Conditions: Hypoparathyroidism
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The purpose of this study is to compare how rhPTH(1-84) affects the body between healthy adults of Japanese descent and matched, healthy Caucasian adults.

Detailed description:

Arms:
arm 1: Subjects will receive single dose of 100 microgram (mcg) rhPTH(1-84) subcutaneous (SC) injection on Day 1. arm 2: Subjects will receive single dose of 100 mcg rhPTH(1-84) SC injection on Day 1; On days 4 and 7, either 25 mcg or 50 mcg SC injection. A washout period of 73 hours will be maintained between each single doses (100 mcg, 50 mcg and 25 mcg) in a cross-over fashion.

Interventions: intervention 1: rhPTH(1-84) intervention 2: rhPTH(1-84) intervention 3: rhPTH(1-84)
Intervention descriptions: intervention 1: 25 mcg rhPTH(1-84) SC injection intervention 2: 50 mcg rhPTH(1-84) SC injection intervention 3: 100 mcg rhPTH(1-84) SC injection

Protocol document:
SAP_002.pdf: 
Protocol SHP634-102 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP634-102 
Protocol Title: 
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 
Drug: 
rhPTH(1-84) 
Sponsor:  
Shire 
300 Shire Way 
Lexington, MA 02421 USA  
Version No. and Date 
Version 1.0, Date 12 June 2017 
 
Version No: Document History 
Description of Update 
Author(s) 
Effective 
Date 
0.1 
First Draft 
 
28April2017 
0.2 
Second Draft 
 
22May2017 
1.0 
Final  
12June2017 
 
Page No.: 1 of 58 
PPD
PPD
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Protocol SHP634-102 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF FIGURES .................................................................................................................... 5 
LIST OF TABLES ...................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................... 7 
1. 
INTRODUCTION .......................................................................................................... 8 
2. 
STUDY DESIGN ........................................................................................................... 9 
2.1 
General Study Design ..................................................................................................... 9 
2.2 
Randomization .............................................................................................................. 12 
2.3 
Blinding ........................................................................................................................ 12 
2.4 
Schedule of Assessments .............................................................................................. 12 
2.5 
Determination of Sample Size ...................................................................................... 18 
2.6 
Multiplicity Adjustments for Type I Error Control ...................................................... 18 
3. 
OBJECTIVES .............................................................................................................. 19 
3.1 
Primary Objective ......................................................................................................... 19 
3.2 
Secondary Objectives ................................................................................................... 19 
3.3 
Exploratory Objective .................................................................................................. 19 
4. 
SUBJECT POPULATION SETS ................................................................................. 20 
4.1 
Enrolled Set .................................................................................................................. 20 
4.2 
Safety Analysis Set ....................................................................................................... 20 
4.3 
Pharmacokinetic Set ..................................................................................................... 20 
4.4 
Pharmacodynamic Set .................................................................................................. 20 
5. 
SUBJECT DISPOSITION ........................................................................................... 21 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 22 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 23 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 24 
8.1 
Exposure to Investigational product ............................................................................. 24 
8.2 
Measurement of Treatment Compliance ...................................................................... 24 
9. 
PRIOR AND CONCOMITANT MEDICATION ........................................................ 25 
10. 
EFFICACY ANALYSES ............................................................................................. 26 
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Protocol SHP634-102 
 
 
 
10.1 
Primary Efficacy Endpoint(s) and Analysis ................................................................. 26 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis ..................................................... 26 
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis ................................................... 26 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses .......................................................... 26 
11. 
SAFETY ANALYSES ................................................................................................. 27 
11.1 
Adverse Events ............................................................................................................. 27 
11.2 
Clinical Laboratory Variables ...................................................................................... 28 
11.3 
Vital Signs .................................................................................................................... 31 
11.4 
Electrocardiogram (ECG) ............................................................................................. 31 
11.5 
Other Safety Variables ................................................................................................. 32 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ................................................................................................................. 33 
12.1 
Pharmacokinetics Population and Pharmacodynamic Population ............................... 33 
12.2 
Handling BLQ, Zero Values, Missing Values ............................................................. 33 
12.3 
Pharmacokinetic Methods ............................................................................................ 33 
12.3.1 Original PTH Concentration Data ......................................................................... 34 
12.3.2 Baseline-adjusted PTH Concentration Data .......................................................... 34 
12.3.3 Pharmacokinetic Parameters .................................................................................. 34 
12.3.4 Statistical Analysis of Pharmacokinetic Parameters .............................................. 36 
12.4 
Pharmacodynamic Methods ......................................................................................... 37 
12.4.1 Original Pharmacodynamic Data ........................................................................... 37 
12.4.2 Baseline-adjusted Pharmacodynamic Data ............................................................ 38 
12.4.3 Serum Pharmacodynamic Parameters ................................................................... 38 
12.4.4 Statistical Analysis of Pharmacodynamic Parameters ........................................... 39 
13. 
OTHER ANALYSES ................................................................................................... 40 
13.1 
Quality of Life Analyses .............................................................................................. 40 
13.2 
Health Economics and Outcomes Research Analyses ................................................. 40 
14. 
INTERIM ANALYSIS ................................................................................................. 41 
15. 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 42 
16. 
COMPUTER METHODS ............................................................................................ 43 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 44 
18. 
DATA HANDLING CONVENTIONS ....................................................................... 45 
18.1 
General Data Reporting Conventions ........................................................................... 45 
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Protocol SHP634-102 
 
 
 
18.2 
Derived Efficacy Endpoints ......................................................................................... 45 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 45 
18.4 
Missing Date of Investigational Product ...................................................................... 45 
18.5 
Missing Date Information for Prior or Concomitant Medications ............................... 46 
18.5.1 Incomplete Start Date and Time ............................................................................ 46 
18.5.2 Incomplete Stop Date and Time ............................................................................ 47 
18.6 
Missing Date and Time Information for Adverse Events ............................................ 47 
18.6.1 Incomplete Start Date and Time ............................................................................ 48 
18.6.2 Incomplete Stop Date and Time ............................................................................ 48 
18.7 
Missing Severity Assessment for Adverse Events ....................................................... 48 
18.8 
Missing Relationship to Investigation Product for Adverse Events ............................. 48 
18.9 
Character Values of Clinical Laboratory Variables ..................................................... 48 
19. 
REFERENCES ............................................................................................................. 49 
20. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .................... 50 
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Protocol SHP634-102 
 
 
 
LIST OF FIGURES 
Figure 1      Study Design Flow Chart ...................................................................................... 11 
 
 
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Protocol SHP634-102 
 
 
 
LIST OF TABLES 
Table 1  
Schedule of Assessments ....................................................................................... 13 
Table 2 
Detailed Schedule of Assessments (non-Hispanic, Caucasian Subjects) .............. 16 
Table 3 
Detailed Schedule of Assessments (Subjects of Japanese Descent) ...................... 17 
Table 4      Criteria for Potentially Clinically Important Laboratory Tests .............................. 29 
Table 5      Criteria for Potentially Clinically Significant Vital Signs ...................................... 31 
Table 6      Criteria for Potentially Clinically Important ECG Values ..................................... 32 
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Protocol SHP634-102 
 
 
 
ABBREVIATIONS 
 
AE 
adverse event 
ANOVA 
analysis of variance 
ATC 
anatomical therapeutic class 
BLQ 
below limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CRC 
clinical research center 
CV 
coefficient of variation 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCI 
potentially clinically important 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PTH 
parathyroid hormone 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 
rhPTH(1-84) 
recombinant human parathyroid hormone (1-84 amino acids) 
RR 
a time interval on an ECG trace starting at the peak of one R wave to the 
peak of the next R wave 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
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Protocol SHP634-102 
 
 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of pharmacokinetic, pharmacodynamics  and safety data as described in 
the study protocol dated 29 Jan 2017 incorporating the most recent amendment 1 (dated 21 
Mar 2017). Specifications for tables, figures, and listings are contained in a separate 
document. Statistical analyses for pharmacokinetic/pharmacodynamic data are included in the 
SAP, as appropriate.    
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Protocol SHP634-102 
 
 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
This study 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%). 
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 between doses 
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 all subjects. 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 is 62 days for a non-Hispanic, Caucasian 
subject 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. 
 
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Protocol SHP634-102 
 
 
 
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 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.
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Protocol SHP634-102 
 
 
 
 
2.2 
Randomization 
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. 
The actual dose (either 25µg or 50µg) given to Group B (subjects of Japanese descent) on 
Day 4 and Day 7 is determined by a randomization schedule.  The randomization schedule 
was produced by Shire Biostatistics. Japanese subjects will be randomized to receive either 
25µg on Day 4 and 50µg on Day 7, or 50µg on Day 4 and 25µg on Day 7 in a 1:1 ratio. 
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. 
2.3 
Blinding 
This is an open-label study, and, as such, there are no special handling considerations for 
blinded data.  
2.4 
Schedule of Assessments 
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Protocol SHP634-102 
 
 
 
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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Protocol SHP634-102 
 
 
 
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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Protocol SHP634-102 
 
 
 
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  
 
 
 
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Protocol SHP634-102 
 
 
 
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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Protocol SHP634-102 
 
 
 
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. Anti-PTH antibody sampling on Day 1 only, not on Day 4 and 7. 
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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Protocol SHP634-102 
 
 
 
2.5 
Determination of Sample Size 
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. 
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%). 
2.6 
Multiplicity Adjustments for Type I Error Control 
Not applicable, as the statistical analyses are for exploratory rather than confirmatory 
purposes. 
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Protocol SHP634-102 
 
 
 
3. 
OBJECTIVES 
3.1 
Primary Objective 
• To compare the PK profile of recombinant human parathyroid hormone (rhPTH[1-
84]), administered as a single SC dose of 100μg, between healthy adult volunteer 
subjects of Japanese descent and matched, non-Hispanic, healthy, adult Caucasian 
subjects. 
 
3.2 
Secondary Objectives 
• To assess the dose proportionality of the selected PK parameters 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 concentration levels vs 
time) 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 concentration levels vs 
time) 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. 
 
3.3 
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. 
 
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Protocol SHP634-102 
 
 
 
4. 
SUBJECT POPULATION SETS 
4.1 
Enrolled Set 
The Enrolled Set consists of all subjects who sign the informed consent form and meet the 
study inclusion/exclusion criteria. 
4.2 
Safety Analysis Set  
The Safety Set consists of all subjects who have received at least 1 dose of investigational 
product. 
4.3 
Pharmacokinetic Set  
The Pharmacokinetic Set consists of all subjects who have received at least 1 dose of 
investigational product and have at least 1 evaluable post dose PK concentration value. 
4.4 
Pharmacodynamic Set  
The Pharmacodynamic Set consists of all subjects who have received at least 1 dose of 
investigational product and have at least 1 evaluable post dose PD concentration value. 
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Protocol SHP634-102 
 
 
 
5. 
SUBJECT DISPOSITION 
Final subject numbers will be presented for subjects that had been re-screened. 
The number of subjects included in each subject set (i.e., Enrolled, Safety, Pharmacokinetic, 
and Pharmacodynamic) will be summarized by ethnic group (Japanese or Non-Hispanic 
Caucasian) and treatment sequence. Details of randomization assignments for randomized 
subjects will be listed. 
Additionally, the number and percentage of subjects who either completed or prematurely 
discontinued during the study will be presented. Reasons for premature discontinuation from 
the study as recorded on the termination page of the eCRF will be summarized (number and 
percentage) by ethnic group and treatment sequence for the Enrolled Set. Details of reasons 
for discontinuation for all subjects who prematurely discontinued during the study will be 
listed. 
For Japanese subjects, the number and percentage of subjects in each subject set, and who 
either completed each treatment period or prematurely discontinued during each treatment 
period including reasons will also be summarized by rhPTH(1-84) dose. Discontinuations will 
be attributed to the last dose that the subject received prior to discontinuation. 
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Protocol SHP634-102 
 
 
 
6. 
PROTOCOL DEVIATIONS 
All protocol deviation data will be listed for the Enrolled Set. 
 
Page No.: 22 of 58 


Protocol SHP634-102 
 
 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented by 
ethnic group and treatment sequence, for the Safety Analysis Set. For Japanese subjects, 
demographic and baseline characteristics will also be summarized by rhPTH(1-84) dose 
for the Safety Analysis Set. 
The following demographic characteristics will be summarized in the following order in 
the tables: age, sex, ethnicity and race. Other baseline characteristics including weight, 
height and BMI will be summarized.   
BMI will be calculated locally at screening for eligibility using the formula below: 
 
 
 
BMI = 
 
A listing will be created to show all the demographic and baseline characteristics for the 
Safety Analysis Set.  
Medical history will be listed for the Safety Analysis Set. 
 
2
[m])
 
(height
[kg]
 
weight
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Protocol SHP634-102 
 
 
 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
A summary table showing number of subjects exposed to each dose will be produced by visit 
and ethnic group for the Safety Analysis Set.  
A listing will be created by subject number and visit giving the date and time of dose 
administration, for the Safety Analysis Set. 
8.2 
Measurement of Treatment Compliance 
Since this is a Phase 1 study in which the study medication is administered at the Clinical 
Research Center (CRC), no summary of treatment compliance will be produced.  
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Protocol SHP634-102 
 
 
 
9. 
PRIOR AND CONCOMITANT MEDICATION  
Version WHODRUG 2017MAR01 DDE (B2 format) will be used to classify prior and 
concomitant medications by preferred term. Medications will also be coded by the 
Anatomical Therapeutic Chemical (ATC) classification system. 
 
Medications starting within 30 days before the first dose of investigational product and up to 
the end of the follow-up period will be collected on the CRF.  
 
Prior medication is defined as any medication with the start date prior to the date of the first 
dose of investigational product.  Concomitant medication is defined as any medication with a 
start date prior to the date of the first dose of investigational product and continuing after the 
first dose of investigational product or with a start date after the date of the first dose of 
investigational product. 
 
Concomitant medication usage will be summarized by the number and proportion of subjects 
receiving each medication by preferred term, by ethnic group and rhPTH(1-84) dose for the 
Safety Analysis Set.  Medications can be counted both as prior and concomitant medication. 
Multiple medication usage by a subject in the same category will be counted only once. 
 
Concomitant medications will be assigned to the dose(s) with which they are concomitant.  A 
medication is concomitant with a dose of rhPTH(1-84) if the subject received that medication 
any time between the time when that dose of rhPTH(1-84) was received and when the next 
dose of rhPTH(1-84) was received, or in the case of the last dose, until the end of the follow-
up period. Therefore, a medication may be concomitant with more than one dose. 
 
All prior and concomitant medication will be listed. 
 
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Protocol SHP634-102 
 
 
 
10. 
EFFICACY ANALYSES 
No efficacy analysis will be performed for this study. 
10.1 
Primary Efficacy Endpoint(s) and Analysis  
Not applicable. 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis  
Not applicable. 
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis 
Not applicable. 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses  
Not applicable. 
 
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Protocol SHP634-102 
 
 
 
11. 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety Analysis Set. Safety variables include 
AEs and TEAEs, clinical laboratory variables, vital signs, and ECG variables. For clinical 
laboratory and vital sign variables, the last value collected before the dose administration will 
be used as baseline for all analyses of that safety variable in the respective dose interval. Thus 
there will be a different baseline for each dose for the Japanese subjects. 
Follow-up visits will be summarized under the 100µg dose, regardless of which sequence the 
subject was randomized to, or which doses they had received. 
11.1 
Adverse Events  
Adverse events will be coded using Version 20.0 or newer of MedDRA. 
An AE (classified by preferred term) that occurs during the study will be considered a TEAE 
if it has a start date/time on or after the first dose of investigational product or if it has a start 
date before the date of the first dose of investigational product, but increases in severity or 
intensity on or after the date/time of the first dose of investigational product. If more than 1 
AE with the same preferred term is reported before the date of the first dose of investigational 
product, then the AE with the greatest severity will be used as the benchmark for comparison 
to the AEs occurring during the study under the preferred term. An AE that occurs after 
follow-up visit will not be counted as a TEAE. However, any SAE that occurs after the 
follow-up visit and is considered related should be counted as a TEAE.         
Adverse events will be allocated to a dose by assigning them to the last dose taken at the time 
of the onset of the AE. 
An overall summary of the number of subjects with TEAEs will be presented by ethnic group 
and dose at onset, including the number and percentage of subjects with any TEAEs, serious 
TEAEs, TEAEs related to investigational product, TEAEs leading to discontinuation of 
investigational product, severe TEAEs, and deaths. 
 
The number and percentage of subjects reporting TEAEs for each ethnic group and dose at 
onset will be tabulated by system organ class (SOC) and preferred term; and by SOC, 
preferred term, and maximum severity.  TEAEs considered related to investigational product 
will also be summarized by SOC and preferred term. If more than 1 AE occurs with the same 
preferred term for the same subject, then the subject will be counted only once for that 
preferred term using the most severe occurrence for the summarization by severity. Serious 
TEAEs and TEAEs leading to discontinuation of investigational product will be summarized 
by SOC, preferred term, ethnic group and dose at onset. 
Listings will be produced for all AEs (including pre-treatment AEs), SAEs, AEs considered 
related to investigational product, AEs leading to discontinuation of investigational product, 
and deaths. 
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Protocol SHP634-102 
 
 
 
11.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point as well as shift tables from baseline to each visit for quantitative 
variables will be presented by ethnic group and dose for the following clinical laboratory 
variables.  
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white blood 
cell count – total and differential (WBC), total neutrophils (absolute), 
eosinophils 
(absolute), 
monocytes 
(absolute), 
basophils(absolute),  
lymphocytes (absolute). 
Biochemistry 
Sodium, phosphorus, β-hCGb, potassium, total protein, magnesium, glucose, 
total CO2 (Bicarbonate), PTHc, blood urea nitrogen, albumin, FSHb, 
creatinine, aspartate transaminase (AST), calcium, alanine transaminase 
(ALT), chloride, gamma glutamyl transferase (GGT), thyroid stimulating 
hormone (TSH) a, alkaline phosphatase (ALP), 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. 
 
Urinalysis 
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte esterase, 
specific gravity. 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 4. The number and percentage of subjects with post-
baseline PCI values will be tabulated by ethnic group and dose.  The percentages will be 
calculated relative to the number of subjects with available assessments at that dose level.  
The numerator is the total number of subjects with at least 1 post-baseline PCI value at that 
dose level.  A supportive listing of subjects with post-baseline PCI values will be provided 
including the subject number, ethnic group, dose, baseline, and post-baseline values.   
Listings for serum and urinary clinical laboratory results will be produced for all patients in 
the Safety Analysis Set. Clinically potential important test results will be listed as well. 
 
 
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Protocol SHP634-102 
 
 
 
Table 4      Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Classification (on 
CDRs) 
Criteria 
 
Biochemistry 
Sodium 
HIGH 
> 5 mmol/L (5 mEq/L) above ULN  
 
LOW 
> 5 mmol/L (5 mEq/L) below LLN 
Potassium 
HIGH + INCREASE 
Above ULN  and increase of > 0.5 mmol/L (0.5 mEq/L) from 
baseline value  
 
LOW + DECREASE 
Below LLN  and decrease of > 0.5 mmol/L (0.5 mEq/L) from 
baseline value  
Creatinine 
HIGH + INCREASE 
> 150µmol/L and increase > 30% from baseline value 
BUN 
HIGH 
> 1.5 x ULN 
Glucose 
(fasting) 
HIGH 
≥ 6.7 mmol/L 
 
LOW 
≤ 4.2 mmol/L 
Calcium 
HIGH and INCREASE 
Above ULN  and Increase of ≥ 0.25 mmol/L (1.0 mg/dL) from 
baseline value  
LOW and DECREASE 
Below LLN  and Decrease of ≥ 0.25 mmol/L (1.0 mg/dL) from 
baseline value  
Magnesium 
HIGH and INCREASE 
Above ULN and  Increase of ≥ 0.21 mmol/L (0.5 mg/dL) from 
baseline value  
 
LOW and DECREASE 
Below LLN  and Decrease of ≥ 0.21 mmol/L (0.5 mg/dL) from 
baseline value  
Phosphorus 
HIGH 
> 0.162 mmol/L (0.5 mg/dL) above ULN 
 
LOW 
> 0.162 mmol/L (0.5 mg/dL) below LLN 
 
Total protein 
HIGH and INCREASE 
Above ULN  and Increase of ≥ 20 g/L (2.0 g/dL) from baseline 
value  
 
LOW and DECREASE 
Below LLN  and Decrease of ≥ 20 g/L (2.0 g/dL) from baseline 
value  
Albumin 
HIGH and INCREASE 
Above ULN  and  Increase of ≥ 10 g/L (1.0 g/dL) from baseline 
value  
LOW and DECREASE 
Below LLN  and Decrease of ≥ 10 g/L (1.0 g/dL) from baseline 
value  
 Uric acid 
(with normal 
diet) 
HIGH and INCREASE 
Above ULN  and Increase of > 0.119 mmol/L (2.0 mg/dL) from 
baseline value  
 
LOW and DECREASE 
Above LLN  and Decrease of > 0.119 mmol/L (2.0 mg/dL) from 
baseline value  
ALT 
HIGH 
> 2 x ULN   
AST 
HIGH 
> 2 x ULN   
ALP 
HIGH 
> 1.5 x ULN   
GGT 
HIGH 
> 1.5 x ULN    
Total 
bilirubin 
HIGH 
> 1.5 x ULN  
 T4 
HIGH 
> 140.28 nmol/L  
LOW 
< 57.92 nmol/L  
 T3 
LOW 
< 0.922 nmol/L  
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Protocol SHP634-102 
 
 
 
Table 4      Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Classification (on 
CDRs) 
Criteria 
 
Biochemistry 
    
HIGH 
> 2.765 nmol/L 
 TSH 
HIGH 
>5.0 µU/L 
LOW 
0.5 µU/L 
Hematology 
 
 
RBC count 
 
HIGH 
>7.5 x1012/L 
LOW 
<3 x1012/L 
Hematocrit 
 
LOW and DECREASE 
≤0.6 x LLN and Decrease of ≥ 0.06  L/L (6.0%) from baseline 
value   
 
HIGH 
>1.3 x ULN 
Hemoglobin 
 
LOW and DECREASE 
< 100g/L (10g/dL) and Decrease of ≥ 20g/L (2.0 g/dL) from 
baseline value  
 
HIGH 
>200 g/L (20g/dL) 
WBC count 
 
HIGH 
>2xULN  OR >16.0 x 109/L   (16 x 103/µL) 
 
LOW 
< 0.5xLLN  OR < 3.0 x 109/L   (3 x 103/µL) 
Neutrophils 
LOW 
< 1.5 x 109/L   (1.5 x 103 µL) OR < 40% 
 
HIGH 
> 6.2 x 109/L   (6.2 x 103 µL) OR > 70 % 
   
Lymphocytes 
HIGH 
> 4.0 x 109/L   (1.5 x 103 µL) OR > 44 % 
 
LOW 
< 0.8 x 109/L   (0.8 x 103 µL) OR < 22 % 
Monocytes 
HIGH 
>11 %  
Eosinophils 
    
HIGH 
> 0.5 x 109/L   (> 500/µL) and > 10.0% 
LOW 
NA 
Basophils 
HIGH 
2% 
LOW 
NA 
Platelet count 
(thrombocyte
s) 
HIGH 
>1.5 x ULN OR > 500 x 109/L   (100 x 103/µL) 
LOW 
0.6 x LLN OR < 100 x 109/L   (100 x 103/µL) 
Urinalysis 
Glucose 
HIGH 
≥ 1+ 
Blood 
HIGH 
≥ 2+ 
Bilirubin  
 
Normally not found 
Protein 
HIGH 
≥ 2+ 
Nitrite  
 
Normally not found 
Ketones 
HIGH 
≥ 2+ 
Leukocyte 
Esterase 
 
Negative 
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Protocol SHP634-102 
 
 
 
 
11.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, and body 
temperature) and their changes from baseline at each post-baseline assessment and at the end 
of study will be presented by ethnic group and dose. All vital signs will be listed for each 
subject in the Safety Analysis Set. 
Vital sign values will be considered PCI if they meet either the low or high PCI criteria listed 
in Table 5.  The number and percentage of subjects with PCI values at each time point will be 
tabulated by ethnic group and dose.  The percentages will be calculated relative to the number 
of subjects with baseline and at least 1 post-baseline assessment at that dose level and time 
point.  The numerator is the total number of subjects with at least 1 PCI post-baseline vital 
sign value at that dose level and time point.  A supportive listing of subjects with post-
baseline PCI values will be provided including the subject number, ethnic group, dose, 
baseline, and post-baseline PCI values.   
Table 5      Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Classification (on CDRs) 
Criteria 
 
Systolic blood pressure 
(mm Hg) 
HIGH and INCREASE 
≥ 140 and increase of ≥ 20 from baseline value 
LOW and DECREASE 
≤ 90 and decrease of ≥ 20 from baseline value 
Diastolic blood 
pressure (mm Hg) 
HIGH and INCREASE 
≥ 90 and increase of ≥ 15 from baseline value 
LOW and DECREASE 
≤ 50 and decrease of ≥ 15 from baseline value 
Pulse rate (bpm) 
HIGH and INCREASE 
≥ 100 and increase of > 15 from baseline value 
LOW and DECREASE 
≤ 45 and decrease of > 15 from baseline value 
Temperature 
HIGH 
> 38.3°C or > 100.9°F 
LOW 
< 35°C or < 95°F 
 
 
11.4 
Electrocardiogram (ECG) 
At each timepoint, ECGs are collected in triplicate (any readings after the first three valid 
readings at a particular timepoint will be considered unscheduled).  For numeric ECG 
variables, the mean of the valid values at each timepoint will be taken.  For qualitative ECG 
results, the worst case will be used. The averages of the ECG triplicate collected predose on 
Day 1 and predose on Days 4 and 7 (for subjects of Japanese descent) will serve as the 
subject’s baseline ECG for the dose received on that day.  
 
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Protocol SHP634-102 
 
 
 
Descriptive statistics for ECG variables (heart rate, PR interval, RR, QRS interval, QT 
interval, and QTc interval) and their changes from baseline at each assessment time point will 
be presented by ethnic group and dose.  QTc interval will be calculated using both Bazett 
(QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not 
available, it will be replaced with 60/hr in the correction formula. ECG interpretation will be 
summarized by visit.  A shift table from baseline to each visit for qualitative ECG results will be 
presented.  
Electrocardiogram variables will be considered PCI if the average value for that subject at that 
time point meets or exceeds the upper limit values listed in Table 6.  The number and 
percentage of subjects with PCI values at each time point will be tabulated by ethnic group 
and dose.  The percentages will be calculated relative to the number of subjects with available 
baseline and at least 1 post-baseline assessment at that dose level and visit.  The numerator is 
the total number of subjects with at least 1 PCI post-baseline ECG value at that dose level and 
visit.  A listing of all subjects with post-baseline PCI values will be provided including the 
subject number, ethnic group, dose, baseline, and post-baseline PCI values. 
Table 6      Criteria for Potentially Clinically Important ECG Values 
Parameter 
Classification (on CDRs) 
Criteria 
Overall Evaluation 
ABNORMAL 
Overall Evaluation is ABNORMAL 
Heart rate (bpm) 
HIGH and INCREASE 
≥ 100 and increase of > 15 from baseline value 
LOW and DECREASE 
≤ 45 and decrease of > 15 from baseline value 
PR interval (msec) 
HIGH and INCREASE 
≥ 200 and increase of ≥ 20  from baseline value 
QRS interval (msec) 
HIGH 
≥ 120 
QTC interval (men) 
(msec) 
HIGH 
> 430 and increase from baseline value > 30 
QTC interval (women) 
(msec) 
HIGH 
> 450 and increase from baseline value > 30 
 
11.5 
Other Safety Variables 
Anti-PTH antibodies will be assessed at Day 1 (pre-dose) and at Follow-up. The results at 
each timepoint will be summarized by ethnic group, and these data will be listed. 
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Protocol SHP634-102 
 
 
 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
12.1 
Pharmacokinetics Population and Pharmacodynamic Population 
The Pharmacokinetic Set consists of all subjects who have received at least 1 dose of 
investigational product and have at least 1 evaluable post dose PK concentration value. 
The Pharmacodynamic Set consists of all subjects who have received at least 1 dose of 
investigational product and have at least 1 evaluable post dose PD concentration value. 
12.2 
Handling BLQ, Zero Values, Missing Values 
The following procedures will be used for original plasma PTH concentrations and serum PD 
data below the lower limit of quantification (LLOQ) and baseline-adjusted PTH and PD 
concentration data: 
 
• Samples that are BLQ are reported as <LLOQ on the data listings, where LLOQ is 
replaced by the actual value for LLOQ for specific PK or PD assay. 
 
• Samples that are BLQ are treated as zero in the calculation of summary statistics (e.g. 
mean, SD, etc.) for the plasma concentrations at individual time points. 
 
• Mean concentrations are reported as zero if all values are BLQ or zero, and no other 
descriptive statistics are reported. If the calculated mean (± SD) concentration is less 
than the LLOQ, the value will be reported as calculated. The mean values derived 
using these conventions will be used to create the mean plasma concentration versus 
time plots. 
 
• For calculation of area under the plasma concentration curve (AUC), BLQ values are 
set equal to zero in the dataset loaded into WinNonlin for pharmacokinetic analysis. 
WinNonlin uses the zero values that occur before the first time point with a 
concentration greater than LLOQ. Values that are BQL after the first measurable 
concentration are set to “missing” in the dataset loaded into WinNonlin. 
 
• Missing values will not be imputed.   
12.3 
Pharmacokinetic Methods 
All summaries and analyses of the pharmacokinetic data will be based on the Pharmacokinetic 
Set. After database lock, a visual inspection of concentration-time profiles and 
pharmacokinetic parameters will be performed by PRA to determine dataset integrity and 
potential outliers. Descriptive statistics of pharmacokinetic parameters may be calculated with 
and without subjects with potential outlier data. Subjects with potential outlier data will be 
reviewed by Shire for inclusion/exclusion from the descriptive statistics on a case-by-case 
basis.  
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Protocol SHP634-102 
 
 
 
12.3.1 
Original PTH Concentration Data 
For non-Hispanic, Caucasian subjects on Day 1 and for subjects of Japanese descent on Day1, 
4 and 7, samples for pharmacokinetic analysis are taken at Predose 1 (within 90 ± 30 min 
prior to dose administration), Predose 2 (within 30 min prior to dose administration), and 10, 
20, 30 and 45 minutes, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 hours after administration of 
the investigational product. Plasma concentrations of PTH will be measured using a validated 
analytical method. 
Individual original PTH concentrations will be listed and summarized with descriptive 
statistics by ethnic group, dose and time point, including number, arithmetic mean, standard 
deviation, coefficient of variation [CV%], median, minimum, and maximum. Figures of 
individual original concentration-time profiles and mean (± SD) by ethnic group and dose 
will be generated on linear and semi-log scale. The mean plot will be created by overlaying 
each ethnic group and dose on the same figure. 
12.3.2 
Baseline-adjusted PTH Concentration Data 
Baseline-adjusted PTH concentrations are to be calculated by subtracting baseline 
endogenous PTH from the original PTH concentrations. Such baseline adjustment is subject- 
and dose-specific. For each subject, baseline is defined for each dosing period as follows: the 
baseline for Day 1 dosing is defined as the average predose concentration on Day 1 (average 
of predose 1 and predose 2 PTH concentrations); for subjects of Japanese descent the baseline 
for Day 4 dosing is defined as the average predose concentration on Day 4 (average of 
predose 1 and predose 2 PTH concentrations); the baseline for Day 7 dosing is defined as the 
average predose concentration on Day 7 (average of predose 1 and predose 2 PTH 
concentrations). If the baseline-adjusted PTH concentration gives a negative value, then the 
baseline-adjusted PTH concentration should be set to zero. In the terminal log-linear phase, if 
two consecutive baseline-adjusted PTH concentrations give negative values, then all the 
subsequent values will be set to zero. 
Individual baseline-adjusted PTH concentrations will be listed and summarized by ethnic 
group and dose as in section 12.3.1. Individual plots and mean plots will be generated in the 
same way as described in section 12.3.1 but using the baseline-adjusted PTH concentrations. 
If the baseline-adjusted PTH concentration is zero, it will be presented as missing on the 
semi-log scale. 
12.3.3 
Pharmacokinetic Parameters 
The pharmacokinetic analysis will be conducted by using WinNonlin Phoenix version 6.3 or 
higher (Pharsight Corporation, Mountain View, California, USA). Pharmacokinetic 
parameters will be determined from the plasma PTH concentration-time data by non-
compartmental analysis. Both original and baseline-adjusted PTH concentrations will be used 
to compute all the PK parameters respectively.  
 
The pharmacokinetic parameters will include, but may not be limited to: 
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Protocol SHP634-102 
 
 
 
• 
Cmax : Maximum observed concentration, to be reported in the unit of pg/mL (both 
original and baseline-adjusted PTH) 
• 
tmax : Time of maximum observed concentration sampled during a dosing interval, to 
be reported in the unit of hour (both original and baseline-adjusted PTH) 
• 
AUClast : Area under the curve from the time of dosing to the last measurable 
concentration. Calculated using the linear up/log down method, to be reported in the 
unit of pg.hr/mL (both original and baseline-adjusted PTH) 
• 
AUC0-inf : Area under the curve extrapolated to infinity calculated as AUClast + 
Clast/λz. Calculated using the linear up/log down method, to be reported in the unit of 
pg.hr/mL (for baseline-adjusted PTH only) 
• 
%AUC extrapolated:  % of AUC extrapolated from the last measurable concentration 
to infinity over AUC(0-inf) (for baseline-adjusted PTH only) 
• 
λz: Elimination rate constant associated with the terminal (log-linear) portion of the 
curve. The log-linear portion of the curve must contain at least three points after Tmax 
and have an r2 value > 0.8 (for baseline-adjusted PTH only) 
• 
t½: Terminal half-life, calculated as 0.693/ λz (for baseline-adjusted PTH only) 
• 
CL/F: Apparent total body clearance, calculated as Dose/AUC0-inf (for baseline-
adjusted PTH only) 
• 
Vdz/F: Apparent volume of distribution, calculated as Dose/AUC0-inf * λz (for baseline-
adjusted PTH only) 
 
All PK parameter calculations will be performed using actual sampling times calculated 
relative to the day of rhPTH(1-84) administration. The PK parameters λz, t1/2, AUC0-inf, CL/F, 
and Vdz/F will not be calculated for subjects with PTH concentration-time profiles (baseline-
adjusted) that do not exhibit a terminal log-linear phase, or if %AUC extrapolated > 20%.  
 
In addition, body-weight adjusted AUClast (calculated as AUClast/body-weight), AUC0-inf 
(calculated as AUC0-inf/body-weight), Cmax (calculated as Cmax/body-weight), CL/F 
(calculated as CL/F/body-weight), and Vdz/F (calculated as Vdz/F/body-weight) will be 
calculated based on baseline-adjusted PTH concentrations.  
 
In addition, dose-normalized AUClast (calculated as AUClast/Dose), AUC0-inf (calculated as 
AUC0-inf/Dose),  and dose-normalized Cmax (calculated as Cmax/Dose)  will be calculated 
based on baseline-adjusted PTH PK parameters. 
 
Baseline-adjusted PK parameters will be the primary PK endpoints, and other PK parameters 
will be the secondary PK endpoints. 
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Protocol SHP634-102 
 
 
 
12.3.4 
Statistical Analysis of Pharmacokinetic Parameters 
12.3.4.1 Descriptive Statistic Analysis of PK Parameters 
All 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, SD, coefficient of variation [CV%], median, minimum, maximum, 
geometric mean, %CV of geometric mean, and 95% confidence interval of the geometric 
means) by ethnic group and dose.. 
 
The geometric mean and individual values of dose-normalized baseline-adjusted PK 
parameters vs dose in Japanese subjects will also be presented in plots. 
 
Box-Whisker plots for selected PK parameters for 100μg dose level will be generated with 
both ethnic groups side by side. These PK parameters are Cmax and AUClast based on original 
concentrations, and baseline-adjusted Cmax, AUClast, AUC0-inf, and body weight adjusted 
baseline-adjusted Cmax, AUClast, and AUC0-inf. 
12.3.4.2 Inferential Analysis of PK Parameters 
Comparison of PK between Ethnic Groups 
 
In order to compare the PK 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(1-84) 100μg dose will be examined between the two ethnic groups using 
Welch’s t-test with Satterthwaite’s approximation to the degrees of freedom. The difference 
between the two means will be back transformed to provide an estimate for the geometric 
mean ratio and its 90% confidence interval (CI). The following PK parameters will be 
evaluated using this test: Cmax and AUClast based on original concentration, baseline-adjusted 
Cmax, AUClast, AUC0-inf.  
 
For Cmax, AUClast (original and baseline-adjusted) and AUC0-inf (baseline-adjusted), Forest 
plots of geometric mean ratios (two-sided 90% CI) between Japanese cohort at 100 μg vs 
Non-Japanese cohort at 100μg will be generated. 
 
In addition, same Welch’s t-test will be applied to compare the PK parameters between 
different doses and ethnic groups. The log-transformed dose-normalized AUClast and Cmax 
will be examined between the Japanese cohort at 50μg dose and the Non-Japanese cohort at 
100μg as well as between the Japanese cohort at 25μg and the Non-Japanese cohort at 100μg. 
The geometric mean ratio estimates and their 90% CI will be provided from the model for 
each comparison.  
 
Evaluation of Dose Proportionality (Exploratory) 
 
Dose proportionality of baseline-adjusted PK parameters, will be examined for the Japanese 
subjects. Dose proportionality will be assessed for baseline-adjusted Cmax, AUClast, and 
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Protocol SHP634-102 
 
 
 
AUC0-inf, 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 ijk) = α + β × ln (Dose in μg) + πj + γi  +  ξk(i)+ εijk  (Patterson and Jones, 2006) 
 
Where α is the intercept, β is the slope, πj and γi identify the period j of sequence i,  ξk(i)  is 
the random-intercept accounting for each subject within sequence as their own control, and 
εijk  denotes within-subject error. Dose proportionality will be assessed by estimating mean 
slope with the corresponding two-sided 90% confidence interval (CI) from the power model. 
The estimate and 90% confidence interval for the slope will be presented. 
 
The example SAS code for the above model could be: 
 
proc mixed method = reml data=ADPP ; 
        class subject sequence period ; 
        model  lnauc = sequence period lndose / s ddfm = kenwardroger cl alpha = .1 ; 
        random intercept/ subject = subject (sequence) ; 
run ; 
 
In addition, a simple regression model will be used to plot the relationship between these 
three above baseline-adjusted PK paramters and dose for Japanese subjects.  
 
ln (Parameter) = intercept + slope × ln (Dose in μg) + residual 
 
Plots of observed geometric mean and observed individual values of baseline-adjusted PK 
parameters Cmax, AUClast and AUC0-inf vs dose in Japanese subjects will be generated. The 
regression line along with the formula and r2 will be presented in the same plot with both axes 
on log scale.  
 
12.4 
Pharmacodynamic Methods  
All summaries and analyses of the PD data will be based on the Pharmacodynamic Set. After 
database lock, a visual inspection of concentration-time profiles and PD parameters will be 
performed by PRA to determine dataset integrity and potential outliers. Descriptive statistics 
of PD parameters may be calculated with and without subjects with potential outlier data. 
Subjects with potential outlier data will be reviewed by Shire for inclusion/exclusion from the 
descriptive statistics on a case-by-case basis.  
12.4.1 
Original Pharmacodynamic Data 
Blood samples for PD analysis will be collected at Predose 2 (within 30 min prior to dose 
administration), 4, 8, 12 and 24 hours after dose administration of rhPTH(1-84) for the 
determination of concentrations of serum calcium (uncorrected [total] and corrected for serum 
albumin levels), phosphate. Serum calcium will be corrected for serum albumin levels using 
the following equation: 
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Protocol SHP634-102 
 
 
 
Corrected calcium (mmol/L) = serum calcium (mmol/L) + 0.02 (40 - serum albumin (g/L)) 
(Parent X, 2009) 
The serum calcium-phosphate product (using albumin-corrected calcium) will also be 
determined. This is calculated as serum calcium concentration (albumin-corrected) x serum 
phosphate concentration. 
Individual original concentrations of serum total calcium, albumin-corrected calcium, 
phosphate and calcium-phosphate product will be listed and summarized with descriptive 
statistics (number, arithmetic mean, SD, CV%, median, minimum, maximum) by ethnic 
group, dose and time point.  
Figures of individual original concentration-time profiles and mean (± SD) will be generated 
on linear scale for serum total calcium, albumin-corrected calcium, phosphate and calcium-
phosphate product by ethnic group and dose. The mean plots will be created for the original 
concentrations of the above four PD markers by overlaying the mean values for each ethnic 
group and dose on the same figure.  
12.4.2 
Baseline-adjusted Pharmacodynamic Data 
Individual serum concentrations of PD markers, calcium (uncorrected and corrected for 
albumin), phosphate and calcium-phosphate product will be baseline-adjusted at each time 
point. Albumin-corrected calcium will be used to calculate the calcium-phosphate product. 
Baseline adjustment is subject- and dose-specific. For each subject, baseline is defined for 
each dosing period as follows: the baseline for Day 1 dosing is defined as the predose 
concentration on Day 1; the baseline for Day 4 dosing is defined as the predose concentration 
on Day 4; the baseline for Day 7 dosing is defined as the predose concentration on Day 7. 
Baseline-adjusted concentrations of PD markers are to be calculated by subtracting the 
appropriate baseline values from the original concentrations at each time point. If the 
baseline-adjusted concentration gives a negative value then the baseline-adjusted 
concentration should be set to zero.  
Individual baseline-adjusted concentrations of serum total calcium, albumin-corrected 
calcium, phosphate and calcium-phosphate product will be listed and summarized with 
descriptive statistics (number, arithmetic mean, SD, CV%, median, minimum, maximum,) by 
ethnic group, dose and time point.  
Figures of individual baseline-adjusted concentration-time profiles and mean (± SD) will be 
generated on linear scale for serum total calcium, albumin-corrected calcium, phosphate and 
calcium-phosphate product by ethnic group and dose. The mean plots will be created for the 
baseline-adjusted concentrations of the above four PD markers by overlaying all ethnic 
groups and doses on the same figure.  
12.4.3 
Serum Pharmacodynamic Parameters 
Pharmacodynamic parameters will be computed from the individual original and baseline-
adjusted concentrations of serum calcium (uncorrected and corrected for serum albumin 
Page No.: 38 of 58 


Protocol SHP634-102 
 
 
 
levels), phosphate and calcium-phosphate product using a non-compartmental approach and 
actual sampling times. Pharmacodynamic parameters will be estimated for each dose.  
The following parameters will be calculated using WinNonlin Phoenix version 6.3 or higher 
(Pharsight Corporation, Mountain View, California, USA): 
• AUClast: the area under the concentration versus time curve, from time of dosing to last 
measurable concentration 
• TEmax: time to maximum effect 
• Emax: maximum effect 
12.4.4 
Statistical Analysis of Pharmacodynamic Parameters 
Pharmacodynamic parameters of serum total calcium, albumin-corrected calcium and 
phosphate and calcium-phosphate product will be listed and summarized with descriptive 
statistics (number, arithmetic mean, SD, CV%, median, minimum, maximum, geometric 
mean, and geometric CV%) by ethnic group, dose and time point. This will be done for both 
original and baseline-adjusted values. 
Box-Whisker plots for AUClast and Emax based on both original and baseline-adjusted 
concentrations will be prepared for the 100μg dose with the Japanese cohort and Non-
Japanese cohort side by side. 
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Protocol SHP634-102 
 
 
 
13. 
OTHER ANALYSES 
 
13.1 
Quality of Life Analyses 
Not applicable. 
13.2 
Health Economics and Outcomes Research Analyses 
Not applicable.  
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Protocol SHP634-102 
 
 
 
14. 
INTERIM ANALYSIS 
No formal interim analysis is planned for this study.  
 
Page No.: 41 of 58 


Protocol SHP634-102 
 
 
 
15. 
DATA MONITORING/REVIEW COMMITTEE 
Not applicable, as no data monitoring review is planned for this study. 
 
 
Page No.: 42 of 58 


Protocol SHP634-102 
 
 
 
16. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment. 
WinNonlin Phoenix version 6.3 or higher (Pharsight Corporation, Mountain View, California, 
USA) will be used for calculating PK and PD parameters. 
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Protocol SHP634-102 
 
 
 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Section 9.8.1.1 (Statistical Analysis of Pharmacokinetic Parameters) of the protocol states 
that: 
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 
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(1-84) 100μg dose will be examined between groups using an analysis of 
variance model. 
However, to take account of the different sequences, the dose proportionality of PK 
parameters will be assessed by the power model with more factors: 
ln (Parameter ijk) = α + β × ln (Dose in μg) + πj + γk + ξk(i)+ εijk  (Patterson and Jones, 2006) 
 
Where α is the intercept, β is the slope, πj and γi identify the period j of sequence i, ξk(i) is the 
random-intercept accounting for each subject within sequence as their own control, and εijk  
denotes within-subject error. Dose proportionality will be assessed by estimating mean slope 
with the corresponding two-sided 90% confidence interval (CI) from the power model. 
 
For the comparison of PKs between subjects of Japanese descent and matched non-Hispanic, 
Caucasian subjects, the differences of log-transformed PK parameters from the rhPTH(1-84) 
100μg dose will be examined between the two ethnic groups using Welch’s t-test with 
Satterthwaite’s approximation to the degrees of freedom, rather than by ANOVA as stated in 
the protocol. The reason for this method of comparison is that the variance in the two ethnic 
groups is not expected to be the same. 
Table 1 Schedule of Assessments from protocol states that randomization takes place on Day 
4 for subjects of Japanese descent. It is changed to be on Day 1 in Table 1 in SAP. 
Table 3 Detailed Schedule of Assessments (Subjects of Japanese Descent) from protocol 
states that anti-PTH antibody sampling occurs at Predose 2 on Day 1, 4 and 7. However, it is 
not consistent with Table 1 in protocol.  Therefore, “Anti-PTH antibody sampling on Day 1 
only, not on Day 4 and 7” is added to the footnote e of Table 3 in SAP. 
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Protocol SHP634-102 
 
 
 
18. 
DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics if not 
otherwise specified:  n, mean, median, standard deviation, minimum, maximum.  Categorical 
and count variables will be summarized by the number of subjects (n) and the percent of 
subjects in each category.  Percentages will be presented to 1 decimal place.  
The rules for the number of decimal places to present data and p-values are listed below:  
1. 
For measures of median and mean, use 1 decimal place beyond those used for the 
measurement. 
2. 
For measures of standard deviation and standard error, use 2 decimal places beyond 
those used for the measurement. 
3. 
For measures of minimum and maximum values, use the same number of decimal 
places as those used for the measurement. 
4. 
>=5 is rounded up away from zero, whereas <5 is rounded down toward zero to account 
for rounding of negative numbers. 
5. 
For p-values use 3 decimal places. 
6. 
Presentation of p-values, display p-values that would round to 0.000 as <0.001. 
7. 
BMI should be rounded to 1 decimal place for reporting. 
18.2 
Derived Efficacy Endpoints  
Not applicable.   
18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the 
results from the final assessment made prior to the start of investigational product will be used 
as baseline.  If post-baseline assessments are repeated, these will be captured as unscheduled 
visits, and the value recorded at the scheduled visit will be used for generating descriptive 
statistics.  However, all post-baseline assessments will be used for PCI value determination 
and all assessments will be presented in the data listings.  
18.4 
Missing Date of Investigational Product  
Since the investigational products will be administered during in-patient confinement at a 
CRC, there should not be any missing dates of investigational product.  
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Protocol SHP634-102 
 
 
 
18.5 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or 
stop date will be imputed.  When the start date and the stop date are both incomplete for a 
subject, impute the start date first.     
18.5.1 
Incomplete Start Date and Time 
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of the first dose 
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day 
• 
If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day.  
Missing/Incomplete Time 
• If the time is missing and the date is complete and is the same as the date of the first dose 
of investigational product, or the date is imputed to be this date, then the time will be set 
to the time of the first dose of investigational product. Otherwise, missing times will be 
imputed as 00:00. 
• If the minutes are given but the hour is not, then the time will be regarded as completely 
missing and handled as above. If the hour is given but the minutes are not, then if the hour 
is the same as the hour of the first dose of investigational product, then the minutes of that 
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Protocol SHP634-102 
 
 
 
dose of investigational product will be assigned to the missing fields. Otherwise 00 will be 
assigned to the missing minutes. 
 
18.5.2 
Incomplete Stop Date and Time 
The following rules will be applied to impute the missing numerical fields.  If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop 
date will be equal to the start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
Missing day only 
• 
If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of investigational product, then the day of the date of the last 
dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational product 
or if both years are the same but the month is before the month of the date of the last 
dose of investigational product, then the last day of the month will be assigned to the 
missing day 
• 
If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
Missing Time 
• If the time is missing it will be imputed as 23:59. 
18.6 
Missing Date and Time Information for Adverse Events  
For AEs, only incomplete (i.e., partially missing) start dates will be imputed.  Incomplete stop 
dates will not be imputed. 
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Protocol SHP634-102 
 
 
 
18.6.1 
Incomplete Start Date and Time 
Follow same rules as in Section 18.5.1. 
18.6.2 
Incomplete Stop Date and Time 
Not applicable. 
18.7 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE 
starting on or after the date of the first dose of investigational product, then a severity of 
“Severe” will be assigned.  The imputed values for severity assessment will be used for 
incidence summaries, while the actual values will be used in data listings. 
18.8 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date 
of the first dose of investigational product, a causality of “Related” will be assigned.  The 
imputed values for relationship to the investigational product will be used for incidence 
summaries, while the actual values will be presented in data listings. 
18.9 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, that a character string is reported for a numerical variable (e.g. <5), then 
the appropriately determined coded value will be used in the statistical analysis.  However, 
the actual values as reported in the database will be presented in data listings. 
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Protocol SHP634-102 
 
 
 
19. 
REFERENCES 
Patterson Scott, Jones Byron 2006. Bioequivalence and statistics in clinical pharmacology. 
Chapman and Hall, New York. 
Parent X, Spielmann C, Hanser AM. 2009. ["Corrected" calcium: calcium status 
underestimation in non-hypoalbuminemic patients and in hypercalcemic patients]. Ann Biol 
Clin (Paris). [Online]. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19654080  
 
Page No.: 49 of 58 


Protocol SHP634-102 
 
 
 
20. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND 
LISTINGS 
 
Table 
Title 
Shire 
Std 
1.1.1.1 
Disposition by Ethnic Group and Treatment Sequence (Enrolled Set) 
Y 
1.1.1.2 
Disposition of Subjects of Japanese Descent by Dose (Safety Analysis Set) 
Y 
1.2.1.1 
Demographic Characteristics by Ethnic Group and Treatment Sequence 
(Safety Analysis Set) 
Y 
1.2.1.2 
Demographic Characteristics of Subjects of Japanese Descent by Dose 
(Safety Analysis Set) 
Y 
1.2.2.1 
Baseline Characteristics by Ethnic Group and Treatment Sequence (Safety 
Analysis Set) 
Y 
1.2.2.2 
Baseline Characteristics of Subjects of Japanese Descent by Dose (Safety 
Analysis Set) 
Y 
1.3.1 
Concomitant Medications by Ethnic Group and Dose (Safety Analysis Set) 
Y 
2.1.1 
Summary of PTH Original Plasma Concentrations (<unit>) versus Time by 
Ethnic Group and Dose  (Pharmacokinetic Set) 
N 
2.1.2 
Summary of PTH Baseline-adjusted Plasma Concentrations (<unit>) versus 
Time by Ethnic Group and Dose  (Pharmacokinetic Set) 
N 
2.1.3 
Summary of PTH Original Plasma Pharmacokinetic Parameters by Ethnic 
Group and Dose  (Pharmacokinetic Set) 
N 
2.1.4 
Summary of PTH Baseline-adjusted Plasma Pharmacokinetic Parameters 
by Ethnic Group and Dose  (Pharmacokinetic Set) 
N 
2.1.5 
Summary of PTH Baseline-adjusted Body-weight Adjusted 
Pharmacokinetic Parameters by Ethnic Group and Dose  (Pharmacokinetic 
Set) 
N 
2.1.6 
Summary of PTH Dose-normalized Baseline-adjusted Pharmacokinetic 
Parameters by Ethnic Group and Dose (Pharmacokinetic Set) 
N 
2.1.7 
Statistical Analysis of PTH Baseline-adjusted Pharmacokinetic Parameters 
by Welch’s T-test  (Pharmacokinetic Set) 
N 
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Protocol SHP634-102 
 
 
 
Table 
Title 
Shire 
Std 
2.1.8 
Statistical Analysis of PTH Original Pharmacokinetic Parameters by 
Welch’s T-test  (Pharmacokinetic Set) 
N 
2.1.9 
Statistical Analysis of PTH Dose-normalized Baseline-adjusted 
Pharmacokinetic Parameters Comparing Different Doses and Ethnic 
Groups by Welch’s T-test  (Pharmacokinetic Set) 
N 
2.1.10 
Dose Proportionality Analysis of PTH Pharmacokinetic Parameters in 
Subjects of Japanese Descent (Pharmacokinetic Set) 
N 
2.2.1 
Summary of Original Concentrations of Serum Total Calcium (<unit>) 
versus Time by Ethnic Group and Dose  (Pharmacodynamic Set) 
N 
2.2.2 
Summary of Original Concentrations of Albumin-corrected Calcium 
(<unit>) versus Time by Ethnic Group and Dose  (Pharmacodynamic Set) 
N 
2.2.3 
Summary of Original Concentrations of Phosphate (<unit>) versus Time by 
Ethnic Group and Dose  (Pharmacodynamic Set) 
N 
2.2.4 
Summary of Original Concentrations of Calcium-phosphate Product 
(<unit>) versus Time by Ethnic Group and Dose  (Pharmacodynamic Set) 
N 
2.2.5 
Summary of Baseline-adjusted Concentrations of Serum Total Calcium 
(<unit>) versus Time by Ethnic Group and Dose (Pharmacodynamic Set) 
N 
2.2.6 
Summary of Baseline-adjusted Concentrations of Albumin-corrected 
Calcium (<unit>) versus Time by Ethnic Group and Dose 
(Pharmacodynamic Set) 
N 
2.2.7 
Summary of Baseline-adjusted Concentrations of Phosphate (<unit>) 
versus Time by Ethnic Group and Dose (Pharmacodynamic Set) 
N 
2.2.8 
Summary of Baseline-adjusted Concentrations of Calcium-phosphate 
Product (<unit>) versus Time by Ethnic Group and Dose 
(Pharmacodynamic Set) 
N 
2.2.9 
Summary of Pharmacodynamic Parameters based on Original Serum Total 
Calcium Concentrations by Ethnic Group and Dose  (Pharmacodynamic 
Set) 
N 
2.2.10 
Summary of Pharmacodynamic Parameters based on Original Albumin-
corrected Calcium Concentrations by Ethnic Group and Dose  
(Pharmacodynamic Set) 
N 
Page No.: 51 of 58 


Protocol SHP634-102 
 
 
 
Table 
Title 
Shire 
Std 
2.2.11 
Summary of Pharmacodynamic Parameters based on Original Phosphate 
Concentrations by Ethnic Group and Dose  (Pharmacodynamic Set) 
N 
2.2.12 
Summary of Pharmacodynamic Parameters based on Original Calcium-
phosphate Product Concentrations by Ethnic Group and Dose  
(Pharmacodynamic Set) 
N 
2.2.13 
Summary of Pharmacodynamic Parameters based on Baseline-adjusted 
Serum Total Calcium Concentrations by Ethnic Group and Dose 
(Pharmacodynamic Set) 
N 
2.2.14 
Summary of Pharmacodynamic Parameters based on Baseline-adjusted 
Albumin-corrected Calcium Concentrations by Ethnic Group and Dose 
(Pharmacodynamic Set) 
N 
2.2.15 
Summary of Pharmacodynamic Parameters based on Baseline-adjusted 
Phosphate Concentrations by Ethnic Group and Dose (Pharmacodynamic 
Set) 
N 
2.2.16 
Summary of Pharmacodynamic Parameters based on Baseline-adjusted 
Calcium-phosphate Product Concentrations by Ethnic Group and Dose  
(Pharmacodynamic Set) 
N 
4.1.1 
Investigational Product Exposures by Ethnic Group and Visit (Safety 
Analysis Set) 
Y 
4.2.1 
Overall Treatment-emergent Adverse Events (TEAEs) by Ethnic Group and 
Dose at Onset (Safety Analysis Set) 
Y 
4.2.2 
Treatment-emergent Adverse Events by System Organ Class, Preferred 
Term, Ethnic Group and Dose at Onset (Safety Analysis Set) 
Y 
4.3.1 
Treatment-emergent Adverse Events by Maximum Severity, System Organ 
Class, Preferred Term, Ethnic Group and Dose at Onset (Safety Analysis 
Set) 
Y 
4.3.2 
Treatment-emergent Adverse Events Considered Related to Investigational 
Product by System Organ Class, Preferred Term, Ethnic Group and Dose at 
Onset (Safety Analysis Set) 
Y 
4.4.1 
Serious Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term, Ethnic Group and Dose at Onset (Safety Analysis Set) 
Y 
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Protocol SHP634-102 
 
 
 
Table 
Title 
Shire 
Std 
4.4.2 
Treatment-emergent Adverse Events Leading to Discontinuation of 
Investigational Product by System Organ Class, Preferred Term, Ethnic 
Group and Dose at Onset (Safety Analysis Set) 
Y 
4.6.1 
Quantitative Clinical Laboratory Results by Ethnic Group and Dose: 
Hematology (Safety Analysis Set) 
Y 
4.6.2 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group and 
Dose: Hematology (Safety Analysis Set) 
Y 
4.6.3 
Potentially Clinically Important (PCI) Laboratory Results by Ethnic Group 
and Dose: Hematology (Safety Analysis Set) 
Y 
4.6.4 
Quantitative Clinical Laboratory Results by Ethnic Group and Dose: 
Biochemistry (Safety Analysis Set) 
Y 
4.6.5 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group and 
Dose: Biochemistry (Safety Analysis Set) 
Y 
4.6.6 
Potentially Clinically Important (PCI) Laboratory Results by Ethnic Group 
and Dose: Biochemistry (Safety Analysis Set) 
Y 
4.6.7 
Quantitative Clinical Laboratory Results by Ethnic Group and Dose: 
Urinalysis (Safety Analysis Set) 
Y 
4.6.8 
Qualitative Clinical Laboratory Results by Ethnic Group and Dose: 
Urinalysis (Safety Analysis Set) 
Y 
4.6.9 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group and 
Dose: Urinalysis (Safety Analysis Set) 
Y 
4.7.1 
Actual Values and Change from Baseline in Vital Signs by Ethnic Group 
and Dose (Safety Analysis Set) 
Y 
4.7.2 
Potentially Clinically Important Vital Signs Results by Ethnic Group and 
Dose (Safety Analysis Set) 
Y 
4.8.1 
Actual Values and Change from Baseline in ECG by Ethnic Group and 
Dose  (Safety Analysis Set) 
Y 
4.8.2 
ECG Interpretation by Ethnic Group and Dose  (Safety Analysis Set) 
Y 
4.8.3 
Shift from Baseline in Qualitative ECG Results by Ethnic Group and Dose 
(Safety Analysis Set) 
Y 
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Protocol SHP634-102 
 
 
 
Table 
Title 
Shire 
Std 
4.8.4 
Potentially Clinically Important (PCI) ECG Results by Ethnic Group and 
Dose (Safety Analysis Set) 
Y 
4.9.1 
Immunogenicity (Anti-PTH Antibody) (Safety Analysis Set) 
N 
 
Figure 
Title 
Shire 
Std 
2.1.1 
Plot of Original Individual Plasma PTH Concentrations versus Time by 
Ethnic Group and Dose on Linear Scale (Pharmacokinetic Set) 
N 
2.1.2 
Plot of Original Individual Plasma PTH Concentrations versus Time by 
Ethnic Group and Dose on Semi-log Scale (Pharmacokinetic Set) 
N 
2.1.3 
Mean Plot of Original Plasma PTH Concentrations versus Time on Linear 
Scale (Pharmacokinetic Set) 
N 
2.1.4 
Mean Plot of Original Plasma PTH Concentrations versus Time on Semi-
log Scale (Pharmacokinetic Set) 
N 
2.1.5 
Plot of Baseline-adjusted Individual Plasma PTH Concentrations versus 
Time by Ethnic Group and Dose on Linear Scale (Pharmacokinetic Set) 
N 
2.1.6 
Plot of Baseline-adjusted Individual Plasma PTH Concentrations versus 
Time by Ethnic Group and Dose on Semi-log Scale (Pharmacokinetic Set) 
N 
2.1.7 
Mean Plot of Baseline-adjusted Plasma PTH Concentrations versus Time 
on Linear Scale (Pharmacokinetic Set) 
N 
2.1.8 
Mean Plot of Baseline-adjusted Plasma PTH Concentrations versus Time 
on Semi-log Scale (Pharmacokinetic Set) 
N 
2.1.9 
Baseline-adjusted PK Parameters by Dose in Subjects of Japanese Descent  
(Pharmacokinetic Set) 
N 
2.1.10 
Dose-normalized PK Parameters by Dose in Subjects of Japanese Descent  
(Pharmacokinetic Set) 
N 
2.1.11 
Box-Whisker Plot of PK Parameters in Both Ethnic Groups  
(Pharmacokinetic Set) 
N 
2.1.12 
Forest Plot of Geometric Mean Ratios of Baseline-Adjusted PK Parameters 
between Ethnic Groups (100µg) (Pharmacokinetic Set) 
N 
2.2.1 
Plot of Original Individual Serum Total Calcium Concentrations versus 
Time by Ethnic Group and Dose on Linear Scale (Pharmacodynamic Set) 
N 
2.2.2 
Plot of Original Individual Albumin-corrected Calcium Concentrations 
versus Time by Ethnic Group and Dose on Linear Scale 
(Pharmacodynamic Set) 
N 
2.2.3 
Plot of Original Individual Phosphate Concentrations versus Time by 
Ethnic Group and Dose on Linear Scale (Pharmacodynamic Set) 
N 
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Protocol SHP634-102 
 
 
 
Figure 
Title 
Shire 
Std 
2.2.4 
Plot of Original Individual Calcium-phosphate Product Concentrations 
versus Time by Ethnic Group and Dose on Linear Scale 
(Pharmacodynamic Set) 
N 
2.2.5 
Plot of Baseline-adjusted Individual Serum Total Calcium Concentrations 
versus Time by Ethnic Group and Dose on Linear Scale 
(Pharmacodynamic Set) 
N 
2.2.6 
Plot of Baseline-adjusted Individual Albumin-corrected Calcium 
Concentrations versus Time by Ethnic Group and Dose on Linear Scale 
(Pharmacodynamic Set) 
N 
2.2.7 
Plot of Baseline-adjusted Individual Phosphate Concentrations versus Time 
by Ethnic Group and Dose on Linear Scale (Pharmacodynamic Set) 
N 
2.2.8 
Plot of Baseline-adjusted Individual Calcium-phosphate Product 
Concentrations versus Time by Ethnic Group and Dose on Linear Scale 
(Pharmacodynamic Set) 
N 
2.2.9 
Mean Plot of Original Serum Total Calcium Concentrations versus Time 
on Linear Scale (Pharmacodynamic Set) 
N 
2.2.10 
Mean Plot of Original Albumin-corrected Calcium Concentrations versus 
Time on Linear Scale (Pharmacodynamic Set) 
N 
2.2.11 
Mean Plot of Original Phosphate Concentrations versus Time on Linear 
Scale (Pharmacodynamic Set) 
N 
2.2.12 
Mean Plot of Original Calcium-phosphate Product Concentrations versus 
Time on Linear Scale (Pharmacodynamic Set) 
N 
2.2.13 
Mean Plot of Baseline-adjusted Serum Total Calcium Concentrations 
versus Time on Linear Scale (Pharmacodynamic Set) 
N 
2.2.14 
Mean Plot of Baseline-adjusted Albumin-corrected Calcium 
Concentrations versus Time on Linear Scale(Pharmacodynamic Set) 
N 
2.2.15 
Mean Plot of Baseline-adjusted Phosphate Concentrations versus Time on 
Linear Scale (Pharmacodynamic Set) 
N 
2.2.16 
Mean Plot of Baseline-adjusted Calcium-phosphate Product Concentrations 
versus Time on Linear Scale (Pharmacodynamic Set) 
N 
2.2.17 
Box-Whisker Plot of Serum Total Calcium PD Parameters in Both Ethnic 
Groups  (Pharmacodynamic Set) 
N 
2.2.18 
Box-Whisker Plot of Albumin-corrected Calcium PD Parameters in Both 
Ethnic Groups  (Pharmacodynamic Set) 
N 
2.2.19 
Box-Whisker Plot of Phosphate PD Parameters in Both Ethnic Groups  
(Pharmacodynamic Set) 
N 
2.2.20 
Box-Whisker Plot of Calcium-phosphate Product PD Parameters in Both 
Ethnic Groups  (Pharmacodynamic Set) 
N 
 
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Protocol SHP634-102 
 
 
 
Listing 
Title 
Shire 
Std 
16.1.7 
Randomization Assignments (Japanese Subjects) 
Y 
1.1 
Subject Disposition (Enrolled Set) 
Y 
1.2 
Subjects Who Discontinued from the Study (Enrolled Set) 
Y 
1.3 
Study Analysis Set Classification (Enrolled Set) 
Y 
2.1 
Listing of Protocol Deviations (Enrolled Set) 
Y 
4.1 
Subject Demographics (Safety Analysis Set) 
Y 
4.2 
Subject Baseline Characteristics (Safety Analysis Set) 
Y 
4.3 
Medical History (Safety Analysis Set) 
Y 
4.4 
Prior and Concomitant Medications (Safety Analysis Set) 
Y 
5.1 
Investigational Product Exposure (Safety Analysis Set) 
N 
5.2 
Pharmacokinetic Blood Sampling and PTH Concentrations 
(Pharmacokinetic Set) 
Y 
5.3 
Original PTH Pharmacokinetic Parameters (Pharmacokinetic Set) 
N 
5.4 
Baseline-adjusted PTH Pharmacokinetic Parameters (Pharmacokinetic Set) N 
5.5 
Baseline-adjusted 
Body-weight 
Adjusted 
PTH 
Pharmacokinetic 
Parameters (Pharmacokinetic Set) 
N 
5.6 
Dose Normalized Baseline-adjusted PTH Pharmacokinetic Parameters 
(Pharmacokinetic Set) 
N 
5.7 
Pharmacodynamic Blood Sampling and Concentrations 
(Pharmacodynamic Set) 
Y 
5.8 
Original Pharmacodynamic Parameters (Pharmacodynamic Set) 
N 
5.9 
Baseline-adjusted Pharmacodynamic Parameters (Pharmacodynamic Set) 
 
N 
7.1 
Adverse Events (Safety Analysis Set) 
Y 
7.2 
Serious Adverse Events (Safety Analysis Set) 
Y 
7.3 
Adverse Events Considered Related to Investigational Product (Safety 
Analysis Set) 
Y 
Page No.: 56 of 58 


Protocol SHP634-102 
 
 
 
Listing 
Title 
Shire 
Std 
7.4 
Adverse Events Leading to Discontinuation from the Study (Safety 
Analysis Set) 
Y 
7.5 
Adverse Events Leading to Death (Safety Analysis Set) 
Y 
8.1.1 
Clinical Laboratory Test Results (Safety Analysis Set) 
Y 
8.1.2 
Subjects with Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set) 
Y 
8.2.1 
Vital Signs (Safety Analysis Set) 
Y 
8.2.2 
Subjects with Potentially Clinically Important Vital Signs  (Safety 
Analysis Set) 
Y 
8.3.1 
12-lead ECG Results and Investigator’s Interpretation (Safety Analysis 
Set) 
Y 
8.3.2 
Subjects with Potentially Clinically Important ECG Results (Safety 
Analysis Set) 
Y 
8.5.1 
Immunogenicity (Anti-PTH Antibody) Results  (Safety Analysis Set) 
N 
 
 
 
 
Statistical 
Appendix 
Title 
Shire 
Std 
Statistical 
Appendix 
2.1.7 
Statistical Analysis of PTH Baseline-adjusted Pharmacokinetic 
Parameters by Welch’s T-test  (Pharmacokinetic Set) 
N 
Statistical 
Appendix 
2.1.8 
Statistical Analysis of PTH Original Pharmacokinetic Parameters by 
Welch’s T-test  (Pharmacokinetic Set) 
N 
Statistical 
Appendix 
2.1.9 
Statistical Analysis of PTH Dose-normalized Baseline-adjusted 
Pharmacokinetic Parameters Comparing Different Doses and Ethnic 
Groups by Welch’s T-test  (Pharmacokinetic Set) 
N 
Page No.: 57 of 58 


Protocol SHP634-102 
 
 
 
Statistical 
Appendix 
Title 
Shire 
Std 
Statistical 
Appendix 
2.1.10 
Dose Proportionality Analysis of PTH Pharmacokinetic Parameters in 
Subjects of Japanese Descent (Pharmacokinetic Set) 
N 
 
Note: There are no shells provided for statistical appendices, since they are raw output from 
SAS. 
Page No.: 58 of 58 

Prot_001.pdf: 






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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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2 1 M ar 2 0 1 7
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


S hire
C O N FI D E N TI A L
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2 1 M ar 2 0 1 7
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:
 ( b usi ness h o urs)
 ( 2 4-h o ur c o v era ge)
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)
 ( 2 4-h o ur c o vera ge)
E mail:
P P D
P P D
P P D
P P D
P P D
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
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.
REFERENCES
Arlt, W, Fremerey, C, Callies, F, Reincke, M, Schneider, P, Timmermann, W & Allolio, B 2002. 
Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving 
standard treatment with calcium and vitamin D. Eur J Endocrinol, 146, 215-22.
Avioli, LV 1974. The therapeutic approach to hypoparathyroidism. Am J Med, 57, 34-42.
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 
Miner Res, 26, 2317-37.
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,
32, 483-502.


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12.
APPENDICES



Prot_000.pdf: 




S hire
C O N FI D E N TI A L
P a ge 3
S H P 6 3 4 -1 0 2 Pr ot oc ol
N at p ar a
2 9 J a n 2 0 1 7
E M E R G E N C Y  C O N TA C T I N F O R M A TI 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 plica 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


S hire
C O N FI D E N TI A L
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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
Te le p h o ne:
 ( b usi ness h o urs)
 ( 2 4-h o ur c o vera ge)
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)
 ( 2 4-h o ur c o v era ge)
E mail:
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire
C O N FI D E N TI A L
P a ge 5
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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 pr 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
P P D


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
ADDITIONAL CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................20
1.
BACKGROUND INFORMATION.......................................................................................25
1.1
Indication and Current Treatment Options...............................................................26
1.2
Product Background.................................................................................................26
1.2.1
Preclinical Information ..........................................................................................26
1.2.2
Clinical Information...............................................................................................27
1.3
Risk/Benefit and Ethical Assessment.......................................................................28
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................30
2.1
Rationale for the Study.............................................................................................30
2.2
Study Objectives ......................................................................................................30
2.2.1
Primary Objective..................................................................................................30
2.2.2
Secondary Objectives.............................................................................................30
3.
STUDY DESIGN ...................................................................................................................32
3.1
Study Design and Flow Chart ..................................................................................32
3.2
Rationale for Dose Selection and Study Design Elements ......................................35
3.3
Duration and Study Completion Definition .............................................................35
3.4
Sites and Regions .....................................................................................................36
4.
STUDY POPULATION.........................................................................................................37
4.1
Inclusion Criteria......................................................................................................37
4.2
Exclusion Criteria.....................................................................................................38
4.3
Restrictions...............................................................................................................39
4.4
Reproductive Potential .............................................................................................40
4.4.1
Female Contraception............................................................................................40
4.4.2
Male Contraception................................................................................................41
4.5
Discontinuation of Subjects .....................................................................................41
4.5.1
Reasons for Discontinuation..................................................................................41


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4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................42
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................43
5.1
Prior Treatment ........................................................................................................43
5.2
Concomitant Treatment............................................................................................43
5.2.1
Permitted Treatment...............................................................................................43
6.
INVESTIGATIONAL PRODUCT ........................................................................................44
6.1
Identity of Investigational Product...........................................................................44
6.1.1
Blinding the Treatment Assignment......................................................................44
6.2
Administration of Investigational Product(s)...........................................................44
6.2.1
Allocation of Subjects to Treatment ......................................................................44
6.2.2
Dosing....................................................................................................................45
6.2.3
Unblinding the Treatment Assignment..................................................................45
6.3
Labeling, Packaging, Storage, and Handling ...........................................................45
6.3.1
Labeling .................................................................................................................45
6.3.2
Packaging...............................................................................................................46
6.3.3
Storage ...................................................................................................................46
6.4
Drug Accountability.................................................................................................46
6.5
Subject Compliance..................................................................................................47
6.6
Retention of Bioavailability and Bioequivalence Testing Samples.........................47
7.
STUDY PROCEDURES........................................................................................................48
7.1
Study Schedule.........................................................................................................48
7.1.1
Screening Period....................................................................................................48
7.1.1.1
Screening Failure....................................................................................48
7.1.1.2
Rescreening of Subjects .........................................................................48
7.1.2
Treatment Period....................................................................................................49
7.1.2.1
Days 1 to 8..............................................................................................49
7.1.2.2
Final Visit...............................................................................................49
7.1.3
Follow-up Period ...................................................................................................49
7.1.4
Additional Care of Subjects after the Study ..........................................................49
7.2
Study Evaluations and Procedures ...........................................................................49
7.2.1
Demographic and Other Baseline Characteristics .................................................49
7.2.1.1
Demographics.........................................................................................49
7.2.2
Safety .....................................................................................................................50
7.2.2.1
Medical and Medication History............................................................50
7.2.2.2
Physical Examination (Including Height and Weight) ..........................50
7.2.2.3
Adverse Event Collection.......................................................................51
7.2.2.4
Vital Signs..............................................................................................51
7.2.2.5
Clinical Laboratory Evaluations.............................................................53


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7.2.2.6
Pregnancy Test .......................................................................................54
7.2.2.7
Drug and Alcohol Screen .......................................................................54
7.2.2.8
Serology Screen......................................................................................55
7.2.2.9
Electrocardiogram ..................................................................................55
7.2.3
Pharmacokinetic Procedures..................................................................................56
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures.............56
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples .....................................57
7.2.3.3
Plasma Drug Assay Methodology..........................................................57
7.2.4
Pharmacodynamic Assessments ............................................................................57
7.2.4.1
Pharmacodynamic Sample Collection and Handling Procedures ..........57
7.2.4.2
Shipment of Serum Pharmacodynamic Samples ...................................58
7.2.4.3
Serum Pharmacodynamic Assay Methodology .....................................58
7.2.5
Immunogenicity Testing for Anti-Parathyroid Hormone Antibodies....................58
7.2.5.1
Sample Collection and Handling Procedures for Immunogenicity 
Testing for Anti-Parathyroid Hormone Antibodies................................59
7.2.5.2
Anti-Parathyroid Hormone Antibody Assay Methodology ...................59
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................60
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................61
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................61
8.1.1
Severity Categorization..........................................................................................61
8.1.2
Relationship Categorization...................................................................................62
8.1.3
Outcome Categorization ........................................................................................62
8.1.4
Clinical Laboratory and Other Safety Evaluations................................................62
8.1.5
Pregnancy...............................................................................................................63
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................63
8.2
Serious Adverse Event Procedures ..........................................................................64
8.2.1
Reference Safety Information................................................................................64
8.2.2
Reporting Procedures.............................................................................................64
8.2.3
Serious Adverse Event Definition .........................................................................65
8.2.4
Serious Adverse Event Collection Time Frame.....................................................65
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................65
8.2.6
Fatal Outcome........................................................................................................66
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................66
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................67
9.1
Data Collection.........................................................................................................67
9.2
Clinical Data Management.......................................................................................67


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9.3
Data Handling Considerations..................................................................................67
9.4
Statistical Analysis Process......................................................................................67
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......67
9.6
Sample Size Calculation and Power Considerations................................................68
9.7
Study Population ......................................................................................................68
9.8
Pharmacokinetic and Pharmacodynamic Analyses..................................................68
9.8.1
Pharmacokinetic Analysis......................................................................................68
9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters ..............................69
9.8.2
Pharmacodynamic Analysis...................................................................................69
9.8.3
Statistical Analysis of Pharmacodynamic Values..................................................70
9.9
Safety Analyses........................................................................................................70
9.9.1
Safety Endpoint(s) .................................................................................................70
9.9.2
Statistical Methodology for Safety Endpoint(s) ....................................................70
9.10
Other Analyses .........................................................................................................71
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................72
10.1
Sponsor’s Responsibilities .......................................................................................72
10.1.1 Good Clinical Practice Compliance.......................................................................72
10.1.2 Indemnity/Liability and Insurance.........................................................................72
10.1.3 Public Posting of Study Information......................................................................72
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................72
10.1.5 Study Suspension, Termination, and Completion..................................................73
10.2
Investigator’s Responsibilities .................................................................................73
10.2.1 Good Clinical Practice Compliance.......................................................................73
10.2.2 Protocol Adherence and Investigator Agreement..................................................73
10.2.3 Documentation and Retention of Records.............................................................74
10.2.3.1
Case Report Forms.................................................................................74
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................74
10.2.3.3
Audit/Inspection.....................................................................................75
10.2.3.4
Financial Disclosure...............................................................................75
10.3
Ethical Considerations..............................................................................................75
10.3.1 Informed Consent...................................................................................................75
10.3.2 Institutional Review Board or Ethics Committee..................................................75
10.4
Privacy and Confidentiality......................................................................................76
10.5
Study Results/Publication Policy .............................................................................77
11. REFERENCES .......................................................................................................................79
12. APPENDICES ........................................................................................................................81


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................20
Table 2
Detailed Schedule of Assessments (non-Hispanic, Caucasian Subjects)......23
Table 3
Detailed Schedule of Assessments (Subjects of Japanese Descent) .............24
Table 4
Volume of Blood to Be Drawn from Each Subject.......................................60
LIST OF FIGURES
Figure 1
Study Design Flow Chart ..............................................................................34
Figure 2
Procedures for Screening Vital Signs (Blood Pressure – Pulse) ...................52
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................81


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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


S hire
C O N FI D E N TI A L
P a ge 1 3
S H P 6 3 4 -1 0 2 Pr ot oc ol
N at p ar a
2 9 J a n 2 0 1 7
S T U D Y  S Y N O PSI 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- over 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 wit 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 me 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 mprisi 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 pla ce 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 ( 5 years), wei g ht ( 1 0 %), 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  su bjects wi ll 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 he 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 de sce 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 (i ncl u di n g meas ure me nt of 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 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 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 (i ncl u di n g meas ure me nt of 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 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 
P P D


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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.
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 (5 years), 
weight (10%), 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 
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.


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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) 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.
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 25 kg/m², inclusive, with a body weight ≥45 kg (99lbs). This inclusion 


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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).
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 
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.


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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 
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.


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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 (AUC0-last) 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 90% 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.
Pharmacodynamic Endpoint(s):
Pharmacodynamic parameters will be computed from individual post dose values of serum calcium (uncorrected and 


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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 with start dates between the time of the first exposure to study drug and the last dose of 
the study drug.


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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
X j
X j
X j
X j
X
Height and weightc
X
X
Serum PTH
X
X
Electrocardiogram (12-
lead)a, g
X
X
X
X j
X j
X j
X j
X
Biochemistry, 
hematology, and 
urinalysisa
X
X
X
X j
X j
Xj
X
HIV, HBsAg, and HCV 
antibodies
X
Pregnancy test (females 
X
X
X
Xj
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
only)a, d
Urine drug and alcohol 
screeninge
X
X
Randomization
X j
Investigational drug 
administration k
X
X j
X j
Pharmacodynamic blood 
samplingf, g
X
X
X j
X j
X j
X j
Anti-PTH antibody 
samplingg
X
Xa
Pharmacokinetic blood 
samplingg
X
X
X j
X j
X j
X j
Check-in to the CRC
X
Discharge from the CRC
Xi
X j
Adverse events/serious 
adverse eventsa
X
X
X
X
X j
X j
X j
X j
X j
X j
Xl
Concomitant medicationa
X
X
X
X
X j
X j
X j
X j
X j
X j
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.
f  Pharmacodynamic blood sampling assessments will include serum calcium and phosphate.


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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
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
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.
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
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
aIn 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.
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). In 1 year spanning 2007-2008 (Powers et al. 2013) the 
incidence of chronic hypoparathyroidism (≥6 months) was said to be approximately 60,000 
subjects in the United States, which rises to approximately 117,000 if the transient 
hypoparathyroid population is included (≤6 months). The same authors suggest that, of those 
117,000 transient hypoparathyroid subjects, about 5% will become chronic.
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). This additional fraction of calcium is instead excreted through the kidneys 
(Shoback 2008), leading to hypercalciuria which, together with a high-calcium-phosphate 


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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.
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 contributes 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.


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In male and female rats, the administration of PTH was associated with an increase in the 
incidence of osteosarcoma. 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 to 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 
at a flexible dose range of 50 to 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 hypoparathryodism program indicated that rhPTH(1-84) 
administered in the dose range of 25 to 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 


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hypercalciuria. Common adverse reactions (ie, reported in at least 1 in every 100 subjects, but 
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 


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outweigh this potential risk. Use of rhPTH(1-84) is to be avoided in subjects who are at 
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.


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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.
Other clinical studies have reported experience with twice-daily use of a fragment of PTH 
(PTH[1-34]) injected SC in the setting of adult and pediatric subjects with hypoparathyroidism 
(Winer et al. 1998; Winer et al. 2003; Winer et al. 2008). In this setting, PTH(1-34) maintained 
eucalcemia and reduced urinary calcium excretion. In these studies, a comparison with calcitriol 
showed that either twice-daily PTH(1-34) or twice-daily calcitriol each maintained similar serum 
calcium levels, although urinary calcium excretion was lower in the PTH(1-34)-treated subjects.
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) 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.
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.


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
To compare the PD profile (including measurement of 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 (including measurement of 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, 50 µg 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.


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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 (±5 years), 
weight (±10%), 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 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.


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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) 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.




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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. Therefore there is no accumulation of plasma rhPTH after repeat 
dosing, and 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.


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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 25 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).
10.
Total serum calcium within laboratory normal limits.
11.
Serum parathyroid hormone (PTH) levels within laboratory normal limits.


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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)

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.


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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.
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 


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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). 

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)


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
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.
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}


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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.


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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:

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)


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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.
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.


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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:

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 


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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.
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.


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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.
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.


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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.
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.


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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.
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


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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
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


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
Cardiovascular

Neurological

Abdomen (including liver and kidneys)
Clinically significant abnormalities identified at the screening visit will be documented in the 
subject’s source documents. 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 
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.




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BODY TEMPERATURE
Oral temperature should be taken by placing a digital thermometer under the tongue as per study 
site documented procedures and the temperature reported in degrees Celsius.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
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.


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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)
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.


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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.
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.


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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 
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


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
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.
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 


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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)
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 


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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:

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. 


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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
4
34
7
59.5
Hematologya
4
4
16
7
28
Anti-PTH Antibody Samplesa
3
2
6
2
6
Total mL
170.5
412
-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 412mL of blood will be drawn from all 
subjects of Japanese descent, regardless of sex. For the non-Hispanic, Caucasian volunteers it is 
expected that 170.5mL 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 170.5mL (non-Hispanic, Caucasian subjects) or 412mL (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.


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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:
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.


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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

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 


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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
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. 


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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.
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) 


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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.
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 


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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 (AUC0-last) 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 90% 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 with start dates between the time of the first exposure to study 
drug and the last dose of the study drug.
9.10
Other Analyses
No other analyses are planned in this study.


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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.
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. 


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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.
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 


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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.). 
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.


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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 
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 


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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 
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).


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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.
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 


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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.
REFERENCES
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Avioli, LV 1974. The therapeutic approach to hypoparathyroidism. Am J Med, 57, 34-42.
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 
Miner Res, 26, 2317-37.
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.
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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 
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Velasco, PJ, Manshadi, M, Breen, K & Lippmann, S 1999. Psychiatric aspects of parathyroid 
disease. Psychosomatics, 40, 486-90.
Winer, KK, Ko, CW, Reynolds, JC, Dowdy, K, Keil, M, Peterson, D, Gerber, LH, Mcgarvey, C 
& Cutler, GB, Jr. 2003. Long-term treatment of hypoparathyroidism: a randomized controlled 
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Winer, KK, Yanovski, JA, Sarani, B & Cutler, GB, Jr. 1998. A randomized, cross-over trial of 
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12.
APPENDICES