Clinical trial NCT02781844
Conditions: Hypoparathyroidism
Sponsor: Shire
Start date: 2017-04-03; Completion date: 2019-03-08
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is being conducted to characterize the effects of twice daily administration of rhPTH(1-84) on the way the body handles rhPTH(1-84) as well as its actions and safety and tolerability over the course of 24 hours as compared with the current once daily dosing regimen of marketed rhPTH(1-84) (marketed in the United States as Natpara® and in the EU as Natpar).

Detailed description:

Arms: arm 1: Participants will be randomized to either receive 25 microgram (mcg) rhPTH(1-84) twice daily with no calcium for treatment period 1 and 100mcg rhPTH(1-84) once daily with no calcium for treatment period 2; or 100mcg rhPTH(1-84) once daily with no calcium for treatment period 1 and 25mcg rhPTH(1-84) BID with no calcium for treatment period 2 arm 2: Participants will be randomized to either receive 50mcg rhPTH(1-84) twice daily with no calcium for treatment period 1 and 100mcg rhPTH(1-84) once daily with no calcium for treatment period 2; or 100mcg rhPTH(1-84) once daily with no calcium for treatment period 1 and 50mcg rhPTH(1-84) twice daily with no calcium for treatment period 2 arm 3: Participants will be randomized to either receive 25mcg rhPTH(1-84) twice daily with calcium for treatment period 1 and 100mcg rhPTH(1-84) once daily with calcium for treatment period 2; or 100mcg rhPTH(1-84) once daily with calcium for treatment period 1 and 25mcg rhPTH(1-84) twice daily with calcium for treatment period 2 arm 4: Participants will be randomized to either receive 50mcg rhPTH(1-84) twice daily with calcium for treatment period 1 and 100mcg rhPTH(1-84) once daily with calcium for treatment period 2; or 100mcg rhPTH(1-84) once daily with calcium for treatment period 1 and 50mcg rhPTH(1-84) twice daily with calcium for treatment period 2
Interventions: intervention 1: 25mcg rhPTH(1-84) intervention 2: 50mcg rhPTH(1-84) intervention 3: 100mcg rhPTH(1-84)
Intervention descriptions: intervention 1: Participants will receive rhPTH(1-84) as twice-daily regimen (12 hours apart) of two 25mcg doses without calcium in cohort 1 and with calcium in cohort 3. intervention 2: Participants will receive rhPTH(1-84) as twice daily regimen (12 hours apart) of two 50mcg doses without calcium in cohort 2 and with calcium in cohort 4 intervention 3: Participants will receive rhPTH(1-84) as once-daily regimen of one 100 mcg dose without calcium in cohort 1 and 2 and with calcium in cohort 3 and 4 in the morning.

Protocol documents:
Prot_000.pdf: 
PROTOCOL: SHP634-101
TITLE:
An Open-Label, Randomized, Crossover Study to Assess the
Pharmacokinetic and Pharmacodynamic Profiles of Once-Dailyand 
Twice-Daily Dose Regimens of recombinant human Parathyroid
Hormone (rhPTH[1-84]) Administered Subcutaneously to Subjects with 
Hypoparathyroidism
DRUG:
rhPTH(1-84)
IND:
076514
BLA:
125511
EUDRACT NO.:
2015-004757-40
SPONSOR: 
Shire
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
PROTOCOL 
HISTORY:
Protocol Amendment 5: 18 Jun 2018
Protocol Amendment 4: 12 Jun 2017
Protocol Amendment 3: 29 Jul 2016
Protocol Amendment 2: 03 Jun 2016
Protocol Amendment 1: 26 Feb2016
Original Protocol: 23 Nov 2015
This document contains confidential and proprietary information of Shire and is disclosed pursuant to
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without theexpress written 
consent of Shire.




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SUMMARY OF CHANGES FROM PREVIOUSVERSION
Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
5
Amendment Date
18 Jun 2018
Global
Item #
Description of Change
Section(s) Affected by
Change
1
The email address to report product quality complaints for 
the European Union and Rest of World has been revised 
from 
to 
Reason for change: Clarification
Product Quality Complaints
2
Language has been added to the protocol to:

Indicate that cohorts must have at least 8 subjects 
who must provide sufficient data to meet study 
objectives. Therefore, the number of subjects per 
cohort has been revised from 8 subjects to at least 8 
subjects and the number of subjects expected to 
complete the study has been revised from 32 
subjects to approximately 32 subjects.

Indicate that the planned safety review will take 
place after 8 subjects have completed Cohorts 1, 2, 
or 3 before a subject can be entered into the next 
cohort rather than after completion of the respective 
cohorts.

Allow previous cohorts to be expanded to include 
additional subjects to ensure that sufficient data for 
analysis are collected to complete study objectives.
Reason for change: The protocol is being amended to allow 
additional enrollment, if needed, to ensure that 8 evaluable 
subjects per cohort complete the trial.
Study Synopsis, Section 
3.1 (including Table 5),
Section 4.5, Section 9.6
3
Study period (planned):
The concluding date of the planned study period has been 
revised from Nov 2017 to May 2019.
The planned study period was revised from approximately 
18 months to approximately 36 months.
Reason for change: Study recruitment has gone more 
slowly than originally anticipated. The anticipated end of 
the study has been revised to May 2019 to reflect the 
expected pace of subject recruitment.
Study Synopsis and 
Section 3.2


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Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
5
Amendment Date
18 Jun 2018
Global
Item #
Description of Change
Section(s) Affected by
Change
4
The following analysis population definitions have been 
revised:
The all-enrolled population was revised from consisting of 
all subjects who meet the inclusion/exclusion criteria and 
sign the informed consent form to consisting of all subjects 
who sign the informed consent form and are randomized in 
the study.
The pharmacokinetic population was revised from 
consisting of subjects who receive at least 1 dose of 
rhPTH(1-84) and have at least 1 evaluable post-dose 
pharmacokinetic concentration value available for 1 dose 
regimen to consisting of all-enrolled subjects who receive 
at least 1 dose of rhPTH(1-84) and have at least 1 
evaluable post-dose pharmacokinetic concentration value 
available for 1 dose regimen.
The pharmacodynamic population was revised from 
consisting of subjects who receive at least 1 dose of 
rhPTH(1-84) and have at least 1 evaluable post-dose 
pharmacodynamic valueavailable for 1 dose regimen to 
consisting of all-enrolled subjects who receive at least 1 
dose of rhPTH(1-84) and have at least 1 evaluable post-
dose pharmacodynamic valueavailable for 1 dose regimen.
Reason for the change: Clarification.
Study Synopsis and 
Section 9.7
5
Sites and regions:
The word “approximately” has been added to indicate that 
more than 1-2 subjects might be enrolled at any 
investigational site.
Reason for change: Clarification needed.
Section 3.3
6
Rescreening of subjects:
Wording has been clarified regarding when a subject may 
be rescreened.
Previously, rescreening was allowed one additional time 
only for subjects whose failure to meet inclusion/ exclusion 
criteria was transient and temporary.  The language has 
been revised to remove the restriction on the number of 
times that these subjects can be rescreened.  
Section 7.2.1.4


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Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
5
Amendment Date
18 Jun 2018
Global
Item #
Description of Change
Section(s) Affected by
Change
These subjects can now be rescreened based on 
investigator discretion and sponsor approval.
Previously rescreening, based on investigator discretion 
and sponsor approval, was also allowed for subjects who 
continued to meet all inclusion/exclusion criteria, but were 
unable participate in the study due to scheduling 
conflicts/timing.  This language has been revised to specify 
that subjects who continued to meet all inclusion/exclusion 
criteria can also be rescreened if they were unable to 
participate in the study due to appropriate slot availability 
at an investigational site. 
Reason for change: Clarification was needed for 
investigational sites that subjects could be rescreened if 
needed based on investigator judgment because of (1) 
screen failure due to conditions that were transient and 
temporary; or (2) scheduling issues.
See Appendices for protocol history, including all amendments


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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical StudySerious 
Adverse Event and Non-serious AEs Required by the Protocol Form within 24 hours to the Shire 
Global Pharmacovigilance and Risk Management Department. Applicable fax numbers and
e-mail address can be found on the form (sent under separate cover). A copy of this form must 
also be sent to the Contract Research Organization (CRO) by fax or e-mail using the details 
below. PPD is the CRO for this study.
PPD e-mail: (for US sites only):
PPD e-mail (for EU sites only):
 PPD Fax (for US 
sites only):
PPD Fax (for EU sites only): 
For protocol- or safety-related issues, the investigator must contact the PPD Safety Hotline:
By telephone at:
PPD 24-hour safety Hotline (for US sites only): 
PPD 24-hour safety Hotline (for EU sites only):
The PPD Medical Monitors for this study are:
, MD: Medical Monitor- North America 
, MD: Medical Monitor- Europe 


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ADDITIONAL CONTACT INFORMATION
In case of any other issues, including non-safety related issues or if the medical monitor is 
unable to be reached, the investigator must contact the CRO (PPD):
or


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PRODUCT QUALITYCOMPLAINTS
Investigators are required to report investigational product quality complaints to Shire (and local 
or regional Regulatory authorities if required) within 24 hours. This includes any instances
wherein the quality or performance of a Shire product (marketed or investigational; including 
Shire provided devices used in the process of drug delivery) does not meet expectations (eg, 
inadequate or faulty closure, product contamination) or that the product did not meetthe 
specifications defined in the application for the product (eg, wrong product such that the label 
and contents are different products). For instructions on reporting AEs related to product 
complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed): 
Shire, Lexington, MA (USA)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE...................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3
EMERGENCY CONTACT INFORMATION.................................................................................6
ADDITIONAL CONTACT INFORMATION.................................................................................7
PRODUCT QUALITY COMPLAINTS..........................................................................................8
ABBREVIATIONS .......................................................................................................................15
STUDY SYNOPSIS.......................................................................................................................17
STUDY SCHEDULE(S)................................................................................................................26
1.
BACKGROUND INFORMATION .......................................................................................34
Indication and Current Treatment Options...............................................................35
1.1
Product Background.................................................................................................35
1.2
1.2.1
Preclinical Information ..........................................................................................35
1.2.2
Clinical Information...............................................................................................36
Risk/Benefit and Ethical Assessment.......................................................................37
1.3
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................39
Rationale for the Study.............................................................................................39
2.1
Study Objectives ......................................................................................................39
2.2
2.2.1
Primary Objectives.................................................................................................39
Secondary Objectives...............................................................................................39
2.3
3.
STUDY DESIGN ...................................................................................................................40
Study Design and Flow Chart ..................................................................................40
3.1
Duration and Study Completion Definition .............................................................46
3.2
Sites and Regions .....................................................................................................46
3.3
4.
STUDY POPULATION.........................................................................................................47
Inclusion Criteria......................................................................................................47
4.1
Exclusion Criteria.....................................................................................................48
4.2
Restrictions...............................................................................................................50
4.3
Reproductive Potential .............................................................................................51
4.4
4.4.1
Female Contraception ............................................................................................51
4.4.2
Male Contraception................................................................................................51
Discontinuation of Subjects......................................................................................52
4.5
4.5.1
Reasons for Discontinuation..................................................................................52
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................52
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................53
Prior Treatment.........................................................................................................53
5.1


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Concomitant Treatment............................................................................................53
5.2
5.2.1
Permitted Treatment...............................................................................................53
6.
INVESTIGATIONAL PRODUCT ........................................................................................54
Identity of Investigational Product...........................................................................54
6.1
Administration of Investigational Product(s)...........................................................54
6.2
6.2.1
Interactive Response Technology for Investigational Product Management.........54
6.2.2
Allocation of Subjects to Treatment ......................................................................54
6.2.3
Dosing....................................................................................................................55
6.2.4
Unblinding the Treatment Assignment..................................................................55
Labeling, Packaging, Storage, and Handling ...........................................................55
6.3
6.3.1
Labeling and Packaging.........................................................................................55
6.3.2
Storage ...................................................................................................................56
Drug Accountability.................................................................................................56
6.4
Subject Compliance..................................................................................................57
6.5
Retention of Bioavailability and Bioequivalence Testing Samples .........................58
6.6
7.
STUDY PROCEDURES........................................................................................................59
Dosing and Procedure Observations ........................................................................59
7.1
Study Schedule.........................................................................................................59
7.2
7.2.1
Screening Period ....................................................................................................59
Administrative Screening and Remote Consent Process........................59
7.2.1.1
Clinical Screening ..................................................................................60
7.2.1.2
Screening Failure....................................................................................61
7.2.1.3
Rescreening of Subjects .........................................................................61
7.2.1.4
7.2.2
Treatment Period....................................................................................................61
7.2.2.1
Day 1 to Day 2 (Treatment Periods 1 and 2)..........................................61
7.2.3
Final Visit...............................................................................................................61
7.2.4
Follow-up Period ...................................................................................................61
7.2.5
Additional Care of Subjects after the Study ..........................................................62
Study Evaluations and Procedures ...........................................................................62
7.3
7.3.1
Demographic and Other Baseline Characteristics .................................................62
Demographics.........................................................................................62
7.3.1.1
7.3.2
Safety .....................................................................................................................62
Medical and Medication History............................................................62
7.3.2.1
Physical Examination (Including Height and Weight)...........................63
7.3.2.2
Adverse Event Collection.......................................................................63
7.3.2.3
Vital Signs, Blood Pressure and Pulse Rate ...........................................63
7.3.2.4
Clinical Laboratory Evaluations.............................................................64
7.3.2.5
Pregnancy Test .......................................................................................66
7.3.2.6


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Drug and Alcohol Screen .......................................................................66
7.3.2.7
Serology Screen......................................................................................66
7.3.2.8
Electrocardiogram ..................................................................................67
7.3.2.9
7.3.3
Pharmacokinetic Procedures..................................................................................68
Pharmacokinetic Blood Sample Collection and Handling Procedures ..68
7.3.3.1
Shipment of Plasma Pharmacokinetic Samples .....................................69
7.3.3.2
Pharmacokinetic Plasma Assay Methodology .......................................69
7.3.3.3
7.3.4
Pharmacodynamic Procedures...............................................................................69
Pharmacodynamic Blood Sample Collection and Handling 
7.3.4.1
Procedures ..............................................................................................70
Shipment of Serum Pharmacodynamic Samples ...................................70
7.3.4.2
Pharmacodynamic Serum Assay Methodology .....................................71
7.3.4.3
Pharmacodynamic Urine Sample Collection and Handling 
7.3.4.4
Procedures ..............................................................................................71
Shipment of Urine Pharmacodynamic Samples.....................................71
7.3.4.5
Pharmacodynamic Urine Assay Methodology.......................................72
7.3.4.6
7.3.5
Volume of Blood to be Drawn from Each Subject ................................................73
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................76
Definition of Adverse Events, Period of Observation, Recording of Adverse
8.1
Events.......................................................................................................................76
8.1.1
Severity Categorization..........................................................................................76
8.1.2
Relationship Categorization...................................................................................77
8.1.3
Outcome Categorization ........................................................................................77
8.1.4
Symptoms of the Disease under Study ..................................................................77
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................78
8.1.6
Pregnancy...............................................................................................................78
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................79
Serious Adverse Event Procedures...........................................................................79
8.2
8.2.1
Reference Safety Information................................................................................79
8.2.2
Reporting Procedures.............................................................................................79
8.2.3
Serious Adverse Event Definition .........................................................................80
8.2.4
Serious Adverse Event Collection Time Frame.....................................................80
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................81
8.2.6
Fatal Outcome........................................................................................................81
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................81
9.
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................82
Data Collection.........................................................................................................82
9.1


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Clinical Data Management.......................................................................................82
9.2
Data Handling Considerations..................................................................................82
9.3
Statistical Analysis Process......................................................................................82
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......83
9.5
Sample Size Calculation and Power Considerations................................................83
9.6
Study Population ......................................................................................................83
9.7
Pharmacokinetic and Pharmacodynamic Analyses ..................................................83
9.8
9.8.1
Pharmacokinetic Analysis......................................................................................83
Statistical Analysis of Pharmacokinetic Parameters...............................84
9.8.1.1
9.8.2
Pharmacodynamic Analysis...................................................................................84
Statistical Analysis of Pharmacodynamic Parameters ...........................85
9.8.2.1
9.8.3
Pharmacokinetic and Pharmacodynamic Analysis ................................................85
9.8.4
Population Pharmacokinetic and Quantitative System Pharmacology 
Modeling and Simulation.......................................................................................85
Safety Analyses ........................................................................................................86
9.9
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................87
Sponsor’s Responsibilities .......................................................................................87
10.1
10.1.1 Good Clinical Practice Compliance.......................................................................87
10.1.2 Indemnity/Liability and Insurance.........................................................................87
10.1.3 Public Posting of Study Information......................................................................88
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................88
10.1.5 Study Suspension, Termination, and Completion..................................................88
Investigator’s Responsibilities .................................................................................88
10.2
10.2.1 Good Clinical Practice Compliance.......................................................................88
10.2.2 Protocol Adherence and Investigator Agreement ..................................................89
10.2.3 Documentation and Retention of Records .............................................................89
Case Report Forms .................................................................................89
10.2.3.1
Recording, Access, and Retention of Source Data and Study 
10.2.3.2
Documents..............................................................................................89
Audit/Inspection .....................................................................................90
10.2.3.3
Financial Disclosure...............................................................................90
10.2.3.4
Ethical Considerations..............................................................................................90
10.3
10.3.1 Informed Consent...................................................................................................90
10.3.2 Institutional Review Board or Ethics Committee ..................................................91
Privacy and Confidentiality......................................................................................91
10.4
Study Results / Publication Policy ...........................................................................92
10.5
11. REFERENCES .......................................................................................................................94


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12. APPENDICES ........................................................................................................................95
Appendix 1 Protocol History ...................................................................................................96
Appendix 2 Remote Informed Consent Process ....................................................................132


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LIST OF TABLES
Table 1
Schedule of Assessments.................................................................................26
Table 2:
Detailed Schedule of Assessments: Day -1 (Prior to Treatment Periods 1 
and2)................................................................................................................30
Table 3:
Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 
1/Day 2 (QD Regimen)....................................................................................31
Table 4:
Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day
1/Day 2 (BID Regimen)...................................................................................32
Table 5:
Treatment Scheme............................................................................................40
Table 6:
Volume of Blood to be Drawn from Each Subject ..........................................73
LIST OF FIGURES
Figure 1: Study Design Flow Chart .........................................................................................44


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ABBREVIATIONS
1,25(OH)2D3
1,25-dihydroxyvitamin D3, 1,25-dihydroxycholecalciferol, calcitriol
25(OH)D
25-hydroxyvitamin D
1(OH)D3
α-calcidol
AE
adverse event
β-HCG
beta-human chorionic gonadotropin
AUC
area under the curve
AUC0-24
area under the curve between two time points (0-24 hours)
AUC0-t
area under the curve between two time points (0-defined time)
AUC0-inf
area under the curve between two time points (0-infinity)
BID
twice-daily
cAMP
cyclic adenosine monophosphate
CaSR
calcium sensing receptor
CL/F
clearance of drug from plasma
Cmax
maximum concentration
CRA
clinical research associate
CRC
clinical research center
CRF
case report form
CRO
contract research organization
CV%
coefficient variation percent
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
EMA
European Medicines Agency
Emax
maximum effect
EU
European Union
FDA
food and drug administration
FGF23
fibroblast growth factor 23
FSH
follicle stimulating hormone
GCP
good clinical practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIPAA
health Insurance portability and accountability act
ICH
international conference on harmonization
IRB
institutional review board
IRT
interactive response technology


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IV
intravenous
Kel
elimination constant
PD
pharmacodynamic
PK
pharmacokinetic
PR
a time interval on an ECG trace starting from the beginning of the P-wave to the 
beginning of the Q-wave
PTH
parathyroid hormone
QD
once-daily
QRS
a time interval on an ECG trace that represents the depolarization of the 
ventricles
QSPM
quantitative system pharmacology model
QT
a time interval on an ECG trace starting at the beginning of the QRS complex and 
finishing at the end of the T-wave (represents the time taken for the ventricles to 
depolarize & then repolarize)
QTc
the QT interval on an ECG trace that has been corrected
QTcB
the QT interval on an ECG trace that has been corrected using Bazett's formula
QTcF
the QT interval on an ECG trace that has been corrected using Fridericia’s 
formula
RACE
PAR C10 008 protocol
rhPTH(1-84)
recombinant human parathyroid hormone (1-84 amino acids)
REPLACE
CL1-11-040 protocol
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
SERMs
selective estrogen receptor modulators
t½
time to elimination of half of the drug
Tmax
time to maximum concentration
TEmax
time to maximum effect
UK
United Kingdom
US
United States
VZ/F
volume of distribution during terminal phase


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STUDY SYNOPSIS
Protocol number:
SHP634-101
Drug:
rhPTH(1-84)
Title of the study:
An Open-Label, Randomized, Crossover Study to Assess the Pharmacokinetic and PharmacodynamicProfiles
of Once-Daily and Twice-Daily Dose Regimens of recombinant human Parathyroid Hormone(rhPTH[1-84])
Administered Subcutaneously to Subjects withHypoparathyroidism
Number of subjects (total and for each treatmentarm):
Approximately thirty-two (32) subjects are expected to complete the study. A sufficient number of subjects will 
be screened and enrolled to ensure that at least 8 subjects complete each treatment in their assigned cohort and 
provide sufficient data to meet study objectives. Enrollment inthe study will be staggered as 4 sequential cohorts 
(of at least 8 subjects/cohort) and, within each cohort, subjects willbe randomly assigned to 1 of 2 treatment 
sequences in that cohort. Each cohort must have 8 subjects completed beforesubjects can be enrolled into the next 
cohort. A safety review will be conducted after 8 subjects have completed in each of Cohorts 1, 2, and 3 at which 
time a decision will be made whether to proceed to the next cohort. Additionally, expansion of previous cohorts 
can occur, if needed to meet study objectives. Subjects may not participate in more than 1cohort.
Replacement subjects may be enrolled in the event that any subject does not complete each treatment(which
would include the crossover dose). Replacement subjects may be enrolled on a case-by-case basis (as a subject
is discontinued), and, if a subject is replaced, that subject will follow the same 2-period treatment sequenceas
the subject who discontinued (regardless of when the subjectdiscontinued). Cohorts may be expanded to 
include additional subjects to ensure that sufficient data for analysis are collected to complete the study 
objectives.
Investigator(s):
Coordinating Investigator:
Site(s) and Region(s):
This is a global study, with sites planned in North America and countries within Europe. Approximately
20-30 study sites are planned to participate in the study.
Study period (planned):
May 2016-May 2019
Clinical phase:
1
Objectives:
Primary:

To assess the pharmacokinetic profile and pharmacodynamic effects (control of serum calciumand
urinary calcium excretion) of rhPTH(1-84) administered as SC doses of 25μg administeredtwice-daily,
50μg administered twice-daily, and 100μg administered once-daily, as well as the effect of
supplemental oral calcium intake, in subjects with hypoparathyroidism.
Secondary:

To assess the safety and tolerability of rhPTH(1-84) administration in subjectswith
hypoparathyroidism.


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Rationale:
This study is being conducted to characterize the effect of twice-daily administration of rhPTH(1-84) on
pharmacokinetics, pharmacodynamics, safety and tolerability over the course of 24-36 hours as comparedwith
the currently approved once-daily dosing regimen, with and without oral calcium and without active vitamin D.
Investigational product, dose, and mode ofadministration:

The investigational product (rhPTH[1-84]) is provided as a lyophilized powder for reconstitution andis
administered as a subcutaneous (SC) injection in alternating thighs. The lyophilized powder andsterile
water are provided in a dual chamber glass cartridge that requires mixing with a provided mixing
apparatus and delivered with a provided injector pen. Doses of rhPTH(1-84) to be used in this studyare
25µg, 50µg and 100µg as SC injections dependent upon cohort assignment and the order oftreatment
according to the randomization schedule.

Dosing of rhPTH(1-84) will be administered in the presence or absence of supplemental oralcalcium
(dependent upon randomized treatment allocation) which will be provided by the subject or the studysite.
No rescue treatment will be provided by the sponsor.
Methodology:
For each cohort, this study will consist of the Administrative Screening Period (up to 120 days prior to first
dose , if needed), the Clinical Screening Period (within 28 days prior to first dose), 2 treatment periods, the
respective doses of which are to be separated by a washout (≥5 days but ≤30 days) between theadministration
of rhPTH(1-84) or the first administration for once daily or twice daily dosing, respectively, in each period,and
a follow-up visit (30±2 days after the last dose of rhPTH[1-84]) is administered). The maximal total duration of
study participation for a subject is 90 days (~3 months), if the maximum clinical screening, washout and
follow- up visit durations are used. If the Administrative Screening Period is required, the maximum duration 
ofstudy participation is 182 days.
The Administrative Screening Period (within 120 days of the first dose) is permitted (if needed) to allow for the
time required to obtain medical records for subjects interested in participating at a site outside of their
immediate care network. In this case, the subject must sign an informed consent in order to have theirmedical
records released to a participating site. Clinical screening will occur within 28 days of the first dose.Subjects
who meet the inclusion/exclusion criteria as specified in the protocol will report to the Clinical Research Center
(CRC) for admission on Day -2 of Treatment Period 1 in order to confirm entry criteria assessed at that timeand
collect 24-hour serum calcium and urinary calcium profiles prior to treatment on Day 1. Subjects will be
randomly assigned to 1 of 2 treatment sequences prior to administration of rhPTH(1-84) on Day 1 ofTreatment
Period 1, only after all entry criteria have been confirmed. The treatment sequence assignments within each
cohort are as follows:
Treatment Scheme
Cohort
Treatment Period 1
(Day 1)
Treatment Period 2
(Day 1)
1 
(n=8*)
n=4
A
(25 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
A
(25 µg BID, no calcium)
2 
(n=8*)
n=4
C
(50 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
C
(50 µg BID, no calcium)
3 
(n=8*)
n=4
D
(25 µg BID, with calcium)
→
E
(100 µg QD, with calcium)
n=4
E
(100 µg QD, with calcium)
→
D
(25 µg BID, with calcium)
4
(n=8*)
n=4
F
(50 µg BID with calcium)
→
E
(100 µg QD with calcium)
n=4
E
(100 µg QD with calcium)
→
F
(50 µg BID with calcium)


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BID=twice-daily; QD=once-daily 
Where:
Treatment A= 25 µg BID, no supplemental oral calcium 
Treatment B= 100 µg QD, no supplemental oral calcium 
Treatment C= 50 µg BID, no supplemental oralcalcium
Treatment D= 25 µg BID, with supplemental oral calcium 
Treatment E= 100 µg QD, with supplemental oral calcium 
Treatment F= 50 µg BID, with supplemental oralcalcium
With/without calcium refers to adjunctive therapy with dose; no active vitamin D
* at least 8 subjects per cohort
On Day 1 of Treatment Period 1:

Subjects in Cohort 1 will receive rhPTH(1-84) as either a twice-daily regimen (12 hours apart)
of two 25µg doses (without calcium; Treatment A) or a once-daily regimen of one 100µg dose
(without calcium) in the morning (Treatment B).

Subjects in Cohort 2 will receive rhPTH(1-84) as either as a twice-daily regimen (12 hours
apart) of two 50µg doses (without calcium; Treatment C) or a once-daily regimen of one 100µg
dose (without calcium; Treatment B).

Subjects in Cohort 3 will receive rhPTH(1-84) either as a twice-daily regimen (12 hours apart)
of two 25µg doses (with calcium; Treatment D) or a once-daily regimen of one 100µg dose 
(withcalcium; Treatment E).

Subjects in Cohort 4 will receive rhPTH(1-84) either as a twice-daily regimen (12 hours apart)
of two 50µg doses (with calcium; Treatment F) or a once-daily regimen of one 100µg dose 
(withcalcium; Treatment E).
On Day 1 of Treatment Period 2, subjects will receive the alternative treatment (according to the randomization
schedule). For example, if a subject was randomized to cohort 1 and they received Treatment A in thefirst
treatment period, they would receive Treatment B in the second treatment period. All rhPTH(1-84) willbe
administered via SC injection into alternating thighs at eachadministration.
Subjects enrolled in the study must require daily doses of calcium supplements of ≥1000mg prior to baseline
(Day 1). Subjects enrolled in the study must also require minimum daily doses of active vitamin D
(1,25[OH]2D3 [1,25-dihydroxycholecalciferol, (eg, calcitriol, α-calcidol [1(OH)D3])]) of ≥0.25µg calcitriolor
equivalent. Subjects will be expected to adhere to standard meals provided during their confinement in the CRC
during each period (from check-in on Day -2 until discharge on Day 2). All subjects (in all treatment arms) will
take their usual doses at the usual regimen of supplemental oral calcium and active vitamin D on Day -2and
Day-1. For all subjects in all cohorts, active vitamin D supplements must be withheld on Day 1 throughthe
completion of all study procedures on Day 2. Subjects may then resume active vitamin D following finalstudy
procedures on Day 2 at the discretion or direction of the investigator.
During Treatments A, B, and C (Cohorts 1 and 2), supplemental oral calcium and active vitamin D willbe
withheld starting on Day 1 (predose), through the completion of all study procedures on Day 2 for boththe
once-daily and twice-daily dosing regimens. Upon completion of all study procedures on Day 2, subjectswill
then resume their usual supplemental oral calcium and active vitamin D at their next usual dailyschedule.
During Treatments D, E, and F (Cohorts 3 and 4), subjects will withhold active vitamin D on Day 1 buttake
their usual dose(s) of supplemental oral calcium according to their usual regimen, regardless of the
schedule/timing of IP administration(s). Critically, oral calcium supplementation should be identical on Day-1,
Day 1 and Day 2 in Treatment Period 1 and Treatment Period 2. On Day 2, subjects will continue withtheir
usual supplemental calcium regimen (ie, identical on Day -1 and Day 1) and, following the completion of all
study procedures, subjects will then re-start their active vitamin D at their next usual dailyschedule.


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18 Jun 2018
During the crossover washout period, subjects will be instructed to take their usual doses of supplemental oral
calcium and active vitamin D.
For all dosing regimens, rhPTH(1-84) will be administered in the morning of Day 1 of each treatment
period following an overnight fast of at least 8 hours. Subjects will continue to fast until approximately 
2 hoursafter rhPTH(1-84) administration, at which time a standardized meal will be served. For subjects 
assigned tothe twice-daily dose regimen, the evening dose of rhPTH(1-84) will be administered 12 hours 
after themorning dose, and 2 hours prior to the evening meal. A snack or light meal may be provided to 
the subjects prior tothe evening dose, provided it is consumed ≥2 hours prior to rhPTH(1-84) dose
administration.
Serial blood samples for pharmacokinetic analyses will be collected on Day 1 of each treatment period for
the determination of PTH concentrations at predose and up to 24 hour postdose (for those randomized to the
twice- daily regimen, serial PK samples will be collected up to 24 hours post the second dose). These blood
samples will be collected according to the schedule of assessment tables. Serial blood and urine samples for
pharmacodynamic analysis will be collected on Day-1 and on Day 1 predose and following the
administration of rhPTH(1-84) according to the schedule of assessment tables.
Additional blood samples for safety purposes will be collected as specified on the schedule of assessment
tables for assessment of anti-PTH antibodies.
Safety and tolerability will be closely monitored during the time the subject is confined to the CRC during
the study. Adverse events will be recorded from the time the informed consent is signed, through 
completion ofthe study at follow-up.
A safety review will be conducted at the completion of 8 subjects in each of Cohorts 1, 2, and 3 (with or 
without the inclusion of the follow-up visit data), before any subject can be enrolled in the next cohort. The
review will include all available safety data and will include, at a minimum, the Coordinating Investigator 
and the PPD and Shire Medical Monitors. Minutesof the review will be disseminated to all participating
investigators.
One or more interim analyses may be performed in this study. If an analysis is deemed to be necessary, thena
prospective statistical analysis plan will be developed prior to the analysis. The plan will include, at a minimum:

rationale to perform the interim analysis; (2) parameters to be analyzed; and (3) the 
distribution list forthe interim analysis results. Interim data may be used for (but not 
limited to) PK/PD modeling and/orregulatory submissions. The trial will not stop due to 
the results of any interim analysis.
Subjects who complete this study may have the opportunity to enroll into an open-label extension trial ifan
open-label extension study is available and approved by the site’sIRB/EC
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject must meet all of the criteria below in order to be eligible for thestudy:
o An understanding, ability and willingness to fully comply with study procedures and
restrictions.
o Ability to voluntarily provide written, signed, and dated informed consent as 
applicableto participate in the study.
o Adult men or women aged ≥18 years, at the time of consent. The date of subject signature 
ofthe informed consent is defined as the beginning of the Screening Period. The Screening 
Period for this study may encompass both the Administrative Screening Period (if needed) 
and theClinical Screening Period. For purposes of this inclusion criterion, age will only be 
assessed at the timethe informed consent is first signed by the study subject.


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18 Jun 2018
o History of hypoparathyroidism for ≥12 months, post-diagnosis, inclusive of historical
biochemical evidence of hypocalcemia with concomitant serum intact PTH concentrations 
below thelower limit of the laboratory normal range.
o Requirement for supplemental oral calcium treatment ≥1000 mg elemental calcium per day.
o Requirement for therapy with active forms of vitamin D at a minimum dose of ≥0.25µg 
perday (ie, ≥0.25µg calcitriol or equivalent per day).
o Serum calcium level within the laboratory normal reference range based on clinical 
chemistrylab results at the Clinical Screening Visit (based on central and/or local lab 
results) and Treatment Period 1, Day -2 (based on central and/or local lab results), or, if 
outside of normal range, considered not clinically significant by the investigator.
o Urinary calcium excretion ≥200mg (5mmol)/24h, based on a 24-hour collection,
collected anytime during the Clinical Screening Period, but prior to check-in to the 
CRC atTreatment Period 1, Day -2 (based on central and/or local lab results).
o Serum magnesium level within the laboratory normal range at the Clinical Screening 
Visit or,if outside of normal range, considered not clinically significant by the
investigator.
o Serum thyroid function tests within normal laboratory limits at the Clinical Screening 
Visit, or,if outside of normal range, considered as not clinically significant by the
investigator.
o Serum 25(OH)D level between the lower limit of normal and 1.5-fold the laboratory upper
limit of normal, or if outside of this range, considered not clinically significant by the 
investigator, atthe Clinical Screening Visit.
o Serum creatinine <1.5mg/dL (<133µmol/L) AND estimated creatinine clearance
>60mL/minute (>1.002mL/s) at the Clinical Screening Visit, and serum creatinine 
<1.5mg/dL (<133µmol/L)at Treatment Period 1, Day -2.
o Male or non-pregnant, non-lactating female who agrees to comply with any
applicable contraceptive requirements of the protocol or females of non-
childbearingpotential.
Exclusion Criteria:
Subjects will be excluded from the study if any of the following exclusion criteria are met:

Participation in any other investigational drug study in which the last dose of 
investigationaldrug occurred within 3 months prior to Day 1 of Treatment Period 1 (or 
within 5 half-lives, ifthe elimination half-life is greater than 18 days).

Presence or history of a clinically significant disorder involving the cardiovascular,respiratory,
renal, gastrointestinal, immunologic, hematologic, endocrine (with exception of thecondition
under study), or neurologic system(s) or psychiatric disease as determined by theinvestigator.

Known history of hypoparathyroidism resulting from an activation mutation in the calcium
sensing receptor (CaSR) gene or impaired responsiveness to PTH
(Pseudohypoparathyroidism).

Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other
than hypoparathyroidism, including but not limited to, active hyperthyroidism; poorly
controlled insulin-dependent diabetes mellitus or type 2 diabetes mellitus; severe and chronic 
cardiac, liveror renal disease; Cushing's syndrome; neuromuscular disease such as 
rheumatoid arthritis;myeloma; pancreatitis; malnutrition; rickets; recent prolonged 
immobility; active malignancy, bone metastases or a history of skeletal malignancies; 
primary or secondary hyperparathyroidism; a history of parathyroid carcinoma; 
hypopituitarism, acromegaly; or multiple endocrine neoplasia types 1 and 2, as determined 
by the investigator.


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SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018

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 
hormoneexposure levels ranging from 3 to 71 times the exposure levels in humans receiving 
a 100µg dose of rhPTH(1-84). Therefore, 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 predisposingto osteosarcoma or subjects with a prior history of external 
beam or implant radiation therapy involving the skeleton are excluded.

Subjects who have a known history of hypercalcemia during initiation of treatment with
PTH, PTH analogues or fragments of PTH.

Subjects who have a known history of hypocalcemia following abrupt withdrawal of
treatment with PTH, PTH analogues or fragments of PTH.

Subjects dependent on regular parenteral calcium infusions (eg, calcium gluconate) to
maintain calcium homeostasis within 3 months prior to enrollment, as determined by the
investigator.

Use of the following medications prior to administration of investigational product within:
o
14 days – thiazide diuretics
o
30 days – loop diuretics, lithium, systemic corticosteroids (medical judgment isrequired
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).
o
3 months – calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or
N- terminal PTH or PTH-related peptide fragments or analogs
o
For females: changes in hormone replacement therapy within 3 months areexcluded.
Stable (≥ 3 months) hormone replacement therapy is acceptable.
o
6 months – fluoride tablets, oral bisphosphonates, methotrexate, growthhormone,
digoxin, raloxifene or similar selective estrogen receptor modulators (SERMs)
o
12 months – intravenous bisphosphonates, drug or alcohol abuse, as determined bythe
investigator.

Presence of any clinically significant results from laboratory tests, vital signs 
assessments,or ECGs, as judged by the investigator.

Twelve-lead ECG values (average of triplicate readings) demonstrating QTc >450msec 
(males) or >470msec (females) at the Clinical Screening Visit and/or any time points up to 
andincluding predose of Day 1 (Period 1).

Any medical condition or prior therapy that, in the opinion of the investigator, would 
makethe subject unsuitable for this study.

Positive test result for any of the following viral infections at the Clinical Screening Visit:
o
Hepatitis B surface antigen
o
Hepatitis C

Known significant bleeding diathesis that could preclude multiple venipunctures as determinedby
the investigator.

Subjects who have donated a total of 100 mL to 499 mL of whole blood within 30 days priorto
dosing, or subjects who have donated a total of more than 499 mL of whole blood within 
56 days prior to dosing.

A positive screen for drugs of abuse at the Clinical Screening Visit, and/or a positive screenfor
drugs of abuse and alcohol at check-in to the CRC at Treatment Period 1. Subjects taking
prescription medications that might be detected during the urine screen for drugs of abuse (listed
in Section 7.3.2.7) may be enrolled per the investigator’s medical judgment.


Shire 
CONFIDENTIAL 
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SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018

History of a clinically significant illness during the 4 weeks prior to dosing (as determined bythe
investigator).

History of any clinically significant surgery or procedure within 8 weeks of first dose,as
determined by the investigator.

History of an allergic response(s) to PTH or PTH analogs, or other clinically significant
allergies, as determined by the investigator.
Maximum duration of subject involvement in thestudy:
The maximal total duration of study participation for a subject is 90 days (~3 months), if the maximumclinical
screening, washout and follow-up visit durations are used. If the Administrative Screening Period isrequired,
the maximum duration of study participation is 182 days.

The Administrative Screening Period (if needed) may be permitted (up to 120 days prior tofirst
dose) to allow for the time required to authorize release and obtain medical records forsubjects
outside of their immediate care network. The subject must sign an informed consent at theonset
of the Administrative Screening Period in order to authorize and have their medical records
released to a participating site.

The Clinical Screening Period is a maximum of 28 days between the first clinical visit to theCRC
and Day 1 of the first treatment period. Note that this period includes the initial overnightperiod
for the first treatment period (Day -2 to Day -1 inclusive).

There are 2 treatment periods; investigational product is administered on Day 1 of eachperiod.
The 2 treatment periods are separated by a minimum of a 120 hour (5 day) washout period anda
maximum of a 30 day washout period between the administration of the dose (QD), or firstdose
(BID) in each period.

The total maximum duration of active study participation is approximately 90 days whichwould
include the full 28 day Clinical Screening Period, Treatment Period 1, a maximum washout of
30 days between treatments, Treatment Period 2 and follow up of 30±2 days following the last
dose of investigational product.

The total overnight stays for the study (independent of the amount of time used for screeningor
washout periods) comprises 3 nights per treatment period. Therefore, a total of 6 overnightstays
are required during treatment.

The follow up for the study is defined as 30±2 days after the last dose of investigationalproduct.
Endpoints and Statistical Analysis:
Analysis populations
Four analysis populations are defined for this study: the all-enrolled, safety, pharmacokinetic,and
pharmacodynamic populations:

The all-enrolled population consists of all subjects who sign the informed consent form and are 
randomized in the study.

The safety population includes enrolled subjects who have received at least 1 dose of 
rhPTH(1-84).All analyses of safety data will be based on this population.

The pharmacokinetic population consists of all-enrolled subjects who, receive at least 
1 dose of rhPTH(1-84)and have at least 1 evaluable postdose pharmacokinetic 
concentration value available for 1 doseregimen.

The pharmacodynamic population consists of all-enrolled subjects who receive at least 
1 dose of rhPTH(1-84)and have at least 1 evaluable postdose pharmacodynamic value 
available for 1 dose regimen.


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CONFIDENTIAL 
Page 24
SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018
Pharmacokinetic Endpoints:
PTH concentrations will be used to calculate the following pharmacokinetic parameters using a
non- compartmental approach: maximum observed concentration maximum (Cmax), time of maximum
concentration (Tmax), area under the concentration curve (from time zero to the last measurable 
concentration and fromtime zero to infinity (AUC0-t and AUC0-inf), area under the concentration curve 
from time zero to 24 hours post the first dose ([AUC0-24h] for those on the QD regimen, and up to 24 hours 
post the second dose for those onthe BID regimen), elimination rate constant (Kel), apparent clearance 
(CL/F), apparent volume ofdistribution (Vz/F) and elimination half-life (t1/2).
All assessment dates will be related to the first day of rhPTH(1-84) administration. This first dayof
investigational product administration is referred to as Day 1. Day-1 is the day that is preceding Day 1, 
and a Day 0 will not be defined.
Pharmacokinetic analyses based on raw and baseline-adjusted PTH concentrations will be performed.The
baseline is defined as the predose endogenous PTH level on Day 1, and baseline-adjusted PTH
concentrations are to be calculated by subtracting baseline PTH from the raw PTHconcentrations.
Pharmacodynamic Endpoints:
Pharmacodynamic parameters will be computed from the individual concentrations of serumcalcium
(uncorrected and corrected for serum albumin levels), phosphate, albumin, creatinine, magnesium,
1,25(OH)2D3, and FGF23 using a non-compartmental approach. The calcium-phosphate product willbe
computed. Pharmacodynamic parameters will be estimated based with and without baseline adjustments.
The following parameters will be calculated using the serum concentrationdata:

AUC0-24h: the area under the concentration versus time curve, from time 0 to 24 hours

TEmax: time to maximum effect

Emax: maximum effect
The parameters representing urinary excretion of each analysis will be calculated, if dataallow:

Total amount of sodium, calcium, magnesium, citrate, phosphate, cyclic AMP 
(cAMP),and creatinine in each sample

Total amount of sodium, calcium, magnesium, citrate, cAMP, and phosphate excreted 
ineach sample relative to the total amount of creatinine excreted

Renal clearance of sodium, calcium, magnesium, citrate, creatinine, and phosphate 
(mL/min)

Fractional excretion of sodium, calcium, citrate, magnesium, and phosphate
Safety Endpoints:
Safety will be assessed by the following evaluations:

AEs including episodes of hypocalcemia, hypercalcemia, and hypercalciuria

Laboratory test results (hematology, serum chemistries, creatinine clearance,
urinary chemistries (24-hr urinary calcium, sodium, citrate, phosphate, cAMP, 
magnesium,and creatinine excretion), immunology (anti-PTH antibody), and
urinalysis


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Page 25
SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018

ECG

Physical examinations (including vital signs).
Sample Size Justification:
At least 8 subjects with sufficient data to meet the study objectives will be required to complete each 
treatment in each cohort. The sample size wasdetermined based on a similar, prior 
pharmacokinetic/pharmacodynamic study. The number of subjects in this study isnot based on statistical 
power considerations because the statistical analyses are primarily descriptive, and no hypothesis testing is 
specified in the study.
Statistical Methodology for Safety Endpoint(s):
Safety data including clinical laboratory tests, anti-PTH antibodies, concomitant medications, AEs, ECG,
and vital signs will be summarized by treatment and time of collection. Descriptive statistics (arithmetic
mean, standard deviation, median, minimum and maximum) will be calculated for quantitative safety data 
as wellas for the difference from baseline, if applicable. Frequency counts will be compiled for 
classification of qualitative safety data.
Statistical Methodology for PharmacokineticEndpoint(s):
Individual concentrations and pharmacokinetic parameters of PTH will be listed and summarized with
descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient of variation [CV%],
median, minimum, maximum, geometric mean, and geometric CV%) by treatment. Figures of individual
and mean (+/-SD) concentration-time profiles of raw and baseline-adjustment plasma PTH will be
generated on both linear and log scales.
Statistical Methodology for PharmacodynamicEndpoint(s):
Individual concentrations and pharmacodynamic parameters of serum total calcium and albumin-corrected
calcium, phosphate, albumin, creatinine, magnesium 1,25(OH)2D3, and FGF23 will be summarized with
descriptive statistics (number, arithmetic mean, SD, CV%, median, minimum, maximum, geometric mean,
and geometric CV%).
The urinary excretion of calcium, sodium, citrate, magnesium, cAMP, and phosphate will also be
expressed relative to that of creatinine and will be summarized with descriptivestatistics.
Pharmacokinetic-pharmacodynamic correlation between PTH concentrations and the above indicators of
PTH bioactivity will be assessed using exploratory figures. If required, pharmacokinetic/
pharmacodynamicmodels may be developed to describe the effect of PTH concentrations and 
biochemical indicators of PTHactivity.


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SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018
STUDYSCHEDULE(S)
Table 1 Schedule of Assessments
Screening
Predose Assessment
Treatment Period 1
Washout
Predose Assessment
Treatment Period 2
Follow-
up
Study Visit
Admin.
Clinical
TP1, D-2
TP1, D-1
TP1, D1
TP1, D2
W a,b
TP2, D-2
TP2, D-1
TP2, D1
TP2, D2
FU
Study Relative Day/
Study Procedures
-120 to -03
–28 to -03
-2
-1
1
2
-2
-1
1
2
Follow-
up c
Informed consent
X d
X
Medical record 
release
X d
X d
Inclusion/exclusion 
criteria
X
X e
X e
Demography and 
medical/medication 
history
X
X e
Physical exam f
X
X e
X g
Randomization
X h
Vital signs (blood 
pressure, pulse) f ,i, j
X
X
X
X
X
X
X
X
Height and weight f
X
X k
X k, g
Electrocardiogram
(12-lead) f , j, l
X
X
X
X
X
X
X
X
Biochemistry,
hematology, and 
urinalysis f
X m
X
X g
X
X g
X
Serum 25(OH)D
X
Anti-PTH antibody
sampling f
X
X
HIV, HBsAg, and 
HCV screen
X
Pregnancy test f, n
X
X
X
X g
X
FSH levels o
X
Urine drug screening
X
X
X


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SHP634-101 Protocol Amendment 5
rhPTH(1-84) 
18 Jun 2018
Table 1 Schedule of Assessments
Screening
Predose Assessment
Treatment Period 1
Washout
Predose Assessment
Treatment Period 2
Follow-
up
Study Visit
Admin.
Clinical
TP1, D-2
TP1, D-1
TP1, D1
TP1, D2
W a,b
TP2, D-2
TP2, D-1
TP2, D1
TP2, D2
FU
Study Relative Day/
Study Procedures
-120 to -03
–28 to -03
-2
-1
1
2
-2
-1
1
2
Follow-
up c
Alcohol breath test 
screening
X
X
Urine collection 
container provided to 
subject
X p
IP administration
X
X
PK blood sampling j
X
X
X
X
PD blood sampling j
X
X
X
X
X
X
PD urine (continuous 
collection) j
X
X
X
X
X
X
Check-in to CRC
X
X
24-hour urine 
collection obtained
X q
In-house 
confinement
X
X
X
X
X
X
Discharge from CRC
(after last
assessment)
X
X
Adverse
events/serious 
adverse events f
X r
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication f
X
X
X
X
X
X
X
X
X
X
X
Administration of
usual supplemental 
oral calcium and 
active vitamin D
X
X
X
X
X
X
X


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SHP634-101 Protocol Amendment 5
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18 Jun 2018
Table 1 Schedule of Assessments
Screening
Predose Assessment
Treatment Period 1
Washout
Predose Assessment
Treatment Period 2
Follow-
up
Study Visit
Admin.
Clinical
TP1, D-2
TP1, D-1
TP1, D1
TP1, D2
W a,b
TP2, D-2
TP2, D-1
TP2, D1
TP2, D2
FU
Study Relative Day/
Study Procedures
-120 to -03
–28 to -03
-2
-1
1
2
-2
-1
1
2
Follow-
up c
Withhold 
supplemental oral 
calcium and active
vitamin D s
X t
X t
Administration of
supplemental oral 
calcium only (no 
active vitamin D) u
X v
X v
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a Washout period should be ≥5 days (ie, 120 hours) and ≤30 days between first dose of each treatment period (whether dosing regimen is BID or QD).
b The investigator may elect to keep the subject in-clinic for the duration of the study, if the washout period is short (eg, 120-172 hours) and/or there are any safety concerns, and 
provided that there is a minimum washout of ≥120 hours between administration of IP in each treatmentperiod.
c A follow-up visit must be completed 302 days after the last dose of IP.
d If applicable.
e Review and update medical history and re-confirm eligibility.
f In the event a subject is prematurely discontinued from the study, every attempt should be made to complete these assessments.
g The safety blood and urine assessments (Period 1 and Period 2), pregnancy test (for all females, Period 2), physical exam (Period 2), and weight (Period 2) should be collected 
after the scheduled serial PK and PD assessments have been completed on this study day, and prior to discharging the subject from the Clinical Research Center.
h Randomization will occur prior to administration of IP at Treatment Period 1, Day 1 only after all eligibility criteria have been confirmed/re-confirmed.
i Vital sign measurements should be collected in the supine position at each time point.
j See Table 2, Table 3, and Table 4 for detailed collection time points.
k Weight measurementonly.
l ECGs will be performed in triplicate measurement at each time point.
m Includes thyroid function tests, and estimated creatinine clearance (Cockcroft–Gault formula) at Clinical screening visit only.
n Serum β-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time points.
o Females only, to confirm menopausal status.
p At the end of the Clinical Screening Visit, subjects will be provided with a urine collection container to take home. Subjects will be given instructions to provide a 24-hour urine 
collection starting anytime during the Clinical Screening Period, but prior to their next admission to the CRC (eg, Day -3 and ending 24 hours later on Day -2). The sample must 
be kept in cold conditions (~4°C) and returned to the CRC upon collection, as per the instructions provided by the site.
q A 24-hour urine sample should be collected and provided to the site anytime during the Clinical Screening Period, but provision of the sample should be no later than check-in to 
the CRC at Period 1, Day-2.
r Adverse events to be collected from time of informed consent. This includes the period of an administrative screen, ifutilized.
s Applies to subjects assigned to Treatment A, Treatment B and Treatment C only.


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Table 1 Schedule of Assessments
Screening
Predose Assessment
Treatment Period 1
Washout
Predose Assessment
Treatment Period 2
Follow-
up
Study Visit
Admin.
Clinical
TP1, D-2
TP1, D-1
TP1, D1
TP1, D2
W a,b
TP2, D-2
TP2, D-1
TP2, D1
TP2, D2
FU
Study Relative Day/
Study Procedures
-120 to -03
–28 to -03
-2
-1
1
2
-2
-1
1
2
Follow-
up c
t Supplemental oral calcium and active vitamin D will be withheld starting on day of dosing, and through the end of Day 1. Subjects will then resume their usual supplemental oral 
calcium and active vitamin D at their next usual daily schedule on Day 2.
uApplies to subjects assigned to Treatment D, Treatment E and Treatment F only.
v Supplemental oral calcium should be taken according to the subject’s usual daily regimen (but active vitamin D must be withheld).


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Table 2: Detailed Schedule of Assessments: Day -1 (Prior to Treatment Periods 1 and2)
Study Day
-1
1
Time point (relative to 
scheduled dosing time on
Day 1 [QD, 1st dose 
BID])
(hour)
Predose
1
1.5
2
3
4
6
8
10
12
13
13.5
14
15
16
18
20
22
24
Vital signs (blood pressure, 
pulse) a, b
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
ECG (12-lead) a, e
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
IP administration
X d
PK blood sampling
X d
PD blood sampling f
X c
X
X
X
X
X
X
X
X
X d
PD urine sampling g , h
X i
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X d
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include blood 
pressure and pulse.
c These assessments should be performed within 30 minutes prior to the relative time of scheduled administration of IP on Day 1.
d Refer to Detailed Schedule of Assessments (Table 3 and Table 4) for collection time points (note: this time point is the same as the predose collection time point on Day 1.
e ECGs will be performed in triplicate measurement at each time point.
f PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, and FGF23.
g 24- hour urine collection for PD analysis will be collected according to the following collection intervals (relative to the Day 1 morning dose): 0-3 hours, 3-6 hours, 6-9 hours, 
9-12 hours, 12-15 hours, 15-18 hours, 18-24 hours. ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
h PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP and creatinine.
i The predose time point for PD urine sampling is used to signify the action that the subject needs to empty his/her bladder immediately before the start of the 0-3 urine collection 
based on the predicted dosing time of Day 1. It is not a separate predose urine collection.


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Table 3: Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (QD Regimen)
Study Day
1
2
Time point
(relative to dosing time
on Day 1)
(h=hour/m=minute)
Pre-
dose
0
10m
20m
30m
1
1.5
2
4
6
8
10
12
13
13.5
14
16
18
20
22
24
Vital signs (blood 
pressure, pulse) a ,b
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X j
ECG (12-lead) a, d
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X j
Randomization
X e
IP administration
X
PK blood sampling
X c
X
X
X
X
X
X
X
X
X
X
X
PD blood sampling f
X c
X
X
X
X
X
X
X
X
X
X
Anti-PTH antibody
sampling g
X c
PD urine sampling h, i
X k
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include blood 
pressure and pulse.
c These assessments should be performed within 30 minutes prior to the scheduled time for IP dose administration on Day 1.
d ECGs will be performed in triplicate measurement at each time point.
e Randomization will occur prior to administration of IP of Treatment Period 1, Day 1 only (and only after all eligibility criteria have been confirmed/re-confirmed).
f PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, andFGF23.
g The anti-PTH antibody sample should only be collected at Treatment Period 1, predose (regardless of BID or QD regimen), and the sample collected within 30 minutes prior to 
dosing.
h 24- hour urine collection for PD analysis will be collected according to the following collection intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours, 12-15 hours, 15- 18 hours, 
18-24 hours. ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
i PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP, and creatinine.
j The last scheduled serial time point (ie, 24 hours) will also serve as the discharge procedure for these assessments on Day2.
k The urine sampling under predose in this table is to signify the stop of Day -1, 18-24 hour PD urine collection period, and the start of the Day 1, 0-3 hour PD urine collection 
period. It is not a separate predosecollection.


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Table 4: Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (BID Regimen)
Study Day
1
2
Time point
(relative to first
dosing time on 
Day 1)
(h=hour/m=minute)
Predose
0
10m 20m 30m
1
1.5
2
4
6
8
10
Pre-
dose
(12hr)
12
12h
10m
12h
20m
12.5
13
13.5
14
16
18
20
22
24
28
32
36
Vital signs (blood 
pressure, pulse) a, b X c
X
X
X
X
X
X
X c
X
X
X
X
X
X
X
X
X
X k
ECG (12-lead)
a,d
X c
X
X
X
X
X
X
X c
X
X
X
X
X
X
X
X
X
X k
Randomization
X e
IP
administration
X
X
PK blood 
sampling
X c
X
X
X
X
X
X
X
X
X f
X
X
X
X
X
X
X
X
X
X
X
PD blood 
sampling, g
X c
X
X
X
X
X
X f
X
X
X
X
X
X
X
X
Anti-PTH 
antibody
sampling h
X c
PD urine 
sampling i, j
X l
→→→→→→→→→→→→
→→→→→→→→→→→→→→
X


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Table 4: Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (BID Regimen)
Study Day
1
2
Time point
(relative to first
dosing time on 
Day 1)
(h=hour/m=minute)
Predose
0
10m 20m 30m
1
1.5
2
4
6
8
10
Pre-
dose
(12hr)
12
12h
10m
12h
20m
12.5
13
13.5
14
16
18
20
22
24
28
32
36
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include blood pressure 
and pulse.
c These assessments should be performed within 30 minutes prior to the scheduled time for IP dose administration on Day 1.
d ECGs will be performed in triplicate measurement at each timepoint.
e Randomization will occur prior to administration of IP of Treatment Period 1, Day 1 only (and only after all eligibility criteria have been confirmed/re-confirmed).
f Predose PK/PD collection for the second dose of the BID regimen should be completed within 15 minutes prior to the dose.
g PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, and FGF23.
h The anti-PTH antibody sample should only be collected at Treatment Period 1, predose (regardless of BID or QD regimen), and the sample collected within 30 minutes prior to 
dosing.
i 36- hour urine collection for PD analysis will be collected according to the following collection intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours, 12-15 hours,15-18 hours, 
18-24 hours, 24-30 hours, 30-36 hours. ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
j PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP, and creatinine.
k The last scheduled serial time point (ie, 36 hour time point) will also serve as the discharge procedure for these assessments on Day 2.
l The urine sampling under predose in this table is to signify the stop of Day -1, 18-24 hour PD urine collection period, and the start of the Day 1, 0-3 hour PD urine collection 
period. It is not a separate predose collection.


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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 thetransient
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 regulatebone 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 “brainfog”
(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. CirculatingPTH
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 ahigh-calcium-phosphate
product, can potentially can lead to nephrocalcinosis and kidney stones and, ultimately, torenal
impairment (Blaine et al., 2015).


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For further details see the rhPTH(1-84) investigator brochure.
Indication and Current Treatment Options
1.1
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 Dhormone
(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.
Product Background
1.2
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 pharmacokinetics, pharmacodynamics 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 beenperformed.


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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 theskeleton).
Currently available results from animal reproductive toxicology studies suggest that
rhPTH(1-84) is not associated with significant fetal or neonatal toxicity; however the safetyof
rhPTH(1-84) in pregnant or nursing women is not established.
For full details see the rhPTH(1-84) investigatorbrochure.
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 50 μg to 100 μg 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 some subjects receiving treatment for more than 3 years.
In clinical trials, rhPTH(1-84) significantly reduced the calcium-phosphate product. Inthese
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 pharmacokinetic/pharmacodynamic study (C09-002) of single dose 
administration of rhPTH(1-84) in patients with hypoparathyroidism in comparison withcalcitriol 
administration.
The Phase 3 clinical study, REPLACE, was the largest, randomized, placebo controlled clinical 
study conducted in hypoparathyroidism population and was the pivotal study demonstratingthat 
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 serumcalcium, 
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 100 μg SC in the thigh once daily for 6 months. The studymet 
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 total serum calcium (ACSC) concentration that was
maintained within a range of 7.5 to 10.6mg/dL.


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A review of safety data across the hypoparathryoidism program indicated that rhPTH(1-84)
administered in the dose range of 25 to 100 μg 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 
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 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; however, patients 
should be advised 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, pharmacokinetics, efficacy and safety of rhPTH(1-84).
Risk/Benefit and Ethical Assessment
1.3
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, thefollowing:

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).


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These data could not exclude a risk to humans. Because of a potential risk of 
osteosarcoma, use rhPTH(1-84) only in subjects 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. Avoid use of rhPTH(1-84) 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 subjectswith
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 experienceda 
post-treatment event of hypocalcemia. Monitoring of serum calcium during thetreatment
process and after withdrawal can mitigate the risk, along with appropriatemedical
treatment.

The safety of rhPTH(1-84) in pregnant or nursing women has not beenestablished.
Pregnancy tests will be performed on all females on 2 occasions prior to entering the
treatment phase of the study and again on admission to Treatment Period 2, andat
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
Rationale for the Study
2.1
Recombinant human PTH (rhPTH[1-84]) is approved for use in the US as an adjunct to calcium 
and vitamin D to control hypocalcemia in patients with hypoparathyroidism. As a once-dailySC
injection for hypoparathyroidism it has been shown to provide a 24-hour sustained increasein 
serum calcium. Administration of rhPTH(1-84) resulted in dose-related increases in totalserum 
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.
The present study is being conducted to characterize the effects of twice-daily administration of 
rhPTH(1-84) on pharmacokinetics, pharmacodynamics, safety and tolerability over the course of
24 hours as compared with the current once-daily dosing regimen.
Study Objectives
2.2
2.2.1
Primary Objectives
To assess the pharmacokinetic profile and pharmacodynamic effects (control of serum calcium 
and urinary calcium excretion) of rhPTH(1-84) administered as SC doses of 25μg administered 
twice-daily, 50μg administered twice-daily, and 100μg administered once-daily, as well as the 
effect of supplemental oral calcium intake, in subjects with hypoparathyroidism.
Secondary Objectives
2.3
To assess the safety and tolerability of rhPTH(1-84) administration in subjectswith 
hypoparathyroidism.


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3. STUDY DESIGN
Study Design and Flow Chart
3.1
The present study is an open-label, randomized, multi-center, 4 cohort, 2-period crossover study 
comparing QD and BID dosing regimens of rhPTH(1-84) and the effect of adjunctive calcium 
(with no active vitamin D) in male and female adult subjects with a history of 
hypoparathyroidism.
A sufficient number of subjects will be screened and enrolled to ensure that at least 8 subjects 
complete each treatment and provide sufficient data to meet the study objectives in their assigned 
cohort. Enrollment in the study will be staggered as 4 sequential cohorts (of at least 8 subjects 
per cohort, including 1 treatment crossover within each cohort), such that at least 8 subjects in 
1 cohort must complete the study before subjects can be enrolled in the next cohort. A safety 
review will be conducted after 8 subjects have completed in each of Cohorts 1, 2 and 3 at which 
time a decision will be made whether to proceed to the next cohort. Cohorts may be expanded to 
include additional subjects to ensure that sufficient data for analysis are collected to complete the 
study objectives. Subjects may not participate in more than 1 cohort. Within each cohort, 
subjects will be randomly assigned to 1 of 2 treatment sequences prior to first dosing on Day 1 of
Treatment Period 1. The treatment sequence assignments within each cohort are as follows:
Table 5: Treatment Scheme
Cohort
Treatment Period 1
(Day 1)
Treatment Period 2
(Day 1)
1 
(n=8*)
n=4
A
(25 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
A
(25 µg BID, no calcium)
2 
(n=8*)
n=4
C
(50 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
C
(50 µg BID, no calcium)
3 
(n=8*)
n=4
D
(25 µg BID, with calcium)
→
E
(100 µg QD, with calcium)
n=4
E
(100 µg QD, with calcium)
→
D
(25 µg BID, with calcium)
4 
(n=8*)
n=4
F
(50 µg BID with calcium)
→
E
(100 µg QD with calcium)
n=4
E
(100 µg QD with calcium)
→
F
(50 µg BID with calcium)
BID=twice-daily; QD=once-daily
Where:
Treatment A= 25 µg BID, no supplemental oral calcium Treatment B= 100 µg QD, no supplemental oral calcium Treatment 
C= 50 µg BID, no supplemental oralcalcium Treatment D= 25 µg BID, with supplemental oral calcium Treatment E= 100 µg 
QD, with supplemental oral calcium Treatment F= 50 µg BID, with supplemental oralcalcium
With/without calcium refers to adjunctive therapy with dose; no active vitamin D
*at least 8 subjects per cohort


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Replacement subjects may be enrolled in the event that any subjects do not complete each 
treatment (which would include the crossover dose). Replacement subjects may be enrolled on a 
case-by-case basis (as a subject is discontinued), and, if a subject is replaced, that subject will 
follow the same 2-period treatment sequence as the subject who discontinued (regardless of 
when the subject discontinued).
This study will consist of the Administrative Screening Period (within 120 days of Day 1 of 
Period 1) that includes the time required to authorize release and obtain medical records for
subjects participating at sites outside their immediate care network (if applicable); the Clinical 
Screening Period; 2 treatment periods which are to be separated by a washout (≥5 days but 
≤30 days) between the dose or first dose of investigational product in each period (for QD or
BID dosing, respectively); and a follow-up visit (30±2 days after the last dose ofinvestigational
product is administered). The maximal total duration of study participation for a subject is
90 days (~3 months), if the maximum clinical screening, washout and follow-up visit durations
are used. If the Administrative Screening Period is required, the maximum duration of study 
participation is 182 days.
Clinical screening will occur within 28 days of the first dose. Subjects who meet the 
inclusion/exclusion criteria as specified in the protocol will report to the Clinical Research 
Center (CRC) for admission on Day -2 of Treatment Period 1, in order to confirm entry criteria 
assessed at that time, and collect 24-hour serum calcium and urinary calcium profiles priorto 
treatment, starting on Day 1. Subjects will be randomized prior to administration of
investigational product on Day 1 of Treatment Period 1, only after all entry criteria have been 
confirmed.
On Day 1 of Treatment Period 1:

Subjects in Cohort 1 will receive rhPTH(1-84) as either a twice-daily regimen (12 hours 
apart) of two 25µg doses (without calcium) or a once-daily regimen ofone 100µg dose 
(without calcium) in the morning

Subjects in Cohort 2 will receive rhPTH(1-84) as either as a twice-daily regimen
(12 hours apart) of two 50µg doses (without calcium) or a once-daily regimen of one 
100µg dose (without calcium)

Subjects in Cohort 3 will receive rhPTH(1-84) either as a twice-daily regimen(12 hours 
apart) of two 25µg doses (with calcium) or a once-daily regimen of one100µg dose (with
calcium).

Subjects in Cohort 4 will receive rhPTH(1-84) either as a twice-daily regimen(12 hours 
apart) of two 50µg doses (with calcium) or a once-daily regimen of one100µg dose (with
calcium).
On Day 1 of Treatment Period 2, subjects will receive the alternative treatment (according to the 
randomization schedule), following a washout period (≥5 days [ie, 120 hours] and ≤30 days)
between administration of the dose or first dose ([for once-daily or twice-dailydosing,
respectively] of each treatment period). All investigational product will be administered via SC 
injection into alternating thighs at each administration.


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At each treatment period, subjects will report to the CRC on Day-2, remain in the CRC through 
Day 2, and be discharged following the last scheduled assessment on Day 2 (investigators may
elect, at their discretion, to keep the subject in-clinic after Treatment Period 1 for the duration of
the washout period, eg, if the washout period is short [eg, 120-172 hours] or there are anysafety 
concerns).
For once-daily treatments (Treatments B and E), subjects will receive a single subcutaneousdose 
of rhPTH(1-84) in the morning on Day 1. For twice-daily treatments (Treatments A, C, D, and
F), subjects will receive a subcutaneous dose of rhPTH(1-84) in the morning followed by the
second dose 12 hours later on Day 1 (in the opposite thigh). If randomized to rhPTH(1-84) with 
calcium, subjects will take their usual supplemental oral calcium on Day 1 per their usual
schedule. Prior to discharge from the CRC at each treatment period, subjects will be given
specific instructions for when to take their supplemental oral calcium and active vitamin D 
supplements during the day(s) when subjects are not in the CRC.
Subjects enrolled in the study must require daily doses of calcium supplements of ≥ 1000 mg 
prior to baseline (Day 1). Subjects enrolled in the study must also require minimum daily doses
of active vitamin D of ≥0.25g (ie, 0.25μg calcitriol or equivalent). Subjects will be expected to 
adhere to standard meals provided during their confinement in the CRC during each period (from 
check-in on Day -2 until discharge on Day 2). All subjects (in all treatments) will take their usual 
doses at the usual regimen of supplemental oral calcium and active vitamin D on Day -2 and
Day -1. For all subjects in all cohorts, active vitamin D supplements must be withheld on Day1 
through completion of all study procedures on Day 2. Subjects may resume active vitamin D 
following final procedures on Day 2 at the discretion or direction of the investigator.
During Treatments A, B, and C (Cohorts 1 and 2), supplemental oral calcium and active vitamin 
D will be withheld starting on Day 1 (predose), through the completion of all study procedures 
on Day 2 for both the once-daily and twice-daily dosing regimens. Upon completion of all study 
procedures on Day 2, subjects will then resume their usual supplemental oral calcium and active 
vitamin D at their next usual daily schedule.
During Treatments D, E, and F (Cohorts 3 and 4), subjects will withhold active vitamin D on 
Day 1 but take their usual dose(s) of supplemental oral calcium according to their usual regimen, 
regardless of the schedule/timing of investigational product administration(s).
Critically, oral calcium supplementation should be identical on Day -1, Day 1 and Day 2 in 
Treatment Period 1 and Treatment Period 2. On Day 2, subjects will continue with theirusual 
supplemental calcium regimen (ie, identical on Day -1 and Day 1), and, following the 
completion of all study procedures, subjects will then re-start their active vitamin D at their next 
usual daily schedule.
During the washout period, subjects will be instructed to take their usual doses of supplemental 
oral calcium and active vitamin D.
Any subject who experiences symptoms of hypocalcemia or hypercalcemia may be treated atthe
investigator’s discretion, as per local standards. This may include, but is not limited to, 
intravenous (IV) calcium and/or fluids.


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For all dosing regimens, rhPTH(1-84) will be administered in the morning of Day 1 ofeach
treatment period following an overnight fast of at least 8 hours. Subjects will continue to fast 
until approximately 2 hours after rhPTH(1-84) administration, at which time a standardized meal 
will be served (see Section 4.3 item 5). For subjects assigned to the twice-daily dose regimen,the 
evening dose of investigational product will be administered 12 hours after the morning dose,
and 2 hours prior to the evening meal. A snack or light meal may be provided to the subjects 
prior to the evening dose, provided it is consumed ≥2 hours prior to investigational product dose
administration. It is suggested that lunch be divided into 2 portions, the first portion consumed at 
lunch, and the second portion consumed as the snack or light meal.
Serial blood samples for pharmacokinetic analysis will be collected on Day 1 of each treatment 
period for the determination of PTH concentrations at predose and up to 24 hours post morning 
dose (up to 24 hours post second dose for the twice-daily regimen). These blood samples willbe
collected according to the Schedule of Assessments (Table 3 and Table 4). Serial blood and urine 
samples for pharmacodynamic analysis will be collected on Day -1, predose and on Day1 
following the administration of rhPTH(1-84) for the determination of concentrations of serum
total calcium (uncorrected and corrected for serum albumin levels), phosphate, magnesium, 
creatinine, albumin, 1,25(OH)2D3, and fibroblast growth factor 23 (FGF23), and urinary 
excretion of calcium, sodium, citrate, phosphate, cAMP, magnesium, and creatinine and the
calcium-phosphate product will be determined. In addition, serum samples will be collected and 
analyzed for anti-PTH antibodies (for safety purposes) at the time points specified in Table 1, 
Table 3, and Table 4. Samples will be analyzed using a validated methodology.
Safety and tolerability will be monitored closely during the time the subject is in-clinicduring the 
study. AEs will be recorded from the time the informed consent is signed, through completion of 
the study at follow-up.
A safety review will be conducted at the completion of 8 subjects in each of Cohorts 1, 2 and 3
(with or without the inclusion of the follow-up visit data), before any subject can be enrolled in 
the next cohort. The review will include all available safety data and will include, at a minimum, 
the Coordinating Investigator and the PPD and Shire Medical Monitors. Minutes of the review 
will be disseminated to all participating investigators. Expansion of previous cohorts can occur 
concurrently if further information is required. Cohorts may be expanded to include additional 
subjects to ensure that sufficient data for analysis are collected to complete the study objectives.
One or more interim analyses may be performed in this study. If the analysis is deemed to be 
necessary, then a prospective statistical analysis plan will be developed prior to the analysis. The
plan will include, at a minimum: (1) rationale to perform the interim analysis; (2) parameters to
be analyzed; and (3) the distribution list for the interim analysis results. Interim data may be used 
for (but not limited to) PK/PD modeling and/or regulatory submissions. The trial will not stop 
due to the results of any interim analysis.
Subjects who complete this study may have the opportunity to enroll into an open-label extension
trial if an open-label extension study is available and approved by the site’s IRB/EC.






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Duration and Study Completion Definition
3.2
The subject’s maximum duration of participation is expected to be approximately 90 days or
3 months (if the maximum Clinical Screening Period, washout and follow-up periods are
utilized). If the Administrative Screening Period is required, the maximum duration of study
participation is 182 days. The study will be completed in approximately 36 months.
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.
Sites and Regions
3.3
It is anticipated that this study will be a multi-site, multi-country study. The regions to be 
targeted include North America and countries within Europe. It is expected that approximately 
20-30 sites in those regions will enroll approximately 1-2 subjects per site.


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4. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
Inclusion Criteria
4.1
The subject will not be considered eligible for the study without meeting all of the criteria below.
Subjects cannot be enrolled or randomized before all inclusion criteria (including test results) are 
confirmed.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated informed consent as applicable 
to participate in the study.
3. Adult men or women aged ≥18 years at the time of consent. The date of subject signature 
of the informed consent is defined as the beginning of the Screening Period. The 
Screening Period for this study may encompass both the Administrative Screening Period 
(if needed) and the Clinical Screening Period. For purposes of this inclusion criterion, age 
will only be assessed at the time the informed consent is first signed by the study subject.
4. History of hypoparathyroidism for ≥12 months, post-diagnosis, inclusive of historical 
biochemical evidence of hypocalcemia with concomitant serum intact PTH 
concentrations below the lower limit of the laboratory normal range.
5. Requirement for supplemental oral calcium treatment ≥1000 mg elemental calcium per 
day.
6. Requirement for therapy with active forms of vitamin D at a minimum dose of ≥0.25µg 
per day (ie, ≥0.25µg calcitriol or equivalent per day).
7. Serum calcium level within the laboratory normal reference range based on clinical
chemistry lab results at the Clinical Screening Visit (based on central and/or local lab 
results) and Treatment Period 1, Day -2 (based on central and/or local lab results), or if 
outside of normal range, considered not clinically significant by the investigator.
8. Urinary calcium excretion ≥200mg (5mmol)/24h, based on a 24-hour collection, 
collected anytime during the Clinical Screening Period, but prior to check-in to the CRC 
at Treatment Period 1, Day -2 (based on central and/or local lab results).
9. Serum magnesium level within the laboratory normal range at the Clinical Screening 
Visit or, if outside of normal range, considered not clinically significant by the 
investigator.
10. Serum thyroid function tests within normal laboratory limits at the Clinical Screening 
Visit, or, if outside of normal range, considered as not clinically significant by the 
investigator.


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11. Serum 25(OH)D level between the lower limit of normal and 1.5-fold the laboratory 
upper limit of normal, or, if outside of this range, considered not clinically significant by 
the investigator, at the Clinical Screening Visit.
12. Serum creatinine <1.5 mg/dL (<133µmol/L) AND estimated creatinine clearance 
>60 mL/minute (>1.002mL/s) at the Clinical Screening Visit, and serum creatinine 
<1.5 mg/dL (<133µmol/L) at Treatment Period 1, Day -2.
13. Male or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
Exclusion Criteria
4.2
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Participation in any other investigational drug study in which the last dose of
investigational drug occurred within 3 months prior to Day 1 of Treatment Period 1 (or 
within 5 half-lives, if elimination half-life is greater than 18 days).
2. Presence or history of a clinically significant disorder involving the cardiovascular, 
respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine (with exception
of the condition under study), or neurologic system(s) or psychiatric disease as 
determinedby the investigator.
3. Known history of hypoparathyroidism resulting from an activation mutation in the CaSR 
gene or impaired responsiveness to PTH (pseudohypoparathyroidism).
4. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis
other than hypoparathyroidism, including but not limited to, active hyperthyroidism;
poorly controlled insulin-dependent diabetes mellitus or type 2 diabetes mellitus; severe 
and chronic cardiac, liver or renal disease; Cushing's syndrome; neuromuscular disease 
suchas rheumatoid arthritis; myeloma; pancreatitis; malnutrition; rickets; recent
prolonged immobility; active malignancy, bone metastases or a history of skeletal
malignancies; primary or secondary hyperparathyroidism; a history of parathyroid
carcinoma; hypopituitarism, acromegaly; or multiple endocrine neoplasia types 1 and 2, 
as determined by the investigator.
5. In male and female rats, parathyroid hormone caused an increase in the incidenceof
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 
humansreceiving a 100µg dose of rhPTH(1-84). Therefore, 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 are excluded.
6. Subjects who have a known history of hypercalcemia during initiation of treatment with 
PTH, PTH analogues or fragments of PTH.


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7. Subjects who have a known history of hypocalcemia following abrupt withdrawalof
treatment with PTH, PTH analogues or fragments of PTH.
8. Subjects dependent on regular parenteral calcium infusions (eg, calcium gluconate)to 
maintain calcium homeostasis within 3 months prior to enrollment, as determined by the
investigator.
9. Use of the following medications prior to administration of investigational product
within:

14 days– thiazide diuretics

30 days – loop diuretics, lithium, 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.
10. Presence of any clinically significant results from laboratory tests, vital signs 
assessments, or electrocardiograms (ECGs), as judged by the investigator.
11. Twelve-lead ECG values (average of triplicate readings) demonstrating QTc>450msec
(males) or >470 msec (females) at the Clinical Screening Visit and/or any time points up
to and including predose of Day 1 (Period 1).
12. Any medical condition or prior therapy that, in the opinion of the investigator, would
make the subject unsuitable for this study.
13. Positive test result for any of the following viral infections at the Clinical Screening Visit:

Hepatitis B surface antigen

Hepatitis C

HIV
14. Known significant bleeding diathesis that could preclude multiple venipunctures as 
determined by the investigator.
15. Subjects who have donated a total of 100 mL to 499 mL of whole blood within 30 days
prior to dosing, or subjects who have donated a total of more than 499 mL of whole blood 
within 56 days prior to dosing.


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16. A positive screen for drugs of abuse at the Clinical Screening Visit, and/or a positive
screen for drugs of abuse and alcohol at check-in to the CRC at Treatment Period 1. 
Subjectstaking prescription medications that might be detected during the urine screen 
for drugs ofabuse (listed in Section 7.3.2.7) may be enrolled per the investigator’s 
medical judgment.
17. History of a clinically significant illness during the 4 weeks prior to dosing (as determined
by the investigator).
18. History of any clinically significant surgery or procedure within the past 8 weeks, as 
determined by the investigator.
19. History of an allergic response(s) to PTH or PTH analogs, or other clinically significant 
allergies, as determined by the investigator.
Restrictions
4.3
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 alcohol 48 hours prior to admission to the CRC and during
the in-house stay at the CRC.
3. Subjects should refrain from use of tobacco or any products containing nicotine within
60 minutes prior to the collection of any vital signs, ECG or blood draw while confined in
the CRC during each treatment period.
4. On Day 1 when the investigational product is to be administered in the morning (for all 
dosing regimens), subjects will be required to fast for at least 8 hours prior to dose of 
administration and continuing through 2 hours after administration of the investigational 
product. For subjects assigned to the BID dose regimen, the evening dose of
investigational product will be administered 12 hours after the morning dose, and 2 hours 
prior to the evening meal. A snack or light meal may be provided to the subjects prior to 
the evening dose, provided it is consumed ≥2 hours prior to investigational product dose
administration.
5. 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 
(meaning that the food options/choices offered to each subject within the site are the 
same, not the specifics of each food choice at each meal). The meal choices for each 
subject in Period 2 should be identical with the meal choices in Period 1. This does not
mean that the same meal choices need to be the same within a treatment period, but must 
be identical per day across both Period 1 and Period 2. Copies of the menus will be 
provided to the sponsor/sponsor’s designee for approval prior to the start of the study for 
each subject (ie, prior to the first in- patient visit per subject at each site). While confined, 
the total daily nutritionalcomposition should be approximately 50% carbohydrate, 35% 
fat, and 15% protein. The daily caloric intake per subject should not exceed 
approximately 3200 kcal.


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Reproductive Potential
4.4
4.4.1
Female Contraception
Sexually active females of child-bearing potential should be using an acceptable form of 
contraception. Females of child-bearing 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 child-bearing 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 30 days following the last dose of
investigational product.
Female subjects should beeither:

Post-menopausal (12 consecutive months of spontaneous amenorrhea).Post-menopausal 
status will be confirmed at Screening with a follicle-stimulating hormone (FSH) 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 child-bearing potential with a negative urine and/or serum -HCG pregnancy 
test at the screening visit, upon check-in for each treatment period, at discharge from 
clinic after the second treatment period and at follow up. Females must agree to abstain 
from sexual activity that could result in pregnancy or agree to use acceptable methods of
contraception.
Acceptable methods of contraceptionare:

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 one 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 last dose of investigational product. Male subjects must be advised 
not to donate sperm during the course of the study and within 3 months of the last dose of 
investigational product. Acceptable methods of contraception for male subjects are:

Double-barrier methods (eg, condoms with spermicidal gel or foam)


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Discontinuation of Subjects
4.5
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 CRF and source documents.
Randomized subjects who discontinue from the study may be replaced at the sponsor’s discretion 
to ensure that at least 32 subjects complete the study and provide sufficient data to meet the study 
objectives.
4.5.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in thesubject’s
medical record and on the CRF. 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 
entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Other (If “Other” is selected, the investigator must specify on the CRF)
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
Prior Treatment
5.1
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins 
[except where required by the study] and non-pharmacological treatment such as psychotherapy,
as appropriate) received within 30 days (or as defined elsewhere in this protocol) or 
pharmacokinetic equivalent of 5 half-lives, (whichever is longer) of the date of first dose of 
investigational product. Prior treatment information must be recorded on the appropriate CRF 
page.
Concomitant Treatment
5.2
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 CRF page. Calcium and vitamin D used prior 
to, and during, the study must be included as concomitant medication.
For this study it is imperative that the administration times and dose strengths of all calcium and 
active vitamin D be documented accurately and completely in the source document andrecorded 
in the CRF for Days -1, 1, and 2 of both treatment periods.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications and supplements during the course of the
study except for those prescribed by their physician (including calcium and vitamin D as 
mandated by protocol) and not excluded in the exclusion criteria. Any medication which is 
considered necessary for the subject’s safety and wellbeing may be given at the discretion of the
investigator. The administration of all medications and supplements (including investigational 
products) must be listed on the appropriate CRF page.


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6. INVESTIGATIONAL PRODUCT
Identity of Investigational Product
6.1
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 test product in the cartridge must be mixed using the provided 
mixing apparatus, and only administered via the injector pen which is also provided. 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.
No additional investigational product will be supplied. It is expected that subjects will continue 
to take their own supplemental oral calcium and vitamin D (except when instructed to hold at the 
times indicated in the current protocol) and that any products required for emergency treatment, 
eg, fluid or calcium replacement, be provided by the study physician.
Administration of Investigational Product(s)
6.2
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomize a subject into the study (for any of the proposed treatment groups). Randomization 
will occur through an interactive response system. Randomization of a subject will trigger 
replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
This is an open label, randomized, 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 screen failures, the screening number will be the identifying number used throughout the 
CRF.
The actual treatment given to individual subjects is determined by a randomization schedule.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, and will be allocated prior to dosing after eligibility has been determined.
A randomization number is allocated immediately prior to dosing once eligibility has been 
determined. Once a randomization number has been assigned, that number must not be used 
again (if for example, a subject is withdrawn from the study). If a randomization number is
allocated incorrectly, the study monitor must be notified as soon as the error is discovered.
Individual subject treatment is automatically assigned by via interactive response technology 
(IRT).


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6.2.3
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 randomly assigned to 1 of 2 
treatment sequences (according to the randomization schedule) prior to dosing on Day 1 of 
Treatment Period 1, and administered investigational product (see Table 5):

On Day 1 of Treatment Period 1, subjects in Cohort 1 will receive rhPTH(1-84) as either 
a twice-daily regimen (12 hours apart) of two 25µg doses (without calcium; Treatment A) 
or a once-daily regimen of one 100µg dose (without calcium) in the morning (Treatment 
B). On Day 1 of Treatment Period 2, subjects in Cohort 1 will receive the alternative
treatment.

On Day 1 of Treatment Period 1, subjects in Cohort 2 will receive rhPTH(1-84) as either 
as a twice-daily regimen (12 hours apart) of two 50µg doses (without calcium; Treatment 
C) or a once-daily regimen of one 100µg dose (without calcium; Treatment B). On Day 1 
of Treatment Period 2, subjects in Cohort 2 will receive the alternative treatment.

On Day 1 of Treatment Period 1, subjects in Cohort 3 will receive rhPTH(1-84) as either 
a twice-daily regimen (12 hours apart) of two 25µg doses (with calcium; Treatment D) or 
a once-daily regimen of one 100µg dose (with calcium; Treatment E). On Day 1 of 
Treatment Period 2, subjects in Cohort 3 will receive the alternative treatment.

On Day 1 of Treatment Period 1, subjects in Cohort 4 will receive rhPTH(1-84) as either 
a twice-daily regimen (12 hours apart) of two 50µg doses (with calcium, Treatment F) or 
a once-daily regimen of one 100µg dose (with calcium, Treatment E). On Day 1 of 
Treatment Period 2, subjects in Cohort 4 will receive the alternative treatment.
A full description of the preparation of the investigational product and guidelines for 
administration can be found in documents that will be provided.
6.2.4
Unblinding the Treatment Assignment
Not Applicable.
Labeling, Packaging, Storage, and Handling
6.3
6.3.1
Labeling and Packaging
Study sites 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.
A caution statement limiting the investigational product to the clinical trial will be appended as 
regionally required. For example, in the US the following statement will be appended ‘For 
clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or US) Law to 
Investigational Use’ and the statement ‘Keep out of the reach of children’.


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Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, and 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.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.2
Storage
The investigator has overall responsibility for ensuring that the 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 study team. The pharmacist/nominated 
team member will enter the unique subject identifier (if allowed by local law/regulations) on the
investigational product labels 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.
Drug Accountability
6.4
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 
medication will be documented on the CRFs 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 thetransfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures andrecords.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used
investigational product 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 (or designated contract research 
organization [CRO]). 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 must be packed in a tamper-evident
manner to ensure product integrity. Contact the sponsor or sponsor representative for
authorization to return any investigational product prior to shipment. Shipment of all returned 
investigational product must comply with local, state, and national laws.
Only in exceptional circumstances, and when agreed by the sponsor in advance, a site may be 
required to destroy the used/unused supplies locally (based on their institution’s SOPs, 
guidelines, hospital/pharmacy regulations, etc.). In this case, and only with the written agreement
of the sponsor, all unused stock, and empty/used investigational product may be destroyed at the 
site or a local facility. In this case, destruction records identifying what was destroyed, when and 
how, must be obtained with copies provided to the sponsor. Destruction of investigational 
products must be in accordance 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.
Subject Compliance
6.5
Compliance must be assessed by observation of dosing by the investigator or designee. The 
investigator/nominated person will record details on the drug accountability log(s) and/or source
documents. In addition, details of the dosing time (time, date, dose level) will be captured in the 
appropriate CRF.


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Retention of Bioavailability and Bioequivalence Testing Samples
6.6
Not Applicable.


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7. STUDY PROCEDURES
Dosing and Procedure Observations
7.1
Study Schedule
7.2
See Table 2, Table 3, and Table 4 schedules of 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 AE reporting

ECG

Vital signs

Pharmacodynamic blood sampling*

Pharmacokinetic blood sampling*

Clinical laboratory tests*

Physical examination
* In order to avoid potential for cross-contamination of tube additives when collecting blood 
samples at one time point for different assays, all tubes requiring serum (eg. pharmacodynamic 
samples, anti-PTH antibody, chemistry panel, T3, T4, TSH, serum β-HCG, FSH, HBsAG, HIV, 
and 25[OH]D samples) should be drawn prior to any tubes requiring plasma (eg, 
pharmacokinetic and hematology samples). This sequence is important because serum samples 
require collection without anticoagulant (red top tube) which should be collected prior to samples 
requiring an anticoagulant (ie, purple top tube: being either a K3EDTA tube or a K2EDTA tube).
NOTE: Blood sampling for pharmacodynamic and pharmacokinetic evaluations must be
performed at the precise protocol-scheduled time. Actual sampling time(s) must be accurately 
recorded in the source document and appropriate CRF.
7.2.1
Screening Period
The Screening Period may consist of the Administrative Screening Period (if needed) prior to the 
Clinical Screening Period.
Administrative Screening and Remote Consent Process
7.2.1.1
The Administrative Screening Period is the time needed to assist those subjects and study sites 
who may need to obtain historical medical records of a potential subject to confirm partial 
eligibility and who may, or may not, be remote from the study site. An informed consent 
document must be signed by the subject at the start of the administrative screen process and be 
provided to the study site. A copy of the signed informed consent must be given to the subject for 
their records.


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The consent process may be performed remotely only if it is in compliance with the site’s local 
and/or regional regulations, and approved by the site’s IRB/EC. Details of the remote consent 
process are provided in Appendix 2. From the time the subject provides a signed consent form,
the subject will be registered as a study participant. The Administrative Screening Period is only 
for information gathering purposes (medical records), and NOT for any active screening
procedures performed on the study subject. As such, it is not part of the active screening process.
The Administrative Screening Period to collect appropriate medical records may be performed 
up to 120 days prior to Day 1 of Treatment Period 1. Adverse events will be captured from the 
date the subject signs the informed consent document. If the subject appears to be eligible for the 
study from a review of the medical records, the subject must then complete a clinical screen 
(described below).
Clinical Screening
7.2.1.2
The Clinical Screening Period differs from the Administrative Screening Period in that the 
subject is physically present at the CRC during the Clinical Screening Visit and/or completes a 
required assessment in the study (outlined in Table 1). Following a subject’s informed consent, 
the study specific screening procedures can be conducted.

For any subject who does not require an administrative screen, the subject must sign an 
informed consent at the Clinical Screening Visit, prior to any study-specific procedures 
being performed.

For any subject who completes an administrative screen, the subject must sign a (new) 
informed consent (and be given a new subject number) at the Clinical Screening Visit, 
prior to any study-specific procedures being performed (the subject will be considered as 
an administrative screen failure under the prior assigned subject number).
Clinical screening visit procedures must be completed within 28 days prior to receiving the first 
dose of Investigational Product. All clinical screening assessments and procedures are to be 
performed by the principal investigator or a qualified designee. See Table 1 for a complete list of 
clinical screening procedures to be performed.
The Clinical Screening Period is comprised of 2 parts, Day -28 to Day -3 and Day -2 to Day -1 of 
Treatment Period 1. In the first part (Day -28 to Day -3) eligibility for study participation will be 
checked on an out-patient basis. In the second part of the Clinical Screening Period, the 
remaining procedures for eligibility will be confirmed as an in-patient. This is outlined in Table 
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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Screening Failure
7.2.1.3
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 randomized or administered 
investigational product(s).
For purposes of data collection, all subjects who give consent to the study, but are not enrolled 
and/or randomized, will be reported as screen failures, even if they were otherwise fully eligible
for the study, for example alternates/reserve subjects.
Rescreening of Subjects
7.2.1.4
Subjects who fail to meet all inclusion/exclusion criteria will be permitted to be rescreened based 
on investigator discretion and sponsor approval if the investigator assesses the reason for screen 
failure is transient and temporary.
Potentially eligible subjects who continue to meet all inclusion/exclusion criteria, but are unable 
to participate in the study due either to scheduling conflicts/timing (including the time required 
to obtain medical records release, if applicable) or appropriate slot availability at an 
investigational site, 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 besigned.
7.2.2
Treatment Period
7.2.2.1
Day 1 to Day 2 (Treatment Periods 1 and 2)
Study assessments for Day 1 to Day 2 of each treatment period are outlined in Table 3 and Table 
4. Subjects will be randomized to treatment assignment prior to dosing on Day 1 of Treatment 
Period 1. Administration of investigational product will occur on Day 1 of each treatment period.
The time points for pharmacokinetic/pharmacodynamic assessments will be performed according
to the BID or QD dose regimen assigned to the subject in the treatment period. Subjects will be 
discharged from the CRC following completion of the last study assessment on Day 2 of
Treatment Period 1. Following a washout of (at least 120 hours [5 days] to 30 days between the 
dose or the first dose of each treatment period [QD or BID dosing, respectively]) subjects will be 
admitted to the CRC for Treatment Period 2 procedures at Day -2.
7.2.3
Final Visit
For this study, the final visit will be the Follow up visit, which is intended to be an out-patient
clinic visit.
7.2.4
Follow-up Period
The follow-up period for this protocol is 30±2 days after the last 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, a blood sample for anti-PTH antibodies, 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).


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7.2.5
Additional Care of Subjects after the Study
There is no planned aftercare in this study.
Subjects who complete this study may have the opportunity to enroll in an open-label extension 
trial if an open-label extension study is available and approved by the site’s IRB/EC.
Study Evaluations and Procedures
7.3
7.3.1
Demographic and Other Baseline Characteristics
Demographics
7.3.1.1
Demographic information will be collected at the initial screening visit. Information to be 
collected will include:

Date of birth

Sex

Race and ethnicity
7.3.2
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this studywill 
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. Unless otherwise noted, any safety assessment that deviates from the
scheduled assessment time set forth in the protocol by more than 15 minutes will beconsidered
a protocol deviation.
AEs (defined as AEs occurring from the time of informed consent signature to first dose of 
investigational product), TEAEs (all AEs occurring after the first 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 blood pressure 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.
Medical and Medication History
7.3.2.1
A complete medical and medication history will be performed at the Clinical 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 use of medication (30 days prior to the first dose of study treatment)


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
History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases
Physical Examination (Including Height and Weight)
7.3.2.2
A complete physical examination will be performed at the time points described in Table 1 by a 
qualified licensed physician, physician’s assistant, or a 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 Clinical Screening Visit will be documented 
in the subject’s source documents and on the medical history CRF. Changes after the Clinical 
Screening Visit will be captured as AEs on the AE CRF, as deemed by the investigator.
Adverse Event Collection
7.3.2.3
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.)
Vital Signs, Blood Pressure and Pulse Rate
7.3.2.4
Blood pressure and pulse rate will be measured at times specified in Table 1, Table 2, Table 3, 
and Table 4 of this protocol. With exception of the predose assessment on Day 1 (which must be
within 30 minutes prior to administration of IP), any subsequently scheduled vital signs 
assessment collected during Periods 1 and 2 that deviates from the scheduled assessment time in 
Table 2, Table 3, and Table 4 by more than 15 minutes will be considered a protocol deviation.


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Additional blood pressure 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 blood pressure 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 mm Hg/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 (as specified in 
the study restrictions; Section 4.3) or within 30 minutes of collection. The subject should be 
instructed to lie down, remain supine and 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).One reading (supine
systolic blood pressure/diastolic blood pressure-pulse) should be taken.
The use of automated devices for measuring pulse rate is acceptable although, when done 
manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. When 
the timing of these measurements coincides with a blood collection, blood pressure and pulse
rate should be obtained prior to the nominal time of the blood collection.
Clinical Laboratory Evaluations
7.3.2.5
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. Samples for all clinical laboratory evaluations will be sent to a central 
laboratory. If an immediate (stat) result is required, a local laboratory may be used but a
duplicate sample must be sent to the central laboratory. A manual fully describing the schedule
and method of sample handling will beprovided.


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In order to qualify the subject for randomization at Treatment Period 1, the site can base 
eligibility on the local lab results if the central lab results are not available, but, if results are 
available from both labs, eligibility should be based on the central lab results.
However, local lab results will not be entered in the eCRF/clinical database, and copies of local 
lab reports must be maintained in the subject source documents. The central lab results(once 
received) will be entered in the eCRF/clinical database.
The following clinical laboratory assessments will be performed:
Biochemistry
Blood samples (8.5 mL) for serum biochemistry will be collected into a gel separator tube at the
timepoints described in Table 1. The following parameters will be assessed:
Sodium
Potassium
Phosphorus
Total protein
-HCG b
FSH b
Glucose
Total CO2 (Bicarbonate)
Magnesium
Blood urea nitrogen
Albumin
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
25(OH)D
Creatinine clearance
(estimated) a
-HCG=beta-human chorionic gonadotropin; FSH=follicle stimulating hormone; T3=triiodothyronine; TSH=thyroid stimulating 
hormone
a See Table 1.
b Females only.
Hematology
Blood samples (4 mL) for hematology will be collected into ethylenediaminetetraaceticacid 
tubes at the time points described in Table 1. 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. The
following parameters will beassessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Calcium
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, andbacteria.
Pregnancy Test
7.3.2.6
A serum β-HCG pregnancy test is to be performed on all females at the Clinical Screening Visit. 
A urine pregnancy test is performed on all female subjects at all subsequent visits as outlined in 
Table 1.
Drug and Alcohol Screen
7.3.2.7
A urine screen for drugs of abuse and 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 breath test 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 clinical screening or drugs of abuse or alcohol on Day-1 
(both treatment periods) will exclude the subject from further participation in the study (except as 
noted in Exclusion Criterion #16).
Serology Screen
7.3.2.8
At the Clinical Screening Visit, a blood sample of approximately 8.5 mL will be drawn into a gel 
separator tube to test for the presence of HIV, hepatitis B surface antigen (HBsAg), and hepatitis 
C virus (HCV) antibody as outlined in Table 1.
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.


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Electrocardiogram
7.3.2.9
Twelve-lead ECGs will be performed at the times specified in Table 1, Table 2, Table 3, and
Table 4. All ECGs will be performed in triplicate (with a minimum 2 minute gap between traces) 
using the equipment supplied by the CRC. Two identical trace ECG recordings for each time 
point will be collected and one original provided to the study sponsor or ECG vendor. With 
exception of the predose assessment on Day 1 (which must be within 30 minutes prior to 
administration of IP) any subsequently scheduled ECG assessment collected during Periods 1and 
2 that deviates from the scheduled assessment time in Table 2, Table 3, and Table 4 by more than 
15 minutes will be considered a protocol deviation.
The following parameters will be provided to the sponsor or the sponsor representative by the 
central ECG reader: heart rate, PR, RR, QRS, and QT intervals along with information on T and 
U-wave morphology; U-waves should be captured as absent/normal or abnormal. The QTcB and 
QTcF will be derived from the data provided by the central ECG reader. 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 recorded in the CRF.
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, alcohol, or nicotine within 
60 minutes prior to collection. The subject must be resting in the supine position for atleast
5 minutes prior to collecting theECG.
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 
approximately the same positions each time in order to achieve precise ECG recordings. Only 
valid ECG tracings will be submitted to the ECG vendor for analysis.
Triplicate recording, including a 10 second rhythm strip, will be obtained approximately
2-4 minutes apart for all assessments. The time and date of each valid ECG tracing obtained with 
the 3 assessments will be recorded in the CRF. The ECG parameters as described above will be 
evaluated by a central reader and the interpretation provided to the sponsor or the sponsor
representative. The average of the triplicate valid ECG measurements collected at each nominal 
time point will be used for analysis. The 3 recordings should be immediately assessed as valid 
recordings and, if not valid, they should be repeated in order to obtain a total of 3 valid 
recordings. Invalid recordings will not be entered in the CRF.
When (triplicate) ECGs are obtained, the average of the triplicate ECG measurements collected 
predose on Day 1 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 baselinemeasurements.
If the QTcF interval (calculated on site) is increased by >45msec 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. 


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If either of the QTcF values from these repeated ECGs remains above the threshold value 
(>45msec increase 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 >45msec increase 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/QTcB value is prolonged, as defined above, repeat measurements may 
not be necessary if a qualified physician’s interpretation determines that the QTcF/QTcB values 
are in the acceptable range.
In cases where a central ECG reader is used, the eligibility of the subject is based on the 
assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the central reader, the investigator, in consultation with the appointed sponsor's 
medical monitor, reconfirms the subject's eligibility to continue to participate in the study.
7.3.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at the/each site and in the Trial Master File at the sponsor. A manual fully 
describing the schedule and method of sample handling will be provided.
Actual pharmacokinetic 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 pharmacokinetic blood samples at the precise protocol scheduled time. Pharmacokinetic 
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 4 hours post-dose and beyond. Samples drawn outside these 
parameters will be considered a protocol deviation.
Pharmacokinetic Blood Sample Collection and Handling Procedures
7.3.3.1
Pharmacokinetic blood samples will be collected at the time specified in Table 1, Table 2, Table 
3, and Table 4 to measure plasma concentrations of PTH.
A full description of the pharmacokinetic 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: SHP634-101

Subject identifier


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
Treatment Period

Nominal day

Nominal time

Matrix identifier (plasma)

Split (primary or back-up).
Shipment of Plasma Pharmacokinetic Samples
7.3.3.2
All pharmacokinetic plasma 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. 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 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.
All pharmacokinetic samples, along with the corresponding documentation will be shipped 
according to the instructions in the provided laboratory manual.
Pharmacokinetic samples will be stored nominally at -70◦C prior to and after analysis at theassay 
laboratory until their disposal is authorized by Shire.
Pharmacokinetic Plasma Assay Methodology
7.3.3.3
Plasma concentrations of PTH will be measured using the most current validated bioanalytical
method according to the relevant Standard Operating Procedure in place at the designated 
bioanalytical contract laboratory. In addition, selected plasma 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.
7.3.4
Pharmacodynamic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at the/each site and in the Trial Master File at the sponsor. A manual fully 
describing the schedule and method of sample handling will be provided.
Actual pharmacodynamic blood sample and urine 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 pharmacodynamic blood and urine 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 4 hours post-dose andbeyond. 
Samples drawn outside these parameters will be considered a protocol deviation.


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Pharmacodynamic Blood Sample Collection and Handling Procedures
7.3.4.1
Pharmacodynamic blood samples will be collected at the time specified in Table 1, Table 2, Table 
3, and Table 4 to measure serum calcium (total and albumin corrected), magnesium, phosphate, 
albumin, creatinine, fibroblast growth factor 23 (FGF23) and 1,25- dihydroxycholecalciferol
(1,25(OH)2D3).
A full description of the pharmacodynamic 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: SHP634-101

Subject identifier

Treatment Period

Nominal day

Nominal time

Matrix identifier (serum)

Analyte (if there is more than 1)

Split (primary or back-up).
Shipment of Serum Pharmacodynamic Samples
7.3.4.2
All pharmacodynamic serum 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. 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 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.
All pharmacodynamic serum samples, along with the corresponding documentation, will be
shipped to the address provided in the laboratory manual.
Pharmacodynamic serum samples will be stored nominally at -70 C prior to and after analysis at 
the assay laboratory until their disposal is authorized by Shire.


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Pharmacodynamic Serum Assay Methodology
7.3.4.3
Pharmacodynamic serum parameter concentrations will be measured using the most current 
validated bioanalytical methods according to the relevant Standard Operating Procedure(s) in 
place at the designated bioanalytical contract laboratory. In addition, selected plasma 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. Raw data will be stored in the archive of the designated bioanalytical
contract laboratory.
Pharmacodynamic Urine Sample Collection and Handling Procedures
7.3.4.4
Pharmacodynamic urine samples will be collected at the time specified in Table 1, Table 2, Table 
3, and Table 4 to measure calcium, sodium, citrate, phosphate, magnesium, cAMP and creatinine.
Urine samples for pharmacodynamic analysis will collected over 24 hours (or 36 hours from the 
first dose of the BID regimen) in discrete time periods according the schedules in Table 1, Table 
2, Table 3, and Table 4. A full description of the pharmacodynamic urine collection, handling
(including additives), storage and shipping can be found in the provided laboratory manual.
Urine 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: SHP634-101

Subject identifier

Treatment Period

Nominal day

Nominal time

Matrix identifier (urine)

Analyte (if there is more than 1)

Split (primary or back-up).
Shipment of Urine Pharmacodynamic Samples
7.3.4.5
All pharmacodynamic urine 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. 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 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.
All pharmacodynamic urine samples, along with the corresponding documentation, will be 
shipped to the assay laboratory outlined in the provided laboratory manual.


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Pharmacodynamic urine samples will be stored nominally at -70◦C prior to and after analysis at 
the assay laboratory until their disposal is authorized by Shire.
Pharmacodynamic Urine Assay Methodology
7.3.4.6
Pharmacodynamic urine parameter concentrations will be measured using the most current
validated bioanalytical methods according to the standard operating procedures at the contract 
bioanalytical laboratory. In addition, selected urine 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.


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7.3.5
Volume of Blood to be Drawn from Each Subject
Table 6: Volume of Blood to be Drawn from Each Subject
Assessment
Sample
Volume
(mL)
# Samples at
Clinical
Screening/Day
-2
#
Baseline
Samples
(Day -1
and/or Day-2)
#
Samples
each QD
regimen
(Days 1-2)
#
Samples
each
BID
regimen
Follow Up
Total #
Samples
Total
Volume
(mL)
PK samples (plasma PTH) a,d
4*
*(unless
otherwise
specified)
0
0
12
*(7 samples
of 3mL +
5 samples
of 4mL)
21
*(11 samples
of 3mL +
10 samples
of 4mL)
0
33
*(18 samples
of 3mL +
15 samples of
4mL)
114
*(54mL+ 
60 mL)
HBsAg, HIV, HCV
6
1
0
0
0
0
1
6
Safety
Biochemistry and
-HCG b
6
1
(Clinical Screening)
2
(TP1 D-2 + TP2 D-2)
1
1
1
6
36
Hematology
2
1
2
1
1
1
6
12
Serum 25(OH)D
2
1
0
0
0
0
1
2
PD
total serum
4
0
18
0
0
0
18
72
samples
Baseline
calcium,
magnesium,
(3mL+1mL
discard)
(9TP1+9TP2)
(D-1)
phosphate,
creatinine,
1,25(OH)2D3
c
FGF23, Albumin
2
0
18
(9TP1+9TP2)
0
0
0
18
36


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Table 6: Volume of Blood to be Drawn from Each Subject
Assessment
Sample
Volume
(mL)
# Samples at
Clinical
Screening/Day
-2
#
Baseline
Samples
(Day -1
and/or Day-2)
#
Samples
each QD
regimen
(Days 1-2)
#
Samples
each
BID
regimen
Follow Up
Total #
Samples
Total
Volume
(mL)
PD
total serum
4
0
0
11
15
0
26
104
samples
(Days 1-
calcium,
magnesium,
(3mL+1mL
discard)
2)
phosphate,
creatinine,
1,25(OH)2D3
c,d
FGF23, Albumin
2
0
0
11
15
0
26
52
anti-PTH antibody
3
0
1
(TP1, 
predose 
l )
0
0
1
2
6
Total mL
440 e
BID=twice-daily; -HCG=beta-human chorionic gonadotropin; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; QD=once=daily.
a If a catheter is used, the first 1mL is to be discarded when the PK sample is collected alone at a time point (ie without collection of a PD sample); then take 3mL into appropriate 
tube for PK sample. A total of 4mL of blood drawn has been used in determination of this sample volume.
b -HCG testing for femalesonly.
c If a catheter is used, the first 1mL is to be discarded; then take 3mL into appropriate tube(s) for PD assessments for total serum calcium, magnesium, phosphate, creatinine, 
1,25(OH)2D3. A total of 4mL of blood drawn has been used in determination of sample volume. An additional sample of 2mL will be collected for FGF23 and albumin in a 
separate tube.
d When a PD and PK sample are collected at the same time point, the PD sample is to be drawn prior to the PK sample (to avoid any potential for cross-contamination of tube
additives), and if a catheter is used for this collection, the first 1mL of blood should be discarded prior to the PD blood sample collection. When either a PK or a PD sampleis 
drawn alone at a scheduled time point, 1mL of blood should be discarded prior to the scheduled blood sample collection.
e This is an approximate calculation of total blood volume required for the study for each subject


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During this study, it is expected that approximately 440 mL of blood will be drawn from all
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount ofblood
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 440 mL. 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
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
8.1
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 (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 7.2.4. 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 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected benefits 
outside the investigational product indication should also be captured on the AE CRF.
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 pre-treatment 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 on the appropriate CRF).
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 ofdaily 
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.


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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, forsuspecting 
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 sourcedocument.
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 theevent.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be
recorded as an AE.


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8.1.5
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 ofa subject, 
whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically significant 
and therefore represents anAE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.2.4.
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 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 AdverseEvent 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.


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8.1.7
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 non-medical 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 theprotocol)

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.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. Medication errors should be collected/reported for all products under 
investigation. The administration and/or use of the unassigned treatment is/are always reportable
as a medication error. The administration and/or use of an expired investigational product should 
be considered as a reportable medicationerror.
Serious Adverse Event Procedures
8.2
8.2.1
Reference Safety Information
The reference for safety information for this study is the rhPTH(1-84) investigator brochure
which the sponsor has provided under separate cover.
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 CRO/Shire Medical Monitor 
within 24 hours of the first awareness of the event. Note: The 24 hours reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see
Section 8.1.7) 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 GlobalPharmacovigilance
and Risk Management Department. 


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A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs Required by the 
Protocol Form (and any applicable follow-upreports) must also be sent to the CRO/Shire 
Medical Monitor using the details specified in the emergency contact information section of the
protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at anydose:

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 in-subject hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for
pre-existing conditions, which 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 in-subject 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 7.2.4, and must be reported
to the Shire Global Pharmacovigilance and Risk Management Department and the CRO/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.


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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 in the US and EU of 
related, unexpected SAEs.
In addition, the CRO (PPD) is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the rhPTH(1-84) program.
The investigator is responsible for notifying the local institutional review board (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
Data Collection
9.1
The investigators’ authorized site personnel must enter the information required by the protocol 
on 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 approximately 3 business days of the subject’s 
visit.
Clinical Data Management
9.2
Data are to be entered into a clinical database as specified in the CRO 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.
Data Handling Considerations
9.3
This is an open-label study, and, as such, there are no special handling considerations for blinded 
data.
Statistical Analysis Process
9.4
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 pharmacokinetic, pharmacodynamic, 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 beaddressed.
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).


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Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
9.5
There is no planned interim analysis, adaptive design, or data monitoring committee (DMC) in 
this study.
One or more interim analyses may be performed in this study. If an analysis is deemed to be
necessary, then a prospective statistical analysis plan will be developed prior to the analysis. The
plan will include, at a minimum: (1) rationale to perform the interim analysis; (2) parameters to
be analyzed; (3) the distribution list for the interim analysis results. Interim data may be usedfor
(but not limited to) PK/PD modeling and/or regulatory submissions. The trial will not stop due to 
the results of any interim analysis.
Sample Size Calculation and Power Considerations
9.6
At least 8 subjects will be required to complete treatment in each cohort. The sample size was 
determined based on a similar, prior pharmacokinetic/pharmacodynamic study. The number of 
subjects in this study is not based on statistical power considerations because the statistical 
analyses are primarily descriptive, and no hypothesis testing is specified in the study.
Study Population
9.7
Four analysis populations are defined for this study: the all-enrolled, safety,pharmacokinetic, and 
pharmacodynamic populations:

The all-enrolled population consists of all subjects who sign the informed consent form
and are randomized in the study.

The safety population includes enrolled subjects who have received at least 1 dose of
rhPTH(1-84). All analyses of safety data will be based on this population.

The pharmacokinetic population consists of all-enrolled subjects who receive at least 
1 dose of rhPTH(1-84) and have at least 1 evaluable post-dose pharmacokinetic
concentration value available for 1 dose regimen.

The pharmacodynamic population consists of all-enrolled subjects who receive at least 
1 dose of rhPTH(1-84) and have at least 1 evaluable post-dose pharmacodynamic value
available for 1 dose regimen.
Pharmacokinetic and Pharmacodynamic Analyses
9.8
9.8.1
Pharmacokinetic Analysis
All pharmacokinetic analyses will be performed using the pharmacokinetic population.
Pharmacokinetic parameters will be determined from the plasma concentration-time data for
PTH and by non-compartmental analysis. Pharmacokinetic analyses based on raw and
baseline-adjusted PTH concentrations will be performed. The baseline is defined as the predose 
endogenous PTH level on Day 1, and baseline-adjusted PTH concentrations are to be calculated
by subtracting baseline PTH from the raw PTH concentrations. All assessment dates will be
related to the first day of rhPTH(1-84) administration. 


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This first day of investigational product administration is referred to as Day 1. Day 1 is the day 
that is preceding Day 1, and a Day 0 will not be defined.
The pharmacokinetic parameters will include, but not be limited to:

maximum observed concentration maximum (Cmax)

time of maximum concentration (Tmax)

area under the concentration curve (from time zero to the last measurable concentration 
and from time zero to infinity (AUC0-t andAUC0-inf)

area under the concentration curve from time zero to 24 hours post the first dose 
(AUC0-24h)

elimination rate constant (Kel)

apparent clearance (CL/F)

apparent volume of distribution (Vz/F)

elimination half-life (t½)
Statistical Analysis of Pharmacokinetic Parameters
9.8.1.1
Individual concentrations and Pharmacokinetic parameters of PTH will be listed and summarized 
with descriptive statistics (number, arithmetic mean, SD, coefficient of variation [CV%], median, 
minimum, maximum, geometric mean, and geometric CV%) by treatment. Figures ofindividual 
and mean (+/-SD) concentration-time profiles of raw and baseline-adjustment plasma PTH will 
be generated.
9.8.2
Pharmacodynamic Analysis
All pharmacodynamic analyses will be performed using the pharmacodynamic population.
Pharmacodynamic parameters will be computed from the individual concentrations of serum 
calcium (uncorrected and corrected for serum albumin levels), phosphate, albumin, creatinine, 
magnesium, 1,25(OH)2D3 and FGF23 using a non-compartmental approach. The
calcium- phosphate product will be computed. Pharmacodynamic parameters will be estimated 
based with and without baseline adjustments.
Individual concentrations and pharmacodynamic parameters of serum total calcium and
albumin- corrected calcium, phosphate, creatinine, albumin, magnesium, 1,25(OH)2D3 and 
FGF23 will be summarized with descriptive statistics (number, arithmetic mean, SD, CV%, 
median, minimum, maximum, geometric mean, and geometric CV%).
The urinary excretion of calcium, sodium, citrate, magnesium, cAMP, and phosphate will also be 
expressed relative to that of creatinine and will be summarized with descriptive statistics.


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Statistical Analysis of Pharmacodynamic Parameters
9.8.2.1
The following parameters will be calculated using the serum concentration data:

AUC0-24h: the area under the concentration versus time curve, from time 0 to 24 hours

TEmax: time to maximum effect

Emax: maximum effect
The parameters representing urinary excretion of each analysis will be calculated, if data allow:

Total amount of sodium, calcium, magnesium, citrate, phosphate, cAMP, and creatinine 
in each sample

Total amount of sodium, calcium, magnesium, citrate, cAMP, and phosphate excreted in 
each sample relative to the total amount of creatinine excreted

Renal clearance of sodium, calcium, magnesium, citrate, creatinine, and phosphate 
(mL/min)

Fractional excretion of sodium, calcium, citrate, magnesium, and phosphate
9.8.3
Pharmacokinetic and Pharmacodynamic Analysis
Pharmacokinetic-pharmacodynamic correlations between PTH concentrations and theabove 
indicators of PTH bioactivity will be assessed using exploratory figures. If required, 
pharmacokinetic/pharmacodynamic models may be developed to describe the effect of PTH 
concentrations and biochemical indicators of PTH activity.
9.8.4
Population Pharmacokinetic and Quantitative System Pharmacology Modeling 
and Simulation
Additional modeling and simulation will be performed to evaluate the PK of PTH and the effect 
on serum calcium concentration and urine calcium excretion from alternative dosing regimens 
other than the once daily and twice daily doses used in the study. A population PK model and a 
quantitative system pharmacology model (QSPM) will be developed by fitting PK and PD data 
obtained from historical studies in hypoparathyroid patients as well as data from this study.
Inter-subject variability on model parameters will be fully evaluated. Once the population PK 
model and the QSPM are satisfactorily validated, simulations using the final validated models
will be performed to explore the effects of alternative dosing other than once-daily and
twice- daily dosing, eg, 3 times daily (TID), pump infusion dosing, and possibly new
formulations of PTH, on the control of serum calcium concentration and urinary excretion of 
calcium in hypoparathyroid patients. A separate data analysis plan and report will be prepared for
this additional modeling and simulation work. These data will not be used in conjunction with 
any study patient identifiers.


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Safety Analyses
9.9
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 AEs 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.
Safety data including clinical laboratory tests, anti-PTH antibodies, concomitant medications, 
adverse events, ECG monitoring and vital signs assessments will be summarized by treatment 
and time of collection. Descriptive statistics (arithmetic mean, standard deviation, median, 
minimum and maximum) 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.
Safety will be assessed by the following evaluations:

AEs and TEAEs (including episodes of hypocalcemia and/or hypercalcemia [including 
paresthesia, numbness, tetany] and hypercalciuria)

Laboratory test results (hematology, serum chemistries, creatinine clearance, urinary 
chemistries (24-hr urinary calcium, sodium, citrate, phosphate, cAMP, magnesium and 
creatinine excretion), immunology (anti-PTH antibody), and urinalysis

ECG

Physical examinations (including vital signs)


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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study will be conducted in accordance with current applicable regulations, ICH, 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.
Sponsor’s Responsibilities
10.1
Unless legally prohibited, study sites taking part in this clinical study must agree that the sponsor 
or sponsor representative may be on-site at the CRC to observe appropriate investigational
product preparation and administration as well as observation of study procedures to ensure that 
the protocol mandated procedures are followed correctly. Study subject privacy will be 
maintained during all procedures including intimate procedures such as ECG lead placement.
In addition to the Sponsor’s responsibilities as outlined in this section and in Section 8 it may be
incumbent upon the individual investigator to report AEs (including SAEs) and any failures of
devices (Injector Pen and/or Mixing Apparatus) to their local, regional, or country specific 
regulatory authorities.
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 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 of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is supplied 
to the investigator before study initiation, per local country guidelines.
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.


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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 non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
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.
The sponsor will make an end-of-study declaration to the relevant competent authorityas
required by Article 10 (c) of Directive2001/20/EC.
Investigator’s Responsibilities
10.2
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 therequired
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.


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A coordinating principal investigator (has been/will be) appointed to review the final clinical 
study report for multicenter studies. Agreement with the final clinical study report will be
documented by the signed and dated signature of the coordinating 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 
multicenter studies, the coordinating investigator according to national provisions and will be 
documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
Case Report Forms
10.2.3.1
Case report forms are supplied by the sponsor or sponsor representative and should be handled in 
accordance with instructions from thesponsor.
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 clinical research associate (CRA)/study monitor will verify the contents against thesource
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
Recording, Access, and Retention of Source Data and Study Documents
10.2.3.2
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s medical records.


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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 the 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 FDA, 
EMA, 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.
Audit/Inspection
10.2.3.3
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 otherUS
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.
Financial Disclosure
10.2.3.4
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).
Ethical Considerations
10.3
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. 


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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 which was
reviewed by the IRB/EC and which 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 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies 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, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
Privacy and Confidentiality
10.4
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with 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.


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After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
may review 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 IRBs/ECs 
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 applicablelaws,
regulations, and guidelines to maintain the confidentiality of subjects’ identities.
Subjects will be 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.
Study Results / Publication Policy
10.5
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 non-commercial 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.


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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 necessaryto 
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 
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 
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, L. V. 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, J. P., Khan, A., Potts, J. T., Jr., Brandi, M. L., Clarke, B. L., Shoback, D., Juppner, 
H., D'Amour, P., Fox, J., Rejnmark, L., Mosekilde, L., Rubin, M. R., Dempster, D., 
Gafni, R., Collins, M. T., 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, M. R. & Cordy, P. E. 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.
Powers, J., Joy, K., Ruscio, A. & Lagast, H. 2013. Prevalence and incidence of 
hypoparathyroidism in the United States using a large claims database. J Bone Miner Res,
28, 2570-6.
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, P. J., Manshadi, M., Breen, K. & Lippmann, S. 1999. Psychiatric aspects of parathyroid 
disease. Psychosomatics, 40, 486-90.
Winer, K. K., Ko, C. W., Reynolds, J. C., Dowdy, K., Keil, M., Peterson, D., Gerber, L. H., 
McGarvey, C. & Cutler, G. B., Jr. 2003. Long-term treatment of hypoparathyroidism: a 
randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and 
calcium. J Clin Endocrinol Metab, 88, 4214-20.
Winer, K. K., Sinaii, N., Peterson, D., Sainz, B., Jr. & Cutler, G. B., Jr. 2008. Effects of once 
versus twice-daily parathyroid hormone 1-34 therapy in children with 
hypoparathyroidism. J Clin Endocrinol Metab, 93, 3389-95.
Winer, K. K., Yanovski, J. A., Sarani, B. & Cutler, G. B., Jr. 1998. A randomized, cross-over 
trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of 
hypoparathyroidism. J Clin Endocrinol Metab, 83, 3480-6.
Zarnegar, R., Brunaud, L. & Clark, O. H. 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


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Appendix 1 Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
23 Nov 2015
Global
Amendment 1
26 Feb 2016
Global
Amendment 2
03 Jun 2016
Global
Amendment 3
29 Jul 2016
Global
Amendment 4
12 Jun 2017
Global
Amendment 5
18 Jun 2018
Global
Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
1
Amendment Date
26 Feb 2016
Global
Item #
Description of Change
Section(s) Affected by
Change
1.
100µg QD with oral calcium treatment arms havebeen
added; treatment arms have been rearranged so that 25µg 
BID and 50µg BID (in the absence or presence of oral 
calcium) are each cross-compared with 100µg QD (in the 
absence or presence of oral calcium). Corresponding
tables, figure(s), and text modified accordinglyto
incorporate this designchange.
Reason for change: To provide direct comparisons within 
the same study of the alternative dosing regimens (BID
with and without oral calcium) to the 100µg QD dose
with and without oral calcium, in order to more fully 
characterize and understand the effects of both the PTH 
dosing regimen and oral calcium on serum calcium 
concentrations and urinary calcium excretion in various 
conditions.
Synopsis; Section 3.1
(including Figure 1);
Section 6.2.3
2.
An additional cohort (of 8 subjects) has been added, 
increasing the total number of subjects required to 
complete the study from 24 to 32.
Reason for change: To accommodate the additional 
comparisons of all BID doses with and without oral 
calcium with the 100µg QD dose with and without oral
calcium in the study design.
Synopsis; Section 3.1 
(including Table 5 and
Figure 1); Section 4.5;
Section 6.2.3
3.
Number of sites has been increased from “approximately 
Synopsis; Section 3.3


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20” to “approximately 20-30”.
Reason for change: The number of sites has been
increased to accommodate for the increase in the number 
of patients required to complete this study.
4.
The planned study period has been extended to Nov2017
(approx. 18 months duration).
Reason for change: To accommodate the increase in the 
number of subjects required to enroll and completethe
study.
Synopsis; Section 3.2
5.
Access to participate in, and reference to the RACE 
(PAR-C10-008) open-label extension study has been 
removed from the protocol.
Reason for Change: The RACE (PAR-C10-008) open
label extension study is no longer available for subjects 
completing this study.
Synopsis; Section 1.3;
Section 7.2.5
6.
Canada has been removed as a participating country.
Synopsis; Section 3.3
7.
Treatment scheme in tabular format added to 
methodology section of synopsis.
Reason for change: Reflects Table 4 of Section 3.1, and 
has been added to the synopsis for ease ofreference.
Synopsis
8.
Inclusion criterion # 6 has been modified to clarify active 
forms of vitamin D and minimum daily dose required for 
study entry.
Reason for change: Clarification.
Synopsis; Section 4.1
9.
Inclusion criterion # 8 has been modified to allow for an
expanded timeframe (from 6 mos. to 12 mos.) for 
historical 24-hour urine calcium excretion. Additionally, 
“calcium concentration” was corrected to “calcium 
excretion”.
Synopsis; Section 4.1


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Section(s) Affected by
Change
Reason for change: To accommodate common clinical 
practice, since qualifying 24-hour urine collection may 
have been performed greater than 6 months prior to 
baseline. Correction to term for calcium excretion.
10.
Inclusion criterion # 9: “calcium concentration” was
corrected to “calciumexcretion”.
Reason for change: Correction to term for calcium 
excretion.
Synopsis; Section 4.1
11.
Inclusion criterion # 11 has been modified to clarify how 
criterion should be interpreted if outside of the normal 
range.
Reason for change: Clarification.
Synopsis; Section 4.1
12.
Exclusion criterion # 9 has been modified to incorporate 
wording re: raloxifine or similar selective estrogen 
receptor modulators (SERMs), and to exclude subjects on 
these medications, due to their potential impact on 
calcium kinetics.
Reason for change: Raloxifine and SERMs as a drug 
class are known potentially to impact bone cell function 
and skeletal metabolism. Since SERMs theoretically 
could impact study pharmacodynamic outcomes with 
respect to calcium (as could eg, bisphosphonates), an 
exclusion for SERMs has beenadded.
Synopsis; Section 4.2
13.
Exclusion criterion # 11 has been revised to specify
>450msec (males) or >470msec (females), based on the 
difference in normal QT/QTc observed in males versus 
females.
Reason for change: The gender-independent QTc 
exclusion of >450msec which is a typical norm for 
healthy volunteer studies has been revised to raise the 
exclusion to >470msec for females. The sex difference in 
the normal QT/QTc between men and women is well 
accepted, and the QTc upper limit of normal is 
Synopsis; Section 4.2


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Section(s) Affected by
Change
commonly accepted as 450msec for men and 470msec
for women.
14.
The minimum washout period between 1st dose in 
Treatment Period 1 and 1st dose in Treatment Period 2 
has been changed from “≥4 days (ie, 96 hours)” to “≥5 
day (ie, 120 hours)”.
Reason for Change: A 120-hour minimum duration 
between first dosing in each treatment period ensures that 
at least 4 days (96) hours duration has elapsed between
the last dose of BID treatment in Treatment Period 1, and 
first dose of QD treatment in Treatment Period 2.
Synopsis; Section 3.1
(including Figure 1);
Section 7.2.2
15.
cAMP (Cyclic AMP) has been added as a urinary analyte 
for pharmacodynamic assay.
Reason for change: Cyclic AMP (cAMP) has been added 
as a pharmacodynamic analyte to help confirm true 
hypoparathyroidism.
Abbreviations; Synopsis; 
Table 2; Table 3; Section
7.3.4.4; Section 9.8.2;
Section 9.8.2.1; Section 9.9
16.
Albumin-corrected calcium has been removed from 
descriptions of PD sample collections in the Table 
footnotes (Tables 2 and 3), and in the assessment column 
for the blood volume table (Table 6).
Reason for change:Correction.
Table 2; Table 3; Table 6
17
Statistical Methodology for Safety Endpoints (Synopsis),
and Safety Analysis (Section 9.9): physical exams were
removed from this section, anti-PTH antibodies were
added to this section.
Reason for change: Physical examinations are deleted 
since they are not summarized by treatment and time of 
collection. Anti-PTH antibodies have been added as a 
safety parameter.
Synopsis; Section 9.9
18.
Footnote “r” of Table 1 is revised to indicatethat
supplemental oral calcium should be taken within 15 
minutes prior to IP administration (for subjects assigned
to treatment D, E and F on Day 1/dosing).
Table 1


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Section(s) Affected by
Change
Reason for change: The time window between oral 
calcium administrations prior to IP dosing was reduced 
from 1 hour prior, to 15 minutes prior to dosing, to align
oral calcium intake as closely as possible to dosing, in 
order to get a true characterizing of calcium kinetics.
19.
For the BID regimen, the PK/PD sample collection 
period has been extended to 24 hours post the second 
dose for BID treatment. In addition, PK and PD sample
collection time points were added at 16 and 24 hours 
after the second dose in the BID treatment regimen 
(corresponding to 28 hours and 36 hours post first dose, 
respectively). In addition, vital signs and ECG
assessments were added at the 28, 32 and 36 hourtime 
points for this regimen.
Reason for change: Sample collection period extended to 
24 hours post-second (BID) dose (including a 16 and 24 
hour time point) to better characterize the PK/PD profile 
at trough and to collect corresponding safety assessments 
(vitals, ECGs) at these same time points.
Table 4; Section 7.3.4.4
20.
For the QD regimen, a PK sample collection time point at 
16 hrs postdose was added.
Reason for change: Added to better characterize the PK 
of rhPTH.
Table 3
21.
These changes (item 19 and 20 above) necessitated the 
reorganization of Table 3 (from the original protocol v 
1.0) to be split into 2 separate tables in the amended 
protocol: Table 3 now summarizes assessments for the 
QD treatment period, and Table 4 (now added)
summarizes assessments for BID treatment period.
Subsequent tables in this protocol were renumbered 
accordingly (ie, Table 4 becomes Table 5, Table5
becomes Table 6).
Reason for change: Clarification to tables.
Table 3; Table 4 (newly 
added)


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22.
Table 2: Day -1 (Prior to Treatments 1 and 2): Table 
revised to remove reference relative to BID post evening 
dose collection time points in the header; streamlined to 
remove time point/columns where no PD sampling is 
required.
Reason for change: Clarification to table.
Table 2
23.
Table 2: Day -1 (Prior to Treatments 1 and 2): PD blood 
collections were removed at 18, 20, and 22 hours post-
dose time points.
Reason for change: To correspond to the revised 
pharmacodynamic sampling time points on Day 1 for QD 
and BID treatment schedules, and to serve as a baseline 
(Day -1) comparison for each respective time point on 
Day 1 of each treatment period. This should enable the 
assessment and comparisons of the treatment effects on 
serum calcium and urinary calcium profiles for eachof 
the 6 treatments to their corresponding respective
baseline time points.
Table 2
24.
Blood volumes required for pharmacodynamic and anti-
PTH antibody assays were revised/corrected. Total blood 
volume required for the study is revised to 468.5mL.
Additionally, table rows and columns were modified,and
pharmacodynamic collections separated according to 
those samples collected at Baseline (D-1), and during 
treatment (Days 1-2), and further specifying which 
pharmacodynamic sample (analytes) can be grouped 
together (eg, FGF23, albumin).
Reason for change: Corrections/revisions required to 
blood sample volumes, based on current information 
from the bioanalytical lab(s) performing the assay work.
Rearrangement to columns based on revisedtreatment 
comparisons (ie, all subjects now receive 1 BID regimen 
and 1 QD regimen, which is reflected in re-ordered 
columns).
Table 6 (previously Table 5, 
per protocol version 1.0)


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Section(s) Affected by
Change
Clarification to pharmacodynamic samples being 
collected.
25.
The following PK/PD sample collection time points were 
removed from the studyschedule:
PK sample collection time points removed:

QD: 5 min, 3 hr, 6 hr postdose.

BID: 5 min, 3 hr, 6 hr post first dose, and 5 min, 3 
hr, 6 hr post second dose.
PD sample collection time points removed:

QD: 18, 22 hrs postdose.
Reason for change: Due to the overall increase in total 
volume of blood samples required forpharmacodynamic
assessments, it was necessary to revise the blood
collection schedule in order to maintain total blood 
volume within safe and acceptable ranges for aclinical
study. The specific collection time points removed do not 
compromise the intent or integrity of the plannedPK/PD
analysis for this study.
Table 3; Table 4; Table 6
26.
Table 1 (Schedule of Assessments): Anti-PTH antibody 
collection time point moved from Treatment Period 1 
Day -2, to Treatment Period 1, Day 1 (predose). This
collection time point has been removed from Table 1, and
newly added as a line item to Table 3 and Table 4, with a 
corresponding footnote that the anti-PTH antibody
sample should be collected at Treatment Period 1, 
predose (regardless of QD or BIDregimen).
Reason for change: The assessment/collection time point 
was moved to predose on Day 1, Period 1, in order to 
avoid the potential (and unnecessary) collection of a 
blood sample on subjects who may screen fail between 
Day -2 and Day 1 at predose.
Table 1; Table 3; Table 4
27.
Schedule of Assessments: Urine pregnancy test added to 
the Follow-up visit.
Table 1


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Section(s) Affected by
Change
Reason for change: To confirm pregnancy status at the 
final in-house study visit.
28.
Schedule of Assessments: Collection time point for
serum 25(OH)D sample was removed from Period 1, Day
-2.
Reason for change: Since serum 25(OH)D results
collected at Period 1, Day -2 are not being used to 
determine eligibility, this sample collection was removed. 
The 25(OH)D sample collected at Screening will be used 
to determine eligibility.
Table 1
29.
An additional safety review has been added after
completion of Cohort 3 (and prior to start of Cohort 4),as 
a result of the additional cohort (4) nowadded.
Reason for change: Added to be consistent with safety 
reviews required after each completed cohort.
Synopsis; Section 3.1
(including Figure 1)
30.
Reproductive Potential (Female and male contraception):
Abstinence has been deleted as an acceptable form of
contraception for females and males participating in the 
study.
Reason for change: Abstinence is not an acceptable form 
of contraception.
Section 4.4.1; Section 4.4.2
31.
Clarification made that calcium and vitamin D used prior
to and during the study be included as aconcomitant
medication.
Reason for change: Clarification.
Section 5.2
32.
Specific labeling requirements have been removed.
Reason for change: To allow for flexibility in labeling. 
Labeling will include all required elements based on 
regional differences, local regulations, and requirements.
Section 6.3.1


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Section(s) Affected by
Change
33.
Pharmacokinetic Plasma Assay Methodology section has 
been revised to reflect the SOPs being followed for 
pharmacokinetic sample assays for this study.
Reason for change: Correction/update warranted.
Section 7.3.3.3
34.
Reference to pharmacodynamic “plasma” samples have 
been changed to pharmacodynamic “serum” samples.
Reason for change: Correction.
Section7.3.4.1; Section 
7.3.4.2; Section 7.3.4.3
35.
Pharmacodynamic (Serum) Assay Methodology section 
has been revised to reflect the SOPs being followed for 
pharmacodynamic sample assays for this study.
Reason for change: Correction/updatewarranted.
Section 7.3.4.3
36.
Pharmacodynamic urine assay methodology has been 
revised to reflect the SOPs being followed for 
pharmacodynamic sample assays for this study.
Reason for change: Correction/update warranted.
Section 7.3.4.6
37.
Reference to Natpara® package insert has been removed 
from the protocol. The reference for safetyinformation
for this study is the rhPTH (1-84) investigator brochure.
Reason for change: This study will be recruiting sites and 
patients internationally. Therefore, the investigator 
brochure is appropriate for referencing safety information 
regarding rhPTH (1-84).
Section 1.1; Section 1.3;
Section 8.2.1
38.
Pharmacodynamic Analysis: creatinine has been addedto
this section.
Reason for change: Creatinine was added to help clarify 
pharmacodynamic data.
Section 9.8.2
39.
The following acronyms/abbreviations have been added: 
1(OH)D3 (α-calcidol), cAMP (cyclic adenosine 
monophosphate), SERMs (selective estrogen receptor 
modulators).
Abbreviations


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Item #
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Section(s) Affected by
Change
Reason for change: Acronyms added to coincide with the 
amended text that has been added to the protocol.
40
A sentence has been added under safety to allowfor
notification of a positive anti-PTH result to the 
Investigator.
Clarification of procedure for safety thatwasn’t
addressed in the original protocol.
Section 7.3.2
41.
Email addresses added to sponsor contact information.
Additional Contact 
Information
42.
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made throughout the document 
as appropriate.
Reason for change: Clarification and/ortypographical
corrections.
All sections (as warranted)


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Item #
Description of Change
Section(s)
Affected
by 
Change
1.
Emergency contact information page has been updated 
with CRO (PPD) contact information.
Emergency Contact 
Information
2.
Additional Contact Information page has been updated 
with CRO (PPD) contact information.
Additional Contact 
Information
3.
Safety reviews at the end of Cohorts 1, 2 and 3 will be 
performed with or without the follow-up visit data for the
corresponding cohort.
Reason for change: Clarification made for when these 
safety review meetings will occur. There is noanticipated
impact to patient safety, given the short half-life ofPTH. 
The primary purpose of the follow-up visit is to collect an 
anti-PTH antibody sample.
Synopsis; Section 3.1
4.
Exclusion criterion 4: Text in parentheticals “(HbA1C
>8%; >64 mmol)” has been deleted for type 2 diabetes
mellitus.
Reason for change: To allow for Investigator discretion in 
determining if subject meets thiscriterion.
Synopsis; Section 4.2
5.
Analysis Populations: PK and PD population definitions 
are bulleted separately for the analysis population.
Reason for Change: Clarification made, since these 2 
populations are needed to define PK and PD assessments 
separately. This change has no impact on subject treatment.
Synopsis; Section 9.7
6.
Table 1: Footnote “e” moved to far left column (study 
procedure column) rather than the Period 2, Day 2 column 
(for procedures whereindicated).
Footnote “k” clarification added to specify that creatinine 
clearance will be calculated using the Cockroft-Gault 
formula.
Reason for change: Clarificationwarranted.
Table 1
7.
Table 3: columns (5 min, 3 hr post-dose) which have no 
assessments to be collected are now deleted.
Reason for change: Clarification warranted.
Table 3
8.
Table 4: columns (5 min, 12 hr 5 min, 15 hr post-dose)
which have no assessments to be collected are now deleted.
The PK and PD sampling predose footnote “f” should be 
Table 4


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Description of Change
Section(s)
Affected
by 
Change
corrected to state footnote “c”.
The last row “1,25 (OH)2D” should be deleted (as this is 
already included in the PD blood sample assessment in the 
same table above, and is already specified in footnote “g”).
Footnote “f” clarified to remove reference to “1,25(OH)2D. 
Footnote “i” 24 hour urine collection corrected to “36”
hour urine collection (ie, 24 hours after the 2nd BID dose).
Reason for change: Minor clarification and/or corrections 
warranted to the table.
9.
Figure 1: Revised to illustrate that safety data reviewwill
occur after Treatment Period 2, but not necessarily afterthe
follow-up visit) for Cohorts 1, 2 and 3.
Reason for change: Clarificationwarranted.
Figure 1
10.
Biochemistry: Magnesium and creatinine clearance have 
been added to the safety lab biochemistrypanel.
Reason for change: to confirm and evaluate Inclusion 
Criterion # 10, and Inclusion Criterion # 13, respectively.
Section 7.3.2.5
11.
Urinalysis: an asterisk was added to the calcium parameter 
being collected (with note provided to clarify that 
eligibility of the subject’s urinary calcium excretion result, 
based on a 24-hour collection prior to check-in to the CRC 
at Treatment Period 1, Day -2, will be based on the 
assessment of these results by the Investigator (using local 
labs, if necessary).
Reason for change: Clarificationwarranted.
Section 7.3.2.5
12.
Table 6: Safety blood volumes reduced forserology,
biochemistry and hematology panel, and increased (by 
1 mL) for serum 25(OH)D sample.
Reason for change: The sample volumes were updated, 
based on the central lab’s confirmation of required sample 
volumes. This resulted in an overall reduction of total 
blood volume required for each subject (ie, from 468.5 mL
to 440 mL).
Section 7.3.5, Table 6
13.
Two sentences were revised to clarify respective roles of 
the sponsor and the CRO in reporting responsibilities to 
regulatory authorities and active study sites.
Section 8.2.7


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Item #
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Section(s)
Affected
by 
Change
Reason for Change: Clarificationwarranted.
14.
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made throughout the document as 
appropriate.
Reason for change: Clarification and/ortypographical
corrections.
All sections (as
warranted)


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1.
Schedule of Assessments:
a) Table 1: The assessments for clinical safety bloodand
urine tests (Treatment Period 1 and Treatment Period
2), pregnancy test (for all females, Treatment Period 2),
physical exam (Treatment Period 2), and weight
(Treatment Period 2) should be collected after the
scheduled serial assessments (for pharmacokinetic [PK]
and pharmacodynamic [PD]) have been completedfor
this study day, and prior to discharging the subject from
the Clinical Research Center. Footnote “s” has been
added to Table 1 to clarify/specify this.
An “X” has also been placed in Table 1 in the washout 
period column for AEs and Concomitant Medications.
b) Tables 3 and 4: The last scheduled serial time point for
vital signs and ECG will also serve as thedischarge
procedure for that assessment on Day 2 for the QD
regimen (see Table 3) and for the BID regimen (see
Table 4). Footnote “j” has been added to Table 3, and
footnote “k” has been added to Table 4, to
clarify/specify this.
Reason for change:
Clarification made that AEs and concomitantmedications 
should be reported during the washout period (Table 1), 
and clarification made to the order of procedures to be 
collected prior to discharge in Tables 1, 3 and4.
Table 1, Table 3, and
Table 4
2.
Schedule of Assessments
a) Table 2: Detailed Schedule of Assessments: Day -1
(Prior to Treatment Periods 1 and 2), PDurine
sampling:
For PD urine sampling, the X under the “pre-dose” 
column in this table is used to signify the action that the 
subject needs to empty his/her bladder immediately 
before the start of the 0-3-hour urine collection based
on the predicted dosing time on Day 1 (eg, if a dose is 
Table 2, Table 3, and
Table 4


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planned to be given at 08.00 on Day 1, the start of the 
0-3 hour PD urine collection on Day -1 should be
08.00). It is not a separate pre-dose collection. Footnote 
“i” in Table 2 has been added to clarify this. Also, 
reference to “pre-dose” in footnote “g” of Table 2 has 
been deleted.
b) Table 3: Detailed Schedule of Assessments: Treatment
Periods 1 and 2, Day 1/Day 2 (QD Regimen), PD urine
sampling:
For PD urine sampling, the X under the “pre-dose” 
column on Day 1 in this table is to signify the stop of 
the Day -1, 18-24 hour PD urine collection period, and 
the start of the Day 1, 0-3 hour PD urine collection 
period. It is not a separate pre-dose collection (this is 
also explained in Table 2, footnote d which indicates 
that the last assessment time point from Day -1 (ie 18-
24 hour PD urine collection) is the same as the pre-dose
collection time point on Day 1, in Table 3). Footnote 
“k” in Table 3 has been added to clarify this. Also, 
reference to “pre-dose” in footnote “h” of Table 3 has 
been deleted.
c) Table 4: Detailed Schedule of Assessments: Treatment
Periods 1 and 2, Day 1/2 (BID Regimen), PD urine
sampling:
For PD urine sampling, the X under the “pre-dose” 
column on Day 1 in this table is to signify the stop of 
the Day -1, 18-24 hour PD urine collection period, and 
the start of the Day 1, 0-3 hour PD urine collection 
period. It is not a separate pre-dose collection. Thisis 
also explained in Table 2, footnote d which indicates
that the last assessment time point from Day -1 (ie 18-
24 hour PD urine collection) is the same as the pre-dose
collection time point on Day 1, in Table 4. Footnote“l”
in Table 4 has been added to clarify this. Also,
reference to “pre-dose” in footnote “i” of Table 4 has 


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been deleted.
Reason for change:
Clarification made to the Schedule of Assessments tables 
to clarify that a separate pre-dose pharmacodynamic urine
sample is NOT required to be collected for Day -1 and Day 
1 of Treatment Periods 1 or 2. Footnotes added to 
respective tables for clarity.
3.
Study Schedule
4th and 5th bullets have been reversed: where it currently 
reads:

“Pharmacokinetic blood sampling

Pharmacodynamic blood sampling”
Has been revised to:

“Pharmacodynamic blood sampling

Pharmacokinetic blood sampling”
Reason for change:
The order of PK and PD sampling was reversed (when 
samples are collected at the same time point) in order to
avoid the potential for EDTA contamination (from PK 
samples requiring an EDTA tube) being collectedbefore
PD serum samples are collected, which could impact assay 
integrity and/or assay results.
Section 7.2
4.
Rescreening of Subjects:
The last sentence of this section which reads: “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.” has been moved as a separate 
paragraph at the end of this section.
Reason for change:
Making this sentence as a separate (stand-alone)paragraph 
indicates that this sentence will apply to all subjects who
are rescreened (per scenarios described in the 1st and2nd
Section 7.2.1.4


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paragraphs in this section).
5.
Pharmacokinetic Procedures:
2nd paragraph, 3rd sentence which read:
“Pharmacokinetic 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 samplesdrawn
beyond 4 hours post-dose.”
Has been changed to read:
“Pharmacokinetic 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 samplesdrawn
4 hours post-dose and beyond.”
Reason for change:
Clarification made that the ±15 minute window will apply 
to samples drawn at the 4 hour post-dose time point.
Section 7.3.3
6.
Pharmacokinetic Blood Sample Collection and Handling 
Procedures, 3rd bullet:
“Cohort” has been deleted from the list of bulleted 
information that will appear on the PK sample labels.
Reason for change:
Correction to tube label information required, following 
confirmation from the bioanalytical lab.
Section 7.3.3.1
7.
Pharmacokinetic Procedures
Section header has been revised from “Pharmacokinetic 
Procedures” to “Pharmacodynamic Procedures”
Reason for change: Section header corrected to be 
consistent with the sub-section headers (and content) below 
it (ie, Sections 7.3.4.1, 7.3.4.2, 7.3.4.3, 7.3.4.4, 7.3.4.5,
Section 7.3.4


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7.3.4.6).
8.
Pharmacokinetics (now corrected to Pharmacodynamics) 
Procedures:
2nd paragraph, 3rd sentence which read: “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 beyond 4 
hours post-dose.”
Has been changed to read:
“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 
4 hours post-dose and beyond.”
Reason for change:
Clarification made that the ±15 minute window will apply 
to samples drawn at the 4 hour post-dose time point.
Section 7.3.4
9.
Pharmacodynamic Blood Sample Collection andHandling
Procedures:
a) “Cohort” should be deleted from the list of bulleted
information that will appear on the PD sample
labels.
b) “Analyte name (if there is more than 1)” should be
added to the bulleted list of information that will
appear on the PD sample labels.
Reason for change:
Correction to tube label information required, following 
confirmation from the bioanalyticallab.
Section 7.3.4.1
10.
Pharmacodynamic Urine Sample Collection andHandling
Procedures:
a) “Cohort” should be deleted from the list of bulleted
Section 7.3.4.4


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information that will appear on the PD sample
labels.
b) “Analyte name (if there is more than 1)” should be
added to the bulleted list of information that will 
appear on the PD sample labels.
Reason for change:
Correction to tube label information required, following 
confirmation from the bioanalyticallab.
11.
Table 6: Volume of Blood to be Drawn from Each 
Subject
a) PK Samples (first line item of table): “PK samples
(serum PTH)a” has been revised to: PK samples
(plasma PTH)a”.
b) Footnote “a” revised and footnote “d” added to clarify
that when a PD and PK sample are collected at the
same time point, the PD sample is to be drawn priorto
the PK sample (to avoid any potential for cross-
contamination of tube additives), and if an indwelling
catheter is used for this collection, the first 1mL of
blood should be discarded prior to the PD blood sample
collection. When either a PK or a PD sample is drawn
alone at a scheduled time point (using a catheter), 1mL
of blood should be discarded prior to the scheduled
blood sample collection.
c) An 18mL adjustment in the blood volumes was made:
the PK volume decreased 18mL, and the PD volume
(Day 1-2) increased 18mL. However, the overall blood
volume required for the study remains unchanged.
d) Footnote “c” added to 8th row description (PD samples
[Day 1-2] for total serum calcium, magnesium,
phosphate, creatinine, 1,25[OH]2D3).
Reason for change:
Section 7.3.5


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a) The sample matrix was corrected to plasma, to be
consistent with the protocol, Section 7.3.3.
b) Clarification made (footnote a and d), regarding the
order of the 1mL discharge, and the PD and PK
sample when collected at the same scheduled time
point.
c) The 18mL volume “shift” (from the PK total
volume to the PD [Day 1-2] total volume) was due
to the 1mL discard being required prior to the PD
sample (instead of the PK sample), when these
samples are collected together using an indwelling
catheter. This “shift” does not change the overall
blood volume required for the study.
d) Footnote “c” was missing for this line item
description in the prior version of the protocol, and
has been added to this version.
12.
Pharmacokinetic Analysis
1st paragraph which states:
“All the pharmacokinetic analyses will be performedusing 
the pharmacokinetic/pharmacodynamicpopulation.”
Has been changed to read:
“All the pharmacokinetic analyses will be performedusing 
the pharmacokinetic population.”
Reason for change:
Reference to pharmacodynamic population in this section 
is incorrect, and has been deleted.
Section 9.8.1
13.
Pharmacodynamic Analysis
New sentence added at the beginning of this section which 
reads:
Section 9.8.2


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“All the pharmacodynamic analyses will be performed 
using the pharmacodynamics population.”
Reason for change:
Sentence added to clarify the population being used for the 
analysis.
14.
Population Pharmacokinetic and Quantitative System 
Pharmacology Modeling and Simulation (new section and 
text added):
“Additional modeling and simulation will be performed to 
evaluate the PK of PTH and the effect on serum calcium 
concentration and urine calcium excretion from alternative 
dosing regimens other than the once daily and twice daily 
doses used in the study. A population PK model and a
quantitative system pharmacology model (QSPM) will be 
developed by fitting PK and PD data obtained from
historical studies in hypoparathyroid patients as well as 
data from this study. Inter-subject variability on model 
parameters will be fully evaluated. Once the populationPK
model and the QSPM are satisfactorily validated,
simulations using the final validated models will be 
performed to explore the effects of alternative dosingother
than once-daily and twice-daily dosing, eg, 3 times daily 
(TID), pump infusion dosing, and possibly new
formulations of PTH, on the control of serum calcium 
concentrations and urinary excretion of calcium in 
hypoparathyroid patients. A separate data analysis plan and 
report will be prepared for this additional modelingand
simulation work. These data will not be used in
conjunction with any study patient identifiers.”
“QSPM” was also added to the list of abbreviations as a 
result of the term added to protocol text.
Reason for change: The addition of text regarding PK/PD 
modeling was provided to recognize that future work (ie, 
modeling and simulation), outside of this protocol, could 
potentially examine alternative dosing regimens. This 
Abbreviations;
Section 9.8.4 (new section 
added)


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added text will not affect the study conduct or patient 
safety in any way. A separate data analysis plan andreport
will be prepared for this work.
15.
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made throughout the document as 
appropriate.
Reason for change: Clarification and/ortypographical
corrections.
All sections (as
warranted)


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1.
Site(s) and Region(s):
“United States” has been changed to “North America” as 
one of the regionsparticipating.
Reason for change:
United States has been corrected to the region it is located 
in (North America). This will also permit additional 
countries within this region that may decide to participate 
in the future (without warranting a subsequent amendment 
for this change).
Synopsis, Section 3.3
2.
An administrative screening (within 120 days of the first 
dose) has been added prior to the normal screening period 
for the study. The administrative screen is only for purpose 
of requesting, authorizing and releasing medical recordsfor 
a potential subject (if needed). As such, it is not part of the
active screening process. The subject must sign an
informed consent and a medical records release
authorization as the first step of the administrative 
screening process. This wording and addition to Table 1 
clarify the current process to obtain any necessary medical 
records.
Reason for change:
To allow for the necessary time required to obtain medical 
records for subjects interested in participating at a site that 
is outside of their immediate care network (if needed).
Synopsis; Table 1;
Section 3.1; Figure 1;
Section 3.2; Section 7.2.1
3.
Details of a remote informed consent process have been
added to the protocol.
Reason for change:
To support remote informed consenting as it relates to 
subjects who are located at a distance from the site and/or
who would require consent and medical record release for 
conducting an administrative screen (see above, item # 2).
To incorporate the wording from the Shire Note to File, 
(dated 06 Dec 2016) entitled “Remote Informed Consent 
Section 7.2.1.1; Appendix
2


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Process” into the protocol.
4.
“Screening” has been re-stated as “ClinicalScreening”,
“Clinical Screening Period”, or “Clinical Screening Visit” 
(as applicable) throughout the document.
Reason for change:
To distinguish the study-specific screening procedures
(now called “Clinical Screening”) from the newlyadded
“Administrative Screening”process.
Synopsis; Table 1;
Section 3.1; Figure 1;
Section 7.2.1, Table 6
5.
Table 1: Schedule ofAssessments
a) Screening Column has been separated into 2
columns: 1 column for Administrative Screening
and 1 column for Clinical Screening.
b) New line item for medical records release has been
added (for admin screen) and informed consent has
been added to the administrative screening. New
footnote (d) regarding medical records release
added.
c) Subsequent footnotes thereafter on this table have
been re-ordered alphabetically.
d) Footnote r (regarding Adverse Events to be
collected at the Administrative Screening Period)
and Footnote q (regarding 24-hr urine sample
collected during the Clinical ScreeningPeriod)
have been added.
e) “Evening check-in to CRC” (22nd row) is corrected
to read “Check-in to CRC”
Reason for changes (a-d):
To distinguish the study-specific screeningprocedures
(now called “Clinical Screening”) from the 
“Administrative Screening”process.
Footnotes have been added forclarity. 
Reason for change (e):
Table 1


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“Evening” should be deleted from description of time to 
check-in to the CRC. This change will allow sites and 
subjects more flexibility in arrival time to CRC on Day -2 
for each period, and based on the schedule and timingof
required study assessments that need to becompleted
and/or results received on this study day.
Per Administrative Clarification Memo # 1 (dated 21 Oct 
2016).
6.
For Cohorts 3 and 4 (Treatment D, E, and F), subjects 
should take their supplemental calcium at their usual 
dose(s)/regimen, and the dose/regimen and timing of their 
calcium administration should be identical at Day -1, Day 1 
and Day 2 in each treatment period.
Furthermore, subjects in Cohorts 3 and 4 (Treatment D, E 
and F) will take their usual supplemental calcium at their 
usual dose(s)/regimen in Day 1, regardless of the rhPTH 
(1-84) dosing regimen.
The 30 minute window in which calcium supplement was 
to be taken prior to IP administration was removed.
Reason for changes:
The intent of the protocol was to allow for subjects to 
continue their usual regimen of supplemental calcium. 
Since many subjects may take multiple calcium 
supplements throughout the day, the present protocol’s 
instructions to take the calcium supplement 30 minutes 
prior to dose are inconsistent with the usual supplement
regimen. The revised wording clarifies that the 
supplements taken on study will be as intended by the
subject’s usual regimen.
The revised wording clarifies that subjects are to continue 
their usual regimen of supplemental calcium as intended on 
study Day 1, regardless of whether subjects are to receive 
one or two doses of rhPTH(1-84) on thatday.
Synopsis; Section 3.1
7.
One or more interim analyses may be performed in this 
study. If an analysis is deemed to be necessary, then a 
prospective statistical analysis plan will be developed prior 
Synopsis; Section 3.1;
Section 9.5


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to the analysis. The plan will include, at a minimum: (1) 
rationale to perform the interim analysis; (2) parameters to 
be analyzed; (3) the distribution list for the interim analysis 
results. Interim data may be used for (but not limited to) 
PK/PD modeling and/or regulatory submissions. The trial 
will not stop due to the results of any interim analysis.
Reason for change:
To indicate that one or more interim analyses maybe
performed, as described above.
8.
Statement added that subjects who complete this study may
have the opportunity to enroll in an open-label extension 
trial.
Reason for change:
Wording has been added to indicate that subjects may have 
an opportunity to enroll in an open-label trial, if an open-
label extension study is available and approved by the 
site’s IRB/EC.
Synopsis; Section 3.1,
Section 7.2.5
9.
Sentence has been added regarding subjects assigned to the 
BID regimen, suggesting that lunch be divided into 2 
portions; the first portion consumed at lunch, and the 
second portion consumed as the snack or light meal.
Reason for change: Statement added to protocol, per
Clarification Memo (21 Dec 2016) regarding Site Meal 
Menus.
Section 3.1
10.
Inclusion criterion #3: the upper age limit has been 
removed. The Screening Period has been defined to 
encompass both the Administrative and Clinical Screening 
Periods, and age assessed at the time the consent is first 
signed by the subject.
Reason for changes:
An upper age limit is unnecessary; deletion of this upper 
limit does not compromise subject safety. Per the US 
Synopsis; Section 4.1


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Package Insert, “Clinical studies of NATPARA did not 
include sufficient numbers of subjects aged 65 and over to 
determine whether response in these subjects is different 
from younger subjects.” NATPARA is therefore indicated
for adults; there is no age limitation. No dose adjustment is 
recommended for patients ≥65 years of age. The US 
Package Insert also notes that physicians should be 
cautious regarding dose and treatment of geriatric patients. 
Exclusions #2 and #12 ensure that medical conditions that 
often tend to occur in geriatric patients are already 
excluded based on investigator judgment.
Clarification regarding when age will be assessed for the 
study.
11.
Inclusion criterion #5: elemental calcium specified.
Reason for change:
Clarification warranted that the strength of supplemental 
calcium required per day is based on the calcium within the 
formulation, irrespective of the counter ion.
Synopsis; Section 4.1
12.
Inclusion criterion #7: serum calcium level range revised to 
state within lab normal reference range, and based on 
central and/or local lab results at the Clinical Screening 
Visit and Period 1, Day -2, and if not within normal range,
considered as not clinically significant by the investigator.
Reason for change:
Prior range (≥7.0 to ≤9.5 mg/dL) was restrictive and not 
consistent with lab normal range for this assessment.
Changed to be consistent with lab normal range but also to 
allow some investigator flexibility in this regard based on 
medical judgment. Subjects will be confined to the CRC 
during treatment periods and will be closely monitoredby 
the investigator for clinical signs of hypocalcemia or
hypercalcemia. Subject safety is not compromised because
of this change.
Synopsis; Section 4.1
13.
Inclusion criterion #8 (historical 24h urinary calcium
Synopsis; Section 4.1


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excretion) has been deleted.
All subsequent criteria in this section have been re-
numbered as a result.
Reason for change:
An historical 24-hr urinary calcium may be variable and 
not predictive of findings during screening; thus it is not 
needed to help identify the patient population for this 
study. The change does not impact subject safety.
14.
Inclusion criterion #9 (re-numbered as #8):
The time window for the 24-hour urine collection is 
expanded; the sample is to be collected anytime during the 
Clinical Screening Period, but prior to check-in to the CRC 
at Treatment Period 1, Day -2. Eligibility to be based on 
central or local lab urine calcium excretion results.
Reason for changes:
To allow for more flexibility in the time interval in which 
the urine collection is obtained during screening.
Clarification made regarding which lab results can be used 
to determine eligibility.
Synopsis; Section 4.1
15.
Inclusion criterion #12 (re-numbered as #11):
The inclusion criterion for serum 25(OH)D has been 
revised to within lower limit of normal and 1.5 fold the 
laboratory upper limit of normal, or, if outside of this 
range, considered not clinically significant by the 
investigator, at the Clinical Screening Visit.
Reason for change:
Changed to allow for some investigator flexibility inthis 
regard based on medical judgment.
Synopsis; Section 4.1
16.
Inclusion criterion #13 (re-numbered as #12):
Study visits at which the serum creatinine value and 
creatinine clearance values must be met have been added to
the text. Creatinine clearance is now corrected to read as 
Synopsis; Section 4.1


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estimated creatinineclearance.
Reason for changes:
Clarificationwarranted.
17.
Exclusion criterion #9 (first bullet)
Thiazide diuretics (within 14 days prior to first 
administration of investigational product) has been added 
as an exclusion criterion, as new (first) bullet.
Reason for change:
This exclusion criterion added to restrict the use of a 
concomitant medication which could have an effect on 
urinary calcium in this study.
Synopsis; Section 4.2
18.
Exclusion criterion #9 (first bullet, now re-positioned as 2nd
bullet):
Antacids have been removed from the list of exclusionary 
medications.
Reason for change:
Subjects may be taking antacid tablets (Tums® for 
example) as a source of supplemental calcium. This
restriction was removed to allow for inclusion of these 
subjects. This change does not compromise subject safety.
Synopsis; Section 4.2
19.
Exclusion criterion #10:
“…(not related to hypoparathyroidism)”… has been 
deleted from the text of this criterion.
Reason for change:
Clarificationwarranted.
Synopsis; Section 4.2
20.
Exclusion criterion #11:
ECG “values (average of triplicate readings)” hasbeen
added and last sentence has beendeleted.
Reason for change:
Synopsis; Section 4.2


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12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
Since triplicate ECG tracings are already being performed
at each time point, clarification was warranted in this 
criterion, and last sentence was unnecessary (therefore 
deleted).
21.
Exclusion criterion #16:
Criterion regarding herbal supplements has nowbeen
deleted.
All subsequent criteria in this section have been re-
numbered as a result.
Reason for change:
The need for the exclusion of herbal supplements is not 
relevant to this study in this patient population and is not 
needed; deletion of this exclusion does not compromise 
patient safety.
Synopsis; Section 4.2
22.
Exclusion criterion #17 (now re-numbered as#16):
Criterion regarding screen for drugs of abuse has been 
modified to allow for investigator discretion to enroll 
subjects who take prescription medications.
Reason for change:
Exclusion criterion has been modified to allow subjects on 
prescription medications that might be detected during the 
urine screen for drugs of abuse (listed in section 7.3.2.7) to 
be enrolled per the investigator medical judgment.
Synopsis; Section 4.2
23.
Restrictions: the following item #s have been deleted:

#2 (grapefruit/Seville oranges products)

#5 (regular use of any medications, includingOTC,
multi-vitamin, herbal, homeopathics)

#6 (foods or beverages containing caffeine/xanthine)
All subsequently numbered restrictions in this section have 
been re-numbered as a result.
Reason for change:
Section 4.3


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Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
The restriction of these food or beverage items and/or 
medications is unnecessary for this patient-population 
study; deletion of these restrictions does not compromise 
subject safety.
24.
Restrictions #4 (re-numbered as #3):
Tobacco (or nicotine products) use has been revised to 
specify that this restriction only applies to its use within 60 
minutes prior to the collection of any vital signs, ECG or
blood draws while confined to the CRC.
Reason for change: Prior restriction was too limiting and 
unnecessary for this patient population. This change does 
not compromise subjectsafety.
Section 4.3
25.
Restriction #8 (re-numbered as#5):
Clarifications added to the text surrounding meal menus, 
food options/choices and the need for meal choices to be 
identical for each subject within a site between Period 1 
and Period 2.
Reason for change:
To incorporate wording from the Sponsor’s Memo to File 
(dated 21 Dec 2016) entitled “Site Meal Menus” which was 
previously forwarded to all participating study sites.
Section 4.3
26.
Concomitant Treatment
Statement added that administration times and dose 
strengths of all calcium and active vitamin D must be 
recorded accurately and completely in subject’ssource
documents.
Reason for change:
Statement added to emphasize this point.
Section 5.2
27.
Text added to allow for local destruction of used/unused 
investigational product/supplies, and only in exceptional 
circumstances (with prior written agreement by the
sponsor).
Section 6.4


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Protocol Amendments
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Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
Reason for change:
To permit local destruction of used/unused supplies for
sites who are not permitted to return them to thevendor 
(due to institution’s SOPs, hospital/pharmacy regulations, 
etc.)
28.
Study Schedule (priority order)
Statement added regarding the order/sequence of blood 
sampling, in order to avoid the potential for cross-
contamination of tube additives when collecting blood 
samples at the same time point for different assays (based 
on tubes requiring serum versus tubes requiring plasma, 
which require ananticoagulant).
Reason for change:
Statement added to protocol, per Administrative 
Clarification Memo #1 (dated 21 Oct2016).
Section 7.2
29.
Rescreening of Subjects
Clarification and statement added that a total of 2 re-
screenings are permitted in this study: one re-screening due 
to failure to meet inclusion/exclusion criteria that is 
considered as transient/temporary, and one re-screening
due to scheduling/timing issues related to the study
schedule (including the time to release medical records, if 
applicable).
Reason for change:
Statement added to protocol, per Administrative 
Clarification Memo # 1 (dated 21 Oct 2016).
Section 7.2.1.4
30.
Vital Signs:
Sentence added regarding scheduled assessment time and 
allowable window in which vital signs must be obtained. A 
measurement made outside of this window would be
considered a protocol deviation.
Section 7.3.2.4


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Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
Reason for change:
Clarificationwarranted.
31.
Clinical Lab Evaluations:
a) Two statements added:
In order to qualify the subject for randomization at 
Treatment Period 1, the site can base eligibility on 
the local lab results if the central lab results arenot 
available, but, if results are available fromboth
labs, eligibility should be based on the central lab 
results.
However, local lab results will not be entered in the
eCRF/clinical database, and copies of local lab
reports must be maintained in the subject source 
documents. The central lab results (once received) 
will be entered in the eCRF/clinicaldatabase.
b) Asterisked Note at end of this section (regarding
urinary calcium eligibility) was deleted as this is 
now redundant with (and encompassed by) the
newly added text.
c) Creatinine clearance is now corrected to readas
estimated creatinine clearance.
Reason for changes:
Clarification warranted regarding the use of local lab 
results for eligibility purposes.
Clarification made to how creatinine clearance was being
assessed.
Section 7.3.2.5
32.
4th paragraph:
Sentence modified to include qualifier statement “(except 
as noted in Exclusion Criterion # 16)” at end of the 
sentence, so it reads:
“Any positive result for drugs of abuse at clinical screening
or drugs of abuse or alcohol on Day -1 (both treatment 
Section 7.3.2.7


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Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
periods) will exclude the subject from further participation 
in the study (except as noted in Exclusion Criterion #16)”
Reason for change:
Clarificationwarranted.
33.
ECGs:
a) Sentence added regarding scheduled assessment time
and allowable window in which ECGs must be
obtained. A measurement made outside of this window
would be considered a protocol deviation.
b) “sponsor representative” has been revised as “ECG
vendor”
c) Added “Only valid ECG tracings will be submittedto
the ECG vendor for analysis”.
d) “Valid” added in 2 places within the 5th paragraphto
clarify the ECG measurements.
e) Third paragraph: sentence which reads: “The subject
should not have exercised or consumed caffeine,
alcohol, or nicotine within 30 minutes prior to
collection” is changed to: “The subject should not have
exercised or consumed caffeine, alcohol, or nicotine
within 60 minutes prior to collection”.
Reason for changes (a-d): 
Clarificationswarranted.
Reason for change (e):
The time (30 minutes) was revised (to 60 minutes) to be 
consistent with the time required for withhold nicotineuse 
Section 7.3.2.9


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Protocol Amendments
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Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
prior to blood collections in the revised restriction # 4 (re-
numbered as # 3).
34.
PD Blood Sample Collection and HandlingProcedures
3rd paragraph, 6th bullet:
“Matrix identifier (plasma)”
is corrected to read
“Matrix identifier (serum)”
Reason for change:
Matrix corrected to be consistent with other sections of the 
protocol (sections 7.3.4.2, 7.3.4.3, 7.3.5).Per
Administrative Clarification Memo # 1 (dated 21 Oct 
2016).
Section 7.3.4.1
35.
Safety Analysis, 3rd paragraph: 1st and 2nd bullets which
read:

AEs and TEAEs

Clinical episodes of hypocalcemia and/or
hypercalcemia (including, paresthesia, numbness,
tetany) and hypercalcemia
These 2 bullets have been combined into 1 bullet which 
reads:

AEs and TEAEs (including episodes ofhypocalcemia
and/or hypercalcemia [including, paresthesia,
numbness, tetany] and hypercalciuria)
Reason for changes:
The term “hypercalcemia” was inadvertently statedtwice
in the 2nd bullet. The 2nd appearance of this term in this 2nd
bullet was a typographical error and is now correctedto
“hypercalciuria”.
The 1st bullet was combined with the 2nd to be consistent 
with the safety endpoints section of thesynopsis.
Section 9.9


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Protocol Amendments
Summary of Change(s) Since Last Version of ApprovedProtocol
Amendment Number
4
Amendment Date
12 Jun 2017
Global
Item #
Description of Change
Section(s) Affected by
Change
36.
Synopsis, Safety Endpoints, 1st bullet
The update made in Section 9.9 (see item #35 above), is
also reflected in the synopsis (Safety Endpoints, 1stbullet).
“AEs including episodes of hypo- and hypercalcemia”
This sentence is now clarified toread:
“AEs including episodes of hypocalcemia, hypercalcemia, 
and hypercalciuria”
Reason for change:
To be consistent with the typographical correction made in 
Section 9.9.
Per Administrative Clarification Memo # 1 (dated 21 Oct 
2016).
Synopsis
37.
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made throughout the documentas 
appropriate.
Reason for change:
Clarification and/or typographicalcorrections.
All sections (as
warranted)


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Appendix 2 Remote Informed Consent Process
The remote informed consent process is primarily intended for any potential patient whois 
distant from a participating study site and also needs to have medical records released to assess
preliminary suitability for participation. The remote consent process may be performed only ifit
is in compliance with the site’s local and/or regional regulations and approved by the site’s 
IRB/EC prior to institution.
The study staff of the site selected will contact the potential study subject (patient) and arrange 
for two copies of their informed consent document to be sent out to the study subject (patient) 
along with two copies of a medical records release form by courier. The initial package will also 
contain a pre-paid self-addressed courier envelope and form for return of signed documents.
Within a reasonable time after the initial package has been mailed, the study site will contact the 
potential study subject (patient) and arrange to go over the informed consent form by telephone. 
This step should include the opportunity for the potential study subject (patient) to ask medical 
questions of a site physician listed on the clinical study Statement of Investigator (FDA 1572) 
form.
Following the telephone call with the study site, if the potential study subject (patient) remains 
interested in the study, the subject would sign and date one copy of the informed consent form
and one copy of the medical record release form and return both documents to the study site in 
the courier envelope provided. One copy of the informed consent form and one copy ofthe
medical release form would be retained by the potential study subject (patient) forreference.
The study site personnel must document this remote consenting process in their source 
documents and include the date and time of when they reviewed this process with the prospective 
subject (patient).
Upon receipt of the signed informed consent and medical release forms, the study site staff will 
register (enroll) the potential study subject (patient) in the study (IRT) and then requesthistorical 
medical records from the potential study subject’s (patient’s) current care provider.
Upon receipt of the signed informed consent document, the study site personnel who discussed 
the informed consent over the telephone should sign and date the last page (with the date of 
signature) of the subject’s signed consent form and indicate that the consent process was carried 
out by telephone. The study site personnel must not sign the consent in the witness block, ifone
exists.
Once the historical medical records are received, the study site physician will review the record 
to determine if the subject (patient) remains potentially eligible for the study (pending 
completion of full screening). The potential study subject (patient) will then be contacted. If the 
potential study subject (patient) does not meet eligibility criteria, they will be informed and 
regarded as a screen failure in the study.
If the potential study subject (patient) appears to be eligible, they will be informed, and the study 
site personnel will arrange travel (if applicable) to the study site for further eligibility screening.


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Based on site policy, the study site may confirm the identity of the potential studysubject
(patient [once at the study site]) to verify the signature on the informed consent document that 
was signed remotely.
Should the potential subject (patient) not be able to complete screening within the designated 
screening window per protocol (eg, due to a delay in the receipt of medical records or becauseof
travel), the potential subject (patient) would be considered a screen failure. In this case, if the 
potential subject (patient) remains interested in study participation, they would sign a new 
informed consent form, either on site or remotely, and restart the screening process (with a new
screen number).

SAP_001.pdf: 






Protocol SHP634-101
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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................4
LIST OF TABLES......................................................................................................................7
ABBREVIATIONS ....................................................................................................................8
1.
INTRODUCTION..........................................................................................................9
2.
STUDY DESIGN .........................................................................................................10
2.1
General Study Design...................................................................................................10
2.2
Randomization..............................................................................................................16
2.3
Blinding ........................................................................................................................17
2.4
Schedule of Assessments..............................................................................................17
STUDY SCHEDULE(S) ..........................................................................................................18
2.5
Determination of Sample Size......................................................................................26
2.6
Multiplicity Adjustments for Type I Error Control......................................................26
3.
OBJECTIVES...............................................................................................................27
3.1
Primary Objectives .......................................................................................................27
3.2
Secondary Objectives ...................................................................................................27
4.
SUBJECT POPULATION SETS.................................................................................28
4.1
Screened Set .................................................................................................................28
4.2
All-Enrolled Set............................................................................................................28
4.3
Safety Analysis Set.......................................................................................................28
4.4
Pharmacokinetic Set .....................................................................................................28
4.5
Pharmacodynamic Set ..................................................................................................28
5.
SUBJECT DISPOSITION............................................................................................29
6.
PROTOCOL DEVIATIONS........................................................................................30
7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................31
8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE.............................32
8.1
Exposure to Investigational product.............................................................................32
8.2
Measurement of Treatment Compliance ......................................................................32
9.
PRIOR AND CONCOMITANT MEDICATION........................................................33


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10.
EFFICACY ANALYSES.............................................................................................34
10.1
Primary Efficacy Endpoint(s) and Analysis .................................................................34
10.2
Key Secondary Efficacy Endpoint(s) and Analysis .....................................................34
10.3
Other Secondary Efficacy Endpoint(s) and Analysis...................................................34
10.4
Exploratory Efficacy Endpoint(s) and Analyses ..........................................................34
11.
SAFETY ANALYSES .................................................................................................35
11.1
Adverse Events.............................................................................................................35
11.2
Clinical Laboratory Variables ......................................................................................36
11.3
Vital Signs ....................................................................................................................38
11.4
Electrocardiogram (ECG).............................................................................................39
11.5
Other Safety Variables..................................................................................................40
12.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES..41
12.1
Pharmacokinetics Population and Pharmacodynamic Population................................41
12.2
Handling BLQ and Missing Values..............................................................................41
12.3
Pharmacokinetic Methods ............................................................................................42
12.3.1 Raw PTH Concentration Data................................................................................42
12.3.2 Baseline-adjusted PTH Concentration Data ..........................................................42
12.3.3 Pharmacokinetic Parameters..................................................................................42
12.3.4 Statistical Analysis of Pharmacokinetic Data ........................................................44
12.4
Pharmacodynamic Methods .........................................................................................44
12.4.1 Raw Pharmacodynamic Data.................................................................................44
12.4.2 Baseline-adjusted serum Pharmacodynamic Data .................................................45
12.4.3 Serum Pharmacodynamic Parameters....................................................................45
12.4.4 Urinary Pharmacodynamic Parameters..................................................................46
12.5
Analyses of Pharmacokinetic/Pharmacodynamic Relationships..................................48
12.6
Population Pharmacokinetic and Quantitative System Pharmacology Modeling and 
Simulation.....................................................................................................................48
13.
OTHER ANALYSES...................................................................................................49
13.1
Quality of Life Analyses...............................................................................................49
13.2
Health Economics and Outcomes Research Analyses .................................................49
14.
INTERIM ANALYSIS.................................................................................................50
15.
DATA MONITORING/REVIEW COMMITTEE.......................................................51
16.
COMPUTER METHODS ............................................................................................52


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17.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL.......................................53
18.
DATA HANDLING CONVENTIONS........................................................................54
18.1
General Data Reporting Conventions...........................................................................54
18.2
Derived Efficacy Endpoints..........................................................................................54
18.3
Repeated or Unscheduled Assessments of Safety Parameters .....................................54
18.4
Missing Date of Investigational Product ......................................................................54
18.5
Missing Date and Time Information for Prior or Concomitant Medications...............55
18.5.1 Incomplete Start Date and Time ............................................................................55
18.5.2 Incomplete Stop Date and Time.............................................................................56
18.6
Missing Date Information for Adverse Events.............................................................57
18.6.1 Incomplete Start Date.............................................................................................57
18.6.2 Incomplete Stop Date.............................................................................................57
18.7
Missing Severity Assessment for Adverse Events .......................................................57
18.8
Missing Relationship to Investigational Product for Adverse Events..........................57
18.9
Character Values of Clinical Laboratory Variables .....................................................57
19.
REFERENCES .............................................................................................................58
20.
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS ....................59


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LIST OF TABLES
Table 1:
Treatment Scheme..................................................................................................11
Table 3:
Detailed Schedule of Assessments: Day -1 (Prior to Treatment Periods 1 and 2).22
Table 4:   Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (QD 
Regimen)................................................................................................................23
Table 5:
Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 
(BID Regimen).......................................................................................................24
Table 6:
Criteria for Potentially Clinically Important Laboratory Tests .....................37
Table 7:
Criteria for Potentially Clinically Significant Vital Signs................................38
Table 8:
Criteria for Potentially Clinically Important ECG Values..............................39


Protocol SHP634-101
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ABBREVIATIONS
AE
adverse event
ATC
Anatomical Therapeutic Chemical
BID
twice-daily
BMI
body mass index
CRC
clinical research centre
DMC
data monitoring committee
eCRF
electronic case report form
ECG
electrocardiogram
PCI
potentially clinically important
QD
once-daily
QRS
a time interval on an ECG trace that represents the depolarization of the 
ventricles
QT
a time interval on an ECG trace starting at the beginning of the QRS 
complex and finishing at the end of the T-wave (represents the time taken 
for the ventricles to depolarize & then repolarize)
QTcB
the QT interval on an ECG trace that has been corrected using Bazett's 
formula
QTcF
the QT interval on an ECG trace that has been corrected 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
SOC
system organ class
TEAE 
treatment-emergent adverse event


Protocol SHP634-101
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1.
Introduction
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of pharmacokinetic and pharmacodynamic data as described in the study protocol 
amendment 5 dated 18 Jun 2018. 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. 


Protocol SHP634-101
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2.
STUDY DESIGN 
2.1
General Study Design
This study is an open-label, randomized, multi-center, 4 cohort, 2-period crossover study to 
characterize the effects of QD and BID dosing regimens of rhPTH(1-84) and the effect of 
adjunctive calcium (with no active vitamin D) in male and female adult subjects with a history of 
hypoparathyroidism for at least 12 months, post-diagnosis, inclusive of historical biochemical 
evidence of hypocalcemia and serum intact PTH concentrations below the lower limit of the 
laboratory normal reference range as well as a requirement for both supplemental oral calcium ≥ 
1000 mg/day and therapy with active forms of vitamin D at a minimum dose of ≥ 0.25 µg/day 
(i.e., 0.25 µg calcitriol or equivalent per day).
A sufficient number of subjects will be screened and enrolled to ensure that at least 8 subjects 
complete each treatment and provide sufficient data to meet the study objectives in their assigned 
cohort. Enrollment in the study will be staggered as 4 sequential cohorts (of at least 8 subjects
per cohort, including 1 treatment crossover within each cohort), such that at least 8 subjects in 1 
cohort must complete the study before subjects can be enrolled in the next cohort. A safety 
review will be conducted after 8 subjects have completed in each of Cohorts 1, 2 and 3 at which 
time a decision will be made whether to proceed to the next cohort. Cohorts may be expanded to 
include additional subjects to ensure that sufficient data for analysis are collected to complete the 
study objectives. Subjects may not participate in more than 1 cohort. Within each cohort, 
subjects will be randomly assigned to 1 of 2 treatment sequences prior to first dosing on Day 1 of 
Treatment Period 1. 
The treatment sequence assignments within each cohort are as follows:


Protocol SHP634-101
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Table 1:
Treatment Scheme
Cohort
Treatment Period 1
(Day 1)
Treatment Period 2
(Day 1)
1
(n=8*)
n=4
A
(25 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
A
(25 µg BID, no calcium)
2
(n=8*)
n=4
C
(50 µg BID, no calcium)
→
B
(100 µg QD, no calcium)
n=4
B
(100 µg QD, no calcium)
→
C
(50 µg BID, no calcium)
3
(n=8*)
n=4
D
(25 µg BID, with calcium)
→
E
(100 µg QD, with calcium)
n=4
E
(100 µg QD, with calcium)
→
D
(25 µg BID, with calcium)
4
(n=8*)
n=4
F
(50 µg BID with calcium)
→
E
(100 µg QD with calcium)
n=4
E
(100 µg QD with calcium)
→
F
(50 µg BID with calcium)
BID=twice-daily; QD=once-daily; N= 32 subjects 
Where:  Treatment A= 25 µg BID, no supplemental oral calcium
              Treatment B= 100 µg QD, no supplemental oral calcium
              Treatment C= 50 µg BID, no supplemental oral calcium
              Treatment D= 25 µg BID, with supplemental oral calcium
              Treatment E= 100 µg QD, with supplemental oral calcium
              Treatment F= 50 µg BID, with supplemental oral calcium
             With/without calcium refers to adjunctive therapy with dose; no active vitamin D
          *at least 8 subjects per cohort
Replacement subjects may be enrolled in the event that any subject does not complete each 
treatment (which would include the crossover dose) or have major protocol deviations such as 
not meeting inclusion/exclusion criteria. Replacement subjects may be enrolled on a case-by-
case basis (as a subject is discontinued), and, if a subject is replaced, that subject will follow the 
same 2-period treatment sequence as the subject who discontinued (regardless of when the 
subject discontinued).
This study will consist of the Administrative Screening Period (within 120 days of Day 1 of 
Period 1) that includes the time required to authorize release and obtain medical records for
subjects participating at sites outside their immediate care network (if applicable); the Clinical 
Screening Period;, 2 treatment periods which are to be separated by a washout (≥5 days but ≤30 
days) between the dose or first dose of investigational product in each period (for QD or BID 


Protocol SHP634-101
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dosing, respectively), and a follow-up visit (30±2 days after the last dose of investigational 
product is administered). The maximal total duration of study participation for a subject is 90 
days (~3 months), if the maximum clinical screening, washout and follow-up visit durations are 
used. If the Administrative Screening Period is required, the maximum duration of study 
participation is 182 days.
Clinical Screening will occur within 28 days of the first dose. Subjects who meet the 
inclusion/exclusion criteria as specified in the protocol will report to the Clinical Research 
Center (CRC) for admission on Day -2 of Treatment Period 1, in order to confirm entry criteria 
assessed at that time, and collect 24-hour serum calcium and urinary calcium profiles prior to 
treatment, starting on Day 1. Subjects will be randomized prior to administration of 
investigational product on Day 1 of Treatment Period 1, only after all entry criteria have been 
confirmed.
Subjects who fail to meet all inclusion/exclusion criteria will be permitted to be rescreened based 
on investigator discretion and sponsor approval if the investigator assesses the reason for screen 
failure is transient and temporary.
Potentially eligible subjects who continue to meet all inclusion/exclusion criteria, but are unable 
to participate in the study due either to scheduling conflicts/timing (including the time required 
to obtain medical records release, if applicable) or appropriate slot availability at an 
investigational site, 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 besigned. Number of screened subjects will reflect the 
number of unique subjects, rather than the number of unique screening IDs.
On Day 1 of Treatment Period 1:

Subjects in Cohort 1 will receive rhPTH(1-84) as either a twice-daily regimen (12 hours 
apart) of two 25μg doses (without calcium) or a once-daily regimen of one 100μg dose 
(without calcium) in the morning

Subjects in Cohort 2 will receive rhPTH(1-84) as either as a twice-daily regimen (12 
hours apart) of two 50μg doses (without calcium) or a once-daily regimen of one 100μg 
dose (without calcium)

Subjects in Cohort 3 will receive rhPTH(1-84) either as a twice-daily regimen (12 hours 
apart) of two 25μg doses (with calcium) or a once-daily regimen of one 100μg dose (with 
calcium).

Subjects in Cohort 4 will receive rhPTH(1-84) either as a twice-daily regimen (12 hours 
apart) of two 50μg doses (with calcium) or a once-daily regimen of one 100μg dose (with 
calcium).
On Day 1 of Treatment Period 2, subjects will receive the alternative treatment (according to the 
randomization schedule), following a washout period (≥5 days [ie, 120 hours] and ≤30 days) 
between administration of the dose or first dose ([for once-daily or twice-daily dosing, 


Protocol SHP634-101
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respectively] of each treatment period). All investigational products will be administered via SC 
injection into alternating thighs at each administration.
At each treatment period, subjects will report to the CRC on Day-2, remain in the CRC through 
Day 2, and be discharged following the last scheduled assessment on Day 2 (investigators may 
elect, at their discretion, to keep the subject in-clinic after Treatment Period 1 for the duration of 
the washout period, eg, if the washout period is short [eg, 120-172 hours] or there are any safety 
concerns).
For once-daily treatments (Treatments B and E), subjects will receive a single subcutaneous dose 
of rhPTH(1-84) in the morning on Day 1. For twice-daily treatments (Treatments A, C, D, and 
F), subjects will receive a subcutaneous dose of rhPTH(1-84) in the morning followed by the 
second dose 12 hours later on Day 1 (in the opposite thigh). If randomized to rhPTH(1-84) with 
calcium, subjects will take their supplemental oral calcium within 30 minutes prior to first dose 
administration. Prior to discharge from the CRC at each treatment period, subjects will be given 
specific instructions for when to resume taking their supplemental oral calcium and active 
vitamin D supplements during the day(s) when subjects are not in the CRC.
Subjects enrolled in the study must require daily doses of calcium supplements of ≥1000 mg 
prior to baseline (Day 1). Subjects enrolled in the study must also require minimum daily doses 
of active vitamin D of ≥0.25µg (ie, 0.25μg calcitriol or equivalent). Subjects will be expected to 
adhere to standard meals provided during their confinement in the CRC during each period (from 
check-in on Day -2 until discharge on Day 2). All subjects (in all treatments) will take their usual 
doses of supplemental oral calcium and active vitamin D on Day -2 and Day -1.
During Treatments A, B and C, supplemental oral calcium and active vitamin D will be withheld 
starting on Day 1 (pre-dose), through the completion of all study procedures on Day 2 for both 
the once-daily and twice-daily dosing regimens. Upon completion of all study procedures on Day 
2, subjects will then resume their usual supplemental oral calcium and active vitamin D at their 
next usual daily schedule.
During Treatments D, E and F, subjects will take their usual dose of supplemental oral calcium 
(but withhold active vitamin D) in the morning on Day 1, prior to investigational product 
administration. On Day 2, following the completion of all study procedures, subjects will then 
re-start their active vitamin D at their next usual daily schedule.
During the washout period, subjects will be instructed to take their usual doses of supplemental
oral calcium and active vitamin D.
Any subject who experiences symptoms of hypocalcemia or hypercalcemia may be treated at the 
investigator’s discretion, as per local standards. This may include, but is not limited to, 
intravenous (IV) calcium and/or fluids.
For all dosing regimens, rhPTH(1-84) will be administered in the morning of Day 1 of each 
treatment period following an overnight fast of at least 8 hours. Subjects will continue to fast 


Protocol SHP634-101
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until approximately 2 hours after rhPTH(1-84) administration, at which time a standardized meal 
will be served. For subjects assigned to the twice-daily dose regimen, the evening dose of 
investigational product will be administered 12 hours after the morning dose, and 2 hours prior to 
the evening meal. A snack or light meal may be provided to the subjects prior to the evening 
dose provided it is consumed ≥2 hours prior to investigational product dose administration.
Serial blood samples for pharmacokinetic analysis will be collected on Day 1 of each treatment 
period for the determination of PTH concentrations at pre-dose and up to 24 hours post morning 
dose (up to 24 hours post second dose for the twice-daily regimen). These blood samples will be 
collected according to the Schedule of Assessments (Table 3 and Table 4). Serial blood and urine 
samples for pharmacodynamic analysis will be collected on Day -1, pre-dose and on Day 1 
following the administration of rhPTH(1-84) for the determination of concentrations of serum 
total calcium (uncorrected and corrected for serum albumin levels), phosphate, magnesium, 
creatinine, albumin, 1,25(OH)2D3, and fibroblast growth factor 23 (FGF23), and urinary 
excretion of calcium, sodium, citrate, phosphate, cAMP, magnesium, and creatinine and the 
calcium-phosphate product will be determined. In addition, serum samples will be collected and 
analyzed for anti-PTH antibodies (for safety purposes) at the time points specified in Error! 
Reference source not found., Table 3, and Table 4. Samples will be analyzed using a validated 
methodology
Safety and tolerability will be monitored closely during the time the subject is in-clinic during 
the study. AEs will be recorded from the time the informed consent is signed, through 
completion of the study at follow-up.
A safety review will be conducted at the completion of Cohorts 1, 2 and 3, (with or without the 
inclusion of the follow-up visit data) before proceeding to the next cohort. The review will 
include all available safety data and will include, at a minimum, the Coordinating Investigator 
and the PPD and Shire Medical Monitors. Minutes of the review will be disseminated to all 
participating investigators.






Protocol SHP634-101
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For screen failures, the screening number will be the identifying number used throughout the 
CRF.
The actual treatment given to individual subjects is determined by a randomization schedule.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, and will be allocated prior to dosing after eligibility has been 
determined.
A randomization number is allocated immediately prior to dosing once eligibility has been 
determined. Once a randomization number has been assigned, that number must not be used 
again (if for example, a subject is withdrawn from the study). If a randomization number is 
allocated incorrectly, the study monitor must be notified as soon as the error is discovered.
Individual subject treatment is automatically assigned via interactive response technology (IRT).
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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Table 2:
Detailed Schedule of Assessments: Day -1 (Prior to Treatment Periods 1 and 2)
Study Day
-1
1
Time point (relative to 
scheduled dosing time on 
Day 1 [QD, 1st dose 
BID]) 
(hour)
Pre-dose
1
1.5
2
3
4
6
8
10
12
13
13.5
14
15
16
18
20
22
24
Vital signs (blood pressure, 
pulse) a, b
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
ECG (12-lead) a, e
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
IP administration
X d
PK blood sampling
X d
PD blood sampling f
X c
X
X
X
X
X
X
X
X
X d
PD urine sampling g , h
X i
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X d
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include blood 
pressure and pulse.
c These assessments should be performed within 30 minutes prior to the relative time of scheduled administration of IP on Day 1.
d Refer to Detailed Schedule of Assessments (Table 3 and Table 4) for collection time points (note: this time point is the same as the pre-dose collection time point on Day 1.
e ECGs will be performed in triplicate measurement at each time point.
f PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, and FGF23.
g 24- hour urine collection for PD analysis will be collected according to the following collection intervals (relative to the Day 1 morning dose): pre-dose, 0-3 hours, 3-6 hours, 
6-9 hours, 9-12 hours, 12-15 hours, 15-18 hours, 18-24 hours.  ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
h PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP and creatinine.
i The predose timepoint for PD urine sampling is used to signify the action that the subject needs to empty his/her bladder immediately before the start of the 0-3 urine collection 
based on the predicted dosing time of Day 1. It is not a separate pre-dose urine collection.


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Table 3:   Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (QD Regimen)
Study Day
1
2
Time point
(relative to dosing time 
on Day 1)
(h=hour/m=minute)
Pre-
dose
0
10m
20m
30m
1
1.5
2
4
6
8
10
12
13
13.5
14
16
18
20
22
24
Vital signs (blood 
pressure, pulse) a ,b
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X j
ECG (12-lead) a, d
X c
X
X
X
X
X
X
X
X
X
X
X
X
X
X j
Randomization
X e
IP administration
X
PK blood sampling
X c
X
X
X
X
X
X
X
X
X
X
X
PD blood sampling f
X c
X
X
X
X
X
X
X
X
X
X
Anti-PTH antibody 
sampling g
X c
PD urine sampling h, i
X k
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include 
blood pressure and pulse.
c These assessments should be performed within 30 minutes prior to the scheduled time for IP dose administration on Day 1.
d ECGs will be performed in triplicate measurement at each time point.
e Randomization will occur prior to administration of IP of Treatment Period 1, Day 1 only (and only after all eligibility criteria have been confirmed/re-confirmed).
f PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, and FGF23.
g The anti-PTH antibody sample should only be collected at Treatment Period 1, pre-dose (regardless of BID or QD regimen), and the sample collected within 30 mins 
prior to dosing.
h 24- hour urine collection for PD analysis will be collected according to the following collection intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours, 12-15 hours, 15-18 
hours, 18-24 hours.  ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP and creatinine.
j The last scheduled serial timepoint (i.e., 24 hours) will also serve as the discharge procedure for these assessments on Day 2.
k The urine sampling under pre-dose in this table is to signify the stop of Day -1, 18-24 hour PD urine collection period, and the start of the Day 1, 0-3 hour PD urine 
collection period. It is not a separate pre-dose collection.


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Table 4:
Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (BID Regimen)
Study Day
1
2
Time point
(relative to 
first dosing 
time on Day 1)
(h=hour/m=minute)
Pre-
dose
0
10m 20m 30m
1
1.5
2
4
6
8
10
Pre-
dose
(12hr)
12
12h
10m
12h
20m
12.5
13
13.5
14
16
18
20
22
24
28
32
36
Vital signs 
(blood pressure, 
pulse) a, b
X c
X
X
X
X
X
X
X c
X
X
X
X
X
X
X
X
X
X k
ECG (12-lead) 
a,d
X c
X
X
X
X
X
X
X c
X
X
X
X
X
X
X
X
X
X k
Randomization
X e
IP 
administration
X
X
PK blood 
sampling
X c
X
X
X
X
X
X
X
X
X f
X
X
X
X
X
X
X
X
X
X
X
PD blood 
sampling, g
X c 
X
X
X
X
X
X f
X
X
X
X
X
X
X
X
Anti-PTH 
antibody 
sampling h
X c
PD urine 
sampling i, j
X l →→→→→→→→→→→→→→→→→→→→→→→→→→
X
a An attempt to perform these assessments and procedures should be made for any subject who withdraws or is removed from the study.
b Vital signs should be collected in the supine position at each time point. Subject should also be supine at least 5 minutes prior to vitals collection. Vital signs include blood 
pressure and pulse.
c These assessments should be performed within 30 minutes prior to the scheduled time for IP dose administration on Day 1.
d ECGs will be performed in triplicate measurement at each time point.
e Randomization will occur prior to administration of IP of Treatment Period 1, Day 1 only (and only after all eligibility criteria have been confirmed/re-confirmed).
f Pre-dose PK/PD collection for the second dose of the BID regimen should be completed within 15 minutes prior to the dose.
g PD blood sampling assessments will include: total serum calcium, magnesium, phosphate, albumin, creatinine, 1,25-dihyroxyvitamin D, and FGF23.
h The anti-PTH antibody sample should only be collected at Treatment Period 1, pre-dose (regardless of BID or QD regimen), and the sample collected within 30 mins prior to 
dosing.


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Table 4:
Detailed Schedule of Assessments: Treatment Periods 1 and 2, Day 1/Day 2 (BID Regimen)
Study Day
1
2
Time point
(relative to 
first dosing 
time on Day 1)
(h=hour/m=minute)
Pre-
dose
0
10m 20m 30m
1
1.5
2
4
6
8
10
Pre-
dose
(12hr)
12
12h
10m
12h
20m
12.5
13
13.5
14
16
18
20
22
24
28
32
36
i 36- hour urine collection for PD analysis will be collected according to the following collection intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours, 12-15 hours, 15-18 
hours, 18-24 hours, 24-30 hours, 30-36 hours.  ‘X’ denotes the start and stop of the entire urine collection period and ‘→’ denotes continuous collection.
j PD urine collection assessments will include: calcium, sodium, citrate, phosphate, magnesium, cAMP and creatinine.
k The last scheduled serial timepoint (i.e., 36 hour timepoint) will also serve as the discharge procedure for these assessments on Day 2.
l The urine sampling under pre-dose in this table is to signify the stop of Day -1, 18-24 hour PD urine collection period, and the start of the Day 1, 0-3 hour PD urine collection 
period. It is not a separate pre-dose collection.


Protocol SHP634-101
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2.5
Determination of Sample Size
At least 8 subjects will be required to complete each treatment in each cohort. The sample size 
was determined based on a similar, prior pharmacokinetic/pharmacodynamic study. The 
number of subjects in this study is not based on statistical power considerations because the 
statistical analyses are primarily descriptive, and no hypothesis testing is specified in the 
study. 
2.6
Multiplicity Adjustments for Type I Error Control
Not applicable, as the statistical analyses are primarily descriptive with no hypothesis testing.


Protocol SHP634-101
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3.
OBJECTIVES
3.1
Primary Objectives
To assess the pharmacokinetic profile and pharmacodynamic effects (control of serum 
calcium and urinary calcium excretion) of rhPTH(1-84) administered as SC doses of 25μg 
administered twice-daily, 50μg administered twice-daily, and 100μg administered once-daily, 
as well as the effect of supplemental oral calcium intake, in subjects with hypoparathyroidism.
3.2
Secondary Objectives 
To assess the safety and tolerability of rhPTH(1-84) administration in subjects with 
hypoparathyroidism.


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4.
SUBJECT POPULATION SETS
4.1
Screened Set 
The Screened Set will consist of all subjects who have signed informed consent.
4.2
All-Enrolled Set
The All-Enrolled Set consists of all subjects who sign the informed consent form and are 
randomized in the study.
4.3
Safety Analysis Set  
The Safety Analysis Set includes enrolled subjects who have received at least 1 dose of 
rhPTH(1-84). All analyses of safety data will be based on this population.
4.4
Pharmacokinetic Set
The Pharmacokinetic Analysis Set consists of all enrolled subjects who do not have major 
protocol violations that affect the validity of the PK results, receive at least 1 dose of 
rhPTH(1-84) and have at least 1 evaluable post-dose pharmacokinetic concentration value 
available for 1 dose regimen. Subjects who do not meet the inclusion criterion for 
hypoparathyroidism will be excluded from the PK set. A listing of subjects excluded from the 
PK Set along with the reason for exclusion is to be generated. In the event of dosing error, 
proven or suspected based on PK data (extremely low post-dose PTH concentrations), PK 
data from the subject for the specific treatment period will be excluded from summary tables 
and figures.  A listing of excluded PK data along with reason for exclusion will be generated.
4.5
Pharmacodynamic Set 
The Pharmacodynamic Analysis Set consists of all enrolled subjects who do not have major 
protocol violations that affect the validity of the PD results, receive at least 1 dose of 
rhPTH(1-84) and have at least 1 evaluable post-dose pharmacodynamic value available for 1 
dose regimen. Subjects who do not meet the inclusion criterion for hypoparathyroidism will 
be excluded from the PD set.  A listing of subjects excluded from the PD Set along with the 
reason for exclusion is to be generated. In the event of dosing error, proven or suspected 
based on PK data (extremely low post-dose PTH concentrations), PD data from the subject 
for the specific treatment period will be excluded. During treatments A, B, and C, if a subject 
takes supplemental oral calcium/active vitamin D within 24 hours post the last rhPTH(1-84) 
dose, PD data from the subject for the specific treatment period will be excluded from 
summary tables and figures. A listing of excluded PD data along with the reason for exclusion 
will be generated.


Protocol SHP634-101
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5.
SUBJECT DISPOSITION
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented along with reasons for screen fail and details of any AEs. Final subject numbers 
will be presented for subjects that had been re-screened.
The number of subjects included in each subject population set (ie, Screened, All-Enrolled,  
Safety, Pharmacokinetic, and Pharmacodynamic) will be summarized by treatment sequence, 
and by treatment. 
For the summary by treatment sequence, the numbers and percentages of subjects who either 
completed or prematurely discontinued during the study will be presented for each treatment 
sequence and overall for the Safety Analysis Set. Reasons for premature discontinuation from 
the study as recorded on the termination page of the eCRF will be summarized (number and 
percentage) for each period (Period 1, Washout, Period 2, and Follow-up) by treatment 
sequence and overall for the Safety Analysis Set. 
A similar summary table will be presented for the summary by treatment, with number and 
percentage of subjects who discontinued during that treatment period for the Safety Analysis 
Set.
All subjects who prematurely discontinued during the study period will be listed by 
discontinuation reason for the All-Enrolled Set.


Protocol SHP634-101
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6.
PROTOCOL DEVIATIONS
A summary of the number and percentage of subjects in the All-Enrolled Set with protocol 
violations or deviations will be produced. 
All protocol violation and deviation data will be listed for the All-Enrolled Set.


Protocol SHP634-101
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7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment sequence and overall for the Safety Analysis Set.
The following demographic characteristics will be summarized in the following order in 
the tables: age, sex, ethnicity, race, weight, height, BMI, and BMI category (Underweight
[<18.5 kg/m2], Normal [18.5 to 24.99 kg/m2], Overweight [25.0 to 29.99 kg/m2], Obese [≥ 
30.0 kg/m2], Missing). In addition, other baseline characteristics will be summarized.  
Height and weight at screening will be used to calculate BMI using the formula below:
BMI = 
A listing will be created to show all the demographics and baseline characteristics for each 
enrolled subject. 
A table for Parathyroid History will summarize the last record of active vitamin D or 
calcium supplementation prior to study medication. The dose of active vitamin D will be 
categorized as low (0-0.25 μg/day), medium (>0.25-0.5 μg/day) or high (>0.5 μg/day), 
and the dose of calcium supplementation will be categorized as 0-2000 mg/day or >2000 
mg/day. The number and percentage of subjects in each category will be presented. 
Duration of hypoparathyroidism will be calculated from the date of informed consent and 
onset of hypoparathyroidism obtained from the medical history page. This will be 
summarized using standard summary statistics and also by number and percent of subjects 
in the categories <=5 years, >5-10 years, and >10 years.
Medical history will be coded using MedDRA version 19.0 or newer, and summarized by 
system organ class (SOC), preferred term (PT), and treatment sequence. Medical history 
will be listed for the Safety Analysis Set.
2
[m])
(height
[kg]
weight


Protocol SHP634-101
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8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
8.1
Exposure to Investigational product 
A summary table showing number of subjects exposed and number of administrations received will be 
produced by period, overall and treatment 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. 


Protocol SHP634-101
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9.
PRIOR AND CONCOMITANT MEDICATION 
Version 2016MARDD (Basic) or newer of the WHODRUG will be used to classify prior and 
concomitant medications by therapeutic class. Medications will also be coded by the
Anatomical Therapeutic Chemical (ATC) classification system.
Medications starting before the first dose of investigational product will be considered prior 
medications. Medications taken during Period 1 and stopping before the first dose of 
investigational product in Period 2 will be considered concomitant with Period 1. Medications 
taken after the first dose of investigational product in Period 2 will be considered concomitant 
with Period 2. If a medication is taken during Period 1 and Period 2 then it will be considered 
concomitant with both periods.
Both prior and concomitant medication usage will be summarized overall and by the number 
and proportion of subjects receiving each medication within each level 1 (anatomical main 
group) ATC group and preferred term for the Safety Analysis Set. Prior medication will be 
summarized by treatment sequence and concomitant medication will be summarized by 
treatment. Medications can be counted both as prior and concomitant medication, and 
concomitant medications can be counted under one or both treatments.  Multiple medication 
usage by a subject in the same category will be counted only once. When calculating the 
number of subjects receiving medications overall for all treatments combined, each subject 
will be counted only once even if the medication is taken in both treatment periods.
All prior and concomitant medication will be listed.
A separate listing will be produced for the prior and concomitant medications of interest, 
which are calcium, vitamin D (any form), and thiazide diuretics.


Protocol SHP634-101
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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.


Protocol SHP634-101
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11.
SAFETY ANALYSES
The safety analysis will be performed using the Safety Analysis Set. Safety variables include 
AEs and TEAEs, clinical episodes of hypocalcemia and/or hypercalcemia, and hypercalciuria, 
clinical laboratory variables, vital signs, and ECG variables. For clinical laboratory and vital 
sign variables, the last value collected before the first dose of investigational product in that 
period will be used as baseline for all analyses of that safety variable in that period.
Assessments at the follow-up visit will be assigned to the last treatment the patient received. 
Early termination visits will be summarized separately, and assigned to the treatment in 
Period 1 if prior to first dose of investigational product in Period 2, and assigned to treatment 
in Period 2 if after the first dose of investigational product in Period 2.
For handling of unscheduled visits, refer to Section 18.
11.1
Adverse Events 
Adverse events will be coded using Version 19.0 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 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 more than 5 days 
(120 hours) after the last dose of investigational product will not be counted as a TEAE.
Adverse events will be assigned to a treatment as follows. If the onset date of the AE is after 
first dose in Period 1, but prior to first dose in Period 2, and is ≤ 5 days after the date of last 
dose in Period 1 it will be counted as a Period 1 AE. If the onset date of the AE is after first 
dose in Period 2, and is ≤ 5 days after the date of last dose in Period 2 it will be counted as a 
Period 2 AE. Period 1 AEs will be assigned to the treatment received in Period 1, and Period 
2 AEs will be assigned to the treatment received in Period 2. AEs with onset date > 5 days 
after the last dose in Period 1 and prior to the first dose in Period 2 will be counted as a 
Washout AE, not assigned to a treatment, and not considered a TEAE. AEs with onset date > 
5 days after the last dose in Period 2 will be counted as a Follow-up AE, not assigned to a 
treatment, and not considered a TEAE.
When summarizing non-TEAEs by treatment, AEs occurring prior to first dose in Period 1 
will be excluded, and other non-TEAEs will be assigned to the last treatment received.
An overall summary of the number of subjects with AEs will be presented by treatment and 
overall, including the number and percentage of subjects with any AEs, serious AEs, AEs 
related to investigational product, AEs leading to discontinuation of investigational product, 
severe AEs, and deaths. The number and percentage of subjects with TEAEs and non-TEAEs 
will be presented for the same categories.


Protocol SHP634-101
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The number and percentage of subjects reporting TEAEs for each treatment will be tabulated 
by system organ class (SOC) and preferred term; 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 and most related occurrence for the summarization by severity and by relationship to 
investigational product. Severe TEAEs, Serious TEAEs and TEAEs leading to 
discontinuation of investigational product will be summarized by SOC, preferred term and 
treatment.
A summary table of TEAEs of special interest will be produced showing the number and 
percentage of subjects reporting TEAEs of special interest for each treatment tabulated by 
preferred term. The TEAEs of special interest are hypercalcemia, hypocalcemia and 
hypercalciuria. 
The above summaries will be repeated for non-TEAEs. A separate summary of all AEs of 
special interest (including TEAEs and non-TEAEs) will also be produced.
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, 
deaths, and AEs of special interest.
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 treatment 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, lymphocytes, 
monocytes, eosinophils, basophils.
Biochemistry
Sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, 
chloride, thyroid stimulating hormone (TSH)a, thyroxine (T4 total)a, 
triiodothyronine (T3)a, 25(OH)Da, phosphorus, total protein, total CO2
(Bicarbonate), albumin, aspartate transaminase, alanine transaminase, 
gamma glutamyl transferase, alkaline phosphatase, total bilirubin, uric acid, 
Creatinine clearancea, β-HCGb, FSHb, Magnesium.
β-HCG=beta-human chorionic gonadotropin; FSH=follicle stimulating hormone; T3=triiodothyronine; 
TSH=thyroid stimulating hormone
a Tests done at Screening only and therefore will not appear in summary tables. They will be listed.
b Females only.
Urinalysis
Glucose, specific gravity, blood, ketones, protein, calcium, bilirubin, pH, 
leukocyte esterase, and nitrites.


Protocol SHP634-101
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Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 5.  The number and percentage of subjects with post-
baseline PCI values will be tabulated by treatment.  The percentages will be calculated 
relative to the number of subjects with available baseline values and at least 1 post-baseline 
assessment.  The numerator is the total number of subjects with at least 1 post-baseline PCI 
value.  A supportive listing of subjects with post-baseline PCI values will be provided for all 
results for the parameter with a PCI value for a subject, including the subject number, site, 
baseline, and post-baseline values.  
Table 5:
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
Unit
Lower Limit
Upper Limit
Chemistry
Albumin
g/L
<=20
>=90
Alkaline Phosphatase
U/L
NA
>2*ULN
ALT
U/L
NA
>3*ULN
AST
U/L
NA
>3*ULN
Bilirubin
µmol/L
NA
>2*ULN
BUN
mmol/L
NA
>=10.7
Chloride
mmol/L
<=80
>=125
Creatinine
µmol/L
NA
>=177
Glucose
mmol/L
<=1.7
>=13.9
Gamma glutamyl transferase
U/L
NA
>=100
Magnesium
mmol/L
<0.7
>1.4
Phosphate (Phosphorus)
mmol/L
NA
>=2
Potassium
mmol/L
<=2.5
>=6.5
Sodium
mmol/L
<=120
>=165
Uric acid
µmol/L
NA
>=624 (males)
NA
>=505 (females)
Hematology
Hematocrit
fraction of 
1
<=0.37 (males)
>0.54 (males)
<=0.32 (females)
NA (females)
Hemoglobin
g/L
<=115 (males)
NA
<=95 (females)
NA
Platelets
x10E9/L
<=75
>=700
RBC count
x10E12/L
<=2.5 (males)
NA
<=2.0 (females)
NA
WBC count
x10E9/L
<=2.8
>=16.0
Basophils/Leukocytes
L/L
NA
>=0.15


Protocol SHP634-101
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Table 5:
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
Unit
Lower Limit
Upper Limit
Eosinophils/Leukocytes
L/L
NA
>=0.10
Lymphocytes/Leukocytes
L/L
NA
>=0.80
Monocytes/Leukocytes
L/L
NA
>=0.40
Neutrophils/Leukocytes
L/L
<=0.15
NA
24-Hour urine
Urine calcium
mg
NA
>300 for men
mg
NA
>250 for women
Listings for serum and urinary clinical laboratory results will be produced for all patients in 
the Safety Analysis Set.
11.3
Vital Signs
Descriptive statistics for vital signs (eg, systolic and diastolic blood pressure, pulse rate, and 
body weight) and their changes from baseline at each post-baseline assessment and at the end 
of study will be presented by treatment. All vital signs will be listed for each subject in the 
Safety Analysis Set.
Vital sign values will be considered PCI if they if they meet either the low or high PCI criteria 
listed in Table 6.  The number and percentage of subjects with PCI post-baseline values will 
be tabulated by treatment.  The percentages will be calculated relative to the number of 
subjects with baseline and at least 1 post-baseline assessment.  The numerator is the total
number of subjects with at least 1 PCI post-baseline vital sign value.  A supportive listing of 
subjects with post-baseline PCI values will be provided including the subject number, site, 
baseline, and post-baseline PCI values.  
Table 6:
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Unit
Lower Limit
Upper Limit
Systolic blood pressure
mmHg
A decrease from Baseline of ≥ 20 to 
a value ≤ 90
An increase from Baseline of  ≥ 20 
to a value ≥ 180
Diastolic blood pressure
mmHg
A decrease from Baseline of ≥ 15 to 
a value ≤ 50
An increase from Baseline of  ≥ 15 
to a value ≥ 105
Pulse rate 
bpm
A decrease from Baseline of ≥ 15 to 
a value ≤ 50
An increase from Baseline of  ≥ 15 
to a value ≥ 120


Protocol SHP634-101
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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. Baseline for numeric ECG results is the mean of the 
available valid values at the last timepoint with any non-missing data prior to the first dose of 
investigational product in that period. For qualitative ECG results, baseline will be the worst 
case at the last timepoint with any non-missing data prior to the first dose of investigational 
product in that period.
Descriptive statistics for ECG variables (eg, heart rate, PR interval, QRS interval, QT interval, 
and QTc interval) and their changes from baseline at each assessment time point will be 
presented by treatment.  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 timepoint for qualitative ECG results 
will be presented. All ECG results will be listed for each subject in the Safety Analysis Set.
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper 
limit values listed in Table 7. Assessment of whether a value is PCI will be based on the 
derived average at each timepoint for each subject. The number and percentage of subjects 
with post-baseline PCI values will be tabulated by treatment.  The percentages will be 
calculated relative to the number of subjects with available non-PCI baseline and at least 1 
post-baseline assessment.  The numerator is the total number of subjects with at least 1 PCI 
post-baseline ECG value.  A listing of all subjects with post-baseline PCI value will be 
provided including the subject number, site, baseline, and post-baseline PCI values.
Table 7:
Criteria for Potentially Clinically Important ECG Values
Parameter
Upper Limit
QTcB
> 500 ms, > 480 ms, >450 ms
QTcF
> 500 ms, > 480 ms, >450 ms
QTcB
An increase from Baseline of >=60 ms and >= 30 ms
QTcF
An increase from Baseline of >=60 ms and >= 30 ms


Protocol SHP634-101
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11.5
Other Safety Variables
Anti-PTH antibodies will be assessed at Treatment Period 1 Day 1 (pre-dose) and at Follow-
up. The results at each timepoint will be summarized for all subjects overall.


Protocol SHP634-101
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12.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES
12.1
Pharmacokinetics Population and Pharmacodynamic Population
The Pharmacokinetic Set consists of subjects who do not have major protocol violations that 
affect the validity of the PK results, receive at least 1 dose of rhPTH(1-84) and have at least 1 
evaluable post-dose pharmacokinetic concentration value available for 1 dose regimen. See 
details in Section 4.4. A listing of subjects excluded from the PK set along with the reasons 
for exclusion will be generated.
The Pharmacodynamic Analysis Set consists of subjects who do not have major protocol 
violations that affect the validity of the PD results, receive at least 1 dose of rhPTH(1-84) and 
have at least 1 evaluable post-dose pharmacodynamic value available for 1 dose regimen. See 
details in Section 4.4. A listing of subjects excluded from the PD set along with the reasons 
for exclusion will be generated.
12.2
Handling BLQ and Missing Values
The following procedures will be used for raw plasma PTH concentrations, raw serum 
pharmacodynamic data, and raw urine pharmacodynamic data below the lower limit of 
quantification (LLOQ):

Plasma samples that are BLQ are reported as <LLOQ on the data listings, where 
LLOQ is replaced by the actual value for LLOQ.

Missing values may be imputed on a case-by-case basis
For plasma PTH concentrations the following guidance will be followed:

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, and no 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
For serum PD concentrations the following guidance will be followed:


Protocol SHP634-101
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
Samples that are BLQ are treated as half the LLOQ in non-compartmental PD analysis 
and the calculation of summary statistics (e.g. mean, SD, etc.) for the plasma 
concentrations at individual time points.
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. 
12.3.1
Raw PTH Concentration Data
For subjects and treatment periods when one dose is received, samples for pharmacokinetic 
analysis are taken at Predose, 10, 20 and 30 minutes, 1, 1.5, 2, 4, 8, 12, 16 and 24 hours. For 
subjects and treatment periods when two doses are received, samples for pharmacokinetic 
analysis are taken at Predose, 10, 20 and 30 minutes, 1, 1.5, 2, 4, and 8 hours. A second 
predose sample will be collected just before the second dose is administered 12 hours after the 
first dose, 10, 20 and 30 minutes following the second dose, and 13, 13.5, 14, 16, 20, 24, 28 
and 36 hours after the first dose. Plasma concentrations of PTH(1-84) will be measured using 
a validated analytical method.
12.3.2
Baseline-adjusted PTH Concentration Data
Baseline-adjusted PTH concentrations (subject- and period-specific) are to be calculated by 
subtracting baseline endogenous PTH from the raw PTH concentrations. The baseline is 
defined as pre-morning-dose endogenous PTH level on Day 1 for each treatment period. 
Since rhPTH(1-84) is administered to subjects with hypoparathyroidism in this study, baseline 
endogenous PTH levels are expected to be low and likely below the lower limit of 
quantification (LLOQ) for PTH.  If the baseline-adjusted PTH concentration gives a negative 
value then the baseline-adjusted PTH concentration should be set to zero. In the terminal 
phase (after the morning dose during the QD treatment and after the evening dose during the 
BID treatment), any positive baseline-adjusted PTH concentrations following a negative value 
will be assigned a value of zero. 
If the pre-dose PTH value is missing, then this is set to 0 for the calculation of the baseline-
adjusted PTH concentration for the purposes of calculating the baseline-adjusted 
pharmacokinetic parameters.
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 


Protocol SHP634-101
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parameters will be determined from the plasma PTH concentration-time data by non-
compartmental analysis. Pharmacokinetic analyses based on raw and baseline adjusted PTH 
concentrations will be performed. In each treatment period, all assessment dates will be 
related to the first day of rhPTH administration. This first day of investigational product 
administration is referred to as Day 1. Day-1 is the day that is preceding Day 1, and a Day 0 
will not be defined.
The pharmacokinetic parameters will include, but may not be limited to:

Time of maximum observed concentration sampled during a dosing interval (tmax ), to 
be reported in the unit of hour (original and baseline-adjusted)

Maximum observed concentration (Cmax), to be reported in the unit of pg/mL (original 
and baseline-adjusted)

Area under the curve from the time of dosing to the last measurable concentration 
(AUClast).  Calculated using the linear up/log down method, to be reported in the unit 
of pg.hr/mL (original and baseline-adjusted)

Area under the curve extrapolated to infinity calculated as AUClast + Clast/λz
(AUC0-inf). Calculated using the linear up/log down method, to be reported in the unit 
of pg.hr/mL (baseline-adjusted only)

% of AUC extrapolated from the last measurable concentration to infinity over 
AUC(0-inf) (%AUC extrapolated) (baseline-adjusted only)

Area under the concentration curve from time zero to 24 hours post the first dose 
(AUC0-24h), to be reported in the unit of pg.hr/mL (calculated using the linear up/log 
down method) (original and baseline-adjusted)

Area under the concentration curve from time zero to 12 hours post the first dose 
(AUC0-12h) calculated using the linear up/log down method, to be reported in the unit 
of pg.hr/mL (for BID treatment only, original and baseline-adjusted)

Area under the concentration curve from the time of the second dose to 12 hours post 
the second dose (AUC12-24h) calculated using the linear up/log down method, to be 
reported in the unit of pg.hr/mL  (for BID treatment only, original and baseline-
adjusted)

Elimination rate constant associated with the terminal (log-linear) portion of the curve 
(λz) (baseline-adjusted only)

Terminal half-life (t½), calculated as 0.693/ λz (baseline-adjusted only)

CL/F Apparent total body clearance, calculated as Dose/AUC0-inf (baseline-adjusted 
only)

Vss/F Apparent volume of distribution at steady state, calculated as MRT xCL/F, 
where MRT is mean residence time calculated as AUMC0-inf/AUC0-inf and 
AUMC0-inf is the area under the first moment curve extrapolated to infinity.
(baseline-adjusted only)


Protocol SHP634-101
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All pharmacokinetic parameter calculations will be performed using actual times calculated 
relative to the start of the study drug administration on Day 1 for each period. The 
pharmacokinetic parameters λz, t1/2, AUC0-inf, CL/F, and Vss/F will not be calculated for 
patients with PTH concentration-time profiles ( baseline-adjusted) that do not exhibit a 
terminal log-linear phase.
If a pre-dose sample is missing, or if a 12 hour sample in the BID treatment is missing, then for the 
purposes of calculating the pharmacokinetic parameters, these values will be set to 0.
12.3.4
Statistical Analysis of Pharmacokinetic Data
Individual PTH concentrations (raw and baseline-adjusted) will be listed and summarized 
with descriptive statistics (number, arithmetic mean, SD, coefficient of variation [CV%], 
median, minimum, and maximum) by treatment and day. Pharmacokinetic parameters of PTH 
(based on raw and baseline-adjusted PTH concentrations) will be listed and summarized with 
descriptive statistics (number, arithmetic mean, SD, coefficient of variation [CV%], median, 
minimum, maximum, geometric mean, and geometric CV%) by treatment. CL/F and Vss/F 
will be listed, but not included in summary tables.
For Treatment B (repeated in Cohort 1 and Cohort 2) and Treatment E (repeated in Cohort 3 
and Cohort 4), summary statistics (for both concentration data and pharmacokinetic
parameters) will be prepared by cohort as well as for overall (combining different cohorts). 
Figures of individual (overlaid by treatment) and mean (+/-SD) concentration-time profiles 
(overlaid by treatment as well as by rhPTH(1-84) dosing regimen) of raw and baseline-
adjusted plasma PTH will be generated on linear and semi-log scales.
12.4
Pharmacodynamic Methods
All summaries and analyses of the pharmacodynamic data will be based on the 
Pharmacodynamic Set. After database lock, a visual inspection of concentration-time profiles 
and pharmacodynamic parameters will be performed by PRA to determine dataset integrity 
and potential outliers. Descriptive statistics of pharmacodynamic 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. A listing of excluded subjects from the pharmacodynamic analysis will be 
provided.
12.4.1
Raw Pharmacodynamic Data
Serial blood and urine samples for pharmacodynamic analysis will be collected on Day -1, 
pre-dose and on Day 1 and Day 2 following the administration of rhPTH(1-84) for the 
determination of concentrations of serum calcium (uncorrected [total] and corrected for serum 
albumin levels), phosphate, magnesium, creatinine, albumin, 1,25(OH)2D3, and fibroblast 
growth factor 23 (FGF23), and urinary excretion of calcium, sodium, citrate, phosphate, 
cAMP, magnesium, and creatinine.


Protocol SHP634-101
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The serum calcium-phosphate product will also be determined. This is calculated as serum 
calcium concentration (albumin corrected) x serum phosphate concentration.
For pharmacodynamic analyses, concentration values of serum total calcium and albumin-
corrected serum calcium, phosphate, magnesium, albumin, creatinine, 1,25(OH)2D3 and 
FGF23, reported as BLQ will be set to half the LLOQ.
12.4.2
Baseline-adjusted serum Pharmacodynamic Data
Individual serum concentrations of pharmacodynamic markers, calcium (uncorrected and 
corrected for albumin), phosphate, magnesium, 1,25(OH)2D3, FGF23, and calcium-phosphate 
product will be baseline-adjusted at each time point. There will be two baseline definitions, 
one for Day -1 and one for Day 1. For Day -1, the baseline value is defined as the last non-
missing value collected before the start of the active vitamin D administration on Day -1; for 
Day 1, the baseline value is defined as the last non-missing value collected before the 
administration of rhPTH(1-84) on Day 1 for each treatment period. Baseline-adjusted 
concentrations of pharmacodynamic markers are to be calculated by subtracting the 
appropriate baseline values from the raw concentrations at each time point.
12.4.3
Serum Pharmacodynamic Parameters
Pharmacodynamic parameters will be computed from the individual raw concentrations of 
serum calcium (mmol/L) (uncorrected and corrected for serum albumin levels), phosphate
(mmol/L), magnesium (mmol/L), 1,25(OH)2D3 (pmol/L) and FGF23 using a non-
compartmental approach and actual times. pharmacodynamic parameters will be estimated for 
both Day -1 and Day 1 in each treatment period. Serum calcium will be corrected for serum 
albumin levels using the following equation:
Corrected calcium (mmol/L) = serum calcium (mmol/L) + 0.02 (40 - serum albumin (g/L))
(Parent X1, 2009)
The following parameters will be calculated from the raw serum concentration data using 
WinNonlin Phoenix version 6.3 or higher (Pharsight Corporation, Mountain View, California, 
USA):

AUC0-24h: the area under the concentration versus time curve, from time 0 to 24 hours

TEmax: time to maximum effect

Emax: maximum effect

TEmin: time to minimum effect

Emin: minimum effect
The same parameters will also be calculated for the calcium-phosphate product.
In addition, serum pharmacodynamic parameters will be estimated based on baseline-adjusted 
serum concentration of pharmacodynamic markers as follows:


Protocol SHP634-101
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
AUCabove: Area under the concentration-time curve that is above the baseline, from time 
0 to 24 hours, as calculated by the linear trapezoidal method

AUCbelow: Area under the concentration-time curve that is below the baseline, from time 
0 to 24 hours, as calculated by the linear trapezoidal method

AUCnet: AUCabove - AUCbelow

TEmax: time to maximum effect

Emax: maximum effect

TEmin: time to minimum effect

Emin: minimum effect
12.4.4
Urinary Pharmacodynamic Parameters
The following parameters will be calculated for both Day -1 and Day 1/Day 2 in each 
treatment period:

Total amount of sodium (mmol), calcium (mmol), magnesium (mmol), citrate (mmol), 
phosphate (mmol), cAMP (µmol) and creatinine (mmol) excreted in urine in each 
collection period where total amount = (total volume [L] of urine in each collection) × 
(concentration [mmol/L, mmol/L or µmol/L]) in pooled urine samples during a collection 
period

Total amount of sodium, calcium, magnesium, citrate, cAMP and phosphate excreted in 
each collection period relative to the total amount of creatinine excreted in the same 
collection interval, mmol/mmol, nmol/mmol, or µmol/mmol

Total amount of sodium, calcium, magnesium, citrate, phosphate, cAMP and creatinine 
excreted in urine over 24 hours post dose, mmol, nmol, or µmol

Total amount of sodium, calcium, magnesium, citrate, phosphate and cAMP excreted in 
urine over 24 hours post dose relative to the total amount of creatinine excreted over 24 
hours post dose, mmol/mmol, nmol/mmol, or µmol/mmol

Renal clearance (CLr) of calcium, magnesium, creatinine and phosphate (mL/min) in each 
collection period where CLr = (Urine concentration) × (urine flow/serum concentration); 
urine flow is calculated as the total urine volume divided by time in the collection interval

Fractional excretion (FE) of calcium, magnesium, and phosphate in each collection 
period, calculated as:
100 × [Urine concentration of the analyte × Serum Creatinine]/[Serum 
concentration of the analyte × Urine Creatinine].
For the calculation of CLr and FE in each collection interval, the serum concentration value
used is that which occurs at or closest to the middle of the urine collection period. For 
example, for the 0-3 hour urine collection, the serum values determined at the 1.5-hour serum 
sample is to be used. Calculation of these parameters will be by each time interval collected in 


Protocol SHP634-101
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the CRF (0-3, 3-6, 6-9, 9-12, 12-15, 15-18, 18-24 hours for QD, and for BID this will also 
include 24-30, and 30-36 hours).
The following table shows the urine collection period and the corresponding timepoint to be 
used for the serum concentration:
Urine Collection Period
Timepoint of Collection of 
Serum Concentration
0-3 hours
1.5 hours
3-6 hours
4 hours
6-9 hours
8 hours
9-12 hours
10 hours
12-15 hours
13.5 hours
15-18 hours
16 hours
18-24 hours
20 hours/24 hoursa
24-30 hoursb
28 hours
30-36 hoursb
36 hours
a 20 hours for Day 1, 24 hours for Day -1
b For BID dose groups only.
12.4.5
Statistical Analysis of Pharmacodynamic Data
For serum pharmacodynamic evaluations,  concentrations (raw and baseline-adjusted) of 
serum total calcium and albumin-corrected calcium, phosphate, creatinine, magnesium, 
1,25(OH)2D3 and FGF23 will be summarized with descriptive statistics (number, arithmetic 
mean, SD, CV%, median, minimum, and maximum) by treatment and day. Pharmacodynamic 
parameters of serum total calcium and albumin-corrected calcium, phosphate, magnesium, 
1,25(OH)2D3 and FGF23 will be summarized with descriptive statistics (number, arithmetic 
mean, SD, CV%, median, minimum, maximum, geometric mean, and geometric CV%) by 
treatment and day. This will be done for both raw and baseline-adjusted values, and will be 
done for both Day -1 and Day 1/2. Note for the Day -1 summaries, the treatment assigned will 
be the treatment the subject takes the following day.
Individual and mean concentration (raw and baseline-adjusted)-time plots of serum 
pharmacodynamic markers (serum total calcium and albumin-corrected calcium, phosphate, 
creatinine, magnesium, 1,25(OH)2D3 and FGF23) will be generated on both linear and 
semilog scales. These figures will be generated as overlay plots by treatment. 
For urine pharmacodynamic evaluations, the individual urinary excretion of calcium, sodium, 
citrate, magnesium, cAMP, and phosphate and amount relative to creatinine of calcium, 
sodium, citrate, magnesium, cAMP and phosphate in each collection period as well as over 24 
hours will be listed and summarized with descriptive statistics by treatment and day (Day -1 
and Day 1/2).


Protocol SHP634-101
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In addition, the renal clearance of calcium, magnesium,, creatinine and phosphate and 
fractional excretion of calcium, magnesium and phosphate in each collection period will be 
summarized with descriptive statistics by treatment and day.
Individual and mean urine pharmacodynamic parameters over time (urine collection interval) 
will be plotted on a linear scale, overlaid by treatment (both Day -1 and Days 1 and 2 will be 
presented on the same plot). 
12.5
Analyses of Pharmacokinetic/Pharmacodynamic Relationships
Pharmacokinetic-pharmacodynamic correlations may be assessed using scatter plot figures of 
selected rhPTH pharmacokinetic parameters (such as but not limited to AUC0-24, Cmax, time 
above threshold of 17.2 pg/mL, AUC above threshold of 17.2 pg/mL, time above threshold of 
25 pg/mL, and AUC above threshold of 25 pg/mL) against time-matched selected 
pharmacodynamic parameters of serum total calcium and albumin-corrected calcium, 
phosphate, creatinine, magnesium, 1,25(OH)2D3 and FGF23 values and selected urine 
pharmacodynamic parameters. Appropriate correlation or regression analysis may be 
explored.
12.6
Population Pharmacokinetic and Quantitative System Pharmacology Modeling 
and Simulation
This will be covered in a separate SAP.


Protocol SHP634-101
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13.
OTHER ANALYSES
13.1
Quality of Life Analyses
Not applicable.
13.2
Health Economics and Outcomes Research Analyses
Not applicable.


Protocol SHP634-101
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14.
INTERIM ANALYSIS
An interim analysis is planned for this study. A separate Interim Analysis SAP will be 
developed to describe the interim analysis. At the end of each cohort a safety review will be 
performed before proceeding to the next cohort. The review will include, at a minimum, the 
Coordinating Investigator and the Shire Medical Monitors. The requirements for the data 
presentations to be used for this safety review will be documented separately.


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15.
DATA MONITORING/REVIEW COMMITTEE
Not applicable, as no data monitoring review is planned for this study.


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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 pharmacokinetic and pharmacodynamics parameters.


Protocol SHP634-101
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17.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
There were no changes to the analysis planned in the latest version of the protocol.


Protocol SHP634-101
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18.
DATA HANDLING CONVENTIONS
18.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics: 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.  In addition to determination of baseline, unscheduled visits will be included in 
PCI value determination. However, for all other summaries only scheduled visits will be used. 
All assessments (including unscheduled) 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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18.5
Missing Date and Time 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. The 
exception to this would be if the year of the start date is the same as the year of the 
treatment period 2 dose, in which case the day and month of the first dose of 
investigational product in period 2 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. The exception to this would be if the month of the start date is the same as 
the month of the treatment period 2 dose, in which case the day of the first dose of 
investigational product in period 2 will be assigned to the missing fields.
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 in either period, or the date is imputed to be one of these dates, then 


Protocol SHP634-101
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the time will be set to the time of the first dose of investigational product on that day. 
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 a dose of investigational product on that day, then the minutes of that 
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.


Protocol SHP634-101
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18.6
Missing Date Information for Adverse Events 
For AEs, only incomplete (i.e., partially missing) start dates will be imputed.  Incomplete stop 
dates will not be imputed.
18.6.1
Incomplete Start Date 
Follow same rules as in Section 18.5.1.
18.6.2
Incomplete Stop Date 
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 Investigational 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.
Table 5:
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables
Clinical Laboratory Test
Possible Results (in SI units)
Coded Value for Analysis
Chemistry:  ALT
<5
0
Chemistry:  AST
<5
0
Chemistry:  Total Bilirubin
<2
0
Urinalysis:  Glucose
55
Positive
0
Negative
Urinalysis:  pH
8.0
8.0


Protocol SHP634-101
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19.
References
Parent X1, 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


Protocol SHP634-101
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20.
TABLE OF CONTENTS FOR FIGURES, TABLES, AND 
LISTINGS
Table
Title
Shire 
Std
1.1.1
Disposition by Cohort (All-Enrolled Set)
Y
1.1.2
Disposition by Treatment (Safety Analysis Set)
Y
1.2.1
Demographic Characteristics by Cohort (Safety Analysis Set)
Y
1.2.2
Baseline Characteristics by Cohort
Y
1.2.3
Parathyroid History by Cohort (Safety Analysis Set)
N
1.2.4
Medical History by System Organ Class, Preferred Term and Cohort (Safety 
Analysis Set)
N
1.3.1
Prior Medications by Cohort (Safety Analysis Set)
N
1.3.2
Concomitant Medications by Treatment (Safety Analysis Set)
N
1.5.1
Protocol Deviations by Site and Treatment (All Enrolled Set)
Y
2.1.1
Summary of PTH Raw Plasma Concentrations (<unit>) versus Time by 
Treatment (Pharmacokinetic Analysis Set)
N
2.1.2
Summary of PTH Baseline Adjusted Plasma Concentrations (<unit>) versus 
Time by Treatment (Pharmacokinetic Analysis Set)
N
2.1.3
Summary of PTH Raw Plasma Pharmacokinetic Parameters by Treatment 
(Pharmacokinetic Analysis Set)
N
2.1.4
Summary of PTH Baseline Adjusted Pharmacokinetic Parameters by Treatment 
(Pharmacokinetic Analysis Set)
N
2.1.5
Summary of PTH Raw Plasma Concentrations (<unit>) versus Time by 
Treatment  and Cohort – Treatments B and E (Pharmacokinetic Analysis Set)
N
2.1.6
Summary of PTH Baseline Adjusted Plasma Concentrations (<unit>) versus 
Time by Treatment and Cohort – Treatments B and E (Pharmacokinetic 
Analysis Set)
N
2.1.7
Summary of PTH Raw Plasma Pharmacokinetic Parameters by Treatment and 
Cohort – Treatments B and E (Pharmacokinetic Analysis Set)
N
2.1.8
Summary of PTH Baseline Adjusted Pharmacokinetic Parameters by Treatment 
and Cohort – Treatments B and E (Pharmacokinetic Analysis Set)
N
2.2.1
Summary of Raw Serum Calcium (uncorrected) Concentrations (<unit>) by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.2
Summary of Raw Serum Calcium (albumin-corrected) Concentrations (<unit>) 
by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.3
Summary of Raw Serum Phosphate Concentrations (<unit>) by Treatment and 
Day 
(Pharmacodynamic Analysis Set)
N
2.2.4
Summary of Raw Creatinine Concentrations (<unit>) by Treatment and Day 
(Pharmacodynamic Analysis Set)
N
2.2.5
Summary of Raw Magnesium Concentrations (<unit>) by Treatment and Day
(Pharmacodynamic Analysis Set)
N
2.2.6
Summary of Raw 1,25(OH)2D3 Concentrations (<unit>) by Treatment and Day
(Pharmacodynamic Analysis Set)
N
2.2.7
Summary of Raw FGF23 Concentrations (<unit>) by Treatment and Day
(Pharmacodynamic Analysis Set)
N


Protocol SHP634-101
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Table
Title
Shire 
Std
2.2.8
Summary 
of 
Raw 
Albumin 
Corrected 
Calcium-Phosphate 
Product 
Concentrations (<unit>) by Treatment and Day (Pharmacodynamic Analysis 
Set)
N
2.2.9
Summary of Baseline-Adjusted Serum Calcium (uncorrected) Concentrations 
(<unit>) by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.10
Summary of Baseline-Adjusted Serum Calcium (albumin-corrected) 
Concentrations (<unit>) by Treatment and Day (Pharmacodynamic Analysis 
Set)
N
2.2.11
Summary of Baseline-Adjusted Serum Phosphate Concentrations (<unit>) by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.12
Summary of Baseline-Adjusted Magnesium Concentrations (<unit>) by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.13
Summary of Baseline-Adjusted 1,25(OH)2D3 Concentrations (<unit>) by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.2.14
Summary of Baseline-Adjusted FGF23 Concentrations (<unit>) by Treatment 
and Day (Pharmacodynamic Analysis Set)
N
2.2.15
Summary of Baseline-Adjusted Albumin Corrected Calcium-Phosphate Product 
Concentrations (<unit>) by Treatment and Day (Pharmacodynamic Analysis 
Set)
N
2.3.1.1
Summary of Raw Serum Calcium (uncorrected) Pharmacodynamic Parameters 
by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.1.2
Summary of Raw Serum Calcium (albumin-corrected) Pharmacodynamic 
Parameters by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.1.3
Summary of Raw Serum Phosphate Pharmacodynamic Parameters by Treatment 
and Day (Pharmacodynamic Analysis Set)
N
2.3.1.4
Summary of Raw Serum Magnesium Pharmacodynamic Parameters by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.1.5
Summary of Raw 1,25(OH)2D3 Pharmacodynamic Parameters by Treatment and 
Day (Pharmacodynamic Analysis Set)
N
2.3.1.6
Summary of Raw FGF23 Pharmacodynamic Parameters by Treatment and Day 
(Pharmacodynamic Analysis Set)
N
2.3.1.7
Summary of Raw Albumin Corrected Calcium-Phosphate Product 
Pharmacodynamic Parameters by Treatment and Day (Pharmacodynamic 
Analysis Set)
N
2.3.2.1
Summary of Baseline Adjusted Serum Calcium (uncorrected) Pharmacodynamic 
Parameters by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.2.2
Summary of Baseline Adjusted Serum Calcium (albumin-corrected) 
Pharmacodynamic Parameters by Treatment and Day (Pharmacodynamic 
Analysis Set)
N
2.3.2.3
Summary of Baseline Adjusted Serum Phosphate Pharmacodynamic Parameters 
by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.2.4
Summary of Baseline Adjusted Serum Magnesium Pharmacodynamic 
Parameters by Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.2.5
Summary of Baseline Adjusted 1,25(OH)2D3 Pharmacodynamic Parameters by 
Treatment and Day (Pharmacodynamic Analysis Set)
N
2.3.2.6
Summary of Baseline Adjusted FGF23 Pharmacodynamic Parameters by 
Treatment and Day (Pharmacodynamic Analysis Set)
N


Protocol SHP634-101
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Table
Title
Shire 
Std
2.3.2.7
Summary of Baseline Adjusted Albumin Corrected Calcium-Phosphate Product 
Pharmacodynamic Parameters by Treatment and Day (Pharmacodynamic 
Analysis Set)
N
2.4.1.1
Summary of Urine Sodium Pharmacodynamic Parameters by Treatment and 
Day – Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.1.2
Summary of Urine Sodium Pharmacodynamic Parameters by Treatment and 
Day– Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.2.1
Summary of Urine Calcium Pharmacodynamic Parameters by Treatment and 
Day – Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.2.2
Summary of Urine Calcium Pharmacodynamic Parameters by Treatment and 
Day – Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.2.3
Summary of Urine Calcium Pharmacodynamic Parameters by Treatment and 
Day – Renal Clearance (Pharmacodynamic Analysis Set)
N
2.4.2.4
Summary of Urine Calcium Pharmacodynamic Parameters by Treatment and 
Day – Fractional Excretion (Pharmacodynamic Analysis Set)
N
2.4.3.1
Summary of Urine Magnesium Pharmacodynamic Parameters by Treatment and 
Day – Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.3.2
Summary of Urine Magnesium Pharmacodynamic Parameters by Treatment and 
Day – Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.3.3
Summary of Urine Magnesium Pharmacodynamic Parameters by Treatment and 
Day – Renal Clearance (Pharmacodynamic Analysis Set)
N
2.4.3.4
Summary of Urine Magnesium Pharmacodynamic Parameters by Treatment and 
Day – Fractional Excretion (Pharmacodynamic Analysis Set)
N
2.4.4.1
Summary of Urine Citrate Pharmacodynamic Parameters by Treatment and Day 
– Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.4.2
Summary of Urine Citrate Pharmacodynamic Parameters by Treatment and Day 
– Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.5.1
Summary of Urine cAMP Pharmacodynamic Parameters by Treatment and Day 
– Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.5.2
Summary of Urine cAMP Pharmacodynamic Parameters by Treatment and Day 
– Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.6.1
Summary of Urine Phosphate Pharmacodynamic Parameters by Treatment and 
Day – Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.6.2
Summary of Urine Phosphate Pharmacodynamic Parameters by Treatment and 
Day – Amount excreted relative to Creatinine (Pharmacodynamic Analysis Set)
N
2.4.6.3
Summary of Urine Phosphate Pharmacodynamic Parameters by Treatment and 
Day – Renal Clearance (Pharmacodynamic Analysis Set)
N
2.4.6.4
Summary of Urine Phosphate Pharmacodynamic Parameters by Treatment and 
Day – Fractional Excretion (Pharmacodynamic Analysis Set)
N
2.4.7.1
Summary of Urine Creatinine Pharmacodynamic Parameters by Treatment and 
Day – Amount Excreted (Pharmacodynamic Analysis Set)
N
2.4.7.2
Summary of Urine Creatinine Pharmacodynamic Parameters by Treatment and 
Day – Renal Clearance (Pharmacodynamic Analysis Set)
N
4.1.1
Investigational Product Exposure by Period and Treatment (Safety Analysis Set)
N
4.2.1
Overall Adverse Events (AEs) by Treatment (Safety Analysis Set)
Y
4.2.2
Treatment-emergent Adverse Events by System Organ Class, Preferred Term 
and Treatment (Safety Analysis Set)
Y


Protocol SHP634-101
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Table
Title
Shire 
Std
4.2.3
Non-Treatment-emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment (Safety Analysis Set)
Y
4.3.1
Treatment-emergent Adverse Events by Maximum Severity, System Organ 
Class, Preferred Term and Treatment (Safety Analysis Set)
Y
4.3.2
Non-Treatment-emergent Adverse Events by Maximum Severity, System Organ 
Class, Preferred Term and Treatment (Safety Analysis Set)
Y
4.3.3
Severe Treatment-emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment (Safety Analysis Set)
Y
4.3.4
Severe Non-Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment (Safety Analysis Set)
Y
4.3.5
Treatment-emergent Adverse Events Considered Related to Investigational 
Product by System Organ Class, Preferred Term and Treatment (Safety Analysis 
Set)
Y
4.3.6
Non-Treatment-emergent Adverse Events Considered Related to Investigational 
Product by System Organ Class, Preferred Term and Treatment (Safety Analysis 
Set)
Y
4.3.7
Treatment-emergent Adverse Events Not Considered Related to Investigational 
Product by System Organ Class, Preferred Term and Treatment (Safety Analysis 
Set)
Y
4.4.1
Serious Treatment-emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment (Safety Analysis Set)
Y
4.4.2
Serious Non-Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment (Safety Analysis Set)
Y
4.4.3
Treatment-emergent Adverse Events Leading to Discontinuation of 
Investigational Product by System Organ Class, Preferred Term and Treatment 
(Safety Analysis Set)
Y
4.4.4
Non-Treatment-emergent Adverse Events Leading to Discontinuation of 
Investigational Product by System Organ Class, Preferred Term and Treatment 
(Safety Analysis Set)
Y
4.5.1
Treatment-emergent Adverse Events of Special Interest by Preferred Term and 
Treatment (Safety Analysis Set)
N
4.5.2
Non-Treatment-emergent Adverse Events of Special Interest by Preferred Term 
and Treatment (Safety Analysis Set)
N
4.5.3
Adverse Events of Special Interest by Preferred Term and Treatment (Safety 
Analysis Set)
N
4.6.1
Quantitative Clinical Laboratory Results by Treatment: Hematology (Safety 
Analysis Set)
Y
4.6.2
Shift from Baseline in Clinical Laboratory Results by Treatment: Hematology 
(Safety Analysis Set)
Y
4.6.3
Potentially Clinically Important (PCI) Laboratory Results by Treatment: 
Hematology (Safety Analysis Set)
Y
4.6.4
Quantitative Clinical Laboratory Results by Treatment: Biochemistry
(Safety Analysis Set)
Y
4.6.5
Shift from Baseline in Clinical Laboratory Results by Treatment: Biochemistry 
(Safety Analysis Set)
Y


Protocol SHP634-101
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Table
Title
Shire 
Std
4.6.6
Potentially Clinically Important (PCI) Laboratory Results by Treatment: 
Biochemistry (Safety Analysis Set)
Y
4.6.7
Quantitative Clinical Laboratory Results by Treatment: Urinalysis
(Safety Analysis Set)
Y
4.6.8
Qualitative Clinical Laboratory Results by Treatment: Urinalysis
(Safety Analysis Set)
Y
4.6.9
Shift from Baseline in Clinical Laboratory Results by Treatment: Urinalysis 
(Safety Analysis Set)
Y
4.6.10
Potentially Clinically Important (PCI) Laboratory Results by Treatment: 
Urinalysis (Safety Analysis Set)
Y
4.7.1
Actual Values and Change from Baseline in Vital Signs by Treatment (Safety 
Analysis Set)
Y
4.7.2
Potentially Clinically Important Vital Signs Results by Timepoint and Treatment 
(Safety Analysis Set)
Y
4.8.1
Actual Values and Change from Baseline in ECG by Timepoint and Treatment 
(Safety Analysis Set)
Y
4.8.2
ECG Interpretation by Timepoint and Treatment (Safety Analysis Set)
Y
4.8.3
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG Results by 
Treatment (Safety Analysis Set)
Y
4.8.4
Potentially Clinically Important ECG Results by Timepoint and Treatment 
(Safety Analysis Set)
Y
4.9.1
Immunogenicity (Anti-PTH Antibody) (Safety Analysis Set)
N
Figures
Title
Shire 
Std
2.1.1
Plot of Raw Mean Plasma PTH Concentrations versus Time by Treatment on a 
Linear Axis (Pharmacokinetic Analysis Set)
N
2.1.2
Plot of Raw Mean Plasma PTH Concentrations versus Time by Treatment on a 
Semi-log Axis (Pharmacokinetic Analysis Set)
N
2.1.3
Plot of Baseline Adjusted Mean Plasma PTH Concentrations versus Time by 
Treatment on a Linear Axis (Pharmacokinetic Analysis Set)
N
2.1.4
Plot of Baseline Adjusted Mean Plasma PTH Concentrations versus Time by 
Treatment on a Semi-log Axis (Pharmacokinetic Analysis Set)
N
2.1.5
Plot of Baseline Adjusted Individual Plasma PTH Concentrations versus Time 
by Treatment on a Linear Axis (Pharmacokinetic Analysis Set)
N
2.1.6
Plot of Baseline Adjusted Individual Plasma PTH Concentrations versus Time 
by Treatment on a Semi-log Axis (Pharmacokinetic Analysis Set)
N
2.4.1
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Calcium (uncorrected) (Pharmacodynamic Analysis Set)
N
2.4.3
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Calcium (albumin-corrected) (Pharmacodynamic Analysis 
Set)
N


Protocol SHP634-101
Page No.: 64 of 68
Figures
Title
Shire 
Std
2.4.5
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Phosphate (Pharmacodynamic Analysis Set)
N
2.4.7
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Magnesium (Pharmacodynamic Analysis Set)
N
2.4.9
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Creatinine (Pharmacodynamic Analysis Set)
N
2.4.11
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – 1,25(OH)2D3 (Pharmacodynamic Analysis Set)
N
2.4.13
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – FGF23 (Pharmacodynamic Analysis Set)
N
2.4.15
Plot of Raw Individual Concentrations versus Time by Treatment and Day on a 
Linear Axis – Albumin Corrected Calcium-Phosphate Product 
(Pharmacodynamic Analysis Set)
N
2.5.1
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment
and Day on a Linear Axis – Serum Calcium (uncorrected) (Pharmacodynamic 
Analysis Set)
N
2.5.3
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment
and Day
on a Linear Axis –
Serum Calcium (albumin-corrected) 
(Pharmacodynamic Analysis Set)
N
2.5.5
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment
and Day on a Linear Axis – Serum Phosphate (Pharmacodynamic Analysis Set)
N
2.5.7
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment
and Day on a Linear Axis – Magnesium (Pharmacodynamic Analysis Set)
N
2.5.9
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment 
and Day on a Linear Axis – Creatinine (Pharmacodynamic Analysis Set)
N
2.5.11
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment 
and Day on a Linear Axis – 1,25(OH)2D3 (Pharmacodynamic Analysis Set)
N
2.5.13
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment
and Day on a Linear Axis – FGF23 (Pharmacodynamic Analysis Set)
N
2.5.15
Plot of Baseline-adjusted Individual Concentrations versus Time by Treatment 
and Day on a Linear Axis – Albumin  Corrected Calcium-Phosphate Product 
(Pharmacodynamic Analysis Set)
N
2.6.1
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Calcium (uncorrected) (Pharmacodynamic Analysis Set)
N
2.6.3
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Calcium (albumin-corrected) (Pharmacodynamic Analysis 
Set)
N
2.6.5
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Serum Phosphate (Pharmacodynamic Analysis Set)
N
2.6.7
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Magnesium (Pharmacodynamic Analysis Set)
N
2.6.9
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Creatinine (Pharmacodynamic Analysis Set)
N
2.6.11
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – 1,25(OH)2D3 (Pharmacodynamic Analysis Set)
N
2.6.13
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – FGF23 (Pharmacodynamic Analysis Set)
N


Protocol SHP634-101
Page No.: 65 of 68
Figures
Title
Shire 
Std
2.6.15
Plot of Raw Mean Concentrations versus Time by Treatment and Day on a 
Linear Axis – Albumin Corrected Calcium-Phosphate Product 
(Pharmacodynamic Analysis Set)
N
2.7.1
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – Serum Calcium (uncorrected) (Pharmacodynamic 
Analysis Set)
N
2.7.3
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – Serum Calcium (albumin-corrected) (Pharmacodynamic 
Analysis Set)
N
2.7.5
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – Serum Phosphate (Pharmacodynamic Analysis Set)
N
2.7.7
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – Magnesium (Pharmacodynamic Analysis Set)
N
2.7.9
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – 1,25(OH)2D3 (Pharmacodynamic Analysis Set)
N
2.7.11
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – FGF23 (Pharmacodynamic Analysis Set)
N
2.7.13
Plot of Baseline-adjusted Mean Concentrations versus Time by Treatment and 
Day on a Linear Axis – Albumin Corrected Calcium-Phosphate Product 
(Pharmacodynamic Analysis Set)
N
2.8.1.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Sodium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.1.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Sodium amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.8.2.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Calcium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.2.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Calcium amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.8.2.3
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Renal Clearance of Calcium (Pharmacodynamic Analysis Set)
N
2.8.2.4
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Fractional Excretion of Calcium (Pharmacodynamic Analysis Set)
N
2.8.3.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Magnesium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.3.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Magnesium amount excreted relative to Creatinine
(Pharmacodynamic Analysis Set)
N
2.8.3.3
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Renal Clearance of Magnesium (Pharmacodynamic Analysis Set)
N
2.8.3.4
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Fractional Excretion of Magnesium (Pharmacodynamic Analysis Set)
N
2.8.4.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Citrate Amount Excreted (Pharmacodynamic Analysis Set)
N


Protocol SHP634-101
Page No.: 66 of 68
Figures
Title
Shire 
Std
2.8.4.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Citrate amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.8.5.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Phosphate Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.5.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Phosphate amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.8.5.3
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Renal Clearance of Phosphate (Pharmacodynamic Analysis Set)
N
2.8.5.4
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Fractional Excretion of Phosphate (Pharmacodynamic Analysis Set)
N
2.8.6.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day –cAMP Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.6.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day –cAMP amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.8.7.1
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Creatinine Amount Excreted (Pharmacodynamic Analysis Set)
N
2.8.7.2
Plot of Individual Urine Pharmacodynamic Parameters over Time by Treatment 
and Day – Renal Clearance of Creatinine (Pharmacodynamic Analysis Set)
N
2.9.1.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Sodium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.1.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Sodium amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.2.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Calcium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.2.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Calcium amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.2.3
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Renal Clearance of Calcium (Pharmacodynamic Analysis Set)
N
2.9.2.4
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Fractional Excretion of Calcium (Pharmacodynamic Analysis Set)
N
2.9.3.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Magnesium Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.3.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Magnesium amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.3.3
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Renal Clearance of Magnesium (Pharmacodynamic Analysis Set)
N
2.9.3.4
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Fractional Excretion of Magnesium (Pharmacodynamic Analysis Set)
N
2.9.4.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Citrate Amount Excreted (Pharmacodynamic Analysis Set)
N


Protocol SHP634-101
Page No.: 67 of 68
Figures
Title
Shire 
Std
2.9.4.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Citrate amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.5.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Phosphate Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.5.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Phosphate amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.5.3
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Renal Clearance of Phosphate (Pharmacodynamic Analysis Set)
N
2.9.5.4
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Fractional Excretion of Phosphate (Pharmacodynamic Analysis Set)
N
2.9.6.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –cAMP Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.6.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –cAMP amount excreted relative to Creatinine (Pharmacodynamic 
Analysis Set)
N
2.9.7.1
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day –Creatinine Amount Excreted (Pharmacodynamic Analysis Set)
N
2.9.7.2
Plot of Mean Urine Pharmacodynamic Parameters over Time by Treatment and 
Day – Renal Clearance of Creatinine (Pharmacodynamic Analysis Set)
N
Listing
Title
Shire 
Std
Listing of Subject Data for Screen Failures
Y
16.1.7
Randomization Assignments (All-Enrolled Set)
Y
1.1
Subject Disposition (All-Enrolled Set)
Y
1.2
Subjects Who Discontinued from the Study (Safety Analysis Set)
Y
1.3
Study Analysis Set Classification (Enrolled Set)
Y
2.1
Listing of Protocol Deviations (All-Enrolled Set)
Y
4.1
Subject Demographics (Safety Analysis Set)
Y
4.2
Subject Baseline Characteristics (Safety Analysis Set)
Y
4.3
Parathyroid History (Safety Analysis Set)
N
4.4
Medical History (Safety Analysis Set)
Y
4.5
Prior and Concomitant Medications (Safety Analysis Set)
Y
4.6
Prior and Concomitant Medications of Special Interest (Safety Analysis Set)
Y
5.1
Investigational Product Exposure (Safety Analysis Set)
Y
5.2
Pharmacokinetic Blood Sampling and PTH Concentrations (Pharmacokinetic 
Analysis Set)
Y
5.3
Raw PTH Pharmacokinetic Parameters (Pharmacokinetic Analysis Set)
N
5.4
Baseline-adjusted PTH Pharmacokinetic Parameters (Pharmacokinetic Analysis 
Set)
N


Protocol SHP634-101
Page No.: 68 of 68
Listing
Title
Shire 
Std
5.5
Pharmacodynamic Blood Sampling ( Pharmacodynamic Analysis Set)
Y
5.6
Pharmacodynamic Concentrations (Pharmacodynamic Analysis Set)
N
5.7
Raw Pharmacodynamic Parameters (Pharmacodynamic Analysis Set)
N
5.8
Baseline-adjusted Pharmacodynamic Parameters (Pharmacodynamic Analysis Set)
N
5.9
Pharmacodynamic Urine Sampling (Pharmacodynamic Analysis Set)
Y
5.10
Pharmacodynamic Urine Parameters (Pharmacodynamic Analysis Set)
N
5.11
Data Excluded from Pharmacokinetic and Pharmacodynamic Analysis
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
7.4
Adverse Events Leading to Discontinuation of Investigational Product (Safety 
Analysis Set)
Y
7.5
Adverse Events with Fatal Outcome (Safety Analysis Set)
Y
7.6
Adverse Events of Special Interest (Safety Analysis Set)
Y
8.1.1
Serum Clinical Laboratory Test Results (Safety Analysis Set)
N
8.1.2
Urinary Clinical Laboratory Test Results (Safety Analysis Set)
N
8.1.3
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