Conditions: Chronic Hypoparathyroidism Hypoparathyroidism
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
Chronic hypoparathyroidism is a life-long and irreversible disease for which the chronic administration of rhPTH(1-84) is a potential treatment option. The group of participants in the AAAE0544 core study has been taking rhPTH(1-84) for the treatment of hypoparathyroidism for up to 11 years. This study is designed to extend this experience and gain knowledge about how safe and effective rhPTH(1-84) is in participants with hypoparathyroidism over a long-term duration.

Detailed description:

Arms:
arm 1: Participants will receive 25, 50, 75, and 100 microgram (mcg) of rhPTH(1-84) subcutaneous injection to the thigh via a multidose pen injector device once daily for 36 months. The dose will be individualized based on albumin-corrected serum calcium (ACSC) and 24-hour calcium urinary excretion to achieve a serum calcium level in the lower half of the normal range.

Interventions: intervention 1: rhPTH(1-84)
Intervention descriptions: intervention 1: Participants will receive 25, 50, 75, and 100 microgram (mcg) of rhPTH(1-84) subcutaneous injection to the thigh via a multidose pen injector device once daily for 36 months. The dose will be individualized based on Albumin-corrected Serum Calcium (ACSC) and 24-hour calcium urinary excretion to achieve a serum calcium level in the lower half of the normal range.

Protocol document:
Prot_002.pdf: 
PROTOCOL: SHP634-402
TITLE:
A Phase 4, Open-Label, Single-Center Clinical Study of Extended use 
of rhPTH(1-84) in Hypoparathyroidism
DRUG:
rhPTH(1-84)
IND
076514
BLA:
125511
SPONSOR
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
 MD
PROTOCOL 
HISTORY:
Protocol Amendment 2:  05 Sep 2018
Protocol Amendment 1:  16 Aug 2017
Original Protocol: 27 May 2016
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 the express written 
consent of Shire.
For non-commercial use only


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SHP634-402 Protocol Amendment 2
rhPTH(1-84)
05 Sep 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The table and the summary below provide an overview of the changes from the previous version 
(Amendment 1, dated 16 Aug 2017) to the current version of the protocol (Amendment 2).
Grammatical, typographical errors, and general formatting revisions are not identified.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Administrative changes: updated dates, moved summary of changes for 
Amendment 1 to Appendix 1; created new Summary of Changes.
Entire document
Added in details from Administrative Memo dated 29 Sep 2017; specifically, 
that the principal investigator was changed from 
 MD to 
 MD as of 31 Aug 2017.
Cover page
Removed secondary Shire medical monitor.
Emergency Contact 
Information
Clarified and removed language to ensure post-study assessments for subjects 
who discontinue early are clear in the text. Specifically, removed relevant 
wording in Section 3.4, Discussion of Study Design.
Section 3.4
Increased option for bone biopsy and 
 to up to 3 times during 
the study.
Study Schedule; Section 
7.2.2.8; Section 7.2.2.9
Added in details from Administrative Memo dated 19 Mar 2018; specifically, 
clarification of the versions of various tools used in the study:

FACT-Cognitive Function (Version 3.0)

The FACIT Fatigue Scale (Version 4.0)

The RAND 36-Item Short Form Survey (SF-36;Version 1.0) 
Section 7.2.2.3; Section 7.2.2.4;
Section 7.2.2.6
Added all available surveys to protocol as appendices. Specifically, added in:

The FACIT Fatigue Scale (now Appendix 4)

HADS Assessment (now Appendix 5)

The RAND SF-36 (now Appendix 6)
Section 7.2.2.4; Section 7.2.2.5;
Section 7.2.2.6; Appendix 4; 
Appendix 5; Appendix 6
Extended study an additional 24 months for a total treatment period of 48 
months.
Synopsis; Study Schedule;
Section 3.2; Section 7
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05 Sep 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the 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:
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................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE ....................................................................................................................18
1
BACKGROUND INFORMATION.......................................................................................20
1.1
Indication and Current Treatment Options...............................................................20
1.2
Product Background.................................................................................................21
1.2.1
Preclinical Information ..........................................................................................21
1.2.2
Clinical Information...............................................................................................22
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
2.2.1
Primary Objectives.................................................................................................24
2.2.2
Secondary Objectives.............................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................25
3.3
Sites and Regions .....................................................................................................25
3.4
Discussion of Study Design .....................................................................................25
4
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................28
4.3.1
Female Contraception............................................................................................28
4.3.2
Male Contraception................................................................................................28
4.4
Discontinuation of Subjects .....................................................................................28
4.4.1
Subject Withdrawal Criteria ..................................................................................28
4.4.2
Reasons for Discontinuation..................................................................................28
4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
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5.1
Prior Treatment ........................................................................................................30
5.1.1
Concomitant Treatment .........................................................................................30
5.1.2
Permitted Treatment...............................................................................................30
5.1.3
Prohibited Treatment .............................................................................................30
5.1.4
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation ....................................................................................................30
5.1.4.1
Active Vitamin D ...................................................................................30
5.1.4.2
Native Vitamin D ...................................................................................31
5.1.4.3
Calcium ..................................................................................................31
5.1.4.4
Magnesium.............................................................................................31
5.1.5
Thiazide Diuretics..................................................................................................31
6
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Blinding the Treatment Assignment ......................................................................32
6.2
Administration of Investigational Product(s)...........................................................32
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dosing....................................................................................................................33
6.2.3
Unblinding the Treatment Assignment..................................................................33
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Packaging...............................................................................................................33
6.3.2
Labeling .................................................................................................................33
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................36
7
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Baseline Visit (Visit 1)...........................................................................................37
7.1.2
Treatment Period....................................................................................................38
7.1.2.1
Visit 2 (Month 6)....................................................................................38
7.1.2.2
Visit 3 (Month 12)..................................................................................38
7.1.2.3
Visit 4 (Month 18)..................................................................................38
7.1.2.4
Visit 5 (Month 24)..................................................................................38
7.1.2.5
Visit 6 (Month 30)..................................................................................38
7.1.2.6
Visit 7 (Month 36)..................................................................................38
7.1.2.7
Visit 8 (Month 42)..................................................................................38
7.1.2.8
EOT Visit (Month 48)............................................................................39
7.1.3
Additional Care of Subjects after the Study ..........................................................39
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7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Demographic and Other Baseline Characteristics .................................................39
7.2.2
Efficacy..................................................................................................................39
7.2.2.1
Biochemical Evaluations........................................................................39
7.2.2.2
Hypoparathyroidism Symptom Diary (HPT-SD) ..................................40
7.2.2.3
Cognition Tool .......................................................................................40
7.2.2.4
FACIT Fatigue Scale..............................................................................40
7.2.2.5
HADS Assessment .................................................................................40
7.2.2.6
Short Form Health Survey-36 ................................................................40
7.2.2.7
Bone Mineral Density ............................................................................41
7.2.2.8
Bone Biopsy...........................................................................................41
7.2.3
Safety .....................................................................................................................42
7.2.3.1
Adverse Event Collection.......................................................................42
7.2.3.2
Clinical Laboratory Evaluations.............................................................42
7.2.3.3
Pregnancy Test .......................................................................................43
7.2.3.4
PTH Antibodies......................................................................................44
7.2.3.5
Vital Signs..............................................................................................44
7.2.3.6
Physical Examination.............................................................................44
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease Under Study .................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................46
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................47
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Data Handling Considerations..................................................................................51
9.4
Statistical Analysis Process......................................................................................51
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......51
9.6
Sample Size Calculation and Power Considerations................................................52
9.7
Study Population ......................................................................................................52
9.8
Efficacy Analyses.....................................................................................................52
9.8.1
Primary Efficacy Endpoint ....................................................................................52
9.8.2
Secondary Efficacy Endpoints...............................................................................52
9.8.3
Exploratory Efficacy Endpoints.............................................................................53
9.9
Safety Analyses........................................................................................................53
9.10
Other Analyses .........................................................................................................53
9.10.1 Health-related Quality of Life Analyses................................................................54
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................55
10.1
Sponsor’s Responsibilities .......................................................................................55
10.1.1 Good Clinical Practice Compliance.......................................................................55
10.1.2 Public Posting of Study Information......................................................................55
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................55
10.1.4 Study Suspension, Termination, and Completion..................................................55
10.2
Investigator’s Responsibilities .................................................................................56
10.2.1 Good Clinical Practice Compliance.......................................................................56
10.2.2 Protocol Adherence and Investigator Agreement..................................................56
10.2.3 Documentation and Retention of Records.............................................................57
10.2.3.1
Case Report Forms.................................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................57
10.2.3.3
Audit/Inspection.....................................................................................57
10.2.3.4
Financial Disclosure...............................................................................58
10.3
Ethical Considerations..............................................................................................58
10.3.1 Informed Consent...................................................................................................58
10.3.2 Institutional Review Board or Ethics Committee..................................................58
10.4
Privacy and Confidentiality......................................................................................59
10.5
Study Results / Publication Policy ...........................................................................60
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LIST OF TABLES
Table 1:
Schedule of Study Assessments ....................................................................18
Table 2:
Recommended Adjustments for Active Vitamin D and Calcium 
Supplements ..................................................................................................32
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................25


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ABBREVIATIONS
ACSC
albumin-corrected serum calcium
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BSAP
bone specific alkaline phosphatase
BLA
Biologics License Application
BMSi
bone material strength index
CI
confidence interval
CRA
Clinical Research Associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
DXA
dual-energy x-ray absorptiometry
EC
Ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
eGRF
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-Cog
Functional Assessment of Cancer Therapy - Cognitive Function
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
HIPAA
Health Insurance Portability and Accountability Act
HPT
Hypoparathyroidism
HPT-SD
Hypoparathyroidism Symptom Diary
HRpQCT
high-resolution peripheral quantitative computerized tomography
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors


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IRB
Institutional Review Board
MedDRA
Medical Dictionary of Regulatory Activities
mmHg
millimeters of mercury
P1NP
procollagen type I amino-terminal propeptide
PTH
Parathyroid hormone
QD
once daily
RBC
red blood cell
rhPTH(1-84)
recombinant human parathyroid hormone
s-CTX
serum carboxy-terminal 4 telopeptide of type I collagen
SAE
serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SC
subcutaneous
SF-36
RAND 36-item Short Form Health Survey
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
WBC
white blood cell


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STUDY SYNOPSIS
Protocol number: SHP634-402
Drug: rhPTH(1-84)
Title of the study: A Phase 4, Open-Label, Single-Center Clinical Study of Extended use of rhPTH(1-84) in 
Hypoparathyroidism
Number of subjects (total and for each treatment arm):
The subject population anticipated in this study is up to 50 subjects. All subjects are exclusively from the core study 
(HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in Hypoparathyroidism) 
Protocol AAAE0544 at Columbia University Medical Center and will all receive active rhPTH(1-84) treatment.
Investigator(s):
Single site located at:
Columbia University
New York, NY 10032
Site(s) and Region(s): 
Columbia University
New York, NY 10032
Study period (planned): 48 months
Clinical phase: 4
Objectives:
Primary:

To evaluate albumin-corrected serum calcium (ACSC) while on rhPTH(1-84) treatment
Secondary:

To evaluate the proportion of subjects who achieve ACSC values above, below, or in the range of 
7.5 mg/dL-upper limit of normal (ULN)

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment

To evaluate symptoms of hypoparathyroidism as measured by the hypoparathyroidism symptom diary 
(HPT-SD), perception of cognitive function, and health-related quality-of-life associated with long-term 
rhPTH(1-84) treatment

To evaluate the skeletal actions of rhPTH(1-84): bone turnover markers, architecture, and histology 
(biopsy)
Rationale:
Chronic hypoparathyroidism (HPT) is a life-long and irreversible disease for which the chronic administration of 
rhPTH(1-84) is a potential treatment option. Thus, long-term safety and efficacy data are important in evaluating the 
proper use of this treatment option in clinical practice.
Investigational product, dose, and mode of administration:
rhPTH(1-84); 25, 50, 75, and 100 µg for once daily subcutaneous injection to the thigh via a multidose pen injector 
device. The dose will be individualized to achieve a serum calcium level in the lower half of the normal range.




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Endpoints and Statistical Analysis: 
Primary Efficacy Endpoint:

Change in albumin-corrected serum calcium
Secondary Efficacy Endpoint(s):

Albumin-corrected serum calcium value above, below, or in the range of 7.5mg/dL -ULN

Change in urinary calcium and serum phosphate

Change in calcium and active vitamin D supplement doses

Change in HPT-related symptoms (as measured by the HPT-SD)

Change in FACT-Cog assessment

Change in FACIT (Fatigue Scale)

Change in HADS (Hospital Anxiety and Depression Scale)

Change in health-related quality-of-life (measured with RAND SF-36 survey)

Change in bone turnover markers (including, but not limited to, serum carboxy-terminal 4 telopeptide of 
type I collagen [s-CTX], procollagen type I amino-terminal propeptide [P1NP], osteocalcin, bone specific 
alkaline phosphatase [BSAP], TRAP-5b, sclerostin), architecture, and histology (biopsy)
Exploratory Efficacy Endpoint: 
Safety Endpoints:

AEs including SAEs

Vital signs including body temperature, heart rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Estimated Glomerular Filtration Rate (eGFR) and creatinine clearance

Measurements of antibodies to parathyroid hormone (PTH)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)
Although no formal hypotheses are being tested, 95% confidence intervals (CI) will be provided as appropriate. 
Continuous variables, including those assessed on a discrete scale, will be summarized using descriptive statistics 
including number of subjects, mean, median, standard deviation, maximum, and minimum. For categorical 
variables, statistical summaries will include number of subjects and percentages.
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from the SHP634-402 baseline, if applicable. Frequency counts will be compiled for classification of 
qualitative safety data (for example shift from baseline according to lab normal range, AEs related to treatment, 
level of severity, etc.).
Other Analyses:
A retrospective analysis of historical data captured from the medical records of subjects (since the start of 
rhPTH(1-84) treatment) will be conducted. All subjects are exclusively from the core study (Protocol AAAE0544 at 
Columbia University Medical Center [HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on 
the Skeleton in Hypoparathyroidism]). 


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Data collected will include but is not limited to, medical history and clinical laboratory data that can be source data 
verified. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment baseline, if 
applicable. 
Interim Analysis:
A retrospective analysis of historical data captured from the medical records of subjects (eg, since the start of 
rhPTH(1-84) treatment) will be conducted. These data will be derived from the medical records from subjects that 
are exclusively from the core study (Protocol AAAE0544 at Columbia University Medical Center [HEXT: The 
Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in Hypoparathyroidism]). Data 
collected will include but is not limited to, medical history and clinical laboratory data that can be data source 
verified. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment baseline, if 
applicable.
There will be no Data Monitoring Committee for this unblinded exploratory study; however, results of the 
prospective data portion of the study will be analyzed as necessary for safety monitoring and publication purposes.






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1
BACKGROUND INFORMATION
Hypoparathyroidism (HPT) 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 (US), which rises to approximately 117,000 if the transient hypoparathyroid population is 
included (≤6 months). The same authors suggest that, of those 117,000 transient hypoparathyroid 
subjects, about 5% will become chronic.
Parathyroid hormone is an 84-amino acid protein that is secreted by the parathyroid glands. 
Parathyroid hormone has a variety of important physiological functions that are outlined below 
to explain the effects of absent or deficient PTH levels. Parathyroid hormone functions to help 
regulate bone metabolism and serum levels of calcium and phosphate. In general, if serum 
calcium concentrations decrease, the parathyroid glands consequently increase PTH secretion, 
and, if serum calcium concentrations increase, the parathyroid glands consequently reduce PTH 
secretion. The parathyroid glands sense the level of extracellular calcium at the surface of the 
parathyroid cell and adjust the synthesis and secretion of PTH accordingly. 
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). 
Hypoparathyroidism has also been linked to effects on mood and ideation (Arlt et al. 2002;
Velasco et al. 1999).
The kidneys are especially vulnerable in subjects with hypoparathyroidism. Circulating PTH 
promotes renal calcium reabsorption, especially at the level of the distal convoluted tubule 
(Blaine et al. 2015). In the absence of PTH, calcium can be over-excreted through the kidneys 
(Shoback 2008), leading to hypercalciuria which, together with a high-calcium-phosphate 
product, can potentially lead to nephrocalcinosis and kidney stones and, ultimately, to renal 
impairment (Blaine et al. 2015).
For further details see the recombinant human PTH (rhPTH[1-84]) investigator brochure.
1.1
Indication and Current Treatment Options 
Prior to 2015, in the absence of an approved PTH replacement therapy, management of 
hypoparathyroidism consisted of supplemental oral calcium and active vitamin D in 
pharmacological doses sufficient to maintain the serum calcium level without the disabling 
symptoms of hypocalcemia. 


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In order to improve the absorption of calcium from the gastrointestinal tract, pharmacological 
supplementation with active forms of vitamin D (eg, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 
calcitriol, 1,25-dihydroxycholecalciferol or α-calcidol [1(OH)D3]) is also required. Since PTH 
also functions in the kidney to stimulate the conversion of 25(OH)D3, the major circulating form 
of vitamin D, to the active vitamin D hormone (1,25[OH]2D3), the relative lack of circulating 
PTH results in a reduction of the production of active vitamin D. Thus, exogenous active vitamin 
D overcomes the synthetic block in endogenous production of the active vitamin D hormone in 
hypoparathyroidism. Together, supplemental oral calcium and active vitamin D have formed the 
mainstay of current treatment of subjects with hypoparathyroidism. 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 (AEs) 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 US on 23 Jan 2015 under the brand 
name Natpara® as a once-daily injectable dose as an adjunct to calcium and vitamin D to control 
hypocalcemia in patients with hypoparathyroidism.
1.2
Product Background 
1.2.1
Preclinical Information
A total of 46 in vivo studies in mouse, rat, rabbit, dog, and rhesus and cynomolgus monkeys 
have evaluated the 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 been performed.
In male and female rats, the administration of PTH was associated with an increase in the 
incidence of osteosarcoma. These data were interpreted as an increased risk for osteosarcoma in 
the clinic. Therefore, administration of rhPTH(1-84) should be avoided in subjects who are 
considered to be at increased risk for osteosarcoma (including those with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase, subjects with hereditary disorders 
predisposing to osteosarcoma or subjects with a history of prior external beam or implant 
radiation therapy involving the skeleton).


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Currently available results from animal reproductive toxicology studies suggest that 
rhPTH(1-84) is not associated with significant fetal or neonatal toxicity; however, the safety of 
rhPTH(1-84) in pregnant or nursing women is not established.
For full details see the rhPTH(1-84) investigator brochure.
1.2.2
Clinical Information
Study CL1-11-040 (REPLACE) was a double-blind, placebo controlled study of once daily (QD) 
SC administration of 50 μg to 100 μg of rhPTH(1-84). The 3-tiered primary endpoint included 
≥50% reduction from baseline in oral calcium supplementation, ≥ 50% reduction from baseline 
in active Vitamin D, and albumin-corrected serum calcium (ACSC) concentration maintained or 
normalized compared to baseline (not exceeding upper limit of normal). The 3-tiered endpoint 
was met in 54.8% of rhPTH(1-84) subjects compared to 2.5% of 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 extension 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 serum calcium-phosphate product. In 
these studies, hypercalciuria was defined as an excretion of calcium in the urine greater than 
300mg per 24 hours. Data from the REPLACE Study and the long-term open label study, RACE, 
show that rhPTH(1-84) has a calcium-sparing effect, consistent with the reduction of urinary 
calcium excretion seen in a previous pharmacokinetic/pharmacodynamic study (C09-002) of 
single dose administration of rhPTH(1-84) in subjects with hypoparathyroidism in comparison 
with calcitriol administration.
The Phase 3 clinical study, REPLACE, was the largest, randomized, placebo controlled clinical 
study conducted in hypoparathyroidism population and was the pivotal study demonstrating that 
rhPTH(1-84) is effective in maintaining serum calcium levels and enabling significant decreases 
in active vitamin D and oral calcium doses. REPLACE also established the rhPTH(1-84) dose 
and dose titration and evaluated the physiologic effects of PTH replacement on serum calcium, 
serum phosphate, urinary calcium excretion, and bone turnover markers. Eighty-four subjects 
were evaluated in the active treatment group and 40 subjects received placebo. Subjects 
received at a flexible dose range of 50 to 100 μg SC in the thigh once daily for 6 months. The 
study met the primary efficacy triple endpoint, with a statistically higher responder rate (54.8%) 
versus placebo (2.5%). To meet the primary endpoint a subject had to fulfill all 3 conditions as 
follows: a 50% or greater reduction in oral calcium requirement, a 50% or greater reduction in 
active vitamin D therapy and an ACSC concentration that was maintained within a range of 
7.5 to 10.6 mg/dL.
A review of safety data across the hypoparathyroidism 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.


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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. 
Because of the potential risk of osteosarcoma, rhPTH(1-84) is recommended only for subjects 
who cannot be well controlled on calcium supplements and active forms of vitamin D alone.
Additional risks include extensions of the pharmacologic effects 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 subjects should be advised to 
take their rhPTH(1-84) dose as soon possible following a missed dose and to take oral calcium.
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).


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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Recombinant human parathyroid hormone has been developed as an adjunct to calcium and 
vitamin D to control hypocalcemia in hypoparathyroidism subjects who cannot be well 
controlled with calcium and vitamin D supplementation alone. Although the development of a 
novel therapeutic agent for the treatment of hypoparathyroidism is encouraging, it is important to 
gain knowledge about the efficacy and safety of long-term use of rhPTH(1-84) due to the chronic 
nature of the condition. 
The AAAE0544 cohort has the longest known duration of rhPTH(1-84) therapy for the treatment 
of hypoparathyroidism to date. This protocol is designed to extend this experience and to provide 
additional data on the long-term safety and efficacy of rhPTH(1-84).
2.2
Study Objectives 
2.2.1
Primary Objectives 

To evaluate ACSC while on rhPTH(1-84) treatment
2.2.2
Secondary Objectives

To evaluate the proportion of subjects who achieve ACSC values above, below, or in the 
range of 7.5mg/dL-upper limit of normal (ULN)

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment 

To evaluate symptoms of hypoparathyroidism as measured by the hypoparathyroidism 
symptom diary (HPT-SD), perception of cognitive function, and health-related quality-of-life 
associated with long-term rhPTH(1-84) treatment.

To evaluate the skeletal actions of rhPTH(1-84): bone turnover markers, architecture, and 
histology (biopsy)




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All subjects will have their total serum calcium checked by a local laboratory as outlined in the 
Schedule of Study Assessments (Table 1). Subjects may have their rhPTH(1-84) dose increased 
in increments of 25 µg to a maximum of 100 µg SC QD by the investigator no more frequently 
than 4 week intervals during the study, with the goal of achieving or maintaining total serum 
calcium levels in the range of 8.0 to 9.0 mg/dL if clinically appropriate. The rhPTH(1-84) dose 
may be adjusted downward at any time as needed to maintain appropriate serum calcium levels 
(approximately 8.0 to 9.0 mg/dL) or due to any safety concerns.
Adjustment of supplemental calcium and calcitriol regimens will be based on serum calcium 
levels, with the goal to be a reduction or removal of calcitriol treatment to the maximum degree 
clinically possible and to decrease the prescribed oral calcium supplementation to ≤500 mg 
daily. 
Subjects generally should have blood draws to assess total serum calcium levels (which may be 
performed locally) 3 to 5 days after ANY dose adjustment of rhPTH(1-84), after any significant 
change in doses of calcium and/or and calcitriol supplements, or at any other time at the 
discretion of the investigator. Results of local total serum calcium levels will be entered on the 
electronic case report form (eCRF). 
Approximately 30 days following the End of Treatment visit, subjects will be contacted by 
telephone in order to assess AEs/serious AEs (SAEs). 


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4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. Subjects in this protocol 
are restricted to those who were treated in the core study (AAAE0544). Approximately 
50 subjects are expected to enroll in this study.
4.1
Inclusion Criteria
The subject must meet all of the following criteria to be eligible for the study:
1. Subjects that are currently or previously enrolled in the core study (AAAE0544) and have 
maintained uninterrupted therapy with rhPTH(1-84) (transient interruptions of up to 
1 month continuously off treatment may be allowed).
2. Signed and dated informed consent form (ICF).
3. Adult men and women 18 to 85 years of age.
4. History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, 
defined by the requirement for supplemental calcium and/or active vitamin D to maintain 
serum calcium along with an undetectable or insufficient PTH concentration.
5. Able to perform daily SC self-injections of study medication (or have designee perform 
injection).
6. Willingness and ability to understand and comply with the protocol. Women must agree to 
pregnancy testing and acceptable methods of contraception, as detailed in the protocol.
4.2
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1. The subject is treated or has been treated with any investigational drug, aside from 
rhPTH(1-84), within 30 days of consent.
2. As assessed by the investigator, the subject has any safety or medical issues that 
contraindicate participation in the study.
3. The subject and/or the subject’s parent(s) or legally-authorized representative(s) are 
unable to understand the nature, scope, and possible consequences of the study. 
4. The subject is unable to comply with the protocol, eg, uncooperative with protocol 
schedule, refusal to agree to all of the study procedures, inability to return for evaluations, 
or is otherwise unlikely to complete the study, as determined by the investigator or the 
medical monitor.
5. The subject is pregnant or lactating.
6. Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s 
disease of bone or unexplained new elevations of alkaline phosphatase, subjects with 
hereditary disorders predisposing to osteosarcoma or subjects with a prior history of 
external beam or implant radiation therapy involving the skeleton.


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4.3
Reproductive Potential
4.3.1
Female Contraception
Women who are postmenopausal (absence of menses for at least 1 year) and women who are 
surgically sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy) can be enrolled. 
Women of childbearing potential must have a negative pregnancy test and agree to use medically 
acceptable methods of contraception for the duration of the study with pregnancy testing at every 
scheduled visit. 
Medically acceptable methods of contraception include: true sexual abstinence (not having any 
type of intercourse or sex play with a male partner); hormonal methods of contraception (oral, 
injected, vaginal rings, patch, implanted, etc.); placement of an intrauterine device or intrauterine 
system; barrier methods of contraception (condom or occlusive diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. Women whose partner is a woman or whose 
partner is a man with a history of vasectomy are exempt.
4.3.2
Male Contraception
Not Applicable.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product [rhPTH(1-84)] with 
the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for End 
of Treatment (EOT) Visit are to be performed as completely as possible. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents and as AEs, as applicable. The reason for termination, date of stopping rhPTH(1-84) 
and the total amount of rhPTH(1-84) taken must be recorded in the electronic case report form 
(eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Subject Withdrawal Criteria
Subjects can withdraw from the study at any time for any reason. 
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF. 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 eCRF. Reasons for discontinuation include but are not limited to:

Completed

Adverse event

Protocol deviation


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
Withdrawal by subject

Lack of efficacy

Lost to follow-up

Other (If “Other” is selected, the investigator must specify on the eCRF: examples are 
provided below)

Death

Physician decision

Pregnancy

Site terminated by sponsor

Study terminated by sponsor
4.4.3
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
All non-study treatment, including but not limited to herbal treatment, vitamins, behavioral 
treatment, non-pharmacological treatment (such as psychotherapy), as appropriate, received 
within 30 days prior to the baseline visit (Visit 1) (or pharmacokinetic equivalent of 5 half-lives, 
whichever is longer) and through the final study contact (including protocol defined follow-up 
period) must be recorded on the appropriate eCRF page.
5.1
Prior Treatment
For the prospective portion of the study, prior treatment includes all treatment, including but not 
limited to herbal treatment, vitamins, behavioral treatment, non-pharmacological treatment (such 
as psychotherapy), as appropriate as of the time of enrollment in Study SHP634-402. Prior 
treatment information must be recorded on the appropriate eCRF page. 
5.1.1
Concomitant Treatment 
For the retrospective portion of the study, concomitant treatment refers to all treatment taken 
from 1 year prior to initiation of treatment with rhPTH(1 84) until enrollment in study 
SHP634-402.
For the prospective portion of the study, concomitant treatment refers to all treatment taken 
between the dates of the first dose of study SHP634-402 rhPTH(1-84) and the end of the 
follow-up period in the SHP634-402 study, inclusive. All available active vitamin D and calcium 
supplement doses from the beginning of rhPTH(1-84) will be recorded. Concomitant treatment 
information must be recorded on the appropriate eCRF page.
5.1.2
Permitted Treatment
Any treatment for an existing or obtained condition(s) will be permitted. Active vitamin D, 
native vitamin D, calcium and magnesium supplementation, and thiazide use are permitted. Prior 
treatment with rhPTH(1-84) is permitted.
5.1.3
Prohibited Treatment
The use of any other investigational product within 30 days prior to study enrollment or at any 
time during the trial is prohibited. Additionally, any medication that affects bone metabolism (eg, 
selective estrogen receptor modulators, calcitonin, bisphosphonates) and any other 
investigational products are prohibited while on study SHP634-402 rhPTH(1-84) treatment. 
5.1.4
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation
5.1.4.1
Active Vitamin D
Subjects enrolled in this study may be taking active vitamin D to control serum calcium levels. 
Prior and concomitant prescribed doses of calcitriol will be entered on the appropriate eCRF. 


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5.1.4.2
Native Vitamin D 
Subjects should receive native vitamin D to maintain the subject’s serum 25(OH) vitamin D level 
in the normal range (≥30 ng/ml and ≤ the upper limit of normal for the laboratory). Prior and 
concomitant doses of native vitamin D must be recorded on the appropriate eCRF.
5.1.4.3
Calcium
Subjects enrolled in this study may be taking oral calcium supplements (either calcium carbonate 
or calcium citrate). Prior and concomitant prescribed doses of calcium will be entered on the 
appropriate eCRF. Subjects will enter their actual doses taken for 14 days prior to each visit, 
following the baseline visit, in a home diary.
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject in a 
diary. 
5.1.4.4
Magnesium 
Subjects with low serum magnesium should receive supplementation to keep the serum 
magnesium level in the normal range. Prior and concomitant doses of magnesium must be 
recorded on the appropriate eCRF.
5.1.5
Thiazide Diuretics
Subjects in this study may be taking thiazide diuretics (hydrochlorothiazide or chlorthalidone) to 
limit the extent and effect of hypercalciuria. Prior and concomitant prescribed doses of thiazide 
diuretics will be entered on the appropriate eCRF.


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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The investigational 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, 75µg, and 100µg. The investigational 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.
6.1.1
Blinding the Treatment Assignment
This is an open-label single-arm study where all subjects will be administered study drug; 
therefore, no blinding will occur.
6.2
Administration of Investigational Product(s)
The following instructions describe how to administer the investigational product:
Adjust dose of active vitamin D or calcium supplement or both based on serum calcium value 
and clinical assessment (ie, signs and symptoms of hypocalcemia or hypercalciuria). Suggested 
adjustments to active vitamin D and calcium supplement based on serum calcium levels are 
provided in Table 2.
Table 2:
Recommended Adjustments for Active Vitamin D and Calcium Supplements
Adjust First
Adjust Second
Serum Calcium
Active Vitamin D Forms
Calcium Supplement
Above the Upper Limit of 
Normal (10.6 mg/dL)
Decrease or Discontinue *
Decrease
Greater than 9 mg/dL and below 
the Upper Limit of Normal (10.6 
mg/dL)
Decrease or Discontinue *
No change or decrease if active 
vitamin D has been discontinued
Less than or equal to 9 mg/dL 
and above 8 mg/dL
No change
No change
Lower than 8 mg/dL
Increase
Increase
*Discontinue in patients receiving lowest available dose


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6.2.1
Allocation of Subjects to Treatment 
This is an open-label, single-center study where all subjects will receive rhPTH(1-84).
6.2.2
Dosing
The dose of rhPTH(1-84) will be individualized based on ACSC and 24-hour calcium urinary 
excretion. The recommended rhPTH(1-84) dose will be the minimum dose required to prevent 
both hypocalcemia and hypocalciuria. This dose will generally be the dose that maintains ACSC 
within the lower half of the normal range (ie, between 8 and 9 mg/dL) without the need for 
active forms of vitamin D and with calcium supplementation sufficient and individualized to 
meet the patient’s daily requirements. 
The doses of rhPTH(1-84), active vitamin D, and calcium supplements will be prescribed on an 
individual basis. Dosing guidelines found in the US package insert will be used but may be 
individualized at the discretion of the investigator. 
Doses of active forms of vitamin D and calcium supplements will be adjusted when using 
rhPTH(1-84).
6.2.3
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Packaging
The study site will receive open label supplies of investigational product, injection pens and 
mixing devices required for dosing.
Each subject will receive 2 pens for use during the study period and sufficient cartridges to 
provide daily doses for the duration of the study. Drug cartridges will be provided in kits 
containing 8 cartridges each and each kit will be sufficient for up to 16 weeks of treatment. Each 
cartridge will contain study drug for 14 doses. Drug cartridges will be provided at each clinic 
visit in sufficient quantity and at appropriate dose levels to ensure uninterrupted administration 
until the next study visit. In the event of drug expiries, a courier may ship drug supplies to 
subjects directly in between their study visits. Subjects may also use the courier service to return 
expired investigational product. Ancillary supplies including single use needles (31-gauge) and 
alcohol wipes will be provided by the CRO to the site. 
6.3.2
Labeling 
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.


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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.”
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.
6.3.3
Storage
The dual-chamber medication cartridge should be stored between 2 – 8 °C. The reconstituted 
medication can be stored for up to 14 days at these conditions. The mixing device and empty 
delivery pen (ie, unloaded) can be stored at room temperature.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained. The temperature should be monitored continuously by using either an in 
house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.


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6.3.4
Special Handling
Do not freeze or shake. Do not use rhPTH(1-84) if it has been frozen or shaken.
6.4
Drug Accountability
The investigator will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (ie, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense 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 dispensed study drug 
will be documented. The investigator is responsible for assuring the retrieval of all study supplies 
from subjects. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational products being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (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 for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational products must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.


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6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Additionally, subjects may use a courier service 
to return expired and empty/used investigational product. Drug accountability will be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level 
for opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form.


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7
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 for a complete list of study procedures. Site visits will be conducted at 6-month 
intervals until the End of Treatment (EOT) visit at Month 48.
A core set of study procedures, conducted at each site visit, are defined as the following:

Prior/concomitant medications (subjects will enter their actual doses of calcium taken for 
14 days prior to each visit, following the baseline visit, in a home diary)

Vital signs

Serum chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
calcium, phosphate, magnesium, albumin, ALT, AST, and ALP).

Should be drawn fasting, prior to administration of calcium or vitamin D supplements 
or rhPTH(1-84) administration. If in the opinion of the investigator, it is necessary for 
a subject to take calcium and/or active vitamin D supplements prior to traveling for 
blood work, the doses of the pre-draw supplements and their timing with respect to 
the blood draw should be consistent throughout the study to the greatest extent 
possible.

Urine pregnancy test

Serum 25-hydroxyvitamin D

Serum 1,25-dihydroxyvitamin D

Bone turnover markers

Serum PTH antibodies (blood samples should be drawn prior to dosing)

24-hour urine for calcium, creatinine, phosphate, sodium excretion, and magnesium. Total 
urinary volume will be recorded. 

HPT-SD 

FACT-Cog (Functional Assessment of Cancer Therapy - Cognitive Function) assessment 

FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue Scale

HADS (Hospital Anxiety and Depression Scale) assessment 


AE/SAE monitoring

Bone mineral density DXA (dual-energy x-ray absorptiometry)

Bone mineral density HRpQCT (High-resolution peripheral quantitative computerized 
tomography)

Dispense/Account for study drug
7.1.1
Baseline Visit (Visit 1)
All study procedures outlined in Table 1 will be conducted at the baseline visit with the 
exception of “Collection of unused study drug & injection pen.” Additionally, the bone biopsy 
and 
 (performed using an OsteoProbe®) are optional procedures, which will be 
performed depending on subject history and consent.


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7.1.2
Treatment Period 
7.1.2.1
Visit 2 (Month 6)
The core set of study procedures will be conducted at this visit.
7.1.2.2
Visit 3 (Month 12)
The core set of study procedures will be conducted at this visit. In addition to the core study 
procedures, the following procedures will be performed:

Physical Examination

SF-36 (RAND 36-Item Short Form Health Survey)
7.1.2.3
Visit 4 (Month 18)
The core set of study procedures will be conducted at this visit.
7.1.2.4
Visit 5 (Month 24)
The core set of study procedures will be conducted at this visit. In addition to the core study 
procedures, the following procedures will be performed:

Physical Examination

Hematology

SF-36 (RAND 36-Item Short Form Health Survey)

Urinalysis (dipstick)
7.1.2.5
Visit 6 (Month 30)
The core set of study procedures will be conducted at this visit. 
7.1.2.6
Visit 7 (Month 36)
The core set of study procedures will be conducted at this visit. In addition to the core study 
procedures, the following procedures will be performed:

Physical Examination

SF-36 (RAND 36-Item Short Form Health Survey)
7.1.2.7
Visit 8 (Month 42)
The core set of study procedures will be conducted at this visit.


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7.1.2.8
EOT Visit (Month 48)
All study procedures outlined in Table 1 will be performed at this visit except for the following:

Informed consent

Inclusion/exclusion

Medical history and demography

Serum thyroid stimulating hormone (TSH) 

Serum pregnancy test

Follicle-stimulating hormone (FSH) level
7.1.3
Additional Care of Subjects after the Study
After the EOT visit or early termination visit, subjects who will not continue rhPTH[1-84] 
treatment will have serum calcium and phosphate levels measured 3 to 5 days after the last dose 
of study medication. Doses of calcium and active vitamin D supplements will be adjusted by the 
investigator as appropriate according to guidelines followed in the US package insert. Thereafter, 
the investigator will repeat serum calcium/phosphate monitoring and supplement dose 
adjustments as appropriate to achieve target serum calcium/phosphate concentrations until the 
follow up phone call 30 days ± 7 days after EOT visit. After the 30-day follow-up phone call, 
further management of hypoparathyroidism will occur as part of the subject’s long-term 
non-study medical care.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics will be recorded at the baseline visit including date of birth, sex, 
and race on the eCRF for each subject. 
Medical history including etiology of hypoparathyroidism and duration of hypoparathyroidism 
will be recorded on the eCRF for each subject. 
Pre-study rhPTH(1-84) treatment will be recorded on the eCRF for each subject.
Pre-study laboratory data will be recorded on the eCRF for each subject.
7.2.2
Efficacy
7.2.2.1
Biochemical Evaluations
Biochemical evaluation including serum calcium, PTH, albumin, phosphate, alkaline 
phosphatase, urine calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D will be 
collected at the time points specified in Table 1 to assess efficacy and bone turnover.


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The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following 
items:
•
symptom subscale (items 1-7)
•
anxiety (item 8)
•
sadness and depression (item 9)
•
impact subscale (items 10-13)
The 24-hour recall version of the instrument will be used in this study (Appendix 2). 
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The FACT-Cog assessment is a 37-item tool (Cella 1997; Version 3.0; Appendix 3). It includes 
4 subscales: perceived cognitive impairments, impact of perceived cognitive impairments on 
quality of life, comments from others and perceived cognitive ability.
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FACIT fatigue questionnaire contains 13 fatigue-related questions (Cella 1997; Version 4.0; 
Appendix 4). The responses to the 13 items on the FACIT fatigue questionnaire are each 
measured on a 4-point Likert scale. Thus, the total score ranges from 0 to 52. High scores 
represent less fatigue.
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The HADS is a 14-item scale that generates ordinal data (Zigmond and Snaith 1983; Appendix 
5). Seven of the items relate to anxiety and seven relate to depression. The scale is designed to 
avoid reliance on aspects of conditions that are also common somatic symptoms of illness.  Each 
item on the questionnaire is scored from 0-3, therefore, a person can score between 0 and 21 for 
either anxiety or depression. Data returned from the HADS is ordinal. The investigator must 
review responses to the HADS before the subject leaves the site and take any appropriate action 
that is clinically indicated based on the responses. 
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The SF-36 is a validated questionnaire that questions subjects about perceived physical and 
mental health and function. The SF-36 consists of 8 scaled scores, which are the weighted sums 
of the questions in their section. Each scale is directly transformed into a 0-100 scale on the 
assumption that each question carries equal weight; the lower the score the more disability. The 
higher the score the less disability ie, a score of zero is equivalent to maximum disability and a 
score of 100 is equivalent to no disability. The eight sections included in the SF-36 assessment 
are vitality, physical functioning, bodily pain, general health perceptions, physical role 
functioning, emotional role functioning, social role functioning, and mental health (Ware and 
Sherbourne 1992; RAND SF-36 Version 1.0; Appendix 6).






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Hematology
Blood samples for hematology will be collected at the time points described in Table 1 and will 
include:
Hemoglobin
Platelet count
Hematocrit
White blood cell (WBC) count
Red blood cells (RBC)
WBC differentials
Urinalysis
A urine sample for urinalysis will be collected at the time points described in Table 1 and will 
include:
pH
Blooda
Nitrites
Glucose
Ketones
Leukocyte esterasea
Proteina
Bilirubin
Specific gravity
aMicroscopic examination will be conducted if protein, leukocyte esterase, and/or blood is/are detected during urinalysis. At a 
minimum, the microscopic examination will consist of red blood cells, white blood cells, casts, and bacteria.
24-Hour Urine
At the beginning of the study, the investigator should recommend an individualized target dietary 
(non-supplement) calcium intake for each subject to ingest consistently throughout the study on 
24-hour urine collection days. The 24-hour urine collections should generally be performed by 
the subject within 2 weeks prior to or within 2 days follow a study visit.  
These 24-hour urine collections may be analyzed in a local laboratory. To the greatest extent 
possible, the same laboratory should analyze the 24-hour urine collections throughout the study. 
Results from the last 24-hour urine collection obtained in Columbia protocol AAAE0544 will be 
used as the baseline assessment in this study.
When collecting 24-hour urine specimens, subjects should take their currently prescribed 
calcium, vitamin D (both parent and active), and rhPTH(1-84) doses.
A 24-hour urine sample will be collected at the time points described in Table 1 and will include:
Calcium
Sodium
Creatinine
Total Volume
Phosphate
Magnesium
7.2.3.3
Pregnancy Test
A serum and urine pregnancy test will be performed on all females of childbearing potential at 
the Baseline Visit and a urine pregnancy test will be performed at the time points described in 
Table 1 (all study visits).


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7.2.3.4
PTH Antibodies
A blood sample for PTH antibodies will be collected at the time points described in Table 1. 
Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any 
subject with newly developed PTH-specific antibodies at the end of treatment visit may require 
follow up. This will be discussed as necessary by the PI and medical monitor on a case-by-case 
basis.
7.2.3.5
Vital Signs
Vital signs include blood pressure, heart rate, body temperature, and respiration rate. Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study). Any clinically significant deviations from baseline (Visit 1) vital 
signs which are deemed clinically significant in the opinion of the investigator are to be recorded 
as an AE.
7.2.3.6
Physical Examination
A physical examination including height and weight will be conducted at the time points 
described in Table 1. Abnormalities identified at the Baseline Visit will be documented in the 
subject’s source documents and on the medical history eCRF. Any clinically significant 
deviations from Baseline in physical examination findings which are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
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 eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
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 assess the relationship to investigational product for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If there is no 
valid reason for suggesting a relationship, then the AE should be classified as “not related.” 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
possible cause-and-effect relationship between the investigational product and the occurrence of 
the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. 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.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital signs 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.


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If, at the end of the treatment phase, there are abnormal clinical laboratory or vital signs 
values which were not present at the pre-treatment 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 (ie, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital signs parameter is clinically significant 
and therefore represents an AE.
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 7.1.3.
Any report of pregnancy for any female 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 postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG (beta-human chorionic gonadotropin) test or ultrasound result will determine the 
pregnancy onset date.
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.


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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 the protocol).
Overdose – Intentional or unintentional intake of a dose of an investigational product exceeding 
a pre-specified total daily dose of 250 µg of the product.
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 an expired investigational product should be considered as a 
reportable medication error.
Acute accidental overdosage of rhPTH(1-84) can result in transient hypercalcemia and 
hypercalciuria. Treatment of suspected overdose should include temporary discontinuation of 
rhPTH(1-84), monitoring of serum calcium, and implementation of appropriate, supportive 
measures such as hydration. Due to the relatively short duration of the pharmacological activity 
of rhPTH(1-84), further measures should not be necessary.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigators brochure, which the 
sponsor has provided under separate cover to all investigators. 
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs 
does not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) 
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 Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol.


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8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it was more severe.

Requires inpatient 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 inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
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 ICF, 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.


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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 and/or CRO is responsible for notifying the relevant regulatory authorities/US 
central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and/or CRO is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the SHP634-402 program. 
The investigator is responsible for notifying the local IRB, local Ethics Committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.


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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF 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. It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the study data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Not Applicable.
9.4
Statistical Analysis Process
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy 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, study treatment exposure, and prior and concomitant medications. The SAP will 
also include a description of how missing, unused and spurious data will be addressed.
All statistical analyses will be performed using Statistical Analysis System (SAS) (SAS 
Institute, Cary, NC, USA) version 9.3 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A retrospective analysis of historical data captured from the medical records of subjects (eg, 
since the start of rhPTH(1-84) treatment) will be conducted. These data will be derived from the 
medical records of subjects that are exclusively from the core study (Protocol AAAE0544 at 
Columbia University Medical Center [HEXT: The Hypoparathyroidism Studies, EXTended: The 
Effect of PTH on the Skeleton in Hypoparathyroidism]). Data collected will include but is not 
limited to, medical history and clinical laboratory data that can be source data verified. There are 
no formal hypotheses testing for the retrospective analysis. 


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Descriptive statistics will be calculated for quantitative safety data as well as for the difference 
from the pre-rhPTH(1-84) treatment baseline, if applicable. 
There will be no Data Monitoring Committee for this unblinded exploratory study, however 
results of the prospective data portion of the study will be analyzed as necessary for safety 
monitoring and publication purposes.
9.6
Sample Size Calculation and Power Considerations
No formal sample size calculation was performed.
9.7
Study Population
The Safety Population will be used for all analysis in this study and consists of all subjects who 
receive at least 1 dose of rhPTH(1-84). 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint

Change in albumin-corrected serum calcium
The primary efficacy endpoint is defined as the change in ACSC concentration at each study 
visit (ie, every 6 months). The baseline serum calcium concentration is the final measurement 
taken prior to initiating treatment.
The change and percentage changes from baseline will be summarized at each visit. No formal 
statistical test will be conducted. 95% confidence intervals (CI) will be provided as appropriate.
9.8.2
Secondary Efficacy Endpoints
The secondary endpoints are defined as follows:

Albumin-corrected serum calcium value above, below, or in the range of 7.5mg/dL-ULN

Change in urinary calcium and serum phosphate

Change in calcium and active vitamin D supplement doses

Change in HPT symptoms (as measured by the HPT-SD)

Change in FACT-Cog assessment

Change in FACIT (Fatigue Scale)

Change in HADS

Change in health-related quality-of-life measured with SF-36 survey

Change in bone turnover markers (including, but not limited to, serum carboxy-terminal 
4 telopeptide of type I collagen [s-CTX], procollagen type I amino-terminal propeptide 
[P1NP], osteocalcin, bone specific alkaline phosphatase [BSAP], TRAP-5b, sclerostin), 
architecture, and histology (biopsy)
For continuous variables, the change and percent changes from baseline will be summarized 
using descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. Selected endpoints will also be analyzed using the subject’s baseline 
immediately prior to rhPTH(1-84) initiation, where data are available. 




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These data will be collected in the following order of priority: 
Priority 1:

Serum calcium and albumin

Urine calcium excretion (to include 24 hour urine collections or estimates of 24 hour 
excretion based on 2 hour collections)

Serum phosphate

Serum creatinine

SF-36 results

24 hour urine creatinine, volume
Priority 2:

Calcium and Vitamin D supplement doses

Serum magnesium

DXA bone density results

HRpQCT results
Priority 3:

25-OH Vitamin D and 1,25-dihydoxy-Vitamin D levels

Medical History/

Bone Turnover Markers

Vital signs (body temperature, heat rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)

24 hour urine phosphate, sodium
Descriptive statistics will used to evaluate the historical data, if applicable.
9.10.1
Health-related Quality of Life Analyses
SF-36 endpoints will be measured. For each endpoint, the change in Quality of Life score from 
baseline to the end of treatment will be measured relative to those measured just prior to 
beginning rhPTH(1-84) treatment and relative to Visit 1 in this study.


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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements. 
The name and address of each third party vendor (ie, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), European Union (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 eCRFs in accordance with current Good Clinical Practice (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
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.
10.1.3
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 (CSR) 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.
10.1.4
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. 


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Additionally, the discontinuation of a registered clinical study which has been posted to a 
designated public website will be updated accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), 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 principal investigator according to national provisions and 
will be documented in the investigator agreement.


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10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms (CRFs) are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. CRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries will be sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
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.
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 eCRF 
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 Food and 
Drug Administration (FDA), European Medicines Agency (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.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data collected for and generated by this study 
must be available for inspection upon request by representatives of, for example, the US FDA (as 
well as other US national and local regulatory authorities), the EMA, the Medicines and 
Healthcare Products Regulatory Agency, other regulatory authorities, the sponsor or its 
representatives, and the IRB/EC for each site.


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10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and ICH GCP. The Informed 
Consent procedure has been modified to allow remote consenting of subjects for this phase 
4 study. A member of the study team will send the Informed Consent document by mail or 
e-mail to the subject and discuss the document by telephone. 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. The subject will return their 
signed informed consent document to the site. Upon receipt of the subject’s consent, the 
authorized consenter who performed the remote informed consent procedure will physically 
sign and date the consent document as well. A copy of the informed consent documentation
(ie, a complete set of subject information sheets and fully executed signature pages) must be 
given to the subject or the subject’s legally-authorized representative, as applicable. This 
document may require translation into the local language. Signed consent forms must remain in 
each subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form 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
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.


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Responsibility for coordinating with IRBs/ECs is defined in the investigator 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/CRO has received written 
IRB/EC approval of and copies of revised documents.
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.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market rhPTH(1-84); national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (ie, 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.


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10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. 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.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must; however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.




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12
APPENDICES




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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
16 Aug 2017
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Clarified that subjects will enter their actual doses of calcium taken 14 days 
prior to each visit, following the baseline visit, in a home diary
Table 1, Section 5.1.4.3, 
Section 7.1
Clarified prior treatment for the prospective portion of the study.
Section 5.1
Clarified that the investigator must review the responses to the HADS before 
the subject leaves the site. 
Table 1, Section 7.2.2.5
Clarified that for the retrospective portion of the study, concomitant treatment 
refers to all treatment taken from 1 year prior to initiation of treatment with 
rhPTH(1 84) until enrollment in study SHP634-402.
For the prospective portion of the study, concomitant treatment refers to all 
treatment taken between the dates of the first dose of study SHP634-402 
rhPTH(1-84) and the end of the follow-up period in the SHP634-402 study, 
inclusive.
Section 5.1.1
Clarified that any medication that affects bone metabolism and any other 
investigational products are prohibited while on study SHP634-402 rhPTH(1-
84) treatment.
Section 5.1.3
Clarified that a courier service may be used to ship supplies to subjects in the 
event of drug expiries and may also be used to return expired and 
empty/unused investigational product.
Section 6.3.1, Section 6.5
Added white blood cell differentials to hematology parameters.
Section 7.2.3.2
Clarified that version 1.0 of the Short Form Health Survey-36 (SF-36) will be 
used for the retrospective portion of the study and version 2.0 of the SF-36 will 
be used for the prospective portion of the study. 
Section 7.2.2.6
Calcium was removed from the urinalysis.
Section 7.2.3.2
Clarified that baseline for selected endpoints will be defined as the subject’s 
baseline immediately prior to rhPTH(1-84) initiation where data are available. 
Section 9.8.2
Moved 24 hour urine creatinine, volume from Priority 2 to Priority 1.
Section 9.10
Removed electrocardiogram (ECG) parameters and bone histology and 
histomorphology from Priority 3.
Section 9.10
Added the 
 as an appendix
Appendix 4
Minor edits for clarity and consistency throughout the document.
Global


APPENDIX 2
HYPOPARATHYROIDISM SYMPTOM DIARY
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Hypoparathyroidism Symptom Diary
For each of the following questions, please choose the one answer that best describes your 
experiences related to hypoparathyroidism during the past 24 hours. 
1. How would you rate any muscle cramps you experienced during the past 24 hours?

0

1

2

3

4

5

6

7

8

9

10
No
Worst
muscle
possible
cramps
muscle
cramps
2. How would you rate any tingling you experienced during the past 24 hours?

None  

Mild 

Moderate 

Severe   

Very severe
3. How would you rate any numbness you experienced during the past 24 hours?

None  

Mild 

Moderate 

Severe   

Very severe
6KLUH
6+33URWRFRO$PHQGPHQW
UK37+
&21),'(17,$/

3DJH

6HS


4. How would you rate any muscle spasms or twitching you experienced during the past 24 
hours?

None  

Mild 

Moderate 

Severe   

Very severe
5. How would you rate any feelings of heaviness you experienced in your arms or legs during 
the past 24 hours?    

None  

Mild 

Moderate 

Severe   

Very severe
6. How would you rate any physical fatigue you experienced during the past 24 hours?    

None  

Mild 

Moderate 

Severe   

Very severe
7. How would you rate any slowed or confused thinking, sometimes called brain fog, you 
experienced during the past 24 hours?  

None  

Mild 

Moderate 

Severe   

Very severe
6KLUH
6+33URWRFRO$PHQGPHQW
UK37+
&21),'(17,$/

3DJH

6HS


8. How would you rate any anxiety you felt during the past 24 hours?    

None  

Mild 

Moderate 

Severe   

Very severe
9. How would you rate any sadness or depression you felt during the past 24 hours? 

None  

Mild 

Moderate 

Severe   

Very severe
10. How did your hypoparathyroidism impact your sleep last night?  

Not at all   

Somewhat

Very much  
11. How did your hypoparathyroidism impact your ability to exercise in the past 24 hours? 
   

Not at all 

Somewhat

Very much  
6KLUH
6+33URWRFRO$PHQGPHQW
UK37+
&21),'(17,$/

3DJH

6HS


12. How did your hypoparathyroidism impact your ability to complete your work (for example, 
at school, at home or at a job) in the past 24 hours? 
   

Not at all 

Somewhat

Very much  
13. How did your hypoparathyroidism impact your relationships with your family members in 
the past 24 hours? 
   

Not at all 

Somewhat

Very much  
6KLUH
6+33URWRFRO$PHQGPHQW
UK37+
&21),'(17,$/

3DJH

6HS


APPENDIX 3
FACT-COGNITIVE FUNCTION 
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APPENDIX 4
FACIT FATIGUE SCALE 
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APPENDIX 5
HADS ASSESSMENT
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APPENDIX 6
RAND SF-36
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SAP_003.pdf: 
Protocol SHP634-402 
STATISTICAL ANALYSIS PLAN 
rhPTH(1-84) 
PHASE IV 
A Phase 4, Open-Label, Single-Center Clinical Study of Extended use of rhPTH(1-84) in 
Hypoparathyroidism 
PROTOCOL IDENTIFIER: SHP634-402 
Study Sponsor(s): 
Shire Human Genetic Therapies,  
Inc. 
300 Shire Way, Lexington, MA 
02421 USA 
Author: 
(RTP) 
, Biostatistics 
PPD 
Protocol: 
Protocol Amendment 2: 05 Sep 2018  
Protocol Amendment 1: 16 Aug 2017 
Original Protocol: 27 May 2016 
SAP Version #: 
Final 3.0 
SAP Date: 
30 Oct 2020 
Status: 
Final 
For non-commercial use only


Protocol SHP634-402 
 
 
 
REVISION HISTORY 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective 
Date 
Final 1.0 
Final SAP 
 
4 Dec 2019 
Final 2.0 
1. In Section 11.2.3  
1) Calculate prescribed daily dose 
prior to target study day in each visit 
window; 
2) Impute missing with 0 for both 
diary and prescribed daily dose; 
3) Remove the condition of 9 
minimal days of data when 
calculating the diary daily dose. 
2. added section 11.3.3  
3. Removed ‘absolute change’ from all 
analysis. 
4. Updated SI unit and conventional 
unit for 24-hour calcium. 
5. Added analysis for ACSC in 
conventional unit 
 
14 Jul 2020 
Final 3.0 
1. Add condition #6 to section 15.3 
2. Updated protocol deviation rules in 
section 7 
3. Removed appendix 1 and indicated 
the software will be used for SF-36 
scoring in section 11.2.8. 
 
30 
Oct 
2020 
 
For non-commercial use only


Protocol SHP634-402 
 
 
 
TABLE OF CONTENTS 
REVISION HISTORY ..................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................. 3 
LIST OF TABLES ............................................................................................................ 5 
ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................ 8 
2. 
STUDY DESIGN ................................................................................................. 9 
2.1 
General Study Design ........................................................................................... 9 
2.2 
Schedule of Assessments .................................................................................... 10 
2.3 
Determination of Sample Size ............................................................................ 11 
3. 
OBJECTIVES AND ENDPOINTS .................................................................... 12 
3.1 
Objectives ........................................................................................................... 12 
3.2 
Study Endpoints ................................................................................................. 12 
4. 
GENERAL CONSIDERATIONS ...................................................................... 14 
4.1 
Visit Window ..................................................................................................... 14 
4.2 
Handling of Dropouts or Missing Data .............................................................. 15 
4.3 
Interim Analyses and Data Monitoring .............................................................. 15 
5. 
SUBJECT POPULATION SETS ....................................................................... 16 
5.1 
Enrolled Subjects ................................................................................................ 16 
5.2 
Safety Population ............................................................................................... 16 
6. 
SUBJECT DISPOSITION ................................................................................. 17 
7. 
PROTOCOL DEVIATIONS .............................................................................. 18 
8. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............. 19 
9. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................... 20 
9.1 
Exposure to Investigational product ................................................................... 20 
10. 
PRIOR AND CONCOMITANT MEDICATION .............................................. 21 
11. 
EFFICACY ANALYSES ................................................................................... 22 
11.1 
Primary Efficacy Endpoint(s) and Analysis ....................................................... 22 
11.2 
Secondary Efficacy Endpoint(s) and Analysis ................................................... 22 
For non-commercial use only


Protocol SHP634-402 
 
 
 
11.3 
Exploratory Efficacy Endpoint(s) and Analyses ................................................ 27 
12. 
SAFETY ANALYSES ....................................................................................... 29 
12.1 
Adverse Events ................................................................................................... 29 
12.2 
Clinical Laboratory Variables ............................................................................ 29 
12.3 
Vital Signs .......................................................................................................... 31 
12.4 
Physical Examination ......................................................................................... 31 
12.5 
Serum and Urine Pregnancy ............................................................................... 32 
12.6 
PTH Antibodies .................................................................................................. 32 
13. 
COMPUTER METHODS .................................................................................. 33 
14. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................. 34 
15. 
DATA HANDLING CONVENTIONS ............................................................. 35 
15.1 
General Data Reporting Conventions ................................................................. 35 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters ........................... 35 
15.3 
Missing Date Information .................................................................................. 35 
15.4 
Missing Severity Assessment for Adverse Events ............................................. 37 
15.5 
Missing Relationship to Investigation Product for Adverse Events ................... 37 
16. 
REFERENCES ................................................................................................... 38 
For non-commercial use only


Protocol SHP634-402 
 
 
 
LIST OF TABLES 
Table 1 Schedule of Assessments ................................................................................... 10 
Table 2 Analysis Visit Window ...................................................................................... 14 
Table 3 Criteria for Potentially Clinically Important Laboratory Tests ......................... 31 
For non-commercial use only


Protocol SHP634-402 
 
 
 
ABBREVIATIONS 
ACSC 
albumin-corrected serum calcium  
AE  
adverse event 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-HCG  
beta-human chorionic gonadotropin 
BMI 
body mass index 
BMSi 
bone material strength index 
BSA 
body surface area 
BSAP 
bone specific alkaline phosphatase 
BUN 
blood urea nitrogen 
CKD-EPI 
CKD-epidemiology collaboration group 
CogQOL 
impact on quality of life subscale 
CogOth 
comments from others subscale 
CogPCA 
perceived cognitive ability subscale 
CogPCI 
perceived cognitive impairments subscale 
CRF  
case report form 
DXA  
dual-energy x-ray absorptiometry 
eCRF  
electronic case report form 
eGFR  
estimated Glomerular Filtration Rate 
EOT 
end of treatment 
FACIT  
Functional Assessment of Chronic Illness Therapy 
FACT-Cog  
Functional Assessment of Cancer Therapy - Cognitive Function 
FSH  
follicle-stimulating hormone 
HADS  
Hospital Anxiety and Depression Scale 
HPT  
hypoparathyroidism 
HPT-SD 
Hypoparathyroidism Symptom Diary 
HRpQCT  
high-resolution peripheral quantitative computerized tomography 
MedDRA  
Medical Dictionary of regulatory activities 
mmHg  
millimeters of mercury 
P1NP 
procollagen type I amino-terminal propeptide 
PCI 
potentially clinically important 
PI 
principle investigator 
PT 
preferred term 
PTH 
parathyroid hormone 
RBC 
red blood cell 
rhPTH(1-84)  
recombinant human parathyroid hormone 
s-CTX 
serum carboxy-terminal 4 telopeptide of type I collagen 
SAE  
serious adverse event 
For non-commercial use only


Protocol SHP634-402 
 
 
 
SAP  
statistical analysis plan 
SAS  
Statistical Analysis System 
SF-36  
36-item Short Form Health Survey 
SI 
système international 
SOC  
system organ class 
TEAE  
treatment-emergent adverse event 
TRAP-5b 
tartrate-resistant acid phosphate-5b 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC  
white blood cell 
WHODrug 
World Health Organization drug dictionary 
For non-commercial use only


Protocol SHP634-402 
 
 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the final study protocol SHP634-
402 version 1.0 dated 27 May 2016 incorporating most recent amendment 2 dated 05 Sep 2018. 
Specifications for tables, figures, and listings are contained in a separate document.  
Chronic hypoparathyroidism (HPT) is a life-long and irreversible disease for which the chronic 
administration of rhPTH(1-84) is a potential treatment option. Thus, long-term safety and 
efficacy data are important in evaluating the proper use of this treatment option in clinical 
practice. 
This study is investigating the effects of rhPTH(1-84) at doses of 25, 50, 75, and 100 μg for 
once daily subcutaneous injection to the thigh via a multidose pen injector device. The dose 
will be individualized to achieve a serum calcium level in the lower half of the normal range. 
For non-commercial use only


Protocol SHP634-402 
 
 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
SHP634-402 is a single-center, open-label, single arm, Phase 4 study of rhPTH(1-84) treatment 
in adult subjects (up to 50 subjects) diagnosed with hypoparathyroidism. Subjects enrolled are 
currently or were previously enrolled in the core study (AAAE0544) and have maintained 
uninterrupted therapy with rhPTH(1-84). Study visits will be scheduled every 6 months up to 
the 48-month end of treatment visit. Specific procedures at each study visit are summarized in 
Table 1. A schematic of the study design is provided in Figure 1. 
Figure 1 Study Design Flow Chart 
 
For non-commercial use only




Protocol SHP634-402 
 
 
 
(can occur at baseline visit as long as complete prior to assessments). 
c Vitals signs include: blood pressure, heart rate, body temperature, and respiration rate. 
d Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
calcium, phosphate, magnesium, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and alkaline phosphatase (ALP). 
e Pregnancy tests for females of childbearing potential. 
f FSH level required for newly menopausal women. 
g Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any subject with 
newly developed PTH-specific antibodies at the end of treatment visit may require follow up. This will be 
discussed as necessary by the principle investigator (PI) and medical monitor on a case-by-case basis. 
h Bone turnover markers include, but are not limited to, the following: serum carboxy-terminal 4 telopeptide of 
type I collagen (s-CTX), procollagen type I amino-terminal propeptide (P1NP), osteocalcin, bone specific 
alkaline phosphatase (BSAP), tartrate-resistant acid phosphate-5b (TRAP-5b), sclerostin. 
i 24-hour urine collection includes urine calcium, creatinine, phosphate, magnesium and sodium analyses. Urine 
volume will be recorded. The 24-hour urine collections should generally be performed by the subject within 2 
weeks prior to or within 2 days follow a study visit. These 24-hour urine collections may be analyzed in a local 
laboratory. To the greatest extent possible, the same laboratory should analyze the 24-hour urine collections 
throughout the study. Results from the last 24-hour urine collection obtained in Columbia protocol AAAE0544 
will be used as the baseline assessment in this study. At the beginning of the study, the investigator should 
recommend an individualized target dietary (non-supplement) calcium intake for each subject to ingest 
consistently throughout the study on 24-hour urine collection days. When collecting 24-hour urine specimens 
subjects should be instructed to take their currently prescribed calcium, vitamin D (both parent and active) and 
rhPTH(1-84) doses. 
j This optional assessment may be performed up to 3 times during the study. 
k The investigator must review responses to the HADS before the subject leaves the site and take any appropriate 
action that is clinically indicated based on the responses. 
 
l Subjects will enter their actual doses of calcium taken for 14 days prior to each visit, following the baseline 
visit, in a home diary. 
2.3 
Determination of Sample Size 
Approximately 50 subjects are anticipated to be enrolled. No formal sample size calculation 
was performed. 


Protocol SHP634-402 
 
 
 
3. 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objectives 
• To evaluate albumin-corrected serum calcium (ACSC) while on rhPTH(1-84) 
treatment 
3.1.2 
Secondary Objectives 
• To evaluate the proportion of subjects who achieve ACSC values above, below, or in 
the range of 7.5mg/dL to ULN 
• To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) 
treatment 
• To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) 
treatment 
• To evaluate patient reported-outcomes assessment including symptoms and impact of 
hypoparathyroidism (HPT-SD), fatigue (FACIT-Fatigue), cognitive function (FACT-
Cog), anxiety and depression (HADS) and health-related quality-of-life (SF-36 v1)  
associated with long-term rhPTH(1-84) treatment 
• To evaluate the skeletal actions of rhPTH(1-84): bone turnover markers, architecture, 
and histology (biopsy) 
3.2 
Study Endpoints 
3.2.1 
Primary Efficacy Endpoint: 
• Change in ACSC at Month 6, 12, 18, 24, 30, 36, 42, 48 (Baseline (402) as defined in 
Section 4) 
3.2.2 
Secondary Efficacy Endpoints: 
• ACSC value above, below, or in the range of 7.5mg/dL to upper limit of normal (ULN) 
at Month 6, 12, 18, 24, 30, 36, 42, 48 
• Change in urinary calcium and serum phosphate at Month 6, 12, 18, 24, 30, 36, 42, 48 
• Change in calcium and active vitamin D supplement doses at Month 6, 12, 18, 24, 30, 
36, 42, 48 
• Change in HPT symptoms (as measured by the HPT-SD) at Month 6, 12, 18, 24, 30, 36, 
42, 48 
• Change in Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) 
assessment (Version 3) at Month 6, 12, 18, 24, 30, 36, 42, 48 
• Change in Functional Assessment of Chronic Illness Therapy (FACIT) (Fatigue Scale 
(Version 4)) at Month 6, 12, 18, 24, 30, 36, 42, 48 
• Change in Hospital Anxiety and Depression Scale (HADS) at Month 6, 12, 18, 24, 30, 
36, 42, 48 




Protocol SHP634-402 
 
 
 
4. 
GENERAL CONSIDERATIONS 
No formal statistical testing will be conducted for this study. 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 as 
whole numbers. Ninety-five percent (95%) confidence intervals will be presented, where 
specified. 
Baseline (402) is defined as the last available pre-dose value in SHP634-402. 
Baseline (rhPTH) is defined as the last assessment value prior to the start of rhPTH(I-84) as 
determined from subject’s medical records obtained from data collected retrospectively from 
the core study (AAAE0544). 
For primary and selected secondary endpoints (specified in Section 11), the analysis will be 
performed with Baseline (402) as well as Baseline (rhPTH). For the analysis using Baseline 
(rhPTH), the retrospective data and data from prospective portion of SHP634-402 study will be 
combined. 
End of treatment (EOT), defined as the last determination of response during the treatment 
period (from the date of first dose to the date of last dose + 1 day), will be analyzed in addition 
to the scheduled visits.  
All summaries will be presented for rhPTH(1-84) only, unless otherwise specified. 
4.1 
Visit Window 
Visits will be summarized based on the analysis visit windows as specified in Table 2. Since 
visit windows are being applied, month number instead of visit number will be used in the 
analysis presentations. 
Table 2 Analysis Visit Window 
For data using baseline (402), the analysis windows will be mapped as follows:  
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1 
<=1 
Month 6 
183 
[153, 213], and ≤last dose day + 1 
Month 12 
365 
[335, 395], and ≤last dose day + 1 
Month 18 
548 
[518, 578], and ≤last dose day + 1 
Month 24 
730 
[700, 760], and ≤last dose day + 1 
Month 30 
913 
[883, 943], and ≤last dose day + 1 
Month 36 
1095 
[1065, 1125], and ≤last dose day + 1 
Month 42 
1278 
[1248, 1308], and ≤last dose day + 1 
Month 48 
1460 
[1430, 1490], and ≤last dose day + 1 


Protocol SHP634-402 
 
 
 
* The study day in Baseline (402) visit window is calculated from the date of first dose of 
investigational product in SHP634-402. 
For data using baseline (rhPTH), the analysis windows will be mapped as follows:  
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1 
<=1 
Month 6 
183 
(1, 274], and ≤last dose day + 1 
Month 12 
365 
[275, 456], and ≤last dose day + 1 
Month 18 
548 
[457, 639], and ≤last dose day + 1 
Month 24 
730 
[640, 821], and ≤last dose day + 1 
… 
… 
… 
Month xx (rhPTH) 
 
round(xx/12*365) 
[target day of last analysis visit+92, target 
day+91) ,] , and ≤last dose day + 1 
* The study day in Baseline (rhPTH) visit window is calculated from the date of first dose of 
of rhPTH from data collected retrospectively. Both retrospective data and data from SHP634-
402 will be mapped into the analysis windows for Baseline (rhPTH). 
The analysis visit will be mapped up to Month 48 for Baseline (402), as only concomitant 
medication and adverse events are collected at Month 49 (Follow-up visit). If there are more 
than one non-missing observations in the same analysis visit window, the following selection 
rules will be applied sequentially to determine which observation will be used for analysis: 
• The observation that is closer to the target day will be used; 
• If observations are equal-distance in days from the target day, the later one based on 
measurement date and time will be used. 
4.2 
Handling of Dropouts or Missing Data 
For all variables, only the observed data from the subjects will be used in the statistical analyses, 
i.e., there is no plan to estimate (impute) missing data, unless otherwise specified. 
4.3 
Interim Analyses and Data Monitoring 
A retrospective analysis of historical data captured from the medical records of subjects (e.g., 
since the start of rhPTH(1-84) treatment) was conducted separately, with details described in 
the separate Interim Analysis SAP Final 1.2, dated 12 January 2017.  
There will be no Data Monitoring Committee for this unblinded exploratory study, however 
results of the prospective data portion of the study will be analyzed as necessary for safety 
monitoring and publication purposes. 


Protocol SHP634-402 
 
 
 
5. 
SUBJECT POPULATION SETS 
5.1 
Enrolled Subjects 
Enrolled Subjects consist of all subjects who have signed informed consent. 
5.2 
Safety Population  
The Safety Population will be used for all analysis in this study and consists of all enrolled 
subjects who receive at least 1 dose of rhPTH(1-84) regardless of study (SHP634-402 or 
AAAE0544 core study).  


Protocol SHP634-402 
 
 
 
6. 
SUBJECT DISPOSITION 
The number of subjects included in Enrolled Subjects and Safety Population will be 
summarized.  
The number and percentage of subjects who completed and early terminated during the study 
will be presented. Reasons for early termination from the study as recorded on study completion 
page of the electronic case report form (eCRF) will be summarized (number and percentage). 
Subject disposition, subjects completing and prematurely discontinued during the study, and 
study analysis sets will be listed by subject for Enrolled Subjects. 


Protocol SHP634-402 
 
 
 
7. 
PROTOCOL DEVIATIONS 
Subjects with at least 1 protocol deviation for each deviation category will be summarized and 
listed. Protocol deviations will be identified programmatically as well as based on protocol 
deviations collected by the study monitors in protocol deviation log. 
 
After the last subject exits the trial and prior to database lock, protocol deviations will be 
reviewed and summarized by category. The protocol deviation categories may include, but not 
limited to the following: 
• ICF Process/Timing 
• Investigator Record Keeping Source Documents 
• Missing Endpoint Assessments 
• Study Procedures/Assessments 
• Study Treatment Admin/Dispense 
• Visit Scheduling 
• Use of Prohibited Concomitant Medications 
All protocol deviations will be listed. 


Protocol SHP634-402 
 
 
 
8. 
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented for the 
Safety Population. 
The following demographic characteristics will be summarized and listed: age (years), age 
category (18-44, 45-64, >=65), sex, ethnicity, race, height (cm), weight (kg), body mass index 
(BMI) (kg/m^2), prescribed vitamin D supplement (as continuous parameter and by categories 
of low dose 0-0.25 μg/day, medium dose >0.25-0.5 μg/day, high dose >0.5 μg/day), prescribed 
calcium supplement (as continuous parameter and by categories of 0-2000 mg/day, >2000 
mg/day), study drug dose at baseline (mcg), duration of HPT (as continuous parameter and by 
categories of < =5 years, >5-10 years, > 10 years) . Duration of HPT is calculated as (date of 
informed consent - date of first diagnosis of HPT) + 1 where date of first diagnosis of HPT is 
captured in the Medical History CRF page. 
Medical and surgical history will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA), Version 19.0. The history will be summarized by system organ class (SOC) and 
preferred term (PT) within system organ class for the Safety Population, with both SOC and PT 
sorted alphabetically. Medical history will be listed for the Safety Population. 
 
 
 


Protocol SHP634-402 
 
 
 
9. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
9.1 
Exposure to Investigational product  
Exposure for the Safety Population during SHP634-402 will be summarized in terms of 
treatment duration in months, which is calculated as [(date of last dose - date of first dose in 
SHP634-402) + 1]/ 30.4375. The extent of exposure during SHP634-402 will also be 
categorized into months (<=1, >1-6, >6-12, >12-18, >18-24, >24-30, >30-36, >36-42, >42-48, 
>48 months) and tabulated. In addition, cumulative exposure to rhPTH(1-84) in years will also 
be calculated from the date of first rhPTH(1-84) as determined from subject’s medical records 
and summarized categorically (<=1, >1-6, >6-12, >12 years). Descriptive statistics will be 
presented for exposure of study drug. 
Exposure information will be listed for each subject. 


Protocol SHP634-402 
 
 
 
10. 
PRIOR AND CONCOMITANT MEDICATION  
Version Jun 2016 of the World Health Organization Drug Dictionary (WHODrug) will be used 
to classify prior and concomitant medications by therapeutic class.  
Prior medication is defined as any medication with the start date prior to the date of the first 
dose of investigational product in prospective portion of SHP634-402.  
For the prospective portion of the study, concomitant medications refers to all medicines taken 
between the dates of the first dose of rhPTH(1-84) in study SHP634-402 and the end of the 
follow-up period in the SHP634-402 study, inclusive. All available active vitamin D and 
calcium supplement doses from the beginning of rhPTH(1-84) will be recorded. Concomitant 
medication information must be recorded on the appropriate eCRF page. 
Partial date imputation for medications is described in Section 15.3. 
Both prior and concomitant medication usage will be summarized by the number and proportion 
of subjects receiving each medication within each level of therapeutic class and preferred term. 
Medications can be counted both as prior and concomitant medication. Multiple medication 
usage by a subject in the same each level of therapeutic class and preferred term will be counted 
only once. Therapeutic classes will be sorted alphabetically while medication preferred terms 
will be sorted by decreased frequency within therapeutic class. 
All prior and concomitant medications and medical/surgical procedures will be listed. 


Protocol SHP634-402 
 
 
 
11. 
EFFICACY ANALYSES 
The EOT value will be mapped to the visit windows as specified in Table 2 and summarized 
under the mapped visit. The EOT will also be included as a separate time point in the summary. 
No formal statistical hypothesis test will be conducted. The efficacy analysis will be performed 
using the Safety Population. For the analysis using Baseline (rhPTH), the retrospective data and 
data from prospective portion of SHP634-402 study will be combined. 
 
11.1 
Primary Efficacy Endpoint(s) and Analysis  
The primary efficacy endpoint is defined as change in ACSC concentration (mmol/L) over time 
at each visit and EOT. ACSC concentration in SI unit (mmol/L) will be derived using the 
formula at the end of this section for retrospective data. For data from SHP634-402 study, 
ACSC concentration (mmol/L) derived by PPD global central laboratory will be used in the 
analysis.  
The baseline serum calcium concentration is the final measurement taken prior to initiating 
investigational product in SHP634-402 (Baseline (402)). The analysis will be repeated using 
Baseline (rhPTH) for combined data from retrospective data and data from prospective portion 
of SHP634-402 study. 95% CI will be provided for the means. 
The observed values, changes and percentage changes from baseline (both Baseline (402) and 
Baseline (rhPTH)) in ACSC (mmol/L) and total serum calcium (mmol/L) will be summarized 
by visit and at EOT. The ACSC and total serum calcium over time will also be evaluated 
graphically using line graph. By-subject listings will be provided. The summary, figure and 
listing of ACSC will be repeated in conventional unit (mg/dL). 
Albumin-corrected Serum Calcium in SI unit (mmol/L) = Total Serum Calcium (mmol/L) + 
0.02 * [40 g/L - Albumin (g/L)], or  
Albumin-corrected Serum Calcium in conventional unit (mg/dL) = Total Calcium (mg/dL) + 
0.8 * [4 g/dL – Albumin (g/dL)]. 
11.2 
Secondary Efficacy Endpoint(s) and Analysis  
Secondary efficacy endpoints will be analyzed using Baseline (402). The same analysis will be 
performed for selected secondary endpoints where data are available using Baseline (rhPTH)  
for combined data from retrospective data and data from prospective portion of SHP634-402 
study. 95% CI will be provided for the means. 
11.2.1 
Albumin-corrected serum calcium value above, below, or in the range of 
1.875mmol/L-ULN 
The number and percentage of subjects with ACSC above, below, or in the range of 
1.875mmol/L -ULN at each study visit will be tabulated. This analysis will be performed using 
Baseline (402) for data from SHP634-402 study and Baseline (rhPTH) for combined data from 


Protocol SHP634-402 
 
 
 
retrospective data and data from prospective portion of SHP634-402 study. For retrospective 
data, the ULN of ACSC is derived from the ULN of calcium normal range. For data from 
SHP634-402 study, the ULN of ACSC is provided by PPD global central lab. 
11.2.2 
Change in Urinary Calcium (mmol/day) and Serum Phosphate (mmol/L) 
The observed values, changes and percentage change from baseline (both Baseline (402) and 
Baseline (rhPTH)) in urinary calcium in SI unit (mmol/day) and serum phosphate in SI unit 
(mmol/L) will be summarized by visit and at EOT, and evaluated graphically using line graph. 
This analysis will be performed using Baseline (402) for data from SHP634-402 study and 
Baseline (rhPTH) for combined data from retrospective data and data from prospective portion 
of SHP634-402 study. Results from the last 24-hour urine collection obtained in Columbia 
protocol AAAE0544 will be used as the Baseline (402). By-subject listings will be provided. 
The summary and figure of urinary calcium and serum phosphate will be repeated in 
conventional unit (mg/day for urinary calcium  and mg/dL for serum phosphate). 
11.2.3 
Change in Calcium and Active Vitamin D Supplement Doses  
Efficacy endpoints based on the calcium and active vitamin D supplement will be derived using 
both the investigator prescribed data and subject diary data. The prescribed data will be 
collected in the Concomitant Medications CRF page and subject diary data will be collected in 
Supplemental Calcium and Active Vitamin D Dosing CRF page. Any medications that are taken 
in addition to the prescribed dose of calcium and active vitamin D supplement, diary data will 
be recorded in Supplemental Calcium and Active Vitamin D Dosing CRF page. Analysis based 
on the investigator prescribed data will be primary. Analysis based on the subject diary data 
will be considered as supportive.  
The daily dose of calcium and active vitamin D supplement based on investigator prescription 
will be determined by using the latest prescribed dose prior to the target study day for each 
analysis visit. If no prescribed supplemental was taken on that analysis visit, the prescribed 
daily dose will be imputed as 0. The prescribed supplemental medication dose at the EOT for 
subjects who complete the treatment or Early Termination will be excluded from the derivation 
of the post-baseline prescribed dose. 
The average daily dose of calcium and active vitamin D supplement based on subject diaries 
will be calculated as the average daily dose of a 14-day interval, i.e. total dose of the 14-day 
interval divided by 14 days. The 14-day interval for each analysis visit includes the dose 
reported during the 14 days on or prior to the assessment date of ACSC. However, this 14-day 
interval should not include or go beyond the assessment date of ACSC for the previous analysis 
visit. Diary data after the last dose date of study drug will be excluded from the derivation. A 
missing daily dose of calcium and active vitamin D supplement from subject diaries will be 
imputed as 0 on that date, as the diary data is collected only if a subject took additional 
calcium/vitamin D than prescribed dose.  
The observed values, changes and percentage change from baseline in calcium and active 
vitamin D supplement will be summarized by visit and at EOT for prescribed daily dose, diary 
daily dose and total daily dose using Baseline (402), and for prescribed daily dose and total 


Protocol SHP634-402 
 
 
 
daily dose using Baseline (rhPTH) too. The daily dose of calcium and active vitamin D 
supplement will be the sum of the prescribed daily dose of all calcium and all active vitamin D 
supplement medications respectively. In addition, the similar analysis will be repeated for the 
elemental calcium daily supplement medications. Change in calcium and active vitamin D 
supplement doses will be evaluated graphically using line graph. In addition, the frequency of 
dose change (0, 1-2, 3-5…) in prescribed calcium and active vitamin D supplement due to 
symptom of low calcium will be presented. By-subject listings will be provided. 
11.2.4 
Change in HPT symptoms (as measured by the Hypoparathyroidism Symptom 
Diary (HPT-SD)) 
The HPT-SD is a 13-item subject-reported outcomes instrument that insists of a symptom 
subscale (items 1-7, score range 0–4 for item 2-7 and score range 0-10 for item 1), anxiety (item 
8, score range 0–4), sadness and depression (item 9, score range 0–4) and impact subscale 
(items 10-13, score range 0–2). The items 2-9 are reported in a 5-point scale:  None (0), Mild 
(1), Moderate (2), Severe (3), Very severe (4). The item 10-13 are reported in a 3-point scale: 
Not at all (0), Somewhat (1), Very much (2). The 24-hour recall version of the instrument will 
be used in this study. The symptom subscale scores will be calculated as average score of the 
items 1-7 and the impact subscale scores will be calculated as average score of the items 1-13. 
5 out of 7 symptom-focused items must be non-missing to compute the HPT-SD symptom 
score. Subjects must have non-missing responses to all 4 impact items to compute impact-
focused subscales score.  Individual item score will be examined as well as the scores of 
symptoms and impact subscales. The HPT-SD was only collected within the SHP634-402 
study.  
The observed values, changes and percentage change from baseline (Baseline (402)) in 
symptom subscale (item 1-7), anxiety item (item 8), sadness or depression item (item 9) and 
impact subscale (items 10-13) will be summarized by visit and at EOT. By-subject listings will 
be provided. 
11.2.5 
Change in FACT-Cog (Functional Assessment of Cancer Therapy - Cognitive 
Function) Assessment (Version 3) 
The FACT-Cog assessment is a 37-item tool (Cella 1997) with each item rated on a 5-point 
scale ranging from 0 to 4. It includes 4 subscales: perceived cognitive impairments (20 items, 
Item #1 - #20, score range 0–72), impact of perceived cognitive impairments on quality of life 
(4 items, Item #34 – #37, score range 0–16), comments from others (4 items, Item #21 – #24, 
score range 0–16) and perceived cognitive ability (9 items, Item #25 - #33 score range 0–28). 
The item response of each question will be converted as described below to obtain an item 
score, except for perceived cognitive ability subscale. The subscale score is computed by 
multiplying the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered. The higher the score, the better the quality of life. FACT-Cog 
was only collected in the SHP634-402 study. 
Perceived cognitive impairments subscale (CogPCI): 


Protocol SHP634-402 
 
 
 
The 18 items (item #1 - #18) from a total of 20 items in perceived cognitive impairments 
subscale are used, except for 2 questions, item #19 ‘I have trouble keeping track of what I am 
doing if am interrupted’ and item #20 ‘I have trouble shifting back and forth between different 
activities that require thinking’. Compute the subscale score for the perceived cognitive 
impairments as follows: 
CogPCI Subscale Score= [sum of (18-item response)]*18/ (#of items answered). 
Impact on quality of life subscale (CogQOL): 
The 4 items (Item #34 – #37) in impact on quality of life subscale are used. Compute the 
subscale score for the impact on quality of life as follows: 
CogQOL Subscale Score = [sum of (4-item response)]*4/ (#of items answered). 
Comments from others subscale (CogOth): 
The 4 items (Item #21 – #24) in comments from others subscale are used. Compute the subscale 
score for the comments from others as follows: 
CogOth Subscale Score = [sum of (4-item response)]*4/ (#of items answered) 
Perceived cognitive ability subscale (CogPCA): 
The 7 items (Item #25 - #31) from a total of 9 items in perceived cognitive ability subscale are 
used, except for 2 questions, item #32 ‘I am able to shift back and forth between two activities 
that require thinking‘ and item #33 ‘I am able to keep track of what I am doing, even if I am 
interrupted’. Compute the subscale score for the perceived cognitive ability as follows: 
CogPCA Subscale Score = [sum of (7-item response)]*7/ (#of items answered). 
The observed values, changes and percentage changes from baseline (Baseline (402)) in 4 
subscale scores listed above will be summarized by visit and at EOT. By-subject listings will 
be provided. 
11.2.6 
Change in FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue 
Scale (Version 4) 
FACIT fatigue questionnaire contains 13 fatigue-related questions (Cella 1997). The responses 
to the 13 items on the FACIT fatigue questionnaire are each measured on a 4-point Likert scale 
(0-4). Thus, the total score ranges from 0 to 52. High scores represent less fatigue and better 
quality of life. 
For 2 questions, item #7 ‘I have energy’ and item #8 ‘I am able to do my usual activities’, the 
item response from questionnaire will be used as item score and   no conversion is needed. For 
the rest of 11 questions, item score is calculated as 4- item response. Compute the fatigue total 
score as follows: 


Protocol SHP634-402 
 
 
 
Fatigue Total Score = [sum of (item scores)]*13/ (#of items answered). 
The observed values, changes and percentage changes from baseline (Baseline (402)) in fatigue 
total score will be summarized by visit and at EOT. By-subject listings will be provided. FACIT 
fatigue scale was only collected in the SHP634-402 study. 
11.2.7 
Change in HADS (Hospital Anxiety and Depression Scale) Assessment 
The HADS is a 14-item scale that generates ordinal data (Zigmond and Snaith 1983). Seven of 
the items relate to anxiety (Item # 1, 3, 5, 7, 9, 11 and13) and seven relate to depression (Item 
# 2, 4, 6, 8, 10, 12 and 14). The scale is designed to avoid reliance on aspects of conditions that 
are also common somatic symptoms of illness. Each item on the questionnaire is scored from 
0-3 and anxiety or depression scale scores are calculated from the sum of 7 items in each scale, 
therefore a person can score between 0 and 21 for either anxiety or depression. Data returned 
from the HADS is ordinal. HADS was only collected in the SHP634-402 study. 
The observed values, changes and percentage changes from baseline (Baseline (402)) in 
depression total score and anxiety total score will be summarized by visit and at EOT. By-
subject listings will be provided. 
11.2.8 
Change in Health-Related Quality-of-Life Measured with RAND SF-36 Survey 
Over Time (Version 1) 
The RAND (Research and Development) SF-36 consists of 8 scaled scores, which are the 
weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 
scale on the assumption that each question carries equal weight; the lower the score the more 
disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum 
disability and a score of 100 is equivalent to no disability. The eight sections included in the 
RAND SF-36 assessment are vitality, physical functioning, bodily pain, general health 
perceptions, physical role functioning, emotional role functioning, social role functioning, and 
mental health. The RAND SF-36 will be scored using the QualityMetric Health Outcomes™ 
Scoring Software. 
The observed values, changes and percentage changes from baseline (both Baseline (402) and 
Baseline (rhPTH)) in 8 scale scores will be summarized by visit and at EOT. By-subject listings 
will be provided. This analysis will be performed using Baseline (402) for data from SHP634-
402 study and Baseline (rhPTH) for combined data from retrospective data and data from 
prospective portion of SHP634-402 study. 
11.2.9 
Change in Bone Turnover Markers  
The observed values, changes and percentage change from baseline (both Baseline (402) and 
Baseline (rhPTH)) in bone turnover biomarkers (including but not limited to s-CTX, P1NP, 
osteocalcin, BSAP, TRAP-5b, sclerostin) will be summarized by visit and at EOT. By-subject 
listings will be provided. Bone turnover markers will be analyzed using Baseline (402) for data 
from SHP634-402 study and Baseline (rhPTH) for combined data from retrospective data and 
data from prospective portion of SHP634-402 study. 


Protocol SHP634-402 
 
 
 
11.2.10 Change in Bone Mineral Density 
The observed values, changes and percentage changes from baseline (both Baseline (402) and 
Baseline (rhPTH)) in Dual X-ray Absorptiometry (DXA) bone density results and High 
Resolution peripheral Quantitative Central Tomography (HRpQCT) results will be summarized 
by visit and at EOT. For HRpQCT results, bone mineral density from different locations (radius 
or tibia) will be summarized separately. By-subject listings will be provided. Bone architecture 
will be analyzed using Baseline (402) for data from SHP634-402 study and Baseline (rhPTH) 
for combined data from retrospective data and data from prospective portion of SHP634-402 
study. 
11.2.11  Change in Bone Histology (Biopsy)  
An optional transiliac bone biopsy will be performed for willing subjects, at the discretion of 
the investigator a maximum of three time during the duration of the study. The observed values, 
changes and percentage changes from baseline (both Baseline (402) and Baseline (rhPTH))  in 
bone biopsy results (including but not limited to cancellous bone volume, cortical width, 
cancellous osteoid surface, cancellous osteoid thickness, cancellous eroded surface, cancellous 
mineralizing surface, cancellous mineral apposition rate, bone formation rate, and adjusted 
apposition rate) will be summarized by visit and at EOT. By-subject listings will be provided. 
Bone histology will be analyzed using Baseline (402) for data from SHP634-402 study and 
Baseline (rhPTH) for combined data from retrospective data and data from prospective portion 
of SHP634-402 study. If there is no sufficient data to summarize the change, the bone histology 
data will be listed only. 
11.3 
Exploratory Efficacy Endpoint(s) and Analyses  
11.3.1 
 
11.3.2 
 
11.3.3 
 


Protocol SHP634-402 
 
 
 
 


Protocol SHP634-402 
 
 
 
12. 
SAFETY ANALYSES 
12.1 
Adverse Events  
Adverse events will be coded using Version 19.0 of MedDRA.  
Treatment emergent adverse events (TEAEs) are defined as AEs whose onset occurs, severity 
worsens, or intensity increases after receiving the first dose of rhPTH(I-84) in SHP634-402 
study drug and <= 30 days after last dose of study drug. If any AE records contain only partial 
dates, these will be handled by imputation as described in Section 15.3. 
An overall summary of the number of subjects with TEAEs will be presented, including the 
number of events (except for summaries by highest category), number and percentage of 
subjects with any TEAEs, treatment-related TEAEs, TEAEs leading to withdrawal, severity 
of TEAEs (any and highest category), serious TEAE, relationship of serious TEAE to 
treatment, severity of serious TEAE, and TEAEs leading to death. 
 
The number of events (except for summaries by highest category), number and percentage of 
subjects reporting TEAEs will be tabulated by system organ class (SOC) and preferred term; 
by SOC, preferred term, and maximum severity; by SOC, preferred term, and relationship. 
TEAE related to investigational product, TEAE leading to withdrawal, SAEs, and deaths will 
be similarly 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. 
Listings will be provided for all AE, AEs related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths. Adverse event listings will provide the verbatim term as well 
as the SOC and PT for each recorded event. 
12.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in both SI and conventional units for 24-
hour urine parameters and in SI unit for other parameters) and changes from baseline will be 
reported by visit and at EOT for quantitative parameters. The EOT value will be mapped to the 
visit windows as specified in Table 2  and summarized under the mapped visit. The EOT values 
will also be included as a separate time point in the summary. Change will only be reported if 
both baseline and the corresponding post-baseline time point are available. Additionally, shift 
tables will be presented, summarizing cross tabulations of low, normal, and high based on the 
parameter normal range, from baseline to each post-baseline visit and EOT. Percentages for 
shift tables will be based on the number of subjects with both baseline and post-baseline values 
at each visit. All the laboratory data below will be listed by parameter, subject and visit. Only 
scheduled laboratory parameters will be included in the laboratory summaries. 
The following clinical laboratory parameters will be summarized, except for the parameters that 
are separately summarized in efficacy analysis:  


Protocol SHP634-402 
 
 
 
Hematology 
Hemoglobin, Platelet count, Hematocrit, White blood cell (WBC) 
count, Red blood cells (RBC), WBC differentials 
Clinical chemistry 
Sodium, Phosphate, Beta-human chorionic gonadotropin (β-HCG) 
(baseline only), Potassium, Magnesium, Follicle-stimulating hormone 
(FSH) (females only at baseline), Blood urea nitrogen (BUN), Total 
CO2 (Bicarbonate), Creatinine, Albumin, Calcium, Aspartate 
transaminase (AST), Chloride, Alanine transaminase (ALT), Thyroid 
stimulating hormone (TSH) (baseline only), Alkaline phosphatase 
(ALP), 25-hydroxyvitamin D and 1,25-dihydoxyvitamin D levels, 
eGFR 
Urinalysis 
pH, Blooda, Nitrites, Glucose, Ketones, Leukocyte esterase, Protein, 
Bilirubin, Specific gravity 
aMicroscopic examination will be conducted if protein, leukocyte esterase, and/or blood is/are detected during 
urinalysis. At a minimum, the microscopic examination will consist of red blood cells, white blood cells, casts, 
and bacteria. 
24-Hour Urine         Calcium, Sodium, Creatinine, Total volume, Phosphate, Magnesium, 
Creatinine clearance 
eGFR 
eGFR (mL/min/1.73m2) will be calculated from serum creatinine using the equation that the 
CKD-Epidemiology Collaboration group (CKD-EPI) developed and validated in 2009, which 
is called the CKD-EPI equation (Levey, 2009). The equation is as follows:  
c
b 
 
993
.0
1)
 
/k,
max(S
 
 
1)
 
/k,
S 
min(
 
141
eGFR
Age
-1 209
Cr
a
Cr
×
×
×
×
×
=
 
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is -0.329 for 
females and -0.411 for males, min indicates the minimum of SCr/k or 1, and max indicates the 
maximum of SCr/k or 1, b is 1.018 for females and 1 for males, c is 1.159 for blacks and 1 for 
others. 
Creatinine clearance 
Creatinine clearance (mL/min) = [Urine creatinine concentration (mg/dl) * Urine flow rate 
(L/day)] / Serum creatinine concentration (mg/dl)*1000/1440 (min/day). Then creatinine 
clearance will be normalized to a body surface area as CrCl * 1.73/BSA. The subject’s BSA 
can be calculated with Dubois formula: 0.20247 × height (m) 0.725 × weight (kg)0.425. 
Potentially Clinically Important Laboratory Test 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 3. The number and percentage of subjects with post-
baseline PCI values will be tabulated. The percentages will be calculated relative to the number 


Protocol SHP634-402 
 
 
 
of subjects with at least 1 post-baseline assessment. The numerator is the total number of 
subjects with at least 1 post-baseline PCI value.  
Table 3 Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Biochemistry 
Albumin 
g/L 
<=20 
>=90 
Alkaline Phosphatase 
U/L 
NA 
>2*ULN 
ALT 
U/L 
NA 
>3*ULN 
AST 
U/L 
NA 
>3*ULN 
BUN 
mmol/L 
NA 
>=10.7 
Calcium (total) 
mmol/L 
<=2.1 
>=3.0 
Chloride 
mmol/L 
<=80 
>=125 
Creatinine 
μmol/L 
NA 
>=177 
Phosphate 
mmol/L 
NA 
>=2 
Potassium 
mmol/L 
<=2.5 
>=6.5 
Sodium 
mmol/L 
<=120 
>=165 
Hematology 
 
 
 
Hematocrit 
 
L/L 
<=0.37 (males) 
<=0.32 (females) 
>0.54 (males) 
NA (females) 
Hemoglobin 
 
g/L 
<=115 (males) 
<=95 (females) 
NA 
Platelets 
10^9/L 
<=75  
>=700 
RBC 
 
10^12/L 
<=2.5 (males) 
<=2.0 (females) 
NA 
WBC 
10^9/L 
<=2.8  
>=16.0 
24-Hour urine 
 
 
 
Urine calcium 
mmol/day 
NA 
>7.5 for men 
>6.25 for women 
Creatinine clearance 
ml/min 
<=60 
NA 
 
12.3 
Vital Signs 
Descriptive statistics for vital signs (blood pressure, heart rate, body temperature, and 
respiration rate) and their changes from baseline at each post-baseline visit and at EOT will be 
presented. The EOT value will be mapped to the visit windows as specified in Table 2  and 
summarized under the mapped visit. The EOT values will also be included as a separate time 
point in the summary. 
12.4 
Physical Examination 
Physical examination results will be listed. 


Protocol SHP634-402 
 
 
 
12.5 
Serum and Urine Pregnancy 
Categorical urinalysis findings and urine pregnancy results will be listed only. 
12.6 
PTH Antibodies 
The number and percentage of subjects classified as having antibodies to PTH at each visit and 
at EOT will be tabulated and listed. The EOT value will be mapped to the visit windows as 
specified in Table 2  and summarized under the mapped visit. The EOT values will also be 
included as a separate time point in the summary. 
 


Protocol SHP634-402 
 
 
 
13. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 of SAS or above on a suitably 
qualified environment. 




Protocol SHP634-402 
 
 
 
15. 
DATA HANDLING CONVENTIONS 
15.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum and 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 as whole numbers.  
For rules on rounding and decimal presentation of these statistics, along with the rules for 
presenting certain derived values, see 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. 
8. 
Derived questionnaire scores, and other similar efficacy parameters recorded as 
integers, should be rounded to 1 decimal place for reporting. 
9. 
Averaged laboratory results e.g. Diastolic/Systolic Blood Pressure and Pulse (when 
taken in triplicate) should be rounded to 1 decimal place for reporting. 
 
15.2 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end of study assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics. 
However, all post-baseline assessments will be used for PCI value determination and all 
assessments will be presented in the data listings.  
15.3 
Missing Date Information 
Complete dates will be imputed from partial dates of adverse events and medications solely for 
the purpose of defining treatment emergence for adverse events and prior/concomitant status 
for medications for data from SHP634-402 study. Dates will be defined using the hierarchy of 
derivations below. 
Adverse event or medication start date: 


Protocol SHP634-402 
 
 
 
1. If year and month are known, and it is the month and year of the first dose date, use the first 
dose date. 
2. If year and month are known, and it is the month and year of the informed consent, use the 
informed consent date. 
3. If year and month are known, and the month is not the month and year of the first dose or 
informed consent, use the first day of the month. 
4. If only year is known, and it is previous to the year of the informed consent, use June 30th 
of that year. 
5. If only year is known, and it is the year of the informed consent, use the informed consent 
date. 
6. If only year is known, and it is after year of the informed consent, use December 31st of that 
year. 
7. Should any of the previous start dates created be after a complete stop date provided, use the 
stop date instead of the date that would otherwise be created. 
8. Otherwise, if start date is unknown leave as missing. 
Medication stop date: 
1. If year and month are known and study medication stopped during that month and year, use 
the stop date of study medication. 
2. If year and month are known and informed consent was provided during that month and year, 
use the date of informed consent. 
3. If year and month are known and study medication stopped after the date of informed consent 
and not in the month that medication stopped, use the last day of the month. 
4. If year and month are known and are prior to the month of informed consent, use the first 
day of the month. 
5. If only year is known and study medication stopped during that year, use the stop date of 
study medication. 
6. If only year is known and study medication stopped after that year, use December 31stof that 
year. 
7. If only year is known and study medication stopped prior to that year, use the first day of the 
year. 
8. Should any of the previous stop dates created be before a start date, either a complete date or 
an imputed one, use the (imputed) start date instead of the date that would otherwise be created. 


Protocol SHP634-402 
 
 
 
9. Otherwise, if stop date is unknown leave as missing.  
For retrospective data, the partial dates from clinical laboratory, RAND SF-36, bone mineral 
density, bone turnover biomarker and bone histology, the partial dates will be imputed as 
follows: If only year exist, then impute the missing month and date with ‘July-01’; if year and 
month exist, then impute the missing day with ‘15’. 
15.4 
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. 
15.5 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date 
of the first dose of investigational product, a causality of “Related” will be assigned. The 
imputed values for relationship to double-blind investigational product will be used for 
incidence summaries, while the actual values will be presented in data listings. 


Protocol SHP634-402 
 
 
 
16. 
REFERENCES 
Cella, D. 1997. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
measurement system. Evanston, IL: Center on Outcomes, Research and Education (CORE). 
Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., 3rd, Feldman, H. I., 
Kusek, J. W., Eggers, P., Van Lente, F., Greene, T., Coresh, J. C. I. N. N., Dec, P. C. a. I. M. 
& Author Reply, P. 2009. A new equation to estimate glomerular filtration rate. Annals of 
internal medicine, 150, 604-12. 
Zigmond, A. S. & Snaith, R. P. 1983. The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 67, 361-70. 

Prot_001.pdf: 
PROTOCOL: SHP634-402
TITLE:
A Phase 4, Open-Label, Single-Center Clinical Study of Extended use 
of rhPTH(1-84) in Hypoparathyroidism
DRUG:
rhPTH(1-84)
IND
076514
BLA:
125511
SPONSOR
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD
PROTOCOL 
HISTORY:
Protocol Amendment 1:  16 Aug 2017
Original Protocol: 27 May 2016
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 the express written 
consent of Shire.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 3
Protocol Amendment 1
SHP634-402 
16 Aug 2017
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The table and the summary below provide an overview of the changes from the previous version 
(dated 27 May 2016) to the current version of the protocol (Amendment 1).
Grammatical, typographical errors, and general formatting revisions are not identified.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
16 Aug 2017
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Revised the sponsor signatory from 
, MD to 
, MD.
Protocol Signature Page
Updated the telephone number for Product Quality Complaints.
Product Quality Complaints
Added a secondary objective and corresponding secondary efficacy endpoint 
to evaluate the proportion of subjects with albumin-corrected serum calcium
(ACSC) values above, below, or in the range of 7.5 mg/dL-upper limit of 
normal (ULN).
Synopsis, Section 2.2.2, 
Section 9.8.2
Provided examples of bone turnover markers that will be assessed.
Synopsis, Table 1, 
Section 9.8.2
Added 
 as an optional assessment to generate data to help 
understand the quality of bone in patients with hypoparathyroidism treated 
with rhPTH(1-84).
Synopsis, Table 1, Section 
7.1.1, Section 7.2.2.9, Section
9.8.3
Revised the hypoparathyroidism multisymptom questionnaire to the 
hypoparathyroidism symptom diary (HPT-SD) and clarified that the HPT-SD 
will be used to measure the symptoms of hypoparathyroidism.
Synopsis, Table 1, Section
2.2.2, Section 7.1, Section
7.2.2.2, Section 9.8.2
Clarified endpoints such that the endpoints can be measured in each subject.
Synopsis, Section 9.8.1, Section
9.8.2
Removed symptoms of hypoparathyroidism as a safety variable.
Synopsis, Section 9.9
Indicated that results of the prospective data portion of the study will be 
analyzed as necessary for safety monitoring and publication purposes.
Synopsis, Section 9.5
Clarified that historical data includes data derived from the medical records of 
subjects (since the start of rhPTH(1-84) treatment) who are from the core study 
(Protocol AAAE0544 at Columbia University Medical Center [HEXT: The 
Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton 
in Hypoparathyroidism] that can be data source verified.
Synopsis, Section 9.5, Section
9.10
Clarified that subjects will enter their actual doses of calcium taken 14 days 
prior to each visit, following the baseline visit, in a home diary
Table 1, Section 5.1.4.3, 
Section 7.1
Clarified prior treatment for the prospective portion of the study.
Section 5.1
Clarified that the investigator must review the responses to the HADS before 
the subject leaves the site. 
Table 1, Section 7.2.2.5
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
Protocol Amendment 1
SHP634-402 
16 Aug 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
16 Aug 2017
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Clarified that for the retrospective portion of the study, concomitant treatment 
refers to all treatment taken from 1 year prior to initiation of treatment with 
rhPTH(1 84) until enrollment in study SHP634-402.
For the prospective portion of the study, concomitant treatment refers to all 
treatment taken between the dates of the first dose of study SHP634-402 
rhPTH(1-84) and the end of the follow-up period in the SHP634-402 study, 
inclusive.
Section 5.1.1
Clarified that any medication that affects bone metabolism and any other 
investigational products are prohibited while on study SHP634-402 rhPTH(1-
84) treatment.
Section 5.1.3
Clarified that a courier service may be used to ship supplies to subjects in the 
event of drug expiries and may also be used to return expired and 
empty/unused investigational product.
Section 6.3.1, Section 6.5
Added white blood cell differentials to hematology parameters.
Section 7.2.3.2
Clarified that version 1.0 of the Short Form Health Survey-36 (SF-36) will be 
used for the retrospective portion of the study and version 2.0 of the SF-36 will 
be used for the prospective portion of the study. 
Section 7.2.2.6
Calcium was removed from the urinalysis.
Section 7.2.3.2
Clarified that baseline for selected endpoints will be defined as the subject’s 
baseline immediately prior to rhPTH(1-84) initiation where data are available. 
Section 9.8.2
Moved 24 hour urine creatinine, volume from Priority 2 to Priority 1.
Section 9.10
Removed electrocardiogram (ECG) parameters and bone histology and 
histomorphology from Priority 3.
Section 9.10
Added the 
 questionnaire as an appendix
Appendix 4
Minor edits for clarity and consistency throughout the document.
Global
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 6
Protocol Amendment 1
SHP634-402 
16 Aug 2017
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the 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:
Shire
Lexington, MA (USA)
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
Protocol Amendment 1
SHP634-402 
16 Aug 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULE ....................................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................21
1.1
Indication and Current Treatment Options...............................................................21
1.2
Product Background.................................................................................................22
1.2.1
Preclinical Information ..........................................................................................22
1.2.2
Clinical Information...............................................................................................23
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
2.2.1
Primary Objectives.................................................................................................24
2.2.2
Secondary Objectives.............................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................27
3.3
Sites and Regions .....................................................................................................27
3.4
Discussion of Study Design .....................................................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.3.1
Female Contraception............................................................................................29
4.3.2
Male Contraception................................................................................................29
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Subject Withdrawal Criteria ..................................................................................29
4.4.2
Reasons for Discontinuation..................................................................................29
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4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................30
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Treatment ........................................................................................................30
5.1.1
Concomitant Treatment .........................................................................................30
5.1.2
Permitted Treatment...............................................................................................31
5.1.3
Prohibited Treatment .............................................................................................31
5.1.4
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation ....................................................................................................31
5.1.4.1
Active Vitamin D ...................................................................................31
5.1.4.2
Native Vitamin D ...................................................................................31
5.1.4.3
Calcium ..................................................................................................31
5.1.4.4
Magnesium.............................................................................................31
5.1.5
Thiazide Diuretics..................................................................................................31
6
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Blinding the Treatment Assignment......................................................................32
6.2
Administration of Investigational Product(s)...........................................................32
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dosing....................................................................................................................33
6.2.3
Unblinding the Treatment Assignment..................................................................33
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Packaging...............................................................................................................33
6.3.2
Labeling .................................................................................................................33
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................36
7
STUDY PROCEDURES........................................................................................................36
7.1
Study Schedule.........................................................................................................36
7.1.1
Baseline Visit (Visit 1)...........................................................................................37
7.1.2
Treatment Period....................................................................................................37
7.1.2.1
Visit 2, (Month 6)...................................................................................37
7.1.2.2
Visit 3 (Month 12)..................................................................................37
7.1.2.3
Visit 4 (Month 18)..................................................................................37
7.1.2.4
EOT Visit (Month 24)............................................................................37
7.1.3
Additional Care of Subjects after the Study ..........................................................37
7.2
Study Evaluations and Procedures ...........................................................................38
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7.2.1
Demographic and Other Baseline Characteristics .................................................38
7.2.2
Efficacy..................................................................................................................38
7.2.2.1
Biochemical Evaluations........................................................................38
7.2.2.2
Hypoparathyroidism Symptom Diary (HPT-SD) ..................................38
7.2.2.3
Cognition Tool .......................................................................................38
7.2.2.4
FACIT Fatigue Scale..............................................................................38
7.2.2.5
HADS Assessment .................................................................................38
7.2.2.6
Short Form Health Survey-36 ................................................................39
7.2.2.7
Bone Mineral Density ............................................................................39
7.2.2.8
Bone Biopsy...........................................................................................39
7.2.3
Safety .....................................................................................................................40
7.2.3.1
Adverse Event Collection.......................................................................40
7.2.3.2
Clinical Laboratory Evaluations.............................................................40
7.2.3.3
Pregnancy Test .......................................................................................42
7.2.3.4
PTH Antibodies......................................................................................42
7.2.3.5
Vital Signs..............................................................................................42
7.2.3.6
Physical Examination.............................................................................42
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................43
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................43
8.1.1
Severity Categorization..........................................................................................43
8.1.2
Relationship Categorization...................................................................................44
8.1.3
Outcome Categorization ........................................................................................44
8.1.4
Symptoms of the Disease Under Study .................................................................44
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................44
8.1.6
Pregnancy...............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................45
8.2
Serious Adverse Event Procedures ..........................................................................46
8.2.1
Reference Safety Information................................................................................46
8.2.2
Reporting Procedures.............................................................................................46
8.2.3
Serious Adverse Event Definition .........................................................................47
8.2.4
Serious Adverse Event Collection Time Frame.....................................................47
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................47
8.2.6
Fatal Outcome........................................................................................................48
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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................48
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................48
9.1
Data Collection.........................................................................................................48
9.2
Clinical Data Management.......................................................................................48
9.3
Data Handling Considerations..................................................................................49
9.4
Statistical Analysis Process......................................................................................49
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......49
9.6
Sample Size Calculation and Power Considerations................................................49
9.7
Study Population ......................................................................................................49
9.8
Efficacy Analyses.....................................................................................................50
9.8.1
Primary Efficacy Endpoint ....................................................................................50
9.8.2
Secondary Efficacy Endpoints...............................................................................50
9.8.3
Exploratory Efficacy Endpoints.............................................................................50
9.9
Safety Analyses........................................................................................................51
9.10
Other Analyses .........................................................................................................51
9.10.1 Health-related Quality of Life Analyses................................................................52
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................52
10.1
Sponsor’s Responsibilities .......................................................................................52
10.1.1 Good Clinical Practice Compliance.......................................................................52
10.1.2 Public Posting of Study Information......................................................................53
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................53
10.1.4 Study Suspension, Termination, and Completion..................................................53
10.2
Investigator’s Responsibilities .................................................................................53
10.2.1 Good Clinical Practice Compliance.......................................................................53
10.2.2 Protocol Adherence and Investigator Agreement..................................................54
10.2.3 Documentation and Retention of Records.............................................................54
10.2.3.1
Case Report Forms.................................................................................54
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................54
10.2.3.3
Audit/Inspection.....................................................................................55
10.2.3.4
Financial Disclosure...............................................................................55
10.3
Ethical Considerations..............................................................................................55
10.3.1 Informed Consent...................................................................................................55
10.3.2 Institutional Review Board or Ethics Committee..................................................56
10.4
Privacy and Confidentiality......................................................................................56
10.5
Study Results / Publication Policy ...........................................................................57




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LIST OF TABLES
Table 1:
Schedule of Study Assessments ....................................................................19
Table 2:
Recommended Adjustments for Active Vitamin D and Calcium 
Supplements ..................................................................................................32
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................26


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ABBREVIATIONS
ACSC
albumin-corrected serum calcium
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BSAP
bone specific alkaline phosphatase
BLA
Biologics License Application
BMSi
bone material strength index
CI
confidence interval
CRA
Clinical Research Associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
DXA
dual-energy x-ray absorptiometry
EC
Ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
eGRF
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-Cog
Functional Assessment of Cancer Therapy - Cognitive Function
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
HIPAA
Health Insurance Portability and Accountability Act
HPT
Hypoparathyroidism
HPT-SD
Hypoparathyroidism Symptom Diary
HRpQCT
high-resolution peripheral quantitative computerized tomography
ICF
informed consent form
ICH
International Conference on Harmonisation


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ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board
MedDRA
Medical Dictionary of Regulatory Activities
mmHg
millimeters of mercury
P1NP
procollagen type I amino-terminal propeptide
PTH
Parathyroid hormone
QD
once daily
RBC
red blood cell
rhPTH(1-84)
recombinant human parathyroid hormone
s-CTX
serum carboxy-terminal 4 telopeptide of type I collagen
SAE
serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SC
subcutaneous
SF-36
36-item Short Form Health Survey
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
WBC
white blood cell


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STUDY SYNOPSIS
Protocol number: SHP634-402
Drug: rhPTH(1-84)
Title of the study: A Phase 4, Open-Label, Single-Center Clinical Study of Extended use of rhPTH(1-84) in 
Hypoparathyroidism
Number of subjects (total and for each treatment arm):
The subject population anticipated in this study is up to 50 subjects. All subjects are exclusively from the core study 
(HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in Hypoparathyroidism) 
Protocol AAAE0544 at Columbia University Medical Center, and will all receive active rhPTH(1-84) treatment.
Investigator(s):
Single site located at:
Columbia University
New York, NY 10032
Site(s) and Region(s): 
Columbia University
New York, NY 10032
Study period (planned): 24 months
Clinical phase: 4
Objectives:
Primary:

To evaluate albumin-corrected serum calcium (ACSC) while on rhPTH(1-84) treatment
Secondary:

To evaluate the proportion of subjects who achieve ACSC values above, below, or in the range of 
7.5 mg/dL-upper limit of normal (ULN)

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment

To evaluate symptoms of hypoparathyroidism as measured by the hypoparathyroidism symptom diary 
(HPT-SD), perception of cognitive function, and health-related quality-of-life associated with long-term 
rhPTH(1-84) treatment

To evaluate the skeletal actions of rhPTH(1-84): bone turnover markers, architecture, and histology 
(biopsy)
Rationale:
Chronic hypoparathyroidism (HPT) is a life-long and irreversible disease for which the chronic administration of 
rhPTH(1-84) is a potential treatment option. Thus, long-term safety and efficacy data are important in evaluating the 
proper use of this treatment option in clinical practice.
Investigational product, dose, and mode of administration:
rhPTH(1-84); 25, 50, 75, and 100 µg for once daily subcutaneous injection to the thigh via a multidose pen injector 
device. The dose will be individualized to achieve a serum calcium level in the lower half of the normal range.


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Methodology: 
Subjects enrolled are currently or were previously enrolled in the core study (AAAE0544) and have maintained 
uninterrupted therapy with rhPTH(1-84). Study visits will be scheduled every 6 months up to the 24-month end of 
study visit. Specific procedures at each study visit are summarized in Table 1. A schematic of the study design is 
provided below:
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject must meet all of the following criteria to be eligible
1.
Subjects that are currently or previously enrolled in the core study (AAAE0544) and have maintained 
uninterrupted therapy with rhPTH(1-84) (transient interruptions of up to 1 month continuously off treatment 
may be allowed).
2.
Signed and dated informed consent form (ICF).
3.
Adult men and women 18 to 85 years of age.
4.
History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, defined by the 
requirement for supplemental calcium and/or active vitamin D to maintain serum calcium along with an 
undetectable or insufficient PTH concentration.
5.
Able to perform daily subcutaneous self-injections of study medication (or have designee perform injection).
6.
Willingness and ability to understand and comply with the protocol. Women must agree to pregnancy testing 
and acceptable methods of contraception, as detailed in the protocol.
Exclusion Criteria:
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1.
The subject is treated or has been treated with any investigational drug, aside from rhPTH(1-84), within 30 
days of consent.
2.
As assessed by the investigator, the subject has a safety or medical issue that contraindicates participation 
in the study.
3.
The subject and/or the subject’s parent(s) or legally-authorized representative(s) is unable to understand the 
nature, scope, and possible consequences of the study. 
4.
The subject is unable to comply with the protocol, eg, uncooperative with protocol schedule, refusal to 
agree to all of the study procedures, inability to return for evaluations, or is otherwise unlikely to complete 
the study, as determined by the investigator or the medical monitor.
5.
The subject is pregnant or lactating.
6.
Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase, subjects with hereditary disorders predisposing to 
osteosarcoma or subjects with a prior history of external beam or implant radiation therapy involving the 
skeleton.
Maximum duration of subject involvement in the study:
Each study visit has a threshold of ±1 month with a total treatment period of 24 months. A follow-up phone call to 
assess safety will occur 30 days after the end of treatment visit.


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Endpoints and Statistical Analysis: 
Primary Efficacy Endpoint:

Change in albumin-corrected serum calcium
Secondary Efficacy Endpoint(s):

Albumin-corrected serum calcium value above, below, or in the range of 7.5mg/dL -ULN

Change in urinary calcium and serum phosphate

Change in calcium and active vitamin D supplement doses

Change in HPT-related symptoms (as measured by the HPT-SD)

Change in FACT-Cog assessment

Change in FACIT (Fatigue Scale [Version 4])

Change in HADS (Hospital Anxiety and Depression Scale)

Change in health-related quality-of-life measured with SF-36 survey

Change in bone turnover markers( including, but not limited to, serum carboxy-terminal 4 telopeptide of 
type I collagen [s-CTX], procollagen type I amino-terminal propeptide [P1NP], osteocalcin, bone specific 
alkaline phosphatase [BSAP], TRAP-5b, sclerostin), architecture, and histology (biopsy)
Exploratory Efficacy Endpoint: 


Safety Endpoints:

AEs including SAEs

Vital signs including body temperature, heart rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Estimated Glomerular Filtration Rate (eGFR) and creatinine clearance

Measurements of antibodies to parathyroid hormone (PTH)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)
Although no formal hypotheses are being tested, 95% confidence intervals (CI) will be provided as appropriate. 
Continuous variables, including those assessed on a discrete scale, will be summarized using descriptive statistics 
including number of subjects, mean, median, standard deviation, maximum, and minimum. For categorical 
variables, statistical summaries will include number of subjects and percentages.
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from the SHP634-402 baseline, if applicable. Frequency counts will be compiled for classification of 
qualitative safety data (for example shift from baseline according to lab normal range, AEs related to treatment, 
level of severity, etc.).
Other Analyses:
A retrospective analysis of historical data captured from the medical records of subjects (since the start of 
rhPTH(1-84) treatment) will be conducted. All subjects are exclusively from the core study (Protocol AAAE0544 at 
Columbia University Medical Center [HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on 
the Skeleton in Hypoparathyroidism]). 


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Data collected will include but is not limited to, medical history and clinical laboratory data that can be source data 
verified. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment baseline, if 
applicable.
Interim Analysis:
A retrospective analysis of historical data captured from the medical records of subjects (eg, since the start of 
rhPTH(1-84) treatment) will be conducted. These data will be derived from the medical records from subjects that 
are exclusively from the core study (Protocol AAAE0544 at Columbia University Medical Center [HEXT: The 
Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in Hypoparathyroidism]). Data 
collected will include but is not limited to, medical history and clinical laboratory data that can be data source 
verified. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment baseline, if 
applicable.
There will be no Data Monitoring Committee for this unblinded exploratory study, however results of the 
prospective data portion of the study will be analyzed as necessary for safety monitoring and publication purposes.


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STUDY SCHEDULE
Table 1:
Schedule of Study Assessments
Study Period
Baseline
Maintenance 
Dosing 
Period
End of 
Treatment
Visit
Visit 1
Visit 2-4
EOT Visita
Study Month
0
6
12
18
24
Study Procedures
±1 month
Informed Consentb
X
Inclusion/Exclusion
X
Medical history and demography
X
Prior/concomitant medications
X
X
X
X
X
Physical examination
X
X
X
Vital signsc
X
X
X
X
X
Hematology
X
X
Serum chemistryd
X
X
X
X
X
Serum TSH
X
Serum pregnancy teste
X
Urine pregnancy test
X
X
X
X
X
FSH levelf
X
Serum PTH antibodiesg
X
X
X
X
X
Serum 25-hydroxyvitamin D
X
X
X
X
X
Serum 1,25-dihydroxyvitamin D
X
X
X
X
X
Bone turnover markersi
X
X
X
X
X
Urinalysis (dipstick)
X
X
24-hour urineh
X
X
X
X
Bone mineral density DXA
X
X
X
X
X
Bone mineral density HRpQCT
X
X
X
X
X
Bone biopsy (optional)
X
 (optional)
X
HPT-SD
X
X
X
X
X
FACT-Cog assessment
X
X
X
X
X
SF-36
X
X
X
FACIT Fatigue Scale
X
X
X
X
X
HADS assessmentj
X
X
X
X
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
Dispense/Account for study drug
X
X
X
X
X
Collection of unused study drug & injection pen
X
Record any use of Calcium, Calcitriol, and/or 
Vitamin D supplementsk
X
X
X
X
X
Abbreviations: AE = Adverse event; DXA = dual-energy x-ray absorptiometry; HPT = Hypoparathyroidism; 
HPT-SD = Hypoparathyroidism Symptom Diary; SAE=Serious adverse event; SF-36 = 36-Item Short Form Health 
Survey; HRpQCT = High-resolution peripheral quantitative computerized tomography.
a For subjects not continuing rhPTH[1-84] treatment, see Section 7.1.3.
b Remote consent allowed. Consent procedure must be complete prior to completing any baseline assessments (can 
occur at baseline visit as long as complete prior to assessments). 
c Vitals signs include: blood pressure, heart rate, body temperature, and respiration rate.
d Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, 
phosphate, magnesium, albumin, ALT, AST, and ALP.


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Table 1:
Schedule of Study Assessments
Study Period
Baseline
Maintenance 
Dosing 
Period
End of 
Treatment
Visit
Visit 1
Visit 2-4
EOT Visita
Study Month
0
6
12
18
24
Study Procedures
±1 month
e Pregnancy tests for females of childbearing potential.
f FSH level required for newly menopausal women.
g Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any subject with newly 
developed PTH-specific antibodies at the end of treatment visit may require follow up. This will be discussed as 
necessary by the PI and medical monitor on a case-by-case basis.
h 24-hour urine collection includes urine calcium, creatinine, phosphate, magnesium and sodium analyses. Urine 
volume will be recorded. The 24-hour urine collections should generally be performed by the subject within 2 weeks 
prior to or within 2 days follow a study visit. These 24-hour urine collections may be analyzed in a local laboratory. 
To the greatest extent possible, the same laboratory should analyze the 24-hour urine collections throughout the 
study. Results from the last 24-hour urine collection obtained in Columbia protocol AAAE0544 will be used as the 
baseline assessment in this study. At the beginning of the study, the investigator should recommend an 
individualized target dietary (non-supplement) calcium intake for each subject to ingest consistently throughout the 
study on 24-hour urine collection days. When collecting 24-hour urine specimens subjects should be instructed to 
take their currently prescribed calcium, vitamin D (both parent and active) and rhPTH(1-84) doses.
i Bone turnover markers include, but are not limited to, the following: serum carboxy-terminal 4 telopeptide of type I 
collagen (s-CTX), procollagen type I amino-terminal propeptide (P1NP), osteocalcin, bone specific alkaline 
phosphatase (BSAP), TRAP-5b, sclerostin.
j The investigator must review responses to the HADS before the subject leaves the site and take any appropriate 
action that is clinically indicated based on the responses.
k Subjects will enter their actual doses of calcium taken for 14 days prior to each visit, following the baseline visit, in 
a home diary.


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1
BACKGROUND INFORMATION
Hypoparathyroidism (HPT) 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 (US), which rises to approximately 117,000 if the transient hypoparathyroid population is 
included (≤6 months). The same authors suggest that, of those 117,000 transient hypoparathyroid 
subjects, about 5% will become chronic.
Parathyroid hormone is an 84-amino acid protein that is secreted by the parathyroid glands. PTH 
has a variety of important physiological functions that are outlined below to explain the effects 
of absent or deficient PTH levels. Parathyroid hormone functions to help regulate bone 
metabolism and serum levels of calcium and phosphate. In general, if serum calcium 
concentrations decrease, the parathyroid glands consequently increase PTH secretion, and, if 
serum calcium concentrations increase, the parathyroid glands consequently reduce PTH 
secretion. The parathyroid glands sense the level of extracellular calcium at the surface of the 
parathyroid cell and adjust the synthesis and secretion of PTH accordingly. 
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). 
Hypoparathyroidism has also been linked to effects on mood and ideation (Arlt et al. 2002;
Velasco et al. 1999).
The kidneys are especially vulnerable in subjects with hypoparathyroidism. Circulating PTH 
promotes renal calcium reabsorption, especially at the level of the distal convoluted tubule 
(Blaine et al. 2015). In the absence of PTH, calcium can be over-excreted through the kidneys 
(Shoback 2008), leading to hypercalciuria which, together with a high-calcium-phosphate 
product, can potentially lead to nephrocalcinosis and kidney stones and, ultimately, to renal 
impairment (Blaine et al. 2015).
For further details see the recombinant human PTH (rhPTH[1-84]) investigator brochure.
1.1
Indication and Current Treatment Options 
Prior to 2015, in the absence of an approved PTH replacement therapy, management of 
hypoparathyroidism consisted of supplemental oral calcium and active vitamin D in 
pharmacological doses sufficient to maintain the serum calcium level without the disabling 
symptoms of hypocalcemia. 


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In order to improve the absorption of calcium from the gastrointestinal tract, pharmacological 
supplementation with active forms of vitamin D (eg, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 
calcitriol, 1,25-dihydroxycholecalciferol or α-calcidol [1(OH)D3]) is also required. Since PTH 
also functions in the kidney to stimulate the conversion of 25(OH)D3, the major circulating form 
of vitamin D, to the active vitamin D hormone (1,25[OH]2D3), the relative lack of circulating 
PTH results in a reduction of the production of active vitamin D. Thus, exogenous active vitamin 
D overcomes the synthetic block in endogenous production of the active vitamin D hormone in 
hypoparathyroidism. Together, supplemental oral calcium and active vitamin D have formed the 
mainstay of current treatment of subjects with hypoparathyroidism. 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 (AEs) 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 US on 23 Jan 2015 under the brand 
name Natpara® as a once-daily injectable dose as an adjunct to calcium and vitamin D to control 
hypocalcemia in patients with hypoparathyroidism.
1.2
Product Background 
1.2.1
Preclinical Information
A total of 46 in vivo studies in mouse, rat, rabbit, dog, and rhesus and cynomolgus monkeys 
have evaluated the 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 been performed.
In male and female rats, the administration of PTH was associated with an increase in the 
incidence of osteosarcoma. These data were interpreted as an increased risk for osteosarcoma in 
the clinic. Therefore, administration of rhPTH(1-84) should be avoided in subjects who are 
considered to be at increased risk for osteosarcoma (including those with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase, subjects with hereditary disorders 
predisposing to osteosarcoma or subjects with a history of prior external beam or implant 
radiation therapy involving the skeleton).


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Currently available results from animal reproductive toxicology studies suggest that 
rhPTH(1-84) is not associated with significant fetal or neonatal toxicity; however, the safety of 
rhPTH(1-84) in pregnant or nursing women is not established.
For full details see the rhPTH(1-84) investigator brochure.
1.2.2
Clinical Information
Study CL1-11-040 (REPLACE) was a double-blind, placebo controlled study of once daily (QD) 
SC administration of 50 μg to 100 μg of rhPTH(1-84). The 3-tiered primary endpoint included 
≥50% reduction from baseline in oral calcium supplementation, ≥ 50% reduction from baseline 
in active Vitamin D, and albumin-corrected serum calcium (ACSC) concentration maintained or 
normalized compared to baseline (not exceeding upper limit of normal). The 3-tiered endpoint 
was met in 54.8% of rhPTH(1-84) subjects compared to 2.5% of 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 extension 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 serum calcium-phosphate product. In 
these studies, hypercalciuria was defined as an excretion of calcium in the urine greater than 
300mg per 24 hours. Data from the REPLACE Study and the long-term open label study, RACE, 
show that rhPTH(1-84) has a calcium-sparing effect, consistent with the reduction of urinary 
calcium excretion seen in a previous pharmacokinetic/pharmacodynamic study (C09-002) of 
single dose administration of rhPTH(1-84) in subjects with hypoparathyroidism in comparison 
with calcitriol administration.
The Phase 3 clinical study, REPLACE, was the largest, randomized, placebo controlled clinical 
study conducted in hypoparathyroidism population and was the pivotal study demonstrating that 
rhPTH(1-84) is effective in maintaining serum calcium levels and enabling significant decreases 
in active vitamin D and oral calcium doses. REPLACE also established the rhPTH(1-84) dose 
and dose titration and evaluated the physiologic effects of PTH replacement on serum calcium, 
serum phosphate, urinary calcium excretion, and bone turnover markers. Eighty-four subjects 
were evaluated in the active treatment group and 40 subjects received placebo. Subjects 
received at a flexible dose range of 50 to 100 μg SC in the thigh once daily for 6 months. The 
study met the primary efficacy triple endpoint, with a statistically higher responder rate (54.8%) 
versus placebo (2.5%). To meet the primary endpoint a subject had to fulfill all 3 conditions as 
follows: a 50% or greater reduction in oral calcium requirement, a 50% or greater reduction in 
active vitamin D therapy and an ACSC concentration that was maintained within a range of 
7.5 to 10.6 mg/dL.
A review of safety data across the hypoparathyroidism 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.


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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. 
Because of the potential risk of osteosarcoma, rhPTH(1-84) is recommended only for subjects 
who cannot be well controlled on calcium supplements and active forms of vitamin D alone.
Additional risks include extensions of the pharmacologic effects 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 subjects should be advised to 
take their rhPTH(1-84) dose as soon possible following a missed dose and to take oral calcium.
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).
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Recombinant human parathyroid hormone has been developed as an adjunct to calcium and 
vitamin D to control hypocalcemia in hypoparathyroidism subjects who cannot be well 
controlled with calcium and vitamin D supplementation alone. Although the development of a 
novel therapeutic agent for the treatment of hypoparathyroidism is encouraging, it is important to 
gain knowledge about the efficacy and safety of long-term use of rhPTH(1-84) due to the chronic 
nature of the condition. 
The AAAE0544 cohort has the longest known duration of rhPTH(1-84) therapy for the treatment 
of hypoparathyroidism to date. This protocol is designed to extend this experience and to provide 
additional data on the long-term safety and efficacy of rhPTH(1-84).
2.2
Study Objectives 
2.2.1
Primary Objectives 

To evaluate ACSC while on rhPTH(1-84) treatment
2.2.2
Secondary Objectives

To evaluate the proportion of subjects who achieve ACSC values above, below, or in the 
range of 7.5mg/dL-upper limit of normal (ULN)

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment 


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
To evaluate symptoms of hypoparathyroidism as measured by the hypoparathyroidism 
symptom diary (HPT-SD), perception of cognitive function, and health-related quality-of-life 
associated with long-term rhPTH(1-84) treatment.

To evaluate the skeletal actions of rhPTH(1-84): bone turnover markers, architecture, and 
histology (biopsy)
3
STUDY DESIGN
3.1
Study Design and Flow Chart
Protocol SHP634-402 is a single-center, open-label, single arm, Phase 4 study of rhPTH(1-84) 
treatment in adult subjects (up to 50 subjects) diagnosed with hypoparathyroidism. 
Pre-study treatment, laboratory data, and medical history information for enrolled subjects will 
be verified. 
Subjects will be treated with rhPTH(1-84) for a two-year treatment period with study visits 
scheduled every 6 (±1) months. 
A schematic representation of the study design is provided in Figure 1. 


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Figure 1:
Study Design Flow Chart
Eligible
Subjects
Informed 
Consent / 
Baseline 
(Visit 1)
6 months     
    12 months                 18 months      
24 months     
       30 days
    Visit 2         
        Visit 3  
Visit 4       
Visit 5(EOT)            Follow-up
Treatment Period


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3.2
Duration and Study Completion Definition
The subject's maximum duration of participation in the study is approximately 25 months. 
The study Completion Date is defined as the date the final subject completes their final 
protocol-defined assessment. Please note that this includes the follow-up phone contact 30 days 
following the EOT (Month 24) visit. 
3.3
Sites and Regions
This is a single-center study that will be conducted at Columbia University Medical Center, New 
York, NY.
3.4
Discussion of Study Design
This protocol is intended only for those subjects who participated and were treated in the 
AAAE0544 study. Limiting enrollment to subjects from the core study (AAAE0544) will allow 
this study to provide long-term safety and efficacy data. 
Administration via injection to the thigh has been shown to be a safe and effective delivery 
method of rhPTH(1-84). Dosing is based upon previous exposure and the recommended dosing 
in the rhPTH(1-84) package insert. The selected dose should reduce calcitriol and oral calcium 
(carbonate or citrate) supplementation to as low as safely possible while maintaining total serum 
calcium levels. All subjects will have their total serum calcium checked by a local laboratory as 
outlined in the Schedule of Study Assessments (Table 1). Subjects may have their rhPTH(1-84) 
dose increased in increments of 25 µg to a maximum of 100 µg SC QD by the investigator no 
more frequently than 4 week intervals during the study, with the goal of achieving or maintaining 
total serum calcium levels in the range of 8.0 to 9.0 mg/dL if clinically appropriate. The 
rhPTH(1-84) dose may be adjusted downward at any time as needed to maintain appropriate 
serum calcium levels (approximately 8.0 to 9.0 mg/dL) or due to any safety concerns.
Adjustment of supplemental calcium and calcitriol regimens will be based on serum calcium 
levels, with the goal to be a reduction or removal of calcitriol treatment to the maximum degree 
clinically possible and to decrease the prescribed oral calcium supplementation to ≤500 mg 
daily. 
Subjects generally should have blood draws to assess total serum calcium levels (which may be 
performed locally) 3 to 5 days after ANY dose adjustment of rhPTH(1-84), after any significant 
change in doses of calcium and/or and calcitriol supplements, or at any other time at the 
discretion of the investigator. Results of local total serum calcium levels will be entered on the 
electronic case report form (eCRF). 
During the week following the last visit (End of Treatment or early termination visit), subjects 
who are discontinuing rhPTH(1-84) treatment (ie, those who are NOT continuing on commercial 
Natpara) will have oral calcium and/or active vitamin D adjusted to compensate for the cessation 
of rhPTH(1-84). Their total serum calcium levels will be checked locally 3 to 5 days after the last 
dose of study medication. Subjects will also be scheduled for a follow-up clinic visit at the end of 
this week in order to have serum calcium and phosphate checked.


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Approximately 30 days following the End of Treatment visit, subjects will be contacted by 
telephone in order to assess AEs/serious AEs (SAEs). 
4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. Subjects in this protocol 
are restricted to those who were treated in the core study (AAAE0544). Approximately 
50 subjects are expected to enroll in this study.
4.1
Inclusion Criteria
The subject must meet all of the following criteria to be eligible for the study:
1. Subjects that are currently or previously enrolled in the core study (AAAE0544) and have 
maintained uninterrupted therapy with rhPTH(1-84) (transient interruptions of up to 
1 month continuously off treatment may be allowed).
2. Signed and dated informed consent form (ICF).
3. Adult men and women 18 to 85 years of age.
4. History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, 
defined by the requirement for supplemental calcium and/or active vitamin D to maintain 
serum calcium along with an undetectable or insufficient PTH concentration.
5. Able to perform daily SC self-injections of study medication (or have designee perform 
injection).
6. Willingness and ability to understand and comply with the protocol. Women must agree to 
pregnancy testing and acceptable methods of contraception, as detailed in the protocol.
4.2
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1. The subject is treated or has been treated with any investigational drug, aside from 
rhPTH(1-84), within 30 days of consent.
2. As assessed by the investigator, the subject has any safety or medical issues that 
contraindicate participation in the study.
3. The subject and/or the subject’s parent(s) or legally-authorized representative(s) are 
unable to understand the nature, scope, and possible consequences of the study. 
4. The subject is unable to comply with the protocol, eg, uncooperative with protocol 
schedule, refusal to agree to all of the study procedures, inability to return for evaluations, 
or is otherwise unlikely to complete the study, as determined by the investigator or the 
medical monitor.
5. The subject is pregnant or lactating.
6. Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s 
disease of bone or unexplained new elevations of alkaline phosphatase, subjects with 
hereditary disorders predisposing to osteosarcoma or subjects with a prior history of 
external beam or implant radiation therapy involving the skeleton.


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4.3
Reproductive Potential
4.3.1
Female Contraception
Women who are postmenopausal (absence of menses for at least 1 year) and women who are 
surgically sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy) can be enrolled. 
Women of childbearing potential must have a negative pregnancy test and agree to use medically 
acceptable methods of contraception for the duration of the study with pregnancy testing at every 
scheduled visit. 
Medically acceptable methods of contraception include: true sexual abstinence (not having any 
type of intercourse or sex play with a male partner); hormonal methods of contraception (oral, 
injected, vaginal rings, patch, implanted, etc.); placement of an intrauterine device or intrauterine 
system; barrier methods of contraception (condom or occlusive diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. Women whose partner is a woman or whose 
partner is a man with a history of vasectomy are exempt.
4.3.2
Male Contraception
Not Applicable.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product [rhPTH(1-84)] with 
the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for End 
of Treatment (EOT) Visit are to be performed as completely as possible. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents and as AEs, as applicable. The reason for termination, date of stopping rhPTH(1-84) 
and the total amount of rhPTH(1-84) taken must be recorded in the electronic case report form 
(eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Subject Withdrawal Criteria
Subjects can withdraw from the study at any time for any reason. 
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF. 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 eCRF. Reasons for discontinuation include but are not limited to:

Completed

Adverse event

Protocol deviation


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
Withdrawal by subject

Lack of efficacy

Lost to follow-up

Other (If “Other” is selected, the investigator must specify on the eCRF: Examples are 
provided below)

Death

Physician decision

Pregnancy

Site terminated by sponsor

Study terminated by sponsor
4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment, including but not limited to herbal treatment, vitamins, behavioral 
treatment, non-pharmacological treatment (such as psychotherapy), as appropriate, received 
within 30 days prior to the baseline visit (Visit 1) (or pharmacokinetic equivalent of 5 half-lives, 
whichever is longer) and through the final study contact (including protocol defined follow-up 
period) must be recorded on the appropriate eCRF page.
5.1
Prior Treatment
For the prospective portion of the study, prior treatment includes all treatment, including but not 
limited to herbal treatment, vitamins, behavioral treatment, non-pharmacological treatment (such 
as psychotherapy), as appropriate as of the time of enrollment in Study SHP634-402. Prior 
treatment information must be recorded on the appropriate eCRF page. 
5.1.1
Concomitant Treatment 
For the retrospective portion of the study, concomitant treatment refers to all treatment taken 
from 1 year prior to initiation of treatment with rhPTH(1 84) until enrollment in study 
SHP634-402.
For the prospective portion of the study, concomitant treatment refers to all treatment taken 
between the dates of the first dose of study SHP634-402 rhPTH(1-84) and the end of the 
follow-up period in the SHP634-402 study, inclusive. All available active vitamin D and calcium 
supplement doses from the beginning of rhPTH(1-84) will be recorded. Concomitant treatment 
information must be recorded on the appropriate eCRF page.


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5.1.2
Permitted Treatment
Any treatment for an existing or obtained condition(s) will be permitted. Active vitamin D, 
native vitamin D, calcium and magnesium supplementation, and thiazide use are permitted. Prior 
treatment with rhPTH(1-84) is permitted.
5.1.3
Prohibited Treatment
The use of any other investigational product within 30 days prior to study enrollment or at any 
time during the trial is prohibited. Additionally, any medication that affects bone metabolism (eg, 
selective estrogen receptor modulators, calcitonin, bisphosphonates) and any other 
investigational products are prohibited while on study SHP634-402 rhPTH(1-84) treatment. 
5.1.4
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation
5.1.4.1
Active Vitamin D
Subjects enrolled in this study may be taking active vitamin D to control serum calcium levels.
Prior and concomitant prescribed doses of calcitriol will be entered on the appropriate eCRF. 
5.1.4.2
Native Vitamin D 
Subjects should receive native vitamin D to maintain the subject’s serum 25(OH) vitamin D level 
in the normal range (≥30 ng/ml and ≤ the upper limit of normal for the laboratory). Prior and 
concomitant doses of native vitamin D must be recorded on the appropriate eCRF.
5.1.4.3
Calcium
Subjects enrolled in this study may be taking oral calcium supplements (either calcium carbonate 
or calcium citrate). Prior and concomitant prescribed doses of calcium will be entered on the 
appropriate eCRF. Subjects will enter their actual doses taken for 14 days prior to each visit, 
following the baseline visit, in a home diary.
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject in a 
diary. 
5.1.4.4
Magnesium 
Subjects with low serum magnesium should receive supplementation to keep the serum 
magnesium level in the normal range. Prior and concomitant doses of magnesium must be 
recorded on the appropriate eCRF.
5.1.5
Thiazide Diuretics
Subjects in this study may be taking thiazide diuretics (hydrochlorothiazide or chlorthalidone) to 
limit the extent and effect of hypercalciuria. Prior and concomitant prescribed doses of thiazide 
diuretics will be entered on the appropriate eCRF.


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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The investigational 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, 75µg, and 100µg. The investigational 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.
6.1.1
Blinding the Treatment Assignment
This is an open-label single-arm study where all subjects will be administered study drug; 
therefore, no blinding will occur.
6.2
Administration of Investigational Product(s)
The following instructions describe how to administer the investigational product:
Adjust dose of active vitamin D or calcium supplement or both based on serum calcium value 
and clinical assessment (ie, signs and symptoms of hypocalcemia or hypercalciuria). Suggested 
adjustments to active vitamin D and calcium supplement based on serum calcium levels are 
provided in Table 2.
Table 2:
Recommended Adjustments for Active Vitamin D and Calcium Supplements
Adjust First
Adjust Second
Serum Calcium
Active Vitamin D Forms
Calcium Supplement
Above the Upper Limit of 
Normal (10.6 mg/dL)
Decrease or Discontinue *
Decrease
Greater than 9 mg/dL and below 
the Upper Limit of Normal (10.6 
mg/dL)
Decrease or Discontinue *
No change or decrease if active 
vitamin D has been discontinued
Less than or equal to 9 mg/dL 
and above 8 mg/dL
No change
No change
Lower than 8 mg/dL
Increase
Increase
*Discontinue in patients receiving lowest available dose


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6.2.1
Allocation of Subjects to Treatment 
This is an open-label, single-center study where all subjects will receive rhPTH(1-84).
6.2.2
Dosing
The dose of rhPTH(1-84) will be individualized based on ACSC and 24-hour calcium urinary 
excretion. The recommended rhPTH(1-84) dose will be the minimum dose required to prevent 
both hypocalcemia and hypocalciuria. This dose will generally be the dose that maintains ACSC 
within the lower half of the normal range (ie, between 8 and 9 mg/dL) without the need for 
active forms of vitamin D and with calcium supplementation sufficient and individualized to 
meet the patient’s daily requirements. 
The doses of rhPTH(1-84), active vitamin D, and calcium supplements will be prescribed on an 
individual basis. Dosing guidelines found in the US package insert will be used but may be 
individualized at the discretion of the investigator. 
Doses of active forms of vitamin D and calcium supplements will be adjusted when using 
rhPTH(1-84).
6.2.3
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Packaging
The study site will receive open label supplies of investigational product, injection pens and 
mixing devices required for dosing.
Each subject will receive 2 pens for use during the study period and sufficient cartridges to 
provide daily doses for the duration of the study. Drug cartridges will be provided in kits 
containing 8 cartridges each and each kit will be sufficient for up to 16 weeks of treatment. Each 
cartridge will contain study drug for 14 doses. Drug cartridges will be provided at each clinic 
visit in sufficient quantity and at appropriate dose levels to ensure uninterrupted administration 
until the next study visit. In the event of drug expiries, a courier may ship drug supplies to 
subjects directly in between their study visits. Subjects may also use the courier service to return 
expired investigational product. Ancillary supplies including single use needles (31-gauge) and 
alcohol wipes will be provided by the CRO to the site. 
6.3.2
Labeling 
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.


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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”.
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.
6.3.3
Storage
The dual-chamber medication cartridge should be stored between 2 – 8 °C. The reconstituted 
medication can be stored for up to 14 days at these conditions. The mixing device and empty 
delivery pen (ie, unloaded) can be stored at room temperature.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained. The temperature should be monitored continuously by using either an in 
house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.


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6.3.4
Special Handling
Do not freeze or shake. Do not use rhPTH(1-84) if it has been frozen or shaken.
6.4
Drug Accountability
The investigator will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (ie, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense 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 dispensed study drug 
will be documented. The investigator is responsible for assuring the retrieval of all study supplies 
from subjects. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational products being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (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 for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational products must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.


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6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used
investigational product packaging to every visit. Additionally, subjects may use a courier service 
to return expired and empty/used investigational product. Drug accountability will be assessed at 
the container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level 
for opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form.
7
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 for a complete list of study procedures. Site visits will be conducted at 6-month 
intervals until the end of treatment (EOT) visit at month 24.
A core set of study procedures, conducted at each site visit, are defined as the following:

Prior/concomitant medications (subjects will enter their actual doses of calcium taken for 
14 days prior to each visit, following the baseline visit, in a home diary)

Vital signs

Serum chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
calcium, phosphate, magnesium, albumin, ALT, AST and ALP).

Should be drawn fasting, prior to administration of calcium or vitamin D supplements 
or rhPTH(1-84) administration. If in the opinion of the investigator, it is necessary for 
a subject to take calcium and/or active vitamin D supplements prior to traveling for 
blood work, the doses of the pre-draw supplements and their timing with respect to 
the blood draw should be consistent throughout the study to the greatest extent 
possible.

Urine pregnancy test

Serum 25-hydroxyvitamin D

Serum 1,25-dihydroxyvitamin D

Bone turnover markers

Serum PTH antibodies (blood samples should be drawn prior to dosing)

24-hour urine for calcium, creatinine, phosphate, sodium excretion, and magnesium. Total 
urinary volume will be recorded. 

HPT-SD 

FACT-Cog (Functional Assessment of Cancer Therapy - Cognitive Function) assessment 

FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue Scale

HADS (Hospital Anxiety and Depression Scale) assessment 


AE/SAE monitoring

Bone mineral density DXA (dual-energy x-ray absorptiometry)

Bone mineral density HRpQCT (High-resolution peripheral quantitative computerized 
tomography)

Dispense/Account for study drug


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7.1.1
Baseline Visit (Visit 1)
All study procedures outlined in Table 1 will be conducted at the baseline visit with the 
exception of ‘Collection of unused study drug & injection pen’. Additionally, the bone biopsy 
and 
 (performed using an OsteoProbe®) are optional procedures, which will be 
performed depending on subject history and consent.
7.1.2
Treatment Period 
7.1.2.1
Visit 2, (Month 6)
The core set of study procedures will be conducted at this visit.
7.1.2.2
Visit 3 (Month 12)
The core set of study procedures will be conducted at this visit. In addition to the core study 
procedures, the following procedures will be performed:

Physical Examination

SF-36 (36-Item Short Form Health Survey)
7.1.2.3
Visit 4 (Month 18)
The core set of study procedures will be conducted at this visit.
7.1.2.4
EOT Visit (Month 24)
All study procedures outlined in Table 1 will be performed at this visit except for the following:

Informed consent

Inclusion/exclusion

Medical history and demography

Serum thyroid stimulating hormone (TSH) 

Serum pregnancy test

Follicle-stimulating hormone (FSH) level
7.1.3
Additional Care of Subjects after the Study
After the EOT visit or early termination visit, subjects who will not continue rhPTH[1-84] 
treatment will have serum calcium and phosphate levels measured 3 to 5 days after the last dose 
of study medication. Doses of calcium and active vitamin D supplements will be adjusted by the 
investigator as appropriate according to guidelines followed in the US package insert. Thereafter, 
the investigator will repeat serum calcium/phosphate monitoring and supplement dose 
adjustments as appropriate to achieve target serum calcium/phosphate concentrations until the 
follow up phone call 30 days ± 7 days after EOT visit. After the 30-day follow-up phone call, 
further management of hypoparathyroidism will occur as part of the subject’s long-term 
non-study medical care.


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7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics will be recorded at the baseline visit including date of birth, sex, 
and race on the eCRF for each subject. 
Medical history including etiology of hypoparathyroidism and duration of hypoparathyroidism 
will be recorded on the eCRF for each subject. 
Pre-study rhPTH(1-84) treatment will be recorded on the eCRF for each subject.
Pre-study laboratory data will be recorded on the eCRF for each subject.
7.2.2
Efficacy
7.2.2.1
Biochemical Evaluations
Biochemical evaluation including serum calcium, PTH, albumin, phosphate, alkaline 
phosphatase, urine calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D will be 
collected at the time points specified in Table 1 to assess efficacy and bone turnover.
7.2.2.2
Hypoparathyroidism Symptom Diary (HPT-SD)
The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following 
items:

symptom subscale (items 1-7)

anxiety (item 8)

sadness and depression (item 9)

impact subscale (items 10-13)
The 24-hour recall version of the instrument will be used in this study (Appendix 2). 
7.2.2.3
Cognition Tool
The FACT-Cog assessment is a 37-item tool (Cella 1997) (Appendix 3). It includes 4 subscales: 
perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, 
comments from others and perceived cognitive ability.
7.2.2.4
FACIT Fatigue Scale
FACIT fatigue questionnaire contains 13 fatigue-related questions (Cella 1997). The responses to 
the 13 items on the FACIT fatigue questionnaire are each measured on a 4-point Likert scale. 
Thus, the total score ranges from 0 to 52. High scores represent less fatigue.
7.2.2.5
HADS Assessment 
The HADS is a 14-item scale that generates ordinal data (Zigmond and Snaith 1983). Seven of 
the items relate to anxiety and seven relate to depression. The scale is designed to avoid reliance 
on aspects of conditions that are also common somatic symptoms of illness. 


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Each item on the questionnaire is scored from 0-3, therefore, a person can score between 0 and 
21 for either anxiety or depression. Data returned from the HADS is ordinal. The investigator 
must review responses to the HADS before the subject leaves the site and take any appropriate 
action that is clinically indicated based on the responses. 
7.2.2.6
Short Form Health Survey-36
The SF-36 is a validated questionnaire that questions subjects about perceived physical and 
mental health and function. The SF-36 consists of 8 scaled scores, which are the weighted sums 
of the questions in their section. Each scale is directly transformed into a 0-100 scale on the 
assumption that each question carries equal weight; the lower the score the more disability. The 
higher the score the less disability ie, a score of zero is equivalent to maximum disability and a 
score of 100 is equivalent to no disability. The eight sections included in the SF-36 assessment 
are vitality, physical functioning, bodily pain, general health perceptions, physical role 
functioning, emotional role functioning, social role functioning, and mental health (Ware and 
Sherbourne 1992). Version 1.0 and Version 2.0 of the SF-36 will be used for the retrospective 
and prospective portions, respectively, of study SHP634-402. 
7.2.2.7
Bone Mineral Density
Dual-energy X-ray Absorptiometry
Dual-energy X-ray absorptiometry scans will be performed at baseline, Month 6, Month 12, 
Month 18, Month 24, and at the EOT visit, if it is greater than 3 months since the previous DXA 
scan. These scans will evaluate bone mineral density and T-scores of the lumbar spine (vertebra 
L1-L4), hip (total and femoral neck), and ⅓ distal radius (arm). 
Please note: DXA will NOT be completed at baseline if subject had a scan performed in the 
previous study.
High-resolution Peripheral Quantitative Computerized Tomography
High-resolution peripheral quantitative computerized tomography will be performed at baseline, 
Month 6, Month 12, Month 18, Month 24, and at the EOT visit. HRpQCT analyses includes 
Individual Trabecula Segmentation (ITS) analysis and finite element modeling.
7.2.2.8
Bone Biopsy
An optional transiliac bone biopsy will be performed for willing subjects, at the discretion of the 
investigator a maximum of one time during the duration of the study. 
Subjects who agree to have the bone biopsy, and have selected to participate in the procedure on 
the Informed Consent Form, will receive two 3-day courses of tetracycline with a 12-day 
window between the first and second course. The bone biopsy must occur 4 to 6 days after the 
second tetracycline course. Subjects should be instructed to avoid food and drink for 6 hours 
before the procedure, although small amounts of clear fluids are allowed. 




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The following clinical laboratory assessments will be performed:
Chemistry
Blood samples for serum chemistry will be collected at the time points described in Table 1 and 
will include:
Sodium
Phosphate
-HCG a,b
Potassium
Magnesium
FSH a,b
Blood urea nitrogen
Total CO2 (Bicarbonate)
Creatinine
Albumin
Calcium
Aspartate transaminase 
Chloride
Alanine transaminase 
Thyroid stimulating hormone (TSH)a
Alkaline phosphatase 
25-hydroxyvitamin D
1,25-dihydroxyvitamin D
Creatinine clearance and glomerular filtration rate will be estimated (eGFR) by the laboratory. 
-HCG=beta-human chorionic gonadotropin; FSH=follicle-stimulating hormone; T3=triiodothyronine; TSH=thyroid stimulating 
hormone.
a Baseline only. 
b Females only.
Hematology
Blood samples for hematology will be collected at the time points described in Table 1 and will 
include:
Hemoglobin
Platelet count
Hematocrit
White blood cell (WBC) count
Red blood cells (RBC)
WBC differentials
Urinalysis
A urine sample for urinalysis will be collected at the time points described in Table 1 and will 
include:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein, leukocyte esterase, and/or blood is/are detected during urinalysis. At a 
minimum, the microscopic examination will consist of red blood cells, white blood cells, casts, and bacteria.
24-Hour Urine
At the beginning of the study, the investigator should recommend an individualized target dietary 
(non-supplement) calcium intake for each subject to ingest consistently throughout the study on 
24-hour urine collection days. The 24-hour urine collections should generally be performed by 
the subject within 2 weeks prior to or within 2 days follow a study visit. 


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These 24-hour urine collections may be analyzed in a local laboratory. To the greatest extent 
possible, the same laboratory should analyze the 24-hour urine collections throughout the study. 
Results from the last 24-hour urine collection obtained in Columbia protocol AAAE0544 will be 
used as the baseline assessment in this study.
When collecting 24-hour urine specimens subjects should be instructed to take their currently 
prescribed calcium, vitamin D (both parent and active) and rhPTH(1-84) doses.
A 24-hour urine sample will be collected at the time points described in Table 1 and will include:
Calcium
Sodium
Creatinine
Total Volume
Phosphate
Magnesium
7.2.3.3
Pregnancy Test
A serum and urine pregnancy test will be performed on all females of childbearing potential at 
the baseline visit (Visit 1). Additionally, a urine pregnancy test will be performed at all 
scheduled study visits.
7.2.3.4
PTH Antibodies
A blood sample for PTH antibodies will be collected at the time points described in Table 1. 
Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any 
subject with newly developed PTH-specific antibodies at the end of treatment visit may require 
follow up. This will be discussed as necessary by the PI and medical monitor on a case-by-case 
basis.
7.2.3.5
Vital Signs
Vital signs include blood pressure, heart rate, body temperature, and respiration rate. Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study). Any clinically significant deviations from baseline (Visit 1) vital 
signs which are deemed clinically significant in the opinion of the investigator are to be recorded 
as an AE.
7.2.3.6
Physical Examination
A physical examination including height and weight will be conducted at baseline, Month 12, 
and Month 24. Abnormalities identified at the baseline visit (Visit 1) will be documented in the 
subject’s source documents and on the medical history eCRF. Any clinically significant 
deviations from baseline (Visit 1) in physical examination findings which are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
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 eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
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 assess the relationship to investigational product for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If there is no 
valid reason for suggesting a relationship, then the AE should be classified as “not related”. 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
possible cause-and-effect relationship between the investigational product and the occurrence of 
the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. 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.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital signs 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. 


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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 or vital signs 
values which were not present at the pre-treatment 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 (ie, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital signs parameter is clinically significant 
and therefore represents an AE.
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 7.1.3.
Any report of pregnancy for any female 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 postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG (beta-human chorionic gonadotropin) test or ultrasound result will determine the 
pregnancy onset date.
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. 


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The categories below are not mutually exclusive; the event can meet more than 1 category.
Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
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 the protocol)
Overdose – Intentional or unintentional intake of a dose of an investigational product exceeding 
a pre-specified total daily dose of 250 µg of the product.
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 an expired investigational product should be considered as a 
reportable medication error.
Acute accidental overdosage of rhPTH(1-84) can result in transient hypercalcemia and 
hypercalciuria. Treatment of suspected overdose should include temporary discontinuation of 
rhPTH(1-84), monitoring of serum calcium, and implementation of appropriate, supportive 
measures such as hydration. Due to the relatively short duration of the pharmacological activity 
of rhPTH(1-84), further measures should not be necessary.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigators brochure, which the 
sponsor has provided under separate cover to all investigators. 
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs 
does not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) 
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 Global Pharmacovigilance 
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-up reports) must also be sent to the Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it was more severe.

Requires inpatient 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 inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.


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In addition, any signs or symptoms experienced by the subject after signing the ICF, 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 and/or CRO is responsible for notifying the relevant regulatory authorities/US 
central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and/or CRO is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the SHP634-402 program. 
The investigator is responsible for notifying the local IRB, local Ethics Committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF 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. It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the study data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.


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Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Not Applicable.
9.4
Statistical Analysis Process
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy 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, study treatment exposure, and prior and concomitant medications. The SAP will 
also include a description of how missing, unused and spurious data will be addressed.
All statistical analyses will be performed using Statistical Analysis System (SAS) (SAS 
Institute, Cary, NC, USA) version 9.3 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A retrospective analysis of historical data captured from the medical records of subjects (eg, 
since the start of rhPTH(1-84) treatment) will be conducted. These data will be derived from the 
medical records of subjects that are exclusively from the core study (Protocol AAAE0544 at 
Columbia University Medical Center [HEXT: The Hypoparathyroidism Studies, EXTended: The 
Effect of PTH on the Skeleton in Hypoparathyroidism]). Data collected will include but is not 
limited to, medical history and clinical laboratory data that can be source data verified. There are 
no formal hypotheses testing for the retrospective analysis. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) 
treatment baseline, if applicable. 
There will be no Data Monitoring Committee for this unblinded exploratory study, however 
results of the prospective data portion of the study will be analyzed as necessary for safety 
monitoring and publication purposes.
9.6
Sample Size Calculation and Power Considerations
No formal sample size calculation was performed.
9.7
Study Population
The Safety Population will be used for all analysis in this study and consists of all subjects who 
receive at least 1 dose of rhPTH(1-84). 




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9.9
Safety Analyses
Safety analysis will be conducted on the safety population as defined in Section 9.7. The 
following safety variables constitute the safety endpoints measured in this study:

AEs including SAEs

Vital signs including body temperature (°C/°F), heat rate (beats per minute), respiratory rate, 
and blood pressure (systolic and diastolic [mmHg])

Estimated Glomerular Filtration Rate (eGFR) and creatinine clearance

Measurement of PTH antibody

Laboratory safety data (eg, clinical chemistry, hematology and urinalysis)
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of treatment-emergent adverse 
events (TEAEs) will be calculated overall, by system organ class (SOC), by preferred term, and 
by treatment group. TEAEs will be further summarized by severity and relationship to 
investigational product. AEs related to investigational product, AEs leading to withdrawal, 
SAEs, and deaths will be similarly summarized/listed. Clinical laboratory tests and vital signs 
findings will be summarized by treatment group and visit. Potentially clinically important 
findings will also be summarized or listed.
9.10
Other Analyses
Any available historical laboratory and medical history data derived from the medical records 
from subjects (since the start of rhPTH(1-84) treatment) will be summarized. All subjects are 
exclusively from the core study (Protocol AAAE0544 at Columbia University Medical Center 
[HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in 
Hypoparathyroidism]).
These data will be collected in the following order of priority: 
Priority 1:

Serum calcium and albumin

Urine calcium excretion (to include 24 hour urine collections or estimates of 24 hour 
excretion based on 2 hour collections)

Serum phosphate

Serum creatinine

SF-36 results

24 hour urine creatinine, volume
Priority 2:

Calcium and Vitamin D supplement doses

Serum magnesium

DXA bone density results

HRpQCT results


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Priority 3:

25-OH Vitamin D and 1,25-dihydoxy-Vitamin D levels

Medical History/

Bone Turnover Markers

Vital signs (body temperature, heat rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)

24 hour urine phosphate, sodium
Descriptive statistics will used to evaluate the historical data, if applicable.
9.10.1
Health-related Quality of Life Analyses
SF-36 endpoints will be measured. For each endpoint, the change in Quality of Life score from 
baseline to the end of treatment will be measured relative to those measured just prior to 
beginning rhPTH(1-84) treatment and relative to Visit 1 in this study.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements. 
The name and address of each third party vendor (ie, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), European Union (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 eCRFs in accordance with current Good Clinical Practice (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.


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10.1.2
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.
10.1.3
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 (CSR) 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.
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995).


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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 principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms (CRFs) are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. CRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries will be sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
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.
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 eCRF 
entries against the source documents. 


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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 Food and 
Drug Administration (FDA), European Medicines Agency (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.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data collected for and generated by this study 
must be available for inspection upon request by representatives of, for example, the US FDA (as 
well as other US national and local regulatory authorities), the EMA, the Medicines and 
Healthcare Products Regulatory Agency, other regulatory authorities, the sponsor or its 
representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and ICH GCP. The Informed 
Consent procedure has been modified to allow remote consenting of subjects for this phase 
4 study. A member of the study team will send the Informed Consent document by mail or 
e-mail to the subject and discuss the document by telephone. 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. The subject will return their 
signed informed consent document to the site. Upon receipt of the subject’s consent, the 
authorized consenter who performed the remote informed consent procedure will physically 
sign and date the consent document as well. 


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A copy of the informed consent documentation (ie, a complete set of subject information 
sheets and fully executed signature pages) must be given to the subject or the subject’s 
legally-authorized representative, as applicable. This document may require translation into the 
local language. Signed consent forms must remain in each subject’s study file and must be 
available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form 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
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.
Responsibility for coordinating with IRBs/ECs is defined in the investigator 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/CRO has received written 
IRB/EC approval of and copies of revised documents.
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.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO/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 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market rhPTH(1-84); national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (ie, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. 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 necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must; however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.




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12
APPENDICES




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APPENDIX 2
HYPOPARATHYROIDISM SYMPTOM DIARY























Prot_000.pdf: 
PROTOCOL: SHP634-402
TITLE:
A Phase 4, Open-Label, Single-Center Clinical Study of Extended use 
of rhPTH(1-84) in Hypoparathyroidism
DRUG:
rhPTH(1-84)
IND
076514
BLA:
125511
SPONSOR
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD
PROTOCOL 
HISTORY:
Original Protocol: 27 May 2016
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 the express written 
consent of Shire.
For non-commercial use only


For non-commercial use only


 
 
 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Not applicable. This is Version 1.0 of the protocol.
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For non-commercial use only


 
 
 
 
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 24 
hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the 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:
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................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE ....................................................................................................................16
1.
BACKGROUND INFORMATION.......................................................................................18
1.1
Indication and Current Treatment Options...............................................................18
1.2
Product Background.................................................................................................19
1.2.1
Preclinical Information ..........................................................................................19
1.2.2
Clinical Information...............................................................................................20
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objectives.................................................................................................22
2.2.2
Secondary Objectives.............................................................................................22
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design and Flow Chart ..................................................................................23
3.2
Duration and Study Completion Definition .............................................................25
3.3
Sites and Regions .....................................................................................................25
3.4
Discussion of Study Design .....................................................................................25
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................28
4.3.1
Female Contraception............................................................................................28
4.3.2
Male Contraception................................................................................................28
4.4
Discontinuation of Subjects .....................................................................................28
4.4.1
Subject Withdrawal Criteria ..................................................................................28
4.4.2
Reasons for Discontinuation..................................................................................28
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4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Treatment ........................................................................................................30
5.2
Concomitant Treatment............................................................................................30
5.2.1
Permitted Treatment...............................................................................................30
5.2.2
Prohibited Treatment .............................................................................................30
5.2.3
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation ....................................................................................................30
5.2.3.1
Active Vitamin D ...................................................................................30
5.2.3.2
Native Vitamin D ...................................................................................30
5.2.3.3
Calcium ..................................................................................................31
5.2.3.4
Magnesium.............................................................................................31
5.2.4
Thiazide Diuretics..................................................................................................31
6.
INVESTIGATIONAL PRODUCT ........................................................................................32
6.1
Identity of Investigational Product...........................................................................32
6.1.1
Blinding the Treatment Assignment......................................................................32
6.2
Administration of Investigational Product(s)...........................................................32
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dosing....................................................................................................................33
6.2.3
Unblinding the Treatment Assignment..................................................................33
6.3
Labeling, Packaging, Storage, and Handling ...........................................................33
6.3.1
Packaging...............................................................................................................33
6.3.2
Labeling .................................................................................................................33
6.3.3
Storage ...................................................................................................................34
6.3.4
Special Handling....................................................................................................34
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................35
7.
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Baseline Visit (Visit 1)...........................................................................................37
7.1.2
Treatment Period....................................................................................................38
7.1.2.1
Visit 2, (Month 6)...................................................................................38
7.1.2.2
Visit 3 (Month 12)..................................................................................38
7.1.2.3
Visit 4 (Month 18)..................................................................................38
7.1.2.4
EOT Visit (Month 24)............................................................................38
7.1.3
Additional Care of Subjects after the Study ..........................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographic and Other Baseline Characteristics .................................................38
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7.2.2
Efficacy..................................................................................................................39
7.2.2.1
Biochemical Evaluations........................................................................39
7.2.2.2
Hypoparathyroidism Multisymptom Questionnaire...............................39
7.2.2.3
Cognition Tool .......................................................................................39
7.2.2.4
FACIT Fatigue Scale..............................................................................39
7.2.2.5
HADS Assessment .................................................................................39
7.2.2.6
Short Form Health Survey-36 ................................................................39
7.2.2.7
Bone Mineral Density ............................................................................40
7.2.2.8
Bone Biopsy...........................................................................................40
7.2.2.9
.............................................................40
7.2.3
Safety .....................................................................................................................40
7.2.3.1
Adverse Event Collection.......................................................................40
7.2.3.2
Clinical Laboratory Evaluations.............................................................41
7.2.3.3
Pregnancy Test .......................................................................................42
7.2.3.4
PTH Antibodies......................................................................................42
7.2.3.5
Vital Signs..............................................................................................43
7.2.3.6
Physical Examination.............................................................................43
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease Under Study .................................................................45
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................45
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................50
9.1
Data Collection.........................................................................................................50
9.2
Clinical Data Management.......................................................................................50
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9.3
Data Handling Considerations..................................................................................50
9.4
Statistical Analysis Process......................................................................................50
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......50
9.6
Sample Size Calculation and Power Considerations................................................51
9.7
Study Population ......................................................................................................51
9.8
Efficacy Analyses.....................................................................................................51
9.8.1
Primary Efficacy Endpoint ....................................................................................51
9.8.2
Secondary Efficacy Endpoints...............................................................................51
9.8.3
Exploratory Efficacy Endpoints.............................................................................51
9.9
Safety Analyses........................................................................................................52
9.10
Other Analyses .........................................................................................................52
9.10.1 Health-related Quality of Life Analyses................................................................53
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................54
10.1
Sponsor’s Responsibilities .......................................................................................54
10.1.1 Good Clinical Practice Compliance.......................................................................54
10.1.2 Public Posting of Study Information......................................................................54
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................54
10.1.4 Study Suspension, Termination, and Completion..................................................54
10.2
Investigator’s Responsibilities .................................................................................55
10.2.1 Good Clinical Practice Compliance.......................................................................55
10.2.2 Protocol Adherence and Investigator Agreement..................................................55
10.2.3 Documentation and Retention of Records.............................................................56
10.2.3.1
Case Report Forms.................................................................................56
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................56
10.2.3.3
Audit/Inspection.....................................................................................56
10.2.3.4
Financial Disclosure...............................................................................57
10.3
Ethical Considerations..............................................................................................57
10.3.1 Informed Consent...................................................................................................57
10.3.2 Institutional Review Board or Ethics Committee..................................................57
10.4
Privacy and Confidentiality......................................................................................58
10.5
Study Results / Publication Policy ...........................................................................59
11. REFERENCES .......................................................................................................................61
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LIST OF TABLES
Table 1-1:
Schedule of Study Assessments ....................................................................16
Table 6-1:
Recommended Adjustments for Active Vitamin D and Calcium 
Supplements ..................................................................................................32
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................24
LIST OF APPENDICES
Appendix 1
Hypoparathyroidism Symptom Diary ....................................................62
Appendix 2
FACT-Cognitive Function ENG ............................................................67
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ABBREVIATIONS
ACSC
albumin-corrected total serum calcium
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BLA
Biologics License Application
CI
confidence interval
CRA
Clinical Research Associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
DXA
dual-energy x-ray absorptiometry
EC
Ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
eGRF
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FACT-Cog
Functional Assessment of Cancer Therapy - Cognitive Function
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
HIPAA
Health Insurance Portability and Accountability Act
HPT
Hypoparathyroidism
HRpQCT
high-resolution peripheral quantitative computerized tomography
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board
MedDRA
Medical Dictionary of Regulatory Activities
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mmHg
millimeters of mercury
PTH
Parathyroid hormone
QD
once daily
RBC
red blood cell
rhPTH(1-84)
recombinant human parathyroid hormone
SAE
serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis System
SC
subcutaneous
SF-36
36-item Short Form Health Survey
SOC
system organ class
TEAE
treatment-emergent adverse event
US
United States
WBC
white blood cell
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STUDY SYNOPSIS
Protocol number: SHP634-402
Drug: rhPTH(1-84)
Title of the study: A Phase 4, Open-Label, Single-Center Clinical Study of Extended use of rhPTH(1-84) in 
Hypoparathyroidism
Number of subjects (total and for each treatment arm):
The subject population anticipated in this study is up to 50 subjects. All subjects are exclusively from the core study 
(HEXT: The Hypoparathyroidism Studies, EXTended: The Effect of PTH on the Skeleton in Hypoparathyroidism) 
Protocol AAAE0544 at Columbia University Medical Center, and will all receive active rhPTH(1-84) treatment.
Investigator(s):
Single site located at:
Columbia University
New York, NY 10032
Site(s) and Region(s): 
Columbia University
New York, NY 10032
Study period (planned): 24 months
Clinical phase: 4
Objectives:
Primary:

To evaluate albumin-corrected serum calcium while on rhPTH(1-84) treatment
Secondary:

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment

To evaluate disease-related symptoms, perception of cognitive function, and health-related quality-of-life 
associated with long-term rhPTH(1-84) treatment

To evaluate the skeletal actions of rhPTH(1-84): bone turnover (markers), architecture, and histology 
(biopsy)
Rationale:
Chronic hypoparathyroidism (HPT) is a life-long and irreversible disease for which the chronic administration of 
rhPTH(1-84) is a potential treatment option. Thus, long-term safety and efficacy data are important in evaluating the 
proper use of this treatment option in clinical practice.
Investigational product, dose, and mode of administration:
rhPTH(1-84); 25, 50, 75, and 100 µg for once daily subcutaneous injection to the thigh via a multidose pen injector 
device. The dose will be individualized to achieve a serum calcium level in the lower half of the normal range.
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Methodology: 
Subjects enrolled are currently or were previously enrolled in the core study (AAAE0544) and have maintained 
uninterrupted therapy with rhPTH(1-84). Study visits will be scheduled every 6 months up to the 24-month end of 
study visit. Specific procedures at each study visit are summarized in Table 1- 1. A schematic of the study design is 
provided below:
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject must meet all of the following criteria to be eligible
1.
Subjects that are currently or previously enrolled in the core study (AAAE0544) and have maintained 
uninterrupted therapy with rhPTH(1-84) (transient interruptions of up to 1 month continuously off treatment 
may be allowed).
2.
Signed and dated informed consent form (ICF).
3.
Adult men and women 18 to 85 years of age.
4.
History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, defined by the 
requirement for supplemental calcium and/or active vitamin D to maintain serum calcium along with an 
undetectable or insufficient PTH concentration.
5.
Able to perform daily subcutaneous self-injections of study medication (or have designee perform injection).
6.
Willingness and ability to understand and comply with the protocol. Women must agree to pregnancy testing 
and acceptable methods of contraception, as detailed in the protocol.
Exclusion Criteria:
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1.
The subject is treated or has been treated with any investigational drug, aside from rhPTH(1-84), within 30 
days of consent.
2.
As assessed by the investigator, the subject has a safety or medical issue that contraindicates participation 
in the study.
3.
The subject and/or the subject’s parent(s) or legally-authorized representative(s) is unable to understand the 
nature, scope, and possible consequences of the study. 
4.
The subject is unable to comply with the protocol, eg, uncooperative with protocol schedule, refusal to 
agree to all of the study procedures, inability to return for evaluations, or is otherwise unlikely to complete 
the study, as determined by the investigator or the medical monitor.
5.
The subject is pregnant or lactating.
6.
Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase, subjects with hereditary disorders predisposing to 
osteosarcoma or subjects with a prior history of external beam or implant radiation therapy involving the 
skeleton.
Maximum duration of subject involvement in the study:
Each study visit has a threshold of ±1 month with a total treatment period of 24 months. A follow-up phone call to 
assess safety will occur 30 days after the end of treatment visit.
Endpoints and Statistical Analysis: 
Primary Efficacy Endpoint:
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
Albumin-corrected serum calcium over time
Secondary Efficacy Endpoint(s):

Urinary calcium and serum phosphate over time

Calcium and active vitamin D supplement doses over time

HPT Disease-related symptoms (Multisymptom questionnaire), FACT-Cog assessment, FACIT (Fatigue 
Scale [Version 4]), and HADS (Hospital Anxiety and Depression Scale)

Health-related quality-of-life measured with SF-36 survey over time

Bone turnover (markers), architecture, and histology (biopsy) over time
Exploratory Efficacy Endpoint: 

Safety Endpoints:

AEs including SAEs

Symptoms of hypoparathyroidism

Vital signs including body temperature, heart rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Estimated Glomerular Filtration Rate (eGFR) and creatinine clearance

Measurements of antibodies to parathyroid hormone (PTH)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)
Although no formal hypotheses are being tested, 95% confidence intervals (CI) will be provided as appropriate. 
Continuous variables, including those assessed on a discrete scale, will be summarized using descriptive statistics 
including number of subjects, mean, median, standard deviation, maximum, and minimum. For categorical 
variables, statistical summaries will include number of subjects and percentages.
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from the SHP634-402 baseline, if applicable. Frequency counts will be compiled for classification of 
qualitative safety data (for example shift from baseline according to lab normal range, AEs related to treatment, 
level of severity, etc.).
Other Analyses:
A retrospective analysis of historical data captured from the medical records of subjects (eg, since the start of 
rhPTH(1-84) treatment) will be conducted. Data collected will include but is not limited to, medical history and 
clinical laboratory data. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics 
will be calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment 
baseline, if applicable.
Interim Analysis:
A retrospective analysis of historical data captured from the medical records of subjects (eg, since the start of 
rhPTH(1-84) treatment) will be conducted. Data collected will include but is not limited to, medical history and 
clinical laboratory data. There are no formal hypotheses testing for the retrospective analysis. Descriptive statistics 
will be calculated for quantitative safety data as well as for the difference from the pre-rhPTH(1-84) treatment 
baseline, if applicable.
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STUDY SCHEDULE
Table 1-1: Schedule of Study Assessments
Study Period
Baseline
Maintenance 
Dosing 
Period
End of 
Treatment
Visit
Visit 1
Visit 2-4
EOT Visita
Study Month
0
6
12
18
24
Study Procedures
±1 month
Informed Consentb
X
Inclusion/Exclusion
X
Medical history and demography
X
Prior/concomitant medications
X
X
X
X
X
Physical examination
X
X
X
Vital signsc
X
X
X
X
X
Hematology
X
X
Serum chemistryd
X
X
X
X
X
Serum TSH
X
Serum pregnancy teste
X
Urine pregnancy test
X
X
X
X
X
FSH levelf
X
Serum PTH antibodiesg
X
X
X
X
X
Serum 25-hydroxyvitamin D
X
X
X
X
X
Serum 1,25-dihydroxyvitamin D
X
X
X
X
X
Bone turnover markers
X
X
X
X
X
Urinalysis (dipstick)
X
X
24-hour urineh
X
X
X
X
Bone mineral density DXA
X
X
X
X
X
Bone mineral density HRpQCT
X
X
X
X
X
Bone biopsy (optional)
X
HPT multisymptom questionnaire
X
X
X
X
X
FACT-Cog assessment
X
X
X
X
X
SF-36
X
X
X
FACIT Fatigue Scale
X
X
X
X
X
HADS assessment
X
X
X
X
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
Dispense/Account for study drug
X
X
X
X
X
Collection of unused study drug & injection pen
X
Record any use of Calcium, Calcitriol, and/or 
Vitamin D supplements
X
X
X
X
X
Abbreviations: AE = Adverse event; DXA = dual-energy x-ray absorptiometry; HPT = Hypoparathyroidism; 
SAE=Serious adverse event; SF-36 = 36-Item Short Form Health Survey; HRpQCT = High-resolution peripheral 
quantitative computerized tomography.
a For subjects not continuing rhPTH[1-84] treatment, see Section 7.1.3.
b Remote consent allowed. Consent procedure must be complete prior to completing any Baseline assessments (can 
occur at Baseline Visit as long as complete prior to assessments). 
c Vitals signs include: blood pressure, heart rate, body temperature, and respiration rate.
d Serum chemistry panel includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, 
phosphate, magnesium, albumin, ALT, AST, and ALP.
e Pregnancy tests for females of childbearing potential.
f FSH level required for newly menopausal women.
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Table 1-1: Schedule of Study Assessments
Study Period
Baseline
Maintenance 
Dosing 
Period
End of 
Treatment
Visit
Visit 1
Visit 2-4
EOT Visita
Study Month
0
6
12
18
24
Study Procedures
±1 month
g Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any subject with newly 
developed PTH-specific antibodies at the end of treatment visit may require follow up. This will be discussed as 
necessary by the PI and medical monitor on a case-by-case basis.
h 24-hour urine collection includes urine calcium, creatinine, phosphate, magnesium and sodium analyses. Urine 
volume will be recorded. The 24-hour urine collections should generally be performed by the subject within 2 weeks 
prior to or within 2 days follow a study visit. These 24-hour urine collections may be analyzed in a local laboratory. 
To the greatest extent possible, the same laboratory should analyze the 24-hour urine collections throughout the 
study. Results from the last 24-hour urine collection obtained in Columbia protocol AAAE0544 will be used as the 
baseline assessment in this study. At the beginning of the study, the investigator should recommend an 
individualized target dietary (non-supplement) calcium intake for each subject to ingest consistently throughout the 
study on 24-hour urine collection days. When collecting 24-hour urine specimens subjects should be instructed to 
take their currently prescribed calcium, vitamin D (both parent and active) and rhPTH(1-84) doses.
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1.
BACKGROUND INFORMATION
Hypoparathyroidism (HPT) 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 (US), which rises to approximately 117,000 if 
the transient hypoparathyroid population is included (≤6 months). The same authors suggest that, 
of those 117,000 transient hypoparathyroid subjects, about 5% will become chronic.
Parathyroid hormone is an 84-amino acid protein that is secreted by the parathyroid glands. PTH 
has a variety of important physiological functions that are outlined below to explain the effects 
of absent or deficient PTH levels. Parathyroid hormone functions to help regulate bone 
metabolism and serum levels of calcium and phosphate. In general, if serum calcium 
concentrations decrease, the parathyroid glands consequently increase PTH secretion, and, if 
serum calcium concentrations increase, the parathyroid glands consequently reduce PTH 
secretion. The parathyroid glands sense the level of extracellular calcium at the surface of the 
parathyroid cell and adjust the synthesis and secretion of PTH accordingly. 
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). 
Hypoparathyroidism has also been linked to effects on mood and ideation (Arlt et al. 2002;
Velasco et al. 1999).
The kidneys are especially vulnerable in subjects with hypoparathyroidism. Circulating PTH 
promotes renal calcium reabsorption, especially at the level of the distal convoluted tubule 
(Blaine et al. 2015). In the absence of PTH, calcium can be over-excreted through the kidneys 
(Shoback 2008), leading to hypercalciuria which, together with a high-calcium-phosphate 
product, can potentially lead to nephrocalcinosis and kidney stones and, ultimately, to renal 
impairment (Blaine et al. 2015).
For further details see the recombinant human PTH (rhPTH[1-84]) investigator brochure.
1.1
Indication and Current Treatment Options 
Prior to 2015, in the absence of an approved PTH replacement therapy, management of 
hypoparathyroidism consisted of supplemental oral calcium and active vitamin D in 
pharmacological doses sufficient to maintain the serum calcium level without the disabling 
symptoms of hypocalcemia. In order to improve the absorption of calcium from the 
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gastrointestinal tract, pharmacological supplementation with active forms of vitamin D 
(eg, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], calcitriol, 1,25-dihydroxycholecalciferol or α-
calcidol [1(OH)D3]) is also required. Since PTH also functions in the kidney to stimulate the 
conversion of 25(OH)D3, the major circulating form of vitamin D, to the active vitamin D 
hormone (1,25[OH]2D3), the relative lack of circulating PTH results in a reduction of the 
production of active vitamin D. Thus, exogenous active vitamin D overcomes the synthetic block 
in endogenous production of the active vitamin D hormone in hypoparathyroidism. Together, 
supplemental oral calcium and active vitamin D have formed the mainstay of current treatment 
of subjects with hypoparathyroidism. 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 (AEs) 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 US on 23 January 2015 under the 
brand name Natpara® as a once-daily injectable dose as an adjunct to calcium and vitamin D to 
control hypocalcemia in patients with hypoparathyroidism.
1.2
Product Background 
1.2.1
Preclinical Information
A total of 46 in vivo studies in mouse, rat, rabbit, dog, and rhesus and cynomolgus monkeys 
have evaluated the 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 been performed.
In male and female rats, the administration of PTH was associated with an increase in the 
incidence of osteosarcoma. These data were interpreted as an increased risk for osteosarcoma in 
the clinic. Therefore, administration of rhPTH(1-84) should be avoided in subjects who are 
considered to be at increased risk for osteosarcoma (including those with Paget’s disease of bone 
or unexplained elevations of alkaline phosphatase, subjects with hereditary disorders 
predisposing to osteosarcoma or subjects with a history of prior external beam or implant 
radiation therapy involving the skeleton).
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Currently available results from animal reproductive toxicology studies suggest that 
rhPTH(1-84) is not associated with significant fetal or neonatal toxicity; however, the safety of 
rhPTH(1-84) in pregnant or nursing women is not established.
For full details see the rhPTH(1-84) investigator brochure.
1.2.2
Clinical Information
Study CL1-11-040 (REPLACE) was a double-blind, placebo controlled study of once daily 
(QD) SC administration of 50 μg to 100 μg of rhPTH(1-84). The 3-tiered primary endpoint 
included ≥ 50% reduction from baseline in oral calcium supplementation, ≥50% reduction from 
baseline in active Vitamin D, and albumin-corrected total serum calcium (ACSC) concentration 
maintained or normalized compared to baseline (not exceeding upper limit of normal). The 
3-tiered endpoint was met in 54.8% of rhPTH(1-84) subjects compared to 2.5% of 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 extension 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 serum calcium-phosphate product. In 
these studies, hypercalciuria was defined as an excretion of calcium in the urine greater than 
300mg per 24 hours. Data from the REPLACE Study and the long-term open label study, RACE, 
show that rhPTH(1-84) has a calcium-sparing effect, consistent with the reduction of urinary 
calcium excretion seen in a previous pharmacokinetic/pharmacodynamic study (C09-002) of 
single dose administration of rhPTH(1-84) in subjects with hypoparathyroidism in comparison 
with calcitriol administration.
The Phase 3 clinical study, REPLACE, was the largest, randomized, placebo controlled clinical 
study conducted in hypoparathyroidism population and was the pivotal study demonstrating that 
rhPTH(1-84) is effective in maintaining serum calcium levels and enabling significant decreases 
in active vitamin D and oral calcium doses. REPLACE also established the rhPTH(1-84) dose 
and dose titration and evaluated the physiologic effects of PTH replacement on serum calcium, 
serum phosphate, urinary calcium excretion and bone turnover markers. Eighty-four subjects 
were evaluated in the active treatment group and 40 subjects received placebo. Subjects received 
at a flexible dose range of 50 to 100 μg SC in the thigh once daily for 6 months. The study met 
the primary efficacy triple endpoint, with a statistically higher responder rate (54.8%) versus 
placebo (2.5%). To meet the primary endpoint a subject had to fulfill all 3 conditions as follows: 
a 50% or greater reduction in oral calcium requirement, a 50% or greater reduction in active 
vitamin D therapy and an ACSC concentration that was maintained within a range of 7.5 to 10.6 
mg/dL.
A review of safety data across the hypoparathyroidism 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.
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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. 
Because of the potential risk of osteosarcoma, rhPTH(1-84) is recommended only for subjects 
who cannot be well controlled on calcium supplements and active forms of vitamin D alone.
Additional risks include extensions of the pharmacologic effects 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 subjects should be advised to 
take their rhPTH(1-84) dose as soon possible following a missed dose and to take oral calcium.
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).
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Recombinant human parathyroid hormone has been developed as an adjunct to calcium and 
vitamin D to control hypocalcemia in hypoparathyroidism subjects who cannot be well 
controlled with calcium and vitamin D supplementation alone. Although the development of a 
novel therapeutic agent for the treatment of hypoparathyroidism is encouraging, it is important to 
gain knowledge about the efficacy and safety of long-term use of rhPTH(1-84) due to the chronic 
nature of the condition. 
The AAAE0544 cohort has the longest known duration of rhPTH(1-84) therapy for the treatment 
of hypoparathyroidism to date. This protocol is designed to extend this experience and to provide 
additional data on the long-term safety and efficacy of rhPTH(1-84).
2.2
Study Objectives 
2.2.1
Primary Objectives 

To evaluate albumin-corrected serum calcium while on rhPTH(1-84) treatment
2.2.2
Secondary Objectives

To evaluate urinary calcium excretion and serum phosphate while on rhPTH(1-84) treatment

To evaluate calcium and active vitamin D supplement doses while on rhPTH(1-84) treatment 

To evaluate disease-related symptoms, perception of cognitive function, and health-related 
quality-of-life associated with long-term rhPTH(1-84) treatment.

To evaluate the skeletal actions of rhPTH(1-84): bone turnover (markers), architecture, and 
histology (biopsy)
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
Protocol SHP634-402 is a single-center, open-label, single arm, Phase 4 study of rhPTH(1-84) 
treatment in adult subjects (up to 50 subjects) diagnosed with hypoparathyroidism. 
Pre-study treatment, laboratory data, and medical history information for enrolled subjects will 
be verified. 
Subjects will be treated with rhPTH(1-84) for a two-year treatment period with study visits 
scheduled every 6 (±1) months. 
A schematic representation of the study design is provided in Figure 3-1. 
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Figure 3-1:
Study Design Flow Chart
Eligible
Subjects
Informed 
Consent / 
Baseline 
(Visit 1)
6 months     
    12 months                 18 months      
24 months     
       30 days
    Visit 2         
        Visit 3  
Visit 4       
Visit 5(EOT)            Follow-up
Treatment Period
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3.2
Duration and Study Completion Definition
The subject's maximum duration of participation in the study is approximately 25 months. The 
study Completion Date is defined as the date the final subject completes their final protocol-
defined assessment. Please note that this includes the follow-up phone contact 30 days following 
the EOT(Month 24) visit. 
3.3
Sites and Regions
This is a single-center study that will be conducted at Columbia University Medical Center, New 
York, NY.
3.4
Discussion of Study Design
This protocol is only intended for those subjects who participated and were treated in the 
AAAE0544 study. Limiting enrollment to subjects from the core study (AAAE0544) will allow 
this study to provide long-term safety and efficacy data. 
Administration via injection to the thigh has been shown to be a safe and effective delivery 
method of rhPTH(1-84). Dosing is based upon previous exposure and the recommended dosing 
in the rhPTH(1-84) package insert. The selected dose should reduce calcitriol and oral calcium 
(carbonate or citrate) supplementation to as low as safely possible while maintaining total serum 
calcium levels. All subjects will have their total serum calcium checked by a local laboratory as 
outlined in the Schedule of Study Assessments (Table 1-1). Subjects may have their 
rhPTH(1-84) dose increased in increments of 25 µg to a maximum of 100 µg SC QD by the 
investigator no more frequently than 4 week intervals during the study, with the goal of 
achieving or maintaining total serum calcium levels in the range of 8.0 to 9.0 mg/dL if clinically 
appropriate. The rhPTH(1-84) dose may be adjusted downward at any time as needed to 
maintain appropriate serum calcium levels (approximately 8.0 to 9.0 mg/dL) or due to any safety 
concerns.
Adjustment of supplemental calcium and calcitriol regimens will be based on serum calcium 
levels, with the goal to be a reduction or removal of calcitriol treatment to the maximum degree 
clinically possible and to decrease the prescribed oral calcium supplementation to ≤500 mg 
daily. 
Subjects generally should have blood draws to assess total serum calcium levels (which may be 
performed locally) 3 to 5 days after ANY dose adjustment of rhPTH(1-84), after any significant 
change in doses of calcium and/or and calcitriol supplements, or at any other time at the 
discretion of the investigator. Results of local total serum calcium levels will be entered on the 
electronic case report form (eCRF). 
During the week following the last visit (End of Treatment or early termination visit), subjects 
who are discontinuing rhPTH(1-84) treatment (ie, those who are NOT continuing on commercial 
Natpara) will have oral calcium and/or active vitamin D adjusted to compensate for the cessation 
of rhPTH(1-84). Their total serum calcium levels will be checked locally 3 to 5 days after the last 
dose of study medication. Subjects will also be scheduled for a follow-up clinic visit at the end of 
this week in order to have serum calcium and phosphate checked.
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Approximately 30 days following the End of Treatment visit, subjects will be contacted by 
telephone in order to assess AEs/serious AEs (SAEs). 
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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed. Subjects in this protocol 
are restricted to those who were treated in the core study (AAAE0544). Approximately 50 
subjects are expected to enroll in this study.
4.1
Inclusion Criteria
The subject must meet all of the following criteria to be eligible for the study:
1. Subjects that are currently or previously enrolled in the core study (AAAE0544) and have 
maintained uninterrupted therapy with rhPTH(1-84) (transient interruptions of up to 1 
month continuously off treatment may be allowed).
2. Signed and dated informed consent form (ICF).
3. Adult men and women 18 to 85 years of age.
4. History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, 
defined by the requirement for supplemental calcium and/or active vitamin D to maintain 
serum calcium along with an undetectable or insufficient PTH concentration.
5. Able to perform daily SC self-injections of study medication (or have designee perform 
injection).
6. Willingness and ability to understand and comply with the protocol. Women must agree to 
pregnancy testing and acceptable methods of contraception, as detailed in the protocol.
4.2
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1. The subject is treated or has been treated with any investigational drug, aside from 
rhPTH(1-84), within 30 days of consent.
2. As assessed by the investigator, the subject has any safety or medical issues that 
contraindicate participation in the study.
3. The subject and/or the subject’s parent(s) or legally-authorized representative(s) are 
unable to understand the nature, scope, and possible consequences of the study. 
4. The subject is unable to comply with the protocol, eg, uncooperative with protocol 
schedule, refusal to agree to all of the study procedures, inability to return for evaluations, 
or is otherwise unlikely to complete the study, as determined by the investigator or the
medical monitor.
5. The subject is pregnant or lactating.
6. Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget’s 
disease of bone or unexplained new elevations of alkaline phosphatase, subjects with 
hereditary disorders predisposing to osteosarcoma or subjects with a prior history of 
external beam or implant radiation therapy involving the skeleton.
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4.3
Reproductive Potential
4.3.1
Female Contraception
Women who are postmenopausal (absence of menses for at least 1 year) and women who are 
surgically sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy) can be enrolled. 
Women of childbearing potential must have a negative pregnancy test and agree to use medically 
acceptable methods of contraception for the duration of the study with pregnancy testing at every 
scheduled visit. 
Medically acceptable methods of contraception include: true sexual abstinence (not having any 
type of intercourse or sex play with a male partner); hormonal methods of contraception (oral, 
injected, vaginal rings, patch, implanted, etc.); placement of an intrauterine device or intrauterine 
system; barrier methods of contraception (condom or occlusive diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository. Women whose partner is a woman or whose 
partner is a man with a history of vasectomy are exempt.
4.3.2
Male Contraception
Not Applicable.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product [rhPTH(1-84)] with 
the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for End 
of Treatment (EOT) Visit are to be performed as completely as possible. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents and as AEs, as applicable. The reason for termination, date of stopping rhPTH(1-84) 
and the total amount of rhPTH(1-84) taken must be recorded in the electronic case report form 
(eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Subject Withdrawal Criteria
Subjects can withdraw from the study at any time for any reason. 
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF. 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 eCRF. Reasons for discontinuation include but are not limited to:
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
Completed

Adverse event

Protocol deviation

Withdrawal by subject

Lack of efficacy

Lost to follow-up

Other (If “Other” is selected, the investigator must specify on the eCRF: Examples are 
provided below)

Death

Physician decision

Pregnancy

Site terminated by sponsor

Study terminated by sponsor
4.4.3
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
All non-study treatment, including but not limited to herbal treatment, vitamins, behavioral 
treatment, non-pharmacological treatment (such as psychotherapy), as appropriate, received 
within 30 days prior to the Baseline Visit (Visit 1) (or pharmacokinetic equivalent of 5 half-lives, 
whichever is longer) and through the final study contact (including protocol defined follow-up 
period) must be recorded on the appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment, including but not limited to herbal treatment, vitamins, 
behavioral treatment, non-pharmacological treatment (such as psychotherapy), as appropriate as 
of the time of enrollment in Study SHP634-402. Prior treatment information must be recorded on 
the appropriate eCRF page. All available active vitamin D and calcium supplement doses from 
the beginning of rhPTH(1-84) will be recorded.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
rhPTH(1-84) and the end of the follow-up period in the SHP634-402 study, inclusive. 
Concomitant treatment information must be recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Any treatment for an existing or obtained condition(s) will be permitted. Active vitamin D, 
native vitamin D, calcium and magnesium supplementation, and thiazide use are permitted. Prior 
treatment with rhPTH(1-84) is permitted.
5.2.2
Prohibited Treatment
The use of any other investigational product within 30 days prior to study enrollment or at any 
time during the trial is prohibited. Additionally, any medication that affects bone metabolism (eg, 
selective estrogen receptor modulators, calcitonin, bisphosphonates) and any other 
investigational products are prohibited while on rhPTH(1-84) treatment. 
5.2.3
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation
5.2.3.1
Active Vitamin D
Subjects enrolled in this study may be taking active vitamin D to control serum calcium levels. 
Prior and concomitant prescribed doses of calcitriol will be entered on the appropriate eCRF. 
5.2.3.2
Native Vitamin D 
Subjects should receive native vitamin D to maintain the subject’s serum 25(OH) vitamin D level
in the normal range (≥ 30 ng/ml and ≤ the upper limit of normal for the laboratory). Prior and 
concomitant doses of native vitamin D must be recorded on the appropriate eCRF.
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5.2.3.3
Calcium
Subjects enrolled in this study may be taking oral calcium supplements (either calcium carbonate 
or calcium citrate). Prior and concomitant prescribed doses of calcium will be entered on the 
appropriate eCRF. 
In the case that extra calcium supplementation is taken by the subject due to symptoms of 
hypocalcemia, the dose/time and associated symptoms should be recorded by the subject in a 
diary. 
5.2.3.4
Magnesium 
Magnesium is required for normal parathyroid function and disordered magnesium levels can 
exacerbate hypoparathyroidism. Subjects with low serum magnesium may receive 
supplementation to keep the serum magnesium level in the normal range. Prior and concomitant 
doses of magnesium must be recorded on the appropriate eCRF.
5.2.4
Thiazide Diuretics
Subjects in this study may be taking thiazide diuretics (hydrochlorothiazide or chlorthalidone) to 
limit the extent and effect of hypercalciuria. Prior and concomitant prescribed doses of thiazide 
diuretics will be entered on the appropriate eCRF.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The investigational 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, 75µg, and 100µg. The investigational 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.
6.1.1
Blinding the Treatment Assignment
This is an open-label single-arm study where all subjects will be administered study drug; 
therefore, no blinding will occur.
6.2
Administration of Investigational Product(s)
The following instructions describe how to administer the investigational product:
Adjust dose of active vitamin D or calcium supplement or both based on serum calcium value 
and clinical assessment (ie, signs and symptoms of hypocalcemia or hypercalciuria). Suggested 
adjustments to active vitamin D and calcium supplement based on serum calcium levels are 
provided in Table 6-1.
Table 6-1: Recommended Adjustments for Active Vitamin D and Calcium Supplements
Adjust First
Adjust Second
Serum Calcium
Active Vitamin D Forms
Calcium Supplement
Above the Upper Limit of 
Normal (10.6 mg/dL)
Decrease or Discontinue *
Decrease
Greater than 9 mg/dL and below 
the Upper Limit of Normal (10.6 
mg/dL)
Decrease or Discontinue *
No change or decrease if active 
vitamin D has been discontinued
Less than or equal to 9 mg/dL 
and above 8 mg/dL
No change
No change
Lowers than 8 mg/dL
Increase
Increase
*Discontinue in patients receiving lowest available dose
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6.2.1
Allocation of Subjects to Treatment 
This is an open-label, single-center study where all subjects will receive rhPTH(1-84).
6.2.2
Dosing
The dose of rhPTH(1-84) will be individualized based on SCAC and 24-hour calcium urinary 
excretion. The recommended rhPTH(1-84) dose will be the minimum dose required to prevent 
both hypocalcemia and hypocalciuria. This dose will generally be the dose that maintains SCAC 
within the lower half of the normal range (ie, between 8 and 9 mg/dL) without the need for 
active forms of vitamin D and with calcium supplementation sufficient and individualized to 
meet the patient’s daily requirements. 
The doses of rhPTH(1-84), active vitamin D, and calcium supplements will be prescribed on an 
individual basis. Dosing guidelines found in the US package insert will be used but may be 
individualized at the discretion of the investigator. 
Doses of active forms of vitamin D and calcium supplements will be adjusted when using 
rhPTH(1-84).
6.2.3
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Packaging
The study site will receive open label supplies of investigational product, injection pens and 
mixing devices required for dosing.
Each subject will receive 2 pens for use during the study period and sufficient cartridges to 
provide daily doses for the duration of the study. Drug cartridges will be provided in kits
containing 8 cartridges each and each kit will be sufficient for up to 16 weeks of treatment. Each 
cartridge will contain study drug for 14 doses. Drug cartridges will be provided at each clinic 
visit in sufficient quantity and at appropriate dose levels to ensure uninterrupted administration 
until the next study visit. Ancillary supplies including single use needles (31-gauge) and alcohol 
wipes will be provided by the CRO to the site.
6.3.2
Labeling 
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.
6.3.3
Storage
The dual-chamber medication cartridge should be stored between 2 – 8 °C. The reconstituted 
medication can be stored for up to 14 days at these conditions. The mixing device and empty 
delivery pen (ie, unloaded) can be stored at room temperature.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an in 
house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Do not freeze or shake. Do not use rhPTH(1-84) if it has been frozen or shaken.
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6.4
Drug Accountability
The investigator will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (ie, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense 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 dispensed study drug 
will be documented on the eCRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational products being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (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 for authorization to return any investigational product prior to shipment. Shipment of all 
returned investigational products must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
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opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1-1 for a complete list of study procedures. Site visits will be conducted at 6-month 
intervals until the end of treatment (EOT) visit at month 24.
A core set of study procedures, conducted at each site visit, are defined as the following:

Prior/concomitant medications

Vital signs

Serum chemistry (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
calcium, phosphate, magnesium, albumin, ALT, AST and ALP).

Should be drawn fasting, prior to administration of calcium or vitamin D supplements 
or rhPTH(1-84) administration . If in the opinion of the investigator, it is necessary 
for a subject to take calcium and/or active vitamin D supplements prior to traveling 
for blood work, the doses of the pre-draw supplements and their timing with respect 
to the blood draw should be consistent throughout the study to the greatest extent 
possible.

Urine pregnancy test

Serum 25-hydroxyvitamin D

Serum 1,25-dihydroxyvitamin D

Bone turnover markers

Serum PTH antibodies (blood samples should be drawn prior to dosing)

24-hour urine for calcium, creatinine, phosphate, sodium excretion. Total urinary volume 
will be recorded. 

HPT multisymptom questionnaire 

FACT-Cog (Functional Assessment of Cancer Therapy - Cognitive Function) assessment 

FACIT (Functional Assessment of Chronic Illness Therapy) Fatigue Scale

HADS (Hospital Anxiety and Depression Scale) assessment 


AE/SAE monitoring

24-hour urine

Bone mineral density DXA (dual-energy x-ray absorptiometry)

Bone mineral density HRpQCT (High-resolution peripheral quantitative computerized 
tomography)

Dispense/Account for study drug
7.1.1
Baseline Visit (Visit 1)
All study procedures outlined in Table 1-1 will be conducted at the baseline visit with the 
exception of ‘Collection of unused study drug & injection pen. Additionally, the bone biopsy is 
an optional procedure, performed once any time during the study, depending on subject history 
and consent.
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7.1.2
Treatment Period 
7.1.2.1
Visit 2, (Month 6)
The core set of study procedures will be conducted at this visit.
7.1.2.2
Visit 3 (Month 12)
The core set of study procedures will be conducted at this visit. In addition to the core study 
procedures, the following procedures will be performed:

Physical Examination

SF-36 (36-Item Short Form Health Survey)
7.1.2.3
Visit 4 (Month 18)
The core set of study procedures will be conducted at this visit.
7.1.2.4
EOT Visit (Month 24)
All study procedures outlined in Table 1-1 will be performed at this visit except for the 
following:

Informed consent

Inclusion/exclusion

Medical history and demography

Serum thyroid stimulating hormone (TSH) 

Serum pregnancy test

Follicle-stimulating hormone (FSH) level
7.1.3
Additional Care of Subjects after the Study
After the EOT visit or early termination visit, subjects who will not continue rhPTH[1-84] 
treatment will have serum calcium and phosphate levels measured 3 to 5 days after the last dose 
of study medication. Doses of calcium and active vitamin D supplements will be adjusted by the 
investigator as appropriate according to guidelines followed in the US package insert. Thereafter, 
the investigator will repeat serum calcium/phosphate monitoring and supplement dose 
adjustments as appropriate to achieve target serum calcium/phosphate concentrations until the 
follow up phone call 30 days ± 7 days after EOT visit. After the 30-day follow-up phone call, 
further management of hypoparathyroidism will occur as part of the subject’s long-term non-
study medical care.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics will be recorded at the Baseline visit including date of birth, sex, 
and race on the eCRF for each subject. 
Medical history including etiology of hypoparathyroidism and duration of hypoparathyroidism 
will be recorded on the eCRF for each subject. 
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Pre-study rhPTH(1-84) treatment will be recorded on the eCRF for each subject.
Pre-study laboratory data will be recorded on the eCRF for each subject.
7.2.2
Efficacy
7.2.2.1
Biochemical Evaluations
Biochemical evaluation including serum calcium, PTH, albumin, phosphate, alkaline 
phosphatase, urine calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D will be 
collected at the time points specified in Table 1-1 to assess efficacy and bone turnover.
7.2.2.2
Hypoparathyroidism Multisymptom Questionnaire 
The Hypoparathyroidism Symptom Diary is a 15-item tool describing the subject’s experience 
related to hypoparathyroidism during the past 24 hours (Appendix 1). 
7.2.2.3
Cognition Tool
The FACT-Cog assessment is a 37-item tool (Cella 1997). It includes 4 subscales: perceived 
cognitive impairments, impact of perceived cognitive impairments on quality of life, comments 
from others and perceived cognitive ability.
7.2.2.4
FACIT Fatigue Scale
FACIT fatigue questionnaire contains 13 fatigue-related questions (Cella 1997). The responses to 
the 13 items on the FACIT fatigue questionnaire are each measured on a 4-point Likert scale. 
Thus, the total score ranges from 0 to 52. High scores represent less fatigue.
7.2.2.5
HADS Assessment 
The HADS is a 14-item scale that generates ordinal data (Zigmond and Snaith 1983). Seven of 
the items relate to anxiety and seven relate to depression. The scale is designed to avoid reliance 
on aspects of conditions that are also common somatic symptoms of illness. Each item on the
questionnaire is scored from 0-3, therefore, a person can score between 0 and 21 for either 
anxiety or depression. Data returned from the HADS is ordinal.
7.2.2.6
Short Form Health Survey-36
The SF-36 is a validated questionnaire that questions subjects about perceived physical and 
mental health and function. The SF-36 consists of 8 scaled scores, which are the weighted sums 
of the questions in their section. Each scale is directly transformed into a 0-100 scale on the 
assumption that each question carries equal weight; the lower the score the more disability. The 
higher the score the less disability ie, a score of zero is equivalent to maximum disability and a 
score of 100 is equivalent to no disability. The eight sections included in the SF-36 assessment 
are vitality, physical functioning, bodily pain, general health perceptions, physical role 
functioning, emotional role functioning, social role functioning, and mental health 
(Ware and Sherbourne 1992).
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7.2.2.7
Bone Mineral Density
DUAL-ENERGY X-RAY ABSORPTIOMETRY
Dual-energy X-ray absorptiometry scans will be performed at Baseline, Month 6, Month 12, 
Month 18, Month 24, and at the EOT visit, if it is greater than 3 months since the previous DXA 
scan. These scans will evaluate bone mineral density and T-scores of the lumbar spine (vertebra 
L1-L4), hip (total and femoral neck), and ⅓ distal radius (arm). 
Please note: DXA will NOT be completed at baseline if subject had a scan performed in the 
previous study.
HIGH-RESOLUTION PERIPHERAL QUANTITATIVE COMPUTERIZED TOMOGRAPHY
High-resolution peripheral quantitative computerized tomography will be performed at Baseline, 
Month 6, Month 12, Month 18, Month 24, and at the EOT visit. HRpQCT analyses includes 
Individual Trabecula Segmentation (ITS) analysis and finite element modeling.
7.2.2.8
Bone Biopsy
An optional transiliac bone biopsy will be performed for willing subjects, at the discretion of the 
investigator a maximum of one time during the duration of the study. 
Subjects who agree to have the bone biopsy, and have selected to participate in the procedure on 
the Informed Consent Form, will receive two 3-day courses of tetracycline with a 12-day 
window between the first and second course. The bone biopsy must occur 4 to 6 days after the 
second tetracycline course. Subjects should be instructed to avoid food and drink for 6 hours 
before the procedure, although small amounts of clear fluids are allowed. 
The incision will be made at the iliac crest, and a bone biopsy needle used to aspirate 1 to 2 
samples of bone from the hip. Investigators will follow their institutional procedures, and use the 
same techniques and equipment if possible.
Subjects should be observed for at least 1 hour postoperatively and advised to abstain from 
vigorous exercise until 1 week post-procedure. 
7.2.2.9
7.2.3
Safety
7.2.3.1
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (ie, “Have you had any health problems since your last visit?”). 
Adverse events will be collected from the time informed consent is signed. (Please refer to 
Section 8, Adverse and Serious Adverse Events Assessment.)
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7.2.3.2
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, maybe 
repeated as soon as possible until confirmed, explained, or resolved, at the discretion of the 
investigator or sponsor.
Lab assessments will be performed during the site visit with the exception of the 24-hour urine 
collection, which will be collected at a local laboratory. The collection of urine may occur up to 
2 weeks before the study visit. 
The following clinical laboratory assessments will be performed:
CHEMISTRY
Blood samples for serum chemistry will be collected at the time points described in Table 1-1
and will include:
Sodium
Phosphate
-HCG a,b
Potassium
Magnesium
FSH a,b
Blood urea nitrogen
Total CO2 (Bicarbonate)
Creatinine
Albumin
Calcium
Aspartate transaminase 
Chloride
Alanine transaminase 
Thyroid stimulating hormone (TSH)a
Alkaline phosphatase 
25-hydroxyvitamin D
1,25-dihydroxyvitamin D
Creatinine clearance and glomerular filtration rate will be estimated (eGFR) by the laboratory. 
-HCG=beta-human chorionic gonadotropin; FSH=follicle-stimulating hormone; T3=triiodothyronine; TSH=thyroid stimulating 
hormone.
a Baseline only. 
b Females only.
HEMATOLOGY
Blood samples for hematology will be collected at the time points described in Table 1-1 and 
will include:
Hemoglobin
Platelet count
Hematocrit
White blood cell (WBC) count
Red blood cells (RBC)
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URINALYSIS
A urine sample for urinalysis will be collected at the time points described in Table 1-1 and will 
include:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Calcium
Microscopic examination will be conducted if protein, leukocyte esterase, and/or blood is/are detected during urinalysis. At a 
minimum the microscopic examination will consist of red blood cells, white blood cells, casts, and bacteria.
24-HOUR URINE
At the beginning of the study, the investigator should recommend an individualized target dietary 
(non-supplement) calcium intake for each subject to ingest consistently throughout the study on 
24-hour urine collection days. The 24-hour urine collections should generally be performed by 
the subject within 2 weeks prior to or within 2 days follow a study visit. These 24-hour urine 
collections may be analyzed in a local laboratory. To the greatest extent possible, the same 
laboratory should analyze the 24-hour urine collections throughout the study. Results from the 
last 24-hour urine collection obtained in Columbia protocol AAAE0544 will be used as the 
baseline assessment in this study.
When collecting 24-hour urine specimens subjects should be instructed to take their currently 
prescribed calcium, vitamin D (both parent and active) and rhPTH(1-84) doses.
A 24-hour urine sample will be collected at the time points described in Table 1-1 and will 
include:
Calcium
Sodium
Creatinine
Total Volume
Phosphate
Magnesium
7.2.3.3
Pregnancy Test
A serum and urine pregnancy test will be performed on all females of childbearing potential at 
the Baseline Visit (Visit 1). Additionally, a urine pregnancy test will be performed at all 
scheduled study visits.
7.2.3.4
PTH Antibodies
A blood sample for PTH antibodies will be collected at the time points described in Table 1-1. 
Blood samples for antibody testing should be collected prior to dosing with PTH[1-84]. Any 
subject with newly developed PTH-specific antibodies at the end of treatment visit may require 
follow up. This will be discussed as necessary by the PI and medical monitor on a case-by-case 
basis.
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7.2.3.5
Vital Signs
Vital signs include blood pressure, heart rate, body temperature, and respiration rate. Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study). Any clinically significant deviations from Baseline (Visit 1) vital 
signs which are deemed clinically significant in the opinion of the investigator are to be recorded 
as an AE.
7.2.3.6
Physical Examination
A physical examination including height and weight will be conducted at Baseline, Month 12, 
and Month 24. Abnormalities identified at the Baseline Visit (Visit 1) will be documented in the 
subject’s source documents and on the medical history eCRF. Any clinically significant 
deviations from Baseline (Visit 1) in physical examination findings which are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
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 eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
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 assess the relationship to investigational product for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If there is no 
valid reason for suggesting a relationship, then the AE should be classified as “not related”. 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
possible cause-and-effect relationship between the investigational product and the occurrence of 
the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. 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.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital signs assessment can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an
already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
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or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory or vital signs values 
which were not present at the pre-treatment 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 (ie, concomitant disease) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital signs parameter is clinically significant 
and therefore represents an AE.
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 7.1.3.
Any report of pregnancy for any female 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 postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG (beta-
human chorionic gonadotropin) test or ultrasound result will determine the pregnancy onset date.
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.
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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 the protocol)
Overdose – Intentional or unintentional intake of a dose of an investigational product exceeding 
a pre-specified total daily dose of 250 µg of the product.
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 an expired investigational product should be considered as a 
reportable medication error.
Acute accidental overdosage of rhPTH(1-84) can result in transient hypercalcemia and 
hypercalciuria. Treatment of suspected overdose should include temporary discontinuation of 
rhPTH(1-84), monitoring of serum calcium, and implementation of appropriate, supportive 
measures such as hydration. Due to the relatively short duration of the pharmacological activity 
of rhPTH(1-84), further measures should not be necessary.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigators brochure, which the 
sponsor has provided under separate cover to all investigators. 
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) 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 Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
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must also be sent to the Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it was more severe.

Requires inpatient 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 inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the ICF, 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 and/or CRO is responsible for notifying the relevant regulatory authorities/US 
central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and/or CRO is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the SHP634-402 program. 
The investigator is responsible for notifying the local IRB, local Ethics Committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF 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. It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the study data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Not Applicable.
9.4
Statistical Analysis Process
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy 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, study treatment exposure, and prior and concomitant medications. The SAP will 
also include a description of how missing, unused and spurious data will be addressed.
All statistical analyses will be performed using Statistical Analysis System (SAS) (SAS 
Institute, Cary, NC, USA) version 9.3 or higher. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A retrospective analysis of historical data captured from the medical records of subjects (eg, 
since the start of rhPTH(1-84) treatment) will be conducted. Data collected will include but is not 
limited to, medical history and clinical laboratory data. There are no formal hypotheses testing 
for the retrospective analysis. Descriptive statistics will be calculated for quantitative safety data 
as well as for the difference from the pre-rhPTH(1-84) treatment baseline, if applicable.
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9.6
Sample Size Calculation and Power Considerations
No formal sample size calculation was performed.
9.7
Study Population
The Safety Population will be used for all analysis in this study and consists of all subjects who 
receive at least 1 dose of rhPTH(1-84). 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint

Albumin-corrected serum calcium over time
The primary efficacy endpoint is defined as the albumin-corrected serum calcium concentration 
over time at each study visit (ie, every 6 months). The Baseline serum calcium concentration is 
the final measurement taken prior to initiating treatment.
The change and percentage changes from baseline will be summarized at each visit. No formal 
statistical test will be conducted. 95% confidence intervals (CI) will be provided as appropriate.
9.8.2
Secondary Efficacy Endpoints
The secondary endpoints are defined as follows:

Urinary calcium and serum phosphate over time

Calcium and active vitamin D supplement doses over time

HPT Disease-related symptoms (Multisymptom questionnaire), FACT-Cog assessment, 
FACIT (Fatigue Scale [Version 4]), and HADS

Health-related quality-of-life measured with SF-36 survey over time

Bone turnover (markers), architecture, and histology (biopsy) over time
For continuous variables, the change and percent changes from baseline will be summarized 
using descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. The same analysis using core study (AAAE0544) baseline will be 
performed. CIs of 95% will be provided as appropriate. For categorical variables, statistical 
summaries will include number of subjects and percentages. 
9.8.3
Exploratory Efficacy Endpoints

Exploratory endpoints will be summarized with descriptive statistics or frequency counts and 
percentage as appropriate.
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9.9
Safety Analyses
Safety analysis will be conducted on the safety population as defined in Section 9.7. The 
following safety variables constitute the safety endpoints measured in this study:

AEs including SAEs

Symptoms of hypoparathyroidism

Vital signs including body temperature (°C/°F), heat rate (beats per minute), respiratory rate,
and blood pressure (systolic and diastolic [mmHg])

Estimated Glomerular Filtration Rate (eGFR) and creatinine clearance

Measurement of PTH antibody

Laboratory safety data (eg, clinical chemistry, hematology and urinalysis)
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of treatment-emergent adverse 
events (TEAEs) will be calculated overall, by system organ class (SOC), by preferred term, and 
by treatment group. TEAEs will be further summarized by severity and relationship to 
investigational product. AEs related to investigational product, AEs leading to withdrawal, 
SAEs, and deaths will be similarly summarized/listed. Clinical laboratory tests and vital signs 
findings will be summarized by treatment group and visit. Potentially clinically important 
findings will also be summarized or listed.
9.10
Other Analyses
Historical laboratory and medical history data on each subject will be summarized. 
Any available historical data will be collected in the following order of priority: 
Priority 1:

Serum calcium and albumin

Urine calcium excretion (to include 24 hour urine collections or estimates of 24 hour 
excretion based on 2 hour collections)

Serum phosphate

Serum creatinine•SF-36 results
Priority 2:

Calcium and Vitamin D supplement doses

Serum magnesium

DXA bone density results

HRpQCT results•24 hour urine creatinine, volume
Priority 3:
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
25-OH Vitamin D and 1,25-dihydoxy-Vitamin D levels

Medical History/

Bone Turnover Markers

Vital signs (body temperature, heat rate, respiratory rate, and blood pressure (systolic and 
diastolic)

Electrocardiogram (ECG) parameters (atrial and ventricular rates and PR, QRS, and QTc 
intervals)

Laboratory safety data (eg, clinical chemistry, hematology, and urinalysis)

24 hour urine phosphate, sodium

Bone histology and histomorphometry results

Descriptive statistics will used to evaluate the historical data, if applicable.
9.10.1
Health-related Quality of Life Analyses
SF-36 endpoints will be measured. For each endpoint, the change in Quality of Life score from 
baseline to the end of treatment will be measured relative to those measured just prior to 
beginning rhPTH(1-84) treatment and relative to Visit 1 in this study.
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC and its 
updates, and local ethical and legal requirements. 
The name and address of each third party vendor (ie, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), European Union (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 eCRFs in accordance with current Good Clinical Practice (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
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.
10.1.3
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 (CSR) 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.
10.1.4
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 
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registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), 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 principal investigator according to national provisions and 
will be documented in the investigator agreement.
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10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms (CRFs) are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. CRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries will be sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
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.
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 eCRF 
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 Food and 
Drug Administration (FDA), European Medicines Agency (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.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data collected for and generated by this study 
must be available for inspection upon request by representatives of, for example, the US FDA (as 
well as other US national and local regulatory authorities), the EMA, the Medicines and 
Healthcare Products Regulatory Agency, other regulatory authorities, the sponsor or its 
representatives, and the IRB/EC for each site.
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10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and ICH GCP. The Informed 
Consent procedure has been modified to allow remote consenting of subjects for this phase 4 
study. A member of the study team will send the Informed Consent document by mail or e-mail 
to the subject and discuss the document by telephone. 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. The subject will return their signed informed consent 
document to the site. Upon receipt of the subject’s consent, the authorized consenter who 
performed the remote informed consent procedure will physically sign and date the consent 
document as well. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form 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
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.
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Responsibility for coordinating with IRBs/ECs is defined in the investigator 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/CRO has received written 
IRB/EC approval of and copies of revised documents.
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.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market rhPTH(1-84); national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (ie, 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.
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10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. 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.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
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 
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(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11.
REFERENCES
Arlt, W., Fremerey, C., Callies, F., Reincke, M., Schneider, P., Timmermann, W. & Allolio, B. 
2002. Well-being, mood and calcium homeostasis in patients with hypoparathyroidism 
receiving standard treatment with calcium and vitamin D. Eur J Endocrinol, 146, 215-22.
Avioli, 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.
Blaine, J., Chonchol, M. & Levi, M. 2015. Renal control of calcium, phosphate, and magnesium 
homeostasis. Clin J Am Soc Nephrol, 10, 1257-72.
Cella, D. 1997. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
measurement system. Evanston, IL: Center on Outcomes, Research and Education 
(CORE).
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.
Ware, J. E., Jr. & Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care, 30, 473-83.
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.
Zigmond, A. S. & Snaith, R. P. 1983. The hospital anxiety and depression scale. Acta Psychiatr 
Scand, 67, 361-70.
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APPENDIX 1 HYPOPARATHYROIDISM SYMPTOM DIARY
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ϴ͘,ŽǁǁŽƵůĚǇŽƵƌĂƚĞĂŶǇĂŶǆŝĞƚǇ ǇŽƵĨĞůƚĚƵƌŝŶŐƚŚĞƉĂƐƚϮϰŚŽƵƌƐ͍

EŽŶĞ

DŝůĚ

DŽĚĞƌĂƚĞ

^ĞǀĞƌĞ

sĞƌǇƐĞǀĞƌĞ
ϵ͘,ŽǁǁŽƵůĚǇŽƵƌĂƚĞĂŶǇƐĂĚŶĞƐƐŽƌĚĞƉƌĞƐƐŝŽŶǇŽƵĨĞůƚĚƵƌŝŶŐƚŚĞƉĂƐƚϮϰŚŽƵƌƐ͍

EŽŶĞ

DŝůĚ

DŽĚĞƌĂƚĞ

^ĞǀĞƌĞ

sĞƌǇƐĞǀĞƌĞ
ϭϬ͘,ŽǁĚŝĚǇŽƵƌŚǇƉŽƉĂƌĂƚŚǇƌŽŝĚŝƐŵŝŵƉĂĐƚǇŽƵƌƐůĞĞƉůĂƐƚŶŝŐŚƚ͍

EŽƚĂƚĂůů

^ŽŵĞǁŚĂƚ

sĞƌǇŵƵĐŚ
ϭϭ͘,ŽǁĚŝĚǇŽƵƌŚǇƉŽƉĂƌĂƚŚǇƌŽŝĚŝƐŵŝŵƉĂĐƚǇŽƵƌĂďŝůŝƚǇƚŽĞǆĞƌĐŝƐĞŝŶƚŚĞƉĂƐƚϮϰŚŽƵƌƐ͍


EŽƚĂƚĂůů

^ŽŵĞǁŚĂƚ

sĞƌǇŵƵĐŚ
6KLUH
6+33URWRFRO
&21),'(17,$/
3DJH
0D\


ϭϮ͘,ŽǁĚŝĚǇŽƵƌŚǇƉŽƉĂƌĂƚŚǇƌŽŝĚŝƐŵ ŝŵƉĂĐƚ ǇŽƵƌĂďŝůŝƚǇƚŽĐŽŵƉůĞƚĞǇŽƵƌǁŽƌŬ;ĨŽƌĞǆĂŵƉůĞ͕
ĂƚƐĐŚŽŽů͕ĂƚŚŽŵĞŽƌĂƚĂũŽďͿŝŶƚŚĞƉĂƐƚϮϰŚŽƵƌƐ͍


EŽƚĂƚĂůů

^ŽŵĞǁŚĂƚ

sĞƌǇŵƵĐŚ
ϭϯ͘,ŽǁĚŝĚǇŽƵƌŚǇƉŽƉĂƌĂƚŚǇƌŽŝĚŝƐŵŝŵƉĂĐƚǇŽƵƌƌĞůĂƚŝŽŶƐŚŝƉƐǁŝƚŚǇŽƵƌĨĂŵŝůǇ ŵĞŵďĞƌƐ ŝŶ
ƚŚĞƉĂƐƚϮϰŚŽƵƌƐ͍


EŽƚĂƚĂůů

^ŽŵĞǁŚĂƚ

sĞƌǇŵƵĐŚ
6KLUH
6+33URWRFRO
&21),'(17,$/
3DJH
0D\


 
 
 
 
APPENDIX 2 FACT-COGNITIVE FUNCTION ENG
Shire 
SHP634-402 Protocol
CONFIDENTIAL 
Page 67 
27 May 2016