPTH(1-84) in pregnant or nursing women has not been established. 
Pregnancy tests will be performed on all females on 2 occasions prior to entering the 
treatment phase of the study, and at discharge after treatment and at follow-up. Both men and 
women must agree to adequate contraception methods (see Section 4.4) before taking part in 
the study.
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Recombinant human PTH (rhPTH[1-84]) is approved for use in the United States (US) as an 
adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. As a 
once-daily SC injection for hypoparathyroidism, it has been shown to provide a 24-hour 
sustained increase in serum calcium. Administration of rhPTH(1-84) resulted in dose-related 
increases in total serum calcium levels, with maximum mean increases (approximately 0.125 to 
0.175 mmol/L) observed 12 hours after dosing. Serum calcium levels did not return to baseline 
levels by 24 hours. This sustained increase may explain the reduction in the observed daily 
amounts of calcium and active vitamin D that were taken in the placebo-controlled trial.
Shire intends to develop rhPTH(1-84) for use in Japan. The Japanese regulatory agencies, 
Pharmaceuticals Medical Devices Agency (PMDA) and the Ministry of Health, Labor and 
Welfare (MHLW), require evidence that current data in non-Japanese subjects can be 
extrapolated to the Japanese population, since Japanese patients may require different doses of 
medication of some drug classes. 
To satisfy the PMDA and MHLW requirements, sponsors will provide data to support doses for 
a later study in Japanese subjects. The present study to compare PK and PD profiles and safety 
and tolerability in Japanese and Non-Hispanic, Caucasian healthy volunteer subjects is designed 
for this reason. In addition, this study will also assess the PK dose-proportionality of rhPTH(1-
84) using three, randomized, single, SC doses of 25µg, 50µg, and 100µg in healthy volunteers of 
Japanese descent.

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2.2
Study Objectives
2.2.1
Primary Objective

To compare the PK profile of recombinant human parathyroid hormone (rhPTH[1-84]), 
administered as a single subcutaneous (SC) dose of 100μg, between healthy adult volunteer 
subjects of Japanese descent and matched, non-Hispanic, healthy, adult Caucasian subjects.
2.2.2
Secondary Objectives

To assess the dose proportionality of the PKs of rhPTH(1-84) in healthy adult volunteer 
subjects of Japanese descent when exposed to single SC doses of rhPTH(1-84) at 25µg, 
50µg, and 100µg.

To compare the PD profile (serum calcium and phosphate levels) of a 100μg SC injection of 
rhPTH(1-84) in healthy adult volunteer subjects of Japanese descent and matched, non-
Hispanic, healthy, adult Caucasian, subjects.

To assess the PD profile (serum calcium and phosphate levels) of a 25μg and 50µg SC 
injection of rhPTH(1-84) in healthy adult volunteer subjects of Japanese descent.

To assess the safety and tolerability of single SC doses of 25µg, 50µg, and 100µg of 
rhPTH(1-84) in healthy adult volunteer subjects of Japanese descent.
To evaluate the safety and tolerability of a 100µg SC injection of rhPTH(1-84) in matched, 
non-Hispanic, healthy, adult volunteer Caucasian subjects.
2.2.3
Exploratory Objective
To evaluate the PK similarity of rhPTH[1-84] administered as a single SC dose at 25μg and 50μg 
between healthy adult volunteer subjects of Japanese descent and matched, non-Hispanic, 
healthy, adult Caucasian subjects using dose-normalized PK data.
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 1, open-label, randomized, cross-over, single-center study to evaluate the PK and 
PD profiles and safety and tolerability of rhPTH(1-84) administered in healthy adult volunteer 
subjects of Japanese descent and matched non-Hispanic, Caucasian healthy adult volunteer 
subjects. The non-Hispanic, Caucasian volunteers will receive a single dose of 100µg rhPTH(1-
84). The Japanese subjects will receive 3 single doses of rhPTH(1-84). On Day 1 the subjects of 
Japanese descent will receive a single SC injection of 100µg. On Days 4 and 7 the subjects of 
Japanese descent will be randomized to receive a single SC injection of either 25µg or 50µg. 
such that all of these subjects are exposed to the 3 dose strengths over a 7-day period to further 
characterize the PK profile in that group. A total of 24 subjects will be enrolled: 12 non-
Hispanic, Caucasian subjects and 12 subjects of Japanese descent (1:1 male: female). Non-
Hispanic, Caucasian subjects will be matched to Japanese subjects based on sex, age (±7 years), 
and body mass index (±15%). 

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All subjects will receive a single dose of 100μg rhPTH(1-84) administered by SC injection in the 
mid-thigh with the Haselmeier injector pen on Day 1. In addition, the subjects of Japanese 
descent will also receive single dose injections of 25µg and 50µg rhPTH(1-84) administered by 
SC injection in the mid-thigh to characterize the PK profile over a range of doses. There will be a 
minimum of 72 hours (maximum 73 hours washout from single dose to single dose for the 
volunteers of Japanese descent. The study duration will comprise of a 28-day screening period, 1 
treatment period for the non-Hispanic, Caucasian group (Days 1 and 2); 1 treatment period for 
the volunteers of Japanese descent (Days 1-8), and a follow-up visit (30±2 days) after the last 
dose of investigation drug is administered for each subject. The total number of nights subjects 
will be expected to stay at the clinical research center (CRC) is 2 for the non-Hispanic, 
Caucasian group and 8 for the volunteers of Japanese descent. The maximal total duration of 
study participation for a non-Hispanic, Caucasian subject is 62 days and 68 days for the 
volunteers of Japanese descent, if the maximum screening, treatment and follow-up visit 
durations are used.
Screening will occur within 28 days of the first dose. Subjects will be admitted to the CRC on 
Day -1.
Treatment Period:

On Day 1, all study subjects will receive rhPTH(1-84) as a single 100μg SC injection in the 
mid-thigh.

On Day 4, and Day 7, all subjects of Japanese descent will receive rhPTH(1-84) as a single 
SC injection in the mid-thigh of either 25µg or 50µg depending upon randomization 
assignment. Administration of rhPTH(1-84) in subjects of Japanese descent in the mid-thigh 
should be randomized locally so that an equal number of subjects receive the first dose in the 
right thigh and an equal number in the left thigh. Subsequent doses should be administered in 
the opposing thigh to the last dose.
Assessments

Serial blood samples for PK analysis will be collected on Day 1 (and Day 4 and Day 7 for the 
subjects of Japanese descent) for the determination of parathyroid hormone (PTH) 
concentrations (original and baseline-adjusted) at pre-dose and up to 24 hours post dose. 
These blood samples will be collected according to the Schedule of Assessments.

Serial blood samples for PD analysis will be collected on Day 1 (and Day 4 and Day 7 for the 
subjects of Japanese descent) at pre-dose and up to 24 hours post dose for the determination 
of serum calcium, phosphate, and albumin concentrations.

Safety and tolerability will be determined through assessment of treatment-emergent adverse 
events (TEAEs) from Day 1 time of dose up to the follow-up visit and vital signs, 
electrocardiogram (ECG) findings, and clinical laboratory evaluations on Day 1 pre-dose and 
up to 24 hours post dose for the non-Hispanic, Caucasian subjects and Day 1 pre-dose and up 
to 24 hours post last dose (Day 8) for the subjects of Japanese descent.

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
Additional blood samples for safety purposes will be collected for assessment of anti-PTH 
antibodies.
Follow-up

A post treatment follow-up visit will be completed 30 (±2) days after the last dose of 
investigational product for each subject.

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3.2
Rationale for Dose Selection and Study Design Elements
The primary objective of this study is to compare the PK profile of plasma rhPTH(1-84) between 
subjects of Japanese descent and non-Hispanic, Caucasian volunteers. Although endogenous 
PTH levels are different between healthy subjects and patients with hypoparathyroidism, 
historically, evaluations of different formulations, injection devices and dose proportionality, 
with PK as the primary objective, have been conducted in healthy subjects due to the distinct PK 
profile of plasma rhPTH(1-84) following subcutaneous administration compared to endogenous 
PTH. The PK profile of rhPTH(1-84) following subcutaneous administration had been shown to 
be similar between healthy subjects and patients with hypoparathyroidism in previous studies. 
Therefore, this study is to be conducted in healthy subjects. Due to the presence of endogenous 
PTH in healthy subjects and that the current PTH assay measures the total PTH concentration 
(combination of both endogenous PTH and rhPTH [the assay cannot distinguish between 
endogenous PTH and administered rhPTH(1-84)]), the PK analysis will be performed based on 
both the original and baseline-adjusted PTH concentrations. Due to the potential differences in 
body weight between enrolled subjects of Japanese descent and non-Hispanic, Caucasian 
subjects, in addition to the non-body weight adjusted PK parameters we will also use body 
weight-adjusted PK parameters for comparison.
rhPTH(1-84) (Natpara), is currently approved in the US at doses of 25, 50, 75, and 100µg 
administered once daily. rhPTH(1-84) has demonstrated dose-proportional PKs over this dose 
range in studies performed in the western countries. No significant differences in either the PKs 
or PDs of  rhPTH(1-84) are anticipated between Japanese and non-Japanese; therefore, the 
100µg dose, the highest marketed dose, will be used in this study for direct comparative 
purposes. Further doses of 25µg and 50µg will be used in the subjects of Japanese descent to 
examine the dose proportionality of PKs in Japanese subjects 
Group comparison of the PK, PD, and safety of rhPTH(1-84) will be evaluated after a single 
dose administration in this study. Following subcutaneous administration of  rhPTH(1-84) at 
100µg, plasma PTH levels quickly increase and reach the first peak concentration 
(approximately 150pg/mL) at around 0.5 hour post dose, which is then followed by a second 
peak of a similar magnitude at 2-3 hours post dose. After the second peak, PTH levels decline 
quickly, with an estimated terminal half-life of about 1-2 hours. PTH levels return to baseline at 
about 12 hours post dose. Since it has been shown that there is no accumulation of plasma rhPTH 
after repeat dosing, single dose treatment is considered sufficient to characterize the comparative 
PKs of rhPTH in this study at that dose. 
To examine the PK dose-proportionality of rhPTH(1-84) in the subjects of Japanese descent, 
Japanese subjects will receive single, SC doses of 25µg, 50µg, and 100µg rhPTH(1-84) and PK 
parameters will be evaluated for dose proportionality.  
3.3
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 62 days for the 
non-Hispanic, Caucasian volunteers and 68 days for the subjects of Japanese descent. The study 
will be completed in approximately 9 weeks.

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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.4
Sites and Regions
It is anticipated that this study will be performed at 1 study site within the United States.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed.
1.
Ability to voluntarily provide written, signed, and dated informed consent as applicable to 
participate in the study.
2.
An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
3.
Age 18-65 inclusive at the time of consent.  The date of signature of the informed consent 
is defined as the beginning of the screening period.  This inclusion criterion will only be 
assessed at the first screening visit.
4.
Subjects must be either:
a.
A subject of Japanese descent born in Japan, who has resided outside of Japan for no 
longer than 5 years and is of Japanese parentage, defined as having 2 Japanese parents, 
and 4 Japanese grandparents, all born in Japan.
b. A non-Hispanic, Caucasian subject who has 2 non-Hispanic, Caucasian parents and 4 
non-Hispanic, Caucasian grandparents.
5.
Male or nonpregnant, nonlactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of nonchildbearing potential.
6.
Considered “healthy” by the investigator.  Healthy status is defined by absence of evidence 
of any active or chronic disease following a detailed medical and surgical history, a 
complete physical examination including vital signs, 12-lead ECG, hematology, blood 
chemistry, and urinalysis.
7.
Body mass index between 18.5 and 28 kg/m², inclusive, with a body weight ≥45 kg 
(99lbs). This inclusion criterion will only be assessed at the first screening visit.

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8.
Willing and able to consume standardized meals during the confinement period of the 
study. All participants will be required to consume the identical meals on study days when 
serial PK and PD blood samples are collected.
9.
A clinical safety laboratory parameter of hemoglobin greater than 11.7g/dL (females) or 
13.1g/dL (males) and less than 16g/dL (females) or 17.4g/dL (males) or, if out of this 
range, deemed not clinically significant by the principal investigator.
10.
Total serum calcium within laboratory normal limits.
11.
Serum parathyroid hormone (PTH) levels within laboratory normal limits.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect 
the action, absorption, or disposition of the investigational product, or clinical or laboratory 
assessments.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to fully complete the study, or any condition 
that presents undue risk from the investigational product or procedures.
3.
Known or suspected intolerance or hypersensitivity to the investigational product(s), 
closely-related compounds, or any of the stated ingredients.
4.
Significant illness, as judged by the investigator, within 2 weeks of the first dose of 
investigational product.
5.
Known history of alcohol or other substance abuse within the last year.
6.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of investigational product.
7.
Use of the following prior to administration of investigational product within:

30 days – loop diuretics, lithium, antacids, systemic corticosteroids (medical judgment is 
required by the investigator. Primarily high doses of systemic corticosteroids [eg, 
prednisone] should be excluded. Stable doses of hydrocortisone [eg, as treatment for 
Addison’s disease] may be acceptable).

3 months – calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or 
N-terminal PTH or PTH-related peptide fragments or analogs

For females: changes in hormone replacement therapy within 3 months are excluded. 
Stable (≥3 months) hormone replacement therapy is acceptable.

6 months – fluoride tablets, oral bisphosphonates, methotrexate, growth hormone, 
digoxin, raloxifene or similar selective estrogen receptor modulators (SERMs)

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
12 months – intravenous bisphosphonates, drug or alcohol abuse, as determined by the 
investigator
8.
Confirmed systolic blood pressure (BP) >139mmHg or <89mmHg, and diastolic BP 
>89mmHg or <49mmHg.
9.
Twelve-lead ECG demonstrating measure of time between the start of the Q wave and the 
end of the T wave using Fridericia’s formula in an electrocardiogram (QTcF) >450msec at 
screening.  If QTcF exceeds 450msec, the ECG should be repeated 2 more times and the 
average of the 3 QTcF values should be used to determine the subject’s eligibility.
10.
Positive screen for drugs of abuse at screening or drugs of abuse or alcohol on Day -1.
11.
Male subjects who consume more than 21 units of alcohol per week or 3 units per day.  
Female subjects who consume more than 14 units of alcohol per week or 2 units per day.  
(1 alcohol unit=1 beer or 1 wine (5oz/150 mL) or 1 liquor (1.5oz/40 mL) or 0.75 oz 
alcohol).
12.
Positive human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
HCV antibody screen.
13.
Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products 
in any form (eg, gum, patch).  Ex-users must report that they have stopped using tobacco 
for at least 30 days prior to receiving the first dose of investigational product.
14.
Routine consumption of more than 2 units of caffeine per day or subjects who experience 
caffeine withdrawal headaches.  (1 caffeine unit is contained in the following items:  one 
6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, three 
1 oz (85 g) chocolate bars.  Decaffeinated coffee, tea, or cola are not considered to contain 
caffeine).
15.
Prior screen failure, randomization, participation, or enrollment in this study or prior 
exposure to any exogenous PTH, PTH fragments or analogs.
16.
Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations; with the exception of hormonal replacement therapy or hormonal 
contraceptives and occasional use of ibuprofen and acetaminophen). Current use is defined 
as use within 14 days of the first dose of investigational product.
17.
History of abnormalities of calcium homeostasis including hyperparathyroidism, 
hypoparathyroidism, hyperthyroidism, osteoporosis, Cushing’s syndrome, hypercalcemia, 
hypocalcemia, or any other calcium disorder.
4.3
Restrictions 
1. Subjects should refrain from strenuous physical exercise 48 hours prior to admission to the 
CRC and during the in-house stays at the CRC.

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2. Subjects should refrain from consuming grapefruit, Seville oranges, and products containing 
these items from 7 days prior to Day 1 of the first treatment period through the completion of 
the last treatment period.
3. Subjects should refrain from alcohol 48 hours prior to admission to the CRC and during the 
in-house stay at the CRC.
4. Subjects should refrain from use of tobacco or any products containing nicotine within 
30 days of Day 1 of the first treatment period through the completion of the last treatment 
period.
5. Subjects should refrain from taking or regularly using any medication (including 
over-the-counter multivitamin, herbal, or homeopathic preparations) with the exception of 
those listed in Section 5.2 from 14 days prior to receiving the first dose of the investigational 
product through the completion of the discharge assessments and procedures at Treatment 
Period 2.
6. Subjects should refrain from foods or beverages containing caffeine/xanthine 48 hours prior 
to admission to the CRC and during the in-house stay at the CRC.
7. On Day -1, Day 1, Day 4, and Day 7 when the investigational product is to be administered, 
subjects will be required to fast for approximately 8 hours prior to dose of administration and 
continuing through 2 hours after administration of the investigational product. Water will be 
allowed ad libitum. 
8. Subjects will be required to follow standardized meal schedules and eat the meals provided 
by the site while housed in the CRC. No outside food or beverages (including gum, mints, 
etc.) will be permitted. Menus will be identical for all subjects at the CRC. Copies of the 
menus will be provided to the sponsor for approval prior to the start of the study. While 
confined, the total daily nutritional composition should be approximately 50% carbohydrate, 
35% fat, and 15% protein. The daily caloric intake per subject should not exceed 
approximately 3200 kcal.
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of 
investigational product. If hormonal contraceptives are used, they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception, as defined below, if they become sexually 
active during the period of the study and for 30 days following the last dose of investigational 
product.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea with follicle-stimulating 
hormone [FSH] concentrations in the laboratory post menopausal range). 

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
Surgically sterile (having undergone one of the following surgical procedures: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post sterilization, or

Females of childbearing potential with a negative serum -hCG pregnancy test at the 
screening visit and at Day -1. Females of childbearing potential must agree to abstain from 
sexual activity that could result in pregnancy or agree to use acceptable methods of 
contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the first dose of investigational product, plus condoms. Note: If subject 
becomes sexually active during the study, they should use 1 of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 30 days.
4.4.2
Male Contraception
Male subjects must be advised to use acceptable contraceptives throughout the study period and 
for 3 months following the dose of investigational product. Male subjects must be advised not to 
donate sperm during the course of the study and within 3 months of last dose of investigational 
product. Acceptable methods of contraception for male subjects are:

Double-barrier methods (eg, condoms with spermicidal gel or foam)
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the early withdrawal 
evaluations listed in Table 1 are to be performed as completely as possible. Whenever possible, 
all discontinued subjects should also undergo the protocol-specified follow-up. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and date of stopping investigational product must be 
recorded in the source documents.
Enrolled subjects who discontinue from the study may be replaced at the sponsor’s discretion.

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4.5.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record. If a subject is withdrawn for more than 1 reason, each reason should be 
documented in the source document and the most clinically relevant reason should be noted.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Physician decision

Other {If “Other” is selected, the investigator must specify the reason}
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
nonpharmacological treatments such as psychotherapy as appropriate) received within 30 days 
(or PK equivalent of 5 half-lives, whichever is longer) of the date of dose of investigational 
product. Prior treatment information must be recorded on the source documentation.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate source document.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study. Any medication which is considered necessary for the subject’s 
safety and well-being may be given at the discretion of the investigator. The administration of all 
medications (including investigational products) must be listed on the appropriate source 
document.
Medications permitted during the study are listed below:

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
Hormonal contraceptives for females of childbearing potential administered according to the 
package insert (see Section 4.4.1)

Hormone replacement therapy that has been in use for at least 30 days prior to date of first
dose of rhPTH(1-84)

Occasional use of a nonsteroidal anti-inflammatory drug as prescribed by the principal 
investigator (or delegate)
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is rhPTH(1-84), which will be provided as a multiple dose, dual chamber, glass 
cartridge containing a sterile lyophilized powder and a sterile diluent for reconstitution at doses 
of 25µg, 50µg, and 100µg.
The study drug cartridge (together with the study drug cartridge holder) is initially placed onto a 
mixing device to break the internal seal and allow the lyophilized powder and diluent to fully 
mix. Once mixed, the study drug and cartridge are placed into the Haselmeier injector pen in 
preparation for dosing.
Please note that in each administration of the drug by the pen injector (Haselmeier), a sterile, 
disposable pen needle is used and is specified as a Becton-Dickinson (BDTM) 0.25 mm x 8 mm 
(31G x 5/16”).
Additional information related to the investigational product, including preparation and 
administration, is provided in the current rhPTH(1-84) investigator brochure, and in an 
investigational product preparation and administration manual that will be provided.
6.1.1
Blinding the Treatment Assignment
Not Applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment
This is an open-label study.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This will be a 4-digit number starting at 
0001.
For eligible subjects, the subject number will be the identifying number used throughout the 
CRF.

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Once a subject number has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If a subject number is allocated incorrectly, the clinical 
research associate/study monitor must be notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from subject numbers, may 
also be assigned to subjects for specific treatment assignment as dictated by the study. In these 
cases, the same investigational product packing identification number may not be assigned to 
more than 1 subject.
Each eligible subject will be assigned to 1 study drug cartridge (with a unique identifier). Each 
study drug cartridge should only be used for the subject to which it is assigned. Although each 
study drug cartridge holds multiple doses, only 1 dose from the cartridge must be used for the 
subject it is assigned to. Study drug cartridges and injector pens must be regarded as single use 
only and never used on more than 1 subject.
A study drug allocation scheme will be provided. The study drug allocation scheme must be 
maintained securely in the pharmacy.
6.2.2
Dosing
After each subject has completed the screening process and found to be eligible to proceed to 
dosing (inclusive of all clinical laboratory values), the subject will be assigned a study cartridge, 
mixing device and injector pen and, following preparation of the study drug, will be administered 
a single dose of investigational product in the mid-thigh on the morning of Day 1 (for all study 
subjects) and Days 4 and 7 (for subjects of Japanese descent only). A detailed pharmacy manual 
will be provided that describes the materials to be used, the preparation of materials and 
administration of study drug.
6.2.3
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
The study site will receive open label supplies of investigational product, injection pens and 
mixing devices required for dosing.
All clinical supplies will be manufactured, tested, labeled and released according to current legal 
and local country specific regulatory requirements and will comply with Good Manufacturing 
Practices.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and initials.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements, but must not:

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
Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.
In addition to labeling requirements for the investigative study drug, rhPTH(1-84), mixing 
devices and injector pens must also be labeled with the unique subject identifier. One mixing 
device and 1 injector pen will be supplied for each subject taking part in the study for each dose. 
Mixing devices and injector pens must never be used between study subjects.
6.3.2
Packaging
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the site study team. The 
pharmacist/nominated study team member will enter the unique subject identifier on the injector 
pen (containing the study drug cartridge) as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a
storage room.

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6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
investigational product will be documented on the source documents and/or other investigational 
product record.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor. For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labeled amount is to be documented in lieu of counting. Shipment return 
forms, when used, must be signed prior to shipment from the site. Returned investigational 
products, if possible, must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any investigational product prior to shipment. 
Shipment of all returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.

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6.5
Subject Compliance
The investigator/nominated person will record details on the drug accountability log(s) and/or 
source documents of study drug administration (including which thigh was used) and dosing 
details (time, date, dose level).
6.6
Retention of Bioavailability and Bioequivalence Testing Samples
Not applicable.
7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1, Table 2 and Table 3 for study procedures.
The following “priority order” will be in effect when more than 1 procedure or assessment is 
required at a particular time point.

Spontaneous or solicited adverse event (AE) reporting

Electrocardiogram (ECG)

Vital signs

Pharmacodynamic blood sampling

Anti-PTH blood sampling

Clinical laboratory tests

PK blood sampling

Physical examination
NOTE: Blood sampling for PD and PK evaluation must be performed at the precise protocol-
scheduled time. Actual sampling time(s) must be accurately recorded in the source document.
7.1.1
Screening Period
Screening procedures must be completed within 28 days prior to receiving the dose of 
investigational product. All screening assessments and procedures are to be performed by the 
principal investigator or a qualified designee. See Table 1 for a complete list of screening 
procedures to be performed. Immediately before dosing on Day 1 (but still within the screening 
period), subjects will check into the CRC (Day -1) for an overnight stay prior to dosing on Day 
1. Eligibility procedures performed on Day -1 must be confirmed as meeting inclusion/exclusion 
criteria before dosing on Day 1.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.

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7.1.1.1
Screening Failure
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been enrolled or administered 
investigational product(s).
7.1.1.2
Rescreening of Subjects
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point.
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to scheduling conflicts/timing may be rescreened based on investigator discretion and 
sponsor approval should their availability to participate fall outside the screening window. In 
these cases, a new screening number must be assigned for each subject who is rescreened and a 
new informed consent form must be signed.
7.1.2
Treatment Period
7.1.2.1
Days 1 to 8
Study assessments for Day 1 to Day 8 of the treatment period are outlined in Table 1,Table 2, 
and Table 3. Administration of investigational product will occur on Day 1 (all study subjects) of 
the treatment period and Days 4 and 7 (subjects of Japanese descent) of the treatment period.
Subjects will be discharged from the CRC following completion of the last study assessment on 
Day 2 (all non-Hispanic, Caucasian subjects) and Day 8 (all subjects of Japanese descent) of the 
treatment period.
7.1.2.2
Final Visit
For this study, the final visit will be the follow-up visit, which is intended to be an out-patient 
clinic visit.
7.1.3
Follow-up Period
The follow-up period for this protocol is 30±2 days after the dose of investigational product. At 
the end of this period there will be a follow-up visit to obtain a blood sample for clinical safety 
labs, to obtain a blood sample for anti-PTH antibodies, and to query for SAEs, AEs, and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Section 8.1.)
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.

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7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
7.2.1.1
Demographics
Demographic information will be collected at the initial screening visit. Information to be 
collected will include:

Date of birth

Sex

Race and ethnicity
7.2.2
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is that 
the investigator will ensure that every effort is made to perform all assessments at the precise 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than ±15 minutes will be considered a protocol deviation 
(unless otherwise noted in the protocol).
Adverse events (defined as AEs occurring from the time of informed consent signature to the 
dose of investigational product), TEAEs (all AEs occurring after the treatment), prior medication 
and concomitant medication use will be assessed and monitored from the time the subject signs 
the informed consent form to completion of study (including to time of screen failure or drop 
out/discontinuation). While confined in the CRC, subject safety will also be closely monitored 
through BP measurements, ECG measurement, clinical safety labs and physician oversight.
In the event anti-PTH antibodies are detected following analysis for a subject, the investigator 
will be notified by the sponsor. It will be the investigator’s responsibility to notify the subject.
7.2.2.1
Medical and Medication History
A complete medical and medication history, as well as demographic information, will be 
performed at the screening visit/time points described in Table 1 by a qualified licensed 
physician, physician’s assistant, or a nurse practitioner. The medical history will be reviewed and 
recorded, including:

Recent ingestion of medication (30 days prior to entering the screening period)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases

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7.2.2.2
Physical Examination (Including Height and Weight)
A complete physical examination will be performed at the time points described in Table 1, 
Table 2, and Table 3 by a qualified licensed physician, physician’s assistant, or nurse 
practitioner.
The physical examination will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys)
Clinically significant abnormalities identified at the screening visit will be documented in the 
subject’s source documents and documented in the medical history. Changes after the screening 
visit will be captured as AEs on the AE source documentation, as deemed by the investigator.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.)
7.2.2.4
Vital Signs
BLOOD PRESSURE AND PULSE RATE
Blood pressure and pulse rate will be measured at times specified in Table 1, Table 2 and Table 3
of this protocol. Additional BP and pulse rate measurements may be performed, as determined 
by the investigator, in order to ensure appropriate monitoring of subject safety and accurate 
recording of vital sign measurements. Any changes from baseline which are deemed clinically 
significant by the investigator are to be recorded as an AE.
The same method for obtaining BP measurement (auscultatory or oscillometric) should be used 
throughout the study for all subjects (and documented). In addition, the conditions of vital sign 
measurements should be controlled and as consistent as possible during the study, in order to 
minimize external variability of the readings. It is advised that measurements be collected at a 
comfortable room temperature with little to no background noise, using the same (appropriately 
sized) cuff placed at the same location of the same arm during the study. The bladder deflation 

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rate should be deflated (calibrated for oscillometric method or manually by auscultatory method) 
at a rate of 2-3 mmHg/s (and the first and last audible sounds recorded as systolic and diastolic 
pressure) after at least 5 minutes of rest in the assumed position.
The cuff should have a bladder length that is 80% and a width that is at least 40% of arm 
circumference (a length-to-width ratio of 2:1). 
The subject should be asked to remove all clothing that covers the location of cuff placement. 
The subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 
minutes of collection. The subject should be instructed to relax as much as possible for at least 5 
minutes prior to collection. The subject should remain quiet during this time and through the 
measurement.
The subject should be lying comfortably, with the legs uncrossed. The arm should be supported 
with a pillow, such that the middle of the cuff on the upper arm is at the level of the right atrium 
(approximately halfway between the bed and the level of the sternum).
At the screening visit, blood pressure should be compared between both arms. If, after a single 
measurement is taken, there is a difference between arms in either systolic or diastolic blood 
pressure of >10mmHg, the site will perform triplicate BP measurements in each arm to 
determine the arm with the higher BP. The arm with the higher BP (based on the average of the 3 
BP measurements for each arm) should be used for inclusion at screening, and the last of the 3 
measurements recorded in the source documentation as the screening BP. The same (right or left) 
arm with the higher blood pressure will be used throughout the study, see Figure 2.

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The following clinical laboratory assessments will be performed:
BIOCHEMISTRY
Blood samples (8.5 mL) for serum biochemistry will be collected into a red top gel separator 
tube at the time points described in Table 1, Table 2 and Table 3. The following parameters will 
be assessed:
Sodium
Phosphorus
-hCGb
Potassium
Total protein
Magnesium
Glucose 
Total CO2 (Bicarbonate)
PTHc
Blood urea nitrogen
Albumin
FSHb
Creatinine
Aspartate transaminase 
Calcium
Alanine transaminase 
Chloride
Gamma glutamyl transferase 
Thyroid stimulating hormone (TSH)a
Alkaline phosphatase 
Thyroxine (T4 total)a
Total bilirubin 
Triiodothyronine (T3)a
Uric acid
CO2=carbon dioxide; FSH= follicle stimulating hormone; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating 
hormone
a
See Table 1, Table 2, and Table 3.
b
Females only.
c
Parathyroid hormone at screening and Day -1 is for baseline eligibility use only and not for PK analysis.
HEMATOLOGY
Blood samples (4mL) for hematology will be collected into a K2-EDTA 
(ethylenediaminetetraacetic acid) tube at the time points described in Table 1, Table 2, and Table 
3. The following parameters will be assessed:
Hemoglobin
Total neutrophils (absolute)
Hematocrit
Eosinophils (absolute)
Red blood cells
Monocytes (absolute)
Platelet count
Basophils (absolute)
White blood cell count; total and differential
Lymphocytes (absolute)

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URINALYSIS
A urine sample for urinalysis will be collected at the time points described in Table 1, Table 2,
and Table 3. The following parameters will be assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria. 
7.2.2.6
Pregnancy Test
A serum -hCG pregnancy test is required for all females at screening, on admission to the CRC 
on Day -1 and upon discharge from the CRC on Day 2 (for non-Hispanic, Caucasian subjects) or 
Day 8 (for subjects of Japanese descent) and at the final follow-up visit for all females. In 
addition, a pregnancy test is required if pregnancy is suspected or on early 
withdrawal/termination from the study.
7.2.2.7
Drug and Alcohol Screen
A urine screen for drugs of abuse and an alcohol breath test will be performed at the time points 
described in Table 1. Additional drug and alcohol screens may be performed at the investigator’s 
discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine.
Results of urine drug and alcohol screens will be reviewed and verified by the study monitor, but 
will not be collected in the CRF database.
Any positive result for drugs of abuse at screening or drugs of abuse and alcohol on Day -1 will 
exclude the subject from further participation in the study.
7.2.2.8
Serology Screen
At the screening visit, a blood sample of approximately 8.5mL will be drawn into a serum 
separator tube to test for the presence of HIV, HBsAg, and HCV antibody.
The test results must be confirmed negative prior to enrollment in the study. If a test result is 
positive, the subject will be excluded from entering the study. Results of the virology screen will 
be reviewed and verified by the study monitor, but will not be collected in the CRF database.
Positive serology results may be reported to the relevant health authorities by study site 
personnel if required by law.

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7.2.2.9
Electrocardiogram
Twelve-lead ECGs will be performed at the times specified in Table 1, Table 2, and Table 3. All 
ECGs will be performed using the equipment supplied by the CRC.
The following parameters will be recorded in the source documentation: heart rate, time elapsed 
from P wave to R wave in an electrocardiogram (PR), the time between heart beats in an 
electrocardiogram (RR), measure of time for the 3 main deflections in an electrocardiogram 
(QRS), and QT intervals along with information on T and U wave morphology (T waves should 
be captured as normal/abnormal; U waves should be captured as absent/normal or abnormal). 
The measure of time between the start of the Q wave and the end of the T wave using Bazett’s 
formula in an electrocardiogram (QTcB) and QTcF will be derived from the data in the database. 
The investigator’s assessment of the ECG tracing as normal or abnormal must be documented, 
and if abnormal, his/her determination of whether the abnormality is clinically significant or not 
will be documented on the tracing and the source documentation (if different).
The subject should be asked to remove all clothing that covers the location of lead placement. 
The subject should not have exercised or consumed caffeine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to
collecting the ECG.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. 
Triplicate ECG recordings, including a 10-second rhythm strip, should be taken at each time 
point. They should be immediately assessed as valid recordings and if not valid, they should be 
repeated. Invalid recordings will not be entered included in the CRF database.
A triplicate ECG recording is to be performed at each time point approximately 2-4 minutes 
apart. The averages of the ECG triplicate collected predose on Day 1 (all subjects) and predose 
on Days 4 and 7 (subjects of Japanese descent) will serve as the subject’s baseline ECG.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.
If the triplicate average QTcF interval (calculated online on site) is increased by >45 msec from 
the baseline or an absolute QTcF value is >500 msec for any scheduled ECG, then 2 additional 
ECGs will be collected, approximately 2-4 minutes apart, to confirm the original measurement. 
If either of the QTcF values from these repeated ECGs remains above the threshold value (>45 
msec from the baseline; or is >500 msec), then a single ECG must be repeated at least hourly 
until QTcF values from 2 successive ECGs fall below the threshold value that triggered the 
repeat measurement. When triplicate ECGs are collected, the mean of the triplicate 
measurements should be used to trigger the decision to collect follow-up ECGs.
If QTcF values remain above 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator) or QTcF intervals get progressively longer, the subject 

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should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator).
If a machine-read QTcF value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTcF values are in the 
acceptable range.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory (Celerion) for this study will be maintained 
in the investigator’s files at the site and in the Trial Master File at the sponsor.
Actual PK blood sample collection times versus time of dosing will be monitored. The sponsor’s 
expectation is that the investigator will ensure that every effort is made to collect all PK blood 
samples at the precise protocol scheduled time. PK blood collection must not deviate from the 
nominal collection time set forth in the protocol by more than 5 minutes from samples drawn 
within 4 hours postdose or by more than 15 minutes for samples drawn at 4 hours post dose and 
beyond. Samples drawn outside these parameters will be considered a protocol deviation.
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures
Pharmacokinetic blood samples will be collected at the time specified in Table 1, Table 2, and 
Table 3 to measure plasma concentrations of PTH. A full description of the PK blood collection, 
handling, storage and shipping can be found in the provided laboratory manual. Plasma sample 
tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels provided by the 
CRC. The labels will contain the following information:

Study number: SHP634-102

Subject identifier

Nominal day

Nominal time

Matrix identifier (plasma)

Split (primary or back-up)
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples
All PK samples should be double-bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday-Wednesday only (do not ship on 
a local, regional or national holiday). Samples should be transported to ensure that they arrive at 
the bioanalytical laboratory between the hours of 9:00 AM and 4:00 PM. The recipient 
(Celerion) and primary Shire contact must be notified by telephone or e-mail when the samples 
are shipped and they must be provided with the shipment tracking number.

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Full directions for shipment of all PK samples, (along with the corresponding documentation) 
can be found in the laboratory manual provided under separate cover.
Pharmacokinetic samples will be stored nominally at -70º C (-94ºF) prior to and after analysis at 
the bioanalytical labs until their disposal is authorized by Shire.
7.2.3.3
Plasma Drug Assay Methodology
Plasma sample analysis will be performed according to the relevant Standard Operating 
Procedures at the contract bioanalytical lab (Celerion).
Plasma concentrations will be measured using the most current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan).
7.2.4
Pharmacodynamic Assessments
The name and address of the bioanalytical laboratory (InVentiv Health) for this study will be 
maintained in the investigator’s files at the site and in the Trial Master File at the sponsor.
Actual PD blood sample collection times versus time of dosing will be monitored. The sponsor’s 
expectation is that the investigator will ensure that every effort is made to collect all PD blood 
samples at the precise protocol scheduled time. Pharmacodynamic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than 5 minutes from 
samples drawn within 4 hours post dose or by more than 15 minutes for samples drawn at 4 
hours post dose and beyond. Samples drawn outside these parameters will be considered a 
protocol deviation.
7.2.4.1
Pharmacodynamic Sample Collection and Handling Procedures
Pharmacodynamic blood samples will be collected at the time specified in Table 1, Table 2, and 
Table 3 to measure serum concentrations of calcium, phosphate and albumin. A full description 
of the PD blood collection, handling, storage and shipping can be found in the provided 
laboratory manual. Serum sample tubes for bioanalysis must be freezer-safe and identified with 
freezer-safe labels provided by the CRC. The labels will contain the following information:

Study number: SHP634-102

Subject identifier

Nominal day

Nominal time

Matrix identifier (serum)

Analyte (calcium/phosphate or albumin)

Split (primary or back-up)

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7.2.4.2
Shipment of Serum Pharmacodynamic Samples
All PD samples should be double-bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday-Wednesday only (do not ship on 
a local, regional or national holiday). Samples should be transported to ensure that they arrive at 
the bioanalytical laboratory between the hours of 9:00 AM and 4:00 PM. The recipient 
(inVentiv) and primary Shire contact must be notified by telephone or e-mail when the samples 
are shipped and they must be provided with the shipment tracking number.
Full directions for shipment of all PD samples, (along with the corresponding documentation) 
can be found in the laboratory manual provided under separate cover.
Pharmacodynamic samples will be stored nominally at -70º C (-94ºF) prior to and after analysis 
at the bioanalytical labs until their disposal is authorized by Shire.
7.2.4.3
Serum Pharmacodynamic Assay Methodology
Serum sample analysis will be performed according to relevant Standard Operating Procedures at 
the contract bioanalytical lab (inVentiv Health).
Serum PD concentrations will be measured using the most current validated bioanalytical 
methods. In addition, selected serum samples may be used to investigate incurred sample 
reproducibility (full details will be described in the bioanalytical study plan). The presence of 
other metabolites or artifacts may be monitored or quantified as appropriate.
7.2.5
Immunogenicity Testing for Anti-Parathyroid Hormone Antibodies
The name and address of the bioanalytical laboratory (Covance) conducting anti-PTH 
immunogenicity testing for this study will be maintained in the investigator’s files at the each 
site and in the Trial Master File at the sponsor.
Actual anti-PTH blood sample collection times versus time of dosing will be monitored. The 
sponsor’s expectation is that the investigator will ensure that every effort is made to collect all 
anti-PTH blood samples at the precise protocol scheduled time. Anti-PTH blood collection will 
be collected on Day 1 prior to dose (within 30 minutes of dose) and at the follow-up visit.
In the event anti-PTH antibodies are detected following analysis for a subject, the investigator 
will be notified by the sponsor. It will be the investigator’s responsibility to notify the subject.
7.2.5.1
Sample Collection and Handling Procedures for Immunogenicity Testing 
for Anti-Parathyroid Hormone Antibodies
Blood samples will be collected at the time specified in Table 1, to detect anti-PTH antibodies in 
serum. A full description of the anti-PTH blood collection, handling, storage and shipping can be
found in the provided laboratory manual. Serum sample tubes for bioanalysis must be freezer-
safe and identified with freezer-safe labels provided by the CRC. The labels will contain the 
following information:

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
Study number: SHP634-102

Subject identifier

Nominal day

Nominal time

Matrix identifier (serum)

Split (primary or back-up)
7.2.5.2
Anti-Parathyroid Hormone Antibody Assay Methodology
Serum sample analysis will be performed according to relevant Standard Operating Procedures at 
the contract bioanalytical lab (Covance).
Detection of anti-PTH antibodies from serum blood samples will use the most currently 
validated bioanalytical method. 
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 4
Volume of Blood to Be Drawn from Each Subject
Caucasian
Japanese
Assessment
Sample 
Volume (mL)
Number of 
Samples
Total 
Volume 
(mL)
Number of 
Samples
Total 
Volume 
(mL)
Pharmacokinetic samplesa
4
18
72
54
216
Serum PTH samplea
2
2
4
2
4
Pharmacodynamic samplesa
6
5
30
15
90
HBsAg, HIV, HCVa
8.5
1
8.5
1
8.5
Safety
Biochemistry, FSH 
and -hCGa, b
8.5
5
42.5
9
76.5
Hematologya
4
5
20
9
36
Anti-PTH Antibody Samplesa
3
2
6
2
6
Total mL
183
437
-hCG=beta-human chorionic gonadotropin; FSH=follicle stimulating hormone, HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus
a If a catheter is in use for any blood draw or series of blood draws then the first 1mL is to be discarded. The 1mL discard has 
been taken into account in the table above and the total blood volume required for study.
b -hCG and FSH testing for females only.
During this study, it is expected that approximately 437mL of blood will be drawn from all 
subjects of Japanese descent, regardless of sex. For the non-Hispanic, Caucasian volunteers it is 
expected that 183mL of blood will be drawn, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 

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should be approximately 183mL (non-Hispanic, Caucasian subjects) or 437mL (subjects of 
Japanese descent). When more than 1 blood assessment is to be done at the time point/period, if 
they require the same type of tube, the assessments may be combined.
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product
(International Conference on Harmonisation [ICH] Guidance E2A 1995).
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
source documents. In addition to untoward AEs, unexpected benefits outside the investigational 
product indication should also be captured on the AE source documentation.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the source documentation).
The medical assessment of severity is determined by using the following definitions:

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Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the source 
documentation. Outcomes are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

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
Unknown
8.1.4
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the contract research 
organization (CRO)/Shire medical monitor using the details specified in the emergency contact 
information section of the protocol. The pregnant female study participant must be withdrawn 
from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and

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Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
The administration of rhPTH(1-84) to an eligible volunteer following an excursion in 
temperature requirements (outlined in the pharmacy manual), without assessment of the 
excursion and permission of the sponsor to proceed, is deemed a medication error.
It is not expected that overdose would occur in this protocol. The investigative product used in 
this study is supplied in 1 strength only, and is administered once only per volunteer, by a trained 
and responsible staff member at the study site with sponsor oversight.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the rhPTH(1-84) investigators brochure 
which the sponsor has provided under separate cover to all investigators.

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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.6) unless 
they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled surgery for 
pre-existing conditions and have not worsened after initiation of treatment should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.

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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire medical 
monitor within 24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE,
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor is responsible for notifying the relevant regulatory authorities and the US central 
Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP634 clinical program. 
The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.

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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
from the source documentation to the CRF. A study monitor will visit each site in accordance 
with the monitoring plan and review the CRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site at 
the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it is 
expected that site personnel will complete the CRF entry within a reasonable window of the 
subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
This is an open label study and therefore there are no particular data handling concerns.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the PK, PD, and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or data monitoring committee (DMC) in 
this study.

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9.6
Sample Size Calculation and Power Considerations
No formal calculations were performed to determine sample size for this study. The sample size 
is based on feasibility and is similar to that of comparable studies.
9.7
Study Population
The following study subject populations are defined for this study:

The safety population includes subjects who have received at least 1 dose of rhPTH(1-84).

The PK population consists of subjects who receive at least 1 dose of rhPTH(1-84) and have 
at least 1 evaluable post dose PK concentration value.

The PD population consists of subjects who receive at least 1 dose of rhPTH(1-84) and have 
at least 1 evaluable post dose PD concentration value.
9.8
Pharmacokinetic and Pharmacodynamic Analyses
9.8.1
Pharmacokinetic Analysis
All the PK analyses will be performed using the PK set.
A PK evaluation of PTH concentrations and baseline-adjusted PTH concentrations will be 
performed following the administration of rhPTH(1-84) administered on Day 1 for non-Hispanic, 
Caucasian subjects and Days 1, 4 and 7 for subjects of Japanese descent.
Pharmacokinetic parameters will be calculated from original and baseline-adjusted plasma 
concentration-time data using noncompartmental methods and all calculations will be based on 
actual sampling times. Baseline is defined as the average Day 1 predose concentration for all 
subjects (and the Day 4 and Day 7 average predose concentration for the subjects of Japanese 
descent for those respective dosing intervals). Pharmacokinetic parameters will be estimated 
based on noncompartmental analysis and will include, but not be limited to, the following:

Cmax: Maximum concentration occurring at tmax

tmax: Time of maximum observed concentration sampled during a dosing interval

AUClast: Area under the curve from the time of dosing to the last measurable concentration

z: First order rate constant associated with the terminal (log linear) portion of the curve

t½: Terminal half-life

CL/F: Apparent clearance

Vdz/F: Apparent volume of distribution
Non-body weight adjusted and body weight-adjusted AUClast, Cmax, CL/F, and Vdz/F will be 
estimated. In addition, dose-normalized baseline adjusted AUClast and Cmax will be calculated.

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9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters
Individual concentrations (original and baseline-adjusted) and PK parameters (original, baseline-
adjusted, body weight-adjusted, and dose-normalized-baseline-adjusted) of rhPTH(1-84) will be 
listed and summarized with descriptive statistics (number, arithmetic mean, standard deviation 
[SD], coefficient of variation [CV%], median, minimum, maximum, geometric mean, and %CV 
of geometric mean. The 95% confidence intervals of the geometric means of PK parameters will 
be presented as well. Figures of individual and mean (±SD) concentration-time profiles of the 
original and baseline-adjusted plasma rhPTH(1-84) will be generated on linear and semi-log 
scales. The mean plots will be generated by overlaying the Japanese cohort and Non-Japanese 
cohort. Figures of baseline-adjusted PK parameters and dose-normalized baseline-adjusted PK 
parameters vs dose in Japanese subjects will be generated. Box-Whisker plots for selected PK 
parameter will be generated with Japanese cohort and Non-Japanese side by side. Forest plots of 
geometric mean ratios for selected PK parameters between Japanese cohort vs Non-Japanese 
cohort will be generated.
Dose proportionality of PK parameters will also be examined for the Japanese subjects. Dose 
proportionality will be assessed for Cmax and AUC (AUClast) using the power model. The power 
model assumes a linear relationship between the natural log transformed parameter and the 
natural log transformed dose.
ln (Parameter) = α + β × ln (Dose) + Random error
Where α is the intercept, β is the slope, and Random error is a random residual error. Dose 
proportionality will be assessed by estimating mean slope with the corresponding two-sided 95% 
confidence interval (CI) from the power model.
In order to compare the PKs of rhPTH(1-84) between subjects of Japanese descent and matched 
non-Hispanic, Caucasian subjects, the differences of log-transformed PK parameters from the 
rhPTH 100ug dose will be examined between groups using an analysis of variance model. The 
geometric mean ratio and its 90% confidence interval (CI) will be provided from the model. 
Baseline-adjusted PK parameters will be the primary PK endpoints, and other PK parameters 
will be the secondary PK endpoints. In addition, the difference of log-transformed dose-
normalized baseline-adjusted AUClast and Cmax will be examined between the Japanese cohort 
estimated at the 50ug dose and the Non-Japanese cohort estimated at 100ug dose, as well as 
between the Japanese cohort estimated at the 25ug dose and the Non-Japanese cohort estimated 
at 100ug dose using an analysis of variance model. The geometric mean ratio and its 90% CI will 
be provided from the model.
9.8.2
Pharmacodynamic Analysis
All the PD analyses will be performed using the PD set.
Pharmacodynamic parameters will be computed from individual post dose values of serum 
calcium (uncorrected and corrected for serum albumin levels and both unadjusted and baseline-
adjusted) and phosphate using non-compartmental methods. Pharmacodynamic parameters will 
be estimated based on both original and baseline-adjusted values of serum calcium and 
phosphate. The calcium-phosphate product will be computed. Baseline is defined as the pre-dose 

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value on Day 1 for all subjects and, additionally, also on Day 4 and Day 7 for the subjects of 
Japanese descent. All calculations will be based on actual sampling times. Pharmacodynamic 
parameters will be estimated based on non-compartmental analyses and will include, but not be 
limited to, the following:

AUClast: Area under the curve from the time of dosing to the last measurable concentration

tmax: Time of maximum observed concentration sampled during a dosing interval

Emax: Maximum effect

TEmax: Time to maximum effect
9.8.3
Statistical Analysis of Pharmacodynamic Values
Individual values (original and baseline-adjusted) and PD parameters (original and baseline-
adjusted) of serum total calcium, albumin-corrected calcium, phosphate and the calcium-
phosphate (albumin-corrected calcium) product will be summarized with descriptive statistics 
(number, arithmetic mean, SD, CV%, median, minimum, maximum, geometric mean, and 
geometric CV%). Figures of individual and mean (±SD) concentration-time profiles of the 
original and baseline-adjusted PD markers, serum calcium (total and corrected for serum 
albumin) and phosphate, will be generated. Mean plots will be overlaid for the Japanese cohort 
and the Non-Japanese cohort. Box-Whisker plots for selected PD parameters will be prepared 
with the Japanese cohort and Non-Japanese cohort side by side.
9.9
Safety Analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of treatment-emergent adverse events will be 
calculated overall, by system organ class, by preferred term, and by treatment group. 
Treatment-emergent adverse events will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
9.9.1
Safety Endpoint(s)
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit as indicated below:

Number, severity, seriousness and causality of treatment-emergent adverse events

Anti-PTH antibodies

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and 
urinalysis) from baseline to post baseline time points
9.9.2
Statistical Methodology for Safety Endpoint(s)
Safety data, including TEAEs, laboratory tests, anti-PTH antibodies, and vital signs, will be 
summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of 

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qualitative safety data. Direct safety comparisons between the two ethnic groups will be 
presented from the rhPTH(1-84) 100µg dosing data. All other safety data from the 25µg and 
50µg in the subjects of Japanese descent will be summarized and listed. Treatment-emergent 
AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens, or intensity increases 
after receiving the study medication of this study to the follow-up visit.
9.10
Other Analyses
No other analyses are planned in this study.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(EU) Directive 2001/20/EC and its updates, and local ethical and legal requirements.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
inter/national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the investigator as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.

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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. 
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
Agreement with the final clinical study report is documented by the signed and dated signature 
of the principal investigator, in compliance with Directive 2001/83/EC as amended by Directive 
2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.

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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the coordinating principal investigator, according to national provisions, and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the sponsor or sponsor representative and should be handled in 
accordance with instructions from the sponsor or sponsor representative.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to the 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). 

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These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration (FDA), European Medicines Agency (EMA), United Kingdom (UK) 
Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 

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investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the clinical trial agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or investigator, or, for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market rhPTH(1-84); national or local regulatory authorities; and the IRB/EC which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 

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and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee. The purpose of 
the publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.

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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.

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11.
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Behaghel, A & Donal, E 2011. Hypocalcaemia-induced transient dilated cardiomyopathy in 
elderly: a case report. Eur J Echocardiogr, 12, E38.
Bilezikian, JP, Khan, A, Potts, JT, Jr., Brandi, ML, Clarke, BL, Shoback, D, Juppner, H, 
D'amour, P, Fox, J, Rejnmark, L, Mosekilde, L, Rubin, MR, Dempster, D, Gafni, R, Collins, 
MT, Sliney, J & Sanders, J 2011. Hypoparathyroidism in the adult: epidemiology, diagnosis, 
pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone 
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Blaine, J, Chonchol, M & Levi, M 2015. Renal control of calcium, phosphate, and magnesium 
homeostasis. Clin J Am Soc Nephrol, 10, 1257-72.
Haussler, MR & Cordy, PE 1982. Metabolites and analogues of vitamin D. Which for what? 
Jama, 247, 841-4.
Page, C & Strunski, V 2007. Parathyroid risk in total thyroidectomy for bilateral, benign, 
multinodular goitre: report of 351 surgical cases. J Laryngol Otol, 121, 237-41.
Shoback, D 2008. Clinical practice. Hypoparathyroidism. N Engl J Med, 359, 391-403.
Thomusch, O, Machens, A, Sekulla, C, Ukkat, J, Brauckhoff, M & Dralle, H 2003. The impact 
of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a 
multivariate analysis of 5846 consecutive patients. Surgery, 133, 180-5.
Velasco, PJ, Manshadi, M, Breen, K & Lippmann, S 1999. Psychiatric aspects of parathyroid 
disease. Psychosomatics, 40, 486-90.
Zarnegar, R, Brunaud, L & Clark, OH 2003. Prevention, evaluation, and management of 
complications following thyroidectomy for thyroid carcinoma. Endocrinol Metab Clin North Am,
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Natpara
21 Mar 2017
12.
APPENDICES