A Long-term Open-label Study Investigating the Safety and Tolerability of NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH[1-84]), for the Treatment of Adults With Hypoparathyroidism - A Clinical Extension Study (RACE)
Phase: PHASE3
Conditions: Hypoparathyroidism
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
 
NCT Number:   
NCT01297309 
 
Study Title:  
A Long-term Open-label Study Investigating the Safety and Tolerability 
of NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH[1-
84]), for the Treatment of Adults with Hypoparathyroidism – A Clinical 
Extension Study (RACE) 
 
Study Number:  
PAR-C10-008 
 
Protocol Version:  
Protocol Amendment 6 
 
Protocol Version Date: 24 October 2016 

NPSP558 (rhPTH[1-84]) 
A Long-term Open-label Study Investigating the Safety and 
Tolerability of NPSP558, a Recombinant Human 
Parathyroid Hormone (rhPTH[1-84]), for the Treatment of 
Adults with Hypoparathyroidism –
A Clinical Extension Study (RACE)
Phase 3
Clinical Protocol PAR-C10-008
US IND Number: 76,514
Shire* 
300 Shire Way
Lexington, MA 02421
*NPS Pharmaceuticals was acquired by Shire on 21 February 2015
ISSUED:  
Original Protocol Version 1.0:
30 December 2010 
Amendment 1 Version 2.0:
29 June 2011
Amendment 2 Version 3.0:
05 October 2011
Amendment 3 Version 4.0:
15 March 2012
Site Amendment 4 Version 5.0:
30 May 2013
Amendment 5 Version 6.0:
3 May 2016
Amendment 6: 
24 October 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.

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SYNOPSIS
Title:  A Long-term Open-label Study Investigating the Safety and Tolerability of NPSP558, a 
Recombinant Human Parathyroid Hormone (rhPTH[1-84]), for the Treatment of Adults with 
Hypoparathyroidism – A Clinical Extension Study (RACE)
Protocol No:  PAR-C10-008 Amendment 6
Phase of Development: Phase 3
Objectives: 
Primary Objective:
The objective of this study is to demonstrate the long-term safety and tolerability of 
subcutaneous (SC) NPSP558 (rhPTH[1-84]) as hormone replacement therapy for the treatment 
of adult subjects with hypoparathyroidism.
Secondary Objectives:

To evaluate the impact of different preparations of calcium on the response to rhPTH[1-84] 
replacement therapy

To demonstrate that dosing with rhPTH[1-84] across a dose range of 25 to 100 μg SC can be 
implemented in a safe and effective manner and can be maintained throughout long-term 
treatment

To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium
Study Rationale
This study is designed to evaluate long-term treatment with rhPTH[1-84]. 
Study Design
This study is a long-term, open-label study using rhPTH[1-84] for the treatment of adult male 
and female subjects with hypoparathyroidism. Subjects can enroll if they either previously 
completed the rhPTH[1-84] RELAY study (PAR-C10-007) (8 weeks of active therapy) and/or 
completed the REPLACE study (CL1-11-040) (Visit 18).
The goal of this study is to optimize rhPTH[1-84] dosing while reducing calcitriol and oral 
calcium (carbonate or citrate) supplementation to as low as safely possible and maintaining total 
serum calcium levels.  Dose adjustments to rhPTH[1-84] and to the calcium/calcitriol 
supplements and safety monitoring of calcium levels are explained in Appendix 2, rhPTH[1-84] 
and Supplement Titration Guideline.  

The starting dose of rhPTH[1-84] for this study will be 25 or 50 g SC once daily (QD).

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
Subjects may have their rhPTH[1-84] dose adjusted by the investigator at any time 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 ANY predose (trough) total serum calcium is >11.9 mg/dL study drug will be stopped.

Subjects will 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 calcitriol supplements, or at any other time at 
the discretion of the investigator.  

Study visits during the first 12 months of the study will be conducted at Weeks 1 (baseline), 
4, 8, and then every 8 weeks thereafter up to Week 48 (Visit 8).  The Week 52 visit (Visit 9) 
is scheduled 4 weeks later.  

At any time following the Week 16 (Visit 4), subjects who are on a stable dose of rhPTH[1-
84] and have a 24-hour urine calcium >300 mg (males) and >250 mg (females) may be 
treated for hypercalciuria with calcium-sparing diuretics, if this therapy had not been 
introduced prior to the study.

At the end of Week 52, subjects will be invited to extend their study drug regimen until 
January 2018 or after the completion of the last patient’s Month 72 visit, whichever comes 
last.

During this time, subjects will return to the clinic for interim visits every 2 months (Months 
14, 16, 18, etc).  

After the End of Treatment visit or early termination visit, subjects who will not continue 
rhPTH[1-84] treatment will have their total 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.  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 4 weeks ± 7days after end of treatment visit.  After the 4 weeks follow up phone 
call, further management of hypoparathyroidism will occur as part of the subject’s long-term 
non-study medical care.
Number of Subjects Planned:  Approximately 50 subjects will be enrolled. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria
Subjects who meet all of the following inclusion criteria may be enrolled in this study: 
1. Signed and dated informed consent form before any study-related procedures are performed
2. Previously completed the rhPTH[1-84] RELAY study (8 weeks of active therapy) and/or 
previously completed the rhPTH[1-84] REPLACE study (Visit 18)
3. Able to perform daily SC self-injections of study medication (or have designee perform 
injection) via a multidose pen injector into the thigh

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4. Willingness and ability to understand and comply with the protocol
5. Women who are: (1) postmenopausal defined as 12 months amenorrhea with appropriate 
serum follicle stimulating hormone levels (> 40 IU/L); (2) surgically sterilized; OR (3) of 
childbearing potential with a negative pregnancy test at screening and who consent to use 
two acceptable methods of contraception for the duration of the study, with pregnancy testing 
at every scheduled visit.  Male subjects who have female partners of childbearing potential 
together also must use two acceptable forms of contraception during the subject’s 
participation in the study.
6. Serum creatinine <1.5 mg/dL at enrollment
7. Total serum calcium ≤ upper limit of normal (ULN) based on local laboratory result prior to 
enrollment
8. Serum 25 hydroxy (OH) vitamin D ≤1.5 times the ULN within approximately 16 weeks prior 
to enrollment
Exclusion Criteria
Subjects who meet any of the following exclusion criteria at baseline (Visit 1) are not eligible for 
enrollment in this study: 
1. Any condition that, in the investigator’s opinion after consultation with the sponsor, would 
preclude the safe use of parathyroid hormone (PTH)
2. Any disease or condition, in the opinion of the investigator, which has a high probability of 
precluding the subject from completing the study or where the subject cannot or will not 
appropriately comply with study requirements
3. Pregnant or lactating women 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, without prejudice to subsequent care.  Withdrawn subjects will not be 
replaced.  
Duration of Study/Treatment:
The duration of the study was originally intended to be about 1 year. The study has been 
extended to up to 80 months of treatment with a 4-week follow up call/visit. Therefore, the 
overall duration of the study is expected to be approximately 81 months.
Study visits will be conducted every 2 months and will continue until the subject voluntarily 
withdraws or until termination of the study. See Section 6.2 for additional follow-up for subjects 
who develop antibodies specific to PTH. See Table 6-4 for additional follow-up for subjects who 
develop antibodies specific to PTH.

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Test Product, Dose, and Mode of Administration: 
At the beginning of the study, subjects will receive rhPTH[1-84] 25 or 50 µg SC QD in an open-
label fashion as described in Section 3.1.  Subjects may have their rhPTH[1-84] dose adjusted 
upwards in increments of 25 µg to a maximum of 100 µg SC QD.  rhPTH[1-84] is to be 
administered into alternating thighs each morning via a multidose pen injector device. 
Supplements: 
Calcium citrate and calcium carbonate will be supplied by the sponsor throughout the study until 
approximately May 2014. Following this date, only calcium citrate will be provided. Calcitriol 
will be supplied by the sponsor through Week 52 only. 
Criteria for Evaluation: 
Safety: 
Safety variables will be assessed by the following evaluations: 

Adverse events (AEs) and serious adverse events (SAEs)

Incidence of AEs of hypocalcemia (eg, paresthesia, numbness, tetany) and hypercalcemia 
(eg, constipation, nausea, poor appetite or vomiting, frequent urination, thirst, and kidney 
stones)

Incidence of hypercalciuria 

Immunogenicity analysis (AEs and SAEs related to PTH antibodies)

Laboratory test results

Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, platelets, 
differential)

Serum chemistries (standard Chem-20 panel)

Serum 25(OH) vitamin D levels

Serum 1,25-dihydroxyvitamin D levels

Creatinine clearance

Serum bone turnover markers

Urinalysis

24-hour urine calcium, phosphate, sodium, and creatinine excretion

PTH and Escherichia coli protein antibodies

Bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA)

Electrocardiogram (ECG) parameters

Physical examinations (including vital signs)

Reason for termination from the study

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Efficacy:  
Efficacy variables will be assessed by one or more of the following evaluations:

Laboratory test results

Total serum calcium 

24-hour urinary calcium excretion

Serum phosphate 

Supplement usage

Concomitant supplemental oral calcium dosage

Concomitant supplemental oral calcitriol dosage 
Statistical Methods: 
Detailed statistical analyses will be conducted as described in the Statistical Analysis Plan (SAP) 
for this study.  Deviations from the SAP (if any) will be described and justified in the Clinical 
Study Report.
Analysis of Demographic and Baseline Variables
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study.  Demographic and/or other variables at baseline will be 
summarized for medical history, demography, physical examination, vital signs, prior 
medications, ECG, and laboratory test results.
The number and percentage of subjects with specific prior medications will be summarized.  The 
number and percentage of subjects will be summarized by system organ class and by high-level 
term and preferred term for each medical history condition. 
Efficacy Variables Summary
Efficacy Endpoints:
The proportion of subjects in whom the following three conditions are fulfilled at Week 52 (Visit 
9) and at the End of Treatment will be summarized:

A ≥50% reduction from baseline in dose of oral calcium supplementation or an oral calcium 
dose of ≤ 500 mg
AND

A ≥50% reduction from baseline in dose of oral calcitriol supplementation or an oral 
calcitriol dose of ≤ 0.25 μg
AND

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
An albumin-corrected total serum calcium concentration that is normalized or maintained 
compared to the baseline value and does not exceed the ULN for the central laboratory
Other Efficacy Endpoints: 

Mean percentage changes from baseline in supplemental oral calcium and supplemental 
calcitriol dosages at each visit

Proportion of subjects achieving the first three conditions of the efficacy endpoints defined 
above, at each visit

Mean change from baseline in 24-hour urine calcium excretion

Impact of calcium source (carbonate vs. citrate) on response

Impact of calcium-sparing diuretics on serum and urinary calcium

Proportion of subjects that maintain a calcium phosphate product in the range of 35 to 
55 mg2/dL2 (4.4 mmol2/L2)     

Distribution of subjects by rhPTH[1-84] doses at the End of Treatment Visit

Change from baseline in bone turnover markers (bone-specific alkaline phosphatase, serum 
carboxy-terminal telopeptide of type I collagen, serum procollagen type 1 amino-terminal 
propeptide, osteocalcin), PTH antibodies, and BMD by DXA 

Additional subgroup analyses that are specified in the SAP
Safety Analysis:
Safety data including vital signs assessments, physical examinations, AEs, SAEs, the frequency 
of AEs of hypocalcemia or hypercalcemia, concomitant medications, clinical laboratory tests, 
ECG monitoring, and termination from study will be summarized by point of time of collection.
Descriptive statistics (arithmetic mean, standard deviation, median, minimum and maximum) 
will be calculated for quantitative safety data as well as for the difference from baseline, if 
applicable.  Frequency counts will be compiled for classification of qualitative safety data.

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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................7
TABLE OF CONTENTS...............................................................................................................13
LIST OF IN-TEXT TABLES ........................................................................................................16
LIST OF IN-TEXT FIGURES.......................................................................................................16
LIST OF APPENDICES................................................................................................................16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................17
1
INTRODUCTION..................................................................................................................19
1.1
Background ..............................................................................................................19
1.2
Rationale for the Clinical Study...............................................................................22
1.3
Rationale for Study Design ......................................................................................25
2
OBJECTIVES.........................................................................................................................26
2.1
Primary Objective ....................................................................................................26
2.2
Secondary Objectives...............................................................................................26
2.3
Endpoints..................................................................................................................26
2.3.1
Safety Endpoints....................................................................................................26
2.3.2
Efficacy Endpoints.................................................................................................27
2.3.3
Other Efficacy Endpoints.......................................................................................27
3
STUDY DESIGN ...................................................................................................................28
3.1
Overall Design and Control Methods.......................................................................28
3.2
Study Duration .........................................................................................................32
4
SUBJECT SELECTION AND PARTICIPATION................................................................32
4.1
Number of Subjects..................................................................................................32
4.2
Inclusion Criteria......................................................................................................32
4.3
Exclusion Criteria.....................................................................................................33
4.4
Subject Withdrawal Criteria.....................................................................................33
5
TREATMENTS AND TREATMENT PLAN........................................................................34
5.1
Treatments Administered .........................................................................................34
5.1.1
Identification of Investigational Product(s) ...........................................................34
5.1.2
Packaging and Labeling.........................................................................................34
5.1.3
Storage, Accountability, and Stability...................................................................35
5.2
Methods of Assigning Subjects to Treatment Groups .............................................36
5.3
Dose Regimens.........................................................................................................36
5.3.1
Selection of Doses in Study...................................................................................36
5.3.2
Selection and Timing of Dose for Each Subject....................................................36
5.3.3
Compliance with Dosing Regimens.......................................................................37
5.4
Prior and Concomitant Medications.........................................................................37

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5.4.1
Exclusionary Prior/Concomitant Medications.......................................................37
5.4.2
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation ....................................................................................................38
6
STUDY EVALUATIONS AND PROCEDURES.................................................................39
6.1
Efficacy Evaluations ................................................................................................39
6.2
Safety Evaluations....................................................................................................39
6.2.1
Adverse Events ......................................................................................................40
6.2.1.1
Adverse Event Definition.......................................................................40
6.2.1.2
Abuse, Misuse, Overdose, and Medication Error ..................................40
6.2.1.3
Procedures for Reporting Adverse Events .............................................41
6.2.2
Serious Adverse Events .........................................................................................42
6.2.2.1
Serious Adverse Event Definition..........................................................42
6.2.2.2
Procedures for Reporting Serious Adverse Events ................................43
6.2.3
Laboratory Evaluations..........................................................................................45
6.2.4
Vital Signs and Body Weight ................................................................................46
6.2.5
Electrocardiograms ................................................................................................46
6.2.6
Physical Examinations...........................................................................................47
6.2.7
Dual-energy X-ray Absorptiometry.......................................................................47
6.2.8
Women of Childbearing Potential .........................................................................47
6.2.9
Pregnancy Reporting..............................................................................................48
6.3
Schedule of Evaluations and Procedures .................................................................48
6.4
Description of Study Procedures..............................................................................55
6.4.1
Visit 1 Baseline Procedures ...................................................................................55
6.4.2
Week 1 Interim Safety Check................................................................................56
6.4.3
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study Clinic Visits.........56
6.4.4
Week 52 (Visit 9)...................................................................................................57
6.4.5
Long-term Extension Visits...................................................................................58
6.4.6
End of Treatment Visit or Early Termination........................................................59
6.4.7
Posttreatment Serum Calcium/Phosphate Follow Up............................................60
6.4.8
Follow-up Telephone Contact................................................................................60
6.4.9
Follow-up assessment for PTH antibodies ............................................................60
7
DATA MANAGEMENT .......................................................................................................60
7.1
Data Collection.........................................................................................................60
7.2
Record Retention......................................................................................................61
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE...................................................61
8.1
Demographic and Baseline Variables ......................................................................62
8.2
Safety Variables .......................................................................................................62
8.3
Efficacy Variables....................................................................................................62

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8.4
Other Variables ........................................................................................................63
8.5
Analysis Populations, Data Sets, and Time Points...................................................63
8.5.1
Analysis Populations..............................................................................................63
8.6
Statistical/Analytical Issues......................................................................................64
8.6.1
Adjustments for Covariates....................................................................................64
8.6.2
Handling of Dropouts or Missing Data..................................................................64
8.6.3
Interim Analyses and Data Monitoring..................................................................64
8.6.4
Multiple Comparisons/Multiplicity .......................................................................64
8.6.5
Use of a Pharmacokinetic Subset of Subjects........................................................64
8.6.6
Examination of Subgroups.....................................................................................64
8.7
Determination of Sample Size..................................................................................64
8.8
Changes to Planned Statistical Analyses..................................................................64
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..................................................64
9.1
Declaration of Helsinki and Ethical Review............................................................64
9.2
Subject Information and Consent.............................................................................65
9.3
Subject Data Protection............................................................................................65
9.4
Financial Disclosure.................................................................................................66
9.5
Changes to the Protocol............................................................................................66
9.6
Investigator Obligations ...........................................................................................67
9.7
Confidentiality/Publication of the Study..................................................................67
9.8
Selection of a Primary Principal Investigator ..........................................................68
9.9
Study Termination....................................................................................................68
10 REFERENCES .......................................................................................................................69

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LIST OF IN-TEXT TABLES
Table 5-1
Prohibited Medications or Therapies.............................................................37
Table 6-1
Schedule of Evaluations and Procedures – First 12 Months of Study ..........49
Table 6-2
Schedule of Evaluations and Procedures – Long-term Extension to 
Month 36 .......................................................................................................51
Table 6-3
Schedule of Evaluations and Procedures – Long-term Extension after 
Month 36 .......................................................................................................53
Table 6-4
Schedule of Follow-up Visits and Procedures for Subjects with 
PTH-specific Antibodies at the Final 2 Visits...............................................55
LIST OF IN-TEXT FIGURES
Figure 3-1
Study Design – First 12 Months of Study .....................................................31
Figure 3-2
Study Design – Long-term Extension ...........................................................31
LIST OF APPENDICES
Appendix 1
INSTRUCTIONS FOR USE FOR THE PTH HASELMEIER PEN 
INJECTOR SYSTEM ...................................................................................70
Appendix 2
RHPTH[1-84] AND SUPPLEMENT TITRATION GUIDELINE...............73
Appendix 3
METHOD OF BIRTH CONTROL...............................................................77
Appendix 4
PROTOCOL HISTORY................................................................................78

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
25(OH) vitamin D
25-hydroxyvitamin D
1,25(OH)2 vitamin D
1,25-dihydroxyvitamin D
-HCG
Beta human chorionic gonadotropin
AE
Adverse event
BMD
Bone mineral density
bpm
Beats per minute
BSAP
Bone-specific alkaline phosphatase
CaSR
Calcium-sensing receptor
CSR
Clinical study report
DNA
Deoxyribonucleic acid
DXA
Dual-energy x-ray absorptiometry
E. coli
Escherichia coli
ECG
Electrocardiogram
ECP
E. coli protein
eCRF
Electronic case report form
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GI
Gastrointestinal
hPTH
Human parathyroid hormone
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFU
Instructions for Use
IRB
Institutional Review Board
IV
Intravenous
NPS
NPS Pharmaceuticals, acquired by Shire 
NPSP558
Recombinant human parathyroid hormone (1-84) 
P1NP
Serum procollagen type 1 amino-terminal propeptide
PMO
Postmenopausal osteoporosis
PTH
Parathyroid hormone
QD
Once daily
QOD
Every other day
RACE
NPSP558 Study PAR-C10-008
REB
Research Ethics Board
RELAY
NPSP558 Study PAR-C10-007
REPLACE
NPSP558 Study CL1-11-040
rhPTH
Recombinant human parathyroid hormone
SAE
Serious adverse event

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
SAP
Statistical analysis plan
SC
Subcutaneous
s-CTx
Serum carboxy-terminal telopeptide of type I collagen
SMT
Safety Management Team 
SUSAR
Suspected, unexpected, serious, adverse reaction
ULN
Upper limit of normal
WMA
World Medical Association
WOCBP
Woman of childbearing potential

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1
INTRODUCTION
The purpose of this study is to demonstrate the long-term safety and tolerability of subcutaneous 
(SC) NPSP558 (rhPTH[1-84]) as hormone replacement therapy for the treatment of adult 
subjects with hypoparathyroidism.
1.1
Background
Compound
NPSP558 (rhPTH[1-84]) is the sponsor’s designation for recombinant human parathyroid 
hormone (rhPTH), a single-chain polypeptide consisting of 84 amino acid residues 
(rhPTH[1-84]).  It is identical in structure to endogenous human parathyroid hormone (hPTH), 
which is the principal regulator of plasma calcium homeostasis through concerted actions on the 
kidneys and bone.  rhPTH[1-84] is manufactured using a strain of Escherichia coli (E. coli) 
modified by recombinant deoxyribonucleic acid (DNA) technology. 
Calcium and Phosphate Absorption, Storage, and Excretion
Dietary calcium is absorbed primarily in the small intestine with an efficiency of 30% to 40%. 
Up to half of absorbed dietary calcium is returned to the gastrointestinal (GI) tract and is 
excreted in the stool.  Most of the remainder is excreted by the kidneys.  The efficiency of 
absorption of dietary phosphate is greater than that of calcium (about 70%) and most is excreted 
by the kidneys.  Approximately 99% of body calcium (the most abundant body cation) and 85% 
of phosphorus are found in bone, where they serve not only a structural role, but also as a 
reservoir for tissue and plasma calcium and phosphate. Most of the remaining phosphorus is 
intracellular.  The majority of the 1% of calcium not found within the skeleton is located in the 
extracellular fluid.  About half of this plasma calcium is ionized and capable of capillary 
diffusion into the intercellular space; the rest is bound to plasma proteins such as albumin or 
other substances (citrate, sulfate, and phosphates).  Ionized calcium, the physiologically active 
moiety, plays a vital role in many physiological processes including bone formation, blood 
coagulation (prothrombin to thrombin conversion), skeletal and smooth muscle function, cardiac 
automaticity and inotropy, nerve impulse initiation, and a host of other key physiological 
functions (Bilezikian et al. 2001). 
Calcium and Phosphate Regulation
Serum calcium and phosphate levels are regulated principally by parathyroid hormone (PTH), 
the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25[OH]2 vitamin D; calcitriol), and 
calcitonin.  PTH maintains an inverse relationship with serum calcium.  Normal total serum 
calcium levels (generally 8.4 to 10.2 mg/dL) and serum phosphate levels (2.5 to 4.5 mg/dL) are 
regulated to yield a calcium phosphate product of approximately 35 mg2/dL2.  This product is 
important because of the potential for calcium phosphate salts to be deposited in soft tissues.  
Levels of the calcium phosphate product that exceed 50 mg2/dL2 are believed to place patients at 
risk for ectopic soft tissue calcification.  PTH is synthesized and secreted by the parathyroid 
glands primarily in response to a fall in serum calcium levels.  Through concerted actions on the 
kidney and bone, PTH is the principal regulator of plasma calcium homeostasis.  In the kidney, 

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PTH increases renal tubular reabsorption of calcium (while inversely inhibiting phosphate 
reabsorption) and increases the synthesis of 1,25(OH)2 vitamin D from its precursor 25-
hydroxyvitamin D (25[OH] vitamin D).  Although 1,25(OH)2 vitamin D has a short in vivo half-
life (approximately 6 hours), it directly increases intestinal calcium and phosphate absorption.  In 
bone, PTH increases the efflux of calcium from bone, both from the rapidly exchangeable pool 
of calcium within bone, and by increasing the number and activity of osteoblasts and osteoclasts, 
thereby increasing bone turnover.  As PTH also acts to inhibit the reabsorption of phosphate in 
the proximal nephron, it prevents an increase in plasma phosphate levels that could result from 
increased intestinal phosphate absorption and efflux of phosphate from bone. Calcitonin, 
secreted by C-cells of the thyroid gland, decreases serum calcium by inhibiting bone resorption 
and promoting renal tubular calcium excretion, but its effects are relatively minor in comparison 
to those of PTH and 1,25(OH)2 vitamin D (Bilezikian et al. 2001). 
Disorders of Calcium Homeostasis
Situations Associated With Hypocalcemia
Hypocalcemia (low serum ionized calcium) may result from abnormally increased calcium 
binding (rapid blood transfusion due to citrate binding or increased serum free fatty acids due to 
stress, medications, alcohol, or acute pancreatitis), abnormal calcium losses (impaired phosphate 
excretion leading to hyperphosphatemia in renal failure), vitamin D deficiency (impaired GI 
calcium absorption and renal or liver disease with associated vitamin D activation impairment), 
inadequate calcium intake, or hypoparathyroidism (Shoback 2008).  Hypocalcemia due to 
deficient protein-bound (non-ionized) calcium may result from decreased serum albumin, but 
this condition is usually asymptomatic because serum ionized calcium levels are typically 
normal.
Hypoparathyroidism and Hypocalcemia
The most common cause of chronic hypocalcemia is hypoparathyroidism, a condition in which 
there is deficient production of PTH from the parathyroid glands.  Hypoparathyroidism results in 
decreased calcium reabsorption from renal tubules, malabsorption of calcium from the GI tract 
and reduced calcium mobilization from bone.  Hypoparathyroidism may result from permanent 
injury to the parathyroid gland(s) during thyroid or parathyroid surgery or other surgical 
procedures in the neck, radiation to the neck region, autoimmune destruction of the parathyroid 
glands, or their congenital absence.  Although rare, hypoparathyroidism can also result from 
genetic mutations, such as activating mutations in the calcium-sensing receptor (CaSR) gene that 
encodes CaSRs present on parathyroid and kidney tubule cells.  Activating mutations of the 
CaSR gene result in an inappropriately low PTH secretion for the prevailing serum calcium level 
and increased fractional clearance of calcium by the kidney.
Since free ionized serum calcium stabilizes neural and muscle cell membranes, hypocalcemia 
can lead to neuromuscular irritability and contribute to the chief signs and symptoms of 
hypoparathyroidism, which are tetany, twitching, paresthesia, tremor, and spasm.  Seizures and 
laryngospasm are severe symptomatic manifestations.  Hypocalcemia may also influence cardiac 
function by inducing arrhythmias, hypotension, or heart failure.  Psychiatric symptoms (anxiety, 

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irritability, depression, or delirium) may also be present in patients with hypocalcemia.  Latent 
tetany may be demonstrated by eliciting a positive Chvostek sign (hyperirritability of the facial 
nerve when tapped) or Trousseau sign (carpal spasm induced by brachial nerve ischemia 
produced by inflating an arm blood pressure cuff above systolic for about 3 minutes).  The 
manifestations of hypocalcemia, when present, vary greatly in severity among patients with 
hypoparathyroidism.
In hypoparathyroidism, concomitant hyperphosphatemia is a frequent occurrence.  A resulting 
high calcium phosphate product may lead to the deposition of calcium phosphate salts in soft 
tissues.  Such soft tissue calcification can result in important morbidities that include renal 
parenchymal damage and premature cataracts.  Imaging studies in patients with 
hypoparathyroidism may reveal calcification of the basal ganglia and the grey-white matter 
interface in the brain.
Clinical effects of hypoparathyroidism can be ameliorated using oral calcium and calcitriol.  
Supplementation with an analog of vitamin D, 1-alpha-(OH) vitamin D3 (alphacalcidol) is used 
in the place of calcitriol in some countries.  The goal is to raise the serum calcium to a point 
where symptoms are no longer present.  This generally means that the serum calcium should be 
maintained just below or at the low-normal range (8.0 to 8.5 mg/dL) (Shoback 2008).  It is also 
desirable to avoid hypercalciuria (Shoback 2008).  Acute or life-threatening tetany may be 
treated with an intravenous (IV) calcium infusion (eg, calcium gluconate) preferably under 
cardiac monitoring (Bilezikian et al 2001).
Hypercalciuria
Parathyroid hormone promotes calcium reabsorption in the distal renal tubules, with decreasing 
nephrogenous cyclic adenosine monophosphate excretion and elevated tubular reabsorption of 
phosphate.  Hypercalciuria is due to the lack of PTH effect on the renal tubules resulting in the 
inappropriate loss of calcium in the presence of normo- or hypocalcemia.    Under normal 
conditions any decrease in serum calcium would result in increased PTH production.  
Parathyroid hormone  then causes the kidney to limit calcium excretion, but without the presence 
of sufficient PTH the kidneys continue to excrete calcium into the urine, causing the 
hypercalciuria.  Elevated vitamin D levels and oral supplementation of calcium to maintain the 
serum calcium level also contribute to hypercalciuria  by increasing small bowel absorption of 
calcium and phosphate, enhancing renal filtration, further decreasing any residual PTH levels, 
and, therefore, additionally reducing renal tubular calcium absorption.  Thiazide diuretics can be 
used to reduce (or prevent) hypercalciuria caused by calcium and vitamin D therapy.  Once the 
24-hour urinary calcium level approaches 250 mg, a thiazide diuretic combined with a low-salt 
diet can be added (Shoback 2008).
Hypercalcemia
Hypercalcemia occurs when calcium entry into the circulation exceeds renal and other routes of 
calcium excretion.  This may occur due to excessive dietary calcium absorption, 
hypervitaminosis D, increased bone resorption due to immobility, malignancy, and thiazide 
diuretics that decrease urinary calcium excretion, or increased PTH levels (hyperparathyroidism).  

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Symptoms of hypercalcemia are generally due to alterations in central and peripheral nervous 
system function (altered mental status, fatigue, weakness, muscle flaccidity) and other organ 
involvement such as the heart (ventricular arrhythmias).  Bone resorption occurs over time.  The 
kidneys are threatened by exposure to high serum calcium concentrations leading at times to 
renal calculi due to calcium phosphate precipitation in the renal pelvis and parenchyma.  Frank 
renal dysfunction is not uncommon during an acute period of hypercalcemia with polyuria being 
a cardinal manifestation (due to antidiuretic hormone interference).  When the albumin-corrected 
total serum calcium exceeds 14 mg/dL, the hypercalcemia needs attention on an urgent basis.  
Such emergencies can lead to many complications, particularly cardiac ones (Bilezikian et al. 
2001). 
1.2
Rationale for the Clinical Study 
Treatment of hypoparathyroidism is complicated by the lack of national or international 
consensus management guidelines (Shoback 2008).  Patients with hypoparathyroidism are 
unable to regulate normal albumin-corrected total serum calcium and phosphate handling 
physiologically.  Current therapy is limited to calcium supplementation and parental or metabolic 
forms of vitamin D.  These therapies, which are suboptimal, present specific challenges for 
adequate clinical care.
Challenges Associated With Vitamin D Therapy
Patients with hypoparathyroidism are unable to efficiently convert precursor 25(OH) vitamin D 
to fully active 1,25(OH)2 vitamin D in the kidney because they lack PTH and are 
hyperphosphatemic, both of which reduce the activity of 1α-hydroxylase, the enzyme that drives 
production of calcitriol.  Therefore, standard therapy for hypoparathyroidism usually relies on 
the administration of active vitamin D metabolites such as calcitriol (Rocaltrol®) or analogs such 
as alphacalcidol, which do not require PTH-dependent 1α-hydroxylation.  To demonstrate any 
appreciable clinical effect with less active forms of vitamin D (eg, cholecalciferol), these must be 
used at very high dosages.  Such high doses of less active, precursor forms of vitamin D are more 
lipophilic than calcitriol and thus have a propensity to accumulate in fat, posing a real threat of 
vitamin D toxicity.  Furthermore, active vitamin D forms can increase both calcium and 
phosphate absorption from the gut, which can, in turn, exacerbate the risk of hyperphosphatemia 
and an abnormal calcium phosphate product with subsequent soft tissue calcification.
Challenges Associated With Oral Calcium Therapy
The US Institute of Medicine/National Academy of Sciences daily Dietary Reference Intake for 
calcium for individuals aged 18 to 70 years is 1000 to 1200 mg/day, while the daily Tolerable 
Upper Intake level (level at which there is no likely risk of adverse events [AEs]) is 2500 mg/day 
for adults.  Patients with hypoparathyroidism typically require supplemental oral calcium therapy 
at or higher than this recommended limit, typically ranging between 2000 and 3500 mg/day.  
Impaired regulation of calcium and phosphate homeostasis due to a lack of PTH and 
pharmacological treatment with vitamin D metabolites/analogs combine with high oral calcium 
intake to increase the likelihood of soft tissue deposition of calcium salts.  These can occur in the 
brain (ie, basal ganglia), kidneys, ocular lens, and other organs leading to structural damage and 

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a loss of function, as seen in premature cataracts, and even Parkinsonism.  Without PTH to help 
conserve the filtered calcium in the kidney, substantial amounts of calcium can be lost leading to 
hypercalciuria with the attendant risks of nephrocalcinosis, hematuria and renal dysfunction.  
Thiazide diuretics such as hydrochlorothiazide may be used to stimulate the reabsorption of 
calcium in the distal nephron.  In cases of profound hypocalcemia patients often require 
treatment with IV calcium along with cardiac monitoring.  Some patients may require a 
permanent catheter placement for IV access. 
In hypoparathyroidism, chronically low bone turnover results in significant abnormalities in bone 
structure, with bone mineral density (BMD) being very high because of increased mineralization.  
Several studies, mostly in animals and in vitro, have suggested that vitamin D and PTH act 
interdependently at the level of bone.  In patients with hypoparathyroidism, the actions of 
vitamin D alone on bone remodeling are relatively minor.  Langdahl et al studied bone biopsies 
in 12 hypoparathyroid patients treated with vitamin D or alphacalcidol and compared them with 
matched normal controls (Langdahl et al. 1996).  With vitamin D alone, trabecular bone volume 
and thickness, marrow space star volume, and trabecular star volume were no different from 
controls, but bone turnover remained low.  In the absence of PTH, therefore, vitamin D therapy 
alone is not able to normalize bone resorption and bone turnover. A recent study reported the 
abnormal structural/dynamic properties of bone in 33 patients with hypoparathyroidism treated 
with conventional oral calcium and vitamin D-based therapy as compared with matched controls 
(Rubin et al. 2008a).  Histomorphometric assessment of iliac crest bone biopsies showed that 
hypoparathyroid patients had significantly greater cancellous bone volume and cortical bone 
width than healthy controls.  In parallel, measures such as mineralizing surface and bone 
formation rate were profoundly decreased below normal in the hypoparathyroid group.  The 
pathological effects of PTH deficiency on bone are largely asymptomatic, but can potentially 
include accumulation of microcracks in an environment of adynamic, dense bone tissue. 
How this situation relates to rhPTH[1-84] and its potential therapeutic use in hypoparathyroidism 
differs fundamentally from its use in osteoporosis.  In osteoporosis, PTH is used to increase 
BMD and improve bone structure, while in hypoparathyroidism, evidence from one recent study 
(Bilezikian 2008) indicates that PTH replacement appears to increase bone turnover from its low 
baseline level, potentially leading to improvements in bone structure. 
Clinical Experience with PTH Peptides in the Treatment of Hypoparathyroidism
Few studies of PTH use have been performed in the setting of hypoparathyroidism.  Winer and 
colleagues have reported experience with twice-daily use of subcutaneously injected rhPTH(1-
34) in the setting of adult and pediatric patients with hypoparathyroidism (Winer et al. 1998; 
Winer et al. 2003; Winer et al. 2008).  In this setting, PTH(1-34) was shown to maintain 
eucalcemia and to reduce urinary calcium excretion.  In these studies, PTH(1-34) was also 
compared to treatment with calcitriol, and showed that twice-daily PTH(1-34) or twice-daily 
calcitriol maintained similar albumin-corrected total serum calcium levels although urinary 
excretion of calcium was lower in the PTH(1-34) treated patients.  PTH(1-34) is identical to the 
34 N-terminal amino acids of the 84-amino acid hPTH, but unlike rhPTH[1-84] is not identical 
to the full 84 amino acid sequence.

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One prospective, open-label clinical trial of PTH in the treatment of hypoparathyroidism is 
ongoing (Bilezikian 2008).  In that study, patients with hypoparathyroidism are treated for 12 
months with 100 g of PTH(1-84) SC every other day (QOD).  Despite the study having off-
PTH days due to QOD dosing, there was, on average, a 30% reduction from baseline in 
supplemental calcium requirements over the course of the study.  Total serum calcium 
concentrations remained stable.   Improved renal calcium handling was also seen, with calcium 
excretion falling to 60% of baseline levels at the end of the study.  Adverse event rates were low 
and PTH(1-84) was well tolerated. 
Two-year data show that 100 μg of rhPTH[1-84] is a safe and effective replacement therapy in 
patients with hypoparathyroidism.  Dosing with 100 μg of rhPTH[1-84] QOD resulted in an 
approximate decrease of 40% in requirements for supplemental calcium and calcitriol.  These 
effects were seen as soon as 1 to 3 months after the onset of rhPTH[1-84] therapy.  PTH(1-84) 
maintained serum calcium within the low normal range.  Bone health was an outcome measure 
for this study and at baseline patients with hypoparathyroidism were reported to have increased 
cancellous bone volume, and increased trabecular and cortical bone width (Rubin et al 2008b, 
Rubin et al. 2008c, Rubin et al. 2008d).  Bone turnover was suppressed and bone formation was 
low.  PTH(1-84) therapy QOD led to a marked increase in bone turnover markers, which were 
accompanied by histopathological changes indicating increased osteoblast activity and alteration 
in BMD at the spine and radius.  PTH(1-84) therapy was well tolerated throughout the 2 years of 
the study.  
A randomized, double-blind, placebo-controlled, phase 3 study in adult subjects with 
hypoparathyroidism recently concluded (CL1-11-040, REPLACE).  This study  investigated the 
effects of daily SC injections of rhPTH[1-84] at doses of 50, 75, or 100 µg administered in the 
thigh.  In addition, a randomized, dose-blinded study investigating fixed doses of rhPTH[1-84] 
25 µg and 50 µg in adult subjects with hypoparathyroidism (PAR-C10-007, RELAY) also 
recently concluded as well as two phase 1 studies.  One of the phase 1 studies (C09-002) was a 
pharmacokinetic/pharmacodynamic study to assess these aspects of rhPTH[1-84] administered at 
single SC doses of 50 and 100 μg in patients with hypoparathyroidism.  The other study (PAR-
C10-005) compared the bioequivalence of the Ypsomed and Haselmeier pen injection devices 
used to administer rhPTH[1-84] in the clinical studies.
Summary
Parathyroid hormone replacement therapy may improve calcium homeostasis and thus reduce 
requirements for supplemental calcium and vitamin D metabolites or analogs in patients with 
hypoparathyroidism.  rhPTH treatment can offset hypocalcemia by increasing bone turnover, 
renal tubular calcium reabsorption (while potentially inversely inhibiting renal phosphate 
reabsorption), and enhancing GI absorption of calcium via normalized endogenous formation of 
1,25(OH)2 vitamin D.  This improved calcium handling may reduce risks of calcification and 
damage of soft tissues.  Furthermore, because rhPTH[1-84] is identical in structure to 
endogenous human PTH(1-84), the potential for hypersensitivity reactions would be low as 
compared to nonbiologically identical peptides.  Results from studies of rhPTH(1-34) twice daily 
SC and from an open-label study of rhPTH[1-84] 100 g QOD SC in patients with 

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hypoparathyroidism provide a framework of information that supports the safety and potential 
clinical utility of PTH replacement therapy in hypoparathyroidism. 
The purpose of the present study is to assess the long-term safety and efficacy of rhPTH[1-84] to 
treat hypoparathyroidism.
1.3
Rationale for Study Design 
Dose
In a phase 2 study of rhPTH[1-84] in osteoporosis, SC daily doses of 50, 75, and 100 µg were
well tolerated.  In these subjects with osteoporosis and intact parathyroid function, a dose-
dependent increased incidence of hypercalcemia was observed.  The recently completed 
REPLACE study evaluated these same doses in hypoparathyroid patients.  An 8-week study of 
fixed doses of 25 and 50 µg (RELAY) was also undertaken to explore a broader range of 
treatment dose options.  The clinical portion of RELAY has recently been completed. The RACE 
study will provide an opportunity for these subjects to continue NPSP558 (rhPTH[1 84]) 
treatment, at their discretion. The purpose of the RACE study is to assess the safety and 
tolerability of varying doses of rhPTH[1-84] during long-term treatment, while reducing 
requirements for supplemental oral calcium and calcitriol, maintaining stable total serum calcium 
levels, and controlling hypercalciuria in adult subjects with hypoparathyroidism. 
Route of Administration
A single daily SC injection of PTH (versus infusion) increases PTH levels transiently.  rhPTH[1-
84] will be administered by daily SC injection into alternating thighs.  The thigh was chosen due 
to the prolongation of the calcemic response when the drug is administered in the thigh 
compared to the abdomen.  

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2
OBJECTIVES
2.1
Primary Objective
The primary objective of this study is to demonstrate the long-term safety and tolerability of SC 
rhPTH[1-84] as hormone replacement therapy for the treatment of adult subjects with 
hypoparathyroidism.
2.2
Secondary Objectives
The secondary objectives of this study are:

To evaluate the impact of different preparations of calcium on the response to rhPTH[1-84] 
replacement therapy

To demonstrate that dosing with rhPTH[1-84] across a dose range of 25 to 100 μg SC can be 
implemented in a safe and effective manner and can be maintained throughout long-term 
treatment

To evaluate the impact of calcium-sparing diuretics on serum and urinary calcium
2.3
Endpoints
2.3.1
Safety Endpoints
Safety variables will be assessed by the following evaluations: 

Adverse events and serious adverse events

Incidence of AEs of hypocalcemia (eg, paresthesia, numbness, tetany) and hypercalcemia 
(eg, constipation, nausea, poor appetite or vomiting, frequent urination, thirst, and kidney 
stones)

Incidence of hypercalciuria 

Laboratory test results

Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, platelets, 
differential)

Serum chemistries (standard Chem-20 panel, including calcium, phosphate, and 
albumin)

Serum 25(OH) vitamin D levels

Serum 1,25-dihydroxyvitamin D levels

Creatinine clearance

Serum bone turnover markers

Urinalysis

24-hour urine calcium, phosphate, sodium, and creatinine excretion

PTH and E. coli protein (ECP) antibodies

Bone mineral density by dual-energy x-ray absorptiometry (DXA) 

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
Electrocardiogram (ECG) parameters

Physical examinations (including vital signs)

Reason for termination from the study

Immunogenicity analysis (AEs and SAEs related to PTH antibodies) 

Injection pen-related events and/or complaints
2.3.2
Efficacy Endpoints
The proportion of subjects in whom the following three conditions are fulfilled at Week 52 (Visit 
9) and at the End of Treatment will be summarized:

A ≥ 50% reduction from baseline in dose of oral calcium supplementation or an oral calcium 
dose of ≤ 500 mg
AND

A ≥ 50% reduction from baseline in dose of oral calcitriol supplementation or an oral 
calcitriol dose of ≤ 0.25 μg
AND

An albumin-corrected total serum calcium concentration that is normalized or maintained 
compared to the baseline value and does not exceed the ULN for the central laboratory
2.3.3
Other Efficacy Endpoints 

Mean percentage changes from baseline in supplemental oral calcium and supplemental 
calcitriol dosages at each visit

Proportion of subjects achieving the first  three conditions of the efficacy endpoints defined 
above, at each visit

Mean change from baseline in 24-hour urine calcium excretion

Impact of calcium source (carbonate vs. citrate) on response

Impact of calcium-sparing diuretics on serum and urinary calcium

Proportion of subjects that maintain a calcium phosphate product ≤55 mg2/dL2 (4.4 
mmol2/L2)       

Distribution of subjects by rhPTH[1-84] doses at the End of Treatment Visit

Change from baseline in bone turnover markers (bone-specific alkaline phosphatase [BSAP], 
serum procollagen type 1 amino-terminal propeptide [P1NP], serum carboxy-terminal 
telopropeptide of type I collagen [s-CTx], and osteocalcin), PTH antibodies, and BMD by 
DXA 

Additional subgroup analyses that are specified in the Statistical Analysis Plan (SAP)

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3
STUDY DESIGN
3.1
Overall Design and Control Methods
This study is a long-term, open-label study using rhPTH[1-84] for the treatment of adult male 
and female subjects with hypoparathyroidism. The subjects must have previously completed the 
NPSP558 RELAY study (8 weeks of active therapy) and/or previously completed the NPSP558 
REPLACE study (CL1-11-040) (Visit 18).
The goal of this study is to optimize rhPTH[1-84] dosing while reducing calcitriol and oral 
calcium (carbonate or citrate) supplementation to as low as safely possible while maintaining 
total serum calcium levels (see Appendix 2, rhPTH[1-84] and Supplement Titration Guideline).  

The starting dose of rhPTH[1-84] for this study will be 25 or 50 g SC once daily (QD). 

Subjects with a total serum calcium value of ≤ 9.5 mg/dL will have a starting dose of 50 μg.  

Subjects with a total serum calcium value of > 9.5 mg/dL will have a starting dose as 
follows:

Subjects who are taking supplements (≥ 500 mg calcium and/or any calcitriol) will 
have the supplements reduced or stopped and will start at a dose of 50 g SC QD. 

Subjects who are taking minimal or no supplemental calcium (< 500 mg) and no 
calcitriol will have a starting dose of 25 g SC QD.  

Study visits during the first 12 months of the study will be conducted at Weeks 1 (baseline), 
4, 8, and then every 8 weeks thereafter up to Week 48 (Visit 8).  The Week 52 visit (Visit 9) 
is scheduled 4 weeks later. 

At the end of Week 52, subjects will be invited to extend their study drug regimen until 
January 2018 or after the completion of the last patient’s Month 72 visit, whichever comes 
last.  During this time, subjects will return to the clinic for interim visits every 2 months 
(Months 14, 16, 18, etc).  

All subjects will have their total serum calcium checked by a local laboratory 3 to 5 days (± 2 
days) following the baseline visit. 

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 at any time 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.  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 will 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 
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at the discretion of the investigator.  Results of local total serum calcium levels will be 
recorded in the source document.

Once a subject achieves a stable serum calcium (target:  between 8.0 and 9.0 mg/dL) with the 
minimum doses of supplements possible, they will be maintained at that dose of rhPTH[1-
84].     

If ANY predose (trough) total serum calcium is > 11.9 mg/dL study drug will be stopped.  
Once total serum calcium returns to the normal range, rhPTH[1-84] can be reintroduced.  The 
rhPTH[1-84] dose may be maintained at the previous level if reductions in oral calcium 
supplements and/or calcitriol are possible.  If oral calcium supplements have been previously 
reduced to ≤ 500 mg daily and calcitriol has been eliminated, then rhPTH[1-84] should be 
reintroduced at the next lowest dose level and supplemental oral calcium and calcitriol 
should then be adjusted accordingly to obtain a predose total serum calcium level of 
approximately 8.0 to 9.0 mg/dL.

If the predose total serum calcium level remains above 10.0 mg/dL for two or more safety 
assessments or study visits on normal dietary intake and study drug alone, then the rhPTH[1-
84] dose may be reduced to the next lowest dose level and supplemental oral calcium and 
calcitriol then adjusted accordingly to obtain a predose total serum calcium level of 
approximately 8.0 to 9.0 mg/dL.  Study medication will be stopped if the predose total serum 
calcium remains above the upper limit of the laboratory normal range (ULN) for two or more 
safety assessments or study visits (no more than 5 days apart) at the lowest dose regimen, 
following withdrawal of all supplementary oral calcium and calcitriol therapy.  Further 
choices on adaptation of treatment regimens, reinstitution of previous therapy, or 
discontinuation from study will be made in consultation with the Shire medical monitor.  

At and any time following the Week 16 (Visit 4), subjects who are on a stable dose of 
rhPTH[1-84] and have a 24-hour urine calcium > 300 mg (males) and > 250 mg (females) 
may be treated for hypercalciuria with calcium-sparing diuretics, if this therapy had not been 
introduced prior to the study.  Newly started calcium-sparing diuretics will be given initially 
at a low dose.

Monitoring for serum potassium, sodium, and calcium will be performed 1 week and again 1 
month following the institution or change in dose of the calcium-sparing diuretic and then at 
each subsequent scheduled clinic visit. 

Monitoring of urine calcium will be performed at Weeks 16, 32, and 52 (Visits 4, 6, and 9) 
and every 4 months thereafter.  For subjects on calcium-sparing diuretics, further dose 
adjustment of the diuretic will be done at the discretion of the investigator, based on urinary 
and serum calcium values.

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 NPSP558 (rhPTH[1-84]).  Their total serum calcium levels will be 
checked locally at an interim visit scheduled 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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
Subjects who terminate or complete the study and opt to continue treatment on commercial 
drug (Natpara), where available, will not require follow-up serum calcium and/or phosphate 
checks as a part of this study, but rather should continue follow-up serum calcium and/or 
phosphate monitoring by a physician according to approved labeling instructions.  These 
subjects will be contacted one week after end of treatment for a wellness check.

Approximately 4 weeks (30 days) following the End of Treatment visit, subjects will be 
contacted by telephone in order to assess AEs/serious AEs (SAEs). 
A schematic representation of the study design is displayed in Figure 3-1 and Figure 3-2.

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*Subjects who terminate or complete the study and opt to continue treatment on commercial drug (Natpara), will not require follow-up serum 
calcium and/or phosphate checks, but should continue treatment under the supervision of a physician under approved labeling instructions.
** Approximately 4 weeks (30 days) following the End of Treatment visit, all subjects will be contacted by telephone in order to assess 
AEs/SAEs.
3.2
Study Duration
The duration of the study was originally intended to be about 1 year. The study has been 
extended to up to 80 months of treatment with a 4-week follow up call/visit. Therefore, the 
overall duration of the study is expected to be approximately 81 months.
Study visits will be conducted every 2 months and will continue until the subject voluntarily 
withdraws or until termination of the study. See Section 6.2 for additional follow-up for subjects 
who develop antibodies specific to PTH. See Table 6-4 for additional follow-up for subjects who 
develop antibodies specific to PTH.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects 
Approximately 50 subjects will be enrolled. 
4.2
Inclusion Criteria
Subjects who meet all the following inclusion criteria can be enrolled into this study:
1. Signed and dated informed consent form (ICF) before any study-related procedures are 
performed
2. Previously completed the NPSP558 RELAY study 8 weeks of active therapy and/or 
previously completed the NPSP558 REPLACE study (Visit 18)
3. Able to perform daily SC self-injections of study medication (or have designee perform 
injection) via a multidose pen injector into the thigh 
4. Willingness and ability to understand and comply with the protocol
5. Women who are: (1) postmenopausal defined as 12 months amenorrhea with appropriate 
serum follicle stimulating hormone (FSH) levels (> 40 IU/L); (2) surgically sterilized; OR (3) 
of childbearing potential with a negative pregnancy test at screening and who consent to use 
two acceptable methods of contraception for the duration of the study, with pregnancy testing 
at every scheduled visit.  Male subjects who have female partners of childbearing potential 
together also must use 2 acceptable forms of contraception during the subject’s participation 
in the study.
6. Serum creatinine <1.5 mg/dL at enrollment 
7. Total serum calcium ≤ ULN based on local laboratory result prior to enrollment

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8. Serum 25(OH) vitamin D ≤ 1.5 times the ULN within approximately 16 weeks prior to 
enrollment
4.3
Exclusion Criteria
Subjects who meet any of the following exclusion criteria at baseline (Visit 1) are not eligible for 
enrollment in this study: 
1. Any condition that, in the investigator’s opinion after consultation with the sponsor, would 
preclude the safe use of PTH
2. Any disease or condition, in the opinion of the investigator, which has a high probability of 
precluding the subject from completing the study or where the subject cannot or will not 
appropriately comply with study requirements
3. Pregnant or lactating woman 
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified without prejudice to subsequent care.  Withdrawn dosed subjects will 
not be replaced.  A subject may be withdrawn from the study under any of the following 
circumstances:

Withdrawal of informed consent

If, in the opinion of the investigator, Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB), Health Authority and/or Shire, it is no 
longer in the subject’s best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any criterion for exclusion

Lack of compliance with study procedures or study drug administration, as determined by the 
investigator

Occurrence of an SAE determined by the investigator to be possibly related to study drug and 
not alleviated with treatment of symptoms

Adverse event 

Hypersensitivity determined by the investigator to be possibly related to study drug

Pregnancy or lactation 

Administrative reasons

Treatment with commercial drug (Natpara)
In all cases, the reason for withdrawal must be recorded in the subject’s medical records.  If the 
reason is not known, the subject must be followed up to establish whether the reason was an AE 
and, if so, this must be reported in accordance with the procedures described in Section 6.2.1.

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As far as possible, all examinations scheduled for the end-of-study evaluations must be 
performed on all subjects who participate but do not complete the study according to protocol.
5
TREATMENTS AND TREATMENT PLAN
5.1
Treatments Administered 
Subjects will self-administer an SC injection of rhPTH[1-84] at a starting dose of either 25 or 
50 μg daily into alternating thighs, based on their total serum calcium level at baseline as 
described in Section 3.1.  
5.1.1
Identification of Investigational Product(s) 
RhPTH[1-84]  is manufactured using a strain of E. coli modified by DNA technology and is 
identical to native human PTH.  rhPTH[1-84] is a single-chain polypeptide containing 84 amino 
acid residues.  The drug substance is clear and colorless to light straw-colored.
rhPTH[1-84] parathyroid hormone (rhPTH) product is provided in a dual-chamber cartridge.  
The front chamber (chamber 1) contains a sterile, white to off-white lyophilized powder 
containing rhPTH[1-84], sodium chloride, mannitol and citric acid.  The rear chamber (chamber 
2) contains a sterile diluent for reconstitution (m-cresol and sterile water for injection).  
This study was initiated with study drug being administered using the Ypsomed pen injection 
device, in which the dual-chamber cartridge is installed by the user into a reusable pen injector 
device, in which reconstitution occurs in a total volume of 1.15 mL.  
Based on the preliminary results of a recent study (PAR-C10-005) comparing the Haselmeier 
pen to the Ypsomed pen, showing that the two pens are bioequivalent; the Haselmeier pen has 
now replaced the Ypsomed pen in this study.  The date the injection pen is switched will be 
recorded for each study subject.  
In the case of the Haselmeier pen, the dual chamber cartridge comes pre-inserted in a cartridge 
holder.  The cartridge in the cartridge holder is reconstituted using the Duoject mixing device 
and then loaded into the Haselmeier pen.  The reconstituted volume is also 1.15 mL.  Instructions 
for Use (IFU) for the Haselmeier pen and mixing device are provided in Appendix 1.
Both pen injectors serve as holders for the cartridge and do not come in contact with rhPTH 
product.  Using either pen injection device, each dual-chamber cartridge is designed to deliver 14 
doses of 71.4 μL, each dose containing either 25, 50, 75, or 100 μg of rhPTH.  The pen and 
reconstituted rhPTH product should be stored under refrigeration.  
5.1.2
Packaging and Labeling
Packaging
The study drug will be packaged, labeled, and delivered to the clinical centers by the sponsor or 
designee.  Each subject will receive two pens for use during the study period and sufficient 
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in kits containing eight 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 also be provided; once the inventory of ancillary kits is 
depleted, the clinical centers will receive the ancillary kit components separately and not as a kit 
(injection pen needles and alcohol prep pads).
Labeling
Study drug will be supplied in individual kits labeled with the following information: 
investigational drug warning, company name, protocol number, lot number, storage conditions, 
contents, instructions regarding general dosing, and brief SC administration instructions.  Label 
space will be provided for recording center and subject numbers.  The label on the kit will be a 
tear-off label, which the study center can affix to the subject’s source document or study
document provided for this purpose.  Boxes containing pens will be labeled with the following 
info: investigational warning, company name, protocol number, lot number, and subject number.
5.1.3
Storage, Accountability, and Stability
The clinical center’s pharmacist or delegate is responsible for ensuring that all study drug 
received at the center is inventoried and accounted for throughout the study.  All study drug must 
be kept in a locked area with access restricted to specific study personnel.  The study drug and 
supplements are to be stored according to the manufacturers’ specifications.  The investigator or 
designee (ie, pharmacist) will conduct an inventory upon receipt of the clinical supplies from the 
sponsor, and will acknowledge receipt of the supplies to the sponsor or designee.  A copy of the 
shipping documents must be maintained for the investigator’s records.  
Prior to reconstitution, cartridges should be stored at 2ºC to 8ºC (36ºF to 46ºF).  After study drug 
reconstitution, the device can be used for up to 14 days when stored refrigerated at 2°C to 8°C 
and with infrequent exposure to room temperature for up to 30 minutes per day.  Cartridges must 
be replaced 14 days after reconstitution.  Cartridges should not be exposed to temperature 
extremes and should not be used if they have been or currently are frozen.  Additional 
instructions for the storage of the Haselmeier pen and Duoject mixing device are included in the 
IFU. 
In this study, subjects will be supplied with cartridges in sufficient quantity to maintain daily 
self-administration of varying dose of rhPTH[1-84].  Subjects should be reminded to return all 
cartridges, even if empty, at each study visit.
Pharmacy records will be maintained to capture the following information by lot number for 
each drug:

quantity received

current quantity on site

quantity administered to each subject

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
quantity removed from stock but not dispensed (eg, damaged, dropped, spilled)

quantity remaining at the end of the study and retained, returned as per the sponsor’s 
instructions
For each subject, dates that study medication was dispensed, administered, returned, or otherwise 
disposed of will be recorded. 
All original containers, whether empty or containing study drug will be returned to the 
pharmacy.  Contents of the study drug containers will not be combined.  Unused study drug will 
be returned according to the sponsor’s instructions.
5.2
Methods of Assigning Subjects to Treatment Groups
Subjects will utilize the same 8-digit subject number that they had been assigned during the 
REPLACE or RELAY study.  The first 4 digits consist of the center number and the last 4 digits 
are the sequential subject number.  Subjects will receive study treatment in an open-label fashion 
at starting doses of rhPTH[1-84] 25 or 50 g SC QD, as described in Section 3.1.  On Day 1, the 
kit number from which cartridges are dispensed to a subject will be recorded on the appropriate 
eCRF.  All subsequent kit numbers will be similarly recorded.  All doses of study medication for 
each subject must be taken from the kit(s) designated for that subject and cartridges from an 
assigned kit will not be dispensed to any other subject.
5.3
Dose Regimens
Daily rhPTH[1-84] SC injections will be self-administered into alternating thighs each morning 
using a multidose pen injection device (see Appendix 1, Instructions for Use for the Haselmeier 
Pen Injector System).   
5.3.1
Selection of Doses in Study
rhPTH[1-84] given as a daily SC injection of 100 g was approved in 2006 in the European 
Union for the treatment of postmenopausal osteoporosis (PMO).  There is an extensive safety 
database with this product in subjects with PMO at doses ranging between 0.02 to 5.0 g/kg.  
The phase 2 and 3 studies alone exposed 2891 subjects with PMO to doses ranging between 50 
to 100 µg of rhPTH[1-84].   
In subjects with hypoparathyroidism, several phase 1/2, single-center, open-label studies have 
demonstrated preliminary biologic activity of rhPTH[1-84] and PTH(1-34) given as daily or 
alternate day SC injections (Bilezikian 2008; Winer et al. 1998; Winer et al. 2003; Winer et al. 
2008).  This current study will utilize varying doses starting at either 25 or 50 g SC QD with 
the potential for upward adjustments in increments of 25 g to a maximum dose of 100 g SC 
QD, in order to assess its long-term effect in hypoparathyroid subjects. 
5.3.2
Selection and Timing of Dose for Each Subject
Subjects will self-administer rhPTH[1-84] in the morning, using the multidose pen injector 
devices.  On the days of clinic visits, the injections of study drug will occur after the serum is 
taken for laboratory assessments and may be administered by the clinic study personnel.  

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Calcium and/or vitamin D should be taken in the morning as normal after the rhPTH[1-84] 
injection. 
5.3.3
Compliance with Dosing Regimens
Paper diaries will be provided for the subjects to record study drug administration and 
supplement regimens.  Subjects should be requested to bring the diaries to each clinic study visit 
for review.  Subjects with ≥80% to ≤120% compliance level will be considered to be compliant 
with regard to study drug administration.  Diaries will be collected at monitoring visits and 
submitted to the sponsor.
5.4
Prior and Concomitant Medications
5.4.1
Exclusionary Prior/Concomitant Medications
Subjects may remain on baseline concomitant medications during the trial (eg, hormone 
replacement therapy, antihypertensives, calcium-sparing diuretics, etc.).  Prohibited prior and 
concomitant medications are generally those that may affect bone metabolism, confound efficacy 
or safety measurements, potentially pose a safety concern, or adversely potentiate or antagonize 
study drug therapy.  Incidental or transient use of most of these medications (see list below) will 
not preclude a subject’s entry into this study.
Exclusionary concomitant medications are shown in Table 5-1.
Table 5-1
Prohibited Medications or Therapies
Medication/Therapy
Raloxifene hydrochloride
Bisphosphonates, intravenous
Bisphosphonates, oral
Calcitonin, cinacalcet or other drugs that influence calcium or bone metabolism
Fluoride tablets
Over the counter medications such as TUMS® are not to be taken as calcium supplementation.  
Please refer to Section 5.4.2 for information on calcium and vitamin D supplementation.
Permissible medications are: 

Nonprescription topical medications (that are not systemically absorbed) 

Acetaminophen

Oral, implantable, vaginal rings, transdermal patch and injectable contraceptives and/or 
hormone replacement therapy 

All prescription and over the counter medication (including vitamins, herbs, or dietary 
supplements) being taken at baseline and all medications started during the study (from 

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signing the ICF through study exit), including administration dates and dosage, are to be 
recorded in the source document.  Any medication which contains either calcium or vitamin 
D must be recorded in the source document with the amount of calcium and/or vitamin D 
content.  To the extent possible, no changes should be made to the concomitant treatment 
during the study.  Any additions, deletions or changes in the dose of these medications during 
the study also will be recorded in the source document.
5.4.2
Active Vitamin D, Calcium, Native Vitamin D, and Magnesium 
Supplementation
Active Vitamin D
Subjects enrolled in this study will be taking active vitamin D to control serum calcium levels.  
Oral calcitriol supplements will be provided during the first 52 weeks of this study by the 
sponsor or designee; no other sources of calcitriol should be used during the first year of study.  
Prescribed doses of calcitriol will be recorded in the source document.  Calcitriol will not be 
supplied for the long-term extension portion of this study.  
Calcium
Oral calcium supplements (either calcium carbonate or calcium citrate) will be provided 
throughout this study through approximately May 2014. Calcium citrate will continue to be 
supplied through the long-term extension; calcium carbonate will not be supplied through the 
remaining long-term extension portion of this study. No other sources of calcium 
supplementation should be used during the study.  Calcium supplements should be taken 
regularly with meals, ideally morning and evening.  Prescribed doses of calcium will be recorded 
in the source document.  
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 the 
diary. 
Native Vitamin D [25(OH) vitamin D]
The serum 25(OH) vitamin D levels will be measured at the beginning of the study and at all 
scheduled study visits through the End of Treatment visit.  During the study, sufficient 
supplemental native vitamin D should be administered in order to maintain the subject’s serum 
25(OH) vitamin D level in the normal range.  Any dose taken by the subject must be recorded in 
the source document.
Magnesium  
Magnesium is required for normal parathyroid function and disordered magnesium levels can
exacerbate hypoparathyroidism.  Subjects with low serum magnesium should undergo 
supplementation at a clinically appropriate level until the serum magnesium is within the normal 
range and normal serum magnesium should be maintained throughout the remainder of the study.  
Any dose taken by the subject must be recorded in the source document.

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6
STUDY EVALUATIONS AND PROCEDURES
6.1
Efficacy Evaluations
Efficacy variables will be assessed by one or more of the following evaluations:

Laboratory test results

Total serum calcium 

24-hour urinary calcium excretion

Serum phosphate 

Supplement usage

Concomitant supplemental oral calcium dosage

Concomitant supplemental oral calcitriol dosage 
6.2
Safety Evaluations
Safety variables will be assessed by the following evaluations: 

Adverse events and serious adverse events

Incidence of AEs of hypocalcemia (eg, paresthesia, numbness, tetany) and hypercalcemia 
(eg, constipation, nausea, poor appetite or vomiting, frequent urination, thirst, and kidney 
stones)

Incidence of hypercalciuria 

Immunogenicity analysis (AEs and SAEs related to PTH antibodies)

Laboratory test results

Hematology (hematocrit, hemoglobin, white blood cells, red blood cells, platelets, 
differential)

Serum chemistries (standard Chem-20 panel, including calcium, phosphate, and 
albumin)

Serum 25-hydroxyvitamin D levels

Serum 1,25-dihydroxyvitamin D levels

Creatinine clearance

Serum bone turnover markers

Urinalysis

24-hour urine calcium, phosphate, sodium, and creatinine excretion

PTH and ECP antibodies (Any subject who tests positive for PTH-specific antibodies 
at the last 2 consecutive visits at which antibodies are measured and does NOT 
continue treatment on commercial Natpara, will have follow-up blood draws for PTH 
antibodies at Months 3 and 6 poststudy. If a subject’s results are negative at Month 3, 
follow-up may be terminated  Subjects may remain on study if they develop 

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PTH-specific antibodies during the study, providing that there are no concurrent AEs 
related to immunogenicity.)

Bone mineral density by DXA 

Electrocardiogram parameters

Physical examinations (including vital signs)

Reason for termination from the study

Pen-related events and/or complaints
6.2.1
Adverse Events
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study.  Adverse events that were ongoing at the end of the 
REPLACE or RELAY study will be recorded and updated for this study.  Any newly occurring 
AEs in this study will be recorded separately. 
6.2.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected or 
diagnosed after study drug administration

Pretreatment or post-treatment events that occur as a result of protocol-mandated procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen
6.2.1.2
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 

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in Section 6.2.2.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding the prescribed daily dose 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.
Medication errors should be collected/reported for NPSP558 (rhPTH[1-84]) only. Cases of 
missed doses are not considered reportable as medication errors. The administration and/or use 
of an expired investigational product should be considered as a reportable medication error.
6.2.1.3
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject, obtained through nonleading 
questioning, or noted during examination of a subject.  All AEs and SAEs will be recorded from 
the signing of the ICF through the last study visit or the last study required procedure (including 
the follow-up telephone call 4 weeks after end of treatment). SAEs will be monitored with a 
telephone call by the investigator, as necessary, for approximately 4 weeks after the last dose of 
study drug, or until resolution or the SAE is judged by the investigator to have stabilized.    
The AE term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  Also recorded are: 

Start and stop date and time

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)

Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities

Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities

Severe:  requires vigorous therapeutic intervention and interrupts usual activities.  
Hospitalization may or may not be required.

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
Relationship to study drug (not related, related): identify relationship as “related” if a causal 
relationship between the investigational product and an AE is at least a reasonable possibility 
(ie, the relationship cannot be ruled out)

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.2.2.2 below.

Actions taken (none; study drug dose changed, interrupted, or discontinued; other medication 
change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives only 
one outcome.
Adverse events that are related to study drug and that have not resolved at the end of treatment 
will be followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study.
6.2.2
Serious Adverse Events
All serious events must be reported as described in Section 6.2.2.2 and recorded in the 
appropriate electronic Case Report Form (CRF) in the EDC system InForm, and electronically 
signed by the investigator within 24 hours of event awareness. In case of EDC system 
unavailability the sponsor’s SAE Form must be used. An SAE requires expeditious handling to 
comply with regulatory requirements. Any SAEs occurring from the signing of the ICF through 
30 days after the last dose of study drug will be captured and must be reported to the Shire 
Pharmacovigilance Department and the Shire Medical Monitor within 24 hours after the 
investigator is made aware of the event.
6.2.2.1
Serious Adverse Event Definition
An SAE is an AE that results in any of the following outcomes:

Death 

Is life-threatening.  A life-threatening AE is any AE that places the subject—in the 
investigator’s opinion—at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more serious form, might have caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

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
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 or may require medical or surgical intervention to prevent 
one of the other 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 hospitalization, or the development of drug 
dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

planned before entry into the clinical study 

are for elective treatment of a condition unrelated to the studied indication or its treatment

occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

are part of the normal treatment or monitoring of the studied indication and not associated 
with any deterioration in condition
6.2.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
notify the sponsor. The SAE information will include the description of the event and the date 
that the investigator became aware of the event. Supplemental data (eg, medical records or lab 
values, if applicable) will be faxed/emailed to Shire Pharmacovigilance and Risk Management 
Department, if requested by the sponsor. This ensures timely reporting of applicable reports to 
Health Authorities. 
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but a serious event criterion.  The SAE term is the medical event that led to the 
hospitalization.  Surgery is not an adverse event, but the event that required the subject to have 
surgery is the SAE term.  Death is not an SAE, but an outcome.
The investigator is responsible for notifying the local, regional, or country-specific authorities of 
all SAEs and device failures that occur at his or her site, as required by local regulations.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see Section 6.2.1.3).  A causality assessment should always be included on the sponsor’s 

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SAE form.  The investigator should make the causality assessment based on the information 
available at the time of the event.  The causality can be updated at a future date if additional 
information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect study 
product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related) 

A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Study Reference Manual.
As required by International Conference of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor or designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Causality, while assessed, 
does not negate reporting requirements to the sponsor.  An AE, whether serious or not serious, is 
designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator Brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 
expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.  As per the Food 
and Drug Administration (FDA) Guidance for Clinical Investigators, Sponsors, and IRBs, 
Adverse Event Reporting to IRBs-Improving Human Subject Protection, January 2009 if it is 

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determined that there is an unanticipated signal, the Shire SMT will analyze the data and prepare 
a summary supporting the determination and interpretation of the findings.  The sponsor or 
designee will send this summary to the investigators with instructions to provide it to their IRB.
The investigator should also comply with the IRB procedures for reporting any other safety 
information (ie, autopsy reports).  
Shire will be responsible for submitting SUSAR reports to the appropriate health authorities.  
These reports will be submitted within the expedited timeframe.  All fatal and life-threatening 
SUSAR reports will be submitted by Shire or designee within 7 days of receipt (Day 0) of the 
initial report.  All other SUSAR reports will be submitted by Day 15 following the event.  
6.2.3
Laboratory Evaluations 
The following laboratory tests will be performed.  Final RELAY study parameters may be used 
as baseline parameters for this study.  Subjects from the REPLACE study who did not participate 
in the RELAY study will have to complete Visit 1 procedures.  All laboratory tests collected 
during the study will be analyzed by a central laboratory, with the exception of all urine 
pregnancy tests and total serum calcium levels obtained at baseline and interim time points for 
safety checks, which will be done at the investigators’ or subjects’ local laboratories.  The 
following laboratory parameters will be collected according to the schedule of procedures as 
noted below and outlined in Table 6-1 and Table 6-2: 

Hematology (fasted): hemoglobin concentration, hematocrit, erythrocyte count, platelet 
count, and leukocyte counts with differential (baseline, Week 52, every 12 months during the 
long-term extension, and at the End of Treatment visit).

Serum Chem-20 panel (fasted): alanine transaminase, aspartate transaminase, alkaline 
phosphatase, lactate dehydrogenase, inorganic phosphate, total and direct bilirubin, creatine 
kinase, blood urea nitrogen, glucose, electrolytes (sodium, potassium, chloride, and 
bicarbonate), creatinine, calcium (standard and albumin-corrected), magnesium, total protein, 
albumin, and uric acid (baseline, Week 52, every 12 months during the long-term extension, 
and at the End of Treatment visit).

Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, and 
microscopic analysis of sediment (baseline, Week 52, and at the End of Treatment visit).

Creatinine clearance (baseline, Weeks 16, 32, and 52, every 4 months during the long-term 
extension, and at the End of Treatment visit).

Total serum calcium (local) (baseline, interim Week 1, as needed at any other time during the 
study, and at the poststudy interim visit) 

Total serum calcium, albumin, and phosphate (every visit through Week 52; calcium and 
phosphate only at every long-term extension visit and at the 1-week follow-up visit)

Serum potassium, sodium, and calcium (1 week and again 1 month following the institution 
or change in dose of the calcium-sparing diuretic and then at each subsequent scheduled 
clinic visit)  

Serum 25 (OH) vitamin D levels (every visit through the End of Treatment visit)

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
Serum 1,25-dihydroxyvitamin D levels (Weeks 24 and 52, every 6 months during the long-
term extension, and at the End of Treatment visit).

24-hour urine calcium, phosphate, sodium, and creatinine (baseline, Weeks 16, 32, and 52, 
every 4 months during the long-term extension, and at the End of Treatment visit).

Serum bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin) (baseline, Weeks 8, 16, 
24, 40, and 52, every 4 months during the long-term extension, and at the End of Treatment 
visit).

Serum beta human chorionic gonadotropin (-HCG) pregnancy test (women of child-bearing 
potential [WOCBP] only) (baseline, Weeks 16, 24, 32, 40, 48, 52 and End of Treatment visit)

An FSH test to confirm postmenopausal status, if necessary (baseline only)

Urine pregnancy test (WOCBP only) (baseline, Weeks 4 and 8, and every 2 months during 
the long-term extension)

PTH and ECP antibodies  (predose at baseline, Weeks 24, 40, 52, every 6 months during the 
long-term extension, and at the End of Treatment visit)

Serum PTH[1-84] for PK analysis (Week 48 only) 
Clinically significant (as determined by the investigator) abnormal laboratory test results will be 
considered AEs.  A result outside of the normal range may be repeated for confirmation.  Any 
laboratory test result that meets the criteria for an SAE (see Section 6.2.2.1) must also be 
recorded in an SAE report so that the sponsor or designee can collect additional information 
about that abnormality, including information regarding relationship to investigational product or 
other causes, any action taken, and outcome. 
6.2.4
Vital Signs and Body Weight
Vital signs will be measured prior to blood draws at baseline and each clinic study visit through 
the End of Treatment visit and will include systolic and diastolic blood pressure (mm Hg), pulse 
(beats per minute or bpm), and body temperature (ºC) after the subject has been sitting for 5 
minutes.  Body weight will also be recorded.
If any of the subject’s measurements are outside of the normal range at screening (prior to 
receiving the first dose) the investigator will determine, based on medical history, whether the 
subject can safely continue in the study.  A measurement outside the normal range may be 
repeated during the course of the visit for confirmation.
6.2.5
Electrocardiograms  
A 12-lead ECG will be done at baseline, Week 52, and at the End of Treatment visit.  Baseline 
and Week 52 ECGs (and early termination visits occurring in the first year) will be done at the 
study center on the same model unit.  The end of treatment ECG may be done locally.  Recorded 
data will include general findings, ventricular rate (bpm) and P-R, QRS, and QTc intervals 
(seconds).  Any ECG abnormalities, as determined by the investigator, at screening will be 
recorded as medical history.  Any clinically significant adverse change from the status at the 
screening visit and noted to be clinically significant by the investigator should be captured as an 

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AE.  All ECGs conducted during the first year of the study will be assessed by a central reader 
and this assessment will be used as the primary data readout for the study.  However, 
investigators are also responsible for providing their own interpretation of the ECG, and this will 
be captured on the ECG print out.  Two copies of the ECG tracings should be retained in the 
subject source record.  The local, end of treatment ECG will not be sent to the central reader, 
unless necessary in order to confirm an ambiguous result or serious abnormality.
6.2.6
Physical Examinations
Full physical examinations will be performed at baseline, Week 52, and at the End of Treatment 
visit and will consist of general assessments of the head, eyes, ears, nose, throat, lymph nodes, 
skin, extremities, and respiratory, gastrointestinal, musculoskeletal, cardiovascular, nervous, and 
dermatologic systems.  The physical examination should be performed by the same person each 
time, whenever possible. Brief physical exams will be conducted every 6 months during the 
long-term extension portion of the study.
Physical examination abnormalities determined by the investigator to be clinically significant at 
screening should be recorded as medical history if they developed since the RELAY or 
REPLACE study. 
Any clinically significant adverse change from the status at the baseline visit and noted to be 
clinically significant by the investigator should be captured as an AE.
6.2.7
Dual-energy X-ray Absorptiometry 
DXA scans will be performed at baseline, Week 52, yearly during the long-term extension 
portion of the study, and at the End of Treatment visit, if it is greater than 3 months since the 
previous DXA scan.  These scans will evaluate BMD of the lumbar vertebra (L1-L4), hip (total, 
trochanter, intertrochanter, Ward’s triangle, and femoral neck), and ⅓ distal radius (arm).  
Calcium supplements should be withheld for 24 hours prior to the scan, if possible.  If a subject 
cannot withhold the calcium supplements due to safety concern, the DXA should be performed 2 
hours after the last calcium tablet has been ingested. Please note: DXA will NOT be completed 
at baseline if subject had a scan performed within the past 6 months within one of the previous 
studies. 
6.2.8
Women of Childbearing Potential
Any subject that has become postmenopausal since entering the RELAY or REPLACE study 
should be re-evaluated at baseline for this study.  For a woman to be considered postmenopausal 
there must have been an absence of menses for 12 consecutive months with appropriate serum 
FSH levels (ie, > 40 IU/L).  
If the result is not in the postmenopausal range and the subject is not surgically sterile, then the 
subject should be considered a woman of childbearing potential (WOCBP).
A WOCBP may be included in the study, but must have a negative serum pregnancy test at 
baseline.  Lack of pregnancy will be confirmed by urine pregnancy tests at baseline and Weeks 4 
and 8 (Visits 2 and 3).  A serum pregnancy test will be repeated at Weeks 16, 24, 32, 40, 48, 52, 

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and at the End of Treatment visit.  A urine pregnancy test will be done at all interim visits during 
the long-term extension portion of the study.  Pregnancy occurring during the trial will 
necessitate immediate withdrawal from study.  A WOCBP must be willing to use 2 medically 
acceptable methods of contraception for the duration of the study (see Appendix 3).  Male 
subjects with female partners of childbearing potential together also must use 2 medically 
acceptable means to avoid pregnancy during the subject’s participation in the study. 
6.2.9
Pregnancy Reporting
Pregnant and lactating women are excluded from participation in this study.  In the event a 
subject becomes pregnant during the study, study drug will be discontinued and the Shire 
Investigational and Marketed Product Pregnancy Report form will be completed to capture 
potential drug exposure during pregnancy and reported to the sponsor or designee within 24 
hours of becoming aware of the pregnancy.  The pregnant subject will be followed until an 
outcome is known (ie, normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic 
abortion).  If a pregnant subject also experiences an SAE, the Shire Clinical Study Serious 
Adverse Event and Non-Serious AEs as Required by the Protocol Form will be completed and 
submitted to the sponsor or designee within 24 hours as discussed above. 
The Shire Investigational and Marketed Products Pregnancy Report Form should be completed 
in the event that a female partner of a male subject becomes pregnant within 30 days after his last 
dose of study drug or study completion, if agreed upon and consented to by the pregnant partner.  
The pregnancy (mother and fetus) will be followed up through delivery with regard to outcome.
6.3
Schedule of Evaluations and Procedures
All clinical study evaluations will be performed according to Table 6-1, Table 6-2, and Table 
6-3.  Details of the exact date and time of medical assessments (day/month/year) will be 
documented in the source document. Any deviations from protocol requirements will be 
documented in the source document. A schedule of follow-up visits and procedures for subjects 
who test positive for PTH-specific antibodies at the last visit is provided in Table 6-4.

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Table 6-1
Schedule of Evaluations and Procedures – First 12 Months of Study
Visit Number
1*
Int.
2
3
4
5
6
7
8
9
Study Procedures / Proposed Study Weeka
BLb
1c
4
8
16
24
32
40
48
52
Visit Windows
± 3 
days
± 2 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
Informed Consent
X
Review Inclusion/Exclusion Criteria
X
Medical History (updated from RELAY/REPLACE)
X
Concomitant medications (ongoing)
X
X
X
X
X
X
X
X
X
Concomitant medications (new)
X
X
X
X
X
X
X
X
X
Adverse event monitoring (ongoing)
X
X
X
X
X
X
X
X
X
Adverse event monitoring (new)
X
X
X
X
X
X
X
X
X
Assessment of clinical episodes of hypocalcemia and hypercalcemia 
X
X
X
X
X
X
X
X
X
Physical examination 
X
X
Vital signsd and weight
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead) (centrally read)
X
X
Bone mineral density by DXAe    
X
X
Hematologyf
X
X
Serum chemistry (20-panel)f
X
X
Serum calcium (local)**
X
X
Serum calcium, phosphate, and albumin
X
X
X
X
X
X
X
X
X
Serum calcium, potassium, sodiumg
X
X
X
X
X
X
Serum 25-hydroxyvitamin D
X
X
X
X
X
X
X
X
X
Serum 1,25-dihydroxyvitamin D
X
X
Serum bone turnover markers
X
X
X
X
X
X
Serum thyroid function testf,h
X
Creatinine clearance (estimated GFR)
X
X
X
X
PTH and ECP antibodiesi
X
X
X
Xl
Serum PTH [1-84] for pharmacokinetic analysis
Xm
FSH (newly menopausal women only)
X
Serum pregnancy test (WOCBP only)
X
X
X
X
X
X
X
Urine pregnancy test (WOCBP only)
X
X
X
Urinalysis
X
X
24-hour urine calcium, phosphate, sodium, creatinine 
X
X
X
X
Diary review j
X
X
X
X
X
X
X
X
Dispense/administration/accountability of study drug and pen 
injectors/ancillary supplies
X
X
X
X
X
X
X
X
X

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Table 6-1
Schedule of Evaluations and Procedures – First 12 Months of Study
Visit Number
1*
Int.
2
3
4
5
6
7
8
9
Study Procedures / Proposed Study Weeka
BLb
1c
4
8
16
24
32
40
48
52
Visit Windows
± 3 
days
± 2 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
± 7 
days
Dispense/accountability of calcium/calcitriol supplements (see guideline)
X
X
X
X
X
X
X
X
X
Dispense subject diaries 
X
X
Collect used/unused study drug and supplementsk
X
X
X
X
X
X
X
X
BL = baseline; DXA = dual-energy x-ray absorptiometry; ECP = E.coli protein; FSH = follicle stimulating hormone; GFR = glomerular filtration rate; Int.= interim visit; 
PTH = parathyroid hormone; WOCBP = women of child-bearing potential
*Note:  Final RELAY study parameters may be used as baseline parameters for this study.  
**Any adjustment of study drug or supplemental calcium and calcitriol doses requires testing of total serum calcium concentrations at interim time points.
a Study visits will be conducted at Weeks 1 (baseline), 4, 8, every 8 weeks thereafter through Week 48, and at Weeks 52. 
b Week 8 from the RELAY study; subjects will return all used/unused drug, supplements, and pens from RELAY/REPLACE.
c After the End of Treatment visit or early termination visit, subjects who will not continue rhPTH[1-84] treatment will have their total 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. 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 4 weeks ± 7days after end of treatment visit. After the 4 week follow up phone call, further management of hypoparathyroidism will occur as part of the 
subject’s long-term non-study medical care.
d Vital signs should be done prior to blood draws.
e Calcium supplements should be withheld for 24 hours prior to the DXA scan.  If a subject cannot withhold the calcium supplements due to safety concern, the DXA should be 
performed 2 hours after the last calcium tablet has been ingested. Please note: DXA will NOT be completed at baseline if subject had a scan performed within the past 6 months in 
one of the previous studies (all subjects will have a DXA performed at Week 52 (Visit 9)
f Fasting for at least 6 to 8 hours prior to test
g Serum potassium, sodium, and calcium is to be collected 1 week and again 1 month following the institution or change in dose of a calcium-sparing diuretic and then at each 
subsequent scheduled clinic visit.  
h Thyroid function tests done for final visit of the RELAY/REPLACE studies only.
i Blood draw for PTH and ECP antibodies will be done predose. 
j A paper diary will be dispensed at baseline for the investigator’s use to assess subject’s compliance and adherence to the protocol procedures.
k Subject is to return unused and used cartridges and supplements at each visit. 
l See Section 6.2 for instructions on follow-up for subjects with PTH-specific antibodies and Table 6-3 for a schedule of follow-up procedures for these subjects.
m Blood samples for pharmacokinetic analysis will be drawn predose (0 hour) and postdose between 1 and 2 hours and between 6 and 10 hours following study drug administration.

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Table 6-2
Schedule of Evaluations and Procedures – Long-term Extension to Month 36
Study Procedures / Proposed Study Montha, b
Months 14/26
Months 16/28
Months 18/30
Months 20/32
Months 22/34
Months 24/36**
Visit Windows
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
Concomitant medications 
X
X
X
X
X
X
Adverse event monitoring, including pen-related 
events/complaints 
X
X
X
X
X
X
Assessment of clinical episodes of hypocalcemia and 
hypercalcemia 
X
X
X
X
X
X
Physical examination 
Xc
Xc
Vital signsd and weight
X
X
X
X
X
X
Bone mineral density by DXAe    
Xf
Hematologyg
X
Serum chemistry (20-panel)g
X
Serum calcium (local)*
Serum calcium, phosphate
X
X
X
X
X
X
Serum calcium, potassium, sodiumh
X
X
X
X
X
X
Serum 25-hydroxyvitamin D
X
X
X
X
X
X
Serum 1,25-dihydroxyvitamin D
X
X
Serum bone turnover markers
X
X
X
Creatinine clearance (estimated GFR)
X
X
X
PTH and ECP antibodiesi, j
X
X
Serum pregnancy test (WOCBP only)
Urine pregnancy test (WOCBP)
X
X
X
X
X
X
Urinalysis
24-hour urine calcium, phosphate, sodium, creatinine 
X
X
X
Diary review k
X
X
X
X
X
X
Dispense/administration/accountability of study drug, calcium, 
and pen injectors/ancillary supplies
X
X
X
X
X
X
Collect used/unused study drug and pen injectorsl
X
X
X
X
X
X

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Table 6-2
Schedule of Evaluations and Procedures – Long-term Extension to Month 36
DXA = dual-energy x-ray absorptiometry; ECP = E. coli protein; EoT = end of treatment; F/up = follow up; GFR = glomerular filtration rate; Int.= interim visit; 
PTH = parathyroid hormone; WOCBP = women of child-bearing potential)
*Any adjustment of study drug or oral calcium and active vitamin D doses requires testing of total serum calcium concentrations at interim time points.
**Following Month 24, the every 2-month visit schedule will repeat (ie, visits procedures for Month 26 are the same as those shown at Month 14.)
a Study visits will be conducted every 2 months during the extension portion and will continue until the subject voluntarily withdraws or until termination of the study.
b After the End of Treatment visit or early termination visit, subjects who will not continue rhPTH[1-84] treatment will have their total 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.  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 4 weeks ± 7days after end of treatment visit.  After the 4 week follow up phone call, further management of hypoparathyroidism will occur as part of the 
subject’s long-term non-study medical care.
c Brief physical exams will be conducted at 6-month intervals.
d Vital signs should be done prior to blood draws.
e Calcium supplements should be withheld for 24 hours prior to the DXA scan.  If a subject cannot withhold the calcium supplements due to safety concern, the DXA should be 
performed 2 hours after the last calcium tablet has been ingested.
f DXA will be performed at End of Treatment visit ONLY if the previous DXA was ≥3 months prior.  
g Fasting for at least 6 to 8 hours prior to test
h Serum potassium, sodium, and calcium is to be collected 1 week and again 1 month following the institution or change in dose of a calcium-sparing diuretic and then at each 
subsequent scheduled clinic visit.  
i Blood draw for PTH and ECP antibodies will be done predose.
j See Section 6.4.9 for instructions on follow-up for subjects with PTH-specific antibodies and Table 6-4 for a schedule of follow-up procedures for these subjects.
k Subjects will record diary information during the 2-week period prior to the next scheduled visit during the long-term extension portion of the study. If the subject does not 
record the diary information as indicated during this time period, he/she may record it during the 2 weeks following the visit, for review at the next visit or via phone.  
l Subjects are to return unused and used cartridges at each visit.  Pens will be collected at the final visit.

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Table 6-3
Schedule of Evaluations and Procedures – Long-term Extension after Month 36
Proposed Study Montha
Study Procedures 
Months 
38/50/62
Months 
40/52/64
Months 
42/54/66/74
Months 
44/56/68/76
Months 
46/58/70/78
Months 
48/60/72/80
End of 
Treatmentb
4 weeks 
F/up
Phonec
Visit Windows
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 1 week
± 7 days
Re-consent subjectd
X
Concomitant medications 
X
X
X
X
X
X
X
Adverse event monitoring, including pen-related 
events/complaints 
X
X
X
X
X
X
X
X
Assessment of clinical episodes of hypocalcemia and 
hypercalcemia 
X
X
X
X
X
X
X
Physical examinatione
Xe
Xd
X
Vital signsf and weight
X
X
X
X
X
X
X
Electrocardiogram (12-lead)  
Xg
Bone mineral density by DXAh    
X
Xi
Hematologyj
X
X
Serum chemistry (20-panel)j
X
X
Serum calcium (local)*
Serum calcium, phosphate
X
X
X
X
X
X
X
Serum calcium, potassium, sodiumk
X
X
X
X
X
X
X
Serum 25-hydroxyvitamin D
X
X
X
X
X
X
X
Serum 1,25-dihydroxyvitamin D
X
X
X
Serum bone turnover markers
X
X
X
X
Creatinine clearance (estimated GFR)
X
X
X
X
PTH and ECP antibodiesl
X
X
Xm
Serum pregnancy test (WOCBP only)
X
Urine pregnancy test (WOCBP)
X
X
X
X
X
X
Urinalysis
X
24-hour urine calcium, phosphate, sodium, creatinine 
X
X
X
X
Diary review n
X
X
X
X
X
X
X
Dispense/administration/accountability of study drug, 
and pen injectors/ancillary supplieso 
X
X
X
X
X
X
X
Collect used/unused study drug / pen injectorsp
X
X
X
X
X
X
X
DXA = dual-energy x-ray absorptiometry; ECP = E. coli protein; EoT = end of treatment; F/up = follow up; GFR = glomerular filtration rate; Int.= interim visit; 
PTH = parathyroid hormone; WOCBP = women of child-bearing potential
NOTE:  Following Month 72, the every 2-month visit schedule will repeat (ie, visits procedures for Month 74 will repeat starting with those shown at Months 26/38/50.)
*Any adjustment of study drug or oral calcium and active vitamin D doses requires testing of total serum calcium concentrations at interim time points.

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Table 6-3
Schedule of Evaluations and Procedures – Long-term Extension after Month 36
Proposed Study Montha
Study Procedures 
Months 
38/50/62
Months 
40/52/64
Months 
42/54/66/74
Months 
44/56/68/76
Months 
46/58/70/78
Months 
48/60/72/80
End of 
Treatmentb
4 weeks 
F/up
Phonec
Visit Windows
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 2 weeks
± 1 week
± 7 days
a Study visits will be conducted every 2 months and will continue until the subject voluntarily withdraws or until termination of the study. At that time, and periodically following 
that milestone, the study will be reviewed in regard to continuation/termination status.
b After the End of Treatment visit or early termination visit, subjects who will not continue rhPTH[1-84] treatment will have their total 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.  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 4 weeks ± 7days after end of treatment visit.  After the 4 week follow up phone call, further management of hypoparathyroidism will occur as part of the 
subject’s long-term non-study medical care.
c Follow-up phone contact 4 weeks after the last dose of study medication to check on any ongoing or new drug-related AEs or SAEs
d Study subjects must be re-consented at their next study visit prior to implementation of Amendment 6. 
e Brief physical exams will be conducted at 6-month intervals. 
f Vital signs should be done prior to blood draws.
g The End of Treatment ECG will be read locally.
h Calcium supplements should be withheld for 24 hours prior to the DXA scan.  If a subject cannot withhold the calcium supplements due to safety concern, the DXA should be 
performed 2 hours after the last calcium tablet has been ingested.
i DXA will be performed at End of Treatment visit ONLY if the previous DXA was ≥3 months prior.  
j Fasting for at least 6 to 8 hours prior to test
k Serum potassium, sodium, and calcium is to be collected 1 week and again 1 month following the institution or change in dose of a calcium-sparing diuretic and then at each 
subsequent scheduled clinic visit.  
l Blood draw for PTH and ECP antibodies will be done predose.
m See Section 6.4.9 for instructions on follow-up for subjects with PTH-specific antibodies and Table 6-4 for a schedule of follow-up procedures for these subjects.
n Subjects will record diary information during the 2-week period prior to the next scheduled visit during the long-term extension portion of the study. If the subject does not 
record the diary information as indicated during this time period, he/she may record it during the 2 weeks following the visit, for review at the next visit or via phone.  
  o Ancillary supplies (ie, needles and alcohol wipes) may be supplied, as allowed by local regulations.  
p Subjects are to return unused and used pen injectors at each visit.  
  

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Table 6-4
Schedule of Follow-up Visits and Procedures for Subjects with PTH-specific 
Antibodies at the Final 2 Visits
Follow-up Proceduresa
Follow-up 
(Month 3)b
Follow-up 
(Month 6)
Visit Number:
F3
F4
Visit Window (± Days)
7
7
Antibodies to PTH
X
X
Adverse events
X
X
AE = adverse event; F = follow-up; PTH = parathyroid hormone
a Follow-up visits will be conducted for only those subjects who are determined to have PTH-specific antibodies at the final two 
consecutive visits (at End of Study or at the time of discontinuation) and are NOT continuing treatment on commercial Natpara. 
See Section 6.4.9.
b Subjects who have negative antibody results at Month 3 do not need the Month 6 follow-up visit.
6.4
Description of Study Procedures
6.4.1
Visit 1 Baseline Procedures 
RELAY study Week 8 procedures must be performed prior to any baseline procedures. Subjects 
must sign an ICF for this study prior to having any study-related procedures performed. 
Additionally, REPLACE completers, who did not participate in the RELAY study, will have to 
undergo ALL Visit 1 procedures.
Subjects will be instructed to come into the study center after having fasted for approximately 6 
to 8 hours.  Appointments should be scheduled accordingly to accommodate this fasting status 
(ie, in the morning).  The following procedures will be performed prior to enrollment:

Update the subject’s medical history, demographic information, ongoing concomitant 
medications, and ongoing AEs from the RELAY/REPLACE study

Review inclusion/exclusion criteria

Record all new prescription and nonprescription medications, dietary and nutritional 
supplements, and vitamins and their doses, frequencies, and durations.

The occurrence of any new or continuing AE, including episodes of hypocalcemia or 
hypercalcemia, will be recorded following the signing of the ICF, regardless of whether or 
not study drug had been administered

Vital signs measurements (prior to blood draws) and weight

Physical examination

12-lead electrocardiogram

Blood samples for serum chemistries (including calcium, phosphate, and albumin), 
hematology, serum 25(OH) vitamin D, creatinine clearance, and bone turnover markers.  The 

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blood sample for serum chemistries will be split and a local total serum calcium will also be 
performed

Blood sample for PTH and ECP antibodies 

Urinalysis and 24-hour urine calcium, phosphate, sodium, and creatinine

Serum -HCG pregnancy test (WOCBP only)

Urine pregnancy test for immediate confirmation of non-pregnant status (WOCBP only)

A BMD test by DXA (omit if subject had a scan performed within the past 6 months in either 
RELAY or REPLACE studies)

An FSH test to confirm postmenopausal status, EXCEPT if subjects have met the definition 
of postmenopausal after the beginning the RELAY/REPLACE study (for newly 
postmenopausal females only)

The first dose of study medication will be administered after appropriate fasting laboratory 
evaluations have been taken

Subjects will be provided with the following study supplies:

Study medication cartridges in sufficient number to supply daily doses until the next 
scheduled clinic visit 

Two pen injectors

Ancillary injection supplies (ie, alcohol swabs, needles, etc.)

Paper diaries 

Calcium (carbonate or citrate) and calcitriol supplements in sufficient quantity to 
supply daily doses until the next scheduled clinic visit
6.4.2
Week 1 Interim Safety Check  
Subjects will have blood drawn locally to assess total serum calcium levels between 3 to 5 days 
(± 2 days) following baseline.  Adjustments of supplemental calcium and calcitriol will be made 
(see Appendix 2, rhPTH[1-84] and Supplement Titration Guideline) based on this value.  If 
further adjustments are made to the rhPTH[1-84] dose or there are significant changes in calcium 
or calcitriol supplements, serum calcium will be retested at approximately 3 to 5 days following 
that change.
6.4.3
Weeks 4, 8, 16, 24, 32, 40, and 48 (Visits 2 through 8) Study Clinic Visits
The following procedures will be performed as indicated:

Record any change in concomitant medications on the appropriate concomitant medication 
eCRF, including dose and frequency (all visits)

Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia (all visits)

Review the subject’s diary for compliance with protocol procedures and dosing/supplement 
regimens (all visits)

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
Collect used and unused drug cartridges and supplements (calcium and calcitriol) for 
assessment of accountability (all visits).

Vital signs measurements (prior to blood draws) and weight (all visits)

Serum 25(OH) vitamin D (all visits)

Serum 1,25-dihydroxyvitamin D (Week 24)

Serum calcium, phosphate, and albumin (all visits)

Serum bone turnover markers (Weeks 8, 16, 24, and 40)

Serum -HCG pregnancy test (WOCBP only) (Weeks 16, 24, 32, 40, and 48)

Urine pregnancy test (WOCBP only) (Weeks 4 and 8)

Creatinine clearance (Weeks 16 and 32) 

24-hour urine calcium, phosphate, sodium, and creatinine (Weeks 16 and 32) 

Blood sample for PTH and ECP antibodies (predose on Weeks 24 and 40)

Blood samples for pharmacokinetic analysis will be drawn predose (0 hour) and postdose 
between 1 and 2 hours and between 6 and 10 hours following study drug administration
(Week 48 only)

Administration of study medication following the predose PTH blood samples for PK 
analysis (Week 48)

If calcium-sparing diuretics are instituted (allowed at Week 16) and/or the dose subsequently 
changed, monitoring for serum potassium, sodium, and calcium will be done 1 week and 
again 1 month later and then at each subsequent scheduled clinic visit.

Subjects will be provided with the following study supplies:

Study medication cartridges in sufficient number to supply daily doses until the next 
scheduled clinic visit 

Ancillary injection supplies (ie, alcohol swabs, needles, etc.)

Calcium (carbonate or citrate) and calcitriol supplements in sufficient quantity to 
supply daily doses until the next scheduled clinic visit

Collection container for 24-hour urine (Dispense on Weeks 8, 24, and 48 for 
collections prior to Weeks 16, 32, and 52)
6.4.4
Week 52 (Visit 9) 
Subjects will be instructed to come into the study center after having fasted for approximately 6 
to 8 hours and prior to taking their study medication.  Appointments should be scheduled 
accordingly to accommodate this fasting status (ie, in the morning).  The following procedures 
will be performed:

Record any change in concomitant medications on the appropriate concomitant medication 
eCRF, including dose and frequency.

Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia

Vital signs measurements (prior to blood draws) and weight

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
Physical examination

12-lead electrocardiogram

Blood samples for serum chemistries (including calcium, phosphate, albumin, and 
magnesium), hematology, serum 25(OH) vitamin D, serum 1,25-dihydroxyvitamin D, 
creatinine clearance, and bone turnover markers 

Blood sample for PTH and ECP antibodies (predose) (See Section 6.2 for additional follow-
up for subjects who develop antibodies specific to PTH.)

Urinalysis 

24-hour urine calcium, phosphate, sodium, and creatinine

A BMD test by DXA 

Serum -HCG pregnancy test (WOCBP only)

Review the subject’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens.

Collect used and unused drug cartridges and supplements (calcium and calcitriol) for 
assessment of accountability.

Subjects will be provided with the following study supplies:

Study medication cartridges in sufficient number to supply daily doses until the next 
scheduled clinic visit 

Calcium (carbonate or citrate) supplements in sufficient quantity to supply daily 
doses until the next scheduled clinic visit

Ancillary injection supplies (ie, alcohol swabs, needles, etc.)

Paper diaries

Collection container for 24-hour urine
6.4.5
Long-term Extension Visits 
Subjects who continue into the long-term extension will have the following evaluations 
performed every 2 months unless otherwise indicated:

Record any change in concomitant medications on the appropriate concomitant medication 
eCRF, including dose and frequency.

Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia

Urine pregnancy test (WOCBP only)

Brief physical examination (every 6 months)

Vital signs measurements (prior to blood draws) and weight

Blood samples for serum chemistries and hematology (every 12 months)

Blood samples for creatinine clearance and bone turnover markers (every 4 months)

Local total serum calcium (as needed)

Blood sample for PTH and ECP antibodies (predose) (every 6 months)

Serum calcium and phosphate 

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
Serum 25(OH) vitamin D

Serum 1,25-dihydroxyvitamin D (every 6 months)

24-hour urine calcium, phosphate, sodium, and creatinine (every 4 months) 

A BMD test by DXA (every 12 months)

If calcium-sparing diuretics are instituted and/or the dose subsequently changed, monitoring 
for serum potassium, sodium, and calcium will be done 1 week and again 1 month later and 
then at each subsequent scheduled clinic visit.

Review the subject’s diary to assess compliance to protocol procedures and 
dosing/supplement regimens.  Subjects will complete the diary for the 2-week period prior to 
the scheduled study visit.  If the subject does not record the diary information as indicated 
during this time period, he/she may record it during the 2 weeks following the visit.  This 
information will then be reviewed with the subject by phone or at the next scheduled visit.

Collect used and unused drug cartridges and pen injectors for assessment of accountability.

Subjects will be provided with the following study supplies:

Study medication cartridges in sufficient number to supply daily doses until the next 
scheduled clinic visit 

Ancillary injection supplies (ie, alcohol swabs, needles, etc.)

Calcium (carbonate or citrate) supplements in sufficient quantity to supply daily 
doses until the next scheduled clinic visit through approximately May 2014. 
Following this date, only calcium citrate will be provided.

Collection container for 24-hour urine 
6.4.6
End of Treatment Visit or Early Termination

Record any change in concomitant medications on the appropriate concomitant medication 
eCRF, including dose and frequency.

Adverse event evaluation/update, including any incidences of hypocalcemia or 
hypercalcemia

Full physical examination

Vital signs measurements (prior to blood draws) and weight

12-lead ECG (may be local)

A BMD test by DXA (if previous DXA was ≥ 3 months prior)

Blood samples for serum chemistries (including calcium and phosphate), hematology, serum 
25(OH) vitamin D, serum 1,25-dihydroxyvitamin D, creatinine clearance, and bone turnover 
markers 

Blood sample for PTH and ECP antibodies (See Section 6.2 for additional follow-up for 
subjects who develop antibodies specific to PTH.)

Administration of the last dose of study medication following the predose PTH samples

Urinalysis 

24-hour urine calcium, phosphate, sodium, and creatinine

Serum -HCG pregnancy test (WOCBP only)

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
Review the subject’s diary 

Collect used and unused drug cartridges and pen injectors, for assessment of accountability, 
and subject diaries.

Subjects will either be prescribed appropriate oral calcium and/or active vitamin D to 
compensate for the cessation of NPSP558 (rhPTH[1-84]) or may opt to continue treatment on 
commercial drug (Natpara). Subjects who continue treatment with Natpara will continue to 
be monitored under the care of a physician according to approved labeling instructions.
6.4.7
Posttreatment Serum Calcium/Phosphate Follow Up 
After the End of Treatment visit or early termination visit, subjects who will not continue 
rhPTH[1-84] treatment will have their total 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.  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 4 weeks ± 7 days after 
end of treatment visit.  After the 4-weeks follow-up telephone call, further management of 
hypoparathyroidism will occur as part of the subject’s long-term non-study medical care.
6.4.8
Follow-up Telephone Contact 
Subjects will be contacted approximately 4 weeks following the last dose of study medication to 
monitor for and/or follow-up on any study drug-related AE or any SAE that may have occurred 
during the study period or any SAE that may have occurred since the last study drug injection.
6.4.9
Follow-up assessment for PTH antibodies
Any subject who tests positive for PTH-specific antibodies at the last 2 consecutive visits at 
which antibodies are measured and does NOT continue treatment on commercial Natpara, will 
have follow-up blood draws for PTH antibodies at Months 3 and 6 poststudy. If a subject’s 
results are negative at Month 3, follow-up may be terminated.  
7
DATA MANAGEMENT
7.1
Data Collection 
Data collected during the study will be recorded in the subject’s eCRF by the study center’s 
research team.  The research team will keep records of the subject’s visit in the files considered 
as source documents for that center, eg, hospital chart, research chart, etc.  To ensure that data 
have been entered correctly on the eCRF, eCRFs will be 100% source-data verified by a monitor 
from the sponsor/designee, who will notify the investigator regarding questions or missing data.  
The investigator or designee will be responsible for the timely recording of subject data.
The investigator will review all eCRFs (including the termination page after the subject’s final 
visit) for completeness and accuracy, and will electronically sign the eCRFs attesting to this prior 
to submitting them to the sponsor.  The investigator will be responsible for submitting the data to 

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the sponsor (or designee) in a timely manner, on the eCRFs provided by the sponsor (or 
designee) for this purpose.  Non-CRF data including, but not limited to central laboratory tests, 
ECG, and radiographic (DXA) results will be sent to the sponsor or designee via a data transfer 
from the appropriate vendor for assimilation into the database.  SAE reporting must be done 
within the times described in Section 6.2.2.2.
All data collected in this study will be integrated into an appropriate preformatted database by 
the sponsor or designee for subsequent statistical evaluation.  Data validation and edit checks 
will be conducted on the data.  Any discrepancies will be noted and queries will be generated by 
the sponsor or designee to be resolved by the center.  Queries should be completed by the 
investigational center and signed by the investigator or approved designee in a timely manner.
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the center, the data will be evaluated for quality purposes.  A clean file 
is defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, data management plan, and data 
entry instructions.  Once the sponsor acknowledges that all data are acceptable, the data will be 
declared to represent a “clean file” and the database will be frozen.
A quality assurance audit will be performed on the data by the Data Management group.  When 
all issues from the audit are resolved, and all data management processes are completed for 
finalizing the database, the database will be locked and ready for analysis. 
The investigator and clinical center must permit study-related monitoring, audits, IRB/IEC/REB 
review, and regulatory inspections by providing direct access to source data/documents.
Subjects will retain the subject number utilized in the RELAY/REPLACE study.  The first four 
digits consist of the center number and the last four digits are the sequential subject number.  
This number is the main identifier for subjects.
7.2
Record Retention
The clinical investigators will maintain drug records, copies of eCRFs, laboratory records, data 
sheets, correspondence records, and signed subject consent documents for at least 5 years or until 
instructed in writing by the sponsor that records may be destroyed or forwarded to the sponsor.  
In accordance with US Federal Regulations, these records will be available for inspection and 
copying if requested by a properly authorized employee of the FDA.
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE 
Detailed statistical analysis methods will be conducted as described in the SAP for this study.  
Deviations from the SAP (if any) will be described and justified in the clinical study report 
(CSR). 

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8.1
Demographic and Baseline Variables
Demographic variables (such as sex, age, race, birthdate, etc.) will be obtained from the 
REPLACE or RELAY study.  Medical history from the RELAY study will be reviewed and 
updated as necessary.  Visit 1 (baseline) for this study (PAR-C10-008, RACE) may be the same 
day as Visit 4 of the RELAY study.  Demographic and/or other variables at baseline will be 
summarized for medical history, demography, physical examination, vital signs, prior 
medications, ECG, and laboratory test results.
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name.  The number and percentage of subjects 
with specific prior medications will be summarized.  Medical history will be coded using the 
Medical Dictionary for Regulatory Activities.  The number and percentage of subjects with 
specific histories will be summarized by system organ class and by high-level term and preferred 
term for each condition. 
8.2
Safety Variables
Safety data including vital signs assessments, physical examinations, AEs, SAEs, pen-related 
events or complaints, concomitant medications, clinical laboratory tests, ECG monitoring, and 
termination from study will be summarized by treatment group and point of time of collection.  
Descriptive statistics (arithmetic mean, standard deviation, median, minimum and maximum) 
will be calculated for quantitative safety data as well as for the difference from baseline, if 
applicable.  Frequency counts will be compiled for classification of qualitative safety data. 
8.3
Efficacy Variables
Efficacy Endpoints:
The proportion of subjects in whom the following three conditions are fulfilled at Week 52 (Visit 
9) and at End of Treatment will be summarized:

A ≥50% reduction from baseline in dose of oral calcium supplementation or an oral calcium 
dose of ≤500 mg
AND

A ≥ 50% reduction from baseline in dose of oral calcitriol supplementation or an oral 
calcitriol dose of ≤0.25 μg
AND

An albumin-corrected total serum calcium concentration that is normalized or maintained 
compared to the baseline value and does not exceed the ULN of the central laboratory
In addition, the following efficacy variables will be summarized: 

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
Mean percentage changes from baseline in supplemental oral calcium and supplemental 
calcitriol dosages at each visit

Proportion of subjects achieving the first three conditions of the efficacy endpoints defined 
above, at each visit 

Mean change from baseline in 24-hour urine calcium excretion

Impact of calcium source (carbonate vs. citrate) on response

Impact of calcium-sparing diuretics on serum and urinary calcium

Proportion of subjects that maintain a calcium phosphate product ≤55 mg2/dL2 (4.4 
mmol2/L2)       

Distribution of subjects by rhPTH[1-84] doses at the End of Treatment Visit

Change from baseline in bone turnover markers (BSAP, s-CTx, P1NP, and osteocalcin), PTH 
antibodies, and BMD by DXA 

Additional subgroup analyses that are specified in the SAP
Note that the baseline parameters for the efficacy variables for the RACE study will be the end 
of study and baseline parameters from the RELAY or REPLACE studies.  The visits will be 
defined in the SAP.  No between-group comparisons with p-values are planned.  No statistical 
testing will be conducted to compare between group differences.
8.4
Other Variables 
Other variables to be analyzed will include the following: 

Calcium and active Vitamin D intake (based on diary entries)

Duration of study medication exposure 

Subject compliance 

The number and percentage of subjects who complete the study, are lost to follow-up, and 
who are discontinued from the study (including reason for study withdrawal) will be 
summarized. 
Subjects will be considered compliant if study drug was taken according to protocol for ≥80% to 
≤120% of doses.  The number and percentage of subjects who were compliant will be 
summarized.
8.5
Analysis Populations, Data Sets, and Time Points
8.5.1
Analysis Populations 
The primary and secondary efficacy analyses will be based on the intention-to-treat (ITT) 
population.  This population includes all subjects who received at least one dose of study drug 
and had at least one efficacy measurement. 
The safety analyses will be based on the Safety population.  This population includes all subjects 
who received at least one dose of study drug with any follow-up information.

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8.6
Statistical/Analytical Issues 
8.6.1
Adjustments for Covariates
No preselected covariates are selected for adjustments.
8.6.2
Handling of Dropouts or Missing Data
No safety data will be imputed. The missing patterns of the efficacy variables will be assessed 
and an unbiased imputations method will be documented in the SAP.
8.6.3
Interim Analyses and Data Monitoring
An interim analysis was performed in 2013. Interim analyses may be performed as necessary to 
support regulatory interactions and/or publications.  
8.6.4
Multiple Comparisons/Multiplicity
No adjustment for multiplicity in treatment is planned.
8.6.5
Use of a Pharmacokinetic Subset of Subjects
No pharmacokinetic subset of subjects was selected for analysis.
8.6.6
Examination of Subgroups
Subgroup analyses (if any), in addition to the possible ones by gender, will be discussed in the 
SAP. 
8.7
Determination of Sample Size
Approximately 50 subjects are anticipated to be enrolled.  Sample sizes were not estimated for 
this extension study. 
8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final CSR. 
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki and its 
amendments concerning medical research in humans (Declaration of Helsinki, 
'Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects', 
Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, 
Republic of South Africa 1996, and Edinburgh 2000 (5th revision), and Notes of Clarification 
added by the WMA General Assembly in Washington 2002 and in Tokyo 2004).

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In accordance with guidelines, the protocol, any advertisements and ICFs will be reviewed and 
approved by the IRB/IEC. The sponsor will supply relevant material for the investigator to 
submit to the IRB/IEC for the protocol’s review and approval.  Verification of the IRB/IEC 
approval of the protocol and the written ICF will be forwarded to the sponsor (or designee).
The investigator will inform the IRB/IEC of subsequent protocol amendments and any SUSARs 
if the Shire SMT has assessed it as an unanticipated problem.  Approval for protocol 
amendments will be transmitted in writing to the investigator.
The investigator will provide the IRB/IEC with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information and Consent
In accordance with applicable guidelines, informed consent shall be documented by the use of a 
written consent form approved by the IRB and signed by the subject before any screening and 
protocol-specific procedures are performed.  A consent form model will be provided by the 
sponsor or designee and adapted by the investigator to meet center, state, and country ethical 
guidelines, as appropriate.
The investigator (or designee) will explain to the subject the nature of the study, the action of the 
test product, and any risks and benefits.  The subject will be informed that participation is 
voluntary and that he or she can withdraw from the study at any time without prejudice to their 
subsequent care.  Information for a WOCBP (and a female of child-bearing potential who is the 
partner of a male subject) and lactating females should be provided in the ICF regarding 
unintended pregnancy and methods of contraception.
The subject will be given a copy of the fully executed consent form and the original will be 
maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor or designee will be identified only by subject number, date of 
birth, and initials, thereby ensuring that the subject’s identity remains unknown.  Subjects should 
be informed in writing, that their data will be stored and analyzed in a computer, with 
confidentiality maintained in accordance with national and local legislation.  Center-specific 
information must be added to the ICF as appropriate.
Subjects also should be informed in writing that authorized representatives of the 
sponsor/designee and/or regulatory authorities may require access to those parts of the 
hospital/clinic records which are relevant to the study, including medical history, for data 
verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, and 

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a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed screening 
must also be maintained and be available for inspection.
9.4
Financial Disclosure
In 2001, the FDA issued a guidance document entitled “Financial Disclosure by Clinical 
Investigators” which provides guidance to industry on its final rule on financial disclosure that 
became effective 02 February 1999 and was published as Title 21 Code of Federal Regulations 
Part 54.  This rule applies to all investigators participating in clinical studies to be submitted to 
the FDA in support of an application for market approval.  The financial disclosure statement 
must be updated annually during the course of the study and for 1 year after the completion of 
the study.
According to the guidance, disclosable financial arrangements are defined as the following: 

Compensation made to the investigator in which the value of compensation could be affected 
by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, trademark, 
copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or the 
investigator’s institution to support activities of the investigator exclusive of the costs of 
conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing research, 
compensation in the form of equipment or retainers for ongoing consultation, or honoraria) 
during the time the clinical investigator is carrying out the study and for 1 year after 
completion of the study
Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes the 
spouse and each dependent child of the investigator.  Participating investigators must provide 
this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA in 
support of a market application.  Companies must meet these financial disclosure requirements, 
and failure to do so may result in the refusal by the FDA to accept an application for market 
approval of the study drug.
9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the sponsor 
and the investigator.  All changes must be documented as signed protocol amendments, or as a 

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revised protocol.  Changes to the protocol may require notification to or approval by the 
IRB/IEC/REB and the regulatory authorities before implementation. Local regulatory 
requirements must be followed.  Instructions for reporting deviations from the protocol can be 
found in the Study Reference Manual.
The sponsor or designee is responsible for the distribution of protocol amendment(s) to the 
principal investigator(s) and those concerned within the conduct of the study.  The principal 
investigator is responsible for the distribution of all amendments to the IRB/IEC/REB and all 
staff concerned at his/her center.
9.6
Investigator Obligations
The principal investigator at each center must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes are 
made that are not reflected on the original FDA Form 1572, a revised FDA Form 1572 form 
must be completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address

Financial disclosure statement for the principal investigator, and subinvestigators (listed on 
the FDA Form 1572).  An updated financial disclosure statement must be provided to the 
sponsor 1 year after completion of the study.

A copy of the original approval for conducting the study from the IRB/IEC. Renewals must 
be submitted at yearly intervals if the study is ongoing or as required by the institution.

A copy of the IRB/IEC-approved ICF

IRB/IEC/REB membership list or Department of Health and Human Services General 
Assurance Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Protocol Signature Page” of this protocol must be signed and dated by the principal 
investigator for the center.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
and/or for submission to regulatory agencies.  In addition, the sponsor reserves the right to 
review data from this study relative to the potential release of proprietary information 30 days 
prior to submission to any publication or for any presentation.

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9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all investigators 
for this study.  The selection will be based on a variety of factors, including rate of enrollment, 
overall enrollment totals, and subject retention.  The principal investigator selected will be 
identified in the synopsis of the CSR as the principal investigator for the study.  Roles, 
affiliations, and qualifications for the principal investigators will be included in the CSR 
appendices.  Where the signature of the principal investigator is required by regulatory 
authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.

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10
REFERENCES
Bilezikian J. PTH[1-84]: A therapy for hypoparathyroidism. Independent Investigator Study 
Report, 2008.
Bilezikian JP, Marcus R, Levine MA (eds). The Parathyroids. Basic and Clinical Concepts 2nd
ed. San Diego: Academic Press; 2001.
Horwitz MJ, Stewart AF. Hypoparathyroidism: is it time for replacement therapy? J Clin 
Endocrinol Metab. 2008 Sep;93(9):3307-9. 
Langdahl BL, Mortensen L, Vesterby A, Eriksen EF, Charles P. Bone histomorphometry in 
hypoparathyroid patients treated with vitamin D. Bone. 1996;18(2):103-8.
Rubin MR, Dempster DW, Zhou H, Shane E, Nickolas T, Sliney J, et al. Dynamic and structural 
properties of the skeleton in hypoparathyroidism. J Bone Miner Res. 2008a;23(12):2018-24. 
Rubin MR, Cremers S, Dempster DW, Sliney J, McMahon DJ, Zhou H, et al. PTH increases 
bone turnover in hypoparathyroidism [abstract]. J Bone Miner Res. 2008b;23:S128.
Rubin MR, Dempster DW, Cremers S, Zhou H, McMahon DJ, Sliney J, et al. Circulating 
osteoblast lineage cells increase with PTH treatment of hypoparathyroidism [abstract]. J Bone 
Miner Res. 2008c;23:S42.
Rubin MR, Dempster DW, Sliney J, McMahon DJ, Zhou H, Nickolas T, et al. PTH reverses 
abnormal bone remodeling and structure in hypoparathyroidism [abstract]. J Bone Miner Res. 
2008d;23:S12.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008 Jul 24; 359(4):391-403. 
Review. 
Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, cross-over trial of once-daily 
versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin 
Endocrinol Metab. 1998 Oct;83(10):3480-6.
Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, et al. Long-term treatment of 
hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) 
versus calcitriol and calcium. J Clin Endocrinol Metab. 2003;88(9):4214-20.
Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-daily 
parathyroid hormone1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol 
Metab. 2008 Sep;93(9):3389-95. Epub 2008 May 20. 

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Appendix 1
INSTRUCTIONS FOR USE FOR THE PTH HASELMEIER PEN 
INJECTOR SYSTEM

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Appendix 2
RHPTH[1-84] AND SUPPLEMENT TITRATION GUIDELINE
In this study the goal is to continue rhPTH[1-84] dosing and to reduce calcitriol and oral calcium 
(carbonate or citrate) supplementation to as low as safely possible, while maintaining total serum 
calcium levels.  In patients with hypoparathyroidism treated with oral calcium and calcitriol, it is 
suggested to maintain total serum calcium levels in the lower half of the normal range (eg, 
between 8.0 and 9.0 mg/dL; Shoback 2008).  This is to reduce symptoms and to avoid the 
hypercalciuria which can occur in the hypoparathyroid patient on calcitriol and oral calcium 
supplementation (Horwitz and Stewart 2008).  In the current trial, all subjects will receive 
rhPTH[1-84].  Hence, down-titration of calcitriol and oral calcium must be undertaken, where 
appropriate, to avoid hypercalcemia.  At all times, changes in calcitriol and oral calcium dosing 
should be undertaken at the discretion of the investigator, based on total serum calcium 
concentrations and the subject’s clinical condition.
To help facilitate a more standardized approach to dose adjustment across study centers, the 
following guideline has been prepared.  The guideline is non-mandatory but the approach 
suggested should be assessed when adjustments in calcitriol and oral calcium are being 
considered.  In the guideline, all references to total serum calcium levels indicate “predose” 
(trough) values drawn prior to administration of study drug, rhPTH[1-84] (ie, approximately 23 
to 24 hours after the previous injection).
The order and magnitude of subsequent reductions in either calcitriol or oral calcium 
supplementation is left to the investigator’s discretion, based on individual subject response.  
After any change in the rhPTH[1-84] dose, or a significant change in calcitriol or oral calcium 
supplement dose, a total serum calcium level MUST be measured 3 to 5 days later for safety 
purposes (unless earlier or more frequent testing is clinically required) and to guide further 
changes in supplement doses.
At the end of the study (this includes any subject that terminates early) subjects must be assessed 
clinically at their study center to ensure that they return safely to an appropriate calcium and 
calcitriol supplementation level.  This includes the performance of necessary testing for total 
serum calcium 3 to 5 days later for safety purposes (unless earlier or more frequent testing is 
clinically required) to ensure a stable total serum calcium level has been achieved.  The 
completion of these procedures should be documented by the site.
Significant Hypercalcemia
Any instances of significant hypercalcemia, which is defined as any total serum calcium level of 
> 11.9 mg/dL (even on a non-trough measurement), require MANDATORY immediate stopping 
of rhPTH[1-84] treatment.  Suspension of dosing with calcitriol and oral calcium as clinically 
appropriate and testing of serum total calcium levels at least daily should be undertaken until the 
subject’s serum total calcium returns to the normal range.  Other clinically appropriate actions 
for the treatment of significant hypercalcemia should be undertaken as usual by the investigator 
to ensure subject safety.  Thereafter, rhPTH[1-84] can be reintroduced with clinically appropriate 
doses of calcitriol and oral calcium, with the aim to avoid further episodes of abnormal serum 
calcium.  

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Hypocalcemia 
If the total serum calcium level falls below 8.0 mg/dL (or below the baseline values, if the 
subject entered the study with a total serum calcium < 8.0 mg/dL), then the subject’s calcitriol 
and oral calcium doses should be checked and the injection technique of rhPTH[1-84] reviewed 
with the subject to ensure proper administration.  At planned study visits (Week 4, 8 etc) the 
rhPTH[1-84] dose can be uptitrated if indicated in the opinion of the investigator following 
discussion with the sponsor.  During interim safety checks, hypocalcemia should be addressed by 
clinically indicated increases in calcitriol or supplemental oral calcium doses according to the 
guideline below, with the goal of attaining a total serum calcium level of 8.0 to 9.0 mg/dL.  
Laboratory testing should be repeated as indicated in order to ensure that changes in dosing are 
accompanied by improved serum calcium levels.

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Appendix 3
METHOD OF BIRTH CONTROL 
Women of childbearing potential must consent to use 2 acceptable methods of birth control from 
the list below: 

Hormonal methods of contraception such as oral, injected, vaginal rings, transdermal patch, 
implanted. 

Placement of an intrauterine device (IUD) or intrauterine system (IUS). 

Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 

Male partner sterilization (vasectomy). 
Male subjects with female partners of childbearing potential together also must use 2 acceptable 
forms of contraception during the subject’s participation.